[Senate Hearing 108-378]
[From the U.S. Government Publishing Office]
S. Hrg. 108-378
FEDERAL AND STATE ROLE IN PHARMACY COMPOUNDING AND RECONSTITUTION:
EXPLORING THE RIGHT MIX TO PROTECT PATIENTS
=======================================================================
HEARING
BEFORE THE
COMMITTEE ON HEALTH, EDUCATION,
LABOR, AND PENSIONS
UNITED STATES SENATE
ONE HUNDRED EIGHTH CONGRESS
FIRST SESSION
ON
EXAMINING STATE AND FEDERAL OVERSIGHT TO ENSURE THE SAFETY AND QUALITY
OF DRUG COMPOUNDING--THE PROCESS OF MIXING, COMBINING, OR ALTERING
INGREDIENTS TO CREATE A CUSTOMIZED MEDICATION FOR AN INDIVIDUAL
PATIENT--BY PHARMACIES
__________
OCTOBER 23, 2003
__________
Printed for the use of the Committee on Health, Education, Labor, and
Pensions
90-129 U.S. GOVERNMENT PRINTING OFFICE
WASHINGTON : 2003
____________________________________________________________________________
For Sale by the Superintendent of Documents, U.S. Government Printing Office
Internet: bookstore.gpo.gov Phone: toll free (866) 512-1800; (202) 512�091800
Fax: (202) 512�092250 Mail: Stop SSOP, Washington, DC 20402�090001
COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS
JUDD GREGG, New Hampshire, Chairman
BILL FRIST, Tennessee EDWARD M. KENNEDY, Massachusetts
MICHAEL B. ENZI, Wyoming CHRISTOPHER J. DODD, Connecticut
LAMAR ALEXANDER, Tennessee TOM HARKIN, Iowa
CHRISTOPHER S. BOND, Missouri BARBARA A. MIKULSKI, Maryland
MIKE DeWINE, Ohio JAMES M. JEFFORDS (I), Vermont
PAT ROBERTS, Kansas JEFF BINGAMAN, New Mexico
JEFF SESSIONS, Alabama PATTY MURRAY, Washington
JOHN ENSIGN, Nevada JACK REED, Rhode Island
LINDSEY O. GRAHAM, South Carolina JOHN EDWARDS, North Carolina
JOHN W. WARNER, Virginia HILLARY RODHAM CLINTON, New York
Sharon R. Soderstrom, Staff Director
J. Michael Myers, Minority Staff Director and Chief Counsel
(ii)
C O N T E N T S
__________
STATEMENTS
THURSDAY, OCTOBER 23, 2003
Page
Bond, Hon. Christopher S., a U.S. Senator from the State of
Missouri....................................................... 1
Ensign, Hon. John, a U.S. Senator from the State of Nevada....... 2
Heinrich, Janet, DrPH, RN, Director of Health Care-Public Health
Issues, U.S. General Accounting Office; and Steven Galson,
M.D., MPH, Deputy Director, Center For Drug Evaluation and
Research, U.S. Food and Drug Administration.................... 4
Roberts, Hon. Pat, a U.S. Senator from the State of Kansas....... 7
Sellers, Sarah L., PHARM.D, Executive Director, The Center For
Pharmaceutical Safety; Daniel A. Herbert, RPh, President Elect,
American Pharmacists Association; Kevin Kinkade, Executive
Director, Missouri Board of Pharmacy; and William Kennedy,
owner, Nephron Pharmaceuticals Corporation..................... 17
ADDITIONAL MATERIAL
Statements, articles, publications, letters, etc.:
Janet Heinrich............................................... 31
Steven K. Galson, M.D........................................ 38
Steven F. Hotze, M.D......................................... 45
Sarah L. Sellers............................................. 46
Daniel A. Herbert............................................ 54
Kevin Kinkade................................................ 58
William P. Kennedy........................................... 73
American Society of Health-System Pharmacists................ 77
Letter to the Committee on Health, Education, Labor, and
Pensions, dated Oct. 23, 2003, from L.D. King, IACP
Executive Director......................................... 80
Letter to Senator Gregg, dated Oct. 30, 2003, from L.D. King,
IACP Executive Director.................................... 83
American Pharmacists Association............................. 85
Response to questions of Senator Gregg from John A. Gans..... 89
Letter to Food and Drug Administration, dated November 3,
2003, from John A. Gans.................................... 94
Response to questions of Senator Kennedy from Janet Heinrich. 130
Response to questions of Senator Kennedy from Kevin Kinkade.. 133
National Association of Chain Drug Stores.................... 136
Response to questions of Senator Kennedy from Sarah Sellers.. 137
Roger L. Williams, M.D....................................... 140
Response to questions of Senator Kennedy from William Kennedy 143
(iii)
FEDERAL AND STATE ROLE IN PHARMACY COMPOUNDING AND RECONSTITUTION:
EXPLORING THE RIGHT MIX TO PROTECT PATIENTS
----------
THURSDAY, OCTOBER 23, 2003
U.S. Senate,
Committee on Health, Education, Labor, and Pensions,
Washington, DC.
The committee met, pursuant to notice, at 10 a.m., in Room
430, Dirksen Senate Office Building, Senator Bond, presiding.
Present: Senators Bond, Roberts, Ensign, and Reed.
Senator Bond. Good morning. The meeting of the Senate
Health, Education, Labor and Pensions Committee will come to
order.
This is a very busy day in the Senate, and many of my
colleagues who wanted to be here have other commitments. I know
Senator Roberts has a great interest in this issue. He has to
be on the Floor, so I'm taking the liberty of starting ahead of
his arrival. I am hoping that others will be able to join us.
But as you all know who have followed the Senate, this is a
time when so many important measures are going on. There is an
Environment and Public Works markup down the hall that I may
have to go down to join to make a quorum, and most other
members face the same challenges I do.
Opening Statement of Senator Bond
Senator Bond. Today we are going to be exploring the
question of Federal and State roles in pharmacy compounding and
reconstitution: exploring the right mix to protect patients.
When people get sick, they want to know that their medicine is
safe and effective, and most importantly, they want to know
that it is just what the doctor ordered. That is why we are
here today.
This hearing is not intended to be an attack on the
practice of compounding. The committee recognizes and
appreciates the vital role that compounded drugs play in the
delivery of health care. Compounding ensures that medications
are available to meet many individualized patient needs. Many
pediatric patients, for example, require flavoring to be added
to mask the bitter taste of some medications. Some patients
have difficulty swallowing a capsule and require a special
dosage form. And some patients are allergic to a preservative
or dye in a manufactured product and require a dye-free or
preservative-free dosage. There is no question that compounding
provides patients critical access to medications that are not
commercially available.
However, recent media coverage and significant adverse
events have brought to our attention a significant number of
very real problems caused by compounded drugs. We have received
reports of nonsterile eye drops causing blindness, spinal
injections contaminated with bacteria and/or fungus, resulting
in hospitalization and, in some cases, death, and children
poisoned as a result of pharmacy compounding errors.
Based on voluntary reporting, media reports and other
sources, the Food and Drug Administration has become aware of
over 200 adverse events involving 71 compounded products since
about 1990. These incidents have heightened concern about the
safety and quality of compounded drug. Yet, when these types of
tragedies occur, there are very few State laws and no Federal
law requiring that the events be reported. Unlike drug
manufacturers, who are required to report adverse events
associated with the drugs they produce, the Food and Drug
Administration does not require pharmacies or any other body to
report adverse events associated with compounded drugs.
Because oversight and surveillance of pharmacy compounding
at the State and Federal level is limited, at best, little is
known about how widespread the practice of compounding is, the
ability of States and the Federal Government to regulate
compounding, and how compounding impacts public health and
safety.
Today's hearing is designed to address those very important
issues. As our population continues to age, and the demand for
pharmaceuticals continues to grow, we have to make sure that
appropriate safeguards are in place to protect patients from
substandard, contaminated, subpotent or superpotent drugs, so
that we can ensure the highest standard of care.
My goal, our goal, is not to federalize the oversight of
pharmacies and compounding pharmacists, or institute additional
needless and burdensome paperwork and regulatory requirements.
But the issue at hand is clear. We have a responsibility to
ensure that patients and doctors are receiving safe and
accurate dosages of compounded drugs. This morning, as we
examine issues surrounding pharmacy compounding, the safety of
patients must always be our guiding force. I look forward to
the testimony of our panels.
Before introducing the two distinguished members of the
first panel, I will call on my colleague, Senator Ensign, for
any comments he wishes to make.
Senator Ensign.
Opening Statement of Senator Ensign
Senator Ensign. Thank you, Mr. Chairman. Thanks for
bringing this important issue to light.
I wanted to share a few things with the committee--just
some personal experiences as a practicing veterinarian and
working in the medical fields. Likewise, I have a lot of
friends who are physicians.
One of the things that I hope, and you mentioned it in your
opening statement, that you didn't want to go too far with what
you are trying to do, while at the same time protecting
patients. Compounding pharmacists, I believe, play a vital role
in the United States. As a veterinarian, there were certain
things we just could not do without compounding pharmacists. We
don't want them to get to where they are only taking different
things and grinding them up. They have to be able to perform
the way that they were trained to perform, and in so doing,
you're always going to have some problems. There are mistakes
made sometimes and there are always bad actors, just like there
are in any profession.
What I don't want to see happen when we're doing this is
for us to, as the old saying goes, ``throw the baby out with
the bath water.'' We don't want to see a very valuable
profession hurt to the point where they cannot operate. As a
practicing veterinarian, there were products that they could
produce for us that we couldn't get anyplace else. We needed
that service, and physicians are the same way, especially when
either these pharmacists are on the cutting edge of the
industry, or when we as practitioners develop a relationship,
especially with certain compounding pharmacists, that are
incredibly valuable. Further, oftentimes when drugs quit being
made, that is the time when compounding pharmacists have to
come into play.
I know you have had some experience with the dilution of
drugs and things like that, and frankly, those people are in
jail--and they should be. But at the same time, we don't want,
at least from my perspective, to go and have this law of
unintended consequences. We have got to make sure we don't end
up with a law that when we're trying to fix one problem ends up
causing problems in other areas.
I appreciate you having the hearing. I won't be able to
stay probably for about another 15 or 20 minutes, but I
appreciate you having this hearing. Thank you.
Senator Bond. Thank you very much, Senator Ensign. We value
your expertise as a practicing veterinarian. You and Senator
Wayne Allard have given me very valuable medical advice when I
couldn't track down Senator Frist on the Floor, to get advice.
Senator Allard was the one who warned me when I had a hip
replacement, that the dogs whose hips he replaced usually ran
around too much and dislocated their hip, so I took that advice
to heart.
Seriously, on the question in front of us, I certainly
share your concerns. We don't want to make it impossible or
very difficult or unduly burdensome to compound, but we had a
tragedy in Kansas City where a now criminally-prosecuted and
convicted pharmacist produced 4,200 phony compounds. There was
no regulation. Do you know how he was found? He was discovered
because a drug salesman noticed that he was not buying enough
drugs to be filling the prescriptions that he was writing.
Now, the free enterprise system works, but I would hate to
have to rely on the drug salesmen to tell us if a compounding
pharmacist is grossly in error.
We have asked two expert agencies to testify today. Dr.
Janet Heinrich, Director of Health Care and Public Health
Issues of the U.S. General Accounting Office, and Dr. Steve
Galson, Deputy Director, Center of Drug Evaluation and
Research, the Food and Drug Administration.
Dr. Heinrich, would you please begin. We will make your
full statements a part of the record. We appreciate you being
here.
STATEMENTS OF JANET HEINRICH, DrPH, RN, DIRECTOR OF HEALTH
CARE-PUBLIC HEALTH ISSUES, U.S. GENERAL ACCOUNTING OFFICE; AND
STEVEN GALSON, M.D., MPH, DEPUTY DIRECTOR, CENTER FOR DRUG
EVALUATION AND RESEARCH, U.S. FOOD AND DRUG ADMINISTRATION
Ms. Heinrich. Mr. Chairman and members of the committee, I
am pleased to be here today as you consider State and Federal
oversight to ensure safety and quality of compounded
prescription drugs.
Compounding, the process of mixing, combining or altering
ingredients to create a customized medication for an individual
patient is, as you say, an important part of the practice of
pharmacy. It is regulated by State Pharmacy Practice Acts which
are enforced by State Boards of Pharmacy.
At the Federal level, the FDA, which oversees the
introduction of new drugs into the marketplace under the Food,
Drug and Cosmetic Act, maintains the compounded drugs are
generally subject to this Act.
The quality and extent of drug compounding have surfaced as
important issues in recent years. You described several
serious, adverse events in your remarks. In addition, concerns
have been raised that some pharmacies are going beyond
traditional drug compounding and selling large quantities of
drugs without meeting safety requirements for new manufactured
drugs. However, the extent of this problem is unknown.
Because of these issues, you asked us to address the
actions taken or proposed by States and national pharmacy
organizations that may affect State oversight of drug
compounding, and to look at Federal authority and enforcement
power regarding compounding drugs.
In our review, we found several efforts at the State level
and among national pharmacy organizations to strengthen State
oversight of compounding. We selected four States for in-depth
review, based on their geographic location and variation in
regulations. Actions among these States included adopting new
regulations, mandatory adverse event reporting, and random
testing of compounded drugs.
At the national level, industry organizations are working
on standards for compounded drugs that could be adopted by
States in their laws and regulations. According to experts,
uniform standards could help ensure that pharmacies across
States consistently produce safe quality products. While these
actions have the potential to improve oversight, the ability of
States to provide this oversight may be affected by available
resources. State pharmacy board officials in three of the four
States we reviewed reported that resources were limited for
inspections.
While FDA has oversight responsibility regarding drug
compounding activities, it generally relies on the States to
regulate the traditional practice of pharmacy, including the
compounding of drugs for the needs of individual patients.
In recent years, Congress has attempted to clarify the
extent of the Federal authority and enforcement power regarding
compounding, and in 1997 Congress passed a law that exempted
drug compounders from key portions of the Food, Drug and
Cosmetic Act, if they met certain criteria. These efforts, as
you know, were nullified in 2002 when the U.S. Supreme Court
struck down a portion of the law's drug compounding section as
an unconstitutional restriction on commercial speech, which
resulted in the entire compounding section being declared
invalid.
Subsequently, FDA issued a compliance policy guide to
provide the compounding industry with an explanation of its
enforcement policy, which included a list of factors the agency
would consider before taking enforcement actions against drug
compounders.
Some representatives of the pharmacist associations and
others have expressed concern that the compliance policy guide
creates confusion regarding when FDA enforcement authority will
be used. For example, they State that terms such as ``very
large quantities'' are not clearly defined. On the other hand,
FDA officials State that the guide allows the agency the
necessary flexibility to respond to a wide variety of
situations where there are public health and safety concerns.
In conclusion, at least some States are taking steps to
strengthen oversight, and national organizations are developing
standards that may strengthen State level efforts. However, the
effectiveness of these measures is unknown, and factors such as
available resources may affect the extent of oversight
activities.
While FDA has authority over the safety and quality of new
drugs, it generally relies on States to regulate drug
compounding. Given State resources, we may need to look even
more to FDA in the future.
Mr. Chairman, this completes my prepared statement. I am
happy to answer any questions you or other members may have.
Senator Bond. Thank you, Dr. Heinrich.
[The prepared statement of Ms. Heinrich may be found in
additional material.]
Senator Bond. We will go to Dr. Galson for his opening
statement, and then we will have an opportunity for questions
and answers.
Dr. Galson. Thank you, Mr. Chairman, and members of the
committee. I am Steve Galson, Captain and medical officer in
the U.S. Public Health Service, and Acting Director of the
Center for Drug Evaluation and Research at FDA. I am pleased to
be here today to discuss the public health issues related to
pharmacy compounding.
Pharmacy compounding, as you know, is the combining, mixing
or altering of ingredients to create a customized medication
for an individual patient in response to a licensed
practitioner's prescription. I have brought along some charts
here, and if you look at the first one there, in the left
column, you see that pharmacy compounding has obvious health
benefits. The patient may have an allergy to a dye or a
preservative, or the patient may be a child or an elderly
individual who has difficulty swallowing. The pharmacist can
convert the drug to a suspension or some other form that is
more useful to the patient. In these cases, pharmacy
compounding serves a clear public health need.
On the other side of the chart, though, we have become
aware of instances involving compounding in which the risks of
obtaining a product of substandard quality may outweigh the
benefits of obtaining the drug. These risks can include
problems with quality, adverse events, and drugs that just
don't work. For example, a compounded narcotic analgesic
``lollipop'' dispensed without the labeling packaging and other
patient safety features required by the agency for that product
could have posed a safety hazard to children.
In another instance, a contaminated injectable steroid drug
that had been compounded by a pharmacy without adequate
controls resulted in serious infections in a number of
patients, one of whom died.
In addition to these cases, we have seen abuses such as
large-scale drug manufacturing operating under the guise of
pharmacy compounding. Sometimes compounding appears to occur
for economic reasons rather than genuine medical need.
We believe that most pharmacists are well trained and well
equipped to safely compound certain medications. However, in
some cases, compounders may lack equipment, training, testing,
or facilities to ensure the right quality of the drug. In
addition, compounding large quantities of drugs and copying
commercially available approved products circumvents the
important public health requirements of the FDA. This type of
compounding undermines the drug approval process, the evidence-
based system of drug review that consumers and health
professionals rely on for their safe and effective drugs.
On the next chart, in 2001, FDA conducted a limited survey
of drugs compounded by 12 pharmacies. The drug products sampled
included hormonal products, antibiotics, steroids and drugs to
treat glaucoma, asthma, iron deficiency anemia, and erectile
dysfunction. Ten of the 29 products we sampled failed one or
more standard quality tests that we perform. Nine with failing
analytical results failed potency testing, and some had less
than 70 percent of their declared potency.
I want to emphasize that this was not a comprehensive
scientific survey. It was a small sample size. But it does
nonetheless demonstrate the seriousness of the problem.
By comparison, on the other side of the chart, each year
FDA routinely samples and analyzes drug products made by
commercial manufacturers. Since 1996, we have analyzed more
than 3,000 samples of these products, and of these 3,000, only
four failed potency tests.
Over the years, FDA has conducted enforcement activity
against inappropriate pharmacy compounding, and my written
testimony details some of our very recent enforcement cases.
We work cooperatively with our State partners, and I would
like to give you an inside look at some of the problems that
the State of Florida uncovered in a compounding pharmacy in the
photos that are being shown there. Again, these photos are not
representative of compounding pharmacies, but they are just to
be illustrative examples of what can go wrong.
The first photo shows empty, uncapped vials used to
compound respiratory therapy products. These vials are located
in an uncovered box on the floor, and in bags on the upper
shelves of a lavatory storage area.
The next photo shows an uncovered box of uncapped unit dose
vials on the floor of a bathroom next to a toilet. The next
photo shows an uncovered, unprotected flask of albuterol
sulfate, a drug for asthma, located in the pharmacy's
refrigerator next to some food. Again, we don't think these are
representative, but they do clearly occur and the public health
requires that we take steps to address them.
My written statement describes our statutory and regulatory
authority over compounding. It covers the compounding
provisions in section 127 of the FDA Modernization Act and the
decision of the Western States versus Shalala case. Since that
decision, FDA issued a compliance policy guide in May, 2002,
that addresses how we will exercise our enforcement discretion
under current law.
We respect the role of the States in matters that relate to
pharmacy regulation. We also believe that there are areas where
the Federal role is appropriate. These include maintaining a
list of drugs that are inappropriate for compounding because
they've been withdrawn from the market for safety reasons; two,
overseeing the quality of bulk drug substances that are used in
compounding; third, in conjunction with the States,
investigating allegations of poor quality compounded drugs; and
finally, determining when a pharmacy crosses the line between
appropriate pharmacy compounding and manufacturing.
In closing, Mr. Chairman, I want to assure you that the
agency's efforts to address pharmacy compounding issues are
designed to balance the legitimate forms of pharmacy
compounding with the need for Federal regulation when pharmacy
compounding threatens to compromise public health.
I am happy to answer any questions, of course.
Senator Bond. Thank you very much, Dr. Galson.
[The prepared statement of Dr. Galson may be found in
additional material.]
Senator Bond. We have been joined by Senator Roberts. I
will call on him for any statements he wishes to make.
Opening Statement of Senator Roberts
Senator Roberts. I apologize to the witnesses and my
colleagues for being late. I think they did a study around here
at one time showing we're supposed to be at two places at the
same time.
Senator Bond, I want to thank you for your leadership and
for your sponsorship of the amendment to the Medicare bill. I
am glad to join you in holding this hearing on an important
topic that has been simply brought to light over the last 2
years, and is gaining even more momentum. I think that most in
the audience, and I know most in Washington, have been reading
the Washington Post series this week on pharmaceutical safety,
and that series of articles raises valid concerns with the
safety of prescription drugs and that market and protecting
patients. I think our committee can play a lead role in
consumer protection. Again, I want to thank you for your
leadership in this area.
As has been said, today's hearing will focus on examining
the overall practice of compounding pharmacies and where the
industry is headed in really trying to address patient
protection. I believe that Senator Bond and I have the same
goal. We want to look at ways that those who enter the
compounding pharmacy are entering into that profession are
properly trained and we want to ensure that the proper checks
are in place to protect patients. We have looked at recent
cases such as the Med 4-Home Pharmacy in Kansas City that have
helped to illustrate the need for greater oversight.
Med 4-Home did not follow proper recall and notification
procedures for a batch of solutions that it had compounded. The
product was an inhalant solution that was distributed
nationwide and used to treat a variety of pulmonary disorders--
and I'm talking about such things as asthma. Thousands of
patients were contacted about the recall of these vials. I know
that Kevin Kinkade of the Missouri State Board of Pharmacy is
here with us today and he can speak about this event.
I fully recognize the benefits of compounding pharmacy.
There's no question about that. They fill an important niche in
the health care delivery system. However, many questions need
to be answered. How do we define manufacturing versus
compounding? What are we doing at the State level to enforce
regulations currently on the books? How can we get States that
do not have adequate regulation on the books to improve, and
are those who are inspecting properly trained? Should we have a
means to test products once they have been compounded to ensure
they are safe and accurate doses? Are schools of pharmacy
properly training individuals to compound and what steps should
they take to do so safely? Why is there not a system of adverse
event reporting?
We have, and have had, two outstanding panels. I hope that
they will be able to assist us in answering these questions.
I'm sure they will.
In addition, Mr. Chairman, I have received comments from a
compounding pharmacist, Dr. Steven Hotze of the Hotze Health
and Wellness Center in Katy, TX. I have met with Dr. Hotze and
he was eager to provide the committee with his input on this
important topic. I would like to submit Dr. Hotze's testimony
for the record at this point.
Senator Bond. Senator Roberts, without objection, it will
be so admitted to the record.
[The prepared statement of Dr. Hotze may be found in
additional material.]
Senator Bond. I have been advised that I am needed to make
a quorum to vote on the chemical safety measure before the EPW
Committee. I will ask Senator Ensign to ask five minutes of
questions, and then Senator Roberts, if you would then ask
questions, and should I be tied up, if you would continue with
the introduction of witnesses.
Senator Roberts. I will be more than happy to do so.
Senator Ensign. Thank you, Mr. Chairman.
I normally don't take witnesses to task, Dr. Galson, but I
do want to take you to task on something. You're a scientist,
and to present nonscientific data studies--and I'm glad you
mentioned that it wasn't--is problematic. You have to remember,
you're not talking to scientists up here. You can influence
public policy. We look at you as an expert, and you presented
that in a fashion that is misleading. Senators look at that as
a scientific study. That's irresponsible and you really
shouldn't do that, especially as a representative of a
governmental body.
We are trying to set public policy. You can create almost
any information like that and call for a Federal Government
regulation. For example, I think of how often we see frivilous
malpractice cases in States, and I could build an incredible
case and use statistics and then say we should have Federal
licensing of physicians. But nobody is calling for that.
We have problems out there, and there are bad actors. There
are mistakes that are made, and there will always be mistakes.
There will always be bad actors no matter what the laws are.
For example, what Senator Bond talked about--that man was
breaking the law. That's the bottom line. There were existing
laws already being broken.
One of the problems that we have with pharmaceutical costs
in this country is that we hear a lot from everybody throughout
the medical field that the FDA is already overburdened and that
the drugs take too long to get to market as it is.
Now, to put an extra burden on the FDA, and let's say we
decide to do this, could the FDA handle it, and do you have an
idea about how much it would cost?
Ms. Heinrich. Not related to the work that we did here on
compounding, GAO recently did a review of the time it takes FDA
to review new drugs. Actually, their review time has come down
rather dramatically over the last, say, 5 years. But having
said that, there is no question that it is costly to bring new
drugs to market.
What you have here in drug compounding is something quite
different, and that is----
Senator Ensign. I know what drug compounding is. My point
is that the FDA already has difficulty doing its primary job
function. Now adding something else on top, will this hurt your
primary job function and do you have an estimate of the cost?
Ms. Heinrich. In our discussions with FDA officials--and
certainly Dr. Galson can speak for himself--but people did say
that they are stretched now to cover their ongoing inspection
requirements, and that to do more inspections in the area of
compounding would be difficult.
Senator Ensign. Dr. Galson?
Dr. Galson. Senator, I definitely appreciate your
perspective, and as you said, I wasn't trying to present these
as scientific data. Most notably, I wasn't trying to use them
to urge or call for a new Federal regulation. It was merely to
provide a few illustrative examples of what can happen.
We are stretched thin. We have extremely important public
health responsibilities across the area--drugs, food,
veterinarian drugs. So for us to embark on any new program in
this area would require additional resources. But again, we're
not calling for that and we haven't taken that position.
Senator Ensign. The only other comment I want to make on
this--and I understand we may have some different viewpoints--
but because of my experience in the medical field, I remember,
we painted a great case up here for patient privacy, and then
we got HIPPA. If you have heard anything about the
implementation of HIPPA, health care professionals all over
this country explain how ridiculous some of this stuff has
become.
That is my fear, that when we try to fix something, we make
a lot more things worse. That happens time after time after
time up here. There is a problem out there, and I freely admit
that. But is the fix going to be worse than the problem? HIPPA
is a good example of where the fix is probably worse than the
problem ever was. I just don't want us to end up in that
situation.
Mr. Chairman, I appreciate you indulging me with this, but
it is something that I have been pretty frustrated with. That
is, watching where we try to over regulate medicine, which is a
very inexact science, as we all know. Compounding will never be
completely as precise as the machines. Because you have human
errors that can get involved. We have to be able to take that
kind of information into account.
Thank you, Mr. Chairman.
Senator Roberts. [presiding]. I think the Senator has made
an excellent point. I am extremely aware of the HIPPA
regulations. When we had our first hearing before the full HELP
committee on HIPPA, it was this Senator who waved the
regulations around and indicated that I didn't think any
Senator had really read all the regulations. I'm not sure if
that's possible, in terms of a full understanding.
But I knew darned well that every hospital administrator in
America had to read the regulations, had to hire people to read
the regulations and interpret the regulations. Now we're into
what is called the ``law of unintended effects''. So you make a
good point.
It is important to pass legislation, but it is also
extremely important to prevent bad legislation or counter-
productive legislation from passing. I don't think Senator Bond
or myself or anybody who wants questions answered--and I know
the two witnesses want these questions answered as well--is
proposing that the Federal Government impose a regulatory
scheme that will pose problems for the FDA and any pharmacist
throughout the country. So your caution is well taken and I
thank you for the comment.
Senator Reed has joined us. I will yield to Senator Reed
for any statement he would like to make and, for that matter,
any questions he would like to raise at this point.
Senator Reed. Thank you, Mr. Chairman. I have no opening
statement so I will just get right to questions.
One area of concern is jurisdictional, between the State
Boards of Pharmacy and the FDA. Apparently the FDA guidance is
rather amorphous. The FDA will let the State boards take ``less
significant'' cases and they will take ``more significant
cases.''
Dr. Galson and Dr. Heinrich, can you comment on that? Does
it make sense that one approach to this issue is to try to
clarify more specifically the breakdown of responsibility
between the FDA and the local boards?
Dr. Galson. We don't really think lack of clarity between
the State and Federal Government in this particular area has
been a problem. When we become aware of egregious cases or
other specific issues, we work closely with the States to
assist them, and when the States want our help about something
they find out about on their own, there hasn't really been a
problem in defining who has which role.
Senator Reed. Do you have any ongoing technical assistance
to the States in terms of this issue, where you are advising
State Boards of Pharmacy on a regular basis about emerging
issues of compounding abuses?
Dr. Galson. We're in constant collaboration with them on
compounding issues, as well as other outside groups.
Senator Reed. Dr. Heinrich, do you have any comments?
Ms. Heinrich. In our review, certainly we heard from
pharmacists, pharmacy organizations, that they do believe there
is a lack of clarity. Indeed, when FDA states that they do have
overall authority under the Food, Drug and Cosmetic Act, that
overlaps with State boards, there is ambiguity.
I think where we come out on this is that maybe we need to
live with that because, with State resources being what they
are, we may need to look to FDA even more in the future.
Senator Reed. Thank you.
It is my understanding that pharmacists are not required to
report adverse medical effects with compounded drugs, is that
correct?
Dr. Galson. That's correct.
Senator Reed. Would it be helpful to have such a
requirement in order to pinpoint more precisely the abuses
before they become widespread?
Dr. Galson. We haven't taken a position on that. Right now,
with the traditionally manufactured drugs, the manufacturers
have the legal responsibility to report those adverse events to
us. As you know, there isn't really a system for the
manufacturers to find out about the problems with drugs that
they are compounding, and the compounders to find out about the
adverse events related to the drugs that they're prescribing.
But that is certainly something we could consider.
Senator Reed. Dr. Heinrich?
Ms. Heinrich. We might want to look at the experience of
some States that, in fact, have required adverse event
reporting. For example, in our review, we found that North
Carolina does require adverse event reporting, and it would be
good to look at their experience.
Senator Reed. Very good.
I might have missed this in your statements, but is there
any sort of trend in terms of compounding that should alarm us,
or at least make us more concerned? Is this going on with
increased frequency or is it something that is happening at a
steady rate?
Dr. Galson. I don't think we have good data, because there
isn't really comprehensive registration and monitoring of the
system. We have seen a constant stream over the last few years
of violations in other specific areas where we're concerned
about public health, where we have taken action. But the trend
data just isn't very good.
Senator Reed. Thank you. Thank you both.
Thank you, Mr. Chairman.
Senator Bond. [presiding]. Thank you very much, Senator
Reed.
Dr. Heinrich, in your written testimony you mentioned that
the extent of drug compounding is unknown but appears to be
increasing in the U.S. Can you give us an idea of the
difficulties that GAO faced in attempting to capture the number
of prescription drugs that are compounded in the U.S., as well
as the number of adverse events?
Ms. Heinrich. Yes. That was one of the issues that you
really asked us to look into. We looked at information that we
could glean from the Food and Drug Administration, trying to
identify whether they could track the amount of bulk purchases
of ingredients, and we found that that data system wasn't good,
either, because you didn't have a common unit of analysis.
We went to pharmacy boards, we went to major compounders,
the industry itself, and asked them if they could provide us
that information, and nowhere could we get reliable data.
It is interesting that there are estimates that people have
put out there. They say from one percent to ten percent of all
prescription drugs are compounded, but when we really dug into
that, there is really no basis for those estimates.
Senator Bond. Frankly, that's surprising, and
disappointing.
In surveying the different States, I notice that you said
Missouri and North Carolina have adverse event reporting
systems, and in North Carolina, it has to really be adverse. I
believe they only call ``death'' an adverse event. I think
there are a lot of other things short of that that could be
adverse.
Elsewhere, other than these two States, are there any other
mandatory adverse reporting systems that you know of?
Ms. Heinrich. Not that we were able to identify, but we
could look into that further if you would like.
Senator Bond. Dr. Galson, don't you think that injuries and
deaths from pharmacy compounding is a health issue that FDA
needs to be more aggressive in addressing?
Dr. Galson. We are very concerned about adverse events
related to compounding. There is no question that that's one of
the areas that concerns us the most. We spent a lot of money,
upwards of $8 million per year, monitoring adverse events
currently for traditionally manufactured drugs. That could be
expanded. It is a cost issue.
Senator Bond. But right now, you get information
anecdotally, really?
Dr. Galson. That's right.
Senator Bond. Do you think the current system of State
oversight of pharmaceutical compounding by State boards of
pharmacy is adequate and would meet the standards that FDA
would establish?
Dr. Galson. We think it's doing a reasonable job with us
assisting the States, when that is necessary. As you know,
there are different standards and different circumstances in
each State.
We are working with the State boards of pharmacy and other
organizations to create consensus type standards that would
enable States to more carefully measure what's happening in
their particular pharmacies against those standards, which will
increase the compliance.
Senator Bond. I gather, in answer to the question from
Senator Reed, you didn't think there's any problem with the
lack of clarity with an uneven patchwork of the State-based and
Federal system. Not only do I not see clarity, I don't see a
system.
Dr. Galson. I'm not saying there aren't, from time to time,
problems. But lack of clarity hasn't stopped us from getting
involved when we've seen a problem. That's really what I meant
to convey.
Senator Bond. I guess a first step is reporting adverse
events. Would that be the logical first step? There are too
many anecdotal reports of serious adverse events, death, fraud,
simple errors, that mean that some patients who receive
compounded pharmaceuticals are not getting what the doctor
ordered, and in some instance are receiving a product
contaminated with dangerous bacteria and fungus.
What do we do about it? What role can we play so you and
the States boards of pharmacy can do a better job?
Dr. Galson. Certainly what we have mentioned about adverse
events is one option, although we haven't taken a position on
it. The Administration is continuing to work on developing a
position on whether more legislative authority, regulatory
authority, would be beneficial. We don't have a position to
announce or to discuss with you right now.
We do think there is a lot of traction to be gained by the
professional organizations and the other organizations working
to develop standards, and then working with the States to make
sure those standards are followed.
Senator Bond. Well, I would hope that this hearing is a
wake up call to all of us, to know that the system is not
working, and in many places I don't see a system. We want to
involve all of the groups who will be represented here today,
the associations, the government, the State boards.
But my urgent message to you and the administration is
let's get with it, because Senator Roberts and I are getting to
the age where we're going to need more compounded drugs.
[Laughter.]
Seriously, there are many, many people who depend upon
compounded drugs, who I know benefit in large measure by
compounding. There is no question about that. We have got to
keep the ability of small businesses, small pharmacies, to
compound. It is vitally important.
But there has to be some reasonable assurance that, if
somebody is making an error, or if there is a grossly inept
situation like the Med 4-Home, or there's a criminal act like
Dr. Courtney in Kansas City, somebody has got to catch them.
And we're not going to depend upon a drug salesman saying, ``By
the way, I have done my own research and found out that he
isn't buying enough to develop the potency of drugs that he's
been prescribing.'' That is not good enough.
Senator Roberts, do you have questions?
Senator Roberts. I have some questions for the GAO.
Registered pharmacies obviously vary greatly from State to
State. In the States that you surveyed, what was the range of
proportion of out-of-State pharmacies versus in-State? The
reason that I'm asking that is there are three concerns:
Were there any differences in the registration requirements
between in- and out-of-State pharmacies, and I think the answer
to that is yes. How often did the experts you interviewed
really believe that pharmacies should be inspected? And
finally, considering there are such dramatic variations from
State to State in their ability to inspect pharmacies due to a
lack of inspectors and obviously the budget holes that our
States find themselves in, is there a concern with the
registration and certification process for registering out-of-
State pharmacies? Out-of-State inspections don't seem to be
very realistic.
Would you care to comment on that? I have probably strung
together four questions, but feel free to answer all of them.
Ms. Heinrich. As you said, there is great variability. It
is difficult enough for many States to do the in-State
inspections. It is much more difficult to monitor the out-of-
State pharmacies, and oftentimes you get some of the
international drugs there as well, to say nothing of what goes
on with the Internet.
The States said consistently that oftentimes it's all they
can do to follow up on complaints, that then they are unable to
do the routine inspections. They would like to be able to do
some every 2 years, every 4 years.
The other issue there is that the individuals who do the
inspections may or may not have training that would help them
provide oversight of compounding. I think only two of the
States we looked at actually had pharmacists that were doing
the inspections. The others were done by law enforcement. So
that's an issue as well.
Senator Roberts. You mentioned the Internet pharmacy, which
has become sort of a tidal wave in regards to consumers who are
looking for cost-effective products--and I emphasize the cost.
Mr. Chairman, there has been a tidal wave, as you know,
every 2 years, when we have these things called elections, you
have candidates making trips and taking senior citizens to
Mexico or Canada to purchase various products, and then coming
back home and holding up the difference in cost.
And now, on the Internet, as evidenced by the Washington
Post series--and I don't want to give them all the credit, but
certainly they are doing a good job in that five-part series--
you have a tidal wave here now of people ordering drugs over
the Internet.
Do you have any comment about that in regards to what you
have found, and how on Earth you could provide any reasonable
inspection so that people are actually getting what they think
they're getting? Feel free, Dr. Galson, to jump in here, if you
would like.
Dr. Galson. Right. We're extremely concerned about this.
There is a flood of drugs coming into the country by various
routes, including the Internet route, and there is really no
system of assuring the safety of those drugs. You don't know
where they're coming from, even they are ordered from a website
that has Canada in the name. You don't really know if they're
coming from there or they have come from some Asian country
where the quality isn't checked.
We have no way to intercept and monitor the packages. There
are millions coming in. It's just impossible for each of these
packages to be examined and looked at. So we are very concerned
that this is escaping the really excellent system of
maintaining the safety and efficacy of the U.S. drug supply.
Senator Roberts. I'm chairman of the Senate Select
Committee on Intelligence, and also the subcommittee chairman
on emerging threats. About four or 5 years ago I got interested
in the food security challenge and danger. We now have that in
the top ten of things that we're worried about.
It seems to me that any terrorist organization or, for that
matter, any organized crime organization, could latch on to
this and do great harm to the American public. I even identify
this as a possible and probable area of concern in regards to
the global war on terrorism. Now, maybe that is stretching it a
little bit, but I don't really think so.
I think if you wanted to do great harm to a community or an
area in the United States, particularly an area affected in
regards to a senior population and the certain maladies that we
all get as we're older, it is a cause of concern.
You stated in your testimony there were difficulties in
interpreting some of the guidelines in the 2002 policy
guidance. Do you intend on clarifying those provisions in the
guidance, and when are you planning on updating that guidance?
Dr. Galson. What we try to do is, when specific situations
of interpretation come up, we do our best to clarify. At this
moment, we believe this is as clear as we can be. Although we
are continuing to think about improvements, we don't have a
specific product or a date to point to when we're going to have
further clarification or further details right now.
Senator Roberts. How do you define small versus large
compounding?
Dr. Galson. The major way we distinguish between acceptable
and unacceptable compounding is if the compounding is being
done for medical need, a legitimate medical need, where there
is a relationship between the physician and the patient and the
pharmacist. We consider that legitimate compounding.
When the compounding looks more like small or large scale
manufacturing, that's when we become concerned, when large
batches of product are made in advance of receipt of
prescriptions. When copies of legitimate drugs are being
prepared, when third parties are involved in reselling the
drugs as well, we consider that large.
I just got a note here that we are working on a revised
compliance policy guide based on public comments that are in
our docket. I just don't have a time for when we're going to
issue those.
Senator Roberts. I understand that.
How do you determine who to inspect and who not to?
Dr. Galson. We inspect for cause, basically, when we hear
about situations that raise concerns, or when information comes
to us from States or some other source of information that lets
us know that there may be a problem, we do an inspection and
work with the States.
Senator Roberts. What do you deem as acceptable or is an
acceptable variance before a recall occurs?
Dr. Galson. Numerically, you're asking?
Senator Roberts. Yes, sir. If you can pin that down, I know
that's a----
Dr. Galson. Yeah. I think I can't give you one number. We
look at the product, we look at whether the product meets our
criteria for quality, which are somewhat different, depending
on the type of product--is it a pill, is it an inhalation, an
injectable kind of drug. We make a call on that based on the
public health risk involved with the product that we discover.
Senator Roberts. Mr. Chairman, I want to thank both
witnesses for taking the time to come. I think this has been
very educational. I have no further questions.
Senator Bond. Thank you very much to our witnesses. We will
call the second panel.
Dr. Galson, if perhaps you could have you assistant turn
that display panel around, so that those who are here may see
the pictures that you took of the compounding pharmacy in
Florida. Also, if you will allow the next witnesses to come
forward, we thank you very much.
In the meantime, since several people have referred to
newspaper articles on this, I am asking unanimous consent to
include in the record a reprint of a three-part special report
that appeared October 6-8, 2002, in the Kansas City Star, which
has an excellent summary of this.
[The report referred to may be found in the Kansas City
Star, October 6-8, 2002.]
Senator Bond. The second panel we would like to welcome and
ask to come forward, please. Dr. Sarah Sellers, Executive
Director of the Center for Pharmaceutical Safety a nonprofit
public safety organization. She has a decade of experience as a
pharmacist and she is completing a master of public health at
Johns Hopkins, and serves on the FDA's advisory committee.
Daniel Herbert is president-elect of the American
Pharmacists Association. A 1966 graduate of the Medical College
of Virginia's School of Pharmacy, he owns three innovative
community pharmacies in Richmond, VA which are involved in
developing economical ways to deliver pharmaceutical care.
I am also pleased to welcome Kevin Kinkade from my home
State of Missouri, a graduate of the State College of Pharmacy,
a licensed pharmacist, and who has served as Executive Director
of the Missouri State Board since 1984.
Also, very importantly, Dr. Bill Kennedy, a professional
pharmacist registered in Florida and South Carolina, who for 20
years compounded pharmaceuticals in a retail pharmacy and
national mail order respiratory pharmacy. He has invested
millions of dollars in building a sterile, FDA-approved
manufacturing facility.
So these witnesses will give us good, new perspectives on
this situation. As I have indicated, you full statements will
be made a part of the record. We would ask you to try to
summarize them in about five minutes.
I would call first on Dr. Sellers.
STATEMENTS OF SARAH L. SELLERS, PHARM.D, EXECUTIVE DIRECTOR,
THE CENTER FOR PHARMACEUTICAL SAFETY; DANIEL A. HERBERT, RPh,
PRESIDENT ELECT, AMERICAN PHARMACISTS ASSOCIATION; KEVIN
KINKADE, EXECUTIVE DIRECTOR, MISSOURI BOARD OF PHARMACY; AND
WILLIAM KENNEDY, OWNER, NEPHRON PHARMACEUTICALS CORPORATION
Mrs. Sellers. Thank you. Mr. Chairman and members of the
committee, thank you for the opportunity to speak with you
today about the serious public health implications of pharmacy
compounding. I am Sarah Sellers, a licensed pharmacist, with
expertise in sterile compounding and public health. In 1998, I
began serving on the FDA's Advisory Committee on Pharmacy
Compounding.
