[Federal Register Volume 63, Number 224 (Friday, November 20, 1998)]
[Rules and Regulations]
[Pages 64556-64588]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 98-31242]



[[Page 64555]]

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Part IV





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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21 CFR Parts 16 and 99



Dissemination of Information on Unapproved/New Uses for Marketed Drugs, 
Biologics, and Devices; Final Rule

Federal Register / Vol. 63, No. 224 / Friday, November 20, 1998 / 
Rules and Regulations

[[Page 64556]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 16 and 99

[Docket No. 98N-0222]
RIN 0910-AB23


Dissemination of Information on Unapproved/New Uses for Marketed 
Drugs, Biologics, and Devices

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is issuing final 
regulations pertaining to the dissemination of information on 
unapproved uses (also referred to as ``new uses'' and ``off-label 
uses'') for marketed drugs, including biologics, and devices. The final 
rule describes the new use information that a manufacturer may 
disseminate and describes the content of and establishes procedures for 
a manufacturer's submission to FDA before it may begin disseminating 
information on the new use. The final rule also describes how 
manufacturers seeking to disseminate information on a new use must 
agree to submit a supplemental application for that use within a 
specified period of time, unless a supplemental application already has 
been submitted or FDA has exempted the manufacturer from the 
requirement to submit a supplement. The final rule provides for 
requests to extend the time period for submitting a supplemental 
application for a new use and describes how a manufacturer can seek an 
exemption from the requirement to submit a supplemental application for 
the new use. Additionally, the final rule discusses FDA actions in 
response to manufacturers' submissions, corrective actions that FDA may 
take or require, and recordkeeping and reporting requirements. The 
final rule implements sections 551 through 557 of the Federal Food, 
Drug, and Cosmetic Act (the act) (21 U.S.C. 360aaa through 360aaa-6) as 
amended by section 401 of the Food and Drug Administration 
Modernization Act of 1997 (FDAMA).

DATES: The final rule is effective November 20, 1998. Written comments 
on the information collection requirements should be submitted by 
January 19, 1999.
ADDRESSES: Submit written comments on the information collection 
requirements to the Dockets Management Branch (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:
    Regarding biological products and devices regulated by the Center 
for Biologics Evaluation and Research: Toni M. Stifano, Center for 
Biologics Evaluation and Research (HFM-602), Food and Drug 
Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-827-3028;
    Regarding human drug products: Laurie B. Burke, Center for Drug 
Evaluation and Research (HFD-40), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2828;
    Regarding medical devices: Byron L. Tart, Center for Devices and 
Radiological Health (HFZ-302), Food and Drug Administration, 2098 
Gaither Rd., Rockville, MD 20850, 301-594-4639.

SUPPLEMENTARY INFORMATION:

I. Introduction

    In the Federal Register of June 8, 1998 (63 FR 31143), FDA 
published a proposed rule that would add to title 21 of the Code of 
Federal Regulations (CFR) a new part 99 entitled, ``Dissemination of 
Information on Unapproved/New Uses for Marketed Drugs, Biologics, and 
Devices.''
    The proposed rule was intended to implement section 401 of FDAMA. 
In brief, section 401 of FDAMA amended the act to permit drug, 
biologic, and device manufacturers to disseminate certain written 
information concerning the safety, effectiveness, or benefits of a use 
that is not described in the product's approved labeling to health care 
practitioners, pharmacy benefit managers, health insurance issuers, 
group health plans, and Federal and State Government agencies, provided 
that the manufacturer complies with certain statutory requirements. For 
example, the information that is to be disseminated must be about a 
drug or device that is being legally marketed; it must be in the form 
of an unabridged reprint or copy of a peer-reviewed journal article or 
reference publication; and it must not be derived from another 
manufacturer's clinical research, unless that other manufacturer has 
given its permission for the dissemination. The information must be 
accompanied by certain information, including a prominently displayed 
statement that the information discusses a use or uses that have not 
been approved or cleared by FDA. Additionally, 60 days prior to the 
dissemination, the manufacturer must submit to FDA a copy of the 
information to be disseminated and any other clinical trial information 
that the manufacturer has relating to the safety or effectiveness of 
the new use, any reports of clinical experience that pertain to the 
safety of the new use, and a summary of such information.
    A detailed description of section 401 of FDAMA appeared in the 
preamble to the proposed rule (see 63 FR 31143 at 31144 and 31145).

II. Highlights of the Final Rule

    Although the statute is very detailed, and the final rule closely 
tracks its provisions, there are some places where the regulation fills 
in the details of the statutory requirements. For example, the final 
rule defines terms that were not defined in the legislation (e.g., 
``supplemental application'' and ``clinical investigation,'' and it 
explains concepts that required additional explanation (e.g., what is 
meant by the term ``unabridged''). The final rule also sets forth the 
more detailed procedures for how to submit the required information to 
FDA before disseminating any new use information (e.g., where the 
information should be submitted and how many copies are required). 
Finally, the final rule defines what is meant by the basic criteria 
that the statute sets forth for granting an exemption from the 
requirement to submit a supplement application on the basis that it 
would be unethical or economically prohibitive to conduct the studies 
needed to submit a supplemental application.
    The final rule has been revised in response to comments received on 
the proposal. For example, Sec. 99.3 was revised to add a definition 
for pharmacy benefit manger, which is not included in the statute. The 
definition of ``clinical investigation'' in Sec. 99.3 also was revised. 
Section 99.101 was revised to reflect FDA's position that most journal 
articles and reference texts (as those terms are defined in the 
regulation) would be considered to be scientifically sound and to 
describe specific instances (e.g., letters to the editor, Phase 1 
trials in healthy individuals) when that would not be the case.
    Section 99.103 revised the mandatory statement that the 
disseminated information has not been approved or cleared by FDA. That 
section also was revised to ensure that the financial disclosures 
required under this part would be consistent with FDA's final rule on 
financial disclosures by clinical investigators.
    Sections 99.201(a)(4)(i)(B) and (a)(4)(ii)(B), 99.203(b), and 
99.401(b) were revised to clarify that for purposes of computing time 
periods that begin on the date of initial dissemination, FDA will look 
to the date that dissemination can begin. This clarification was

[[Page 64557]]

necessary because FDA will not know when a manufacturer actually begins 
to disseminate materials.
    Sections 99.203 and 99.303 were revised to clarify that there are 
two different ways that FDA can extend the time period for completing 
the studies needed to submit a supplemental application for a new use: 
One before any studies have begun and one after the studies have begun. 
FDA also revised the standard for granting an exemption from the 
requirement to submit a supplemental application on the basis that it 
would be economically prohibitive. The focus is now on the revenue from 
the new use rather than the revenue from the product.
    In Sec. 99.301, FDA clarified when it would require a manufacturer 
to keep records identifying the individual recipients of new use 
information as opposed to just the categories of such recipients. 
Finally, the final rule was revised to ensure that a decision on a new 
use submission would be made within 60 days.

III. Responses to Comments on the Proposed Rule

    FDA received over 50 written comments on the proposed rule. In 
addition, on July 8, 1998, FDA held a public meeting on the proposed 
rule. Thirteen speakers commented on the proposal. In general, the 
comments expressed a diverse range of opinions, both favoring and 
opposing the proposed rule, and were submitted by health professionals, 
medical organizations, consumer groups, patient groups, a medical 
journal, members of Congress, trade associations, and manufacturers.

