[Federal Register Volume 73, Number 185 (Tuesday, September 23, 2008)]
[Notices]
[Pages 54831-54834]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-22300]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2008-N-0481]
Topical Drug Products Containing Papain; Enforcement Action Dates
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing its
intention to take enforcement action against unapproved topical drug
products containing papain and persons\1\ who manufacture or cause the
manufacture of such products or their shipment in interstate commerce.
Topical drug products containing papain are marketed, without approved
applications, to debride necrotic tissue and liquefy slough in acute
and chronic lesions. Potentially serious adverse events have been
reported with topical drug products containing papain. Topical drug
products containing papain are new drugs that require approved
applications because they are not generally recognized as safe and
effective. Currently no firm has an approved application to market a
topical drug product containing papain. Manufacturers who wish to
market topical drug products containing papain must obtain FDA approval
of a new drug application (NDA) or an abbreviated new drug application
(ANDA).
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\1\ A ``person'' includes individuals, partnerships,
corporations, or associations (21 U.S.C. 321(e)).
DATES: This notice is effective September 23, 2008. For information
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about enforcement dates, see SUPPLEMENTARY INFORMATION, section III.B.
ADDRESSES: All communications in response to this notice should be
identified with Docket No. FDA-2008-N-0481 and directed to the
appropriate office listed as follows:
Regarding applications under section 505(b) of the Federal Food,
Drug, and Cosmetic Act (the act) (21 U.S.C. 355(b)): Division of
Dermatology and Dental Products, Office of New Drugs, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Silver Spring, MD 20993-0002.
All other communications: Jennifer Devine, Center for Drug
Evaluation and Research (HFD-310), Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 51 (rm. 5240), Silver Spring, MD 20993-0002.
FOR FURTHER INFORMATION CONTACT: Jennifer Devine, Office of Compliance,
Division of New Drugs and Labeling Compliance, Center for Drug
Evaluation and Research (HFD-310), Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 51 (rm. 5240), Silver Spring, MD 20993-0002,
301-796-3347, e-mail: [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
Papain is a protein-cleaving enzyme derived from papaya fruit
(Carica papaya) and certain other plants. The latex of the papaya plant
and its green fruits contain two proteolytic enzymes, papain and
chymopapain. The latter is most abundant, but papain is twice as
potent. The presence and effects of proteases in papaya fruit latex
have been well known since the 1750s, but it was not until the 1870s
that the importance of papaya latex as a source of enzymes was
recognized. Although the exact year is unknown, marketing of topical
papain drug products in the United States began before 1962.
Topical drug products containing papain are used for the
debridement of necrotic tissue and liquefication of slough in acute and
chronic lesions, such as diabetic ulcers, pressure ulcers, varicose
ulcers, and miscellaneous traumatic infected wounds. These products
generally combine papain with other active ingredients (such as urea,
chlorophyllin copper complex, and copper sodium chlorophyllin), which
are intended to promote healthy granulation, control local
inflammation, reduce wound odors, and rehydrate skin. In addition,
papain is marketed in oral formulations for a variety of indications,
including as an aid in protein digestion.\2\ It is also used in the
food industry as a meat tenderizer.\3\
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\2\ Lacy, D.F., Armstrong, L.L., Goldman, M.P., Lance, L.L.,
eds., Drug Information Handbook, 2008-2009; 17th edition.
\3\ See http://www.foodreference.com/html/fmeatttenterizer.html.
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Papain-containing drug products in topical form historically have
been marketed without approval, and because no firm obtained an
application for them prior to passage of the Drug Amendments of 1962,
they were not included in the Drug Efficacy Study Implementation (DESI)
review.
II. Safety and Efficacy Issues in the Use of Topical Papain Drug
Products
Adverse events associated with the use of topical papain products
reported to FDA raise serious safety concerns regarding these products.
Through January 2008,\4\ FDA has received 37 reports of adverse events
associated with topical papain products. In addition to several
complaints that the products were ineffective, the reports include
cases of potentially life-threatening hypersensitivity reactions.
Reactions described include serious cases of anaphylaxis and
anaphylactic shock that started within 15 minutes of topical papain use
and resulted in hospitalizations, including admissions to the intensive
care unit. Published literature also describes incidents of
hypersensitivity to other papain-containing products, including meat
tenderizer, contact lens solution, and adhesive removers in the beauty
industry. Another concern exists regarding patients with latex
sensitivity. Cross-reactivity between latex and papaya has been
documented in medical literature, and one of the cases reported to FDA
involved anaphylactic shock in a patient with a history of allergy to
latex. It is notable that labeling for currently marketed topical
papain products does not provide any warnings regarding
hypersensitivity reactions and latex cross-reactivity.