It is unsettling that at a time when we are concerned about
the quality of drugs accessed outside our borders because they
may not meet our Federal regulatory standards, that we have a
flourishing, unregulated drug industry within our own borders.
I began my career in a small, home care pharmacy that
provided pharmacy compounded injections to patients for
administration on their homes. When I asked permission to
substitute the compounded drugs with FDA-approved products
because of safety concerns, I was cautioned that it would be
less profitable for the pharmacy. These compounded dosage forms
did not undergo a validated sterilization procedure, were not
tested for potency or purity, and the risks of using such a
product were not identified, analyzed, or communicated to
physicians or their patients.
This practice concerned me for both medical and ethical
reasons. Patients were unknowingly exposed to drugs that did
not meet strict Federal standards for safety and efficacy,
manufacturing or labeling, to ensure safe use.
Based on my study of what is happening with pharmacy
compounding, I believe there are four critical factors that
need to be addressed. One, pharmacy compounded drugs do not
meet our Federal safety requirements.
Two, as you heard from the GAO this morning, accurate,
complete and unbiased information about the size and scope of
the compounding industry in the United States is not available.
Three, current State compounding regulations are in some
cases inadequate to protect public health and safety, and to
prevent individual patient exposures to unacceptable risks.
Four, lack of oversight of the compounding industry has
created new avenues to introduce commercial quantities of
unapproved drugs into the marketplace through wholesale
transactions.
Pharmacists are trained in pharmacy school to convert
tablets to liquids and to make topical formulations to meet
exceptional medical needs that cannot be met with approved
products. But this practice, based on medical necessity, is
very different from contemporary compounding. Contemporary
compounding exploits current lapses in the law and resource
constraints with regulators. This has resulted in the emergence
and growth of a substandard industry.
Because pharmacists are not required to detect or report
problems associated with drugs they compound, the known cases
of deaths, injuries, exposures and recalls of dangerous
products are considered tip of the iceberg by public health
experts.
Pharmacy compounded products have been associated with
other injuries and deaths throughout the Nation. Last year, the
CDC warned physicians and health systems to consider
substandard compounded drug exposures in cases of unexplained
infections following intraspinal injections, after an outbreak
of fungal meningitis was associated with compounded products.
CDC further warned that health systems may not even realize
that they are purchasing compounded drugs.
In my opinion, the amendment to the Senate version of the
Prescription Drug and Medicare Improvement bill, offered by
Senators Bond and Roberts, to establish an FDA Advisory
Committee on Compounding, is a critical first step, but it is
only a first step. I believe new Federal legislation is
necessary to protect patients and preserve the integrity of our
current Federal system of drug regulation which is respected
around the globe.
This legislation should consider the following:
One, there should be full disclosure to patients and
prescribers when a prescription is filled with a compounded
drug.
Two, compounding of drugs that are too difficult to make in
a pharmacy setting should be prohibited and large-scale
manufacturing of any drug product should be regulated by the
FDA.
Three, there should be a strict paper trail for all
chemicals used in compounding and reporting of any adverse
events related to compounded products by pharmacists.
The basic assurances to public health and safety provided
by the Federal Food, Drug and Cosmetic Act, that all citizens
of this country rely on, should not be undermined.
Unfortunately, I believe the unchecked growth and expansion of
pharmacy compounding is threatening the Act's integrity.
I thank you for your time and would be pleased to answer
any questions you may have.
Senator Bond. Thank you very much, Dr. Sellers.
[The prepared statement of Ms. Sellers may be found in
additional material.]
Senator Bond. Now we will invite Mr. Herbert for his
testimony
Mr. Herbert. Good morning, Mr. Chairman.
Members of the committee, thank you for the opportunity to
appear before you today and present the views of the American
Pharmacists Association. I am Dan Herbert, a pharmacist, and
president-elect. I have been in practice for 37 years and
currently own three community pharmacies in Richmond, VA.
I have been involved in compounding throughout that entire
career, and have been involved in a hospital setting, hospice,
home infusion therapy, and community practice.
APhA represents the largest group of pharmacies in any
association in the country who practice in virtually every
practice setting. APhA supports the committee goal that
patients receive safe and effective medication. As pharmacists,
we rely upon quality as the first step in our work to help
patients get the most of their medication therapy. When
providing a quality product involves tailoring a medication for
an individual patient, we use our scientific training and
education to compound the medication to meet the patient's
needs.
My goal today is to share with you my experience with
pharmacy compounding, the value it can bring when performed for
the right reasons and in the right way. I compound 10 to 20
times per day in my practice, and while it is challenging to
quantify the actual number of APhA members who regularly
compound, I think it is safe to say that virtually every
pharmacist is involved in compounding at some point in their
career, and many on a daily basis.
The committee has so eloquently stated many of our
positions in your opening statements that I am going to skip
over the justification of why we need to preserve compounding.
You have already acknowledged that it is a vital patient care
service and that keeping it available to the public is an
important thing to do.
We fully recognize the need for pharmacy compounding to
conform to high professional standards. The question that you
have already asked and that plagues the profession and our
regulators, the State boards of pharmacy, is how to distinguish
between what I do, compounding, and manufacturing. It has been
a difficult distinction to implement because of the complexity
and range of legitimate compounding activities. The key element
in making any such distinction is the existence of a
pharmacist-prescriber-patient relationship.
Furthermore, compounded drugs are not for resale but,
rather, are personal and responsive to a patient's immediate
needs. My compounding practice is for those patients that I
serve every day, and their physicians.
APhA is undertaking several activities to advance and
improve pharmacist compounding, such as publishing resources
for pharmacists to improve the practice. Also, I am chairing an
APhA committee setting strategic directions for the profession,
including proposing steps for advancing compounding quality.
One aspect of our committee's work to date is the
preliminary categorization of compounding to distinguish
between the types of compounding a pharmacist can provide based
on his basic pharmacy education and that type of compounding
that may require additional specialized training, and perhaps
even certification or accreditation. Because compounding
encompasses a broad scope of activities, this categorization is
important in focusing quality improvement efforts and
resources.
Finally, in collaboration with the National Association of
Boards of Pharmacy and the United States Pharmacopeia, APhA has
recommended exploring the value of voluntary programs to
improve compounding activity in certain categories. Improving
our efforts to provide quality compounded products will require
collaborative efforts of consumers, the profession, the boards
of pharmacy, and the FDA. Each stakeholder has an expertise
that is essential in assuring the continued availability of
this practice with the quality patients deserve.
The profession must take the lead in guiding the regulatory
agencies on how to draw the line between compounding and
manufacturing, and in developing guidelines to make those
standards real in everyday practice. The State boards of
pharmacy should maintain their primary regulatory role of
pharmacy practice, including compounding, and will likely be
tasked with new initiatives to enhance the current regulatory
efforts. Pharmacists and APhA are ready to partner with
stakeholders to develop effective strategies to continue to
improve the quality of compounding practices.
Thank you for the opportunity
Senator Bond. Thank you very much, Mr. Herbert. We
certainly look forward to working with you when we have the
results of your recommendations.
[The prepared statement of Mr. Herbert may be found in
additional material.]
Senator Bond. Now I turn to Mr. Kinkade and find out what
is going on in Missouri since we last talked. Welcome.
Mr. Kinkade. Good morning.
Mr. Chairman, members of the committee, thank you for the
invitation to speak here today on a matter that is very
important to consumers and regulators, as well as the medical
and pharmacy professions.
While not all pharmacies practice the art of compounding,
those that do provide a time-honored and valued service to
their patients. Just as in the past, there are situations today
where only compounded drug products can fulfill the need that
some patients have for effective drug therapies.
As technology and science increase our ability to
manufacture new drugs, so do these same elements have an impact
on the practice of compounding. This places new and complex
challenges before State boards of pharmacy, who are charged
with the protection of public health and safety on a State
level.
A number of cases around the Nation have brought national
attention to the practice of compounding. The Robert Courtney
case in Kansas City, which was an example of outrageous and
demoralized conduct, certainly brings to light what great harm
to others a single criminal can do. Other cases of incompetent
acts or actions that resulted in errors that have harmed or
even caused the death of patients have also garnered attention.
Our primary concern must always be for the health and safety of
our citizens who receive health care, and concerning today's
subject, compounded products.
My written testimony outlines in more detail the major
changes and regulations and processes that have been made in
Missouri in order to maintain adequate minimum standards of
practice in pharmacies that compound.
We have also reviewed our inspection process in all areas
in order to ensure that our field staff of the board of
pharmacy are functioning with the latest knowledge base
possible.
Whether or not the issue is criminal fraud against
consumers, or it is a matter of incompetent or negligent
practices, we must be in a position to act quickly and
effectively. Resources for the proper inspection of pharmacies,
as well as the ability to respond timely to consumer complaints
through the use of investigations, must be the first priority.
Additionally, appropriate quality assurance practices, both in
pharmacies that practice compounding as well as with the boards
of pharmacy that regulate them, must be included as well.
As an example, the Missouri Board of Pharmacy has chosen to
test samples of compounded drugs from State-licensed pharmacies
on a random, unannounced basis. Once a sample is obtained, it
will be tested using certified laboratory procedures that will
also include full chain of custody controls for each item
tested. Pharmacies will be reimbursed for their cost for
whatever samples that are selected.
All States have in place a voluntary compliance program
that utilizes State inspectors to review standards of practice
in pharmacies. Missouri utilizes this approach, when possible,
to seek any corrective actions that may be necessary within a
particular practice setting. However, when necessary, in
Missouri we use discipline power as well as authority to seek
relief in State courts to halt unsafe practices through
restraining orders and permanent injunctions.
Legislation was introduced this last year that would have
provided additional authorities to the Board. Some of these
included embargo authority, the provision of a specific class
of license for pharmacies that compound, and to allow expedited
procedures against licensees that the Board believes are
practicing pharmacy in an unsafe manner. The bill that was
introduced in both the House and the Senate did not pass due to
some differences between the State association and the Board.
If we are successful in the next legislative session, such
authorities will further enhance our ability to act effectively
when situations warrant such use of those powers.
Finally, Federal agencies such as the FDA can work with
various States and the National Association of Boards of
Pharmacy to develop national definitions and guidelines to
maintain an appropriate balance between State and Federal
regulatory responsibilities. An improved definition of
compounding versus manufacturing on the Federal level would
help define the role of State and Federal agencies as well.
The Missouri Board of Pharmacy again wishes to thank the
committee for this opportunity to testify, and is certainly
available to work with Congress and Federal agencies on
improving oversight over compounding practices.
Thank you.
Senator Bond. Mr. Kinkade, obviously I'm very proud of the
way that Missouri has responded. We had a horrible tragedy, and
several others, and I hope other States can learn a positive
lesson without having to go through the very real problems that
were caused in our State. The response, given the State of
knowledge, seems to be outstanding and perhaps a model, and we
welcome comments on it. But I want to commend you and the State
Board for being very, very aggressive and we look forward to
seeing how the system continues to work in Missouri.
[The prepared statement of Mr. Kinkade may be found in
additional material.]
Senator Bond. With that, let me turn now to the testimony
from Mr. Kennedy. Thank you so much for being here and for
sharing your experience on both the compounding and
manufacturing side.
Mr. Kennedy. Thank you.
Mr. Chairman and members of the committee, thank you
sincerely for your efforts to shed public light on the
phenomenon in the country today of pharmacists boldly
compounding massive quantities of prescription drugs. I believe
that I am uniquely qualified to speak to you on this topic.
I am both a licensed pharmacist who was involved in a
large-scale compounding, and I am now the owner of an FDA-
approved manufacturing facility in Orlando, FL. We produce
sterile product, oral inhalation solutions, so most of my
comments are going to be toward the inhalation market. The drug
albuterol has already been mentioned, and the term Med 4-Home
has been mentioned earlier about Missouri, so a lot of my
comments are related to oral inhalation.
Since we have been an FDA-approved plant, we have been able
to win a contract from the Veterans Administration, the VA
contract, which is one of the largest contracts in the country
for being able to provide albuterol and ipratropium. We were
selected by the Government and we won it on quality and we won
it on price, to be able to provide all of the albuterol and
ipratropium that is manufactured that VA hospitals and patients
at home use in their nebulizers.
The public is at risk, an alarming great risk, and you are
to be commended for your interest in and pursuit of non-FDA
compliant compounding.
At this time I would like to point out that I agree fully
with what other pharmacists are saying, what Mr. Herbert said,
as the president of the American Pharmacists Association. If
that model is followed, I don't think we have that great a
problem. I think the problem becomes all of a sudden when you
have the independent pharmacy who is compounding items and
doing a great job for the community--like if you go to your
local pharmacists in any town in America and get a product
compounded, whether it be a veterinarian who has written a
prescription, or your general practice doctor, or your dentist,
in which your prescription needs to be altered so that your
medication is more usable for you, every American citizen
deserves that.
My contention and my problem is when we try to do something
like this as a pharmacist and try to do it on a large, massive
scale, and compound or manufacture whatever the FDA wants to
call it, millions of doses per month. For example, Med 4-Home
as was mentioned earlier. So I think the problems come in when
you try to do it on a massive scale and you're not a
manufacturer.
You have large companies, you have public companies, you
have large private companies that are hiding behind the
auspices of a compounding pharmacy that should be considered
manufacturing due to the scale of product and number of
prescriptions they are producing on a monthly basis.
I would like to give you my history and background and show
sort of my relationship that I have had with the FDA.
In 1972, I purchased my own retail drug store, Thayer's
Colonial Pharmacy, Inc., located in Orlando, FL. This drug
store had been in Orlando for many years, with a reputation for
finding unique prescription drugs and compounding various
discontinued formulations. Included in this were many
combinations of two or more drugs. It could be dermatology
products, it could be respiratory products, it could be gastric
products, it could be changing formulations for pediatrics so
that they wouldn't have adverse side effects.
But in the mid-1880s at Thayer's, we began compounding
various respiratory medications on a broader scale. This
business grew rapidly, including a large portion of mail order
transactions. We attracted much attention from the industry
because of the size we grew to in a short period of time.
Around 1990, the FDA paid us a visit. Their mission was to
investigate my compounding pharmacy. After 2 weeks of intense
scrutiny, they determined that I should be labeled a
manufacturer and ordered that I cease and desist this
compounding division of Thayer's, the part in which we were
doing massive respiratory drugs, not the part of doing
dermatological preparations or individual compounds where you
have the physician-patient-pharmacist relationship that Mr.
Herbert spoke of.
The FDA representative said, ``If you want to be in the
manufacturing business, then you must have an FDA-approved
manufacturing facility.'' Of course, the back room of my drug
store did not qualify, okay? We're talking 1990, and today
we're talking, of course, 2003.
In 1991, following the FDA's instruction, I set out to
secure the approvals and financing necessary to open a proper
manufacturing facility. Although I was a bit naive at the
outset, I soon learned that I was involved in a daunting
process. In my case, it took over 6 years, 6 years, to secure
approval for my first generic drug product, which is an ANDA,
Abbreviated New Drug Application, in my plant. It was arduous,
capital intensive, and certainly the most challenging endeavor
of my career in health care. However, I now understood the
rules and knew this was necessary to begin providing
prescription drugs on a large scale to the public.
How did I know this? I knew this because the FDA had told
me so.
In 1997, Nephron Pharmaceuticals was up and running as an
FDA-approved and registered facility. Our focus is oral
inhalation solutions to treat asthma, bronchitis, and Chronic
Obstructive Pulmonary Disease. And by the way, COPD is the
fourth leading cause of death in this country today, and is
fast becoming the third leading cause of death. So this is a
big field, oral inhalation solutions, for these patients. As
you can see in my written testimony, I have six different
ANDAs.
Now, by national pharmaceutical standards, Nephron is a
little guy. We are very small. Even so, I just want to show you
what it entails to manufacture drugs as a small manufacturer.
Our 76,000 square foot facility is designated for full FDA
compliance. Our production room design houses controlled
environment rooms, based on the 1997 ISPE sterile manufacturing
facilities guidelines and was developed with the help of FDA.
I also have some exhibits in my package which show you the
different parts of our plant, the sterility part, the water
system, and what we have to go through.
Senator Bond. Mr. Kennedy, those will all be accepted in
the record. We very much appreciate that.
Mr. Kennedy. Thank you.
One other thing I would like to quickly mention is that in
this facility, just to show you the number of people that it
requires to be FDA approved for a small plant the size of a
gnat, compared to a large company.
In our regulatory department we have four people that are
responsible for nothing but FDA compliance and reporting. We
have a quality assurance department that consists of 41 people
that do nothing but handle document control for the FDA--
validation, batch records. We have nine degreed chemists that
work in our lab, and they have technicians. We have 19 degreed
microbiologists and technicians who continually monitor the
environment of the plant. We have 117 production personnel, and
we have specialists that do blow, fill and seal, which is the
type of technology we use to manufacture. These personnel
operate at the facility in compliance with the regulations.
Now, just to talk about some of the standards, called
standard operating procedures.
Senator Bond. Mr. Kennedy, we have a time deadline, and
actually you have answered and I will take that off my
questioning time. But you have answered the questions about the
costs. We are very interested in that. But if you could wrap it
up and submit as much of your testimony as possible, we would
appreciate it.
Mr. Kennedy. OK.
Perhaps to attack this problem, the FDA instituted a rule
that all oral inhalation drugs have to be sterile. That was in
May of 2002. There still seems to be some discussion within the
FDA and the industry where this applies to compounding pharmacy
or not for oral inhalation.
However, in my trips around the country marketing my
products, I encounter time after time non-FDA approved
companies that are actually compounding millions and millions
of doses of these products per month.
Thank you.
Senator Bond. Thank you very much, Mr. Kennedy.
[The prepared statement of Mr. Kennedy may be found in
additional material.]
Senator Bond. Let me go back to Mr. Kinkade. As I
indicated, Missouri is the first State to institute random
testing. What do you think the merits are, what is the status
of implementation, what are the problems? This was one of the
first things that we discussed, I think, when I met with you
and representatives of pharmacies and prescribing physicians.
How does the system work and what is the status of
implementation?
Mr. Kinkade. Well, the status at this point is that we are
receiving bids in from various laboratories that will be
contracted with to do the actual testing of the drugs. Missouri
requires that on this type of system, or to expend this much
money out of State budgets, you are required to have a bidding
process. So that is a fairly time-consuming process that we are
about to conclude, and we expect to start testing next month.
Along with that, of course, I might want to add here that
not only will the Board be doing its random testing, but our
new standards, our new regulations will require pharmacies to
do their own testing of certain lots of products that they
produce and have those results on hand.
The testing that the Board will do primarily was in the
area of how samples would be collected. There are various ways
to do that, depending on whether the product has a shelf life
or whether it is the type of product that is compounded and
then used or administered immediately. There will be methods to
be able to take material in both of those cases, as well as
situations where we may receive public complaints and actually,
in a few cases, have to go or use undercover operations in
order to take a random test. But we are setting up procedures
for all of those types of scenarios that we find exist in the
marketplace, with the type of compounds that are being made.
I also emphasize here that we are not just talking about
sterile products, although that is our primary concern, because
in addition to potency issues are products that we will be
testing for, with sterile products, we will also be testing for
such things as sterility and pyrogenicity in these products, to
make sure that they do, in fact, meet the claims and standards
that they are supposed to when compounded.
Senator Bond. Thank you very much, Mr. Kinkade. We
obviously would be interested to learn how the system works
when it gets implemented.
Let me go back to Dr. Sellers. You mentioned loopholes that
the contemporary pharmacy compounders are taking advantage of.
You gave us four very good ideas for legislation. Are there any
other things that you see need to be addressed?
Mrs. Sellers. I think it's very important that both
physicians and patients are apprised of the risks that may be
associated with compounded drugs. Typically, physicians
outsource the information on the risks associated with
compounded drugs to pharmacists, and if there is not a
requirement for the pharmacist to disclose those risks, it
becomes very difficult to make an autonomous decision about a
prescription medication that is in the best interest of a
patient. So I think there needs to be a balanced reporting of
both benefits and risks for these products.
Senator Bond. Let me ask one question. I assume we're all
going along with this, but if you have any comments on it, let
me ask for your comments.
No. 1, does anybody think we should not have a mandatory
Federal system of reporting adverse events? Anyone? Mr.
Herbert.
Mr. Herbert. APhA would support voluntary reporting.
Senator Bond. Voluntary, not mandatory.
Mr. Herbert. Voluntary, nonpunative.
Senator Bond. Would you support mandatory reporting at the
State level?
Mr. Herbert. I think so. I'm not sure what we're talking
about. The nature of compounding itself is such that we don't
often have the information to report any adverse effects. I'm
not sure you would get anything. Mandating you to report
something that you would hardly ever know about, you would
always be reporting something after the fact. As you are
describing, you would be reporting deaths, and they seldom
happen. But I'm not sure what the value of that reporting is.
So you are creating a bureaucracy that reports something that
I'm not sure does anything.
Mrs. Sellers. I would also like to comment, that before you
can report a problem, you need to detect the problem. If we are
not looking for problems with the medications that we are
making, we are not going to be able to report them.
Senator Bond. A good point.
Any comments, Mr. Kinkade, Mr. Kennedy?
Mr. Kinkade. I would make the comment that, at least from
our standards that we have in Missouri now, we have included
requirements not only for recalls, when necessary, but the type
of information that is required and who is to be contacted on
the type and seriousness of the recall.
One of the things we learned in the Med 4-Home case was
that that particular facility had received some complaints from
patients that we weren't aware of. So one of the new standards
that we have implemented in Missouri is that all compounding
pharmacies maintain files so that inspectors can review those
files on any complaints that patients would provide a licensee
on a compounded product.
In addition to that, any adverse reactions, again recalls
on infection rates on any types of compounded products, do have
to be reported to the Board now.
Senator Bond. One other item. I thought I heard agreement
that if a pharmacy is making quantities of compounded drugs--
not compounding for the individual prescription written by a
doctor for a specific patient--should this be an FDA regulated
manufacturing pharmacy? Mr. Kennedy, I think that was your
point.
Mr. Herbert?
Mr. Herbert. I would say quantity, in and of itself, is not
the best indicator, but the existence of a relationship that
you are filling the order pursuant to a physician's order for a
specific person--but you could do that for many patients. So
it's not just the quantity; it is the relationship.
Senator Bond. Is it a specific doctor prescribing for a
patient or patients. If one doctor has 20 patients that need a
compounded drug----
Mr. Herbert. Exactly.
Senator Bond. --then that pharmacist is compounding for
those patients.
Mr. Herbert. Exactly. So the quantity alone is not the
indicator. It is the relationship that exists, and are you
doing it to meet a medical need. It is not just creating it to
put on the shelf and go out and market the stuff.
Senator Bond. Any other comments on that?
Mr. Kinkade. Just briefly, we have run into some pharmacies
who, perhaps due to a shortage of a manufactured drug on the
market, have attempted to sell compounded products on a
wholesale basis--in other words, outside the prescription/
patient/prescriber relationship. In those cases, it is
certainly our interpretation that we feel the Federal law is
clear, that that is manufacturing and not the practice of
pharmacy.
Senator Bond. Sounds reasonable to me.
At this point I am going to turn the rest of the hearing
over to Senator Roberts, because I have a commitment that I
have to keep. I thank all of our witnesses today. It has been
very helpful.
I am asking unanimous consent that we will include in the
record the statement of the American Society of Health-System
Pharmacists, and testimony from the International Academy of
Compounding Pharmacists.
[The statements of the American Society of Health-System
Pharmacists and the International Academy of Compounding
Pharmacists may be found in additional material.]
Senator Bond. We will keep the record open for a week for
further comments. I think we have raised some questions, and
maybe we have some misunderstandings, so if you wish to submit
something to clarify those, we would appreciate your doing it
within a week. We may have some additional questions, and other
members of the committee may have some questions. We would
appreciate if you would try to respond to those promptly.
Finally, as we are all looking at what we should introduce
on the Federal level, whether we should introduce it on a
Federal level, we would appreciate receiving your advice by
January 15th on whether you think the time is ripe for some
kind of reporting, if some kind of regulation is necessary. If
you would report to us by that time, we would very much welcome
your input.
Again, our sincere thanks for enlightening us. It is a
complicated subject, and obviously, I have got to learn more.
But I thank you for your guidance.
I will turn the gavel over to Senator Roberts.
Senator Roberts. [presiding]. Thank you, Mr. Chairman.
Again, I want to thank you for your leadership. I am very happy
to cosponsor our amendment.
I might say at the outset that when we meet with the
Finance Committee staff as of this next week to try to work out
the amendment as part of the overall bill, that the first step
is what Dr. Sellers indicated, i.e., at least an advisory
board.
We gave a lot of leeway to the Secretary to make sure that
all groups are represented, and if we get this right, we are
talking about the National Association of Boards of Pharmacy,
the pharmacy groups, the physician groups, the hospital groups,
the consumer and patient advocate groups, law enforcement
agencies, which are very important, victims of unsafe or
diluted compound drugs or their families, and those that would
be determined appropriate by the Secretary. So we haven't
really defined the universe yet, but we want to make sure that
it is comprehensive and that all groups and all advice and
counsel would be considered in the advisory process.
I'm going to ask Mr. Kennedy a question because it gets to
the Hobson's choice or the Catch-22, or what Senator Ensign was
talking about, in an effort to try to bring some degree of
control and safety to this whole issue.
You went through 6 years, six long years with the FDA, and
as you have indicated in your statement, you have, in order to
comply with the FDA, to maintain your business, which now has
FDA approval, of course, four people responsible for all FDA
compliance, 41 people in regards to document control--that
sounds like ``Dr. K'' over in Iraq--quality control, nine
degreed chemists, 19 degreed microbiologists, 117 production
personnel, four blow, fill, seal specialists--I don't know what
that means, but I will take it for granted that they are
necessary--and 22 production equipment assistance and ``one
partridge in an FDA regulatory tree.'' [Laughter.]
Mr. Kennedy. Correct.
Senator Roberts. Dr. Sellers, you have given excellent
testimony, and you have had an experience associated with your
home care pharmacy in compounding experience. You are the duty
expert here on the panel in regards to this universe that we
really haven't got our arms around.
How on Earth can we make progress without getting into a
regulatory nightmare and having a manufacturer having to go
through 6 years of a gauntlet in regards to FDA? I'm not trying
to pick on the FDA. They have their requirements as well. But
that seems to me to be a real problem area.
Mrs. Sellers. Yes, sir. There are other countries that have
dealt with this issue by creating small manufacturers licenses
to produce drugs that are not commercially manufactured. That
may be one option to explore as a potential solution. There may
be State licensed facilities that may be able to fill this role
as well.
I think we should incentivize small businesses that can
meet those needs and do it in a manner that produces uniform
quality products that are needed by specific patient
populations.
Senator Roberts. This 6 years business and all of this
employment, all that's involved is the cost driver, that
basically is one of the causes that we have a problem with. It
is going to be a real challenge for us.
Talking to Dr. Sellers, what actions did you take after
wrestling with the medical and ethical issues associated with
your home care pharmacy compounding experience, and what was
the outcome of your course of action?
Mrs. Sellers. I initially contacted the State Board of
Pharmacy in Florida, and they took no action one compounding in
the State of Florida. I left that practice and went to other
practices in my community and found the same type of
compounding existed in those pharmacies as well. That is when I
decided to start studying the issue more fully and began
efforts to gain more education in public health.
Senator Roberts. Well, you actually answered my next
question. You stated you quickly learned that your compounding
experience was not unique. How did you learn this, and you have
already addressed that. And then what action did you take upon
learning this, and your action was your current capacity.
What do you believe are the loopholes, the major loopholes,
in regards to the contemporary pharmacy compounders, that
they're really taking advantage of?
Mrs. Sellers. I think there is overlapping regulatory
authority which creates a situation where there is a
questionable role in State and Federal regulation that can be
exploited. I have seen where there have been difficulties when
the FDA has attempted to go in and regulate a pharmacy that the
FDA believes is actually manufacturing, and they have been
denied entry into pharmacies, denied access to inspect, because
the pharmacy has stated that they are regulated by the State.
So perhaps it's a better way to State that the overlapping
authorities and the unclear mandates between the Federal and
State Governments creates a situation where it is very
difficult to have effective oversight.
The infrastructure for oversight is further complicated by
the fact that pharmacies are not registered with the FDA, so,
in fact, the FDA may not know where mass manufacturing is going
on or where unsafe practices exist. On the State level, because
we have limited resources and so few inspectors who may not be
trained to look for public health problems, we may not be
identifying problems.
Senator Roberts. Mr. Herbert, that leads me to the question
I wanted to ask you. What can we do to work with the schools of
pharmacy to improve their curriculum, and then, obviously, you
get into a better training situation?
Mr. Herbert. To work with the schools of pharmacy?
Senator Roberts. Yes, sir.
Mr. Herbert. I'm not sure I can answer that. The schools of
pharmacy, for the most part, are not teaching compounding these
days. It is not part of the curriculum in many schools of
pharmacy in the country. Whether you have the ability to
require that is something I can't answer.
Having standards for what the practice is about may back in
that process. If you have to meet standards when you're
practicing, then you would have to learn them somewhere, and
that may precipitate the reinstitution of training programs in
schools of pharmacy. But, frankly, it is not part of the
curriculum in most of them today.
Senator Roberts. It occurs to me that I should have asked
you, basically, do you feel that the schools of pharmacy are
providing adequate training for pharmacy compounding, and the
answer to that is probably no.
Mr. Herbert. The answer to that is no.
Senator Roberts. Some pharmacy technicians are allowed to
compound. Do you feel they have the proper training to
compound, and I would guess the answer to that is no.
Mr. Herbert. I don't know that I would agree with that. I
think they can be trained to properly compound.
Senator Roberts. Obviously, I think they should be required
to have some minimum requirements in terms of training and
education.
What is your opinion about States licensing or, at the
minimum, registering a pharmacy technician?
Mr. Herbert. Registering a pharmacy technician?
Senator Roberts. Yes, sir.
Mr. Herbert. I think it should be done.
Senator Roberts. All right.
Mr. Herbert. It is done in our State.
Senator Roberts. That concludes the questions I had. I want
to associate myself with the remarks of the distinguished
chairman, and would ask if any member of the panel would like
to add anything at this point before we conclude the hearing.
Mr. Kennedy. Yes, sir, I would like to add one point.
With the present enforcement of the FDA in compounding, and
as I talk about the quantity and size of the compounding, of
the commercialization of the compounding going on, I don't
understand why, even with the regulations and rules that are on
the books today for the FDA, why there cannot be more of a
determination of whether a company is a manufacturer or a
compounder. I think they have the ability to do that, but for
some reason, I think that is being overlooked.
Senator Roberts. That doubtlessly should be a priority
issue for the advisory board, if we can get that first step
done.
Thank you for taking the time out of a very busy schedule
to come and testify on a growing national health concern.
This hearing is concluded.
[Additional material follows.]
ADDITIONAL MATERIAL
Prepared Statement of Janet Heinrich, GAO
Prescription Drugs
State and Federal Oversight of Drug Compounding by Pharmacies
Why GAO Did This Study
Drug compounding--the process of mixing, combining, or altering
ingredients--is an important part of the practice of pharmacy because
there is a need for medications tailored to individual patient needs.
Several recent compounding cases that resulted in serious illness and
deaths have raised concern about oversight to ensure the safety and
quality of compounded drugs. These concerns have raised questions about
what States--which regulate the practice of pharmacy--and the Food and
Drug Administration (FDA) are doing to oversee drug compounding. GAO
was asked to examine (1) the actions taken or proposed by States and
national pharmacy organizations that may affect State oversight of drug
compounding, and (2) Federal authority and enforcement power regarding
compounded drugs.
This testimony is based on discussions with the National
Association of Boards of Pharmacy (NABP) and a GAO review of four
States: Missouri, North Carolina, Vermont, and Wyoming. GAO also
interviewed and reviewed documents from pharmacist organizations, FDA,
and others involved in the practice of pharmacy or drug compounding.
What GAO Found
A number of efforts have been taken or are under way both at the
State level and among pharmacy organizations at the national level that
may strengthen State oversight of drug compounding. Actions among the
four States reviewed included adopting new regulations about
compounding and conducting more extensive testing of compounded drugs.
For example, the pharmacy board in Missouri is starting a program of
random testing of compounded drugs for safety, quality, and potency. At
the national level, industry organizations are working on standards for
compounded drugs that could be adopted by the States in their laws and
regulations, thereby potentially helping to ensure that pharmacies
consistently produce safe, high-quality compounded drugs. While these
actions may help improve oversight, the ability of States to oversee
and ensure the quality and safety of compounded drugs may be affected
by State-specific factors such as the resources available for
inspections and enforcement.
FDA maintains that drug compounding activities are generally
subject to FDA oversight, including its authority to oversee the safety
and quality of new drugs. In practice, however, the Agency generally
relies on States to regulate the limited compounding of drugs as part
of the traditional practice of pharmacy. In 1997, the Congress passed a
law exempting drug compounders that met certain criteria from key
provisions of the Federal Food Drug and Cosmetic Act (FDCA), including
the requirements for the approval of new drugs. These exemptions,
however, were nullified in 2002 when the U.S. Supreme Court ruled part
of the 1997 law to be an unconstitutional restriction on commercial
speech, which resulted in the entire compounding section being declared
invalid. Following the court decision in 2002, FDA issued guidance to
indicate when it would consider taking enforcement actions regarding
drug compounding. For example, it said the Agency would defer to States
regarding ``less significant'' violations of the Act, but would
consider taking action in situations more analogous to drug
manufacturing.
Mr. Chairman and Members of the Committee: I am pleased to be here
today as you consider State and Federal oversight to ensure the safety
and quality of compounded prescription drugs. Drug compounding--the
process of mixing, combining, or altering ingredients to create a
customized medication for an individual patient--is an important part
of the practice of pharmacy. Common examples of compounded drugs
include tailor-made medications for patients who are allergic to an
ingredient in a manufactured drug. Drug compounding is part of pharmacy
education and, like other aspects of pharmacy practice, it is regulated
by State pharmacy practice acts, which in turn are enforced by State
boards of pharmacy. All 50 States describe drug compounding in their
State laws and regulations on pharmacy practice, although specific
statutes or regulations vary across States. At the Federal level, the
Food and Drug Administration (FDA), which oversees the introduction of
new drugs into the marketplace under the Federal Food, Drug and
Cosmetic Act (FDCA),\1\ maintains that compounded drugs are generally
subject to the act.
---------------------------------------------------------------------------
\1\ See 21 U.S.C. 355.
---------------------------------------------------------------------------
While drug compounding is an important part of ensuring that
medications are available to meet individual patient needs, the quality
and extent of drug compounding have surfaced as important issues in
recent years. For example, several compounding cases in the past
several years have resulted in serious illnesses and deaths, raising
concern about oversight to ensure the safety and quality of compounded
drugs. In addition, concerns have been raised by FDA and others that
some pharmacies are going beyond traditional drug compounding for
individual patients by, for example, compounding and selling large
quantities of drugs without meeting safety and other requirements for
new manufactured drugs. Because both States and the Federal Government
have oversight responsibilities, you asked us to address (1) the
actions taken or proposed by States and national pharmacy organizations
that may affect State oversight of drug compounding, and (2) Federal
authority and enforcement power regarding compounded drugs.
My testimony today is based in part on discussions with the
National Association of Boards of Pharmacy (NABP), as well as a review
we conducted of four States: Missouri, North Carolina, Vermont, and
Wyoming. We selected these States based on their geographic location
and variation in compounding regulations. Two of the States came to our
attention as having taken unique steps with regard to oversight of
compounded drugs, and the other two had each adopted new regulations on
drug compounding. For each of the four States, we reviewed State
statutes and regulations, interviewed officials from the State board of
pharmacy, and reviewed relevant documents such as pharmacy inspection
forms. In addition to examining State-level actions, we examined
national industry efforts by interviewing officials from the American
Pharmacists Association, the International Academy of Compounding
Pharmacists, the American Society of Health-System Pharmacists, the
National Association of Chain Drug Stores, and Professional Compounding
Centers of America, which provides training to pharmacists and also
sells bulk ingredients for drug compounding. We also contacted and
obtained information from the United States Pharmacopeia (USP), which
is a nonprofit agency that develops standards for pharmaceuticals.
Finally, to examine Federal authority and enforcement power, we
reviewed Federal statutes, FDA compliance policy guides, court
decisions, and other relevant documents, and interviewed FDA officials
and industry experts. We conducted our work from August 2003 to October
2003 in accordance with generally accepted government auditing
standards.
In summary, efforts at the State level and among pharmacy
organizations at the national level have been taken or are under way to
potentially strengthen State oversight of drug compounding. Actions
among the four States we reviewed included adopting new statutes and
regulations about compounding, such as requirements for facilities and
equipment, and conducting more extensive testing of compounded drugs.
For example, the pharmacy board in Missouri is starting a program of
random testing of compounded drugs for safety, quality, and potency. At
the national level, industry organizations are working on standards for
compounded drugs that could be adopted by the States in their laws and
regulations, thereby helping to ensure that pharmacies consistently
produce safe, high-quality compounded drugs. While these actions may
help improve oversight, the ability of States to oversee and ensure the
quality and safety of compounded drugs may be affected by State-
specific factors such as the resources available for inspections and
enforcement. For example, in three of the four States we reviewed,
pharmacy board officials indicated that resource limitations affected
their ability to conduct routine inspections.
FDA maintains that drug compounding activities are generally
subject to its oversight, including its authority to oversee the safety
and quality of new drugs. In practice, however, the Agency generally
relies on States to regulate the compounding of drugs as part of the
traditional practice of pharmacy. In 1997, the Congress passed a law
exempting drug compounders that met certain criteria from key FDCA
provisions, including safety and efficacy requirements for the approval
of new drugs. However, the entire section of the law dealing with drug
compounding was nullified in 2002 after the U.S. Supreme Court ruled
that part of it was an unconstitutional restriction on commercial
speech. Following the court decision in 2002, FDA issued guidance to
indicate when the Agency would consider taking enforcement actions
regarding drug compounding. For example, it said the Agency would
generally defer to the States for ``less significant'' violations of
the FDCA but would consider taking action in situations more analogous
to drug manufacturing.
BACKGROUND
For most people and many pharmacies, filling a prescription is a
matter of dispensing a commercially available drug product that has
been manufactured in its final ready-to-use form. This has been
particularly true in the U.S. since the rise of pharmaceutical
manufacturing companies. In addition to meeting Federal safety and
efficacy requirements before a new drug is marketed, the drugs
manufactured by these companies are routinely tested by FDA after
marketing. According to FDA, the testing failure rate for more than
3,000 manufactured drug products sampled and analyzed by FDA since
fiscal year 1996 was less than 2 percent. Drug manufacturers are also
required to report adverse events associated with their drugs, such as
illness and death, to FDA within specified time frames.
Drug compounding, which has always been a part of the traditional
practice of pharmacy, involves the mixing, combining, or altering of
ingredients to create a customized medication for an individual
patient. According to the American Pharmacists Association, some of the
most commonly compounded products include lotions, ointments, creams,
gels, suppositories, and intravenously administered fluids and
medication. Some of these compounded drugs, such as intravenously
administered chemotherapy drugs, are sterile products that require
special safeguards to prevent injury or death to patients receiving
them. For example, sterile compounding requires cleaner facilities than
nonsterile compounding, as well as specific training for pharmacy
personnel and testing of the compounded drug for sterility.
The extent of drug compounding is unknown, but it appears to be
increasing in the U.S. While industry representatives, the media, and
others have cited estimates for the proportion of prescription drugs
that are compounded ranging from 1 percent to 10 percent of all
prescriptions, we found no data supporting most estimates.\2\ FDA does
not routinely collect data on the quantity of prescriptions filled by
compounded drugs. Similarly, we found no publicly available data,
either from FDA or from industry organizations, on the amount of bulk
active ingredients and other chemicals that are used in drug
compounding in the U.S. However, many State officials, pharmacist
association representatives, and other experts we interviewed reported
that the number of compounded prescriptions, which had decreased when
pharmaceutical manufacturing grew in the 1950s and 1960s, has been
increasing over the past decade.
---------------------------------------------------------------------------
\2\ A 2001 draft report of a study contracted by FDA included an
estimate that about 6 percent of all prescriptions were compounded but
cautioned that there was considerable uncertainty around this estimate
due to limited data. The report acknowledged that definitive statistics
on compounding activities were not available. Eastern Research Group
Inc., Profile of the Pharmaceutical Compounding Industry, draft final
report prepared for the Food and Drug Administration, August 27, 2001.
---------------------------------------------------------------------------
Problems have come to light regarding compounded drugs, some of
which resulted in death or serious injury, because the drugs were
contaminated or had incorrect amounts of the active ingredient. Unlike
drug manufacturers, who are required to report adverse events
associated with the drugs they produce, FDA does not require pharmacies
to report adverse events associated with compounded drugs. Based on
voluntary reporting, media reports, and other sources, FDA has become
aware of over 200 adverse events involving 71 compounded products since
about 1990. These incidents, including 3 deaths and 13 hospitalizations
following injection of a compounded drug that was contaminated with
bacteria in 2001, have heightened concern about compounded drugs'
safety and quality. In addition, a limited survey conducted by FDA's
Division of Prescription Drug Compliance and Surveillance in 2001 found
that nearly one-third of the 29 sampled compounded drugs were
subpotent--that is, they had less of the active ingredients than
indicated.
FDA and others have also expressed concern about the potential for
harm to the public health when drugs are manufactured and distributed
in commercial amounts without FDA's prior approval. While FDA has
stated that traditional drug compounding on a small scale in response
to individual prescriptions is beneficial, FDA officials have voiced
concern that some establishments with retail pharmacy licenses might be
manufacturing new drugs under the guise of drug compounding in order to
avoid FDCA requirements.
ACTIONS TAKEN OR UNDER WAY BY STATES AND NATIONAL ORGANIZATIONS TO
STRENGTHEN STATE OVERSIGHT OF DRUG COMPOUNDING, BUT AFFECT LIKELY TO
VARY FROM STATE TO STATE
We found efforts at the State level and among national pharmacy
organizations to potentially strengthen State oversight of drug
compounding. Actions among the four States we reviewed included
adopting new drug compounding regulations and random testing of
compounded drugs. At the national level, industry organizations are
working on standards for compounded drugs that could be adopted by
States in their laws and regulations. According to experts we
interviewed, uniform standards for compounded drugs could help ensure
that pharmacists across States consistently produce safe, quality
products. While these actions may help improve oversight, the ability
of States to oversee and ensure the quality and safety of compounded
drugs may be affected by their available resources and their ability to
adopt new standards and enforce penalties.