A. General Comments

    Several comments addressed the concept of disseminating information 
on unapproved or new uses rather than the proposed rule itself. Other 
comments sought further restrictions on the dissemination of 
information on unapproved or new uses, while still other comments 
sought to expand the rule to cover more products.
    1. A number of comments expressed concern that the proposed rule 
could result in harm to patients. One comment expressed concern over 
the self-policing aspects of the rule. Another comment cited several 
examples where drugs were administered for unapproved uses and proved 
to be harmful. The comment stated that dissemination of information on 
unapproved uses for approved drugs would further encourage the use of 
``untested'' drugs and discourage clinical trials that would show 
whether the drugs are safe and effective for their intended uses. The 
comment asked FDA to ``revise or abandon these regulations so as to 
continue to protect consumers from untested and potentially dangerous 
drugs.'' One comment argued that the new rule was not ``warranted'' 
because the disseminated information may be inappropriate and would 
pose a significant risk to public health. The comment further argued 
that current practices in this area are the best way to handle 
information on unapproved uses. Finally, a number of comments expressed 
concern that FDA does not have sufficient resources to implement the 
regulation in a manner that can adequately protect the public health. 
Such comments urged FDA to direct adequate resources to implementation.
    Section 401(c) of FDAMA required FDA to issue regulations to 
implement sections 551 through 557 of the act by November 21, 1998. The 
final rule, which closely tracks the statutory language, represents 
FDA's effort to comply with that requirement. FDA is committed to 
implementing this new statutory authority consistent with its 
obligation to protect the public health.
    2. Several comments claimed that dissemination of information on 
unapproved or new uses of drugs for which pediatric labeling is not 
available would be contrary to section 505A of the act (21 U.S.C. 355A) 
as it pertains to pediatric studies of drugs because it would impede 
the development of pediatric data. Several comments said that 
dissemination of information on unapproved uses for pediatric therapy 
should be limited to drugs that have ``sufficient labeling in the ages 
of the children addressed by the information disseminated.'' Another 
comment noted that dissemination of information for an unapproved use 
of a drug in children when the drug's approved use has not been tested 
for safety in pediatric patients may pose even more risk than 
unapproved uses generally. Others said that for drugs without labeling 
for pediatric populations or specific age populations, drug 
manufacturers should not be able to disseminate unapproved use 
information about pediatric populations or about specific age 
populations not specified in the label, unless such information is 
specifically requested by the physician.
    FDA declines to amend the rule as suggested by the comments. It is 
FDA's hope that the statutory scheme set forth in section 401 of FDAMA 
and implemented by this part will actually stimulate research and the 
development of data on new uses, including pediatric uses. Moreover, 
nothing in section 401 of FDAMA or its legislative history suggests 
that Congress intended to exclude pediatric uses from section 551 of 
the act or to further limit how information on such uses can be 
disseminated. Finally, the act does not require that the disseminated 
information be specifically requested by a physician in order to be 
disseminated.
    Although FDA is not amending the codified language in any way, it 
does recognize that the potential dangers of unapproved uses in 
children may be greater than for adults because few drugs have been 
tested in children. The agency will take this into account in making a 
determination as to whether a proposed dissemination of information on 
a new use poses a significant risk to public health such that the 
dissemination under this part should not be permitted.
    3. One comment would revise the rule to exclude drugs that may be 
covered by orphan drug exclusivity. The comment explained that a 
manufacturer may obtain orphan drug exclusivity for a particular use of 
a drug, but that other manufacturers could be marketing the same drug 
for non-orphan indications. The comment stated that such other 
manufacturers could disseminate information on the orphan indication, 
thereby undermining the value of orphan drug exclusivity.
    There is no indication in section 401 of FDAMA or its legislative 
history that Congress intended the dissemination of information on 
unapproved uses of drugs and devices to undermine patent protection or 
exclusivity granted to a product under the Orphan Drug Act, the Waxman-
Hatch Amendments, or the pediatric exclusivity provisions in section 
111 of FDAMA. Therefore, an indication that is not included in a 
particular sponsor's approved product labeling because the indication 
is protected by patent or exclusivity is not eligible for dissemination 
under part 99.
    4. Several comments urged FDA to broaden the proposal to include 
over-the-counter (OTC) drug products being marketed under an OTC 
monograph.
    Section 401 of FDAMA requires that in the case of a drug, there be 
in effect for the drug an application filed under section 505(b) or (j) 
of the act. OTC drugs being marketed under an OTC monograph do not have 
an application filed under section 505(b) or (j) of the act in effect. 
Therefore, FDA declines to revise the rule as suggested in these 
comments.
    5. One comment stated that companies sometimes assist physicians 
and patients in obtaining reimbursement from Medicare, Medicaid, and 
private insurers by furnishing copies of journal articles and reference 
publications on unapproved

[[Page 64558]]

uses to the insurer or government agency when reimbursement is denied 
on the ground that use of the product is experimental. The comment 
concluded that this practice appeared to be legal prior to the passage 
of section 401 of FDAMA and asked FDA to clarify that it did not become 
illegal as a result of FDAMA.
    Prior to passage of FDAMA, the practice described in this comment 
was not permissible unless the unapproved use information was provided 
in response to an unsolicited request for such information. FDA's 
policy, which allows manufacturers to provide unapproved use 
information in response to an unsolicited request, was not affected by 
FDAMA (see section 557(a) of the act). Accordingly, manufacturers who 
wish to furnish unapproved use information as described in the comment 
may do so if it is in response to an unsolicited request. Otherwise, 
they must comply with the requirements set forth in section 401 of 
FDAMA and this part.
    6. One comment asserted that the proposal should recognize the 
specific legal authorization for manufacturers to provide off-label 
information to health care practitioners in response to an unsolicited 
request.
    Section 401 of FDAMA added a new section 557(a) of the act, which 
provides that nothing in section 551 of the act shall be construed as 
prohibiting a manufacturer from disseminating information in response 
to an unsolicited request from a health care practitioner. Although FDA 
does not construe section 557(a) of the act as a specific legal 
authorization for manufacturers to provide off-label use information to 
health care practitioners in response to an unsolicited request, 
Sec. 99.1(b) of the final rule recognizes this statutory provision.
    7. One comment stated that FDA should exempt manufacturers from the 
``pre-approval and reporting requirements'' when the primary focus of a 
publication is on the approved uses of the product.
    Section 401 of FDAMA and this part do not cover publications 
regarding approved uses. FDA intends to permit manufacturers to 
disseminate certain information that focuses primarily on approved uses 
and that report the results of studies that have been relied on by FDA 
in its approval or clearance of a drug or device without meeting all of 
the requirements set forth in this part. (Cf. Guidance to Industry on 
Dissemination of Reprints of Certain Published Original Data (61 FR 
52800, October 8, 1996). The agency was enjoined from applying this 
guidance document in Washington Legal Foundation v. Friedman, CA No. 
1:94CV1306 (D.D.C. July 30, 1998) (hereinafter referred to as WLF v. 
Friedman). FDA sought clarification on the scope of the order through a 
motion to amend the judgment in that case.) FDA plans to issue guidance 
on this issue at some time in the future pending clarification by the 
court.
    8. One comment suggested that FDA exempt manufacturers from the 
requirements set forth in this part if the new use that is the subject 
of the information being disseminated has been accepted as standard 
medical practice (i.e., indications listed in the United States 
Pharmacopoeia Drug Information for the Health Care Professional (USP 
DI) or American Hospital Formulary Service, etc.).
    FDA declines to create an exemption from the entire rule as 
suggested by the comment. Regardless of whether the unapproved use is 
listed in the USP DI or American Hospital Formulary Service, the 
statutory requirements in sections 551 through 557 of the act apply to 
a manufacturer who intends to disseminate information on the unapproved 
use for an approved product to health care practitioners, pharmacy 
benefit managers, health insurance issuers, group health plans, or 
Federal or State governmental agencies. Evidence that the unapproved 
use represents standard medical care may, however, enable the 
manufacturer to seek an exemption from the requirement to submit a 
supplemental application for the unapproved use if the manufacturer can 
demonstrate that it would be unethical to conduct the studies necessary 
for a supplemental application for the new use. A discussion of the 
``unethical'' exemption appears later in section III of this document.
    9. Some comments stated that the proposal properly reflects the 
intent of Congress and achieves the important goals of assuring the 
public health and encouraging the dissemination of information. Others 
argued that the proposal is contrary to congressional intent, 
paternalistic and cumbersome, and would restrict, rather than 
facilitate, access to information about new uses.
    Although FDA drafted the proposed rule to reflect congressional 
intent, the agency has revised the rule in response to specific 
comments. These revisions are meant to ensure that the final rule more 
accurately reflects congressional intent.