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\4\ Data in the current system date back to 1969, when FDA first
implemented an adverse event reporting system.
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FDA is particularly concerned about adverse events associated with
the use of papain-containing topical drug products in light of the
dearth of published well-controlled studies demonstrating the
effectiveness of those products. Given the absence of the kinds of
scientific studies routinely conducted by sponsors and submitted for
agency review as part of the FDA approval process, it is impossible for
the agency to assess either the amount of risk associated with these
products or the extent to which their benefits might justify their
risks, including severe, systemic, potentially life-threatening
hypersensitivity reactions.
III. Legal Status
A. Topical Papain Products Are New Drugs Requiring Approved
Applications
Based both on the safety considerations previously described and
the absence of published literature documenting that topical drugs
containing papain are safe and effective, such drugs are not generally
recognized as safe and effective under section 201(p) of the act (21
U.S.C. 321(p)) for any indication, including for the debridement of
necrotic tissue and liquefication of slough in acute and chronic
lesions. Therefore, a topical drug product containing papain, alone or
in combination with other drugs, is regarded as a new drug as defined
in section 201(p) of the act and is subject to the requirements of
section 505 of the act. As set forth in this notice, approval of an NDA
or an ANDA under section 505 of the act is required as a condition for
manufacturing or marketing all topical drug products containing papain.
After the dates identified in this notice, FDA intends to take
enforcement action as described in this notice against unapproved
topical drug products containing papain and persons who
[[Page 54833]]
cause the manufacture or interstate shipment of such products. Any
person who submits an NDA or an ANDA for a topical product containing
papain but has not received approval must comply with this notice.
This notice does not affect drugs containing papain in oral dosage
forms, which FDA intends to address at a later date.
B. Notice of Enforcement Action
Although not required to do so by the Administrative Procedure Act,
the act, or any rules issued under its authority, or for any other
legal reason, FDA is providing this notice to persons who are marketing
unapproved topical drug products containing papain that the agency
intends to take enforcement action against such products and those who
manufacture them or cause them to be manufactured or shipped in
interstate commerce. Manufacturing or shipping unapproved topical
products containing papain can result in enforcement action, including
seizure, injunction, or other judicial or administrative proceeding.
Consistent with policies described in the agency's guidance entitled
``Marketed Unapproved Drugs--Compliance Policy Guide'' (the Marketed
Unapproved Drugs CPG), the agency does not expect to issue a warning
letter or any other further warning to firms prior to taking
enforcement action relating to unapproved papain-containing topical
drug products. The agency also reminds firms and individuals that, as
stated in the Marketed Unapproved Drugs CPG, any unapproved drug
marketed without a required approved drug application is subject to
agency enforcement action at any time. The issuance of this notice does
not in any way obligate the agency to issue similar notices or any
notice in the future regarding marketed unapproved drugs.\5\
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\5\ The agency's general approach in dealing with these products
in an orderly manner is spelled out in the Marketed Unapproved Drugs
CPG. That CPG, however, provides notice that any product that is
being marketed illegally, and the persons responsible for causing
the illegal marketing of the product, are subject to FDA enforcement
action at any time.
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As described in the Marketed Unapproved Drugs CPG, the agency may,
at its discretion, identify a period of time during which the agency
does not intend to initiate an enforcement action against a currently
marketed unapproved drug on the ground that it lacks an approved
application under section 505 of the act in order to, for example,
preserve access to medically necessary drugs or ease disruption to
affected parties. With respect to unapproved topical drug products
containing papain, the agency intends to exercise its enforcement
discretion for only a limited period of time because these are drugs
with potential safety risks that lack scientific evidence of
effectiveness. Therefore, the agency intends to implement this notice
as follows.
For the effective date of this notice, see the DATES section of
this document. FDA intends to take action to enforce section 505(a) of
the act against any unapproved topical drug product containing papain
that is not listed with FDA in full compliance with section 510 of the
act (21 U.S.C. 360) before September 22, 2008, and that is
manufactured, shipped, or otherwise introduced or delivered for
introduction into interstate commerce by any person on or after
September 23, 2008. FDA also intends to take action to enforce section
505(a) of the act against any unapproved topical drug containing papain
that has a National Drug Code (NDC) number listed with FDA in full
compliance with section 510 of the act but is not being commercially
used or sold\6\ in the United States on September 22, 2008, and that is
manufactured, shipped, or otherwise introduced or delivered for
introduction into interstate commerce by any person on or after
September 23, 2008.