FOUR STATES REVIEWED HAVE TAKEN A VARIETY OF APPROACHES TO STRENGTHEN
OVERSIGHT
The four States we reviewed have taken a variety of approaches to
strengthen State oversight.
Missouri. The pharmacy board in Missouri has taken a
different approach from other States: it is in the process of
implementing random batch testing of compounded drugs. No other State
has random testing, according to an NABP official. Random testing will
include both sterile and nonsterile compounded drugs and the board
plans on testing compounded drugs for safety, quality, and potency. A
Missouri pharmacy board official said testing will include random
samples of compounded drugs in stock in pharmacies in anticipation of
regular prescriptions, random selection of prescriptions that were just
prepared, and testing of compounded drugs obtained by undercover
investigators posing as patients. The official added that random
testing will help to ensure the safety and quality of compounded drugs
and is also intended to serve as a deterrent for anyone who might
consider purposely tampering with compounded prescriptions.
North Carolina. North Carolina is the only State in the
country that requires mandatory adverse event reporting involving
prescription drugs, including compounded drugs, according to an NAPB
official. Regulations in North Carolina require pharmacy managers to
report information to the pharmacy board that suggests a probability
that prescription drugs caused or contributed to the death of a
patient. This reporting system, which does not extend to incidents of
illness or injury, allows the board to investigate all prescription-
drug-related deaths and determine whether an investigation is
warranted.
Vermont. The pharmacy board in Vermont overhauled the
State's pharmacy rules in August 2003 to address changes in pharmacy
practice, including the increase in Internet and mail-order pharmacies,
according to the pharmacy board chairman. For example, the chairman
reported that prior to the adoption of the new rules, Vermont had no
definition of out-of-state pharmacies and no requirements for these
pharmacies to have a Vermont license to do business in the State. The
board chairman said that the new rule requiring licensing for out-of-
state pharmacies would provide a mechanism to monitor pharmacies that
ship prescription drugs, including compounded drugs, into the State. In
addition, he added that the board revised the rules for compounding
sterile drugs by including specifics on facilities, equipment, and
quality assurance measures.
Wyoming. Prior to March 2003, Wyoming did not have State
laws or rules that established specific guidelines for drug
compounding, aside from a definition of drug compounding, according to
a pharmacy board official. The new rules include requirements for
facilities, equipment, labeling, and record keeping for compounded
drugs, as well as a specific section on compounding sterile drugs. In
addition, under the new rules, the official added that pharmacy
technicians-in-training are no longer allowed to prepare compounded
drugs, including sterile products, which is a more complex procedure
requiring special equipment to ensure patient safety.
EFFORTS OF NATIONAL ORGANIZATIONS MAY HELP STATES STRENGTHEN OVERSIGHT
OF DRUG COMPOUNDING
At the national level, industry organizations are working on
uniform practices and guidelines for compounded drugs and a committee
of national association representatives recently began work on
developing a program that would include certification and accreditation
for drug compounding that could be used for State oversight. Groups
such as the NABP concluded that State oversight of drug compounding
would be strengthened if the States had uniform standards and other
tools that could be adopted to address the quality and safety of
compounded drugs. Several experts that we spoke with said national
standards for compounding drugs that could be incorporated into State
laws and regulations could help to ensure the quality and safety of
compounded drugs. One expert noted that an advantage to incorporating
compliance with national compounding standards into State laws is that
it would be easier for States to keep up with updated standards without
going through the process of legislative changes.
NABP developed and updated a Model State Pharmacy Act that provides
standards for States regarding pharmacy practice. Recently revised in
2003, the model act includes a definition of drug compounding and a
section on good drug compounding practices. According to the executive
director of NABP, many States have incorporated portions of the model
act into their State pharmacy statutes or regulations by including
similar definitions of drug compounding and components of NABP's good
drug compounding practices. For example, officials in Missouri and
Wyoming reported using the model act's good drug compounding practices
as a guideline for developing their drug compounding regulations. In
addition, USP has established standards and guidelines for compounding
nonsterile and sterile drug products, both of which are being updated
by expert committees. An official told us that these revisions would be
completed early in 2004.
In addition, recognizing that there is no coordinated national
program to oversee compounding practices and that States' oversight may
vary, NABP recently began working with other national organizations,
including the American Pharmacists Association and USP, to create a
steering committee to develop a national program to provide a national
quality improvement system for compounding pharmacies and the practice
of compounding. The committee, which held its second meeting in October
2003, is developing a program that is anticipated to include (1) the
accreditation of compounding pharmacies, (2) certification of
compounding pharmacists, and (3) requirements for compounded products
to meet industry standards for quality medications. To strengthen State
oversight of drug compounding, these accreditations, certifications,
and product standards, once developed, could be adopted by the States
and incorporated into their requirements for compounding pharmacists
and pharmacies.
FACTORS SUCH AS AVAILABLE RESOURCES MAY AFFECT STATES' ABILITY TO
OVERSEE COMPOUNDED DRUGS
Although there are several efforts by States and national
organizations that may help strengthen State oversight, some States may
lack the resources to provide the necessary oversight. State pharmacy
board officials in three of the four States reported that resources
were limited for inspections, for example:
The Missouri pharmacy board director reported that
pharmacy inspections typically occur every 12 to 18 months; however, an
increase in complaints has resulted in less frequent routine pharmacy
inspections, because investigating complaints takes priority over
routine inspections.
North Carolina has six inspectors for about 2,000
pharmacies, which the State pharmacy board director said are inspected
at least every 18 months. The director added that it is difficult to
keep up with this schedule of routine inspections with the available
resources while also investigating complaints, which take first
priority.
In Vermont, the pharmacy board chairman reported that, for
a period of about 8 years until January 2003, pharmacy inspectors were
only able to respond to complaints and not conduct routine inspections
because of a shortage of inspectors. Vermont now has four full-time
inspectors that cover the State's 120 pharmacies; however, in addition
to routine pharmacy inspections, the inspectors are also responsible
for inspecting other facilities such as nursing homes and funeral
homes. The chairman added that the board would like to have pharmacies
inspected annually but it is difficult to keep up with the current
schedule of inspections once every 2 years.
Since drug compounding may occur in mail-order and Internet
pharmacies, the compounding pharmacy may be located in a State
different from the location of the patient or prescribing health
professional. Three of the four States we reviewed had a large number
of out-of-state pharmacies that were licensed to conduct business in
those States, and inspection and enforcement activities may differ for
these pharmacies. For example, Wyoming has 274 licensed out-of-state
pharmacies, which is nearly twice as many as the number of in-state
licensed pharmacies. The four States we reviewed said that they have
authority to inspect out-of-state pharmacies licensed in their states
but because of limited resources, they generally leave inspections to
the State in which the pharmacy is located. Regarding enforcement
authority, all four States reported having authority to take
disciplinary action against out-of-state pharmacies licensed in their
States.
While the pharmacy boards in all four States we reviewed can
suspend or revoke pharmacy licenses or issue letters of censure,
enforcement mechanisms vary. For example, Missouri and North Carolina
are not authorized to charge fines for violations; however, Wyoming can
fine a pharmacist up to $2,000 and Vermont can fine a pharmacy or
pharmacist $1,000 for each violation. Further, not all State pharmacy
boards have the authority to take enforcement action independently. For
example, in Missouri when attempting to deny, revoke, or suspend a
license through an expedited procedure, the pharmacy board must first
file a complaint with an administrative hearing commission. Only after
the commission determines that the grounds for discipline exist may the
board take disciplinary action.
Pharmacy board officials reported relatively few complaints and
disciplinary actions involving drug compounding. For example, of the
307 complaints received and reviewed by the board of pharmacy against
pharmacies and pharmacists in Missouri in fiscal year 2002, only 5 were
related to drug compounding.\3\
---------------------------------------------------------------------------
\3\ The State pharmacy board officials that we spoke with reported
that most complaints and disciplinary actions cover dispensing errors
related to manufactured drugs, such as incorrectly counting the number
of pills for a prescription.
---------------------------------------------------------------------------
FDA ASSERTS OVERSIGHT AUTHORITY UNDER FDCA BUT GENERALLY RELIES ON
STATES TO REGULATE DRUG COMPOUNDING
FDA maintains that drug compounding activities are generally
subject to FDA oversight, including the ``new drug'' requirements and
other provisions of the FDCA. In practice, however, the Agency
generally relies on the States to regulate the traditional practice of
pharmacy, including the limited compounding of drugs for the particular
needs of individual patients. In recent years, the Congress has
attempted to clarify the extent of Federal authority and enforcement
power regarding drug compounding. In 1997, the Congress passed a law
that exempted drug compounders from key portions of the FDCA if they
met certain criteria. Their efforts, however, were nullified when the
Supreme Court struck down a portion of the law's drug compounding
section as an unconstitutional restriction on commercial speech, which
resulted in the entire compounding section being declared invalid.\4\
In response, FDA issued a compliance policy guide to provide the
compounding industry with an explanation of its enforcement policy,
which included a list of factors the Agency would consider before
taking enforcement actions against drug compounders.
---------------------------------------------------------------------------
\4\ Thompson v. Western States Medical Center, 535 U.S. 357 (2002).
---------------------------------------------------------------------------
FDA ASSERTS JURISDICTION TO REGULATE DRUG COMPOUNDING UNDER FDCA
FDA maintains that FDCA requirements, such as those regarding the
safety and efficacy requirements for the approval of new drugs, are
generally applicable to pharmacies, including those that compound
drugs. The Agency recognized in its brief submitted in the 2002 Supreme
Court case that applying FDCA's new drug approval requirements to drugs
compounded on a small scale is unrealistic--that is, it would not be
economically feasible to require drug compounding pharmacies to undergo
the testing required for the new drug approval process for drugs
compounded to meet the unique needs of individual patients. The Agency
has stated that its primary concern is where drug compounding is being
conducted on a scale tantamount to manufacturing in an effort to
circumvent FDCA's new drug approval requirements. FDA officials
reported that the Agency has generally left regulation of traditional
pharmacy practice to the States, while enforcing the act primarily when
pharmacies engage in drug compounding activities that FDA determines to
be more analogous to drug manufacturing.
FDA MODERNIZATION ACT EXEMPTED DRUG COMPOUNDERS FROM SOME FDCA
REQUIREMENTS BUT WAS DECLARED INVALID
Federal regulatory authority over drug compounding attracted
congressional interest in the 1990s, as some in the Congress believed
that ``clarification is necessary to address current concerns and
uncertainty about the Food and Drug Administration's regulatory
authority over pharmacy compounding.'' \5\ The Congress addressed this
and other issues when it passed the FDA Modernization Act of 1997
(FDAMA), which included a section exempting drugs compounded on a
customized basis for an individual patient from key portions of FDCA
that were otherwise applicable to manufacturers.\6\ According to the
congressional conferees, its purpose was to ensure continued
availability of compounded drug products while limiting the scope of
compounding so as ``to prevent manufacturing under the guise of
compounding.'' \7\
---------------------------------------------------------------------------
\5\ S. Rep. No. 105-43, at 67 (1997).
\6\ These portions covered ``adequate directions for use''
labeling, manufacturing, and new drug approval requirements. See former
21 U.S.C. 353a(a). Pub. L. No. 105-115, 111 Stat. 2296, former
section 503A.
\7\ H.R. Conf. Rep. No. 105-399, at 94 (1997).
---------------------------------------------------------------------------
In order to be entitled to the exemption, drug compounders had to
meet several requirements, including one that prohibited them from
advertising or promoting ``the compounding of any particular drug,
class of drug, or type of drug.'' \8\ This prohibition was challenged
in court by a number of compounding pharmacies and eventually resulted
in a 2002 Supreme Court decision holding that it was unconstitutional.
As a result, the entire drug compounding section was declared
invalid.\9\ However, the Court did not address the extent of FDA's
authority to regulate drug compounding.
---------------------------------------------------------------------------
\8\ See former 21 U.S.C. 353a(c).
\9\ Both the district and appellate courts held that the
prohibition was unconstitutional. However, the district court held that
the prohibition was ``severable'' and that the rest of the pharmacy
compounding section remained good law. While the appellate court agreed
with the district court on the constitutional question, it disagreed on
the severability issue and invalidated the entire section. The Supreme
Court agreed with both courts on the constitutional issue, but because
the severability decision was not challenged, the Court did not rule on
it, and left it in place. See Thompson v. Western, States Medical
Center, 69 F. Supp. 2d 1288 (D. Nev. 1999), aff'd in part and rev'd in
part, 238 F. 3d 1090 (9th Cir. 2001), aff'd, 535 U.S. 357.
---------------------------------------------------------------------------
CURRENT FDA ENFORCEMENT FOCUSES ON DRUG COMPOUNDING OUTSIDE OF THE
TRADITIONAL PRACTICE OF PHARMACY
FDA issued a compliance policy guide in May 2002, following the
Supreme Court decision, to offer guidance about when it would consider
exercising its enforcement authority regarding pharmacy
compounding.\10\ In the guide, FDA stated that the traditional practice
of drug compounding by pharmacies is not the subject of the guidance.
The guide further stated that FDA will generally defer to State
authorities in dealing with ``less significant'' violations of FDCA,
and expects to work cooperatively with the States in coordinating
investigations, referrals, and follow-up actions. However, when the
scope and nature of a pharmacy's activities raise the kinds of concerns
normally associated with a drug manufacturer and result in significant
violations of FDCA, the guide stated that FDA has determined that it
should seriously consider enforcement action and listed factors, such
as compounding drug products that are commercially available or using
``commercial scale manufacturing or testing equipment,'' that will be
considered in deciding whether to take action.\11\
---------------------------------------------------------------------------
\10\ This guide was similar to an earlier compliance policy guide
published by FDA in 1992. After the drug compounding section of FDAMA
was declared invalid, FDA determined that it needed to issue new
guidance to the compounding industry on what factors the Agency would
consider in exercising its enforcement discretion regarding drug
compounding.
\11\ ``Compliance Policy Guide: Compliance Policy Guidance for FDA
Staff and Industry'', Chapter 4, Sub Chapter 460, May 2002.
---------------------------------------------------------------------------
Some representatives of pharmacist associations and others have
expressed concern that FDA's compliance policy guide has created
confusion regarding when FDA enforcement authority will be used. For
example, some pharmacy associations assert that FDA's guidance lacks a
clear description of the circumstances under which the Agency will take
action against pharmacies. In particular, they pointed to terms in the
guide, such as ``very limited quantities'' and ``commercial scale
manufacturing or testing equipment'' that are not clearly defined, and
noted that FDA reserved the right to consider other factors in addition
to those in the guide without giving further clarification. FDA
officials told us that the guide allows the Agency to have the
flexibility to respond to a wide variety of situations where the public
health and safety are issues, and that they plan to revisit the guide
after reviewing the comments the Agency received, but did not have a
time frame for issuing revised guidance.
In several reported court cases involving FDA's regulation of drug
compounders, the courts have generally sided with FDA. Two cases we
identified involved drug compounders engaged in practices that were
determined to be more analogous to drug manufacturing. In a district
court case decided this year, the court upheld FDA's authority to
inspect a pharmacy specializing in compounding, noting that it believed
that FDA's revised compliance policy guide was a reasonable
interpretation of the statutory scheme established by FDCA.\12\
---------------------------------------------------------------------------
\12\ In the Matter of Establishment Inspection of Wedgewood Village
Pharmacy, Inc., 270 F. Supp. 525, 549 (D. N.J. 2003).
---------------------------------------------------------------------------
CONCLUDING OBSERVATIONS
While drug compounding is important and useful for patient care,
problems that have occurred raise legitimate concerns about the quality
and safety of compounded drugs and the oversight of pharmacies that
compound them. However, the extent of problems related to compounding
is unknown. FDA maintains that drug compounding activities are
generally subject to FDA oversight under its authority to oversee the
safety and quality of new drugs, but the Agency generally relies on
States to provide the necessary oversight. At the State level, our
review provides some indication that at least some States are taking
steps to strengthen State oversight, and national pharmacy
organizations are developing standards that might help strengthen
oversight if the States adopted and enforced them. However, the
effectiveness of these measures is unknown, and factors such as the
availability of resources may also affect the extent of State
oversight.
Mr. Chairman, this completes my prepared statement. I would be
happy to respond to any questions you or other Members of the Committee
may have at this time.
Contact and Acknowledgments
For further information, please contact Janet Heinrich at (202)
512-7119. Individuals making key contributions to this testimony
included Matt Byer,Lisa A. Lusk, and Kim Yamane.
GAO's Mission
The General Accounting Office, the audit, evaluation and
investigative arm of Congress, exists to support Congress in meeting
its constitutional responsibilities and to help improve the performance
and accountability of the Federal Government for the American people.
GAO examines the use of public funds; evaluates Federal programs and
policies; and provides analyses, recommendations, and other assistance
to help Congress make informed oversight, policy, and funding
decisions. GAO's commitment to good government is reflected in its core
values of accountability, integrity, and reliability.
Obtaining Copies of GAO Reports and Testimony
The fastest and easiest way to obtain copies of GAO documents at no
cost is through the Internet. GAO's Web site (www.gao.gov) contains
abstracts and full-text files of current reports and testimony and an
expanding archive of older products. The Web site features a search
engine to help you locate documents using key words and phrases. You
can print these documents in their entirety, including charts and other
graphics.
Each day, GAO issues a list of newly released reports, testimony,
and correspondence. GAO posts this list, known as ``Today's Reports,''
on its Web site daily. The list contains links to the full-text
document files. To have GAO e-mail this list to you every afternoon, go
to www.gao.gov and select ``Subscribe to e-mail alerts'' under the
``Order GAO Products'' heading.
Order by Mail or Phone
The first copy of each printed report is free. Additional copies
are $2 each. A check or money order should be made out to the
Superintendent of Documents. GAO also accepts VISA and Mastercard.
Orders for 100 or more copies mailed to a single address are discounted
25 percent. Orders should be sent to: U.S. General Accounting Office
441 G Street NW, Room LM, Washington, D.C. 20548. To order by Phone:
Voice: (202) 512-6000, TDD: (202) 512-2537, Fax: (202) 512-6061.
To Report Fraud, Waste, and Abuse in Federal Programs: Contact: Web
site: www.gao.gov/fraudnet/fraudnet.htm E-mail: [email protected].
Automated answering system: (800) 424-5454 or (202) 512-7470.
Public Affairs: Jeff Nelligan, Managing Director, [email protected]
(202) 512-4800, U.S. General Accounting Office, 441 G Street NW, Room
7149 Washington, D.C. 20548.
Prepared Statement of Steven K. Galson, M.D., M.P.H.
INTRODUCTION
Mr. Chairman and Members of the Committee, I am Steve Galson, the
Deputy Director of the Center for Drug Evaluation and Research at the
Food and Drug Administration (FDA or the Agency). I am also the Acting
Director of the Center while Dr. Janet Woodcock is on detail to the
Office of the Commissioner.
I appreciate the opportunity to discuss FDA's role with regard to
pharmacy compounding. In my testimony, I will discuss the Agency's
activities and strategies for addressing public health issues
associated with pharmacy compounding. I will touch on our current
statutory and regulatory authority, how the Agency has exercised that
authority, and our future plans in this area.
BACKGROUND
By most estimates, pharmacy compounding is a growing business. Many
compounding pharmacies have established Internet websites to promote
and sell their products. The Agency's strategies for addressing
pharmacy compounding have had to evolve to respond to the public health
challenges associated with this growing area while at the same time
preserving the benefits that pharmacy compounding offers in meeting a
public health need.
FDA views traditional pharmacy compounding as the combining,
mixing, or altering of ingredients to create a customized medication
for an individual patient in response to a licensed practitioner's
prescription.\1\ In its simplest form, it may involve taking an
approved drug substance and making a new formulation to meet the
medical needs of a specific patient. For example, it may involve
formulating the product without a dye or preservative in response to a
patient allergy. Or it might involve making a suspension or suppository
dosage form for a child or elderly patient who has difficulty
swallowing a tablet or a capsule. These traditional forms of pharmacy
compounding are an important component of our pharmaceutical
armamentarium. Although these products technically may be considered
unapproved new drugs because they differ from the approved formulation
of the drug, FDA has exercised enforcement discretion to allow these
legitimate forms of pharmacy compounding, which are regulated under
State laws governing the practice of pharmacy.
---------------------------------------------------------------------------
\1\ Under the compounding-related provisions of the Food and Drug
Administration Modernization Act, pharmacy compounding was not defined
to include mixing or reconstituting commercial products in accordance
with the manufacturer's instructions or the product's approved
labeling. Reconstituting means the return, usually by adding liquid, of
a drug previously altered for preservation and storage to its original
state for administration to a patient. This type of manipulation, when
done in accordance with approved labeling, should not adversely affect
the safety or efficacy of the drug. (The provisions were struck down by
the Supreme Court on April 29, 2002.)
---------------------------------------------------------------------------
We believe that the vast majority of pharmacies engaging in
pharmacy compounding provide a valuable medical service that is an
integral part of our modern health care system. However, we have become
aware of instances involving compounding in which the risks of
obtaining a product of substandard quality may outweigh the benefits of
obtaining the compounded drug. In addition, we have seen abuses, such
as large-scale drug manufacturing under the guise of pharmacy
compounding.
In recent years, we have witnessed some compounding pharmacies
creatively marketing new compounded products that they assert are
``better'' than available therapies. We are not aware of data
supporting these claims. Sometimes these pharmacies compound a product
containing a form of an active ingredient that has not been approved by
FDA, such as 4-aminopyridine, an experimental drug compounded for
patients with multiple sclerosis. In other instances, drugs are
compounded even though FDA has removed them from the market after
determining that they were unsafe. We also have seen drugs compounded
that are essentially copies of commercially available products.
Compounding pharmacies then sell these copies for less than the
approved commercially available product. These appear to be compounded
for economic reasons rather than genuine medical need. In such cases,
we believe the consumer would be better served by the commercially
available drug, which has been determined to be safe and effective and
manufactured under rigorous good manufacturing practice requirements.
Although there is limited hard data on the actual amount of
pharmacy compounding that is occurring in this country, pharmacy
compounding appears to be a big and growing business. In April 2001, we
commissioned a study on the compounding industry by the Eastern
Research Group, Inc. According to their August 2001 report, over 650
pharmacies fill more than 13 million prescriptions for compounded
products per year.
Although many more pharmacies compound (some estimates put the
number at more than 3,000 compounding pharmacies) this relatively small
number of pharmacies that specialize in compounding appear to account
for a majority of the drugs compounded nationally. Some estimate that
compounding represents one percent of all of the prescriptions filled
each year. In 2003, according to one estimate, this would amount to 30
million prescriptions for compounded products. In some cases, these
prescriptions may be compounded in pharmacies that dispense only
compounded medications or in other pharmacies for which compounding is
a large percentage of their business.
Pharmacy compounding, by definition, involves making a new drug
whose safety and efficacy have not been demonstrated with the kind of
data that FDA ordinarily would require in reviewing a new drug
application.\2\ Although most pharmacists are well-trained and well-
equipped to safely compound certain medications, not all pharmacists
have the same level of skills and equipment, and some products that are
compounded may be inappropriate for compounding. In some cases, we have
reason to be concerned about the quality of the drugs being compounded
and the potential risks to patients who may take them. In some
instances, compounders may lack sufficient controls (equipment,
training, testing, or facilities) to ensure product quality or to
compound difficult products such as sterile or modified release drugs.
If compounding is done on a large scale and is not done properly,
compounders can expose large numbers of patients to health risks
associated with unsafe or ineffective medications. This may be of
particular concern if patients are taking an ineffective compounded
product in lieu of a proven therapy. In addition, compounding large
quantities of drugs and copying commercially available approved
products in compounding pharmacies circumvents important public health
requirements and undermines the drug approval process--the evidence-
based system of drug review that consumers and health professionals
rely on for safe and effective drugs.
---------------------------------------------------------------------------
\2\ In some cases, it may simply involve taking an approved drug
and making a new formulation.
---------------------------------------------------------------------------
Recent Enforcement Activity
The following examples of recent FDA enforcement actions against
compounding pharmacies illustrate some of these concerns:
Fentanyl ``Lollipops'': In August 2002, during in a joint FDA/New
Hampshire inspection, FDA determined that a pharmacy was compounding
Fentanyl ``Lollipops'' and dispensing them without the labeling and
other packaging and patient safety features required by FDA for the
approved product. Fentanyl is a narcotic analgesic that could pose a
safety hazard to children if distributed without appropriate safety
measures. FDA issued a ``warning letter'' to the firm and the firm
agreed to cease distribution of this product.
Methylprednisolone Acetate: In September 2002, a compounding
pharmacy in South Carolina recalled all lots of its methylprednisolone
acetate products based on reports of four patients who developed a rare
fungal infection after taking the drug. Ultimately, a total of six
patients were infected, and one died. A joint FDA/South Carolina
inspection revealed that the firm did not have adequate controls over
its compounding operations to ensure the necessary sterility. When the
firm refused to voluntarily recall other injectable products or to
provide FDA with a complete list of all products distributed, FDA
issued a nationwide alert on all injectable drugs prepared by the firm.
FDA is aware of several other cases of contamination and adverse events
associated with compounded sterile injectable products.
Large Volume Interstate Shipments: In September 2002, FDA issued a
``warning letter'' to a California pharmacy after it determined during
a joint FDA/California inspection that the firm was not operating as a
retail pharmacy. The firm was using commercial scale manufacturing
equipment and making large quantities of drugs for shipment across
California and to patients in other States. In March of 2002, the firm
issued a recall of compounded inhalation solutions due to microbial
contamination.
In each of these cases, as is the case in most pharmacy compounding
actions, FDA has proceeded jointly with the State in which the pharmacy
is located. In many of the cases, however, questions have arisen
concerning FDA's authority over the compounding activities. In some
cases, FDA had difficulty obtaining access to the compounding pharmacy
to determine whether the firm was engaging in dangerous practices. The
pharmacies argued that they were not subject to FDA regulation because
they were compounding pharmacies. FDA had to get a warrant to obtain
access to the facilities and records of compounding activities. One of
these incidents is discussed in more detail below.
Wedgewood Village Pharmacy: On July 7, 2003, a U.S. Magistrate
Judge in the U.S. District Court of New Jersey denied Wedgewood
Pharmacy's motion to quash FDA's warrant for administrative inspection
of the pharmacy. The warrant application was filed after the U.S. Drug
Enforcement Agency's (DEA) requested assistance from FDA in conducting
an on-site inspection of Wedgewood.
The Magistrate Judge held, in part, that (1) FDA had authority to
apply for a warrant to inspect the pharmacy; (2) it is not FDA's burden
to prove that the entity it seeks to inspect is not entitled to the
pharmacy-related exemptions from FD&C Act; and (3) the Compliance
Policy Guide stating that FDA would not attempt to regulate traditional
pharmacy compounding practices was a reasonable interpretation of the
FD&C Act. The pharmacy owner appealed to the District Court Judge the
magistrate's order denying the motion to quash the administrative
inspection warrant. The District Court held a hearing on October 16,
2003. A ruling in this case is pending.
Because FDA was not permitted to complete its inspection in this
case and several others, the Agency has been delayed, from obtaining
the evidence needed to assess whether drug manufacturing is occurring
under the guise of compounding or if compounding practices that raise
public health concerns are present.
STATUTORY AND REGULATORY AUTHORITY
Although compounding was widespread when the FD&C Act was first
enacted in 1938, there were no provisions specifically dedicated to
compounding, as distinguished from manufacturing of drugs. After the
1962 amendments to the Act expanded the universe of drugs that require
FDA pre-market approval to include drugs that are not already generally
recognized by experts as effective, courts have interpreted expansively
the Act's provisions to require pre-market approval of virtually all
prescription drugs. It is widely recognized, however, that compounded
drugs could not meet the approval requirements, in part because they
traditionally are made in small amounts for individual patients
according to a prescription. In addition, it is usually not feasible to
study them in clinical trials to establish their safety and efficacy or
prepare new drug applications for all of the different types of
compounded products that might be prescribed.
Several of the Act's provisions that pertain to drugs generally
include compounded drugs. The specific statutory provisions that may
apply to compounded drugs are: (1) the definition of ``drug'' (section
201 (g) of the Act); (2) the misbranding and adequate directions for
use requirements for drugs (section 502 of the Act); (3) the
adulteration and current good manufacturing practice (cGMP)
requirements for drugs (section 501(a)(2)(B) of the Act); and (4) the
new drug approval provisions (section 505 of the Act). Literal
application of these statutory drug authorities could mean that,
technically, virtually all compounded drugs violate the Act, despite
the long history of allowing certain types of compounding and the
important public health benefits provided by such compounding of
medically necessary drugs that are not otherwise available. Until the
1997 provision discussed below, Congress had not explicitly exempted
compounded drugs from the preceding requirements of the Act.
Today, the Act does specifically address compounding in two
specific provisions; the registration provisions and the inspection
provisions. In each case, it provides an exemption that is narrowly
tied to the specific requirements of those two provisions. Under the
requirements for drug registration, although compounding is
specifically included among the activities that would require an
establishment to register with FDA (section 510(c) of the Act), an
exemption is provided for pharmacies that, among other conditions, do
not compound for sale ``other than in the regular course of their
business of dispensing or selling drugs . . . at retail'' (section
510(g)(1) of the Act). The same language limits the types of records
that FDA may review during an inspection of a pharmacy (section 704 of
the Act).
Because these exemptions do not extend to other statutory
requirements, such as pre-approval requirements that would
significantly restrict compounding, FDA has historically exercised its
enforcement discretion in a manner that defers to the States, as the
regulators of the practice of pharmacy, to serve as the primary
regulators of the practice of pharmacy compounding. FDA's focus in
recent years has been on drug manufacturing that operates under the
guise of pharmacy compounding. FDA also has worked cooperatively with
the National Association of Boards of Pharmacy (NABP) and the U.S.
Pharmacopeial Convention (USP) to address good compounding practices,
and with the States on a case-by-case basis to address instances of
compounding that raise public health and safety issues.
Compliance Policy Guide of 1992
In March 1992, FDA issued a compliance policy guide (CPG), to
delineate the Agency's enforcement policy on pharmacy compounding. This
CPG relied on the exercise of enforcement discretion rather than legal
exemptions from new drug and other statutory requirements. The pharmacy
community expressed concerns about how FDA intended to exercise its
enforcement discretion and sought legislation to clarify the boundaries
of FDA's authority over pharmacy compounding. In 1997, Congress enacted
the Food and Drug Administration Modernization Act of 1997 (FDAMA) to
specifically address FDA's role in the regulation of pharmacy
compounding.
Food and Drug Administration Modernization Act of 1997
On November 21, 1997, the President signed FDAMA (P.L. 105-115).
Section 127 of FDAMA added sections 503A to the FD&C Act, to clarify
the status of pharmacy compounding under Federal Law. Under section
503A, drug products that were compounded by a pharmacist or physician
on a customized basis for an individual patient were entitled to
exemptions from three key provisions of the Act: (1) the adulteration
provision of section 501(a)(2)(B) (concerning the good manufacturing
practice requirement, or cGMP); (2) the misbranding provision of
section 502(f)(1) (concerning the labeling of drugs with adequate
directions for use); and (3) the new drug provision of section 505
(concerning the approval of drugs under new drug or abbreviated new
drug applications). To qualify for these exemptions, a compounded drug
product was required to satisfy several requirements, some of which
were to be the subject of FDA rulemaking or other actions. Section 503A
of the Act took effect on November 21, 1998, 1 year after FDAMA was
signed into law.
Thompson v. Western States Medical Center
In November 1998, the solicitation and advertising provisions of
section 503A were challenged by seven compounding pharmacies as an
impermissible regulation of commercial speech. The U.S. District Court
for the District of Nevada ruled in the plaintiffs' favor. FDA appealed
to the U.S. Court of Appeals for the Ninth Circuit. On February 6,
2001, the Court of Appeals declared section 503A to be invalid in its
entirety (Western States Medical Center v. Shalala, 238 F.3rd 1090 (9th
Cir. 2001)). The government petitioned for a writ of certiorari to the
U.S. Supreme Court for review of the Ninth Circuit's decision that the
solicitation and advertising provisions of section 503A were
unconstitutional restrictions on commercial speech. The Supreme Court
granted the writ and issued its decision in the case on April 29, 2002.
The Supreme Court affirmed the Ninth Circuit's decision that
section 503A of the FD&C Act was invalid in its entirety because it
contained unconstitutional restrictions on commercial speech (i.e.,
prohibitions on soliciting prescriptions for and advertising specific
compounded drugs). The Court did not rule on, and therefore left in
place, the Ninth Circuit's holding that the unconstitutional
restrictions on commercial speech could not be severed from the rest of
section 503A. Accordingly, all of section 503A is now invalid.
Compliance Policy Guide of May 2002
Once the statutorily created exemptions from the new drug,
misbranding and adequate directions for use requirements were deemed
invalid for compounded drugs, FDA determined that it needed to issue
guidance to the compounding industry on what factors the Agency would
consider in exercising its enforcement discretion in this area under
current law. In May 2002, FDA issued a Guidance for Industry--Pharmacy
Compounding--Compliance Policy Guide, which is based on the CPG of
March 1992.
The guidance states that FDA recognizes that pharmacists
traditionally have extemporaneously compounded and manipulated
reasonable quantities of drugs upon receipt of a valid prescription for
an individually identified patient from a licensed practitioner. This
traditional compounding activity is not the subject of the guidance.
However, when the scope and nature of a pharmacy's activity raise
the kinds of concerns normally associated with a drug manufacturer and
result in significant violations of the new drug, adulteration, or
misbranding provisions of the FD&C Act, the guidance states that FDA
will consider enforcement action. In determining whether to initiate
such an action, the guidance states that the Agency will consider
whether the pharmacy engages in any of the following acts:
1. Compounding, except in very limited quantities, of drugs in
anticipation of receiving prescriptions in relation to the amounts of
drugs compounded after receiving valid prescriptions.
2. Distributing inordinate amounts of compounded products out of
State.
3. Compounding finished drugs from bulk active ingredients that are
not components of FDA-approved drugs without an FDA sanctioned
investigational new drug application (IND) that is in effect in
accordance with section 505(1) of the Act and 21 CFR 312.
4. Receiving, storing, or using drug substances without first
obtaining written assurance from the supplier that each lot of the drug
substance has been made in an FDA-registered facility.
5. Receiving, storing, or using drug components not guaranteed or
otherwise determined to meet official compendial (USP monograph)
requirements.
6. Using commercial scale manufacturing or testing equipment for
compounding drug products.
7. Compounding drugs for third parties who resell to individual
patients or offering compounded drug products at wholesale to other
State-Iicensed persons or commercial entities for resale.
8. Compounding drug products that are commercially available in the
marketplace or that are essentially copies of commercially available
FDA-approved drug products. In certain circumstances, it may be
appropriate for a pharmacist to compound a small quantity of a drug
that is only slightly different than an FDA-approved drug that is
commercially available. In these circumstances, FDA will consider
whether there is documentation of the medical need for the particular
variation of the compound for the particular patient.
9. Failing to operate in conformance with applicable State law
regulating the practice of pharmacy.
The above list of factors is not intended to be exhaustive, as
other factors may be appropriate for consideration in a particular
case.
Although the CPG was immediately effective when it was issued in
May 2002, the Agency indicated it would be interested in receiving
public comments on the guide. FDA received public comments and is in
the process of revising the CPG in response to the comments. The Agency
plans to publish a new draft of the CPG and will seek comments on it.
LIMITED FDA SURVEY OF COMPOUNDED DRUG PRODUCTS
Since 1990, FDA has become aware of more than 55 product quality
problems associated with compounded products, many of which resulted in
product recalls. In 2001, FDA's Division of Prescription Drug
Compliance and Surveillance conducted a limited survey of drugs
compounded by 12 compounding pharmacies that allowed compounded
products to be ordered over the Internet. The goal of the survey was to
gather information on the quality, purity, and potency of compounded
drug products in the marketplace. The compounded products surveyed were
selected from a cross-section of commonly compounded dosage forms based
on FDA's assessment of the potential health risks resulting from
improper compounding. FDA collected the samples via air mail order in
the same manner a consumer would order the products over the Internet.
The 29 products sampled included hormonal products, antibiotics,
steroids, anesthetics and drugs to treat glaucoma, asthma, iron
deficiency anemia, and erectile dysfunction. Five different dosage
forms (i.e., sterile injectables, ophthalmic products, pellet implants,
inhalation products, and oral dosage forms) were sampled.
Ten (34 percent) of the 29 sampled products failed one or more
standard quality tests performed. Nine with failing analytical results
failed assay (potency) testing, with a range of 59 percent to 89
percent of expected potency.
Each year, FDA routinely samples drug products made by commercial
manufacturers and analyzes these samples in FDA laboratories. More than
3,000 products from commercial manufacturers have been sampled and
analyzed by FDA since fiscal year 1996. The analytical testing failure
rate for commercially produced samples has been less than 2 percent for
all tests, but for assay (potency) tests there were 4 failures out of
3,000. Compared to the 2 percent failure rate, the percentage of
sampled compounded products failing analytical testing in our 2001
survey (34 percent) was higher than expected. Although the 2001 survey
had several limitations including a small sample size, it provided
valuable preliminary information on the quality of selected compounded
drug products currently marketed. We believe that these laboratory
results need to be interpreted cautiously and should not be generalized
beyond the particular drugs and pharmacies involved. Further, we
believe that the results call for additional study and consideration by
FDA, the State regulatory authorities, professional organizations, and
pharmacies.
OUTREACH ACTIVITIES
FDA has interacted on many occasions with stakeholders involved
with pharmacy compounding. We have attended the annual meetings of the
International Academy of Compounding Pharmacists participating on
panels with representatives of the American Pharmacists Association
(APhA), NABP, the USP, the National Association of Community
Pharmacists, and others. In addition, we met separately with many of
these stakeholders seeking to find common ground in how to approach the
regulation of pharmacy compounding. We have participated in stakeholder
meetings sponsored by the USP to address various initiatives including
the accreditation of pharmacies that compound medications.
POSITIVE ACTIONS AND CHALLENGES
Some of the stakeholder groups with whom we have interacted are
engaged in activities intended to provide greater confidence in the
quality of compounded medications. For example, the NABP has a model
code governing pharmacy compounding that substantially has been adopted
by 10 States. The model code provides State Boards of Pharmacy with a
framework for developing requirements for compounding pharmacies. The
USP has developed a new chapter in the U.S. Pharmacopeia addressing
sterile drug compounding practices. The chapter sets standards for the
preparation of sterile compounded drugs. The American Society of
Health-System Pharmacists also has such guidelines. The APhA, NABP, and
USP have been discussing the possibility of developing an accreditation
program that would set standards for and monitor compounding
pharmacies. All of these activities are positive steps in ensuring that
pharmacy compounding is done with appropriate protections for patients,
and we support them.
FDA recognizes that States have the direct ability to regulate
pharmacy compounding and direct access to prescription records.
However, limited State resources and varying standards and regulatory
requirements are factors that affect the adequacy of State regulation.
Pharmacy self-inspection is allowed in four States, which consists of
pharmacist self-evaluation by questionnaire of the pharmacy's
compliance with laws and regulations. In addition, there is variability
in commitment to regulate pharmacy compounding among the States.
Sometimes there is conflict between State Boards of Pharmacy and Health
Departments based on disparate regulatory philosophies.
Clearly, when pharmacy compounding more closely approximates
commercial manufacturing, FDA has an interest in regulating that
practice as it does all other drug manufacturing. One difficult issue
is where to draw that line. If the line is to be drawn based on volume,
how much volume makes a compounder a manufacturer? There are many large
compounding pharmacies, some of which are exclusively drug compounders.
Similarly, there are many small drug manufacturers that snake drugs
under approved new drug or abbreviated new drug applications. Through
our review of these applications, we ensure that the drugs are safe and
effective and that the processes by which the drugs are made produce
consistently high quality products that maintain their safety and
efficacy throughout their shelf life. This system of evidence-based
medicine provides public health benefits to American consumers and
health professionals because patients are able to rely with confidence
on the medications they take and avoid ineffective therapies or those
for which the risks do not exceed the benefits.
It is important to ensure that the production of drugs in pharmacy
compounding does not undermine the incentives to develop and submit new
drug applications to FDA with evidence of the safety and efficacy. At
the same time, we recognize that pharmacy compounding is necessary
where there is a medical need of a particular patient for a product
that is not commercially available in an approved form. We must
exercise our regulatory authority in such a way as to support pharmacy
compounding that is necessary, while curbing abuses.
With this in mind, we can describe a few key areas where the Agency
has taken action and where we believe a Federal role is appropriate:
First, as a result of FDAMA, we developed a list of drugs
that were inappropriate for compounding because they have been
withdrawn from the market for safety reasons. In many cases, FDA
reviewed the data concerning adverse events from our spontaneous
reporting system and other databases and determined that the risks for
these drugs exceeded the benefits for the uses to which they were
approved. FDA has access to nationwide and global data concerning
adverse events and we have the expertise to evaluate the risks of a
therapy in relation to its benefits. Once FDA has determined that the
risks of a therapy exceed its benefits to the extent that the drug
should be removed from the market, it would be inappropriate to expose
patients to the risks of the product by allowing compounding of that
drug. FDA intends to continue to maintain this list and take action
against pharmacies that compound unsafe products. Similarly, if FDA has
specific information about significant potential risks associated with
compounding a particular drug (e.g., one that was considered for but
denied FDA approval), FDA may take action against such compounding,
preferably in support of, or in conjunction with, the State
authorities. Furthermore, FDA has continuing concerns about
compounding, without an investigational new drug application in effect
using ingredients that are ``experimental'' or not components of FDA
approved drugs.
Second, FDA believes it is in the best position to address
the quality of bulk drug substances used in compounding. Many of these
drugs are imported from abroad and individual States are unlikely to
have the ability to conduct inspections of foreign producers and ensure
the quality of these active ingredients in compounded products. As
addressed in the CPG, drugs should not be compounded using active
ingredients that were manufactured at facilities that are not even
registered with FDA or that fail to meet accepted USP compendia)
standards for quality.
Third, FDA believes it is appropriate for the Agency to
continue to investigate allegations of poor quality compounded drugs,
in conjunction with the States, whenever possible. However, we also
must act without States when State involvement is not forthcoming
because of resource constraints or for other reasons. For example, an
Internet or mail order pharmacy might be operating in a State with few
resources for pharmacy inspections, but shipping poor quality
compounded products nationwide. In such cases, FDA believes it plays an
important role in addressing these dangerous practices. FDA believes
that when issues regarding the quality of compounded drugs are
significant enough to raise public health issues, FDA should continue
to play a role in working with the States to address these public
health matters, and in the event that a State is unwilling or unable to
join FDA, then the Agency in some cases must be allowed to unilaterally
protect the public health from compounded drugs that pose unreasonable
risks.