B. Comments on Specific Provisions

1. Subpart A--General Information
    a. Scope (Sec. 99.1). Proposed Sec. 99.1 described the scope of 
part 99, explaining that the part applies to the dissemination of 
information on human drugs, including biologics, and devices where the 
information to be disseminated pertains to the safety, effectiveness, 
or benefit of a use that is not included in the approved labeling for 
an approved drug or device or in the statement of intended use for a 
cleared device and the information is to be disseminated to a health 
care practitioner, pharmacy benefit manager, health insurance issuer, 
group health plan, or Federal or State Government agency.
    10. Several comments urged FDA to add pharmacists to the list of 
recipients of information under this part.
    Section 401 of FDAMA specifically lists who can receive the new use 
information under this provision and proposed Sec. 99.1 tracked that 
statutory provision. Therefore, FDA declines to amend the regulation as 
requested. However, to the extent that pharmacists fall within the 
definitions of ``health care practitioner,'' ``pharmacy benefit 
manager,'' health insurance issuer,'' or ``group health plan'' (see 
Sec. 99.3) they will be included as recipients of this information.
    b. Definitions (Sec. 99.3). Proposed Sec. 99.3 defined various 
terms, such as ``clinical investigation'' (proposed Sec. 99.3(b)), 
``health care practitioner'' (proposed Sec. 99.3(d)), ``new use'' 
(proposed Sec. 99.3(g)), ``scientific or medical journal'' (proposed 
Sec. 99.3(i)), and supplemental application (proposed Sec. 99.3(j)).
    11. One comment urged FDA to include a definition for ``pharmacy 
benefit manager'' and to include pharmacists in that definition.
    Although the statute defines the other recipients of information 
under this provision (i.e., health care practitioner, health insurance 
issuer, and group health plan), it does not define pharmacy benefit 
manager. FDA has revised the rule to define a ``pharmacy benefit 
manager'' (PBM) as ``a person or entity that has, as its principal 
focus, the implementation of one or more device and/or prescription 
drug benefit programs.'' PBM's, which generally include pharmacists, 
typically provide claims processing services for devices and/or 
prescription drugs; negotiate device and/or prescription drug prices; 
negotiate volume purchase agreements with medical device and/or 
pharmaceutical manufacturers, develop formularies, and institute 
formulary

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compliance programs (e.g., mandatory generic substitution programs). 
The new definition is in Sec. 99.3(h) and the agency has redesignated 
the remaining definitions accordingly.
    12. Proposed Sec. 99.3(b) defined a ``clinical investigation'' as 
an ``investigation in humans that is prospectively planned to test a 
specific clinical hypothesis.'' Several comments argued that FDA should 
delete the proposed definition of ``clinical investigation.'' They 
argued that restricting clinical investigations to those that are 
prospectively planned is not part of the statute, that it would 
preclude the use of retrospective studies, modeling studies, open label 
studies, metanalysis, reference articles, and consensus standards, 
which these comments assert may be useful, and that Congress never 
intended for the definition to be limited in this manner. One comment 
argued that the prospective planning criteria should not have to meet 
the criteria for investigational new drug applications (IND's).
    FDA believes that many of these comments misconstrued what the 
agency meant by the phrase ``prospectively planned.'' FDA does not 
consider modeling studies, which are not actual studies, but rather 
extrapolations of information or data that are used to predict how a 
study might come out, to be clinical investigations. Moreover, FDA does 
not consider consensus standards and reference articles to contain 
adequate detail about ``clinical investigations'' as defined by this 
rule. However, it was the agency's intent that the definition could 
include historically controlled studies, retrospective analyses, open 
label studies, and metanalyses if they are testing a specific clinical 
hypothesis. To avoid any confusion, FDA is eliminating the phrase 
``prospectively planned'' from the definition of ``clinical 
investigation.'' In the final rule, FDA has defined a clinical 
investigation to mean ``an investigation in humans that tests a 
specific clinical hypothesis.''
    13. Several comments urged FDA to revise the definition of ``health 
care practitioner'' in Sec. 99.3(d) to include pharmacists.
    Section 556(1) of the act (21 U.S.C. 360aaa-5(1)) defines the term 
``health care practitioner'' to mean a physician, or other individual 
who is a provider of health care, who is licensed under the law of a 
State to prescribe drugs or devices.'' FDA's proposed regulation 
tracked this statutory definition. FDA declines to revise the 
definition. To the extent that pharmacists fall within this definition, 
they will be eligible to receive information disseminated under this 
part.
    14. Proposed Sec. 99.3(g) defined ``new use'' to mean a use that is 
not included in the approved labeling of an approved drug or device, or 
a use that is not included in the statement of intended use for a 
cleared device. The preamble to the proposed rule explained that a new 
use is one that would require approval or clearance of a supplemental 
application in order for it to be included in the product labeling.
    The preamble to the proposed rule explained that ``new uses,'' 
include, but are not limited to: A completely different indication; 
modification of an existing indication to include a new dose, a new 
dosing schedule, a new route of administration, a different duration of 
usage, a new age group (e.g., unique safety or effectiveness in the 
elderly), another patient subgroup not explicitly identified in the 
current labeling, a different stage of the disease, a different 
intended outcome (e.g., long-term survival benefit, improved quality of 
life, disease amelioration), effectiveness for a sign or symptom of the 
disease not in the current labeling; and comparative claims to other 
agents for treatment of the same condition (see 63 FR 31143 at 31145).
    A number of comments supported FDA's definition of new use. 
However, others disagreed with the specific examples set forth in the 
preamble as too broad. Most of the latter comments objected to the 
inclusion of patient subgroups and comparative claims for approved 
indications. They argued that their inclusion in the definition is 
inconsistent with the agency's prescription drug advertising 
regulations, which permit companies to promote patient subgroups and 
comparative claims if certain conditions are met. Several comments 
disagreed with the inclusion of a new age group--specifically 
children--in the definition of new use. One comment argued that 
children should not be considered a ``use,'' but a ``user.'' One 
comment stated that the definition should focus only on information 
that differs from the current labeling; it should not include 
information that is consistent with, but more detailed than what is 
described in the approved labeling. Finally, one comment disagreed with 
the agency's characterization of a different intended outcome as an 
off-label use.
    FDA agrees with the comments discussed previously, which note that 
FDA's prescription drug advertising regulations permit companies to 
make comparative claims about two approved uses, without getting the 
claims on the approved label if the companies have on file, substantial 
evidence or substantial clinical experience to support such claims. 
(See Sec. 202.1(e) (21 CFR 202.1(e)).) FDA did not intend to change the 
provision found in its prescription drug advertising regulations. In 
addition, FDA agrees that as long as the comparison is between two 
approved claims, there technically is not a new ``use'' involved. 
Therefore, FDA is deleting comparative claims about approved uses from 
its interpretation of ``new use.'' Manufacturers who want to make such 
claims for a drug, must submit a labeling supplement or must meet the 
requirements set forth in FDA's drug advertising regulations. (See 
Sec. 202.1(e).) Manufacturers who want to make such claims for a 
medical device must meet the requirements set forth in 
Secs. 807.81(a)(3)(ii) or 814.39 (21 CFR 807.81(a)(3)(ii) or 814.39).
    With respect to claims of efficacy in a new patient subgroup, 
including a new age group, claims that are more detailed than the 
approved labeling, and claims that relate to different intended 
outcomes (as well as with respect to some of the other types of new use 
claims listed in the preamble to the proposed rule), FDA's prescription 
drug advertising regulations may permit companies to make such claims 
about prescription drugs in certain circumstances, without submitting a 
supplement, provided they have on file the required evidence to support 
the claim. (See Sec. 202.1(e).) However, FDA does consider such claims, 
including claims regarding children, to be new uses in some cases. In 
cases where such claims constitute new uses, manufacturers also can use 
the procedures set forth in this part to disseminate journal articles 
and reference publications about those claims. For medical devices, 
manufacturers can use the procedures set forth in this part to 
disseminate journal articles and reference publications about these 
types of claims. Otherwise, they must comply with the requirements set 
forth in Secs. 807.81(a)(3)(ii) or 814.39.
    15. Proposed Sec. 99.3(i) (now redesignated as Sec. 99.3(j)) 
defined ``scientific or medical journal,'' in part, as a journal that 
is indexed in Index Medicus. It excluded scientific and medical 
publications that are in the form of special supplements that have been 
funded in whole or in part by one or more manufacturers. One comment 
agreed that special supplements are not appropriate for dissemination 
under this part. One comment, however, stated that the definition was 
too narrow by requiring that the publication be listed