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\6\ For the purposes of this notice, the term ``commercially
used or sold'' means that the product has been used in a business or
activity involving retail or wholesale marketing and/or sale.
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However, for unapproved topical drug products containing papain
that are commercially used or sold in the United States, have a NDC
number listed with FDA, and are in full compliance with section 510 of
the act before September 22, 2008 (``currently marketed and listed''),
the agency intends to exercise its enforcement discretion as follows.
FDA intends to initiate enforcement action against any currently
marketed and listed unapproved topical product containing papain that
is manufactured on or after November 24, 2008 or that is shipped on or
after January 21, 2009.\7\ Further, FDA intends to take enforcement
action against any person who manufactures or ships such products after
the dates set forth above. Any person who submits a new drug
application for a topical drug product containing papain but has not
received approval must comply with this notice.
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\7\ If FDA finds it necessary to take enforcement action against
a product covered by this notice, the agency may take action
relating to all of the defendant's other violations of the act at
the same time. For example, if a firm continues to manufacture or
market a product covered by this notice after the applicable
enforcement date has passed, to preserve limited agency resources,
FDA may take enforcement action relating to all of the firm's
unapproved drugs that require applications at the same time (see,
e.g., United States v. Sage Pharmaceuticals, 210 F. 3d 475, 479-480
(5th Cir. 2000) (permitting the agency to combine all violations of
the act in one proceeding, rather than taking action against
multiple violations of the act in ``piecemeal fashion'')).
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The agency, however, does not intend to exercise its enforcement
discretion as outlined previously if the following apply: (1) A
manufacturer or distributor of an unapproved topical drug product
containing papain covered by this notice is violating other provisions
of the act (including but not limited to, violations related to FDA's
current good manufacturing practices, adverse drug event reporting, or
labeling requirements) or (2) it appears that a firm, in response to
this notice, increases its manufacture or interstate shipment of
unapproved topical drug products containing papain above its usual
volume.
Nothing in this notice, including FDA's intent to exercise its
enforcement discretion, alters any person's liability or obligations in
any other enforcement action or litigation, or precludes the agency
from initiating or proceeding with enforcement action in connection
with any other alleged violation of the act, whether or not related to
an unapproved drug product covered by this notice. Similarly, a person
who is or becomes enjoined from marketing unapproved drugs may not
resume marketing of unapproved topical drug products containing papain
based on FDA's exercise of enforcement discretion as set forth in this
notice.
Drug manufacturers and distributors should be aware that the agency
is exercising its enforcement discretion as described previously only
in regard to topical papain drug products that are marketed under an
NDC number listed with the agency in full compliance with section 510
of the act before September 22, 2008. As previously stated, unapproved
topical drug products containing papain that are not currently
marketed, or that are currently marketed but not listed with the agency
on the date of this notice must have approved applications prior to
their shipment in interstate commerce. Moreover, any person or firm
that submits an NDA or an ANDA but has yet to receive approval for such
products is still responsible for full compliance with this notice.
C. Discontinued Products
Some firms may have previously discontinued the manufacturing or
distribution of products covered by this notice without removing them
from the listing of their products under section
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510(j) of the act. Other firms may discontinue manufacturing or
marketing listed products in response to this notice. Firms that wish
to notify the agency of product discontinuation should send a letter,
signed by the firm's chief executive officer, fully identifying the
discontinued product(s), including the product NDC number(s), and
stating that the product(s) has (have) been discontinued. The letter
should be sent to Jennifer Devine (see ADDRESSES). Firms should also
update the listing of their products under section 510(j) of the act to
reflect discontinuation of unapproved topical papain drug products.
Updating of listing information may be advantageous for a firm because
FDA plans to rely on its existing records, the results of a subsequent
inspection, or other available information when we evaluate whether to
initiate enforcement action.
This notice is issued under sections 502 and 505 of the act (21
U.S.C. 352) and under authority delegated to the Deputy Commissioner
for Policy under section 1410.10 of the FDA Staff Manual Guide.
Dated: September 8, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-22300 Filed 9-22-08; 8:45 am]
BILLING CODE 4160-01-S