Finally, the Agency should be able to determine when a
pharmacy crosses the line between appropriate pharmacy compounding and
manufacturing.
CONCLUSION
In summary, FDA welcomes this committee's interest in pharmacy
compounding and would like to assure the committee that the Agency's
efforts to address pharmacy compounding issues are designed to balance
the need to allow legitimate forms of pharmacy compounding with the
need for Federal oversight when pharmacy compounding threatens to
compromise public health.
This concludes my testimony, Mr. Chairman. I will be glad to answer
any questions you may have.
Prepared Statement of Steven F. Hotze, M.D.
Federal intervention into the practice of pharmacy, specifically
compounding pharmacy, would prove detrimental to the health of
Americans.
As a physician who has used compounded pharmacy medications for
years, and who currently owns a compounding pharmacy, I have a unique
perspective on the need to insure that compounded drugs are readily
available to patients who need them. It is common for a doctor to
determine that prescription drugs off the shelf are not adequate to
meet the medical needs of an individual patient. This is where
compounding pharmacy helps insure the individualized treatment that
patients both need and demand. For this reason, I am somewhat concerned
that this important sector of medical care is not better represented on
the formal witness panels today to address more adequately the
questions you may have.
The Food, Drug, and Cosmetic Act (FDCA) of 1938 established the
authority of the Food and Drug Administration (FDA) over the
pharmaceutical manufacturing of drugs. Pharmacies were specifically
exempted from FDA regulation and their governance was relegated to the
various State boards of pharmacy. At that time, all pharmacies
practiced the compounding of medications. Pharmacies, including
compounding pharmacies, should remain under the regulation of the
States.
This hearing is the result of public outcry to the actions of a
Kansas City pharmacist who violated State laws in reconstituting
chemotherapeutic medications, a task which is not a compounding
pharmacy procedure. His criminal actions were uncovered. He was
stripped of his license and is currently serving time in prison. This
isolated incidence had nothing to do with the practice of compounding
pharmacy and does not provide a compelling argument for a Federal
investigation, much less Federal intervention into the practice of
pharmacy.
The issue is really philosophical. The FDA and its supporters
believe that the Federal Government can ensure the public's health
safety by acquiring jurisdictional authority over pharmacies,
specifically compounding pharmacies. This flies in the face of the
facts. According to an article published in the July 26, 2000 issue of
the Journal of the American Medical Association, 106,000 individuals
die each year in hospitals due to non-error, adverse effects of FDA
approved, doctor prescribed medication. Fully 225,000 individuals die
annually due to iatrogenic, treatment based, causes. This is the 3rd
leading cause of death in America. Millions more suffer severe side
effects from medical treatment. In these cases, the adage, that the
``treatment is worse than the disease'', rings true.
May I recommend that this Senate committee investigate the role of
FDA approved drugs and iatrogenic causes leading to the deaths of
225,000 Americans annually.
There are others, who believe that most pharmacists, like others in
business, realize that their self-interest is best served by operating
their enterprises with the interests of their customers in mind. To do
otherwise would result in a loss of business. State laws address the
issue of fraudulent and dangerous business practices. State boards of
pharmacy establish guidelines for safely conducting pharmacy practices
and procedures. Ultimately, the pharmacist is responsible for his or
her own behavior. Regulatory agencies cannot prevent an individual from
committing a criminal act. However, regulatory agencies can, and often
do, adversely affect the efficient, safe and productive practice of
businesses.
Pharmacists who specialize in compounding prepare customized
medications in accordance with a doctor's prescription in order to meet
the need of an individual patient. These medications, which are not
produced by pharmaceutical companies, are prepared using FDA approved
bulk products and are provided to meet specific patient requirements.
Through clinical experience, a physician may decide to use alternative
delivery systems for a specific medication, e.g., suppositories,
creams, gels, liquids or capsules. Some compounded medications are not
commercially available in the strength requested by the physician. In
other cases, a patient may be allergic to the dyes, additives or
excipients found in drugs produced by pharmaceutical manufacturers. In
this case the solution would be the preparation of a compounded product
without the allergy causing ingredients. Compounding pharmacy allows
physicians and pharmacists to provide patients with alternative
therapies otherwise not commercially available.
The recent results of the Women's Health Initiative study
demonstrate the danger of drug company, FDA-approved, counterfeit
hormones. Compounding pharmacies are able to offer physicians a
natural, safe and effective treatment for women in midlife. That
treatment is biologically identical hormone therapy that provides women
with the same hormones that their bodies used to produce or currently
produce in less than adequate amounts. With the baby boomer population
aging, there are millions upon millions of women who would benefit from
the replenishment of these hormones, enabling them to obtain and
maintain health and wellness, naturally.
This is what concerns me about this hearing. The FDA has openly
expressed its goal to regulate compounding pharmacies as manufacturers.
At the June 2003 meeting of the International Academy of Compounding
Pharmacists, two FDA regulators, Jane Axelrad and David Horowitz,
clearly stated their intent to reclassify compounding pharmacies as
manufacturers based upon the volume of prescriptions compounded. If
this were to be implemented, then the FDA would require new drug
applications (NDA) for compounded products in those pharmacies which
exceeded their volume guidelines. To acquire an NDA costs hundreds of
millions of dollars per product and the process takes 8-10 years. If
the FDA were to be given regulatory power over compounding pharmacies,
then they would end up classifying many large compounding pharmacies as
manufacturers, thus driving them out of business. This would
drastically limit the availability and affordability of compounded
products to the public. More specifically, this would have a tragic
effect on women in midlife who need biologically identical hormone
therapy.
In the broad scheme of things, compounding pharmacies are part of
the solution in providing needed care to millions of patients. While
regulation at the State level can be improved, we need not to lose
sight of the fact that over regulation of the compounding pharmacy
profession could result in the denial of the very care and well being
of our citizens of which this committee is vitally interested.
In summary, pharmacies, including compounding pharmacies, should
continue to be regulated by their State boards of pharmacy.
Thank you for giving me the privilege of presenting my written
testimony on behalf of compounding pharmacies.
Prepared Statement of Sarah L. Sellers, PharmD MPH Candidate, Johns
Hopkins Bloomberg School of Public Health
Mr. Chairman and Members of the Committee, thank you for the
opportunity to speak with you today about the serious public health
implications of pharmacy compounding--a topic which has been the focus
of my professional practice and research for the past 8 years.
I am a licensed pharmacist with a specialization in sterile
compounding. I have served as a member of the FDA's Advisory Committee
on Pharmacy Compounding--a committee established to assist with the
implementation of Federal pharmacy compounding regulations under the
1997 FDA Modernization Act. I am currently completing my Master of
Public Health degree at Johns Hopkins Bloomberg School of Public
Health, with a focus on pharmacoepidemiology and drug safety within the
Department of Health Policy and Management.
More recently, I have established a small non-profit organization
to study, analyze and communicate drug safety issues to concerned
stakeholders.
I have survived two cancers and have lived with chronic rheumatic
disease since my early childhood. I have come to rely on the
exceptional quality of federally regulated pharmaceuticals from both a
personal and professional perspective--the basic assurances to public
health and safety provided by the Federal Food, Drug, and Cosmetic Act,
that all citizens rely on, should not be undermined.
Over a decade ago, I began my career as a community pharmacist with
a homecare pharmacy that provided injections to patients for
administration in their homes. The pharmacy was making purportedly
sterile injections from scratch using non-sterile ingredients. When I
asked permission to order and substitute FDA-approved products because
of safety concerns, I was cautioned that it would be less profitable
for the pharmacy. At that time, a sterile drug for continuous
intraspinal infusion had an acquisition cost of approximately $400.00.
However, using non-sterile, raw chemical ingredients the drug could be
made for less than $10.00. Although Medicare reimbursed close to
$1,000.00 for the drug at the time under Medicare Part B, profits could
be maximized by making the drugs from scratch. The compounded dosage
forms did not undergo a validated sterilization procedure, were not
tested for potency or purity, and the risks of using such a product
were not identified, analyzed or communicated to physicians or their
patients. This emerging practice concerned me for both medical and
ethical reasons--patients were unknowingly exposed to drugs that did
not meet strict Federal standards for safety and efficacy,
manufacturing or labeling to ensure safe use. I quickly learned that my
experience was not unique--the practice was becoming ``standard of
care'' in certain medical settings.
In 1998 I was appointed to the FDA's Advisory Committee on Pharmacy
Compounding. During the implementation process, a group of compounding
pharmacies challenged advertising restrictions in the new law, which
led to a U.S. Supreme Court ruling that ultimately resulted in the
nullification of Section 503a of FDA Modernization Act and the return
of pre-FDAMA enforcement discretion on the part of the FDA. The absence
of Federal compounding regulations has created vulnerabilities in our
gold standard system for pharmaceutical regulation. Currently,
compounding regulations are disparate and minimally enforced at the
State level. Moreover, FDA simply does not have the information or
resources to track down violative pharmacy compounding operations.
What is Traditional Pharmacy Compounding?
On a practical level, pharmacists are trained during their tenure
in pharmacy school to convert tablets to liquids and to make topical
formulations to meet exceptional medical needs that cannot be met with
approved products. For instance, a 2-year-old transplant patient may
require an anti-rejection medication that is only available in tablet
form. In such a case, the tablet may be reformulated into an oral
liquid for administration--such a medication would be considered life-
sustaining and the expected benefits would likely outweigh risks
associated with the use of an unlicensed product.
What is Contemporary Pharmacy Compounding?
Contemporary pharmacy compounding represents an emerging,
substandard drug industry that exploits the traditional role of
compounding by taking advantage of current loopholes in the law and
resource constraints with regulators. The industry is supported and
driven by profiteering distributors that supply chemicals (including
active and inactive ingredients), equipment (including industrial size
mixers, capsule and tablet machines), recipes, training and marketing
tools for compounding pharmacists. This has resulted in the emergence
and growth of a substandard industry of unregulated drug manufacturing,
marketing, promotion and sales throughout the U.S. Recently, Reuters
Health reported an estimate of 3,000-4,000 compounding pharmacies
nationwide \2\--some of which dispense over 100 unregulated, compounded
prescriptions per day. In some instances, compounding pharmacies have
begun to attempt the tactics of mainstream drug manufacturers, and are
seeking to employ sales representatives that would detail doctors about
the availability and supposed benefits of their products.
What Are the Benefits and Risks of Contemporary Pharmacy Compounding?
The claimed benefits of contemporary compounding include creating
patient specific and individualized dosage forms to meet any dosing
requirement; providing varying strengths, sizes and shapes, dye-free,
preservative free, and lactose free dosage forms; providing custom
flavoring, and the provision of unavailable, unformulated and
discontinued items; and providing increases in profitability for
pharmacies and medical practices. Such benefits are broadly marketed
through advertisements over the Internet, directly to physicians
through professional detailing, and through the media. But such
advertisements do not meet Federal requirements for presenting balanced
information on risks. Pharmacists, through such advertisements, misuse
the public trust in pharmacy and place patients and prescribers at a
significant disadvantage for selecting safe and effective treatments.
Physicians have come to expect products to be uniform in quality and
may not appreciate the risks that are enhanced or created with
compounded agents.\3\
The full range of risks associated with the use of compounded drugs
have not been identified, analyzed or communicated to patients or
prescribers. Section 502(n) of the FD&C Act requires that a
manufacturer include a summary of risks in advertising--all materials
and statements, including press materials, oral statements, and sales
materials for managed care organizations and hospitals must meet FDA
requirements for truthfulness, fair balance and full disclosure.\6\
Compounded drugs do not meet such requirements--promotional information
for drugs made by pharmacists is devoid of risk information.
The true benefits of contemporary compounding may be financial. In
a recent Medicare fraud case involving the mass manufacturing of
adulterated and misbranded respiratory drugs an underlying reason for
compounding was explained by a witness who said ``it is cheaper to make
a compound solution and sell this medication than to buy an industrial
product from an authorized supplier, it is much more expensive, so the
profit you are going to obtain with a brand is much less than the one
you are going to obtain with compounding. That is the reason for
compounding, it is only profit.'' \7\ In an article examining the
acquisition cost of respiratory drugs which appeared in the homecare
trade journal HME News, a compounding supplier noted that ``providers,
especially small ones, will risk compounding before losing that kind of
money'' and further acknowledged that ``it's illegal, but profitability
often overrules what's legal and illegal.'' \8\ The article further
notes that compounding would be difficult to detect because of how
Medicare is billed ``Hence, there's no way for the FDA to know whether
a provider is using the premixed drug or compounding the two drugs
themselves.'' The financial incentives to compound drugs raise serious
concerns regarding conflict of interest for compounding pharmacists who
promote their use. If physician self-referral is constrained under the
Stark laws, so too should compounding pharmacist self referral be
penalized and restrained. In a debate appearing in the Journal of the
American Academy of Child and Adolescent Psychiatry, physicians
disputed the rationale for compounded hormone treatments for use in
adolescent patients and questioned the proprietary interests of
compounding pharmacists who promoted their use.\9\ \10\ \11\
What Are the Public Health Implications of Contemporary
PharmacyCompounding?
In 1996, former FDA Commissioner David Kessler, MD warned that
exempting pharmacy compounding from provisions of the Food, Drug, and
Cosmetic Act would create a shadow industry of unapproved drug
manufacturing thus undermining the FDA's authority to protect the
public from ineffective or unsafe products.\12\
Compounded drugs are produced outside our Federal regulatory
framework and carry risks of subpotency, superpotency and/or
contamination. Complete and unbiased information on the size and scope
of the industry has not been generated--we cannot estimate with
accuracy the exposures of patients to unapproved, pharmacy made drugs
and the associated effects on morbidity and mortality.
The ability of States to adequately protect the public from
substandard drug exposure may be confounded by discrepant, over-lapping
and in some cases non-existent State regulations, a lack of resources
and lack of will. Professional standards for sterile compounding have
not been consistently applied,\14\ \15\ and newly introduced,
enforceable standards issued by the United States Pharmacopeia are
optional for State boards to adopt and enforce.\15\
Pharmacists Are Drug Experts, Not Manufacturing Experts
A recent letter to the American Journal of Health System
Pharmacists noted that pharmacy curricula do not give attention to
sterile compounding procedures, and that this deficit is more
pronounced in the U.S. than in Europe.\16\ Pharmacists who compound
drugs may not understand the complex system of drug regulations that
provide public health protections. For instance, a pharmacist may not
know that a raw bulk chemical that has been manufactured for use in an
oral dosage form may not meet specifications for use by the intravenous
or intraspinal route of administration. Pharmacists may generalize that
a particular filter will sterilize any solution, independent of the
properties of the solution or potential adulterants present. John
Perrin Ph.D., professor emeritus from the University of Florida
confirms that ``Technology has been downplayed in pharmacy schools for
the last 25 years; we are not training pharmacists to make value
judgments on what can and cannot be compounded and yet compounding is
the fastest growing branch of the profession.'' \17\ Indeed, a
compounding pharmacy advertises ``No longer are you limited to
`standard' medicine. Your choices now include new routes of
administration, dosage strengths, pharmaceutical combinations and the
ability to develop new, potentially helpful compounds. Medicine can be
as large as your imagination.'' \18\ In other words, if a physician can
imagine it, a compounding pharmacist can make it--without prior
approval for safety or efficacy, without adherence to current Good
Manufacturing Practices and without adhering to labeling, marketing or
advertising requirements.
Analyses of Compounded Drugs
How well do pharmacists exact specific dosages? A recent study of
prescription dispensing errors found that pharmacy compounding errors
had significantly more serious outcomes and that children are
``particularly at risk because of the increased potential for error in
the preparation and use of liquids.'' \19\ Such concerns have been
heightened by a recent FDA survey of compounded drugs which found a 34
percent failure rate for drugs analyzed for potency and/or purity--of
those drugs that failed potency tests, more than half contained less
than 70 percent of their labeled content.\20\ An analysis of a
pharmacy-compounded remedy for treating ulcer disease concluded that
the mixture was not stable and would undergo hydrolysis rendering it
partially inactive immediately after mixing.\21\ Other published
reports and studies have found super and sub-potency, unacceptable
levels of microbial contamination and the presence of impurities in
pharmacy-compounded drug products.\22\ \23\ Of great concern, as of
today over a million doses of pharmacy-compounded drug products
distributed throughout the U.S. have been recalled for bacterial or
fungal contamination.\24\ \25\ These risks of pathologic contamination
are particularly disturbing when one considers that the compounding
industry targets respiratory and parenteral routes of administration,
and particularly to the home care market which largely serves a
vulnerable and immunocompromised elderly population.
Quality of Chemicals Used in Compounding
The quality of raw bulk chemicals used in compounding is suspect.
Pharmacists generally do not have the ability to test chemicals for
identity, potency, purity and/or contamination. Because the 1987
Prescription Drug Marketing Act's Pedigree Requirements have not been
implemented, the ability to trace the raw chemicals used in compounding
back to original manufacturers for information on quality, packaging,
storage and shipment conditions is demonstrably difficult.
A 2000 hearing before the House E&C Committee chaired by the
Honorable Fred Upton cited compounding pharmacies as a primary route of
entry for counterfeit bulk drugs: ``Lured by high prices and potential
profits in the U.S., counterfeit bulks can get into our prescription
drugs in several ways: (1) as imported ingredients to U.S.
manufacturers; (2) as imported ingredients to pharmaceutical
compounders; and (3) as source ingredients for Internet pharmacies
marketing to the U.S. The counterfeiters use sophisticated methods such
as preparing false labeling, containers, seals and certificates of
analysis, or using a manufacturing process that differs from the filed
manufacturing process.'' \26\ This problem has also been recognized by
authorities in Canada--a notice was recently sent to pharmacies
alerting pharmacists that non-compliant, raw bulk chemicals were being
offered for sale to pharmacies for compounding.\27\ A letter from the
Commerce Committee requesting information from former FDA Commissioner
Jane Henney, MD which preceded the hearing, cautioned that counterfeit
bulk drugs: ``pose a real or potential health hazard because their
manufacturer is often unknown'' \28\ and that the ``impurity profile is
[also] unknown, and the age, the storage, the manufacturing
environment, or the synthesis of the product cannot be determined''
\28\ creating a situation where ``no amount of finished product testing
can build quality into the product.''\28\ In the U.S., although
surveillance is limited, large quantities of chemicals for use in
compounding have been recalled because bulk drug packages contained the
wrong chemical ingredient, and for potential contamination or failed
purity tests.\29\
Compounding pharmacists have also expressed concerns regarding the
quality of bulk chemicals available for compounding. A Kansas City,
Missouri compounding pharmacy's website notes that ``inexpensive
chemicals that are past or near expiration, with no independent
verification, are available, but unacceptable to O'Brien
Pharmacy.''\30\ The same pharmacy however, has marketed a narcotic
morphine sulfate injection for intraspinal administration that exceeds
the physical solubility for the chemical under normal storage
conditions.\31\
At Risk Populations
Certain patient populations may be exposed to unapproved,
compounded drugs more than others. Marketing and advertising for
compounded drugs targets special populations including pediatric
patients for which reflavoring is often suggested to make medicines
more palatable, respiratory care patients who require treatments with
nebulizers, elderly patients and hospice patients who may require
alternate dosage forms, women to whom specialized hormone treatments
are marketed, and men for sexual dysfunction treatments. Compounded
drugs are also marketed directly to physicians' offices to improve
profit margins for providing in-office injections.
Much attention has been focused on the long term safety of hormone
replacement treatments--recent epidemiologic studies have found
increased risks for certain cancers. This new risk information is now
communicated to prescribers and patients for weighing therapeutic
options and in order to manage risks. Compounding pharmacies are using
this new information to promote alternative, unapproved hormone
treatments--a compounding pharmacy claimed: ``Women are no longer
willing to accept the risks associated with synthetic hormones, and are
searching for safer alternatives. An estimated two million women are
now benefiting from natural `plant-derived bio-identical' estrogens and
progesterone.'' \32\ There is no scientific substantiation for such
claims. In fact, the hormone treatments marketed by compounding
pharmacies may share similar or even greater risks--women are
unknowingly receiving unproven, experimental therapies that may harm
them in the absence of informed consent.
Adverse Events
The use of unregulated, pharmacy-compounded dosage forms has been
associated with morbidity and mortality throughout the nation:
An outbreak of bacterial meningitis in California was
associated with compounded spinal injections--three patients died and
eight were hospitalized.
CDC warned physicians and health systems to consider
substandard, compounded drug exposures in cases of unexplained
infections following intraspinal or intra-articular injections after an
outbreak of fungal meningitis was associated with compounded drugs--CDC
further cautioned that health systems may not be aware that they are
purchasing compounded drugs, thus actually requiring vigilance to
prevent compounded drugs from inadvertently entering supply chains.
Compounded spinal injections were associated with
neurologic complications including paralysis in an epidemiologic cohort
study of patients who received unapproved, pharmacy-compounded
continuous intrathecal infusions.\23\
Three cases of poisonings in children have been associated
with unapproved drugs compounded for Attention Deficit Hyperactivity
Disorder.\35\ \36\
A 5-year-old died as a direct result of receiving an
unapproved compounded drug for bed-wetting.\37\
Two patients developed septicemia and were hospitalized
after receiving compounded vitamin injections contaminated with
bacteria.\38\
Three patients were hospitalized in critical condition
after receiving compounded thyroid remedies.\39\
A cancer patient died after receiving a compounded
injection of herbal tea.\40\
A patient became blind after using compounded eye-drops
that were not sterile.\20\
A study comparing a compounded prostaglandin dosage form
with a licensed product found a higher incidence of cesarean delivery
associated with the compounded drug.\41\
An estimated 4,000 cancer patients received diluted, sub-
therapeutic chemotherapeutic agents compounded in Missouri.\31\
The above mentioned cases are considered the ``tip of the iceberg''
by public health experts because pharmacists, unlike licensed
manufacturers, are not required to detect or report problems associated
with compounded drugs they make. These problems have come to the
attention of the public only when the numbers of persons affected by a
single incident or the severity of an incident have been significant
enough to gain the attention of the media--not through surveillance and
vigilance.
Surveillance
Compounded drugs are hard to trace making it difficult to measure
or assess overall efficacy and safety. A 1998 report in Drug Topics
examined 285 clonidine poisonings that were reported to the Kentucky
Regional Poison Center during a 6-year period. Clonidine was primarily
prescribed for ADHD with the largest demographic age group of 1-3 years
(99 children).\42\ Because a pediatric dosage form for clonidine did
not exist, much of what was being administered was likely compounded.
Of serious concern, pharmacy compounded, sustained-release clonidine
dosage forms have been marketed to prescribers--a physician's practical
guide states: ``it has been recommended to substitute the usual
nighttime clonidine dosing with a pharmacy-compounded clonidine
sustained release form, made by compounding clonidine with a hydroxyl-
propylmethylcellulose extended-release polymer or with guanfacine''
\43\ The erratic and unpredictable release from a pharmacy-compounded,
purportedly sustained-release dosage form or from simple calculation
errors may contribute to observed cases of clonidine toxicity--such
dosage forms have not been tested to confirm extended-release and
pharmacokinetic profiles. Three cases appearing in the medical
literature have associated pharmacy-compounded clonidine preparations
with clonidine poisonings in children,\35\ \36\ but such associations
are difficult to make without adequate surveillance.
Cost
Pharmacists make more money when they dispense unapproved,
compounded formulations.\44\ The average gross profit for a compounded
prescription is estimated at $31.50 based on 1998 figures. According to
Thomas Kaye RPh, MBA with Blue Cross Blue Shield of Oklahoma, the
frequency of prescribing and reimbursement claims for compounded drugs
has been increasing for many plans in recent years--he cautions that
incidents associated with the use of such unapproved products ``add to
overall patient cost, as well as morbidity and mortality.''\45\
State Oversight
State Boards of Pharmacy oversight of pharmacy compounding is
discrepant and regulations are minimally enforced. While some States
have adopted compounding rules that provide some public health
protections, other States permit unrestricted distribution of
compounded drugs that are not dispensed pursuant to an authorized,
unsolicited prescription.
New Federal Regulations Are Necessary
It is ironic that so much concern is currently focused on the
importation of drugs from other countries that may not match our gold
standard system of regulation for pharmaceuticals, while we have within
our own borders a flourishing, unregulated drug industry that
manufactures, markets, and sells substandard products throughout the
U.S.
If we do not act in the interest of public health and safety now,
the history of substandard drug exposures and the related morbidity and
mortality that led to the Kefauver-Harris Drug Amendments of 1962 will
be relived through contemporary pharmacy compounding.
Recommendations To Protect the Public From the Hidden Risks of
Unregulated, Pharmacy Compounded Drugs
1. Disclosure to prescribers and patients that compounded drugs are
not FDA-approved and consumers should be advised of alternative FDA
approved products.
2. Disclaimer on all compounded drug containers: THIS DRUG HAS NOT
BEEN TESTED OR REVIEWED BY THE FOOD AND DRUG ADMINISTRATION (FDA) FOR
SAFETY OR EFFECTIVENESS AND HAS NOT BEEN PRODUCED IN A FACILITY MEETING
GOOD MANUFACTURING PRACTICES GUIDELINES.
3. Requirement that prescribers be notified before a compounded
product is dispensed.
4. Prohibition against the compounding of drugs too difficult to
compound for safety reasons.
5. Strict pedigree requirements for all chemicals used in
compounding.
Summary of Testimony
1. Pharmacy-compounded drugs do not meet Federal requirements for
establishing safety and efficacy (21 U.S.C. 355), for manufacturing
(21 U.S.C. 351(a)(2)(b)) or labeling for safe use (21 U.S.C.
352(0(1)).
2. Accurate, complete and unbiased information about the size and
scope of the compounding industry in the U.S. is not available.
3. Federal compounding regulations (1997 FDA Modernization Act
Section 503a) were nullified through a U.S. Supreme Court ruling in
2002. Current State compounding regulations are inadequate to protect
public health and safety and to prevent individual patient exposures to
unacceptable risks.
4. Lack of oversight of the compounding industry has created
avenues to introduce commercial quantities of unapproved drugs into the
market place through wholesale transactions.\1\
5. Morbidity and mortality associated with compounded drugs has
been observed but because pharmacists are not required to detect or
report problems associated with drugs they compound, the known cases of
deaths, injuries, exposures and recalls of dangerous products are
considered ``tip of the iceberg'' by public health officials.\20\ \23\
\31\ \33\ \34\ \35\ \36\ \37\ \38\ \39\ \40\ \41\
6. To address this issue, Senator's Bond and Roberts have offered
an amendment to the Senate version of the Prescription Drug and
Medicare Improvement bill (S. 1) to establish an advisory committee
within the FDA to examine whether patients are receiving necessary,
safe, and accurate dosages of compounded drugs. This is a critical
first step in examining the public health risks associated with this
newly emerging industry.
7. New Federal legislation for pharmacy compounding is necessary to
protect patients and preserve the integrity of our Federal system of
regulation for drug approval, manufacturing, and safety.
REFERENCES
1. Department of Health and Human Services Food and Drug
Administration WARNING LETTER to Unique Pharmaceuticals, October 10,
2001.
2. Pallarito, Karen. Legal-FDA ban on ads for drug compounding
violates free speech. Reuters Health 2-14-2001.
3. Bouts, B. The Misuse of Compounding by Pharmacists.
QuackWatch.com. Accessed 08/01/02 from http://quackwatch.com/01
QuackeryRelatedTopics/compounding.html.
4. IACP Letter to Missouri State Board of Pharmacy Re: Proposed
Rule 4 CSR 220-2.200 Sterile Pharmaceuticals, January 31, 2003.
5. Johnson PE. Legal and practice concerns with extemporaneously
compounded medications. Journal of Pharmaceutical Care in Pain &
Symptom Control 1997; 5(3):47-57.
6. Pina, Kenneth R. and Pines, Wayne L., Ed. A Practical Guide to
Food and Drug Law and Regulation. Washington, D.C. Food and Drug Law
Institute, 1998.
7. United States v. Idania Arias et al., Case No. 00-683-CR-LENARD.
United States District Court, Southern District of Florida.
8. Beaulieu E. Duoneb pricing spells trouble for HMEs. HME News
July 2001 accessed 7/23/02 from http://www.hmenews.com/july2001/news/
topstory4.htm.
9. Schaller JL, Briggs B, Briggs M. Progesterone organogel for
premenstrual dysphoric disorder. J Am Acad Child and Adolesc Psychiatry
2001; 39(3):261.
10. Bashford RA, Horrigan JP. Comment by Drs. Bashford and
Horrigan, at the invitation of the editor on Progesterone organogel for
premenstrual dysphoric disorder. J Am Acad Child and Adolesc Psychiatry
2001; 39(3):261.
11. Capps S. Progesterone organogel for premenstrual dysphoric
disorder. J Am Acad Child and Adolesc Psychiatry 2001; 40(3):261.
12. Fairfax RA. ``Phederalism'': The Regulation of Pharmacy
Compounding and Two Years in the Regulatory Turf War Between Pharmacy
and the Food and Drug Administration accessed 10/21/03 from http://
leda.law.harvard.edu/leda/data/211/rfairfax.html.
13. American Pharmaceutical Association--About Importing
Medications and Internet Pharmacies. Importing Medications: Getting
Your Questions Answered. Accessed 10/19/03 from http://
www.pharmacyandyou.org/InternetPharmacy.html.
14. Trissel L. Compounding our problems--again. Am J Health-Syst
Pharm 2003 Mar; 60:432.
15. Thompson C. USP publishes enforceable chapter on sterile
compounding. Am J Health-Syst Pharm 2003; Sept 60:1814-17.
16. Sabra K. Standards for pharmacy compounding. Am J Health-Syst
Pharm 2003; Sept 60:18141817.
17. Perrin JH. Comments on drugs difficult to compound and the
quality of chemicals used in compounding. Drug Development and
Industrial Pharmacy 1999; 25(4):553-57.
18. McGuff Compounding Services, Inc. Explanation of Compounding
Pharmacy and What to Look for in a Compounding Pharmacy. Accessed 10/
19/03 from http://www.mcguffpharmacy.com/images/pdf%20Files/
explanation_of_compounding_main.pdf.
19. Seifert SA. Pharmacy prescription errors reported to a regional
poison control center. Journal of Toxicology CLINICAL TOXICOLOGY 2002;
40(7):919-23.
20. Subramaniam V, Sokol G, and Zenger V et al. Survey of drug
products compounded by a group of community pharmacies: Findings from
an Food and Drug Administration study. Accessed 10/19/03 from http://
fda.gov/cder/pharmcomp/communityPharmacy/default.htm.
21. Dansereau RJ, Lowe E, and Stella M. Alternative to bismetet
available-A compounding formula presented for informational purposes
only was found not to be stable by Proctor and Gamble researchers; a
commercial alternative is described. American Druggist 1997:58.
22. Sarver JG et al. Analysis of extemporaneous alprostadil
formulations. International Journal of Pharmaceutical Compounding 1999;
3(2):148-54.
23. Jones TF, Feler CA, Simmons BP et al. Neurologic complications
including paralysis after a medication error involving implanted
intrathecal catheters. The American Journal of Medicine 2002;
112(1):31-36.
24. FDA Enforcement Reports accessed 10/13/03: October 16, 2002
Portage Pharmacy http://www.fda.gov/bbs/topics/enforce/2002/
ENF00765.html; April 9, 2003 Lee Pharmacy http://www.fda.gov/bbs/
topics/enforce/2003/ENF00790.html; February 12, 2003 Urgent Care
Pharmacy http://www.fda.gov/bbs/topics/enforce/2003/ENF00782.html;
March 27, 2002 Med-Mart Pulmonary Services http://www.fda.gov/bbs/
topics/enforce/2002/ENF00736.html.
25. Missouri Department of Economic Development News Release
Missouri Board of Pharmacy takes action against Kansas City Company.
March 10, 2003. Accessed 10/19/03 from http://www.ded.state.mo.us/
regulatorylicensing/professionalregistration/pharmacy/pdfs/pharmacy
31003pressrelease.pdf.
26. Prepared Statement of the Honorable Fred Upton before the House
Commerce Committee Subcommittee on Oversight & Investigations Subject-
Counterfeit Bulk Drugs. June 8, 2000.
27. National Association of Pharmacy Regulatory Authorities. Health
Canada Notice March 7, 2003 accessed 10/15/03 from http://
www.napra.org/docs/0/310/398.asp.
28. The Honorable Tom Bliley, chairman, The Committee on Commerce.
United States House of Representatives Letter to The Honorable Jane
Henney, M.d. May 8, 2000.
29. FDA Enforcement Reports accessed 10/19/03 Medisca
Pharmaceutique April 23, 2003 http://www.fda.gov/bbs/topics/enforce/
2003/ENF00792.html; Hawkins Chemical August 15, 2000 http://
www.fda.gov/bbs/topics/enforce/2003/ENF00792.html; Paddock Labs March
15, 2000 http://www.fda.gov/bbs/topics/ENFORCE/ENF00633.html;
Professional Compounding Centers of America August 19, 1992 http://
www.fda.gov/bbs/topics/ENFORCE/ENF00166.html.
30. O'Brien Pharmacy Quality Assurance Procedure. Accessed 10/13/03
from http://www.obrienrx.com/o_brien_pharm/sterile/quality/qual_chem/.
31. Morris M and McGuire D. Three-Part Special Report: Rx for
disaster: Some pharmacists who mix medicines dispense unsafe drugs. The
Kansas City Star October 6-8, 2002.
32. South River Compounding Pharmacy. Accessed 12/27/02 from http:/
/www.customdrugs.com/hrt.htm.
33. Russell S and Hallissy E. Chronicle Investigation: Who's mixing
your drugs? Bad medicine: Pharmacy mix-ups a recipe for disaster. San
Francisco Chronicle June 23, 2002. Available at: http://www.sfgate.com/
cgi-bin/article.cgi?file=/chronicle/archive/2002/06/23/MN12273.DTL.
34. Centers for Disease Control Exophiala Infection from
contaminated injectable steroids prepared by a compounding pharmacy--
United States, July-November 2002. MMWR December 13, 2002/51(49);1109-
1112. Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm5l49al.htm.
35. Suchard JR and Graeme KA. Pediatric clonidine poisoning as a
result of pharmacy compounding error. Pediatric Emergency Care 2002
18(4):295-96.
36. Ramano MJ and Dinh A. (2001) A 1000-fold overdose of clonidine
caused by a compounding error in a 5-year-old child with ADHD.
Pediatrics 108(2):471-72.
37, Glod M. Pharmacist penalized in death of boy, 5; Va. Board
rules in medication error. The Washington Post. August 17, 2000.
38. Department of Health and Human Services Food and Drug
Administration WARNING LETTER to College Pharmacy, April 7, 1999.
39. Teegardin C, Probe questions safety of pharmacy-made drugs. The
Atlanta Journal--Constitution Friday March 30, 2001.
40. Hartman T. Springs pharmacy sued in injected tea death. The
Gazette April 11, 1999.
41. Sanchez-Ramos L, Farah LA, and Kaunitz AM et al. Preinduction
cervical ripening with commercially available prostaglandin E2 gel: a
randomized, double-blind comparison with a hospital compounded
preparation. Am J Obstet Gynecol 1995; 173(4):1079-84.
42. Gebhart, Fred (1998) Clonidine implicated in household
poisonings. Drug Topics, Nov 2:27.
43. Oesterheld A, Tervo R. (1996) Clonidine: a practical guide for
usage in children. South Dakota Journal of Medicine: 234. Retrieved 8/
18/01 from http://med.usd.edu/sdsma/1996/9607234.htm.
44. Coyne PJ, Hansen LA, Watson AC. Compounded Drugs: Are
customized prescription drugs a salvation, snake oil or both? American
Journal of Nursing 2003; 103(5) 78-85.
45. Kaye T. The quandary of compounding for MCOS: Administrative
costs, risks, and waste. MANAGED CARE 2003: 42-8.
46. Department of Health and Human Services Food and Drug
Administration WARNING LETTER to Carneys Drug May 27, 2003.
47. Department of Health and Human Services Food and Drug
Administration WARNING LETTER to Med-Mart Pulmonary Services September
30, 2002.
48. American Society of Health-System Pharmacists Board of
Directors. ASHP Report ASHP Guidelines on managing drug product
shortages. Am J Health-Syst Pharm 2001; 58:14451450.
49. Harlow S. Missouri officials begin tracking contaminated drug.
The Kansas City Star March 13, 2003.
50. Erickson SJ, Duncan A. Clonidine poisoning: an emerging
problem: epidemiology, clinical features, management and prevention
strategies. J Paediatr Child Health 1998; 34:280-82.
Prepared Statement of Daniel A. Herbert
Good morning. Thank you for the opportunity to appear before you
today and present the views of the American Pharmacists Association. I
am Dan Herbert, a pharmacist and the President-elect of APhA. I have
been in practice for 37 years and currently own three community
pharmacies in Richmond, Virginia. Founded in 1852 as the American
Pharmaceutical Association, we are the largest national pharmacist
organization in the United States, representing more than 53,000
practicing pharmacists, pharmaceutical scientists, student pharmacists
and pharmacy technicians. APhA members practice in virtually every area
of pharmacy practice, including independent and chain community
pharmacy, hospital pharmacy, nuclear pharmacy, long term care pharmacy,
home health care and hospice.
Let me first provide APhA's support of the Committee's goal that
patients receive safe and effective medications. As pharmacists, we
rely upon quality products as the first step in our work to help
patients make the best use of their medications. When providing a
quality product involves tailoring a medication for an individual
patient, we use our scientific training and education to compound the
medication.
Compounding medications is an important component of pharmacy
practice-mine and that of my colleagues. While it is challenging to
quantify the actual number of APhA's members who engage in drug
compounding activities on a regular basis, virtually all practicing
pharmacists will be involved with compounding activities at some point
during their career-and most practitioners engage in some element of
compounding in each week of practice. APhA has a compelling interest in
helping pharmacists, in collaboration with practicing physicians,
compound drug formulations to meet the needs of patients. Our
compounding activities are a critical component of the American health
care system, allowing physicians to prescribe medication therapy to
best meet the needs of their patients.
My comments today will provide a brief history of pharmacist
compounding, a description of the important role it plays in our health
care system, the challenging task of distinguishing between compounding
and manufacturing, and ways in which we can attempt to appropriately
protect our patients by improving the quality of practice and
identifying and stopping ``bad actors''.
COMPOUNDING: A TRADITIONAL COMPONENT OF PHARMACY PRACTICE
Compounding is a traditional component of pharmacy practice; only
the drugs, dosage forms, and equipment or techniques have changed as
pharmacy practice has advanced. As noted in the Chronicles of Pharmacy,
``[p]harmacy, or the art of selecting, extracting, preparing and
compounding medicines from vegetable, animal, and mineral substances,
is an acquirement that must have been almost as ancient as man himself
on earth.'' The early practice of pharmacy required the compounding of
virtually all medications, because there were few, if any, commercially
available products. The need for compounded products has diminished
with the founding of pharmaceutical companies, although the need for
this practice still exists today. Because the preparation of an
extemporaneous pharmaceutical dosage form is not a trivial exercise,
our position is that when an FDA-approved, commercially available
product can meet a patient's needs, it should be employed as the
preferred course of action. However, when a patient's particular
situation obviates the use of commercial products, the knowledge and
skills of a compounding pharmacist can be extremely valuable, even
lifesaving.
It is a fundamental responsibility of the pharmacy profession to
extemporaneously compound quality prescription products for patients
who have unique medication needs. Through their education and
licensure, pharmacists assume an ethical obligation to the public to
maximize the intended benefits of drug therapy while minimizing the
unintended side effects and adverse reactions. Some states require
licensed pharmacies to offer compounding services [see 49 Pa. Code '
27.18(p)(2) (2003);
W. Va. Code St. R. ' 15-1-19.4 (2003)]. Compounding enables
pharmacists to use their knowledge and expertise of medication use to
produce individualized medications that meet patient needs and improve
health outcomes. Without compounding, pharmacists and physicians would
be limited to a ``one size fits all'' strategy, which would have a
direct, immediate, negative impact on the ability of health care
providers to provide care to patients.
COMPOUNDING NECESSARY FOR MANY PATIENTS
As I stated earlier, it is challenging to quantify the actual
number of pharmacists who engage in drug compounding activities on a
regular basis, virtually all practicing pharmacists will be involved
with compounding activities at some point. The unique knowledge and
skill set of pharmacists enables them to extemporaneously compound
medications to individualize patient care through the preparation of
patient-specific products.
Compounding allows pharmacists and physicians to address the health
care needs of patients who do not fall within the range of commercially
available dosage strength and formulations. Patient needs vary from
extremely small doses and specific combinations of drugs, to
preservative-free products, to liquid dosage forms, to delivery systems
that are not commercially available. In many situations, large-scale
manufacturers are unable to tailor-make a medication in a cost
effective manner. Without compounding, many patients would not have
access to the correct combination of ingredients, the appropriate dose
and dosage form, or the best delivery system.
In addition to unique patient needs, manufacturing and market
limitations may require medications to be compounded. For example, some
therapies, such as hyaluronidase injection (used as an adjunct to
ophthalmologic surgery) must be compounded because the therapies
generate insufficient revenue to pharmaceutical companies to justify
large-scale manufacturing. Other medications, such as radioactive drugs
used to diagnose or treat cancers or other diseases, must be compounded
because they do not have sufficient ``shelf life'' to withstand the
commercial distribution process and therefore need to be prepared at
the time of dispensing. And finally, many manufactured ``finished
pharmaceutical'' products are only ``finished'' in the sense of being
ready to ship and then store in the pharmacy. These products must still
be compounded, or in some cases merely reconstituted, by the pharmacist
to provide a dosage form suitable for a patient's treatment.
Compounding involves different activities in different pharmacy
practice settings. It may mean the preparation of oral liquids,
topicals, or suppositories; the conversion of one dose or dosage form
into another; the preparation of specific dosage forms from bulk
chemicals; the preparation of intravenous admixtures, parenteral
nutrition solutions, or pediatric dosage forms from adult dosage forms;
the preparation of radioactive isotopes; or the preparation of
cassettes, syringes, and other devices with drugs for administration in
the home setting. Examples of some of the most common compounded
products include lotions, ointments, creams, gels, suppositories,
intravenously administered fluids and medications, total parenteral
nutrition products, and oral suspensions.
Although compounding may be required in any pharmacy practice
setting and for any type of disease, there are concentrations of
compounding practice. For example, due to the nature of the care they
provide, hospital pharmacies have historically had a strong compounding
component to their practice. And due to the nature of the disease and/
or the patient size or age, compounding frequently occurs for patients
with cancer, for pediatric care, and for hospice care.