[[Page 64560]]

in Index Medicus and by excluding special supplements.
    The definition in FDA's rule, which excludes journals not indexed 
in Index Medicus and scientific and medical publications that are in 
the form of special supplements that have been funded in whole or in 
part by one or more manufacturers, tracks the statutory definition. 
(See section 556(5) of the act.) Accordingly, no changes to the final 
rule have been made.
    16. Proposed Sec. 99.3(j) (now redesignated as Sec. 99.3(k)) 
defined ``supplemental application'' as a supplement to support a new 
use to an approved new drug application (NDA) for human drugs or a 
supplement to an approved license application for biologics. Several 
comments argued that the definition of a supplemental application for a 
drug should be expanded to include the possibility that a ``new use'' 
could require a new NDA rather than just a supplemental NDA. One 
comment claimed that there are certain review divisions in the Center 
for Drug Evaluation and Research (CDER) that require NDA's for all new 
uses.
    There may be times when a manufacturer would be required to submit 
an NDA rather than a supplemental NDA to support a new use. In these 
instances, the unapproved use would not be covered by this part. 
However, it would not be appropriate to exclude new uses from this part 
merely because a review division assigns a new NDA number to the 
supplement for administrative convenience. In the latter instance, the 
difference would be in name only. Therefore, although FDA is declining 
to revise the regulation as suggested by the comments, FDA will treat 
applications that have been assigned a new NDA number for 
administrative convenience as a supplemental NDA for purposes of this 
part.
    17. One comment recommended expanding the definition of 
supplemental application to cover OTC drugs that are subject to a 
monograph.
    As set forth previously, OTC drugs that are subject to a monograph 
are not covered by this provision. Therefore, FDA declines to expand 
the definition as requested.
    18. For devices, proposed Sec. 99.3(j) (now redesignated as 
Sec. 99.3(k)) defined ``supplemental application'' as a new 510(k) 
submission, if the device that is cleared for marketing is the subject 
of a 510(k) submission, or a supplement to an approved premarket 
approval application (PMA), if the device that is marketed is the 
subject of an approved PMA. One comment recommended expanding the 
definition of supplemental application for devices to include a 510(k) 
to a 510(k) exempt device.
    FDA agrees that the statutory provision covers 510(k) exempt 
devices and so has amended the definition of supplemental application 
accordingly.
    19. Several comments disagreed with FDA's definition of 
supplemental application for devices because it did not include a PMA 
for a new use for a device on the market under section 510(k) of the 
act (21 U.S.C. 360(k)).
    Because there are no supplemental applications for 510(k) devices, 
FDA could have interpreted the statute to exclude all 510(k) devices 
from the scope of the rule. FDA drew a distinction between those that 
require a new 510(k) and those that require a PMA because the agency 
determined that this was similar to the distinction between a 
supplemental NDA and an NDA (i.e., a supplemental NDA and a 510(k) are 
filed on products about which the agency has some accumulated knowledge 
and experience such that it is not required to start its review from 
scratch; an NDA and a PMA are filed for products about which the agency 
has no such accumulated knowledge or experience upon which to base a 
decision).
    FDA disagrees with the comment that an original PMA submission 
should be included in the definition of ``supplemental application'' 
for a device that entered the marketplace through the 510(k) process. 
The 510(k) process and the PMA process are designed to provide 
different ways to market regulated products, are supported by a 
different extent and kind of data, and are predicated on different 
concepts of how to assure consumer protection.
    A product entering the market via the 510(k) process does so 
because the agency agrees with the sponsor that the new device is 
substantially equivalent to a device commercially distributed before 
May 28, 1976, or to a newer predicate device for the same intended use. 
For a 510(k) product, the consumer protection objective of the act is 
met in part by the accumulated experience with the predicate devices 
and the review and establishment of the device category in the 
appropriate class and a modicum of device specific information. 
Information on manufacturing and premarket assurance of conformance to 
good manufacturing practices (GMP's) are not addressed. The agency does 
not, in the case of a 510(k), make an individual product determination 
of safety or effectiveness.
    The act requires a PMA for a device for which there is a new 
intended use with no predicate, or which raises new issues of safety 
and effectiveness. Evidence required under a PMA is substantial and the 
sponsor must show, through the use of well-controlled clinical trials 
or, at the discretion of the agency, other valid scientific evidence, 
that there is a reasonable assurance the product is safe and effective 
for its intended use. As part of its review of a PMA, FDA reviews and 
audits clinical trial information and the GMP's employed by the 
manufacturer.
    Allowing an original PMA submission to be regarded in this context 
as a supplement for a device already marketed under a 510(k) would 
undermine the statutory and regulatory requirements established to 
ensure the safety and effectiveness of products subject to PMA's. It 
would be analogous to applying the dissemination provision to new 
devices that were never legally marketed. For a PMA product, a new 
intended use supplement is intended to provide the agency with 
additional data supporting a new use for an approved device. It relies, 
in large part, on information previously reviewed regarding product 
materials, biocompatibility, design, performance, and basic safety 
data. For a 510(k) product, a PMA would not be providing additional 
information; it would be providing all of the information.
    To illustrate, a product not currently marketed, but that was 
marketed as a general use tool without any known labeling or identified 
product specific intended use in the 1960's preamendment period may be 
re-introduced through a 510(k) for that same (implied) intended general 
tool use (e.g., it ablates or thermally destroys tissue). The product 
will be regarded as an unclassified preamendment product. If a 
manufacturer wished to market it for a specific intended purpose where 
that new purpose creates a new use with attendant questions of safety 
and effectiveness of the new use, it must do so through a PMA. In a 
recent instance, a company sought to market its unclassified 
preamendment product, an interuterine probe for a cryosurgery machine 
(using freezing to thermally destroy tissue), for ablation of the 
uterine endometrium with ultrasound control of the location and extent 
of tissue being frozen to control excessive menstrual bleeding. By 
moving to a tissue and anatomic specific intended use and indication, 
as well as by incorporation of a new (external) control procedure, the 
manufacturer has created a new intended use. The product's underlying 
safety and manufacture have never been evaluated. Even the presumption 
that ultrasound

[[Page 64561]]