Compounding in the hospital setting is a vital service that
addresses the unique needs of patients requiring highly individualized
medications. The primary compounding activity in hospitals is the
preparation of intravenous admixtures ranging from simple fluid
replacement to the delivery of complicated, individualized chemotherapy
regimens. Because daily intravenous therapy is provided through
compounding of medications, nearly every person who has ever been
admitted to a hospital -and those who will be admitted today and likely
in the future- has received a compounded medication. In fact, the
immediate availability of extemporaneous compounding by a pharmacist
provides the hospital physician with literally any form or strength of
medication needed for a patient's specific needs.
Cancer patients frequently benefit from compounding pharmacists'
knowledge and skills. Almost all chemotherapy involves drugs and drug
combinations that are compounded, or at least reconstituted, by
pharmacists. It is imperative that a patient receive the correct drug
dosage based upon the patient's body size, the type of cancer, the size
and type of tumor, and the clinical condition of the patient including
their kidney and liver function. This can often only be accomplished by
using compounded, patient-specific medication preparations.
The compounding of pediatric dosage forms has also been an area of
extensive activity, because many drugs used to treat children are only
available in adult dosage forms. As the Committee is aware, finding the
right drug, dose and dosage form to treat sick children is a
complicated task. This Committee has made great strides in establishing
incentives to improve the utility of manufactured products in treating
children, but frequently, compounding is the only available avenue to
achieve the desired clinical outcomes. Commercially manufactured
products for adult use must be modified and compounded for use in
children. It has been estimated that more than 40% of doses given in
pediatric hospitals require compounding to prepare a suitable dosage
form. Indeed, utilization of compounded medications is essential for
the provision of medical care to hospitalized children.
As the Committee is aware, hospice programs provide care for
patients near the end of their lives who can no longer benefit from
curative treatment and generally have a life expectancy of six (6)
months or less. Patients suffering from incurable cancer have very
special needs. Relief of pain near the end of life is an important
element of maintaining the dignity and comfort of a dying patient and
their loved ones. Hospice pharmacists often use compounded medications
to alleviate pain and to control nausea and vomiting for patients in
the hospice setting. A problem for many hospice patients is that pain
medications are not manufactured in the required dosages. If commercial
products that provide the precise dose(s) required are not available,
the hospice pharmacist can often remedy the situation by
extemporaneously preparing an individualized product. Additionally,
some patients are not physically capable of swallowing the number of
commercially manufactured tablets or capsules required or cannot take
medications orally. A pharmacist can address these issues by either
compounding a stronger product, by transforming tablets or capsules
into a liquid, or by creating a preparation that can be applied
topically or delivered rectally.
CONTINUOUS QUALITY IMPROVEMENT
Pharmacy compounding conforming to the highest possible
professional standards is essential to optimal patient care. But
maintaining quality and advancing practice requires the profession to
be vigilant, and continually improve our professional standards and
regulatory efforts. One question that continues to plague the
profession and our regulators-the state boards of pharmacy-is how to
distinguish between compounding and manufacturing; with one practice
regulated by state boards of pharmacy and the other process, by the
Food and Drug Administration.
Compounding has traditionally been characterized by the triad
relationship of the physician, pharmacist and patient; working together
to individualize care for maximum patient benefit. Pharmacy compounding
is performed in response to a prescription from a licensed prescriber,
or in preparation for a reasonably anticipated prescription, based upon
prior experience and expected needs of individual patients.
APhA supports the National Association of Boards of Pharmacy's
(NABP) definition of compounding, which states:
Compounding--The preparation, mixing, assembling, packaging, or
labeling of a drug or device (i) as the result of a
practitioner's Prescription Drug Order or initiative based on
the pharmacist/patient/prescriber relationship in the course of
professional practice or (ii) for the purpose of, as an
incident to research, teaching, or chemical analysis and not
for sale or dispensing. Compounding also includes the
preparation of drugs and devices in anticipation of
Prescription Drug Orders based on routine, regularly observed
patterns. [emphasis added] (Good Compounding Practices
Applicable to State Licensed Pharmacies, Subpart A. Park Ridge,
IL:NABP, 1993.)
The profession's definition of compounding does not encompass the
preparation of massive amounts of a drug product with the contemplation
of distribution to a mass market of unknown users in unknown venues.
Rather, the definition supports our assertion that the purpose of
pharmacist compounding is to prepare an individualized drug treatment
for a patient based on an order from a duly licensed prescriber.
Manufacturing, on the other hand, is defined by NABP as follows:
Manufacturing--The production, preparation, propagation,
conversion or processing of a Drug or Device, either directly
or indirectly, by extraction from substances of natural origin
or independently by means of chemical or biological synthesis,
and includes any packaging or repackaging of the substance(s)
or Labeling or relabeling of its container, and the promotion
and marketing of such Drugs or Devices. Manufacturing also
includes the preparation and promotion of commercially
available products from bulk compound for resale by pharmacies,
Practitioners, or other Persons. (Id.)
As clear as this difference may seem to the profession of pharmacy,
it has been a difficult distinction to implement because of the
complexity and range of legitimate compounding activities. In public
comments, even the Food and Drug Administration has suggested that the
difference between compounding and manufacturing is better represented
by the intersection of two jagged jigsaw puzzle pieces rather than a
straight line.
The fundamental difference between compounding and manufacturing,
and the key element in making any such distinction, is the existence of
a pharmacist/prescriber/patient relationship. This triad should control
the preparation of a drug product. Furthermore, compounded drugs are
not for resale, but rather, are personal and responsive to a patient's
immediate needs. Conversely, drug manufacturers produce batches
consisting of millions of tablets or capsules at a time for resale,
while utilizing many personnel and large scale manufacturing equipment,
without knowledge of the specific patient who will ultimately consume
them.
There are numerous factors to consider in distinguishing the FDA-
regulated practice of manufacturing from the state-regulated practice
of compounding. Such factors-though none is exclusive-include the
volume of compounding by a particular pharmacist or pharmacy, the
number of different products being compounded, the scope of the
pharmacist's and pharmacy's practice, and of course, the presence of
individual prescriptions for each compounded product.
ONGOING ACTIVITIES; OPPORTUNITIES FOR THE FUTURE
As professionals, pharmacists continually strive to provide the
best patient care possible, including continuous review of practices
and taking steps to improve medication use and advance patient care.
While some may assert that little is being done to advance and improve
pharmacist compounding, they are mistaken. APhA publishes resources for
pharmacists to improve the practice, including The Art, Science and
Technology of Pharmaceutical Compounding and Trissel's Stability of
Compounded Formulations. And I am currently chairing an APhA committee
setting strategic directions for the profession-including compounding.
In our year of meetings, we have proposed some steps for advancing
compounding practice as part of our commitment to providing safe and
effective pharmaceutical care to the citizens of this country.
One aspect of our committee's work to date is the preliminary
categorization of compounding to distinguish the types of compounding a
pharmacist should be prepared to provide based on our pharmacy
education and training, from the types of compounding that may require
enhanced education or perhaps accreditation or certification processes.
Because compounding encompasses a broad scope of activities-from the
preparation of rather simple lotions for application to the skin to the
preparation of radiopharmaceuticals for injection imaging, this
categorization is important in focusing quality improvement efforts and
resources. Our committee is also considering a proposal that
pharmacists identify all compounded products for patients, so that
patients understand that they will be using a non-commercially
available product prepared specifically for their needs.
Other groups are pursuing efforts to improve pharmacy compounding
practice as well. The United States Pharmaceopeia (USP), the official
drug standard setting body for our country, has a long history of
addressing pharmacy compounding, especially in the area of sterile
preparations. Various state boards of pharmacy are exploring changes in
statute and regulation to more clearly articulate the boundaries of
practice for pharmacists in their jurisdiction. In my home state of
Virginia, legislation passed in the 2003 session made changes to our
compounding requirements. Specifically, the legislation clarified that
compounded products be prepared and dispensed pursuant to a
prescription and in the context of a bona fide practitioner-patient-
pharmacist relationship; or in expectation of receiving a valid
prescription based on observed prescribing patterns. All compounded
products must be labeled and include a beyond-use date. In addition, a
pharmacist is required to maintain and comply with a policy and
procedure manual if their practice involves compounding products that
are at high risk for contamination, radiopharmaceuticals, or dose-
critical or specialized preparation dosages.
And APhA and other representatives of the profession of pharmacy
are evaluating the issue and proposing solutions as well. In
collaboration with the National Association of Boards of Pharmacy and
the United States Pharmacopeia, our groups have recommended exploring
the value of voluntary programs to improve compounding activity in
certain categories. For example, should pharmacists engaged in
compounding complex sterile products-such as those prepared from non-
sterile bulk chemicals-have their pharmacy practice complete a site
accreditation process to assess the policies and procedures employed?
Should pharmacists engaged in other complex compounding activities
complete specific training and education programs, or even an
individual certification process to demonstrate their knowledge and
skills? While this work is early in development, we are making progress
and will continue our work to assure that patients get the compounded
medications they need, at the level of quality they should expect.
Improving our efforts to provide quality compounded products will
require collaborative efforts of consumers, the profession, state
boards of pharmacy, and the FDA. Each stakeholder has an expertise that
is essential in assuring the continued availability of this practice
with the quality patients deserve. Consumers must play a role in all of
our efforts, as we are pursuing this work for them. The profession must
take the lead in guiding the regulatory agencies in how to draw the
line between compounding and manufacturing, and in developing
guidelines and voluntary accreditation or certification processes to
demonstrate compliance with those guidelines. The state boards of
pharmacy, responsible for regulating the profession, should maintain
their primary regulatory role of pharmacy practice, including
compounding, and will likely be tasked with new initiatives to enhance
current regulatory efforts. The FDA has a role in regulating
manufacturers, as well as defining some broad guidance, such as the
identification of substances that should not be used in manufacturing
or compounding because the substances have been withdrawn from the
market for safety and efficacy concerns. All of these efforts require
collaboration, coordination, and ongoing communication.
Through compounding, pharmacists fulfill a legitimate and essential
need -providing patients with medications tailored to their needs. The
professional education and training of pharmacists provides the unique
knowledge and skills necessary to fulfill this health care need. The
profession continues to research the most stable and appropriate
mechanisms to produce compounded products, utilizing available and
emerging technologies. By working together, prescribers and pharmacists
help patients access otherwise unavailable therapies such as cream for
breast cancer patients' radiation burns, or anticonvulsants in a
suppository form when patients' veins are not accessible for injection.
Without compounding, many physicians, pharmacists and patients would
lose access to valuable treatments.
APhA supports the Committee's efforts to discuss this important
issue. Pharmacist compounding improves patients' lives every day, but
we must continually improve our practices to provide the best patient
care. Pharmacists are ready to partner with stakeholders to develop
effective strategies to improving the quality of compounding practices.
APhA appreciates the opportunity to share the perspective of
pharmacists on this issue.
Prepared Statement of Kevin Kinkade
Mr. Chairman, and Members of the Committee: I am pleased to be here
today to be able to discuss with you the important issues surrounding
the proper regulation of the role of pharmacists in the areas of
compounding of pharmaceutical products. As I am sure all of you know,
the art of compounding has been a traditional part of the practice of
pharmacy for centuries. In fact, until after World War II when drug
manufacturing became more prominent, compounding was one of the
principal practices used to provide needed drugs to patients. While the
need for compounding of products has changed since then, the importance
of compounding certain products by prescription is still a very
important and necessary part of the practice of pharmacy. Many
physicians and patients across the United States depend on pharmacists
to compound products that they need. This need may stem from different
factors such as allergies to a commercial product, availability of the
needed drug delivery system or the lack of the availability of the drug
commercially. In any case, present day compounding has taken on a
larger role through the use of new technologies and in some cases can
be successful in meeting the special healthcare needs of patients.
What regulators must realize is that due to the increased practice
by some pharmacies of compounding medicines and due to the complexity
of some of these compounds, state law and resources can be challenged.
State standards for compounding must be maintained as broad enough to
encompass all areas of compounding that can occur yet also remain
specific as to what requirements must be met in order to ensure safe
and effective products are always provided to consumers.
MISSOURI BOARD OF PHARMACY
The board of pharmacy is comprised of seven members. Five members
are full time practicing pharmacists from various practice settings
within the state. One member, by law, must be a full time pharmacist
employed in an institutional setting such as a hospital or long term
care facility. One member is a consumer with no ties to the
pharmaceutical industry. The board licenses and regulates pharmacists,
pharmacies, drug distributors (wholesalers, manufacturers) and
registers technicians. The field staff consists of seven inspectors who
are all licensed pharmacists. The executive director, who is also a
licensed pharmacist, is responsible for the operation of the board
which includes the execution and management of all policy decisions
made by the board. The practice act for pharmacy in Missouri is Chapter
338 RSMo.
MISSOURI REGULATIONS GOVERNING COMPOUNDING
The Board of Pharmacy of the state of Missouri has regulated and
enforced standards for the compounding of drugs through the
promulgation of rules since their effective date of February of 1993
for sterile pharmaceuticals (4CSR 220-2.200) and April of 1996 for
general compounding practices (4CSR 220-2.400). A need for such
regulations was observed by the board due to 1) an increase in the
number of pharmacies that were engaging in various forms of compounding
which translated into an increase in the number of prescriptions being
written and dispensed for such products and 2) the complexity of some
of the compounded products and the concern for competent practices and
standardization of formulas and procedures in pharmacies.
Several issues have warranted that the board review present
standards again. The Robert Courtney case which was a criminal case of
diluting compounded products for profit made headlines in Kansas City
and all over the nation and had consumers, physicians and regulators
wondering about the safety of the drug distribution system. While this
case received tremendous publicity, it should not be considered the
driving force that caused the board to change existing rules on
compounding. Working on a major overhaul of the rules was already being
considered. Proposals that had been either drafted or finalized by
national organizations such as the United States Pharmacopoeia (Chapter
797) and the American Society of Health System Pharmacists were
reviewed. Concerns over the competency of personnel preparing
compounded products as well as adequate quality assurance measures
within compounding practices was of chief concern. In addition, there
was observed an increase in inter-state marketing and selling of
compounded products by some pharmacies which seemed to border on
manufacturing practices that would fall within the federal food, drug
and cosmetic laws.
The standards for general compounding practices (4 CSR 220-400)
were amended to include stricter definitions to better differentiate
between the practice of compounding vs. manufacturing. Record
requirements for compounded products were updated to include methods
for compounding of the particular product and to track the source, lot
number and the beyond use date of each drug product/ingredient used. A
new section on the management of compounding was added that includes
requirements for ensuring that products are pure and must be
individually inspected before release to a patient. Pharmacies must
also now have in place, a drug monitoring program that will evaluate
compounding services through the monitoring of adverse reaction
reports, infection rates, incidence of recalls and the tracking of
complaints from prescribers and consumers. Recalls must be initiated
when a product is deemed to be misbranded or adulterated. Prescribers
of the product must be notified along with adequate information to take
any corrective actions necessary. Patients must be notified when the
recalled product could present a danger to patient health or safety.
The board of pharmacy must be notified in the case of all recalls
within three business days.
Standards for sterile product compounding were much more sweeping
and required that the present rule be rescinded and a new, updated rule
be promulgated in its place. Due to the complex and, in some cases,
costly changes that the rule will require pharmacies to undergo, the
effective date for compliance was selected as July 1st 2004. Strict
definitions governing the equipment as well as the environment that
such compounds are made in will require any pharmacy attempting to mix
or create sterile compounds adhere to the highest standards of practice
available in the present marketplace. The type of product produced as
well as the storage time will govern the type of quality assurance
procedures (process validation and testing of product) that must be
included with every batch of product produced. Products that are
compounded and considered to be of a low ``risk'' potential for adverse
or untoward effects will require process validation. Those products
considered to have a high risk potential in addition to process
validation will need to be quarantined and tested by the pharmacy for
sterility, pyrogenicity and potency. Examples of such products could
include ophthalmic preparations and cardioplegic solutions. Depending
on the expected shelf life of a product, pharmacies will have to
arrange for an instrumental analysis of a product for a guarantee of
potency.
MISSOURI TO BEGIN RANDOM TESTING OF COMPOUNDED PRODUCTS
Missouri has experienced several episodes of serious compounding
misfortunes. As noted previously, the Robert Courtney case was of
criminal conduct by one pharmacist to intentionally dilute compounded
products that brought serious harm to cancer patients. Such conduct was
blatant and willful and is, as far as the profession of pharmacy is
aware, the first case of its kind. Even so, state agencies responsible
for the protection of consumers must be willing to consider changes in
how standards are derived and enforced. In cases such as Courtney's, it
is doubtful that any kind of state or federal inspection as we know
today would uncover this type of criminal conduct. No amount of record
reviews, inventory counts and reviews or equipment analysis would
provide information that would lead to a discovery of this type of
criminal conduct. Audits of drug inventories vs. usage have been
suggested by some. However, the time and effort to audit the number of
drugs in most pharmacies is simply not within the resources of any
state or federal program.
This is where an idea for a system of randomized quality assurance
can be of use. This past session of the Missouri legislature saw tight
budgets and withholding of portions of agency appropriations in order
to meet a constitutional requirement for a balanced budget. In this
backdrop, the board was able to secure several areas of newly funded
items, one of which, were funds for the testing of drug products that
are compounded by state licensed pharmacies. Funding of approximately
$159,000 was secured for this purpose. Such funds became available to
the board on July 1st of this year.
Missouri law requires a bidding process to be completed in order to
award an exclusive contract to a laboratory for the testing of
compounds. Both sterile and non-sterile products will be tested for
potency. Sterile products will also be tested for sterility and
pyrogencicity.
While the amount of funds appropriated will not allow for
consistent testing of the multitude of all compounded products provided
to consumers, it will provide for randomized testing of products to 1)
establish the level of competent practice patterns within a pharmacy or
with a specific product class across a number of pharmacies and 2) in
the remote chance that any pharmacist or pharmacy operation would
contemplate a fraud on consumers, the randomization of the testing
program would help dissuade such activities.
Funds from the appropriation will be used to pay a laboratory for
testing of product samples and for reimbursing pharmacies for samples
retrieved. Results of tests will be reviewed and, in most cases, shared
with the pharmacy. When a test result is reported to be below existing
standards for that product then a determination by the board will be
made as to a course of action. This could include one or more of the
following scenarios: 1) Retrieve more samples for further testing to
see if multiple lots of the product are affected; 2) Should the result
of a test reflect a potential harm if used by a consumer then explore
what corrective actions to be executed on a voluntary basis by the
pharmacy or by the board through discipline of the license or by
restraining/injunctive court orders.
Over time, accumulated data could be analyzed to see if certain
types of compounds do not meet the claims or benefits made for the
products or that a specific pharmacy may not provide adequate services
in order to competently compound a specific product or set of products.
The board does not believe that the system of testing described
here will, by itself, guarantee that all products provided to consumers
will be safe and effective. However, random testing and a thorough
review of pharmacy compounding operations of pharmacies through
adequate inspections will improve the chances that relevant standards
for compounding of drugs are in place in those pharmacies that choose
to provide such products. Anyone contemplating criminal fraud of
consumers will have to consider these new policies and procedures as a
real deterrent to offering or selling misbranded or adulterated
products.
In summary, the board of pharmacy supports measures to secure
additional resources to further voluntary compliance activity at the
state level. Effective laws and sufficient appropriations need to be
pursued in order to ensure adequate enforcement of state and federal
drug laws. All fifty states maintain a board of pharmacy with the
mandate of providing for the proper enforcement of laws in order to
provide consumers with adequate minimum standards of practice. The
profession of pharmacy should not be indicted for the outrageous and
demoralizing acts of one individual. Criminal behavior must be dealt
with separately from the enforcement of administrative laws over
professional practice standards. While criminal acts within the
profession are rare, they cannot be ignored. Measures that afford
effective and random checks to licensees need to be the focus of boards
of pharmacy who are in the best position to initiate and maintain
adequate inspections of state licensed facilities. In addition, FDA
should pursue by amendments to federal law or through the provision of
an updated compliance guide, a strict definition of what is compounding
vs. manufacturing and provide assistance in enforcement when violations
of the act occur within interstate commerce.
In this regard, we would also urge the FDA to continue to work with
the National Association of Boards of Pharmacy (NABP) in developing
these definitions to maintain the appropriate balance of state and
federal regulatory responsibilities and facilitate the implementation
of the definitions across all states. Other components of state
regulation of pharmacy compounding can be developed through NABP,
working with the FDA, USP and other stakeholders. Incorporating these
new definitions into NABP's Model State Pharmacy Act and Model Rules,
which includes Good Compounding Practices Applicable to State Licensed
Pharmacies, would also be encouraged as the Model Act has served as a
useful guide to the states in the area of regulating compounding.
Thank you again for the opportunity to address this important issue
today.
Prepared Statement of William P. Kennedy, Owner, Nephron
Pharmaceuticals Corporation FDA-Approved Manufacturing Facility/Orlando
Mr. Chairman and Members of the Committee, thank you sincerely for
your efforts to shed public light on the phenomenon in the country
today of pharmacies boldly compounding massive quantities of
prescription drugs. I believe that I am uniquely qualified to speak to
you on this topic. I am both a licensed pharmacist who was involved in
large scale compounding and I am now the owner of an FDA-approved
manufacturing facility in Orlando, Florida. I know this issue inside
out. The American public is at risk and you are to be commended for
your interest in and pursuit of non-FDA compliant compounding.
In 1966 I graduated from the University of South Carolina's College
of Pharmacy and became a registered pharmacist in that State. A year
later, I moved to Florida and began to pursue my career in pharmacy in
earnest.
In 1972 I purchased my own retail drugstore, Thayer's Colonial
Pharmacy, Inc., located in Orlando, Florida. This drugstore had been in
Orlando for many years with a reputation for finding unique
prescription drugs and compounding various discontinued formulations.
Included in this were many combinations of two or more drugs. For
example, dermatological preparations and respiratory drugs were
commonly compounded.
In the mid-1980's we began compounding various respiratory
medications on a broader scale. This business grew rapidly, including a
large portion of mail order transactions. We attracted much attention
within the industry.
Around 1990, the FDA paid us a visit. Their mission was to
investigate my compounding pharmacy. After 2 weeks of intense scrutiny,
they determined that I should be ``labeled'' a manufacturer, and
ordered that I cease and desist this compounding division of Thayer's.
The FDA representatives said, ``If you want to be in the manufacturing
business, then you must have an FDA-approved manufacturing facility''.
Of course, the back room of my drug store did not qualify.
In 1991, following the FDA's instruction, I set out to secure the
approvals and financing necessary to open a proper manufacturing
facility. Although I was a bit naive at the outset, I soon learned that
I was involved in a daunting process. In my case, it took over 6 years
to secure approval for my first new drug product, and my plant. It was
arduous, capital intensive and certainly the most challenging endeavor
of my career in health care. However, I now understood the rules and
knew this was necessary to begin providing prescription drugs on a
large scale to the public. I knew this because the FDA had told me so.
In 1997 Nephron Pharmaceuticals was up and running as an FDA-
approved and registered facility. Our focus is oral inhalation
solutions used to treat asthma, bronchitis and Chronic Obstructive
Pulmonary Disease. Nephron owns six approved Abbreviated New Drug
Applications (ANDA's) for prescription drugs:
Albuterol Sulfate Inh. Sol., 0.083 percent
Albuterol Sulfate Inh. Sol., 0.5 percent
Ipratropium Bromide Inh. Sol., 0.02 percent
Isoetharine Inh. Sol., 1 percent
Metaproterenol Sulfate Inh. Sol., 0.4 percent
Metaproterenol Sulfate Inh. Sol., 0.6 percent
Now, by national pharmaceutical standards, we are little guys. Even
so, here is what is entailed in the manufacture of our drugs:
Our 76,000 square foot facility is designed for full FDA
compliance. Our production room design houses controlled environment
rooms, based on the 1997 ISPE Sterile Manufacturing Facilities
Guideline that was developed with the help of the FDA.
Main Room classified as ``Pharmaceutical'' ``D Grade'',
Class 100,000 in operation;
Gown Room, Class 100,000
Mix Room, Class 10,000
Filling Room, Class 10,000 with Class 100 HEPA Shrouded
fill nozzle systems
All rooms use positive pressure, cascading air filtration
systems.
The attached exhibits show the design of this facility (Attachment
#1), the structured materials flow chart (Attachment #2), the complex
HVAC system required (Attachments #3 and #4), and one of the Water for
Injection systems required for operation (Attachment #5).
In this facility we have the following Departments/Personnel
required to comply with drug manufacturing regulations (21 CFR 210/
211)
Regulatory Department: 4 people responsible for all FDA
compliance/reporting
Quality Assurance Department: 41 people involved in
document control, validation, training, batch record review and
production line control;
Quality Control: 9 degreed chemists/technicians to analyze
all active and inactive ingredients and finished product stability
studies; 19 degreed microbiologists/technicians who do environmental
monitoring of all clean room, samples of WFI and Pure Steam condensate,
sampling of raw materials and production components;
Production Department: 117 production personnel;
Engineering Department: 4 Blow/Fill/Seal specialists whose
technology requires no human contact with the product or its immediate
container during filling and is recognized by the US Pharmacopoeia
(USP) as an advanced technology for the manufacture of liquid solution
in unit-dose forms; 22 production equipment assistants.
And these personnel operate at this facility in compliance with
Federal Regulations (21 CFR 210/211), which requires the following:
517 Production Standard Operating Procedures (SOP's);
30 Microbiology SOPs;
47 Chemistry SOPs;
29 Microbiology Validated Test Methods;
20 Chemistry Validated Test Methods;
219 Equipment Installation/Operation Qualification
Procedures;
310 Performance Qualifications/Validated Processes.
As you can see, this is a highly complex industry. The FDA
requirements, which are incredibly demanding, seem never-ending.
However, as a manufacturer, I have the comfort of knowing that all FDA-
approved facilities are subject to the same sets of regulations and
requirements. These rules are not frivolous; they are there for a
purpose. And that is to protect the public by insuring a uniform
standard of integrity in the prescription drugs produced in our
country.
Let me give you an example. We have to test the raw ingredients
used in the manufacture of a batch of drugs at the beginning of the
batch and at the end of the batch. If the composition of the raw
ingredients does not meet their predefined specifications at the end of
the batch, all the drugs in that batch MUST BE DESTROYED.
And yet, while these high standards are uniform with the FDA
facilities, there is another sphere of drugs, in my case, inhalation
drugs, which are produced throughout the country today with no similar
level of accountability. Pharmacies, like Thayers, are producing drugs
that should be identical to those produced by my company, but fall far
short.
I have attached four reports (Attachments #6 to #9), of pharmacy-
produced products sent to my chemistry lab at Nephron for analysis. As
you can see, they miss the mark on potency and quantity. A recent study
by the FDA itself showed a failure rate of more than 34 percent. These
failures result from inadequate facilities as well as inadequate
testing of raw ingredients.
Perhaps to attack this problem, the FDA instituted a rule that all
oral inhalation drugs have to be sterile. Initially, receipt of this
ruling reconfirmed to me that I had made the correct decision in 1991
to pursue FDA certification. However, in my trips around the country
marketing my products, I encounter time after time non-FDA approved
companies in the inhalation drug market willfully mass compounding
their products. Let me assure you, their product is rampant. I know. I
ran a similar operation in the 80's. I can tell you there is no
comparison to the way I produced Albuterol in the back room at Thayers
to the way Albuterol is now produced at Nephron.
Which brings us to the importance of the hearing you are holding
today. Americans across the country believe that the drugs they
purchase to fill a doctors prescription are the same . . . the same
chemistry, the same sterility, the same integrity. This is certainly
the ideal toward which the FDA and its registered manufacturers work.
However, this is far from the reality. The consumer is at risk and does
not even know it. The consumers do not know how to protect themselves
from non-FDA drugs, or that they even do.
Clearly, the integrity of the prescription drug market in this
country is under siege. Companies and individuals are willfully
breaking the rules and regulations long established by the FDA. Given
my background, and I find this situation is stunning. The consumer,
however, should find it frightening. As you know from documented press
stories, the result of this mass compounding outside the FDA arena can
be lethal.
Again, thank you for providing this public forum to discuss this
crisis. I am confident that with your attention, the double standard
prevalent in the inhalation drug market will no longer be tolerated. I
would be happy to answer any questions you might have.
Prepared Statement of the American Society of Health-System
Pharmacists, ASHP
The American Society of Health-System Pharmacists (ASHP) is pleased
to submit this statement for the record of the Senate Health,
Education, Labor, and Pensions Committee hearing on pharmacy
compounding. ASHP is the 30,000-member national professional
association that represents pharmacists who practice in hospitals,
long-term care facilities, home care, hospice, health maintenance
organizations, and other components of health care systems.
ASHP is as concerned as this committee about inappropriate and
fraudulent behaviors that have placed patients at risk of harm from
their medications. One must distinguish however, between an intentional
criminal act and pharmacy compounding.
ASHP has a long history of promoting safe medication use and has
developed practice standards for pharmacy compounding in hospitals and
other components of health systems. We foster the application of those
standards through various articles published in our peer-reviewed,
professional practice journal, and through educational sessions
featured at our clinical meetings.
In an effort to help assure patients receive safe and appropriate
medications, ASHP recognizes the need to collect additional information
about all medication distribution systems, including compounded
preparations. It is important to fit this examination into the proper
regulatory framework.
ASHP strongly supports the current regulatory system, with State
boards of pharmacy regulating pharmacy compounding and the FDA
regulating the manufacturing of drug products. This regulatory
framework is consistent with the way other health professions are
regulated and is effective.
Throughout this testimony we will look at the nature and extent of
pharmacy compounding and the system for regulating this practice. We
will also examine ways to continue to improve the safety of the
medication system.
ORIGINS OF THIS HEARING NOT COMPOUNDING
It is important to note that the origins of this hearing stem not
from the practice of compounding as described below, but rather from
the fraudulent and criminal acts of a Kansas City pharmacist who
intentionally diluted the potency of chemotherapy drugs for his own
economic gain. This pharmacist's actions were inexcusable,
indefensible, and an embarrassment to the profession. His actions are
not representative of the necessary, accurate, and admirable
compounding that pharmacists perform everyday for patients in hospitals
and health systems.
As the committee assesses the adequacy of current regulatory
framework, it must not overlook this fact. The current justice and
regulatory system is well-designed to deal with criminal action.
PHARMACY COMPOUNDING TODAY
The practice of compounding is an important and long-standing
component of the pharmacy profession. In the early days of medicine,
compounding frequently occurred because there were few commercially
available products. Today, compounding allows pharmacists to customize
manufactured products to meet individual patient needs or to create
necessary alternatives to commercially available products.
Compounding occurs when a medication is prepared by combining,
mixing, or altering two or more ingredients, or components, for a
patient based on the receipt of a valid prescription or in anticipation
of prescriptions based on the medication order history from the
pharmacist-physician-patient relationship.
Pharmacists in health system settings generally prefer not to
compound if there is a viable product commercially available, since
compounding requires extra time, staff training, proper equipment, and
other important quality control measures. However, proper patient care
requires the compounding of certain medications. In fact, in hospitals,
many commercially available products require compounding processes to
prepare them for administration.
It is impossible for manufacturers to meet every conceivable
patient need. For example, the variety of doses needed for geriatric
and pediatric patient populations or the customization of intravenous
fluids needed to correct a given patient's blood-chemistry
deficiencies.
Further, manufacturers cannot manufacture certain items. The
classic example of this is a sterile fluid for intravenous feeding of
patients (``parenteral nutrition''). While manufacturers covet this
large potential market, they have not been able to manufacture a stable
product. The moment the necessary concentration of glucose and protein
are mixed together, the ingredients begin to decompose. Parenteral
nutrition has been an established therapy for 35 years, but
manufacturers have not been able to resolve this chemical stability
problem and provide a usable product to the health systems caring for
these patients. Hence, pharmacists (for example in hospitals and home
care) must do the compounding. For many patients, this is literally
life-saving therapy.
Medications are also compounded when a prescriber determines, in
his or her professional judgment, that the use of a compounded
preparation is necessary. For example, when a patient cannot use a
commercially available product due to an allergy to one of the
ingredients--sensitivity to the dye used for coloring, lactose, or
other excipients used in many classes of drugs. Or, when a patient
cannot swallow tablets or capsules and the drug can be transformed into
a liquid, lozenge, suppository, or other form.
The compounding of medications that would not have been otherwise
available has saved many lives. This is thanks to the dedication,
skill, and professional judgment of pharmacists. It is clearly within
the public interest to preserve this important practice.
regulatory oversight of pharmacy compounding is well established
The Federal Food, Drug, and Cosmetic Act of 1938 (FDCA) was created
to regulate drug manufacturing, marketing, and distribution, not
compounding or pharmacy practice. The Food and Drug Administration
Modernization Act of 1997 (FDAMA), which ASHP worked with Congress to
develop, reinforced the legitimacy of pharmacy compounding as a State
regulated activity and clarified the inapplicability of the FDCA to
compounding. Although the compounding provision of FDAMA was overturned
by the Supreme Court in 2002 due to its constraints on advertising,
this should not eliminate the line between Federal and State
jurisdiction.
The oversight of pharmacy practice by State regulatory authorities
is well established. States, through their boards of pharmacy,
determine the education and licensure requirements of pharmacists, as
well as licensure requirements for pharmacies. State boards of pharmacy
have the authority to take disciplinary action, including license
revocation or suspension, against pharmacists for misconduct or failure
to abide by State laws or regulations, including those pertaining to
pharmacy compounding. This is equivalent to the way physicians and
other health care professionals are regulated.
The role of enforcing the application of specific quality assurance
standards in pharmacy practice is one that is well established in law
and in practice for State boards of pharmacy. The FDA recognized this
in its December 28, 1998, draft ``Memorandum of Understanding on
Interstate Distribution of Compounded Drug Products.'' In that document
the agency states that ``the standard MOU also reflects FDA's policy to
defer to State and local officials for the regulation of the day-to-day
practice of pharmacy, to the extent permitted under the Federal Food
Drug and Cosmetic Act.''
The State boards of pharmacy are admittedly at different stages in
their efforts to regulate compounding practice, with some States
aggressively addressing good compounding practice. California, for
example, has adopted regulations establishing standards for compounding
injectable preparations, requiring special licenses for those who
prepare sterile formulations, and increasing investigation of
compounding pharmacies.
Other States may need to continue to strengthen their regulatory
authority of pharmacy compounding. Over the past few years, public
awareness of pharmacy compounding has grown and many States are in the
process of addressing the issue. The National Association of Boards of
Pharmacy (NABP), in a continued effort to provide guidance to the
States, has strengthened its model practice act on compounding.
The United States Pharmacopeia (USP) has also promulgated a revised
chapter on the compounding of sterile products, known as General Tests
and Assays Chapter 797 or ``Pharmaceutical Compounding--Sterile
Preparation.'' Beginning January l, 2004, this chapter could be
enforced by State boards of pharmacy if adopted by State statute or
regulation and cited during visits by FDA and accreditation personnel.
This chapter provides a standard for sterile compounding. The USP also
provides a similar standard on non-sterile compounding.
BUILD UPON THE CURRENT FEDERAL--STATE PARTNERSHIP
Much can be done to build upon the existing Federal--State
partnership to ensure patient safety. For example, ASHP strongly
supports the development and widespread distribution of minimum
standards and appropriate guidance for pharmacists and others on
pharmacy compounding. While ASHP believes State boards of pharmacy are
the appropriate body to enforce compounding standards, the FDA has a
role to play in ensuring that the State boards fulfill this
responsibility through the State adoption of uniform standards. ASHP
believes that it is appropriate for the FDA to suggest to State boards
the standards that the States should apply. This will foster the
establishment of a national quality assurance standard for compounding
in all pharmacy settings, rather than 50 different standards. The use
of both the USP chapters and ASHP guidelines on sterile and non-sterile
compounding, as well as the latest scientific knowledge in the
literature, would provide the assurance the committee is seeking for
the safety and effectiveness of these preparations.
The FDA could also play an important role in bolstering State
enforcement efforts. State boards have limited resources to hire
inspectors and to train them properly. The FDA could offer a training
program for State inspectors enforcing the minimum national standards
for compounding practice. This could be run similar to the Federal
program whereby States receive dollars to help maintain their roads
when the State chooses to enforce the 65 mile per hour speed limit. The
FDA should also have clear procedures for State inspectors to call in
the FDA when activities seem to border on manufacturing.
Finally, it would be beneficial if there was more clarity and
consistency in the definitions of compounding and manufacturing. When
section 127 of FDAMA was overturned, this became less clear. In the
policy compliance guide on pharmacy compounding issued by the FDA in
June 2002, the FDA identified nine factors that it would use
collectively to determine when the scope and nature of activities raise
the kinds of concerns normally associated with drug manufacturing. In
the FDA's revision of the compliance policy guide, it may be helpful if
the FDA provides a definition of what actually constitutes
manufacturing rather than just providing examples of what oversteps the
bounds of ``traditional pharmacy compounding.'' The USP in its draft
chapter 1075, ``Good Compounding Practice,'' also provides a definition
for compounding and manufacturing. The FDA and USP should be encouraged
to coordinate finalization of their respective compliance guides and
chapters so that their definitions and criteria for compounding and
manufacturing are consistent.
CONCLUSION
The existing Federal--State partnership provides a good framework
for regulating medication distribution, including compounded
preparations. This committee should build on the existing framework in
the ways suggested above rather than adding additional Federal
regulatory oversight.
International Academy of Compounding Pharmacists
(IACP),
Sugar Land, Texas 77487,
October 23, 2003.
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, DC 20510.
Mr. Chairman and Members of the Committee: The International
Academy of Compounding Pharmacists (IACP) appreciates the opportunity
to present this written discussion of pharmacy compounding. IACP's
mission includes increasing awareness of the importance of compounding
by providing accurate information. on the benefits of compounding and
providing assistance to pharmacists in improving their compounding
practices. In this capacity, IACP wishes to address a number of issues
relevant to this hearing. IACP submits these comments on behalf of its
1,800 member compounding pharmacists and their pall patients, who
benefit from compounded medications.
The Importance of Compounding
Compounding of medication for patient use has been a fundamental
component of pharmacy practice and healthcare since ancient times.
Compounding is the origin of the practice of pharmacy and has continued
to be a vital element of healthcare throughout the evolution of
pharmacy and medicine.
Pharmacy compounding is traditionally characterized by a physician/
pharmacist/patient relationship, in which professionals work, together
to customize or individualize medications for a patient. Compounding is
performed under the supervision of a pharmacist, who is trained in the
unique knowledge and skill required for compounding during pharmacy
education and is subsequently licensed by State Boards of Pharmacy.
Compounding is defined by the National Association Boards of
Pharmacy (NABP) Model Pharmacy Act as:
Compounding--The preparation, mixing, assembling, packaging, or
labeling of a drug or device (I) as the result of a practitioner's
Prescription Drug Order or initiative based on the pharmacist/patient/
prescriber relationship in the course of professional practice or (ii)
for the purpose of, as an incident to research, teaching, or chemical
analysis and not for sale or dispensing. Compounding also includes the
preparation of drugs and devices in anticipation of Prescription Drug
Orders based on routine, regularly observed prescribing patterns.
Every State authorizes pharmacists to compound.
Compounding may involve a variety of different activities in
different practice settings. Examples of compounding activities include
the preparation of oral liquids, topical ointments, and suppositories;
the conversion of one dosage form into another; the flavoring of
medication to make the medication palatable for a patient; and the
preparation of pediatric dosage forms from adult dosage forms.
Physicians and pharmacists recognize that some individual
healthcare needs cannot be met by commercially available, manufactured,
mass-produced drug products, produced in limited formulations and
strengths. Many patients need customized medications to address
specific medical problems. Manufacturers are unable to tailor-make a
customized medication for a single patient or a small group of patients
in an efficient and cost effective manner. Without compounding in these
cases, patients would be forced to forego their medications or to
substitute a product that may not meet their medical heeds.Compounding
pharmacists work in their communities, alongside the physicians who
write prescriptions for compounded medications, as problem solvers to
meet these unique needs.
Compounding provides life-saving therapy to many classes of
patients who would otherwise be unable to obtain necessary medications.
Pediatric or geriatric patients may need extremely small dosages. The
American Pharmacists Association (APhA) has reported an. estimate that
more than 40 percent of doses given in pediatric hospitals require
compounding to prepare a suitable dosage form. Further, compounding
pharmacists provide therapy for many hospice patients nearing the end
of their lives, who can no longer benefit from curative treatment and
generally have a life expectancy of six (6) months or less. Many of
these patients can no longer swallow their pills; for others,
commercial doses are inadequate. Compounding pharmacists help to
develop drug therapy programs that minimize pain and symptoms for
hospice patients and work to enhance the quality of life for hospice
patients in their final days. In addition, patients may be allergic to
specific ingredients in a commercially available product. Compounding
pharmacists can work with physicians to alleviate this problem by
omitting the problematic ingredient in a formulation or by customizing
a similar medication to meet the patient's need.
In sum, compounding is a critical component of pharmacy and
healthcare. Indeed, just last year the U.S. Supreme Court, in the
Thompson v. Western States Medical Center case, acknowledged the
importance of compounding.
How Does Compounding Differ From Manufacturing?
The NABP Model Pharmacy Act defines manufacturing as:
Manufacturing--The production, preparation, propagation, conversion
or processing of a Drug or Device, either directly or indirectly, by
extraction from substances of natural origin or independently by means
of chemical or biological synthesis, and includes any packaging or
repackaging of the substance(s) or Labeling or relabeling of its
container, and the promotion and marketing of such Drugs or Devices.
Manufacturing also includes the preparation and promotion of
commercially available products from bulk compound for resale by
pharmacies, Practitioners, or other Persons.
The fundamental difference between compounding and manufacturing is
the presence of a physcian/pharmacist/patient relationship, which
controls the preparation and distribution of a compounded drug
medication. Pharmacy compounding is performed at the pharmacy site for
nearly immediate dispensing or administration to the patient.
Compounded medications are not offered for resale, but instead are
customized to meet a patient's specific medical needs. The profession's
definition of compounding does not encompass the preparation of massive
amounts of a drug product with the purpose of distribution to a mass
market of unknown users in unknown venues. Instead, the pharmacist
directly interacts with the patient and is available to advise patients
on characteristics and use of a compounded medication. Pharmacists,
unlike drug manufacturers, offer counseling to patients. Based on this
relationship between pharmacist and patient, a pharmacist may often
monitor a patient's reaction to a compounded medication and advises
patients to immediately report adverse reactions.
This relationship between the compounding pharmacist and the
practitioner provides an appropriate system of checks and balances to
ensure that the patient's health is protected and served. A legally
compounded medication by a pharmacist is authorized by a prescription
from a physician. The pharmacist acts as a valuable resource for
determining the customized elements of a compounded medication such as
dosage formulation, drug compatibility, etc., to meet the patient's
needs and to facilitate prescribe-intended outcomes. The pharmacist may
also refuse to dispense a prescription that requires compounding of a
drug which is not appropriate for that patient or cannot be compounded.
The relationship between physician, pharmacist, and patient likewise
provides an appropriate level of checks and balances to ensure patient
care.
Manufacturing, on the other hand, involves the production of
batches of drug products consisting of millions of dosage units, such
as tablets or capsules, for resale. Manufactured products are
distributed through the normal chains of interstate commerce to
individuals unknown to the company. Manufacturers are not required to,
and do not, monitor individual patients' response to medications or
answer patient questions.
The Robert Courtney Case
It is important to note that reconstitution, the pharmacy practice
engaged in by Robert Courtney, is a practice that is generally not
considered to be compounding. The oversight actions initiated by
Senators Bond and Roberts, including this hearing, stem from
understandable concerns about the criminal activity and professional
misconduct of Robert Courtney, a former pharmacist in Kansas City, MO.
Courtney intentionally diluted the potency of cancer drugs over a
sustained period of time for profit and, as a result of these criminal
activities, has been convicted and imprisoned. IACP condemns the
actions of Courtney. However, we strongly believe that Courtney's
actions cannot be extrapolated to represent the profession of pharmacy
in general, or more importantly, compounding pharmacy, While Courtney's
actions were reprehensible, it is important to note that his actions
were the actions of one individual and should not be used to judge the
thousands of pharmacists that practice in this country. Pharmacists are
highly committed to the care of their patients and compliance with high
professional and ethical standards. The Courtney case should not prompt
Congress to challenge the integrity or oversight of the profession of
pharmacy.
Reconstitution of a commercial product according to the
manufacturer's FDA-approved instructions, a routine practice virtually
every hospital and the action performed by pharmacist Robert Courtney
in preparing chemotherapy products, is not considered to be
``compounding.'' Congress, in the Food and Drug Administration
Modernization Act of 1997 (FDAMA), specifically exempted from its
definition of compounding ``reconstituting . . . that [is] performed in
accordance with directions contained in approved labeling provided by
the product's manufacturer and other manufacturer directions consistent
with that labeling.'' Further, the FDA's current approach to oversight
of compounding practices, its Pharmacy Compounding Compliance Policy
Guide (CPG), does not address reconstitution. According to broadly
accepted definitions, Robert Courtney's criminal activities would not
be identified as compounding. Courtney's illegal acts in no way provide
justification for imposing new restrictions on compounding.
How is Compounding Regulated?
Since compounding is a traditional component of the practice of
pharmacy, compounding is appropriately regulated by State Boards of
Pharmacy. The State Boards of Pharmacy and standard-setting
organizations such as the U.S. Pharmacopeia (USP) and the National
Association of Boards of Pharmacy (NABP) have effectively regulated the
practice of. compounding pharmacy for many years.
A majority of the State Boards of Pharmacy have regulations in
place that specifically address compounding practices. In addition,
many States have recently revised or are currently updating their
compounding regulations. As part of its Model Pharmacy Act, NABP also
has made model Good Compounding Practices (GCPs) available to State
Boards of Pharmacy as a template for compounding regulations. Further,
the United States Pharmacopeia has recently revised four guidance
chapters on pharmacy compounding: Chapter 795, Pharmaceutical
Compounding--Nonsterile Preparations; Chapter 797, Pharmacy
Compounding--Sterile Preparations; Chapter 1075, Good Compounding
Practices; and Chapter 1161, Pharmaceutical Calculations in
Prescription Compounding.
In 1997, Congress addressed the practice of pharmacy compounding in
the Food and Drug Administration Modernization Act (FDAMA). In this
Act, Congress recognized compounding as a vital healthcare service that
must be preserved, leaving the role of the State boards as its
regulators intact. The subsequent decision by the Supreme Court to void
the Act was premised on the lack of a severability clause and the
unconstitutionality of constraints on commercial free speech. In view
of the Court's decision, FDA is now in the process of refining its CPG,
which would articulate its views on Federal jurisdiction.
The Roles of State and Federal Regulatory Bodies in Compounding and
Manufacturing
Drug manufacturers are regulated, among other entities, by the U.S.
Food and Drug Administration (FDA) under the authority of the Food,
Drug, and Cosmetic Act of 1938 (FDCA). The provisions of the FDCA have
been designed to prevent the production of ineffective or dangerous
manufactured drugs and their introduction into commerce.
The FDCA and the processes it requires were designed to address
situations where a drug product would be developed, approved as to its
safety and efficacy, marketed throughout the United States, and
ultimately dispensed to patients with whom the manufacturer has had no
contact. There is an obvious distinction between a manufactured drug
and a compounded medication. A compounded medication is one that is
formulated for a specific patient need, such as an allergy to an
ingredient, that cannot be met by a mass manufactured drug.
In short, FDA regulates manufacturing of medications, while State
Boards of Pharmacy regulate pharmacy practices, including the
compounding of medications. FDA should work with State Boards of
Pharmacy and pharmacy organizations to develop the distinction between
pharmacy compounding and manufacturing. However, compounding
pharmacists must not be subject to regulation by FDA under the FDCA and
must, instead, remain within the regulatory control of State Boards of
Pharmacy. There has been no evidence shown to support federalization of
pharmacy oversight.
Quality Assurance for Compounded Medications
The quality of compounded medications can be assured through
adequate State and self-regulation of compounding practices, training
and other mechanisms. While there have been some compounding pharmacies
that have had significant quality problems they represent a small
minority. The overwhelming majority of compounded medications meet
these quality standards. Nevertheless, IACP and the pharmacy profession
arc committed to improving quality and training.
Initially, we must assist State Boards of Pharmacy in assuring that
they have regulations that address the practice of compounding. Most
States already have regulations in place or are in the process of
developing regulations. However, we must assist the few Boards of
Pharmacy that do not have regulations for pharmacy compounding in
either adopting the NABP Good Compounding Practices (GCPs) or in
crafting their own regulations. Further, we must ensure that State
Boards of Pharmacy have the funding required to monitor compounding
practices in their States and to enforce compounding regulations.
Providing necessary resources and fiscal support to State Boards of
Pharmacy is essential for assuring the quality of compounded
medications.
In addition, the United States Pharmacopeia has developed
guidelines that help to ensure the quality of compounding medications.
Pharmacists' knowledge of and adherence to the guidelines will result
in continuous quality improvement of compounded preparations.
Personnel education is also an essential factor in compounded
medication quality. In recent years, there has been tremendous growth
in the availability of American Council of Pharmaceutical Education
(ACPE) accredited education programming related to quality compounding
pharmacy practice. We must work together to increase and enhance such
programs.
Finally, IACP is currently leading efforts to develop profession-
driven, comprehensive standards of practice for compounding with the
goal of educating compounding pharmacists on best practices and
processes that can be used to ensure quality compounded medications for
patients. We are also developing an accreditation program for
pharmacies where compounding occurs. Such an accreditation program
would assess and improve compliance to standards of practice.
These combined factors will effectively address the quality of
compounded medications.
IACP appreciates the opportunity to share this testimony with the
Senate HELP Committee. If we can be of any assistance, or if you have
any questions, please do not hesitate to contact me at (281) 933-8400.
Respectfully submitted,
L.D. King,
IACP Executive Director.
______
International Academy of Compounding Pharmacists,
Sugar Land, TX 77487,
October 30, 2003.
Hon. Judd Gregg,
Chairman,
Committee on Health, Education, Labor and Pensions ,
U.S. Senate,
Washington, DC 20510.
Dear Chairman Gregg: During the Thursday, October 23 hearing,
``Federal and State Role in Pharmacy Compounding and Reconstitution:
Exploring the Right Mix to Protect Patients,'' hearing chairman Senator
Kit Bond indicated his intent to keep the record open to receive
supplemental remarks. The International Academy of Compounding
Pharmacists (IACP) would greatly appreciate your incorporating the
following into the hearing record.
Mr. Chairman, you are likely to have been aware of our concerns
about the witnesses invited to testify and the committee's need to
receive a balanced viewpoint. Several witnesses were predictably
hostile toward compounding; however, most notable were the comments of
others. The General Accounting Office (GAO) observed ongoing efforts at
the State-level (through State boards of pharmacy) and national-level
(through professional organizations) that should provide confidence to
the committee that significant steps are underway to strengthen
oversight of compounding. The Food and Drug Administration, while
chastised for its use of a limited survey to convey anecdotal
information critical of compounding, nonetheless acknowledged continued
deference to the States' enforcement. While we may disagree on some of
the specific statements they made, we are heartened by both agencies'
acknowledgement of the unique and beneficial role that pharmacy
compounding plays in the Nation's health care.
Three areas of discussion at the hearing, however, require IACP's
supplemental comments:
1. Reference was made to a provision in pending Medicare drug
benefit legislation that would create an advisory committee at FDA to
examine pharmacy compounding. We continue to oppose this provision and
note that the hearing produced little evidence to alter this
perspective. If anything, acknowledgement of the predominant States'
role and efforts underway to improve regulation at the State level call
for continued deference to the States and not, as the amendment
suggests, imposition of Federal authority over what has been the
States' task. As the GAO pointed out, a number of States also have new
initiatives to tighten regulations. The examples cited by the GAO are
not unique, for example, California recently implemented new
regulations and Texas is in the process of adopting new regulations.
Further, IACP believes that the advisory committee is an inefficient
use of FDA resources and energies, particularly when there has been
little justification for Federal intervention. This is particularly
true at a time when FDA needs to expend its resources regulating
illegal internet pharmacies and drug diversions. FDA should not divert
its resources to pharmacy practices that are already licensed and
regulated by the States.
2. IACP asks the committee to take note of the relatively limited
number of adverse events (GAO estimates 200 over the past several
years) compared to the 30 million estimated compounded prescriptions
dispensed each year. While we are concerned about the adverse events
that have occurred and are taking steps to prevent future occurrences,
it is also important to note that compounding pharmacy has a strong
overall safety record. All observers have acknowledged the paucity of
hard data relating to compounding. Regulatory bodies (State or Federal)
would have to redirect energies and resources at a ``problem'' where no
analytic data exists to show a troubling incidence of unreported
events. While we believe compounding can be improved, and we are
working toward that goal, the low incidents of adverse events do not
justify requiring a new reporting system.
IACP believes that adverse event reporting is better accomplished
by the national professional organizations who have an ability to
assess information and then develop informational and educational
resources to address any problematic trends that are identified. IACP
would direct your attention to a voluntary reporting system established
by U.S. Pharmacopeia (USP) in the 1990s--``MedMaRX.'' This adverse
reporting mechanism exists today, although it would require greater
visibility and participation by professional pharmacists. IACP views
this or a comparable system developed by national professional
organizations as a credible alternative. We hasten to add that any
system must be voluntary, primarily because it is critical for
pharmacists, physicians, and patients first to assess whether an
adverse event has in fact occurred. The routine, mandatory and
uncritical reporting of all possible such events will inundate the
system, which will become so overloaded with raw data that it would
have little practical value.
Further, capturing adverse events is an issue that the entire
pharmaceutical industry is working to address. It is commonly
understood throughout all of healthcare that we must do a better job of
capturing data related to adverse events. Likewise, compounding
pharmacy practice is not unique in this venue.
3. Several Senators and witnesses commented on whether there is a
lack of clarity on FDA's regulatory authority. For example, some asked
if there should be a ``bright line'' separating compounding from
manufacturing. Also, others noted areas within the Compliance Policy
Guide (CPG) that are seen as overly vague.
IACP believes that there is a process within FDA that is entirely
appropriate to resolve these criticisms. Let us note for the record
that IACP has been a stern critic of the current CPG. We have sought
substantial change. We are, however, willing to let this process
continue. At the hearing, FDA committed to responding to the comments
it had received. We believe that FDA's internal review process should
be completed before Federal legislation is contemplated.
Mr. Chairman, IACP greatly appreciates your consideration of our
views. We look forward to working with you constructively in developing
the appropriate balance between Federal and State jurisdiction.
Sincerely,
L.D. King,
IACP Executive Director.
______
Prepared Statement of the American Pharmacists Association
Good morning. Thank you for the opportunity to appear before you
today and present the views of the American Pharmacists Association. I
am Dan Herbert, a pharmacist and the President-elect of APhA. I have
been in practice for 37 years and currently own three community
pharmacies in Richmond, Virginia. Founded in 1852 as the American
Pharmaceutical Association, we are the largest national pharmacist
organization in the United States, representing more than 53,000
practicing pharmacists, pharmaceutical scientists, student pharmacists
and pharmacy technicians. APhA members practice in virtually every area
of pharmacy practice, including independent and chain community
pharmacy, hospital pharmacy, nuclear pharmacy, long term care pharmacy,
home health care and hospice.
Let me first provide APhA's support of the committee's goal that
patients receive safe and effective medications. As pharmacists, we
rely upon quality products as the first step in our work to help
patients make the best use of their medications. When providing a
quality product involves tailoring a medication for an individual
patient, we use our scientific training and education to compound the
medication.
Compounding medications is an important component of pharmacy
practice--mine and that of my colleagues. While it is challenging to
quantify the actual number of APhA's members who engage in drug
compounding activities on a regular basis, virtually all practicing
pharmacists will be involved with compounding activities at some point
during their career--and most practitioners engage in some element of
compounding in each week of practice. APhA has a compelling interest in
helping pharmacists, in collaboration with practicing physicians,
compound drug formulations to meet the needs of patients. Our
compounding activities are a critical component of the American health
care system, allowing physicians to prescribe medication therapy to
best meet the needs of their patients.
My comments today will provide a brief history of pharmacist
compounding, a description of the important role it plays in our health
care system, the challenging task of distinguishing between compounding
and manufacturing, and ways in which we can attempt to appropriately
protect our patients by improving the quality of practice and
identifying and stopping ``bad actors''.
Compounding: A Traditional Component of Pharmacy Practice
Compounding is a traditional component of pharmacy practice; only
the drugs, dosage forms, and equipment or techniques have changed as
pharmacy practice has advanced. As noted in the Chronicles of Pharmacy,
``[p]harmacy, or the art of selecting, extracting, preparing and
compounding medicines from vegetable, animal, and mineral substances,
is an acquirement that must have been almost as ancient as man himself
on earth.'' The early practice of pharmacy required the compounding of
virtually all medications, because there were few, if any, commercially
available products. The need for compounded products has diminished
with the founding of pharmaceutical companies, although the need for
this practice still exists today. Because the preparation of an
extemporaneous pharmaceutical dosage form is not a trivial exercise,
our position is that when an FDA-approved, commercially available
product can meet a patient's needs, it should be employed as the
preferred course of action. However, when a patient's particular
situation obviates the use of commercial products, the knowledge and
skills of a compounding pharmacist can be extremely valuable, even
lifesaving.
It is a fundamental responsibility of the pharmacy profession to
extemporaneously compound quality prescription products for patients
who have unique medication needs. Through their education and
licensure, pharmacists assume an ethical obligation to the public to
maximize the intended benefits of drug therapy while minimizing the
unintended side effects and adverse reactions. Some Sates require
licensed pharmacies to offer compounding services [see 49 Pa. Code
27.18(p)(2) (2003);W. Va. Code St. R. 15-1-19.4 (2003)]. Compounding
enables pharmacists to use their knowledge and expertise of medication
use to produce individualized medications that meet patient needs and
improve health outcomes. Without compounding, pharmacists and
physicians would be limited to a ``one size fits all'' strategy, which
would have a direct, immediate, negative impact on the ability of
health care providers to provide care to patients.
Compounding Necessary for Many Patients
As I stated earlier, it is challenging to quantify the actual
number of pharmacists who engage in drug compounding activities on a
regular basis, virtually all practicing pharmacists will be involved
with compounding activities at some point. The unique knowledge and
skill set of pharmacists enables them to extemporaneously compound
medications to individualize patient care through the preparation of
patient-specific products.
Compounding allows pharmacists and physicians to address the health
care needs of patients who do not fall within the range of commercially
available dosage strength and formulations. Patient needs vary from
extremely small doses and specific combinations of drugs, to
preservative-free products, to liquid dosage forms, to delivery systems
that are not commercially available. In many situations, large-scale
manufacturers are unable to tailor-make a medication in a cost
effective manner. Without compounding, many patients would not have
access to the correct combination of ingredients, the appropriate dose
and dosage form, or the best delivery system.
In addition to unique patient needs, manufacturing and market
limitations may require medications to be compounded. For example, some
therapies, such as hyaluronidase injection (used as an adjunct to
ophthalmologic surgery) must be compounded because the therapies
generate insufficient revenue to pharmaceutical companies to justify
large-scale manufacturing. Other medications, such as radioactive drugs
used to diagnose or treat cancers or other diseases, must be compounded
because they do not have sufficient ``shelf life'' to withstand the
commercial distribution process and therefore need to be prepared at
the time of dispensing. And finally, many manufactured ``finished
pharmaceutical'' products are only ``finished'' in the sense of being
ready to ship and then store in the pharmacy. These products must still
be compounded, or in some cases merely reconstituted, by the pharmacist
to provide a dosage form suitable for a patient's treatment.
Compounding involves different activities in different pharmacy
practice settings. It may mean the preparation of oral liquids,
topicals, or suppositories; the conversion of one dose or dosage form
into another; the preparation of specific dosage forms from bulk
chemicals; the preparation of intravenous admixtures, parenteral
nutrition solutions, or pediatric dosage forms from adult dosage forms;
the preparation of radioactive isotopes; or the preparation of
cassettes, syringes, and other devices with drugs for administration in
the home setting. Examples of some of the most common compounded
products include lotions, ointments, creams, gels, suppositories,
intravenously administered fluids and medications, total parenteral
nutrition products, and oral suspensions.
Although compounding may be required in any pharmacy practice
setting and for any type of disease, there are concentrations of
compounding practice. For example, due to the nature of the care they
provide, hospital pharmacies have historically had a strong compounding
component to their practice. And due to the nature of the disease and/
or the patient size or age, compounding frequently occurs for patients
with cancer, for pediatric care, and for hospice care.
Compounding in the hospital setting is a vital service that
addresses the unique needs of patients requiring highly individualized
medications. The primary compounding activity in hospitals is the
preparation of intravenous admixtures ranging from simple fluid
replacement to the delivery of complicated, individualized chemotherapy
regimens. Because daily intravenous therapy is provided through
compounding of medications, nearly every person who has ever been
admitted to a hospital--and those who will be admitted today and likely
in the future--has received a compounded medication. In fact, the
immediate availability of extemporaneous compounding by a pharmacist
provides the hospital physician with literally any form or strength of
medication needed for a patient's specific needs.
Cancer patients frequently benefit from compounding pharmacists'
knowledge and skills. Almost all chemotherapy involves drugs and drug
combinations that are compounded, or at least reconstituted, by
pharmacists. It is imperative that a patient receive the correct drug
dosage based upon the patient's body size, the type of cancer, the size
and type of tumor, and the clinical condition of the patient including
their kidney and liver function. This can often only be accomplished by
using compounded, patient-specific medication preparations.
The compounding of pediatric dosage forms has also been an area of
extensive activity, because many drugs used to treat children are only
available in adult dosage forms. As the committee is aware, finding the
right drug, dose and dosage form to treat sick children is a
complicated task. This committee has made great strides in establishing
incentives to improve the utility of manufactured products in treating
children, but frequently, compounding is the only available avenue to
achieve the desired clinical outcomes. Commercially manufactured
products for adult use must be modified and compounded for use in
children. It has been estimated that more than 40 percent of doses
given in pediatric hospitals require compounding to prepare a suitable
dosage form. Indeed, utilization of compounded medications is essential
for the provision of medical care to hospitalized children.
As the committee is aware, hospice programs provide care for
patients near the end of their lives who can no longer benefit from
curative treatment and generally have a life expectancy of 6 months or
less. Patients suffering from incurable cancer have very special needs.
Relief of pain near the end of life is an important element of
maintaining the dignity and comfort of a dying patient and their loved
ones. Hospice pharmacists often use compounded medications to alleviate
pain and to control nausea and vomiting for patients in the hospice
setting. A problem for many hospice patients is that pain medications
are not manufactured in the required dosages. If commercial products
that provide the precise dose(s) required are not available, the
hospice pharmacist can often remedy the situation by extemporaneously
preparing an individualized product. Additionally, some patients are
not physically capable of swallowing the number of commercially
manufactured tablets or capsules required or cannot take medications
orally. A pharmacist can address these issues by either compounding a
stronger product, by transforming tablets or capsules into a liquid, or
by creating a preparation that can be applied topically or delivered
rectally.
Continuous Quality Improvement
Pharmacy compounding conforming to the highest possible
professional standards is essential to optimal patient care. But
maintaining quality and advancing practice requires the profession to
be vigilant, and continually improve our professional standards and
regulatory efforts. One question that continues to plague the
profession and our regulators--the State boards of pharmacy--is how to
distinguish between compounding and manufacturing; with one practice
regulated by State boards of pharmacy and the other process, by the
Food and Drug Administration.
Compounding has traditionally been characterized by the triad
relationship of the physician, pharmacist and patient; working together
to individualize care for maximum patient benefit. Pharmacy compounding
is performed in response to a prescription from a licensed prescriber,
or in preparation for a reasonably anticipated prescription, based upon
prior experience and expected needs of individual patients.
APhA supports the National Association of Boards of Pharmacy's
(NABP) definition of compounding, which states:
Compounding--The preparation, mixing, assembling, packaging, or
labeling of a drug or device (i) as the result of a practitioner's
Prescription Drug Order or initiative based on the pharmacist/patient/
prescriber relationship in the course of professional practice or (ii)
for the purpose of, as an incident to research, teaching, or chemical
analysis and not for sale or dispensing. Compounding also includes the
preparation of drugs and devices in anticipation of Prescription Drug
Orders based on routine, regularly observed patterns. [emphasis added]
(Good Compounding Practices Applicable to State Licensed Pharmacies,
Subpart A. Park Ridge, IL:NABP, 1993.)
The profession's definition of compounding does not encompass the
preparation of massive amounts of a drug product with the contemplation
of distribution to a mass market of unknown users in unknown venues.
Rather, the definition supports our assertion that the purpose of
pharmacist compounding is to prepare an individualized drug treatment
for a patient based on an order from a duly licensed prescriber.
Manufacturing, on the other hand, is defined by NABP as follows:
Manufacturing--The production, preparation, propagation, conversion
or processing of a Drug or Device, either directly or indirectly, by
extraction from substances of natural origin or independently by means
of chemical or biological synthesis, and includes any packaging or
repackaging of the substance(s) or Labeling or relabeling of its
container, and the promotion and marketing of such Drugs or Devices.
Manufacturing also includes the preparation and promotion of
commercially available products from bulk compound for resale by
pharmacies, Practitioners, or other Persons. (Id.)
As clear as this difference may seem to the profession of pharmacy,
it has been a difficult distinction to implement because of the
complexity and range of legitimate compounding activities. In public
comments, even the Food and Drug Administration has suggested that the
difference between compounding and manufacturing is better represented
by the intersection of two jagged jigsaw puzzle pieces rather than a
straight line.
The fundamental difference between compounding and manufacturing,
and the key element in making any such distinction, is the existence of
a pharmacist/prescriber/patient relationship. This triad should control
the preparation of a drug product. Furthermore, compounded drugs are
not for resale, but rather, are personal and responsive to a patient's
immediate needs. Conversely, drug manufacturers produce batches
consisting of millions of tablets or capsules at a time for resale,
while utilizing many personnel and large scale manufacturing equipment,
without knowledge of the specific patient who will ultimately consume
them.
There are numerous factors to consider in distinguishing the FDA-
regulated practice of manufacturing from the State-regulated practice
of compounding. Such factors--though none is exclusive--include the
volume of compounding by a particular pharmacist or pharmacy, the
number of different products being compounded, the scope of the
pharmacist's and pharmacy's practice, and of course, the presence of
individual prescriptions for each compounded product.
Ongoing Activities; Opportunities for the Future
As professionals, pharmacists continually strive to provide the
best patient care possible, including continuous review of practices
and taking steps to improve medication use and advance patient care.
While some may assert that little is being done to advance and improve
pharmacist compounding, they are mistaken. APhA publishes resources for
pharmacists to improve the practice, including The Art, Science and
Technology of Pharmaceutical Compounding and Trissel's Stability of
Compounded Formulations. And I am currently chairing an APhA committee
setting strategic directions for the profession--including compounding.
In our year of meetings, we have proposed some steps for advancing
compounding practice as part of our commitment to providing safe and
effective pharmaceutical care to the citizens of this country.
One aspect of our committee's work to date is the preliminary
categorization of compounding to distinguish the types of compounding a
pharmacist should be prepared to provide based on our pharmacy
education and training, from the types of compounding that may require
enhanced education or perhaps accreditation or certification processes.
Because compounding encompasses a broad scope of activities--from the
preparation of rather simple lotions for application to the skin to the
preparation of radiopharmaceuticals for injection imaging, this
categorization is important in focusing quality improvement efforts and
resources. Our committee is also considering a proposal that
pharmacists identify all compounded products for patients, so that
patients understand that they will be using a non-commercially
available product prepared specifically for their needs.
Other groups are pursuing efforts to improve pharmacy compounding
practice as well. The United States Pharmacopeia (USP), the official
drug standard setting body for our country, has a long history of
addressing pharmacy compounding, especially in the area of sterile
preparations. Various State boards of pharmacy are exploring changes in
statute and regulation to more clearly articulate the boundaries of
practice for pharmacists in their jurisdiction. In my home State of
Virginia, legislation passed in the 2003 session made changes to our
compounding requirements. Specifically, the legislation clarified that
compounded products be prepared and dispensed pursuant to a
prescription and in the context of a bona fide practitioner-patient-
pharmacist relationship; or in expectation of receiving a valid
prescription based on observed prescribing patterns. All compounded
products must be labeled and include a beyond-use date. In addition, a
pharmacist is required to maintain and comply with a policy and
procedure manual if their practice involves compounding products that
are at high risk for contamination, radiopharmaceuticals, or dose-
critical or specialized preparation dosages.
And APhA and other representatives of the profession of pharmacy
are evaluating the issue and proposing solutions as well. In
collaboration with the National Association of Boards of Pharmacy and
the United States Pharmacopeia, our groups have recommended exploring
the value of voluntary programs to improve compounding activity in
certain categories. For example, should pharmacists engaged in
compounding complex sterile products--such as those prepared from non-
sterile bulk chemicals--have their pharmacy practice complete a site
accreditation process to assess the policies and procedures employed?
Should pharmacists engaged in other complex compounding activities
complete specific training and education programs, or even an
individual certification process to demonstrate their knowledge and
skills? While this work is early in development, we are making progress
and will continue our work to assure that patients get the compounded
medications they need, at the level of quality they should expect.
Improving our efforts to provide quality compounded products will
require collaborative efforts of consumers, the profession, State
boards of pharmacy, and the FDA. Each stakeholder has an expertise that
is essential in assuring the continued availability of this practice
with the quality patients deserve. Consumers must play a role in all of
our efforts, as we are pursuing this work for them. The profession must
take the lead in guiding the regulatory agencies in how to draw the
line between compounding and manufacturing, and in developing
guidelines and voluntary accreditation or certification processes to
demonstrate compliance with those guidelines. The State boards of
pharmacy, responsible for regulating the profession, should maintain
their primary regulatory role of pharmacy practice, including
compounding, and will likely be tasked with new initiatives to enhance
current regulatory efforts. The FDA has a role in regulating
manufacturers, as well as defining some broad guidance, such as the
identification of substances that should not be used in manufacturing
or compounding because the substances have been withdrawn from the
market for safety and efficacy concerns. All of these efforts require
collaboration, coordination, and ongoing communication.
Through compounding, pharmacists fulfill a legitimate and essential
need --providing patients with medications tailored to their needs. The
professional education and training of pharmacists provides the unique
knowledge and skills necessary to fulfill this health care need. The
profession continues to research the most stable and appropriate
mechanisms to produce compounded products, utilizing available and
emerging technologies. By working together, prescribers and pharmacists
help patients access otherwise unavailable therapies such as cream for
breast cancer patients' radiation burns, or anticonvulsants in a
suppository form when patients' veins are not accessible for injection.
Without compounding, many physicians, pharmacists and patients would
lose access to valuable treatments.
APhA supports the committee's efforts to discuss this important
issue. Pharmacist compounding improves patients' lives every day, but
we must continually improve our practices to provide the best patient
care. Pharmacists are ready to partner with stakeholders to develop
effective strategies to improving the quality of compounding practices.
APhA appreciates the opportunity to share the perspective of
pharmacists on this issue.
American Pharmacists Association, APhA,
Washington, DC 20037-2985,
January 15, 2004.
Hon. Judd Gregg,
Chairman,
Health, Education, Labor, & Pensions Committee,
U.S. Senate,
Washington, DC 20510.
RE: October 23, 2003 Hearing, ``On Federal and State Role in Pharmacy
Compounding and Reconstitution: Exploring the Right Mix to
Protect Patients''
Dear Chairman Gregg: Thank you for providing the American
Pharmacists Association (APhA) the opportunity to present its views at
the October 23, 2003 Health, Education, Labor, and Pensions (HELP)
Committee hearing on Pharmacy Compounding. At the hearing, interested
parties were invited to provide additional input on several questions
by January 15, 2004. This letter responds to those questions and
further details AMA's support for quality pharmacy compounding.
The practice of compounding is an important and long-standing
component of the pharmacy profession. It has always been a basic part
of pharmacy practice, beginning with the early practice of pharmacy,
which required the compounding of virtually all medications because
there were few, if any, commercially manufactured products. The need to
compound continues. Today, pharmacists compound alternatives to
commercially available products or modify a manufactured product by
adjusting the dose, changing the form of the drug (e.g., tablet to a
liquid), or preparing an alternative that does not contain offending
preservatives, dyes, or other allergens. Compounding allows a
pharmacist to tailor a medication to an individual patient's needs.
Question 1. How does one define the line between compounding and
manufacturing? Regarding that defining line, what inspection and
enforcement authorities does the U.S. Food and Drug Administration
(FDA) need?
Answer 1. APhA supports compounding, pursuant to or in anticipation
of a prescription or diagnostic preparation order, as an essential part
of health care. A patient/physician/pharmacist triad is the essential
element distinguishing between compounding and manufacturing. Pharmacy
compounding is performed in response to a prescription from a licensed
prescriber, or in preparation for a reasonably anticipated prescription
based upon prior experience and expected needs of individual patients.
State Boards of Pharmacy must continue their role as the regulatory
authority for pharmacy practice. When and if a State Board, through its
own investigative process, determines that a pharmacy is manufacturing,
then the FDA should get involved. The FDA's current inspection and
enforcement authority is sufficient.
Question 2. Is there large-scale compounding that warrants more
active regulation by the FDA? If so, would you recommend regulation
short of regulations as a manufacturer? And if so, what would you
recommend?
Answer 2. The primary factor distinguishing compounding from
manufacturing is the existence of a physician/patient/pharmacist triad
that includes a prescription or the expectation of a prescription based
on prior experience with the pharmacist's patient base. For example, a
pharmacy may serve a large population requiring a certain type of
medication, but a proportion of that same population may also be
allergic to a specific ingredient in the commercially available
product. By responding to the individual patients' needs, the
pharmacist may have a high volume of compounding, but that activity is
performed on a case-by-case basis in response to a prescription.
Manufacturing, by contrast, involves the mass production of thousands
of dosage forms with no connection between the producer of the
medication and the ultimate user. No volume of compounding warrants
more active regulation by the FDA, as all compounding in response to a
specific patient prescription, within the physician/patient/pharmacist
triad remains within the realm of pharmacy practice.
Question 3. Dr. Sellers included a proposal of Federal legislation
enhancing the regulation of compounding. Please comment on her
proposal. What portion of her proposal do you believe must be
accomplished at the Federal level and what portion can safely be
achieved at the State level?
Answer 3. Dr. Sellers' proposal includes the following
recommendations: disclosure to prescribers and patients that compounded
drugs are not FDA-approved and advise consumers of alternative FDA-
approved products; include a disclaimer on all compounded drug
containers; require that prescribers be notified before a compounded
product is dispensed; prohibit compounding of drugs too difficult to
compound because of safety reasons; and require strict pedigree
requirements for all chemicals used in compounding.
APhA recommends that pharmacists communicate with patients about
their use of compounded medications, and that the compounded product
should be designated as such on the product label. For example,
pharmacists could include the statement, ``This medication was
specifically compounded for your use at the direction of your doctor.''
Such a requirement could be incorporated into State law. We do not
support Federal legislation requiring pharmacists to inform patients of
alternative FDA-approved products. Pharmacists compound only at the
request of a prescriber, in response to a prescription for an
individual patient (or in anticipation of a prescription based upon the
pharmacist's experience). The prescriber, through the specifications of
the prescription they issue, is aware that the pharmacist will need to
compound the special formula; it is through their direction that the
compounding is performed. Because the preparation and dispensing of the
compounded product is driven by the patient/prescriber/pharmacist
relationship, the evaluation of alternative, commercially manufactured
products has already occurred.
Similarly, a Federal law requiring notification of the prescriber
before a compounded product is dispensed is redundant and unnecessary.
Compounding is performed at the direction of the physician or other
prescriber, and is directed by that practitioner's prescription.
Prescriptions for a commercially available manufactured product may not
be randomly converted by pharmacists to prescriptions for compounded
medications. Enactment of a Federal regulation prohibiting this
practice would not change that reality.
The development of a list of medications that should not be
compounded maybe appropriate, although the list must be developed
through a collaborative process of stakeholders, including patients and
pharmacists: Additionally, the list would need to be updated
periodically to reflect advances in technology and compounding pharmacy
practice.
The pedigree recommendation is intriguing, and may be appropriate.
As outlined in our November 3, 2003 comments to the FDA on their Anti-
Counterfeit Drug Initiative (Attachment A), APhA recognizes the value
of requiring documentation of prescription drug distribution
transactions and agrees that pedigrees, in concept, may be an
appropriate tool to track prescription drugs from manufacturer, to
wholesaler/distributor, to pharmacist. Recognizing the need: for
enhanced technology to assure the validity of such a pedigree and to
protect against the opportunity to counterfeit a paper pedigree, we
would support a pedigree system for products used in compounding where
the benefit of such a system is documented.
Question 4. Is it legitimate for a pharmacist to dispense a
compounded drug if the prescriber has not indicated in the prescription
that a specially compounded drug is required by the patient, or if the
pharmacist has not verified with the prescriber that it is appropriate
to dispense a compounded product?
Answer 4. No. This question appears to assume that compounding
occurs absent prescriber direction. Pharmacists compound within the
physician/patient/triad, in response to a prescriber's request. When a
physician prescribes a medication and designates that a certain
ingredient be excluded because of a patient's allergy, for example, the
physician is indicating the need for a compounded product. By
indicating a need for a product that differs from the commercially
available product, the prescriber is aware that the pharmacist will
have to create a compounded product. If the pharmacist must change the
prescription due to a review of the patient's medication profile, the
pharmacist must contact the prescriber to modify the prescription
before the medication is dispensed. This is a daily part of the
practice of pharmacy and involves not just compounded products but also
medication adjustments among commercially available products to avoid
drug/drug interactions, other potential adverse events, or compliance
with third-party payor formulary requirements.
Question 5. Do you believe that a pharmacist who compounds drugs
that are distributed interstate is in fact a manufacturer? Can a
pharmacist who distributes drugs interstate truly have a pharmacist/
prescriber/patient relationship? Can a pharmacist who is not licensed
in a State lawfully dispense compounded drugs to patients in that
State? Do you believe that interstate distribution of compounded drugs
should itself be grounds for regulation by the FDA?
Answer 5. The places to which a pharmacist distributes its
compounded products does not convert their activity from compounding to
manufacturing. The elements used to determine whether a pharmacist is
compounding include whether or not a physician/patient/pharmacist
relationship exists and whether the compounding is in response to a
prescription or in expectation of prescriptions based upon their
patient population and experience. The distribution of the compounded
product interstate is a function of where the patient resides as
compared with where they secure their health care services. A
relationship among prescribers, pharmacists and patients can exist
across State lines, and such relationships exist every day, for
example, in the Washington DC metropolitan area. Although a patient may
reside in the Commonwealth of Virginia, they may choose to use a
physician and pharmacist located in Washington DC. Similarly, patients
from Massachusetts who move to Florida for the winter may prefer to
maintain their health care services from Massachusetts. And with the
advances of telemedicine, distance no longer precludes the development
and maintenance of relationships between health care professionals and
their patients. Distribution of compounded medications in interstate
commerce does not convert compounding to manufacturing.
Question 6. What can Congress do to encourage the States to
regulate pharmacy compounding more thoroughly?
Answer 6. Congress has already taken positive steps to encourage
State Boards of Pharmacy to review their compounding regulations and
improve their oversight of the practice. By holding the successful
hearing last October, the profession and State regulators were again
reminded of our important role in improving the quality of this
practice. To underscore the messages from the hearing, APhA will be
sending a copy of the GAO report/testimony from the October hearing to
the individual State Boards of Pharmacy with a letter encouraging the
State regulatory bodies to examine their current compounding
regulations and determine if they should be revised or strengthened.
State Boards of Pharmacy take their responsibility of regulating the
profession and protecting patients very seriously and we expect them to
respond appropriately.
Question 7. Do you believe that the National Association of Boards
of Pharmacy Model Act which includes voluntary guidelines are being
adopted and implemented or is there a need for mandatory regulations?
Answer 7. The National Association of Boards of Pharmacy's (NABP)
Model Act serves as an appropriate baseline model for regulating
pharmacy compounding, and is particularly helpful because it is updated
periodically. Compounding continues to be important to State Boards of
Pharmacy and many Boards have reviewed (or are reviewing) their
regulations to make sure that they meet today's standard of pharmacy
practice. It is not necessary to mandate regulations.
Question 8. Do you support a system of batch testing?
Answer 8. APhA supports quality improvement processes in pharmacy
practice, including the incorporation of both internal and external
batch testing for compounding conducted at a certain level. The
preparation of a few topical products for a few patients would likely
not benefit from such testing, nor would it be feasible when very
limited quantities are prepared. In other situations, however, periodic
batch testing in appropriately regulated labs could be beneficial.
Appropriate internal and external batch testing improves the quality of
the practice, and documenting such activity and the results provides
State regulators with important information.
Question 9. Should there be a system of credentialing pharmacy
compounders and if so, where is the APhA in developing the
credentialing system?
Answer 9. APhA supports a voluntary system of accrediting pharmacy
sites where a specified level of compounding practice occurs. Other
practices should meet minimum site standards, personnel should have
appropriate education, and the environments must support quality
compounding practice.
AMA's Strategic Directions Committee prepared a preliminary
categorization of compounding practice to distinguish the compounding a
pharmacist should be prepared to provide based on pharmacy education
and training from the compounding that may require enhanced education
or accreditation or certification processes. Because compounding
encompasses a broad scope of activities--from the preparation of rather
simple lotions for application to the skin to the preparation of
radiopharmaceuticals for injection imaging--this categorization is
important in focusing quality improvement efforts and resources. We are
continuing our work with stakeholders to develop this site
accreditation process for certain compounding activities. Efforts to
coordinate involvement are continuing, and we should have a process
underway by the end of this year.
Question 10. Do you feel that schools of pharmacy are providing
adequate training for pharmacy compounding? If not, what should be done
to work with schools of pharmacy to improve their curriculum?
Answer 10. Pharmacy education, including formal curricula and
experiential rotations in the final year of pharmacy school, provides a
base level of training and skill development in pharmacy compounding.
Part of our Strategic Directions Committee's activity and the
stakeholder work on accreditation involves articulating the level of
compounding at which all student pharmacists. should be trained. This
information will be valuable to schools and colleges of pharmacy and
help guide their curriculum development and clerkship rotations.
Question 11. Some pharmacy technicians are allowed to compound. Do
you feel they have the proper training to compound? Should they be
required to have some minimum education requirements? Should pharmacy
technicians be required to have State licenses or at minimum be
registered?
Answer 11. Pharmacy technicians fulfill a valuable role in pharmacy
practice, and should be allowed to compound under the supervision of a
compounding pharmacist. The scope of that activity, however, should fit
within two parameters: it should not exceed the level of compounding
for which the supervising pharmacist is trained nor exceed the level
for which the technician has been trained. Technicians who compound
need adequate training and education, and there are numerous programs
to provide such training. Additionally, external programs should be
supplemented by on-site training to assure familiarity with facility
procedures and quality control mechanisms.
APhA supports technician certification by the Pharmacy Technician
Certification Board as a mechanism to document the technician's
knowledge. APhA supports registration of pharmacy technicians by State
Boards of Pharmacy as a mechanism to monitor technician activity and
provide appropriate information to supervising pharmacists.
Technicians, regardless of their credentials, work under the direct
supervision of a pharmacist.
Question 12. What is your position on reporting adverse events from
compounded products?
Answer 12. APhA supports medical error and adverse event reporting
systems that are voluntary, confidential, and non-punitive. These
systems should include all medical adverse events including errors and
adverse events related to compounded products. In the context of
current Congressional debate, we support S. 720, the Patient Safety and
Quality Improvement Act, a bill designed to encourage a culture of
safety and quality in the United States health care system by providing
for legal protection of information voluntarily reported to support
quality improvement and patient safety efforts.
Question 13. What is the role of the FDA?
Answer 13. Pharmacists rely on the FDA for strong, consistent
regulation of pharmaceutical manufacturing. When activity goes beyond
the patient/physician/pharmacist triad and is thus manufacturing, we
rely on the FDA to assure that these processes yield a safe and
effective product, when those medications are used appropriately. We
agree with the General Accounting Office's (GAO) testimony at the
October hearing, which delineates the FDA's role in regulating
considered manufacturing (although we do not agree with the GAO's
labeling of this activity as ``compounding''):
. . . The Agency has stated that its primary concern is where drug
compounding is being conducted on a scale tantamount to manufacturing
in an effort to circumvent FDA's new drug approval requirements. FDA
officials reported that the Agency has generally left regulation of
traditional pharmacy practice to the States, while enforcing the act
primarily when pharmacies engage in drug compounding activities that
FDA determines to be more analogous to drug manufacturing.\1\
---------------------------------------------------------------------------
\1\ United States General Accounting Office, Testimony Before the
Committee on Health, Education, Labor, and Pensions, U.S. Senate,
October 23, 2003, page 10.
---------------------------------------------------------------------------
In addition, the FDA could provide a list of active ingredients
that should not be used to compound, specifically those active
ingredients removed from the market for safety reasons. Many States
prohibit compounding using any drug that the FDA has identified as
withdrawn or removed from the market for safety reasons. We encourage
State boards of pharmacy to include this restriction in their
regulations if they have not already done so.