measurement of the extent of tissue being frozen accurately predicts 
the extent of tissue necrosis and allows proper positioning of the 
probe remains unevaluated. Nevertheless, the comments would argue that 
this product could be the subject of an article or text disseminated 
under section 401 of FDAMA.
    In passing section 401 of FDAMA, Congress intended to provide 
health care practitioners important scientific information about 
unapproved uses of approved products. The risks to the public of 
disseminating information in a case such as that described previously 
are closer to the risks from instances where there has never been an 
approved product than those for a new use of a previously approved 
product. FDA believes that these risks are far greater than those 
authorized by section 401 of FDAMA.
2. Subpart B--Information To Be Disseminated
    a. Information that may be disseminated (Sec. 99.101). Proposed 
Sec. 99.101 discussed the types of information concerning the safety, 
effectiveness, or benefit of a new use that a manufacturer may 
disseminate. For example, the proposal required (among other things) 
that the written information to be disseminated concern a drug or 
device that has been approved, licensed, or cleared for marketing by 
FDA and be in the form of an unabridged reprint or copy of a peer-
reviewed scientific or medical journal article or an unabridged 
reference publication that pertains to a clinical investigation 
involving the drug or device and that is considered scientifically 
sound by experts who are qualified to evaluate the product's safety or 
effectiveness. Proposed Sec. 99.101 also described criteria for 
determining whether the information to be disseminated is false or 
misleading, whether a clinical investigation is ``scientifically 
sound,'' and whether a reprint or copy of an article or reference 
publication is ``unabridged.''
    20. One comment urged FDA to include a 60-day window in advance of 
a drug's Prescription Drug User Fee Act date during which time a 
manufacturer could submit proposed material for review. In other words, 
the comment urged FDA to accept dissemination materials for review 
before a drug has been approved.
    FDA declines to adopt this approach. The statute does not direct 
FDA to accept submissions on products that have not yet been approved 
or cleared. If FDA accepts submissions on products that have not yet 
been approved or cleared, it may be wasting resources reviewing 
submissions on products that never get approved or cleared.
    21. One comment urged FDA to make clear that this part does not 
permit the verbal dissemination of unapproved use information. Another 
comment suggested that companies that disseminate information on a new 
use should be permitted to discuss the clinical investigation that is 
the subject of the disseminated materials with the recipient.
    FDA agrees with the first comment that neither this part nor 
section 401 of FDAMA, would permit the verbal dissemination of 
information about unapproved uses. Section 551(a) of the act and 
Sec. 99.101 refer clearly and specifically to ``written'' information. 
Therefore, a manufacturer (or its representatives or agents) is not 
permitted to discuss with a recipient the clinical investigation that 
is the subject of the written materials disseminated under this part.
    22. Several comments asked whether Internet or electronic 
dissemination would be permitted under this part.
    Although, as set forth previously, FDA agrees that the provision 
was not meant to cover verbal dissemination, it could cover electronic 
dissemination. However, a manufacturer seeking to disseminate 
information electronically would have to ensure that all of the 
requirements under this part could be met for electronic dissemination. 
For example, the manufacturer would have to ensure that the recipients 
of the information are appropriately limited and that all of the 
required information and disclosures can be attached in accordance with 
this part. FDA may, in the future, issue guidance on this subject.
    23. One comment noted the importance of requiring manufacturers to 
disseminate unabridged journal articles so that information from a 
clinical study is not pulled out of context or released without all 
relevant data.
    FDA agrees with this comment. Both the statute and the regulation 
require that a journal article or reference publication disseminated 
under this part be unabridged.
    24. Several comments objected to the requirement that a reprint or 
copy of an article be published prior to submission for FDA for review. 
These comments argued that manufacturers should be allowed to send FDA 
final manuscripts. Another comment opposed allowing submissions to 
include manuscripts or preprints of articles that have been accepted 
for publication. This comment stated that it could take months for 
these manuscripts to be published and that they might be submitted 
before the peer-review process is complete.
    FDA understands manufacturers' desire to disseminate new use 
information as quickly as possible. However, section 552 of the act (21 
U.S.C. 360aaa-1) requires that the peer-reviewed journal articles 
disseminated under this part be published. If FDA were to accept 
manuscripts before publication, it could not be sure that what gets 
published, and then disseminated, is exactly what it was given to 
review. The agency might not even be sure that the peer-review process 
has been completed. FDA does not have the resources to verify this 
information or to conduct duplicative reviews. Therefore, FDA is not 
revising the rule to permit submission of unpublished manuscripts.
    25. Several comments took issue with the statement in the proposal 
that information can be false or misleading if it includes only 
favorable publications. These comments argued that dissemination should 
not be prohibited if the only information that has been published is 
favorable and the research is scientifically rigorous. These comments 
noted that FDA should make clear that a single favorable publication 
can be disseminated if it is objective, balanced, and discusses 
appropriate safety information. One comment noted that a more 
appropriate manner in which to state the issue would be to cite the 
exclusion of an unfavorable publication as the example.
    FDA agrees that new use information is not necessarily without 
balance or misleading just because there is no unfavorable information 
disseminated with it and FDA did not intend to suggest the contrary. 
FDA agrees that it would be inappropriate to find a favorable article 
misleading just because it is disseminated without an unfavorable 
publication when no unfavorable publication exists. What FDA will be 
looking for is whether the manufacturer has failed to include 
unfavorable information that exists and that is necessary to provide 
balance. FDA has revised the rule to clarify this point.
    26. One comment said that proposed Sec. 99.101(a)(4) was unclear on 
what ``other information concerning risks and adverse effects that are 
or may be associated with the new use'' a company would have to include 
to ensure that the disseminated information is not false or misleading.
    The other information refers to the additional information that FDA 
can require under Sec. 99.103(a)(4). FDA has revised the rule to 
clarify this point.

[[Page 64562]]

    27. Proposed Sec. 99.101(a)(5) required that the disseminated 
information not be derived from clinical research conducted by another 
manufacturer unless the manufacturer disseminating the information has 
the permission of such other manufacturer to make the dissemination.
    One comment noted that the rule should clarify that contracts or 
agreements between sponsors may specify how the data are to be used by 
the sponsoring companies. In other words, cosponsoring companies should 
be responsible for maintaining their own agreements without FDA input. 
Several other comments opined that once a peer-reviewed article is 
published, it is in the public domain and a sponsor should be able to 
pursue use of the data published by the original sponsor (i.e., without 
first obtaining permission) as long as proper credit is given. One 
comment asked FDA to clarify the rule to show that research conducted 
by an independent academic or similar organization can be disseminated 
if the information meets the standards for dissemination and is legally 
available for such use.
    Section 551(b)(3) of the act prohibits the dissemination of 
information derived from research conducted by another manufacturer 
without that other manufacturer's permission. The fact that an article 
has been published does not eliminate the need to get permission from 
the researching company. If it did, this requirement in the statute 
would be meaningless because all information disseminated under this 
part must be published. Therefore, FDA declines to revise the rule to 
permit the dissemination of all published articles reporting on 
research conducted by another manufacturer without that manufacturer's 
permission. However, FDA agrees that cosponsoring companies can make 
agreements without FDA's input and that research conducted by 
independent parties does not, by the terms of the statute, require that 
party's permission.
    28. One comment noted that reference publications will include many 
unapproved use discussions that reflect research conducted by other 
manufacturers and that proposed Sec. 99.101(a)(5) would appear to make 
the disseminating company get permission from every one of those 
manufacturers.
    As set forth in the proposal, FDA expects that manufacturers that 
disseminate reference publications under this part will flag the 
section of the text that describes the clinical investigation of a 
specific unapproved use (otherwise, they would have to commit to study 
all of the unapproved uses discussed in the reference publication). 
Therefore, FDA would expect that a manufacturer would be required only 
to seek the permission of another manufacturer if that other 
manufacturer conducted the study for that specific discussion of an 
unapproved use.
    29. Proposed Sec. 99.101(b)(1) provided that the determination of 
whether a clinical investigation is considered to be ``scientifically 
sound'' will rest on whether the design, conduct, data, and analysis of 
the investigation described or discussed in a reprint or copy of an 
article or in a reference publication reasonably support the 
conclusions reached by the authors. It further provided that a clinical 
investigation described or discussed in an article or reference 
publication must include a description of the study design and conduct, 
data presentation and analysis, summary of results, and conclusions 
pertaining to the new use. The proposal also stated that a clinical 
investigation presented in a format that does not represent a 
reasonably comprehensive presentation of the study design, conduct, 
data, analyses, and conclusions (e.g., letters to the editor, review 
abstracts, abstracts of a publication) would not qualify for 
dissemination under this provision.
    The preamble to the proposal provided that in order to provide a 
basis for determining whether the conclusions are reasonably supported 
and the findings represent evidence of safety and effectiveness of the 
new use, the article or reference publication should provide, where 
applicable, evidence that the investigation: (1) Was prospectively 
planned; (2) enrolled an appropriately defined and diagnosed patient 
population for the specific clinical condition of interest; (3) 
accounted for all patients enrolled, including all patients who 
discontinued therapy prematurely; (4) utilized clinically meaningful 
endpoints or utilized surrogate endpoints that are reasonably likely to 
predict safety and effectiveness; (5) used a well described treatment 
regimen with a clear description of dose, schedule, duration, and route 
of administration; (6) used an appropriate control group or made 
reference to an appropriate historical control; (7) collected and 
reported adequate information on adverse experiences, and the need for 
dose reductions and treatment interruptions due to toxicity; and (8) 
was analyzed in a scientifically appropriate manner. (See 63 FR 31143 
at 31146 and 31147.)
    Some comments supported FDA's interpretation and applauded the 
agency's efforts to ensure that journal articles and reference 
publications are scientifically sound. These comments noted that FDA's 
interpretation reflected what is required by most peer-reviewed 
journals.
    In contrast, a number of comments objected to FDA's approach. Some 
of these comments objected to FDA making any determination that an 
article or reference publication is scientifically sound. They stated 
that it was not Congress' intent to have FDA ``do its own peer 
review.'' Others criticized the criteria set forth in the proposed 
codified language and/or the eight criteria in the preamble to the 
proposal. They argued that FDA would be requiring more detail than is 
ever found in articles or reference publications and/or that FDA's 
standard is akin to that for a supplemental application. One comment 
said that FDA should require only enough detail to determine if the 
article or publication is scientifically sound. One comment urged FDA 
to adopt a broader definition of scientifically sound by removing the 
specific requirements, i.e., prospectively planned, and recognizing the 
value of scientifically sound studies as long as any limitations (e.g., 
epidemiological data) are fully disclosed. One comment said that FDA 
should require the journal article to include the ``typical level of 
detail'' and, if it does not, then the company should be able to attach 
it to the article. Several comments opposed the specific exclusion of 
abstracts. Finally, a number of comments specifically criticized the 
requirement that the clinical investigation be prospectively planned.
    FDA has a role to play with respect to whether an article or 
reference publication is scientifically sound. The statute includes a 
requirement that the disseminated article or reference publication 
pertain to a clinical investigation that would be considered to be 
scientifically sound by experts qualified by scientific training or 
experience to evaluate the safety or effectiveness of the drug or 
device involved. FDA believes that this provision indicates that 
Congress meant for FDA to look at whether experts would find that the 
article or publication is about an investigation that experts would 
consider to be scientifically sound. However, FDA also believes that 
its role in determining whether an article or publication is 
scientifically sound is limited. This approach is consistent with the 
proposed rule and FDA fully expected that most journal articles about a 
clinical investigation from reputable peer-reviewed journals would meet 
the definition of scientifically sound set