Question 14. Please identify the scientific evidence and the
anecdotal evidence that compounded drugs are safe and effective.
Answer 14. The pharmaceutical literature is replete with evidence
of the value of pharmacy compounding, as well as efforts to improve the
quality of the practice. We have enclosed representative copies of the
APhA peer-reviewed publication Journal of the Pharmaceutical Sciencies
(JPharmSci) and the International Journal of Compounding Pharmacy. At
your request, we would be pleased to provide copies of APhA textbooks
in this area (including Trissel's Stability of Compounded Formulations
and The Art, Science and Technology of Pharmaceutical Compounding) as
well as resource books from other publishers.
Anecdotal evidence of the safety and effectiveness of compounded
medications comes from the positive patient outcomes occurring every
day as--a result of compounding in hospitals, community pharmacies,
hospice programs, and myriad other environments. These practices are
described in the attached amicus brief (Attachment B), submitted to the
Supreme Court for their consideration last year in the Western States
case.
Question 15. Please identify the scientific evidence and the
anecdotal evidence that compounded drugs are not safe or effective.
Answer 15. As part of quality improvement activities in any
profession, identification of practices or procedures that yield
questionable results is important. Recommendations for identifying and
addressing those practices are published in the same literature cited
in the previous question.
Question 16. If the balance of evidence does not clearly indicate
that compounded drugs are safe and effective, how should that affect
our decisions about the sort of regulation that is required, even
taking into account the acknowledged need for compounded drugs?
Answer 16. The balance of evidence supports the understanding that
compounded medications are safe and effective. Although the quantity of
patient use of compounded medications is, appropriately, very small
when compared with patient use of manufactured medications, it is
estimated that thousands of patients successfully use compounded
medications. And as with manufactured medications, problems can occur.
The profession continues our work to identify the root causes of such
problems and improve practice to decrease or eliminate those problems.
And as we stated above, APhA supports the reporting of all medication-
related adverse events as long as the process is voluntary, non-
punitive, and can serve as an educational tool within the profession of
pharmacy to improve compounding practice and our efforts to improve
medication use and advance patient care.
Question 17. If the balance of evidence indicates that problems of
safety or effectiveness of compounded drugs are infrequent or isolated
and not systemic, and considering the acknowledged need for compounded
drugs, how should that affect our decisions about the sort of Federal
regulation required?
Answer 17. The balance of evidence shows that problems with
compounded medications are limited. But even with infrequent or
isolated problems, those problems must be addressed by the profession
and State regulators. APhA continues to support State efforts to assure
the safety of compounded practices, and to support the profession's
efforts to improve the quality of this work. Any Federal regulation
should focus on the FDA's role in regulating manufacturing and the
Agency's collaboration with State regulators when distinguishing
compounding from manufacturing.
Question 18. If an active ingredient or the indication for an
active ingredient is patented, how does compounding a drug using the
active ingredient or using the active ingredient for the indication
affect the rights of the patent owner?
Answer 18. Compounding should not involve the production of
significant quantities of exact copies of commercially available
products--the only situation where compounding activity could be
perceived to violate the rights of the patent owner.
Summary
The profession of pharmacy is focused on improving medication use
and advancing patient care, including improving the use of compounded
medications. State regulatory authorities regulate the profession to
protect the public health, and the profession works continually to
improve the quality of our service to our patients. States require the
licensure of both the professional (the pharmacist) and the place of
practice (the pharmacy). States determine the licensure requirements of
pharmacists, as they do with physicians and other health care
professionals. State Boards of Pharmacy have the authority to take
disciplinary action, including license revocation or suspension,
against pharmacists for misconduct or failure to abide by State laws or
regulations. States also work in cooperation with Federal authorities
with violations of the Federal Food, Drug and Cosmetic Act.
State regulatory authorities are capable of monitoring and
regulating the pharmacy profession as they do with other health care
professionals, and we urge State legislative bodies to provide
sufficient resources to conduct these vital activities. Rather than
developing a net new set of Federal regulations and enforcement
structure, patients would be better served by a focus on ensuring that
these State agencies are adequately funded to perform their regulatory
activities that assure the delivery of quality health care.
We appreciate this opportunity to expand upon our initial comments
and to answer some of the specific questions raised during the hearing.
We look forward to continuing to work with you and your staff to ensure
that patients receive safe medications that meet their specific needs.
Please contact Kristina Lunner; APhA's Director of Federal Government
Affairs, with any additional questions. She may be reached at 202/429-
7507 or at [email protected] And if you or your staff would like to
meet directly with pharmacists to discuss this issue, we would be happy
to arrange such a meeting. Thank you for your interest in this
important issue.
Sincerely,
John A. Gans,
PharmD, Executive Vice President.
______
American Pharmacists Association,
Washington, DC 20037-2985,
November 3, 2003.
Division of Dockets Management (HFA-305),
Food and Drug Administration,
630 Fishers Lane, Room 1061,
Rockville, MD 20852.
Docket No. 2003N-0361
Dear Sir/Madam: The American Pharmacists Association (APhA) is
pleased to submit comments on the Food and Drug Administration's (FDA)
Anti-Counterfeit Drug Initiative as published in the September 5, 2003
Federal Register. APhA, founded in 1852 as the American Pharmaceutical
Association, is the largest national professional society of
pharmacists in the nation, representing more than 53,000 practicing
pharmacists, pharmaceutical scientists, student pharmacists, and
pharmacy technicians.
The protection of our medication supply is obviously of vital
interest to pharmacists, including efforts to prevent the introduction
of counterfeit products into the system and the quick identification
and elimination of such products from the system if the medication
supply is infiltrated. Pharmacists rely upon a safe and pure medication
supply to help patients make the best use of their medications. APhA
applauds the efforts by the FDA to stem these illegal activities which
are straining our regulatory system and are putting American patients
at risk. The FDA's report that since the year 2000 counterfeit drug
investigations have increased to an average of over 20 per year
indicates a need to strengthen our regulatory system.
These comments address questions raised in the September 5, 2003
Notice of Public Hearing as well as those questions raised in the FDA
Counterfeit Task Force Interim Report in four basic areas: the
advantages and disadvantages of various anti-counterfeit technologies;
regulatory and legislative challenges; public education needs and
strategies; and the role that pharmacists will play in implementing new
anti-counterfeit activities. APhA sees value in enhancing our efforts
to combat counterfeiting through advanced technologies and coordination
of efforts by all interested parties including manufacturers,
wholesalers, pharmacists, and patients. APhA's support is only tempered
by the reality that we are working with limited resources and therefore
must look at both the costs and benefits of any new activity prior to
its implementation.
Technology Cost--Benefit Analysis
Technology advances present an opportunity to strengthen the safety
of our drug supply. However, it is important to recognize that these
advances do not come without a cost. As some of these technologies will
be implemented at the pharmacy level, pharmacists and pharmacies will
bear some of the additional costs necessary to employ new anti-
counterfeit technologies. Depending on the technology and the necessary
equipment, this may involve a substantial financial contribution. While
providing an anticounterfeit benefit, the burdens associated with
infrastructure upgrades must be taken into account as the Agency
develops its policies around anti-counterfeit technologies. The
benefits of anti-counterfeit technologies should not become overly
burdensome, financially or administratively, for the health care
practitioners providing patient care.
Numbers & Types of Technology
In determining the number and types of anti-counterfeiting
technologies that should be used on packaging and labeling, one
overriding consideration is involved: are the technologies sufficient
to protect against counterfeiting? Anti-counterfeiting initiatives must
be continuously reviewed and updated to keep ahead of counterfeiters.
However, we recognize the resource limitations of the Agency and
interested parties. In an ideal world with unlimited resources, we
would have a sophisticated anticounterfeit system for every drug--but
resources are limited. We recommend that the Agency focus its efforts
on those drugs most likely to be counterfeited. We recognize that this
list of drugs may change, given the activities of the counterfeiters,
and recommend that the Agency equip itself with mechanisms that will
allow it to rapidly respond to new counterfeit efforts.
To assist in the identification of these priority products, APhA
recommends that the Agency develop criteria for determining what drugs
are most likely to be counterfeited. Ideally, that list of criteria
would include anything that would stimulate a counterfeiter to
counterfeit. We agree that at a minimum, that list should include the
following criteria from the Interim Report: potential impact on public
health if the product was counterfeited; any history of or potential
for counterfeiting, tampering, or diversion of the product; volume of
the product sold; the dosage form of the product; approved and
unapproved uses of the product; current and potential misuse or abuse
of the product; and other products in the class with a history of being
counterfeited. It is also important to consider a product's cost when
developing this list. But considering drug cost has its limitations.
Cost becomes a much less important factor when a counterfeiter is
focused on harming a patient population. In that circumstance, they
might counterfeit a less expensive medication with a higher potential
to cause harm to a broad population.
When considering covert and overt technologies, APhA recommends
using a combination of these technologies. Counterfeiters have proven
themselves sophisticated and adaptable to advances in technology and
changes in anti-counterfeiting efforts. While overt technologies, such
as specific colors and fonts for labels, can provide pharmacists
helpful clues about the validity of the drug they are dispensing,
instituting only overt technologies could provide the counterfeiter a
``blue print'' on how to circumvent the system. While each type of
anti-counterfeit technology, alone, provides a benefit, creating a
system builds upon the strength of each technology and helps create a
less penetrable system, because advantages and disadvantages exist with
each type of technology. For example, bar codes, a type of track and
trace technology, are often discussed as an anti-counterfeiting
technology that should be adopted industry-wide. Incorporating bar
codes may provide many benefits beyond simply assisting in anti-
counterfeit efforts, such as inventory control, reducing medication
errors, identifying theft and diversion, and implementing recalls. The
value of bar codes to anti-counterfeiting initiatives, however, must
consider the ease of copying bar codes and circumventing the
protections by creating fake bar codes. While still an important option
for a base-line anti-counterfeit strategy, no single technology will
prevent counterfeiters. Sophisticated criminal activities require
sophisticated countermeasures.
Unit-of-Use Packaging
Many of the Report's technology-related questions focused on unit-
of-use packaging. APhA supports adoption of unit-of-use packaging as
the industry standard \1\. Unit-of-use packaging may enhance patient
safety, patient compliance, and efficiencies in drug distribution.
While most other groups will focus on the manufacturers' and re-
packagers' role in unit-of-use packaging, it is important to consider
the role of the pharmacist, and the accompanying revisions to state law
that may be necessary to fully implement the concept. In current
practice, pharmacists receive prescriptions for many different
quantities--for 28-, 30- or 31-day supplies--supplies that may not
match unit-of-use packaging. For effective implementation of unit-of-
use packaging, pharmacists must be permitted to modify prescribed
quantities to correspond with commercially available unit-of-use
packages. Without such authority, pharmacists will bear the burden of
contacting prescribers to amend the prescription, not for clinical
concerns but to comply with available packaging.
---------------------------------------------------------------------------
\1\ The following policy statement was adopted in 2003 by the APhA
House of Delegates: Unit-of-Use Packaging: APhA advocates for the
adoption of ``unit of use'' packaging as the industry standard to
enhance patient safety, patient compliance, and efficiencies in drug
distribution. APhA shall collaborate with the pharmaceutical industry,
third party payors, and appropriate federal agencies to affect the
changes necessary for the adoption of ``unit of use'' packaging as the
industry standard. APhA encourages the enactment of legislation and
regulations to permit pharmacists to modify prescribed quantities to
correspond with commercially available `` unit of use'' packages.
---------------------------------------------------------------------------
Establishing standards for unit-of-use packaging is another
necessary element to successful implementation. Expanding the scope of
unit-of-use packaging provides an opportunity to create more consumer-
friendly packaging and help pharmacists and patients improve medication
use. Allowing for a number of different unit-of-use formats, however,
could actually stimulate patient and pharmacist confusion. For example,
one drug's unit-of-use packaging could be designed in a circle,
requiring a patient to take tablets in a clockwise fashion, and another
drug's unit-of-use packaging could be designed in a rectangle, with the
patient taking pills from left to right, moving from the top row to the
bottom. While arguably self-evident to a patient using just one
medication, a patient using multiple medications must then also master
multiple types of packaging and presentation of the medication.
Setting standards for unit-of-use packaging could also help address
some of the shelf space issues at the pharmacy. Pharmacies are
challenged with stocking a multitude of drug products in a limited
space. Efficiencies in space are created when product boxes are similar
in size. Without standards, manufacturers could greatly vary the box
sizes of their products, creating inefficiencies and impacting the
ability of pharmacies to stock all products. Standards could preclude
great variations in box sizes and therefore could assist pharmacies as
they work to appropriately stock pharmacy shelves.
Direct Shipment to End-Users
While an interesting option to solving the challenges created by
having too many intermediaries in the supply system, direct shipments
to pharmacies and other end-users may pose additional problems. In
current practice, multiple pharmaceutical manufacturers deal with a
relatively small number of wholesalers and large purchasers, and the
wholesalers and large purchasers then distribute products to
pharmacies. This system provides efficiencies to both the manufacturer
and the pharmacy by allowing each end of the distribution system to
work with a smaller number of distributors. A direct-shipment-to-end-
user system that removes the wholesaler function would require
pharmacies to work with multiple manufacturers, and manufacturers to
work with tens of thousands of pharmacists and pharmacies, creating
administrative challenges for all participants in the distribution
system.
In an effort to limit those administrative burdens, manufacturers
could choose to ship their products only to large pharmacy operators
and leave smaller pharmacies and their patients without access to
medications. All pharmacies must have access to all medications to
ensure that patients may conveniently receive their medications from
their pharmacist of choice and in doing so, take advantage of the
pharmacist-provided consumer protections against drug interactions,
adverse events, etc. Additionally, an end-user distribution system
assumes that the pharmacy is the last stop in the medication
distribution system. In some circumstances, a pharmacy may provide
medications to another pharmacy, such as when there is a shortage of a
particular medication. This is an important element of providing
patients timely access to necessary medication. Although it is
impossible to predict the impact of such a dramatic change in our drug
distribution system, it is clear that current efficiencies in the
central wholesaler system would be lost, or at least compromised, with
a direct-to-end-user system.
Managing the System
The FDA must play a strong role in reviewing the use of various
anti-counterfeiting technologies, whether in the form of special
packaging, taggants incorporated into the product, or track and trace
technologies. To better ensure an effective security system, the FDA
should be a leader in managing the system. We would support having some
anti-counterfeiting technologies identifiable only by the manufacturer
and/or the FDA, as well as efforts to limit the number of persons/
entities with access to any anti-counterfeiting-related data. Entities
other than the FDA who desire access to this data must demonstrate
clear need. As such, the FDA should, at a minimum, set a baseline for
industry to meet for all anti-counterfeit activities.
In addition to setting a baseline, the FDA should play a strong
role in guiding the industry through this process. In particular, the
FDA could help the process of establishing this new system by
clarifying the role of each interested party within the new system. One
often misunderstood area is the intersection of authority between the
FDA and state regulators, such as the state Boards of Pharmacy. State
Boards of Pharmacy play a significant role in regulating pharmacies,
pharmacists, and wholesale distributors. The new system would benefit
from a coordinated, consistent approach from the FDA and other
regulators, and including this type of information as part of the
industry guidance document.
Regulatory and Legislative Issues--Prescription Drug Marketing Act
In our June 30, 2000, comments on the Agency's final rule
implementing the Prescription Drug Marketing Act of 1987 (PDMA) as
amended, APhA expressed concerns that the changes to the wholesale
distribution of prescription medications would erect barriers adversely
impacting pharmacists' ability to obtain prescription drugs. APhA's
concerns included creating two categories of drug distributors
(authorized and unauthorized), each with their own regulatory
requirements, and requiring unauthorized wholesale distributors to
provide a drug origin statement or paper ``pedigree'' detailing each
previous transaction of the drug upon each subsequent sale or trade of
the drug.
APhA recognizes the value of requiring a trail of transactions for
a prescription drug and agrees that pedigrees, in concept, may be an
appropriate tool to track prescription drugs from manufacturer, to
wholesaler/distributor, to pharmacist. However, our concerns with a
paper-based system have not dissipated since our 2000 comments,
although our confidence in the distribution system has changed
dramatically. A paper pedigree system could negatively impact the
security of our drug distribution system by creating a false sense of
security when the mere presence of a paper pedigree could be proof of
little. The value of a paper-based system is reduced by the ease of
counterfeiting paper pedigrees. A paper-based pedigree system may
provide a track record of the product movement, or simply provide a
counterfeit record of the product movement-a trail as fake as the
product it accompanies. If an entity is sophisticated enough to
counterfeit the product, the same entity would be equally capable of
counterfeiting a paper pedigree.
Proposals to issue an electronic, universal pedigree address our
concerns regarding PDMA's affect on drug availability. Early iterations
of PDMA implementation created a two-tiered system by developing a
system of authorized and unauthorized distributors. It is highly
unlikely that a manufacturer would provide an unauthorized distributor
with a pedigree when it is not required to--and forcing unauthorized
distributors to construct a pedigree is an insurmountable burden that
would likely reduce the number of legitimate distributors in the
system. Fewer legitimate distributors could lead to a decrease in
competition, an increase in prescription drug prices, and a disruption
in drug distribution. Because of these concerns, APhA supports a
carefully constructed, electronic universal pedigree.
We continue to support a pedigree requirement in concept and
recommend that the Agency consider alternative formats, such as an
electronic pedigree system or other approaches less likely to be
falsely produced by counterfeiters. As with any new system, such steps
should be implemented after a costbenefit analysis has been conducted.
Access to Quality, Regulated Drugs
APhA firmly believes that one of the greatest risks to patients
receiving counterfeit drugs is personal importation of medications from
outside the U.S. Importation, particularly personal importation, raises
patients' risk of receiving a substandard or fake medication
substantially by making the world a patient's pharmacy--a drug provider
that is often unregulated or at least regulated very differently.
Members of Congress and state policymakers, in an effort to increase
access to medications for their constituents, have begun efforts to
facilitate and/or legalize this unsafe practice. Simply strengthening
existing regulatory enforcement to address importation would reduce the
risk of patients receiving a counterfeit medication.
Over the last year, so-called storefront operations have popped up
around the country to facilitate personal importation of
pharmaceuticals. These facilities are clearly participating in the
delivery of medications to patients. State Boards of Pharmacy, with
whom enforcement of the practice of pharmacy lies, find themselves
struggling with jurisdictional issues when trying to close down these
storefront operations. Often walking the fine line of ``practicing
pharmacy'', these storefronts occasionally fall in a regulatory vacuum.
Any changes necessary to directly address these entities--thereby
providing either federal or state regulators the authority to shut down
these operations--must be made. In addition, APhA supports the proposal
to increase penalties for counterfeiting medications. Such action would
send a strong message to counterfeiters that we do not condone this
illegal, unsafe, and unscrupulous practice.
State Pharmacy Practice Acts
As stated previously, personal importation is the greatest risk to
patients receiving counterfeit drugs and State Boards of Pharmacy are
struggling with jurisdictional issues when trying to regulate
``storefront'' operations. Therefore, APhA would support efforts to
enhance the ability of state Boards of Pharmacy to regulate all
entities engaging in pharmacy practice, including so-called
storefronts. Additionally, APhA supports strengthening wholesaler
regulations, such as requiring a site visit to a wholesaler before
issuing a license. This step would enhance regulators' efforts to
ascertain that the wholesalers seeking licensure are legitimate
businesses.
Education & Communication--Role of the Public
Patients play a very important role in identifying and reporting
suspected counterfeit drugs. Occasionally, counterfeit drugs may be
identified only through patient experience with medications--only after
the drug interacts with a human body. But for patients to fulfill this
role of reporter, they first need to be aware of the importance of
reporting. Second, patients must know where to report--that they should
tell their pharmacist when a drug looks, smells, feels, or tastes
different than what they had previously experienced or expected. Even
if the change in appearance or effect is not related to a counterfeit
medication, this conversation may help limit adverse drug events or
side effects, it may help improve medication use and advance patient
care. Third, patients also need to understand how easily drugs can be
counterfeited and how difficult it is to detect counterfeit drugs.
Without such education, patient may not consider an odd effect the
result of a counterfeit drug and may assume that the pharmacist would
have ``seen'' (with the naked eye) whether a drug was counterfeit.
Neither assumption is true and should be clarified. A call to action
and consumer tips on what to watch for will help patient reporting of
suspected counterfeit medications. APhA consumer tips are posted on our
website (http://www.pharmacyandyou.org/InternetPharmacy.html) and are
attached for your information.
Messaging
Effective and efficient notification of counterfeit medication
requires a consistent message in a consistent format. Inconsistent,
conflicting messages will only perpetuate unnecessary chaos.
Notification should take place in priority order as well, with an
optimal situation notifying the pharmacy community first, with
immediate subsequent notification of the public and the rest of the
health care system. By communicating first with the pharmacy
community--both pharmacies and pharmacists--the Agency helps prepare
the community most likely to receive questions about the situation, and
the community most likely to have the information necessary to
proactively contact affected patients. Organizations such as APhA can
play an integral role in these emergency communications.
Messages to pharmacists should focus on information the pharmacist
needs to address their patient population, such as: name of the
product, lot number, specifics about identifying the counterfeit
product, and information on the risks to patients. This type of
information will allow the pharmacist to determine the likelihood that
their drug supply was infiltrated by the particular product in question
and to immediately notify the affected patients.
Collaboration
APhA recommends that the Agency collaborate with private
stakeholders in designing communication strategies among stakeholders.
This public/private partnership could facilitate efforts to standardize
anti-counterfeit communications and to augment and coordinate
communication systems. APhA specifically recommends utilizing our
website of resources for pharmacy professionals, www.Pharmacist.com to
deliver FDA messages about counterfeiting. Pharmacist.com is the
singlesource site for the professional resources that are vital to the
continuous professional development needs of pharmacists, student
pharmacists, and pharmacy technicians. Pharmacist.com, a collaborative
effort of APhA and the National Association of Boards of Pharmacy,
assembles in one place the resources pharmacists need. As a medium
developed by pharmacy for pharmacy, Pharmacist.com provides information
in a useful format. Pharmacist.com could be used to link to MedWatch to
facilitate pharmacists reporting suspected counterfeits. In addition to
Pharmacist.com, APhA has another internet-based communication tool that
could be used to send information about counterfeit medication events.
Pharmacist.com Focus is a weekly publication that is emailed to more
than 65,000 pharmacists and student pharmacists and could be easily
used to focus the attention of this audience on anticounterfeit
activities. However, Pharmacist.com Focus is not restricted to a weekly
distribution schedule. In a crisis, APhA has the ability to send
special alerts to Pharmacist.com Focus subscribers--an invaluable tool
during an emergency situation. An advantage of these systems is that
they already exist, and it is more efficient to augment a currently
existing system than to create a net new one that must be introduced to
pharmacists. Pharmacists are already familiar with these systems and
will be responsive to their information as they are seen as fair and
unbiased resources for information.
Creating efficient and effective public/private collaborations is a
challenge when trying to meet the needs of a wide spectrum of
interested parties. Involving interested parties early in the process
can assist in these efforts. A common understanding of how systems will
work will better prepare everyone to handle an emergency situation, and
the creation of templates supports efforts to ensure that messages stay
consistent. Having as much of a ``system'' in place prior to an event
is an effective way to manage a situation. Creating consistency before
an emergency helps prevent unnecessary mishaps.
Industry and Health Professional Issues--Role of the Pharmacist
As the medication experts on the health care team and the health
care practitioners with the most comprehensive set of drug information
for the patients they serve, pharmacists should take a leadership role
in identifying counterfeits, preventing their introduction into the
distribution chain, and educating consumers about counterfeits and how
to address a suspected counterfeit medication.
Pharmacists have the responsibility of partnering with patients to
share information about medication use, to ask patients to report
anything different about their medication. Patients need to know, for
example, that a drug that stings when injected could, in a rare
situation, be counterfeit, or, more commonly, that they could be
suffering an adverse reaction. Pharmacists are essential in efforts to
help patients make the best use of their medications.
Pharmacists must also play a reporting role, and need education to
focus them on the most efficient reporting procedures. While
pharmacists better understand the ease of counterfeiting medications,
many have not dealt directly with the situation. Pharmacists need
information about how and to whom they should report suspected
counterfeit medications: reporting to FDA and the pharmaceutical
manufacturers. APhA supports efforts to increase the understanding by
pharmacists of the role that they play in preventing counterfeit
medications from reaching patients, and has published a continuing
education piece on protecting the integrity of the prescription
medication supply, which will be distributed to more than 120,000
pharmacists in the November, 2003 issue of Pharmacy Today.
In addition, the profession can address the practice of safe drug
distribution by developing best business practices for buying
medications. These guidelines could then be widely distributed to
pharmacists to assist them in preventing the introduction of
counterfeit medications in their pharmacy and to facilitate the
identification of counterfeit drugs.
Finally, APhA commends the Task Force for recognizing that this
effort must go beyond our own borders and must include the
international pharmacist community. In devising international
activities, APhA recommends that the Task Force work with the
International Pharmaceutical Federation (FIP), a world-wide federation
of national pharmaceutical (professional and scientific) associations.
FIP has expressed concerns regarding the proliferation of counterfeit
medications. At its 2003 World Congress in Sydney, Australia, the FIP
Council adopted a Statement of Policy on Counterfeit Medicines, which
can be accessed at http://www.fip.org/pdf/counterfeitmedicines2003.pdf
APhA is pleased that the FDA is addressing this important issue.
This review of current policies and systems is timely, given recent
increases in counterfeit medications and importation by individual
patients. As the FDA considers the steps to limit drug counterfeiting,
the analysis must consider the costs associated with the
recommendations--costs in terms of both time and money. Pharmacists and
other members of the pharmaceutical supply system are ready to invest
in appropriate measures, but we should invest wisely in those
strategies that will provide the best value for the cost. APhA urges
the FDA to consider our recommendations as they finalize their anti-
counterfeit drug initiative. Thank you for the opportunity to share our
thoughts on this issue. If you need additional information, please
contact Susan Bishop, APhA's Senior Manager of Regulatory Affairs and
Political Action, at 202-4297538 or [email protected].
Sincerely,
John A. Gans, PharmD,
Executive Vice President.
______
About Importing Medications and Internet Phamacies
The American Pharmaceutical Association (APhA), the national
professional society of pharmacists, addresses consumer questions
regarding the importation of medications and offers helpful advice on
the risky practice.
What does ``importation'' refer to?
Importation refers to patients obtaining medications outside of the
United States . It is the practice of bringing medications from one
country to another.
Why would a person engage in the practice?
Consumers-feeling the financial pressures of expensive prescription
drugs-look for alternative ways of obtaining the medication they need.
However, importing medications only offers short-term cost savings,
because if the medication is wrong or used incorrectly it can cause
greater harm to the patient, thus resulting in higher long-term costs.
Importing drugs sounds illegal. Can just anyone bring drugs from one
country to another?
Just as bringing fruit from a foreign country into the U.S. is
illegal, importing medications is also illegal. Under federal law, only
the manufacturer of a drug may import prescription medications, because
the federal government regulates the manufacturing of prescription and
nonprescription medications. The federal government has processes to
ensure the safety of products manufactured according to its rules but
not an imported product brought in from another country by an
individual.
In using the fruit analogy, the U.S. prohibits a person from
bringing fruit from a foreign country into the U.S. because the fruit
may be contaminated and potentially bring disease and devastation to
our nation's harvest. In similar terms, neither the pharmacist nor the
public has assurance that imported products are effective, safe, or
have been produced under U.S. quality control requirements. Imported
products may be subpotent (contain too little active ingredient) or
superpotent (contain too much active ingredient). In the worst cases,
imported medications may be contaminated, which can harm or permanently
damage the body, causing paralysis, organ malfunction, or even death.
SAFEGUARD YOURSELF WITH KNOWLEDGE & CONSIDER THIS ADVICE
1. Are you getting what you ordered? Once a product leaves the U.S.
regulatory system, the product is at risk of becoming contaminated.
Understand that other distributors are not held to certain storage
standards or product labeling. You could be consuming a product that
has become faulty due to temperature conditions or one that is simply
the wrong product.
2. Do your local doctors and pharmacists know what you are taking?
Drug interactions with other medications are something doctors and
pharmacists consider before prescribing and dispensing prescription
medications to patients. You may be taking a medication that will
become ineffective
OR CAUSE HARM WHEN TAKEN IN CONJUNCTION WITH ANOTHER MEDICATION.
Patients often see different doctors for different examinations,
creating the potential for drug interactions. To protect against this
risk, patients should use ONE pharmacy for their medication needs.
Pharmacists ensure that a patient receives the right medication in the
right dose. Pharmacists also check for interactions by maintaining a
patient's medication history, thus protecting the patient from
receiving the wrong medication. If you choose to import your
medications, be sure to discuss those medications with your doctor and
pharmacist.
In addition, some web sites offer medications for sale without the
patient receiving a physical examination. Bypassing direct contact with
a doctor or pharmacist puts the patient at higher risk to receive
inappropriate medications.
3. Are you getting the most from your medication? Medications are
powerful technology and are only safe when used appropriately.
Appropriate medication use involves more than just getting the product;
it also requires understanding how to use the medication, including
monitoring for unwanted side effects and potential interactions with
other medications. Pharmacists are the patient's partner in making the
best use of medications.
WHAT YOU SHOULD KNOW ABOUT INTERNET PHARMACIES
There is a portion of our population for whom Internet Pharmacies
offer valuable benefits. Some patients may feel more comfortable
communicating personally sensitive health information to a pharmacist
via the Internet. There are two important points patients must be aware
of when selecting any pharmacy:
MEDICATIONS ARE SAFE--WHEN USED CORRECTLY
As part of that correct use of medications, patients should keep
the following things in mind when choosing a pharmacy whether a local
pharmacy, mail order pharmacy, or an Internet pharmacy.
Preferably, patients should use only ONE pharmacy source. Using
just one pharmacy decreases the possibility of patients suffering a
harmful drug interaction because they've gotten their medications from
multiple sources such as an Internet pharmacy and their community
pharmacy.
If getting acute prescription medications (like an antibiotic) from
a local pharmacy, the patient should alert the local pharmacist about
other medications they are already taking.
Patients should always have access to a pharmacist. All patients
should have a telephone number to contact their pharmacist, whether
they use a local pharmacy, mail order pharmacy, or Internet pharmacy.
This is particularly significant for patients using a mail order
pharmacy or an Internet pharmacy. They do not have the option of
visiting the pharmacist to ask questions about their medications in
person.
SOME SERVICES PROVIDED BY YOUR LOCAL PHARMACIST CANNOT BE TRANSMITTED
OVER A MODEM
Patients choosing to use an Internet Pharmacy should consider the
following:
1. With current technology, an Internet pharmacist cannot check the
patient's blood pressure or blood cholesterol level to help the patient
monitor his drug therapy. Unless the Internet Pharmacy and consumer
both have video teleconferencing capabilities, allowing the patient and
pharmacist to see one another as they interact, pharmacists will not be
able to observe signs or behaviors that may be important indicators of
symptoms and potential adverse responses to drug therapy.
2. Are Internet pharmacies licensed to serve patients in my State?
Assuming the internet pharmacy is located in the United States ,
individual state boards of pharmacy license pharmacists and pharmacies
and establish the regulatory framework for protecting the public
health.
The National Association of Boards of Pharmacy (NABP) developed a
system to verify licensure of Internet Pharmacies-the Verified Internet
Pharmacy Practice Site TM (VIPPS) certification. NABP is located in
Park Ridge , Illinois . The organization can be reached by telephone at
(847) 698-6227. Their Internet Site URL is http://www.nabp.net.
3. Will I have access to a pharmacist to answer my questions about
medication use? Regardless of the type of pharmacy, patients should
select a pharmacy that has a pharmacist available to answer questions.
In order to help make the best use of their medications, patients
should consult a pharmacist to make sure that they receive the RIGHT
medication, in the RIGHT dose, with the RIGHT information.
Response to Questions of Senator Kennedy From Janet Heinrich
Question 1. I would like your views about how the line between
compounding and manufacturing should be drawn. However you would
propose it be drawn, please describe what inspection and enforcement
authorities the U.S. Food and Drug Administration would need to enforce
the definitional line.
Answer 1. During our work for the committee's October 23, 2003,
hearing on pharmacy compounding, a number of officials reported a
variety of opinions on how to draw the line between pharmacy
compounding and manufacturing. These included state pharmacy board
officials in four states; national pharmacy association officials,
including the National Association of Boards of Pharmacy; FDA
officials; and pharmacy experts. Several sources commented that they
believed that a triad relationship among prescribing health care
practitioner, patient, and pharmacist (including a prescription)
distinguishes drug compounding from manufacturing. Others commented
that FDA should provide further clarification on the line between
compounding and manufacturing. One pharmacy expert, who was the former
Chair of the FDA Pharmacy Compounding Advisory Committee, said he
believed that, if available, commercial products should be used rather
than a compounded drug.
Regarding FDA inspection and enforcement authorities, a few
officials we interviewed said that states regulate compounding and FDA
regulates manufacturing and that states may notify FDA when they
suspect a pharmacy is manufacturing. FDA officials said that FDA's
longstanding position has been that all compounding is technically a
violation of the Federal Food Drug and Cosmetic Act (FDCA), although
FDA will generally defer to state authorities in dealing with ``less
significant'' violations.
Further, several officials we interviewed said that the former
compounding section in FDAMA \1\ provided the clarification they
thought was needed to distinguish between legitimate compounding and
manufacturing and also defined the role of FDA regarding oversight of
compounding. Many officials, including state pharmacy board and
pharmacy association officials, added that they would support similar
legislation, for example, language similar to the compounding section
that was in FDAMA without the advertising provisions.
\1\ In 1997, Congress passed the FDA Modernization Act of 1997
(FDAMA), which exempted drug compounders that met certain criteria from
key provisions of the FDCA, including the requirements for the approval
of new drugs. These exemptions, however, were nullified in 2002 when
the United States Supreme Court ruled part of the 1997 law to be an
unconstitutional restriction on commercial speech, which resulted in
the entire compounding section being declared invalid.
Question 2. However you might define compounding, might there
nonetheless be large-scale compounding that warrants more active
regulation by the Food and Drug Administration? If so, would you
recommend regulation short of regulation as a manufacturer, and if so,
what would you recommend?
Answer 2. Concerns have been raised by FDA and others that some
pharmacies are going beyond traditional drug compounding for individual
patients by, for example, compounding and selling large quantities of
drugs without meeting safety and other requirements for new
manufactured drugs. FDA maintains that FDCA requirements, such as those
regarding the safety and efficacy requirements for the approval of new
drugs, are generally applicable to pharmacies, including those that
compound drugs. FDA officials reported that the agency has taken action
with pharmacy compounders that they believe have become small
manufacturers and where there is a genuine public health threat. State
pharmacy board officials in two of the states we reviewed told us that
they have worked with FDA officials in compounding investigations
involving both large and small quantities of compounded drugs.
Question 3. Dr. Sellers included a proposal for Federal legislation
enhancing the regulation of compounding. Please comment on her
proposal. What portion of her proposal do you believe must be
accomplished at the Federal level and what portion can safely be
achieved at the State level?
Answer 3. This question is beyond the scope of the work we
conducted for the committee's October 23, 2003, hearing.
Question 4. Is it legitimate for a pharmacist to dispense a
compounded drug if the prescriber has not indicated in the prescription
that a specially compounded drug is required by the patient, or if the
pharmacist has not verified with the prescriber that it is appropriate
to dispense a compounded product?
Answer 4. This question is beyond the scope of the work we
conducted for the committee's October 23, 2003, hearing.
Question 5. Do you believe that a pharmacist who compounds drugs
that are distributed interstate is in fact a manufacturer? Can a
pharmacist who distributes drugs interstate truly have a pharmacist-
prescriber-patient relationship? Can a pharmacist who is not licensed
in a State lawfully dispense compounded drugs to patients in that
State? Do you believe that interstate distribution of compounded drugs
should itself be grounds for regulation by the Food and Drug
Administration?
Answer 5. Since drug compounding may occur at mail-order and
Internet pharmacies, the compounding pharmacy may be located in a
different state from the patient or prescribing health professional.
Three of the four states we reviewed reported having a large number of
out-of-state pharmacies licensed to conduct business in their states,
and inspection and enforcement activities may differ for these
pharmacies. For example, Wyoming reported having 274 licensed out-of-
state pharmacies, which is nearly twice as many as the number of in-
state licensed pharmacies. Officials in the four states we reviewed
said that they have authority to inspect out-of-state pharmacies
licensed in their states but because of limited resources, they
generally leave inspections to the state in which the pharmacy is
located. Regarding enforcement authority, all four states reported
having authority to take disciplinary action against out-of-state
pharmacies licensed in their states.
Regarding the triad relationship among prescribing health care
practitioner, patient, and pharmacist (including a prescription), one
pharmacy expert we interviewed, the Chairman of the United States
Pharmacopeia (USP) Pharmacy Compounding Expert Committee, commented
that, as long as a pharmacy does not ship a drug before receiving a
prescription, the triad relationship is intact.
Question 6. What can Congress do to encourage the States to
regulate pharmacy compounding more thoroughly?
Answer 6. State pharmacy board officials we interviewed reported
that state resources for pharmacy inspections were limited, which
affected their ability to oversee pharmacies that compound drugs.
Officials did offer some suggestions to improve oversight. For example,
one pharmacy board official said that states could become more
proactive in ensuring the quality of compounded drugs if FDA could
appropriately contract with state boards of pharmacy to collect and
test samples of compounded drugs. Another pharmacy board official
suggested that FDA could provide a central lab for states to use for
testing and that states and FDA could share the expense. The official
added that this could provide FDA with a database of compounded drugs,
which could be a good resource for state pharmacy boards.
Question 7. Please identify the scientific evidence and the
anecdotal evidence that compounded drugs are safe and effective.
Answer 7. While conducting our work for the committee, we did not
identify scientific evidence regarding the overall safety and
effectiveness of compounded drugs. Although anecdotal evidence suggests
that compounded drugs are not always safe and effective, we did not
find data to determine the frequency of problems related to compounded
drugs. The extent of drug compounding is unknown, and therefore a
comprehensive figure on the relative frequency of adverse events is not
available. Estimates for the proportion of prescription drugs that are
compounded range from 1 percent to 10 percent of all prescriptions, but
we found no data supporting most estimates.
Question 8. Please identify the scientific evidence and the
anecdotal evidence that compounded drugs are not safe or are not
effective.
Answer 8. As we reported in October, problems have come to light
regarding compounded drugs, some of which resulted in death or serious
injury, because the drugs were contaminated or had incorrect amounts of
the active ingredient. Based on voluntary reporting, media reports, and
other sources, FDA has become aware of over 200 adverse events
involving 71 compounded products since about 1990. These incidents,
including 3 deaths and 13 hospitalizations following injections of a
compounded drug that was contaminated with bacteria in 2001, have
heightened concern about compounded drugs' safety and quality.
Although we are not aware of any comprehensive scientific evidence
on the safety and efficacy of compounded drugs, we did identify one FDA
report titled Limited FDA Survey of Compounded Drug Products. This
report summarizes the results of a limited survey conducted by FDA's
Division of Prescription Drug Compliance and Surveillance in 2001 that
found that nearly one-third of the 29 sampled compounded drugs were
subpotent--that is, they had less of the active ingredient than
indicated.
In addition, officials and experts we interviewed reported that the
risk levels for compounded drugs differ depending on the type of drug.
For example, sterile compounded drugs have a higher risk level than
nonsterile drugs and involve a more complex procedure and require
special equipment to prepare.
Question 9. If the balance of evidence does not clearly indicate
that compounded drugs are safe and effective, how should that affect
our decisions about the sort of regulation that is required, even
taking into account the acknowledged need for compounded drugs?
Answer 9. Although FDA and others have expressed concern about the
potential for harm to public health when drugs are manufactured and
distributed in commercial amounts without FDA's prior approval, FDA and
other pharmacy experts we interviewed have stated that traditional drug
compounding on a small scale in response to individual prescriptions is
beneficial. In addition, some state pharmacy board officials and
pharmacy experts reported that testing compounded drugs for safety and
quality could help in the oversight of compounded drugs; however,
officials reported that resources to implement testing are an issue.
Question 10. If the balance of evidence indicates that problems of
safety or effectiveness of compounded drugs are infrequent or isolated
and not systemic, and considering the acknowledged need for compounded
drugs, how should that affect our decisions about the sort of Federal
regulation required?
Answer 10. While conducting our work for the committee, we did not
find data to determine the relative frequency of problems related to
compounded drugs. Unlike drug manufacturers, who are required to report
adverse events associated with the drugs they produce, FDA does not
require pharmacies to report adverse events associated with compounded
drugs. While the FDA has become aware of over 200 adverse events
involving 71 compounded drugs since about 1990, the number of
prescription drugs that are compounded remains unknown. As a result,
the relative frequency of adverse events associated with compounded
drugs cannot be determined.
Question 11. If an active ingredient or the indication for an
active ingredient is patented, how does compounding a drug using the
active ingredient or using the active ingredient for the indication
affect the rights of the patent owner?
Answer 11. Our work for the committee's October 23, 2003, hearing
did not include a review of patent rights.
Response to Questions of Senator Kennedy From Kevin Kinkade
Question 1. I would like your views about how the line between
compounding and manufacturing should be drawn. However you would
propose it be drawn, please describe what inspection and enforcement
authorities the U.S. Food and Drug Administration would need to enforce
the definitional line.
Answer 1. There are several areas that can be addressed to
establish differences between compounding and manufacturing. First, it
should be clear that compounding is limited to where a prescription is
provided for a specific patient. The product is to be compounded due to
the lack of an available commercial product or some other therapeutic
reason that justifies providing a compounded product in lieu of a
manufactured one. Secondly, volume can be a vehicle to address this
issue. If a pharmacy is providing a compounded product by prescription
and the amount of product available within its inventory reflects the
amount of product used over a specified period of time, then this could
be used as a tool to measure whether the pharmacy is compounding
products that are used on a timely basis or whether there is an excess
of product that is held in inventory for longer periods of time where
concern for stability and potency would be an issue. As an example, in
Missouri, we require that limited quantities be maintained within an
inventory based on prescription history of the product. No more then a
supply reflective of a three month need is allowed. Any situations/
inventory beyond this is defined as hatching which is a practice
considered to be manufacturing.
Connected with volume as well, is the practice of some pharmacies
to provide compounded drugs across state lines. Interstate marketing
and sales of products to patients that are geographically distant
usually require large inventories of drugs. This could be an area where
federal authorities could enforce standards due to the fact that such
compounded products have truly entered interstate commerce.
Question 2. However you might define compounding, might there
nonetheless be large-scale compounding that warrants more active
regulation by the Food and Drug Administration? If so, would you
recommend regulation short of regulation as a manufacturer, and if so,
what would you recommend?