[[Page 64563]]

forth in its proposal. Nevertheless, to ensure that the provision will 
be implemented consistent with congressional intent, FDA is revising 
Sec. 99.101(b)(1) to provide that FDA will find that all journal 
articles and reference publications (as those terms are defined in 
Sec. 99.3) are scientifically sound except: (1) Letters to the editor; 
(2) abstracts of a publication; (3) those regarding Phase 1 trials in 
healthy people; (4) flagged reference publications that contain little 
or no substantive discussion of the relevant clinical investigation; 
and (5) those regarding observations in four or fewer people that do 
not reflect any systematic attempt to collect data, unless the 
manufacturer demonstrates to FDA that such reports could help guide a 
physician in his/her medical practice.
    Section 552(a)(2) of the act prohibits the dissemination of 
information that is false or misleading. That provision prohibits the 
dissemination of journal articles and reference publications that 
contain conclusions that are not supported by the study results. FDA 
has revised Sec. 99.101(a)(4) accordingly.
    30. One comment asked what FDA would do if an article discussed 
multiple unapproved uses, but the manufacturer wanted to focus on just 
one unapproved use.
    FDA expects that there may be articles that discuss multiple 
unapproved uses and that such articles may be disseminated only if the 
requirements are met for each of those uses. There also may be 
instances when an article discusses multiple unapproved use(s), but 
there is one (or more) predominant unapproved use(s) discussed in the 
article. Under certain circumstances, it may make sense for the 
manufacturer to have to meet the requirements set forth in this part 
only for the predominant use(s). However, FDA will have to make this 
determination on a case-by-case basis.
    31. One comment argued that dissemination of reference publications 
is not consistent with the purpose of section 401 of FDAMA because, by 
their very nature, reference publications are considerably out of date 
at the time of their publication. The comment further opined that 
because the authors do not report the methods used to assess the 
current scientific literature, reference publications should be 
considered the authors' opinion and thus, not scientifically sound.
    FDA agrees that many reference publications may not be up to date. 
However, Congress did include reference publications within the scope 
of section 401 of FDAMA. There is no basis to presume that all 
reference publications are not scientifically sound.
    32. Several comments opposed the requirement that disseminated 
information in the form of a reference publication ``pertain to a 
clinical investigation regarding the drug or device.'' Instead, they 
argued, the reference publication should ``include information about'' 
such a study. Some comments interpreted this to mean that the study 
should meet all of the criteria to establish scientific soundness, but 
the information about such a study should not be required. One comment 
said that the language means that the information needs to be based on 
a scientifically sound clinical investigation, it need not be about or 
describe such clinical investigation.
    Both the act and this part provide that reference publications must 
``include information about a clinical investigation.'' However, this 
does not mean that the information about that clinical investigation 
should be any less complete than the information included in a journal 
article. It means only that the text may have a lot of additional 
information that is not about the clinical investigation. The idea 
behind the dissemination provision is that physicians and other 
recipients be in a position to make treatment decisions based on 
published reports of clinical trials. If the information that is 
disseminated gives them little or no information about the actual 
trial, then it would be difficult to argue that they have a reasonable 
basis upon which to make such treatment decisions.
    33. A number of comments argued that the proposal has written 
reference publications out of the statute by requiring the same level 
of detail as would appear in journal articles. One comment said that 
FDA should accept the dissemination of peer-reviewed reference 
publications. Some comments argued that the proposal would make text 
book dissemination more difficult than it was prior to passage of FDAMA 
and that FDA should adopt a final rule that is consistent with its 
existing reference text guidance or it should leave that guidance in 
place. One comment argued that the statute makes it clear that FDA must 
allow the dissemination of reference publications that meet the 
requirements of the statute and that the agency's decision to issue a 
guidance document on this issue is not an option.
    As set forth previously, FDA does not believe that Congress meant 
that reference publications disseminated under this part could have 
less detail about clinical investigations than journal articles. In 
addition, reference publications are not subject to classic peer-
review. Therefore, FDA rejects the comment that FDA accept all peer-
reviewed reference publications. As discussed in the preamble to the 
proposal, however, FDA recognizes that it will be difficult for many 
reference publications to meet the statutory criteria. Moreover, as set 
forth in many of the comments, the new statutory scheme in most 
respects makes it more difficult to disseminate reference publications 
than was possible before FDAMA. Thus, FDA plans to permit companies to 
distribute unabridged reference publications (as defined in the statute 
and Sec. 99.3(i)) without meeting all of the requirements set forth in 
this part if the company does not focus on or point to a specific 
unapproved use in the publication and it includes a disclaimer that the 
publication includes information about unapproved uses. (Cf. Guidance 
for Industry Funded Dissemination of Reference Texts (61 FR 52900, 
October 8, 1996). The agency was enjoined from applying this guidance 
document in WLF v. Friedman. FDA sought clarification on the scope of 
the order in that case through a motion to amend the judgment.) FDA 
plans to issue guidance on this issue at some time in the future 
following clarification by the court. Of course, manufacturers that 
want to focus or point to a specific unapproved use will have the 
option of doing so by meeting the requirements set forth in this part.
    34. One comment argued that Congress intended for manufacturers to 
be able to disseminate reference publication chapters.
    Section 552(a)(1) of the act clearly requires that the reference 
publication be unabridged. A chapter from a textbook does not meet this 
requirement.
    35. Proposed Sec. 99.101(b)(2) provided that journal articles and 
reference publications disseminated under part 99 cannot be 
disseminated with any information that is promotional in nature. One 
comment strongly agreed with the concept of prohibiting promotional 
material to be distributed with scientific information on a new use. 
One comment opposed the concept, stating that there is no policy or 
legal rationale for prohibiting companies from distributing information 
on approved uses with these reprints. A number of comments requested 
clarification of this statement. These comments were concerned that it 
could preclude a sponsor from delivering a promotional piece on a 
labeled use during the same office visit or detail. These comments 
suggested that FDA

[[Page 64564]]