Answer 2. I see no benefit to another class of provider, whether
through a state or federal regulatory scheme. State boards of pharmacy,
as with other health professions, regulate the practice of pharmacy.
Taking into account, the responses made to question #1, a clear line
needs to be drawn between compounding and manufacturing with the FDA
enforcing manufacturing standards when that line has been crossed. It
should not be lost within the debate that many physicians are
compounding products for their patients as well. In most cases, they
have not attempted to compound drug products that enter into any of the
areas described in my response to question #1. However, to my
knowledge, most state boards of medicine are not conducting any reviews
or inspections concerning the quality of products that are provided in
this manner.
Question 3. Dr. Sellers included a proposal for Federal legislation
enhancing the regulation of compounding. Please comment on her
proposal. What portion of her proposal do you believe must be
accomplished at the Federal level and what portion can safely be
achieved at the State level?
Answer 3. The portion of Dr. Sellers recommendations of providing
warnings to patients that a compounded drug is being used within their
prescription is not well founded. The type of warning she provides
would do more to confuse and increase fear in patients that might not
understand what the warning is for or its meaning. If we believe that
compounds provided by pharmacies do, in most cases, provide needed
therapeutic care for patients, initiatives that might decrease
compliance such as warnings about the product do not serve a good
purpose. In most cases, prescribers know when they are prescribing a
compounded product vs. a manufactured one. Requiring additional
documentation to relay that a compounded product is being used will not
serve a real public health purpose and will only serve to increase
technical issues on each prescription that is compounded in a pharmacy
that does not provide a tangible benefit. An exception to this would
include those situations where compounding in order to mimic a
commercially available product is being done. When these situations
occur without a specified clinical purpose then economic gain is
usually the overriding factor. Further requirements to show appropriate
communication with the prescriber and patient in these cases is
important. Dr. Sellers advocates a list of drugs that are to complex to
compound. I would agree that here, the federal government has an
important role. In the last compounding law passed by Congress, an
advisory panel was created within FDA that provided a list of drugs
that were either to complex or dangerous to compound. The federal
courts struck this law down but this portion was not the reason for the
law to be deemed invalid by the courts. This committee or some
mechanism on a federal level should be reinstated in order to have a
uniform list that can be enforced by state governments. FDA should also
be given authority to intervene and enforce the list when necessary. In
addition, requiring a pedigree for raw ingredients used in compounding
should be pursued as well. Pedigrees are a good idea for both
compounded and manufactured drug products.
Question 4. Is it legitimate for a pharmacist to dispense a
compounded drug if the prescriber has not indicated in the prescription
that a specially compounded drug is required
by the patient, or if the pharmacist has not verified with the
prescriber that it is appropriate to dispense a compounded product?
Answer 4. I believe it is. Compounding comprises a wide array of
different products. Many compounds are produced for administration by
another qualified health professional. As previously mentioned,
prescribers already are usually aware and understand the fact that the
prescription they are providing will be compounded since most such
products are made due to the lack of any commercial product either in
the form or at the strength called for in the prescription. There are
certain cases where additional communication may be warranted between
the pharmacist, the prescriber and the patient, this type of
interaction is of a professional discretionary nature and would be
difficult if not impossible to mandate by law without causing more
undue contact and technical requirements then is necessary. Again, it
must be stressed here that when products are compounded that are
similar to available commercial products then appropriate documentation
for the reason to provide a compounded prescription should be required.
Question 5. Do you believe that a pharmacist who compounds drugs
that are distributed interstate is in fact a manufacturer? Can a
pharmacist who distributes drugs interstate truly have a pharmacist-
prescriber-patient relationship? Can a pharmacist who is not licensed
in a State lawfully dispense compounded drugs to patients in that
State? Do you believe that interstate distribution of compounded drugs
should itself be grounds for regulation by the Food and Drug
Administration?
Answer 5. A qualified yes. Again because of the extreme diversity
in compounding services and products it is difficult to provide a
simple answer. There are legitimate reasons why a pharmacist could have
a pharmacist-prescriber-patient relationship on an interstate basis.
The structure of how the prescription is obtained is important as well
as the appropriate clinical need for the product. As an example, a
medical clinic may wish to contract with a pharmacy in another state in
order to provide very specialized forms of chemotherapy. Assuming the
pharmacy is licensed in the state it is doing business in, that a
patient specific prescription is received for the drug and appropriate
communications concerning clinical and therapeutic issues are
maintained such a relationship is possible. On the other hand, if the
pharmacy is marketing itself directly to patients, the products it
provides have no unique therapeutic value but mimic commercially
available products and neither the prescriber or the patient are
communicated with concerning the reason for the substitution of the
product, then a general lack of a proper professional relationship
exists in these cases.
The nature of state regulation in most cases is to require
licensure of any pharmacy that provides drugs into the state. The
courts have shown concern over interference with interstate commerce
when states have tried to require all pharmacists to be licensed. Some
states require the pharmacist in charge of the pharmacy to be licensed
in addition to the pharmacy itself. The FDA should have a clear role in
protecting the health of citizens anytime drug commerce crosses state
lines.
Question 6. What can Congress do to encourage the States to
regulate pharmacy compounding more thoroughly?
Answer 6. Guidelines could be written through the federal register
providing for certain minimum enforcement standards that states would
need to follow if they are to retain authority over compounding of drug
products in that state. As long as it can be shown the state is doing
its job then the federal authorities would not play a role within
enforcement. If a state is not maintaining its role, then perhaps after
corrective actions are proposed by the FDA and time is given for that
state to improve in its enforcement practices the FDA would assume any
role necessary in that state for maintaining reasonable assurance of
patient safety.
Question 7. Please identify the scientific evidence and the
anecdotal evidence that compounded drugs are safe and effective.
Answer 7. Publications such as journals published by the American
Pharmaceutical Association, the American Society of Health System
Pharmacists and the International Association of Compounding
Pharmacists all contain articles within them that will cover different
compounding issues and in some cases, studies of certain compounds and
compounding procedures are discussed. Over the years, much has been
written about research on the safe and effective use of various
compounded products.
Question 8. Please identify the scientific evidence and the
anecdotal evidence that compounded drugs are not safe or are not
effective.
Answer 8. The only documented evidence I am aware of is the limited
study done by FDA last year concerning the testing of certain drug
products that they obtained through the mail. Other articles have been
written concerning specific episodes where compounded drugs caused harm
to patients due to equipment malfunctions, lack of following specified
compounding procedures or incompetence of the individual pharmacist.
Question 9. If the balance of evidence does not clearly indicate
that compounded drugs are safe and effective, how should that affect
our decisions about the sort of regulation that is required, even
taking into account the acknowledged need for compounded drugs?
Answer 9. As stated previously, a list of drugs to complex or
dangerous to compound is necessary. Compounding of drugs cannot be
lumped together into one body of practices that can then be judged as
safe or unsafe. There is simply to many types and practices of
compounding that make such an overall judgement unfair. If the balance
of evidence at some point can show that a specific compound or
compounding practice requires specific knowledge and/or expertise or
equipment then this should be required and enforced by state boards of
pharmacy. A good example is sterile product compounding. Not all
pharmacists are familiar with this type of compounding nor do they
maintain the equipment to do it properly. In Missouri, the law
presently holds pharmacists accountable for such practices. Reference
should be made back to my response in question #6 concerning federal
guidelines as a further response if the balance of evidence is as
outlined.
Question 10. If the balance of evidence indicates that problems of
safety or effectiveness of compounded drugs are infrequent or isolated
and not systemic, and considering the acknowledged need for compounded
drugs, how should that affect our decisions about the sort of Federal
regulation required?
Answer 10. I think that within the responses provided here that the
recommendations made for both regulation on a state level as well as
roles for FDA have been identified and should be pursued regardless of
the debate over how safe or effective some compounding is.
Question 11. If an active ingredient or the indication for an
active ingredient is patented, how does compounding a drug using the
active ingredient or using the active ingredient for the indication
affect the rights of the patent owner?
Answer 11. This is a legal question I am not totally prepared to
answer. However, if a drug is compounded using a patented ingredient
but, the compounded product is restricted to pathways of administration
or strengths that are not made available by the patent holder and are
not approved by the FDA, then such compounding should be held
legitimate when ordered for therapeutic reasons by a prescriber and
through standards that I have outlined within this report.
Another issue at hand here that we have observed a few times by
large companies compounding drugs is where the company seeks and
receives a patent on a compounded drug that is not approved by FDA. The
patent supposedly prevents other practitioners from compounding the
product but the patent holder becomes the sole source of the product
and provides it in bulk within interstate commerce. Distributions are
made sometimes by prescription, sometimes by invoice. This type of
practice would seem to fall under the definition of manufacturing but,
to my knowledge, no enforcement by FDA has been forthcoming. In
addition, no data on the compound or its clinical efficacy has been
submitted to FDA for review or analysis in these cases.
Prepared Statement of the National Association of Chain Drug Stores
The National Association of Chain Drug Stores (NACDS) is providing
a written submission for the record on the hearing held on October 23,
2003 regarding ``Federal and State Role in Pharmacy Compounding and
Reconstitution: Exploring the Right Mix to Protect Patients.'' NACDS
represents 210 chain pharmacy companies that operate nearly 35,000
community retail pharmacies in the United States and provide more than
70 percent of the approximately 3.1 billion prescriptions dispensed in
the United States.
Prescription compounding is a traditional function of the practice
of pharmacy that has been and should continue to be regulated by state
boards of pharmacy. Compounding is an important part of patient care
because many patients need prescription products that are not made
commercially by drug manufacturers, and compounding by pharmacists is
the only way these products can be made available.
The definition of what constitutes compounding is consistent from
State to State. It generally involves mixing two or more drug
substances together to deliver a drug to a patient that is generally
not commercially available in the form or quantity prescribed. Most
retail based prescription compounds are for creams, lotions, ointments,
liquids, or suppositories that are not generally commercially
available. Some pharmacies do more compounding than others, depending,
for example, if they are located near dermatologists' offices.
Pharmacists are trained to compound prescriptions and are tested on
this competency. State boards license pharmacies after ensuring, among
other things, that they have the proper tools and equipment to compound
prescription products. State boards also regularly inspect pharmacies,
including their compounding practices. The extent of compounding varies
widely among pharmacies. Some pharmacies may only compound one or two
products per day, while others might compound more.
Some chain pharmacies may have a local or regional central
compounding facility that they use to compound frequently-ordered
products that are not commercially available, such as suppositories,
which are then distributed to individual retail stores in that chain.
These compounded products are being made in anticipation of
prescriptions for these products based on historical prescribing
patterns of physicians.
While there may not be any specific amount of product that can be
made before ``compounding'' becomes ``manufacturing'', the FDA's
compounding compliance guideline serves as a good basis for making the
distinction. Most traditional compounding is based on individual
prescription orders for individual patients for products that are not
commercially available, as described above. We believe that this
standard--compounds being made in response to or in anticipation of
prescriptions being ordered--is a good way to distinguish compounding
from manufacturing.
Sometimes, a physician will want a pharmacist to make a different
dosage form of a commercially available product, or a different
strength of a commercially available product. These functions fall
within the scope of pharmacy compounding.
FDA and State boards should work together to identify sites that
are in violation of FDA's compounding compliance guideline and both
parties should take action to stop practices that are more akin to
manufacturing than compounding. We want to work with the committee to
assure that only safe, effective, and quality-compounded products are
provided to patients.
Response to Questions of Senator Kennedy From Sarah Sellers
Questions 1. I would like your views about how the line between
compounding and manufacturing should be drawn. However you would
propose it be drawn, please describe what inspection and enforcement
authorities the U.S. Food and Drug Administration would need to enforce
the definitional line.
Answer 1. The line should be consistent with federal animal drug
regulations under the Animal Medicinal Drug Use Clarification Act
(AMDUCA). Compounding should be restricted to the traditional practice
of manipulating FDA-approved products for the special needs of patients
pursuant to a prescriber, patient and pharmacist relationship (referred
to by compounding pharmacists as ``the triad''). The triad relationship
must include full disclosure of risk to patients and prescribers and
financial incentives for pharmacists to compound should be discussed.
This definition of compounding is consistent with current pharmacists'
professional training in compounding, which was admitted by the
American Pharmacists' Association to be limited at the October 2003
hearing. The introduction of and access to raw chemical ingredients for
compounding has resulted in the growth and commercialization of an
unregulated drug manufacturing industry under the guise of compounding-
it is this emerging industry which has raised important safety
concerns.
Question 2. However you might define compounding, might there
nonetheless be large-scale compounding that warrants more active
regulation by the Food and Drug Administration? If so, would you
recommend regulation short of regulation as a manufacturer, and if so,
what would you recommend?
Answer 2. Yes. There are cases where large scale compounding
warrants more active regulation by the FDA. In 2001, the FDA issued a
warning letter to IV Systems Division of Baxter Healthcare Corp. then
engaged in the large scale compounding and interstate distribution of
intravenous solutions outside the scope of the approved drug labeling
(the company extended the expiration dating on the pharmacy-mixed
solutions). The inspection also revealed significant violations of the
Current Good Manufacturing Practice for Finished Pharmaceuticals (CGMP)
21, CFR 210 and 211. Such findings raise concerns regarding population
exposures to drugs produced and labeled outside of FDA oversight that
carry greater risks of being substandard (sub or super-potent or
adulterated with bacterial, fungal or other contamination). For the
case above, where the starting materials were FDA-approved dosage forms
manipulated or mixed into final products for administration, a system
short of federal oversight may be sufficient. Unfortunately, most state
boards of pharmacy have little or no public health expertise.
Pharmacists are not trained public health experts, and most Board
inspectors are not even trained health professionals. Without very
specifically written inspection protocols and advanced training in good
manufacturing practices, it is doubtful that Boards could have any
meaningful oversight of such practices. However, state health
departments may. In some states the Boards of Pharmacy fall under the
departments of professional regulation, while in other states the
Boards fall under the state departments of health. The state of Florida
has a pharmacy services division that oversees drug manufacturing
issues for the state, works closely with the FDA, and is independent of
the Florida Board of Pharmacy. There is likely to be greater access to
public health experts in states where the boards fall within the
departments of health-this may provide for more effective oversight.
Question 3. Dr. Sellers included a proposal for Federal legislation
enhancing the regulation of compounding. Please comment on her
proposal. What portion of her proposal do you believe must be
accomplished at the Federal level and what portion can safely be
achieved at the State level?
Answer 3. The level of regulation of compounding must be decided
through an analysis of risk. The following framework is suggested:
Professional/State Regulation
Formulate: To include reconstitution, and admixing (both sterile
and non-sterile) where the starting materials are FDA-approved dosage
forms, and approved inactive ingredients. Risk levels based on:
+ Starting materials
+++ Environmental factors (setting, training, etc)
++ Dosage form
+ PK factors (liberation and absorption)
+++ QA factors
State/Federal Regulation
Reformulate: To include change in dosage form (both sterile and
non-sterile) where the starting materials are FDA approved dosage
forms, and approved inactive ingredients. Risk levels based on:
+ Starting materials
+++ Environmental factors (setting, training, etc)
+++ Dosage form
+++ PK factors (liberation and absorption)
+++ QA factors
Federal Regulation
Manufacture: To include the de novo formulation of a dosage form
from bulk API's and approved inactive ingredients. Risk levels based
on:
+++ Starting materials
+++ Environmental factors (setting, training, etc)
+++ Dosage form
+++ PK factors-all
+++ QA factors
Question 4. Is it legitimate for a pharmacist to dispense a
compounded drug if the prescriber has not indicated in the prescription
that a specially compounded drug is required by the patient, or if the
pharmacist has not verified with the prescriber that it is appropriate
to dispense a compounded product?
Answer 4. No. In addition, a compounded drug should not be
dispensed if the prescriber has not specifically requested a compounded
product, and this request should not be solely based on a solicitation
from a compounding pharmacist. In some cases, compounding pharmacies
are claiming certain drugs are experiencing shortages and that the only
options are compounded versions of the FDA-approved drugs. In other
cases, pharmacists are recommending compounded products for unconfirmed
``allergies'' without discussing the unique risks of using compounded
drugs with prescribers or patients. Physicians and patients who are not
aware of the risks associated with the use of compounded drug products
may assume that the products are uniform in standards with FDA-approved
products when in fact they are not. This issue raises the concern over
pharmacist self-referral and solicitation for profit at the expense of
consumers (vulnerable, sick patients). Historically, physicians have
identified the need for compounded drugs and have written specific
prescriptions for the specialized dosage forms noting what specific
ingredients to use and how the drug should be formulated. Increasingly,
pharmacists are designing their own recipes, formulating and
substituting compounded drugs for FDA-approved products without the
educated and knowledgeable consent of prescribers and/or patients. This
should not be permitted.
Question 5. Do you believe that a pharmacist who compounds drugs
that are distributed interstate is in fact a manufacturer? Can a
pharmacist who distributes drugs interstate truly have a pharmacist-
prescriber-patient relationship? Can a pharmacist who is not licensed
in a State lawfully dispense compounded drugs to patients in that
State? Do you believe that interstate distribution of compounded drugs
should itself be grounds for regulation by the Food and Drug
Administration?
Answer 5. Yes. Health professionals have suggested that patients
receiving compounded drugs be very closely monitored for any adverse
events (including therapeutic inefficacy) precisely because the drugs
are unpredictable, without uniform standards, without determinations of
safety and efficacy and produced outside GMP regulations. This requires
both communication and observation, which cannot be done from a
distance. If a compounded drug has been made improperly it may be very
difficult to get a timely replacement resulting in the patient's
delayed access to effective treatment (for example, a mixture in which
the active drug precipitates out thus rendering it ineffective). The
homecare industry has set up special contracts with local pharmacies
for such emergencies which would be difficult to achieve for
compounding pharmacies.
Question 6. What can Congress do to encourage the States to
regulate pharmacy compounding more thoroughly?
Answer 6. State boards of pharmacy lack public health expertise. A
review of the mission statements of some boards reflect an economic-
based focus with weak public health mandates. Boards in general are
good at enforcing licensing and education requirements for
professionals and for detecting diversion and substance abuse; however,
they lack an appreciable understanding of public health, pharmaceutical
regulation and risk management. The regulation of compounding requires
an infrastructure where these subjects are well understood. It is
reasonable to suggest such oversight include state departments of
health, where public health expertise is concentrated.
Question 7. Please identify the scientific evidence and the
anecdotal evidence that compounded drugs are safe and effective.
Answer 7. By definition, compounded drugs are not ``safe and
effective''. ``Safe and effective'' is a regulatory designation for
drugs that have undergone the rigors of the FDA approval process-a
system established by Congress in response to major public health
threats from adulterated, substandard and fraudulent products that have
had harmful health effects on consumers throughout history. The FDA
relies on well-designed pre-clinical and clinical trials and post
marketing surveillance for weighing whether the intended benefits of
specific drugs in specific dosage forms outweigh potential risk of harm
to patients. Compounded drugs should never be represented as ``safe and
effective'', but rather with respect to risk-under very specific
circumstances the benefits of using a compounded drug may outweigh the
risks associated with using the unregulated, pharmacymade product.
Question 8. Please identify the scientific evidence and the
anecdotal evidence that compounded drugs are not safe or are not
effective.
Answer 8. The risks of drugs are identified through scientific
research including postmarketing surveillance, a safety system which
compounded drugs are not subjected to. Drugs that have not undergone
the drug approval process, which are not manufactured under Good
Manufacturing Practices and which are not labeled for safe use are not
``safe and effective''. To suggest otherwise misleads consumers and
undermines the federal drug approval process. Scientific evidence
published in the form of case reports, epidemiologic studies and
compounded drug analyses have concluded that compounded drugs can pose
significant health risks to patients. In addition, reports in the media
have drawn attention to deaths, paralyses and poisonings caused by
compounded drugs.
Question 9. If the balance of evidence does not clearly indicate
that compounded drugs are safe and effective, how should that affect
our decisions about the sort of regulation that is required, even
taking into account the acknowledged need for compounded drugs?
Answer 9. Compounded drugs are not ``safe and effective-compounding
should therefore be limited to the traditional practice of manipulating
FDA-approved products according to unsolicited prescriptions from
licensed prescribers where the intended benefit of using an unregulated
product is likely to outweigh the inherent risks(subpotency,
superpotency, adulteration, contamination)-such decisions must be made
by prescribers educated in the risks of unregulated drug production and
patients in consultation with pharmacists.
Question 10. If the balance of evidence indicates that problems of
safety or effectiveness of compounded drugs are infrequent or isolated
and not systemic, and considering the acknowledged need for compounded
drugs, how should that affect our decisions about the sort of Federal
regulation required?
Answer 10. The notion that problems of safety or effectiveness with
compounded drugs are infrequent or isolated has been supported by some
pharmacy trade groups; however, there is actually very little
``evidence'' to support this conclusion. As the GAO pointed out at the
hearing, there is an absence of effective oversight and surveillance of
compounding and the use of compounded drugs. Public health experts have
pointed out that the cases of deaths, injuries, contaminations and
substandard drug exposures are ``tip of the iceberg cases"-because of
the lack of surveillance, most of the problems are likely undetected.
It is logical to assume that drugs produced outside a regulatory
framework established to minimize population exposures to ineffective,
adulterated and/or misbranded medications are likely to carry greater
risks to consumers. This was suggested by the FDA survey which found a
34% failure rate for potency and purity for compounded drugs purchased
and shipped interstate. This study was admitted to lack
generalizability by the FDA, though it was indeed hypothesis
generating-it does not take a large sample size to find a big problem.
Question 11. If an active ingredient or the indication for an
active ingredient is patented, how does compounding a drug using the
active ingredient or using the active ingredient for the indication
affect the rights of the patent owner?
Answer 11. Though I am not a patent attorney, I am familiar with
some of the concerns represented to me by industry.
Pre-marketing,
For some small manufacturers and biotech companies, compounders are
competing with drugs that are still in clinical trials which may affect
their ability to bring safe and effective, FDA-approved drugs to
market. Direct competition with compounders may reduce the size of the
market for ethical manufacturers, and may in fact cause greater harm to
companies if the compounded copies of drugs in trials are unsafe and
result in patient injuries. Compounded sustainedrelease versions of
Acorda's 4-aminopyridine are being compounded and marketed for MS-some
of the dosage forms analyzed have not released the drug properly which
may result in toxicity (the drug has the potential to cause seizures).
Compounded versions of Provensis's polydocanol injection are being
marketed to physicians as an injectable varicose vein treatment;
however, the raw chemical ingredient is only available as a non-sterile
industrial grade chemical.
Marketed
For already marketed drugs, compounding can also reduce markets
directly and indirectly through safety concerns. The makers of the
drugs Viagra and Oxycontin have had safety concerns associated with
compounded copies of their drugs. For drugs reimbursed under Medicare
Part B, drug makers have asserted large percents their markets have
been taken over by compounders who are making inferior, unsafe
products. Evidence to support the industry's claims exists in recalls
and warning letters issued by the FDA (Med-Mart Pharmacy, Unique
Pharmaceuticals, Lee Pharmacy, Med-4-Home, Urgent Care Pharmacy, Docs
Pharmacy, Portage Pharmacy/Innovative Services).
Market Failures
Finally, where a substantial compounding market already exists,
manufacturers may decide not to bring a product through the approval
process under an NDA or ANDA as is the case currently with drugs used
in implanted spinal pumps and drugs used in nasal nebulizers.
Prepared Statement of Roger L. Williams, M.D.
Senator Bond, Senator Roberts, Chairman Gregg, Ranking Member
Kennedy, and distinguished members of the Committee, my name is Roger
L. Williams, M.D., and I am Executive Vice President and Chief
Executive Officer of United States Pharmacopeia. USP appreciates the
opportunity to provide its views as they relate to efforts by this
Committee and Congress to assure the quality and safety of compounded
drugs and to protect patients who rely on these customized medications
to meet their medical treatment needs.
United States Pharmacopeia is the nation's oldest and most
respected standard-setting organization committed to advancing public
health. Founded in 1820, this non-profit entity ensures the quality and
consistency of medicines; promotes the safe and proper use of
medications; verifies ingredients in dietary supplements; and focuses
on optimal health care delivery for professionals, patients, and
consumers.
USP standards are developed by a unique process of public
involvement and are accepted worldwide. The organization achieves its
goals through the contributions of volunteers representing pharmacy,
medicine, and other health care professions, as well as science,
academia, the federal government, the pharmaceutical industry, and
consumer organizations. USP provides standards for more than 4,000
prescription and non-prescription drugs, dietary supplements,
veterinary drugs, and health care products. These standards are
presented in a combined text consisting of two compendia--the United
States Pharmacopeia (USP) and the National Formulary (NF). This text is
continuously revised to account for new therapeutic ingredients and
products and advances in analytical procedures. Revised text appears in
an annual edition, which becomes official in January of each year and
two Supplements.
Congress has repeatedly recognized USP's expertise as a standard-
setting body. Principal recognition occurs as a result of Congress's
recognition of USP-NF as official compendia of the United States.
Congress's Federal Food, Drug and Cosmetic Act (FDCA) makes them
enforceable by the Food and Drug Administration (FDA). These standards
are also recognized by state laws and are used to govern state
practices, such as those involving pharmacy practice.
We commend you for your leadership in convening this hearing in the
wake of deaths and serious injuries caused by contaminated or subpotent
compounded medications. We believe this Committee's examination of the
quality and safety of compounded prescription drugs, as well as its
evaluation of the extent and effectiveness of federal and state
regulatory oversight of compounding, will result in stronger patient
and consumer protection.
As you undertake this inquiry beginning with today's hearing and
continue it through future hearings, USP stands ready to assist you by
making available our expertise and professional advice. Specifically,
USP believes it can play a leading and helpful role, working with this
Committee and Congress, federal and state government, compounding
pharmacists, and other relevant organizations, in developing effective
national standards not only for compounded preparations but also for
the practice of compounding. USP achieves these process and product
standards by working with involved stakeholders who create draft
documents for public comment. USP's public comment process occurs via
the Pharmacopeial Forum and is similar to the federal government's
Federal Register.
OVERVIEW AND IMPORTANCE OF PHARMACY COMPOUNDING
Drug compounding is the process of mixing, combining, or altering
two or more ingredients, or components, to produce a medication
designed to meet an individual patient's need. Pharmacy compounding is
regarded as a core component of pharmacy practice. It ranges from
preparation of simple topical products to highly complex mixtures
intended for parenteral administration. According to one estimate,
compounded drugs account for between one and ten percent of all
prescriptions written.
The modern-day practice of pharmacy traces its roots to compounding
in the formative years of medicine when few commercial products were
readily available. This method was used to prepare medicines for
thousands of years, but declined with the rise of modern pharmaceutical
manufacturing. Despite the advent of modern, mass-produced drug
therapies, compounding still plays a critical role in health care
delivery. Indeed, compounding has enjoyed a resurgence in recent years
due to product line discontinuations, shortages of manufactured
medicines, and customization of medicines for individuals.
Today, physicians and pharmacists turn to compounding when patient
needs cannot be met by commercially manufactured medications produced
for the mass market. Patients often require therapies with different
formulations and strengths, and compounding enables physicians to
create a ``customized'' treatment to address their specific medical
problem. Given the added cost and effort involved in developing
customized drug therapies for a handful of patients, it makes no
economic sense for drug companies to produce them. For this reason,
compounding ensures that these patients can obtain the effective drug
treatments they need. Pharmacy compounding also provides treatment
alternatives for patients who are allergic to commercially available
products, as well as for administration in special cases.
Compounded drugs are prepared by a pharmacist as authorized by a
prescription from a treating physician. Unlike pharmaceutical
manufacturing, which entails mass production and distribution, the
compounding of drugs involves physicians, pharmacists, and patients in
ensuring proper patient care, monitoring, and follow-up.
REGULATION OF PHARMACY COMPOUNDING
State boards of pharmacy have traditionally regulated compounding
as a component of pharmacy practice. Because pharmacy compounding
results in the preparation of drug products, federal drug laws also
apply. The provisions in the governing law, the Federal Food, Drug, and
Cosmetic Act (FDCA), are generally directed to pharmaceutical
manufacturers. In 1997, the FDCA was amended to include a section
(503A) specifically governing pharmacy compounding. In 2002, however,
this law was struck down as unconstitutional. Subsequently, FDA
reissued a pharmacy compounding compliance policy guide, CPG 460.200
(originally issued in 1992), which attempts to distinguish between
pharmacy compounding and manufacturing but is not intended to provide
uniform, specific parameters and standards to guide compounding
practice. Currently, there is no national standard for compounded drug
products other than the United States Pharmacopeia-National Formulary.
USP'S ROLE IN SETTING QUALITY STANDARDS FOR COMPOUNDED DRUGS
The United States Pharmacopeia plays a significant role in setting
critical quality standards for compounded drugs. Its role evolved from
its expertise and experience in formulating similar standards for
manufactured drugs. The first USP was published in 1820 and began as a
``recipe'' book to promote uniformity in drugs (a drug includes its
active ingredient[s] and excipients) that were generally available in
the United States at that time. Prior to the publication of USP, the
quality of drugs varied between cities and regions and from apothecary
to apothecary. In 1820, and for many years thereafter, the preparation
of a medicine by a pharmacist or other professional, now termed
compounding, was the order of the day. Over the last several decades,
this practice has generally been supplanted by modern pharmaceutical
manufacturing.
In recognition of this transition, the USP, through the activities
of its Council of Experts (formerly the Committee of Revision), changed
the content of USP and reduced the recipes for the compounding
professional and for pharmaceutical and other manufacturers to
standards that help assure their quality, purity, and strength. These
standards can be enforced by federal, state, and other regulatory
bodies in the United States and are also used in many other countries.
In 1975, USP acquired the National Formulary (NF), which contains
standards for excipients.
USP-NF provides monographs for ingredients and products. These
monographs contain standards (i.e., definitions, descriptions, labeling
and storage statements, specifications) for drugs, which include
biologics, devices, and dietary supplements. A specification provides
specific tests, together with procedures for the test and acceptance
(pass/fail) criteria. USP-NF continues to contain recipes for
compounded preparations, but these are only a small fraction
(approximately 100) of the many monographs (approximately 4,000) in
USP-NF. As before, the purpose of the USP-NF is to provide a single
standard for medicines used in the United States to ensure product
uniformity and quality. This is especially important given the number
of manufacturers and compounding professionals who prepare drugs that
have the same names.
The Federal Food, Drug and Cosmetic Act (FDCA) states that drugs
recognized in the USP-NF must adhere to compendial standards for
quality, purity, and strength. If a drug does not meet these standards,
it is considered adulterated, unless the final drug product is labeled
as ``not USP'' and provides the differences from the compendia in
quality, purity, and strength standards. The FDCA does not
differentiate between manufactured and compounded drugs. Therefore,
this section of the law applies to all drugs--manufactured and
compounded--that are available in the United States. With respect to
manufactured drugs, pharmacists who purchase drugs from reputable
manufacturers and store them appropriately are most likely to dispense
drugs that adhere to compendial standards. Compounded drugs prepared
pursuant to a practitioner's prescription must also meet compendial
requirements, if the prescription uses the compendial name. Pharmacists
must be aware that if they prepare medications that are named in the
USPNF, these products must meet USP-NF standards for quality, purity,
and strength. This includes adherence to ingredient standards and/or
recipes provided in the compendia for their preparation. Alternatively,
if a drug product does not meet USP-NF standards, the drug label should
include the words ``not USP'' and must state the way in which the
product deviates from the standards in the USP-NF.
When a physician writes a prescription for a manufactured or
compounded drug that appears in the USP-NF the law expects the
pharmacist to dispense the drug called for in the prescription or else
the dispensed drug may be considered misbranded. A physician does not
have to designate the item as USP.
The appearance of compounding monographs in the USP-NF is one of
several important elements to assure the good quality and benefit of a
compounded medicine. It provides uniformity in the prescribing and
preparation of these medicines as required by law. In recent years,
with the resurgence of compounding, USP began adding monographs with
formulas for preparations of specific compounded drugs and preparing
General Chapters for compounding practice. To date, the USP-NF contains
approximately 100 monographs that can be used in pharmacy compounding
practice. In addition, the compendia contain two General Chapters on
pharmacy compounding: Chapter <795> ``Pharmaceutical Compounding-
Nonsterile Preparations'' and Chapter <797> ``Pharmaceutical
Compounding, Sterile Preparations.'' These standards and guidelines are
being updated. Two new General Chapters are proposed--Chapter <1075>
``Good Compounding Practices'' and Chapter <1061> ``Pharmaceutical
Calculations'' for inclusion in the compendia.
A prescriber who writes a prescription for a particular compound
that appears in the USP-NF has defined the medicine to be prepared.
Pharmacists who adhere to the compendia prepare a medicine with defined
quality standards. Most importantly, adherence to compendial
requirements is required by the FDCA. The benefit (safety and efficacy)
of a compounded preparation is the responsibility of the practitioner
who writes the prescription, subject to practice standards and
applicable federal and state laws. When the USP-NF does not contain a
monograph for a compounded preparation or ingredient, compounding
professionals should use their judgment and conform to the standards of
practice, as well as applicable laws, in compounding a medicine.
A professional who compounds a drug that has a recipe that is
recognized in the USP-NF must adhere to that recipe. If the compounding
professional does not do so, he or she checks with the prescriber to
authorize the alternative formula. Then, depending on the nature of the
difference, the product should be labeled appropriately, either with a
different name or by an indication that it is not USP and how it
differs. If an ingredient appears in the USP-NF, a pharmacist should
compound the medicine by use of ingredients that meet the compendial
standards. A drug that appears in the USP-NF with analytical standards
but with no formula for preparation may be compounded by a pharmacist,
who must use his or her professional judgment, but the compounded
product must technically meet the standards required in the monograph
when tested with the analytical procedure in the monograph. This is
likely to be an issue if the pharmacist prepares an inferior product
which is subsequently shown to fall outside compendial standards.
USP's Pharmacy Compounding Expert Committee has issued several
recipes for the preparation of compounded products. These recipes
appear in the USP-NF and include:
Cefazolin Ophthalmic Solution
Cocaine and Tetracaine Hydrochlorides and Epinephrine Topical
Solution
Hydralazine Oral Solution
Indomethacin 1 % Topical Gel
Ketoconazole Oral Suspension, Plain
Ketoconazole Oral Suspension, Sugar-Free
Morphine Sulfate High Potency Suppositories, PEG and FA Base
Progesterone Suppositories, PEG and FA Base
Rifampin 1% Oral Suspension
Sodium Hypochlorite Topical Solution
Suspension Structured Vehicle, Plain
Suspension Structured Vehicle, Sugar-Free
Tetracycline Oral Suspension, Plain
Tetracycline Oral Suspension, Sugar-Free
Xanthan Gum Solution
Many more (approximately 1,000) of these recipes are needed to
cover the types of preparations now compounded in the United States.
The development of these recipes for USP is not easy and requires
laboratory testing to confirm that the preparation has the quality
attributes required by the monograph and that these attributes are
maintained during the period of use by the patient.
Overall, compounded preparations are generally agreed to be a
useful element in the therapeutic armamentarium of the practitioner.
Together, federal and state officials, USP, practitioners, consumers,
and many others can create an environment whereby patients can receive
wellcompounded preparations that contribute to their health and well-
being.
USP is exploring with the American Pharmacists Association, the
National Association of Boards of Pharmacy, and other organizations the
development of a voluntary national program that will promote
consistently high quality compounded medication by accrediting
compounding pharmacies, certifying compounding pharmacists, and
requiring adherence to USP-NF standards. This program would be a
coordinated national program to oversee compounding practices. As part
of this program, USP hopes to expand the availability of compounded
preparation monographs in USP-NF and expand practice standards where
needed. Adequate resources will be needed for the proposed program,
just as adequate resources are needed for FDA to control pharmaceutical
manufacturing.
CONCLUSION
We appreciate the opportunity to provide our views with respect to
concerns that have surfaced about compounded drug products in an effort
to improve the quality and safety of these medications and protect
patients and consumers who rely on them. Over the next several months,
we look forward to working with you, this Committee, other members of
Congress, FDA, stakeholders in the proposed program, and the public at
large to develop effective solutions that will increase the quality and
safety of compounded drugs, safeguard consumers, ensure better health
outcomes for patients, and protect pharmacists and other healthcare
practitioners who legally and appropriately compound medicines. Thank
you.
Response to Questions of Senator Kennedy From William Kennedy
Question 1. I would like your views about how the line between
compounding and manufacturing should be drawn. However you would
propose it be drawn, please describe what inspection and enforcement
authorities the US Food and Drug Administration would need to enforce
the definitional line.
Answer 1. I believe the FDA should have authority to regulate and
enforce compounding regulations. Simply enforcing the regs currently on
the books would have a huge impact on the mass compounding market
proliferating around the country. All drug manufacturers in the United
States must be approved and regulated/policed by the FDA. Compounding
is manufacturing. The US consumers deserve the protection afforded by
an active FDA. While I am not an expert on FDA enforcement, I believe
the use of ``cease and desist'' orders by local FDA employees, as well
as confiscation of product manufactured outside an FDA approved
facility, would send a strong message to the industry.
Question 2. However you might define compounding, might there
nonetheless be large-scale compounding that warrants more active
regulation by the Food and Drug Administration? If so, would you
recommend regulation short of regulation as a manufacturer, and, if so,
what would you recommend.
Answer 2. No. I do not believe there is any acceptable role for
large scale compounding. Manufacturing is manufacturing pure and
simple. We have laws and regulations in this country stating that drug
manufacturing must be subject to FDA standards. Pharmaceutical
companies have made massive investments based on this fact. Consumers
assume all drugs purchased in the United States are safe and produced
under safe conditions. Mass compounding outside regulated facilities
flies in the face of this belief.
The only exception for compounding should be the traditional
compounding of single prescriptions by licensed pharmacists, a service
that should continue to be available to the public. I, myself, am a
licensed pharmacist and a strong proponent of compounding on a
prescription by prescription basis.
Question 3. Dr. Sellers included a proposal for Federal legislation
enhancing the regulation of compounding. Please comment on her
proposal.
Answer 3. While I have not read Dr. Sellers proposal, I will say
that I was most impressed with her resume and her knowledge in this
field. She brings a national reputation to this process. I would
welcome her involvement as we seek a good outcome for the consumers of
this country.
Question 4. Is it legitimate for a pharmacist to dispense a
compounded drug if the prescriber has not indicated in the prescription
that a specially compounded drug is required by the patient, or if the
pharmacist has not verified with the prescriber that it is appropriate
to dispense a compounded product?
Answer 4. NO!
Question 5. Do you believe that a pharmacist who compounds drugs
that are distributed interstate is in fact a manufacturer? Can a
pharmacist who distributes drugs interstate truly have a pharmacist-
prescriber-patient relationship? Can a pharmacist who is not licensed
in a state lawfully dispense compounded drugs to patients in that
State? Do you believe that interstate distribution of compounded drugs
should itself be grounds for regulation by the FDA?
Answer 5. Yes, a pharmacist who compounds drugs distributed
interstate is clearly a manufacturer.
No. It should be obvious that a pharmacist who distributes drugs
interstate does NOT have a pharmacist-prescriber-patient relationship
that I refer to in the second part of my answer to question 2.
If the pharmacist has a patient relationship, I believe he could
dispense a single prescription made for the unique needs of that
patient. If a pharmacist is licensed in Missouri and has a pharmacy in
Kansas City and the patient comes from Kansas to have the prescription
filled, I could accept that. This is a far cry, however, from
documented cases in that area where literally millions of doses of
compounded drugs have entered commerce.
Question 6. What can Congress to encourage the States to regulate
pharmacy compounding more thoroughly?
Answer 6. I do not believe that the states can regulate pharmacy
compounding. I believe you will find that the majority of the members
of State Boards of Pharmacy are practicing pharmacists. In today's
highly competitive pharmacy/drug store market, independent pharmacists
are having a very difficult time making a living. Mass compounding
becomes attractive to them as a way to help supplement income. Self
regulation on a state by state basis will NOT work. You can cite
example after example of this throughout the country today.
Question 7. Please identify the scientific evidence and the
anecdotal evidence that compounded drugs are safe and effective.
Answer 7. I am the wrong person to ask this question. I believe the
testimony presented to the Committee has starkly displayed the dangers
to the consumer inherent in drugs compounded in non-FDA regulated
facilities. The most frightening aspect of this to me is the lack of
testing of the chemical components used to make drugs BEFORE the
manufacturing begins. In my facility I employ professional scientists
who must test all our raw ingredients for safety and integrity before
we begin manufacturing. In mass compounding facilities, they simply rip
the lid off the drum and begin mixing. Untested white powder can be
many things other than what a paper label states. Am I the only person
frightened at this prospect?
Question 8. Please identify the scientific evidence and the
anecdotal evidence that compounded drugs are not safe or are not
effective.
Answer 8. I would point to the news paper stories from across the
country which cite sickness and death resulting from unregulated mass
compounding. Further, FDA surveys which randomly tested the integrity
of compounded drugs showed a significant deficit in the integrity of
the drugs.
Question 9. If the balance of evidence does not clearly indicate
that compounded drugs are safe and effective, how should that affect
our decisions about the sort of regulation that is required, event
taking into account the acknowledged need for compounded drugs?
Answer 9. In the pharmaceutical industry, there is no confusion
about mass compounded, non-FDA regulated drug manufacture and FDA
regulated drug manufacture. The pharmacists and companies participating
in non-conforming drug manufacture know what they are doing and they
know they are outside the FDA lines. They are willing to risk this
because no one is lifting a hand to stop them. It is my feeling that
once even a small bit of enforcement begins, perhaps coupled with
significant financial penalties, you will find the industry will begin
to police itself. We have a desperate need to redefine the boundaries.
Once that is done, I believe you will see the mass compounding that is
now rampant decline.
Question 10. If the balance of evidence indicates that problems of
safety or effectiveness of compounded drugs are infrequent or isolated
and not systemic, and considering the acknowledged need for compounded
drugs, how should that affect our decisions about the sort of Federal
regulation required?
Answer 10. Please reference my comments in answering question 9. We
agree that single prescriptions, patient specific, should be compounded
by a pharmacist. What we are seeing is millions of doses being made and
shipped across the country for use as though they were FDA approved
products. How can anyone call this infrequent or isolated. The
economics of private pharmacies are such that this is becoming
systemic. The fact that classes are being offered publicly on how
pharmacists can benefit financially from compounding should tell you
this is systemic. The FDA must act, and soon!
Question 11. If an active ingredient or the indication for an
active ingredient is patented, how does compounding a drug using the
active ingredient or using the active ingredient for the indication
affect the rights of the patent owner?
Answer 11. I believe this is a question better answered by an
attorney.
[Whereupon, at 11:45 a.m., the committee adjourned.]