clarify that so long as the promotional material concerns an approved 
use and is kept physically distinct from the unapproved use 
information, FDA would not consider the two to be distributed together.
    FDA did not intend to prohibit a sponsor from delivering 
promotional pieces on an approved or cleared use during an office visit 
or detail in which it has delivered information on an unapproved use. 
Any unapproved use information, however, must be kept physically 
distinct from the promotional materials, and the sponsor may not 
verbally promote the unapproved use or include materials about the 
unapproved use, beyond those permitted or required under this part.
    b. Mandatory statements and information (Sec. 99.103). Proposed 
Sec. 99.103 described the information that must accompany the journal 
article or reference publication. For example, it required a 
prominently displayed statement disclosing (among other things) that 
the information being disseminated is about a use that has not been 
approved or cleared by FDA and is being disseminated under section 551 
et seq. of the act and, if applicable, a statement that there are 
products or treatments that have been approved or cleared for the use 
that is the subject of the dissemination. It also required the official 
labeling and a bibliography of other articles to accompany the 
disseminated information. In addition, the proposal described what is 
meant by a ``prominently displayed'' statement by setting forth 
criteria that are consistent with the agency's regulations on 
prescription drug advertising (Sec. 202.1(e)(7)(viii)) and labeling (21 
CFR 201.10(g)(2)). Proposed Sec. 99.103 required the statement that the 
use has not been approved and the additional information required by 
FDA to be attached to the front of the disseminated materials and that 
all other mandatory information be attached to the disseminated 
information.
    36. Although some comments supported FDA's position on mandatory 
statements, there were others that thought the proposal was unduly 
restrictive. For example, although some comments supported the 
requirement for a uniform statement disclosing that the new use has not 
been approved by FDA, there were a number of comments that thought 
manufacturers should be allowed to use alternative language to convey 
this message. One comment specifically objected to the phrase ``and is 
being disseminated under section 551 of the Federal Food, Drug, and 
Cosmetic Act.'' This comment said that the phrase was unnecessary and 
could be confusing.
    FDA continues to believe that it is important to have a uniform 
disclosure stating that the new use has not been approved by FDA. 
Different statements can be confusing and recipients of the information 
may believe that they have different meanings. FDA agrees, however, 
that the phrase: ``and is being disseminated under section 551 et seq. 
of the Federal Food, Drug, and Cosmetic Act'' is unnecessary and has 
therefore dropped it from the final rule.
    37. One comment stated that clarification is needed regarding 
articles that discuss more than one use because, as written, 
Sec. 99.103(a)(1)(i) uses singular and plural forms in a way that is 
confusing.
    FDA agrees that clarification was needed and has revised the final 
rule accordingly.
    38. Proposed Sec. 99.103(a)(1)(iii) required a statement disclosing 
any authors who have a significant financial interest in the 
manufacturer. One comment noted that, although the disclosure is 
appropriate, the final rule should make clear that such disclosure be 
in line with the level required by the rule on financial disclosure and 
should apply only to the financial interests at the time the study was 
conducted and not the author's current interest.
    In the preamble to the proposed rule, FDA stated that an author 
would have a significant financial interest in a manufacturer when 
there is a relationship that may give rise to actual or perceived 
conflicts of interest and that when there is a question as to whether a 
relationship is significant, it should be disclosed (see 63 FR 31143 at 
31147). Manufacturers may consult the final rule on financial 
disclosure by clinical investigators (codified at 21 CFR part 54) to 
learn the types of financial interests of greatest concern to the 
agency. However, because the purposes and terminology of this final 
rule and the final rule on financial disclosure by clinical 
investigators are different, manufacturers should consult the 
provisions of this final rule for the requirements that apply to 
disclosures regarding authors. FDA agrees that the financial disclosure 
should not necessarily apply to the author's current financial 
interest. FDA believes, however, that it should apply to the author's 
financial interests during the time the study was conducted up through 
1 year after the time the journal article or reference publication was 
written and published. FDA has revised the final rule to reflect this 
time limitation. FDA's revision is consistent with part 54.
    39. One comment urged FDA to require that the statement that there 
are products or treatments that have been approved or cleared for the 
use that is the subject of the dissemination list the names of other 
drugs that have been approved by FDA. Another comment asked whether 
such statement should address adjuvant or supporting therapies.
    FDA's regulation tracks the statute, which does not require a 
manufacturer to identify the specific products that have been approved 
or cleared for the new use or the adjuvant or supporting therapy for 
the new use. (See section 551(b)(6)(A)(v) of the act.) Although FDA can 
see the benefit of having those specific product names listed, it would 
be difficult to develop a complete and accurate list. Moreover, the 
information could be misleading if the manufacturer merely provided a 
list of names. FDA also does not believe that the statement should 
address adjuvant or supporting therapies. The idea behind the 
disclosure is to let health care practitioners and other recipients 
know that approved/cleared alternatives exist. Therefore, FDA is 
retaining the requirement that the manufacturer only disclose that such 
approved/cleared products exist.
    40. Proposed Sec. 99.103(a)(2) provided that the manufacturer must 
attach the official labeling of the product to the unapproved use 
information. In the preamble to the proposed rule (63 FR 31143 at 
31147), FDA noted that devices, unlike drugs, do not always include a 
package insert in the same form and manner as drugs. Therefore, the 
agency would expect device manufacturers to provide the same 
information that is generally found in package inserts, namely: (1) The 
name of the device, including its trade or proprietary name; (2) the 
manufacturer's name, address, and telephone number; (3) a statement of 
intended use, including a general description of the diseases or 
conditions that the device is intended to diagnose, treat, cure, or 
mitigate; (4) a description of the patient population for which the 
device is intended; (5) a description of indications that have been 
approved or cleared by FDA; (6) a description of any limitations or 
conditions that have been placed on the sale, distribution, or use of 
the device; and (7) all warnings, contraindications, side effects, and 
precautions associated with the use of the device.
    One comment suggested that a device's official labeling be 
interpreted as: (1) The package insert for the device; (2) the 
accompanying documents that a manufacturer distributes with its legally

[[Page 64565]]

marketed device to comply with the requirements of 21 CFR 801 or 809.10 
for in vitro diagnostic products; or (3) the new labeling vehicle 
created by a manufacturer that contains the listed items from the 
preamble.
    FDA agrees that this interpretation of official labeling for 
devices is appropriate provided the third option is used only when the 
first two options are not available or not feasible and provided the 
third option includes only the information listed in the preamble 
(i.e., no promotional statements or representations are included).
    41. Proposed Sec. 99.103(a)(3) required the manufacturer to attach 
a bibliography of other articles (that concern reports of clinical 
investigations both supporting and not supporting the new use). One 
comment noted that a bibliography is not required every time--only when 
one is not present in the disseminated information. Another comment 
stated that the bibliography requirement is vague regarding what needs 
to be included and under what circumstances a bibliography included in 
the publication is sufficient.
    FDA's proposal provided that the manufacturer need not include a 
separate bibliography if the disseminated information already includes 
a bibliography that meets the requirements set forth in 
Sec. 99.103(a)(3). The bibliography requirement would be met by a list 
of all other published articles from scientific reference publications 
or scientific or medical journals that discuss clinical investigations 
and are specific to the new use discussed in the disseminated 
information. The bibliography must include articles about clinical 
investigations that both support and do not support the new use and it 
must identify which articles relate to the new use. A bibliography 
already included with the disseminated information would meet this 
requirement only if it includes all other such published articles. The 
manufacturer would still have to include its search strategy to show 
that it took reasonable steps to ensure that the bibliography includes 
all relevant published articles as described in Sec. 99.103(a)(3).
    42. Proposed Sec. 99.103(a)(4) required a manufacturer to include 
any additional information required by FDA, including objective and 
scientifically sound information pertaining to the safety or 
effectiveness of the new use that FDA determines is necessary to 
provide objectivity and balance, including information that the 
manufacturer has submitted to FDA or, where appropriate, a summary of 
such information, and any other information that can be made publicly 
available; and an objective statement prepared by FDA, based on data or 
other scientifically sound information, bearing on the safety or 
effectiveness of the new use of the product.
    Several comments noted that this provision should specify that FDA 
must provide the manufacturer notice and an opportunity to meet before 
requiring such information.
    FDA agrees that a manufacturer must be provided notice and an 
opportunity to meet before being required to include this additional 
information. Redesignated Sec. 99.301(a)(2) provides this opportunity 
and FDA has revised the final rule at Sec. 99.103(a)(4) to include a 
reference to Sec. 99.301(a)(2).
    43. Several comments opposed the requirement that the statement 
that the use has not been approved and the additional information 
required by FDA be attached to the front of the disseminated materials 
and that all other mandatory information be attached to the 
disseminated information. One comment suggested that the FDA-required 
information be attached to the back, and that FDA permit the use of a 
sticker on the front of the disseminated material stating that the FDA-
required information is attached to the back.
    FDA believes that it is important to permanently affix the 
statement indicating that the disseminated information is about an 
unapproved use to the front of the materials. The recipients of such 
materials should know, in advance, that they are reading information 
about an unapproved use. However, FDA agrees that it could be 
appropriate to attach the additional information required by FDA to the 
back of the materials, provided there is a sticker or notation on the 
front referring the recipient to that information. The agency has 
amended Sec. 99.103(a)(4) accordingly.
    FDA also believes it is important to attach the remaining 
information to the disseminated materials. Congress included this 
mandatory information because it determined that it was important for 
the recipient to receive it. If such information is not attached, it 
can easily be separated from the disseminated material and never seen 
by the recipient. This is the information that helps to ensure that the 
disseminated materials are objective, balanced, and not misleading.
    44. Although some comments stated that the criteria in proposed 
Sec. 99.103(c) for determining whether the mandatory information is 
prominently displayed are appropriate, others opposed the factors that 
FDA will consider in determining whether the mandatory information is 
prominently displayed. The latter comments argued that manufacturers 
should retain some flexibility and discretion in this area.
    FDA's approach is flexible. Section 99.103(c) sets forth the 
factors that FDA will consider and provides that the required 
statements shall be outlined, boxed, highlighted, or otherwise 
graphically designed and presented in a matter that achieves emphasis 
or notice and is distinct from the other information being disseminated 
(emphasis added). Such an approach is not as proscriptive as the 
comments imply. FDA has retained this approach in the final rule.
    45. One comment suggested that FDA permit manufacturers to post 
information, such as balancing articles required by FDA, on the 
Internet so long as the Internet address is prominently displayed on 
the information that was disseminated. The comment said that this would 
reduce paperwork burdens and provide a continuous source of current 
information.
    FDA does not think that it would be appropriate for manufacturers 
to use the Internet to balance a published reprint disseminated in hard 
copy format or to provide recipients of unapproved use information with 
only part of the information required by the statute and regulations. 
The idea behind the provision was that physicians would receive, at one 
time, a balanced package. Such balance would not be achieved if a 
manufacturer could hand a physician an article and then advise the 
physician that he/she has to take steps on his/her own to retrieve the 
balancing information.
    46. Several comments urged FDA to require manufacturers to provide 
patient labeling for drugs that are the subject of the disseminated 
information. The comments noted that such labeling should identify the 
drug by name, notify consumers that the drug has been promoted for an 
unapproved use, and indicate FDA-approved uses for the drug. They 
further argued that the patient labeling must include information about 
the potential risks of the drug and meet the quality and content 
standards of FDA's 1995 proposed Medication Guide rule. This comment 
said that FDA-approved patient labeling must be in commercial 
distribution at the level of the pharmacy before dissemination under 
this part can begin. One comment stated that the labeling should state 
that these products are not tested in certain populations and should 
say ``use at your own risk.''

[[Page 64566]]

    FDA recognizes the importance of providing consumers access to 
information about the products they use. Since 1968, FDA has 
occasionally required and often encouraged manufacturers to produce 
patient labeling for certain prescription drugs. However, the comments' 
request for additional patient labeling on drugs that are the subject 
of information disseminated under part 99 is outside the scope of 
section 401 of FDAMA.
    47. Several comments argued that the lack of availability of 
pediatric studies on a particular use should be clearly and prominently 
stated in the information being disseminated to health professionals. 
These comments also urged FDA to require an additional statement for 
drugs that have not undergone pediatric testing: ``Safety and 
effectiveness in pediatric populations have not been established for 
this product for the use that has been approved by FDA or for the use 
suggested by this information.''
    The suggestion that for drugs and devices that have not undergone 
pediatric testing, the disseminated information should include a 
statement to that effect is beyond the scope of this rule. However, for 
unapproved pediatric uses that are the subject of the information being 
disseminated, there will be a statement that the use has not been 
approved or cleared by FDA.
    c. Recipients of information (Sec. 99.105). Proposed Sec. 99.105 
identified who may receive information disseminated under this part. 
Specifically, a health care practitioner, pharmacy benefit manager, 
health insurance issuer, group health plan, or Federal or State 
Government agency could receive information disseminated under part 99.
    48. Several comments urged FDA to add pharmacists to the list of 
recipients of information under this part.
    As previously discussed, section 401 of FDAMA specifically lists 
who can receive the unapproved use information under this provision. To 
the extent that pharmacists are included in the definitions of ``health 
care practitioner,'' ``pharmacy benefit manager,'' ``health insurance 
issuer,'' or ``group health plan'' (see Sec. 99.3), they will be 
included as recipients of this information.
3. Subpart C--Manufacturer's Submissions, Requests, and Applications
    a. Manufacturer's submission to the agency (Sec. 99.201). Proposed 
Sec. 99.201 described the contents of a manufacturer's submission to 
FDA. This submission would be made 60 days before disseminating 
information on an unapproved or new use and would include items such as 
a copy of all of the information to be disseminated, all other clinical 
trial information that the manufacturer has relating to the safety or 
effectiveness of the new use, any reports of clinical experience 
pertinent to the safety of the new use, and, if a supplement for the 
new use has not been submitted, a certification that the manufacturer 
will submit a supplement or an application for an exemption from the 
requirement to submit a supplement. The proposal also discussed what 
types of information must be submitted when the certification provides 
that the studies have been completed or that studies will be conducted 
as well as the contents of the certification. Proposed Sec. 99.201 also 
provided that the 60-day period begins to run when FDA receives a 
complete submission.
    49. One comment agreed that manufacturers should have to submit any 
clinical trial information that they have relating to the safety and 
effectiveness of the new use. However, another comment argued that the 
requirement for any clinical trial information is far more exhaustive 
than that required by the statute.
    Section 551(b)(4)(B) of the act requires manufacturers to submit 
``any clinical trial information the manufacturer has relating to the 
safety or effectiveness of the new use, any reports of clinical 
experience pertinent to the safety of the new use, and a summary of 
such information.'' Proposed Sec. 99.201(a)(2) tracked this requirement 
and described what it included. In the final rule, FDA is making clear 
that, for effectiveness information, the requirements are limited to 
information on clinical investigations of the new use; safety 
information is broader and must include all relevant new data from 
human experience.
    50. One comment urged FDA to require manufacturers to report only 
those adverse experiences that they have received directly because 
companies do not have access to the details of cases submitted to other 
manufacturers and thus, are unable to evaluate the reports. That same 
comment stated that FDA should permit adverse experience reports to be 
submitted in summary or tabular form rather than as individual case 
reports. Several other comments requested the ability to reference 
files that FDA already has about adverse experiences. Finally, one 
comment noted that the search requirements for adverse reports should 
be more clearly delineated.
    Under the statute and these regulations, manufacturers would have 
to submit only those adverse experience reports that they have. This 
would include reports originally made to other manufacturers. If the 
reports were originally submitted to other manufacturers and the 
disseminating manufacturer does not know whether to attribute the 
adverse experience to the new use, it should submit the information to 
FDA. Manufacturers can submit adverse experience reports in summary or 
tabular form if FDA already has the individual case reports. With 
respect to search requirements for postmarket adverse event reports, 
FDA does not think that it is necessary to be any more specific. 
Manufacturers gather this information on a regular basis.
    51. One comment said that the literature search requirements in 
Sec. 99.201(a)(3) should be more clearly delineated. Several comments 
stated that the requirement for the submission of a search strategy is 
not required by statute and should be eliminated because it is 
unnecessary and burdensome and could delay the process.
    FDA believes that it is necessary to include the search strategy. 
This is how FDA will be able to determine whether the bibliography 
meets the statutory criteria. FDA has revised Sec. 99.201(a)(3), 
however, to clarify the bibliography search strategy requirements.
    52. FDA, on its own initiative, revised Sec. 99.201(a)(4)(i)(B) and 
(a)(4)(ii)(B) to clarify that, for purposes of computing time periods 
that begin on the date of initial dissemination, FDA will look to the 
date on which dissemination can begin. This clarification was necessary 
because FDA will not know when a manufacturer actually begins to 
disseminate materials. The same revision was made to Secs. 99.203(b) 
and 99.401(b).
    53. Proposed Sec. 99.201(a)(4)(ii) required a manufacturer that has 
planned studies that will be needed for a supplement to submit the 
proposed protocols and schedule for conducting such studies. The 
protocols must comply with FDA's IND or investigational device 
exemption (IDE) regulations. One comment asked FDA to clarify whether a 
manufacturer who has planned studies and wishes to disseminate 
information must submit a complete IND or IDE in addition to the 
information required in a submission under this rule. One comment 
stated that if the protocols are to be treated as IND's, IDE's, or 
amendments thereto, the manufacturer should be able to commence the 
studies within 30 days unless the agency places the study on clinical 
hold. The same comment said that if the agency does not place a

[[Page 64567]]

clinical hold on the protocol within 30 days, the agency should not be 
able to determine that the protocols are inadequate on day 60 and if 
the protocol is put on clinical hold within 30 days, it should not be 
dispositive of the decision. The comment further stated that if the 
agency decides that the protocols are adequate, it should be bound by 
this decision and the final rule should reflect this. Finally, several 
comments urged FDA to permit manufacturers to cross reference IND's and 
IDE's rather than resubmitting such information.
    FDA intends that the protocols for planned studies under this 
provision be submitted in compliance with the IND or IDE regulations. 
However, a manufacturer will not be required to submit these materials 
twice. If a protocol has already been submitted to an IND or IDE, the 
IND or IDE can be cross referenced in the dissemination submission.
    Moreover, FDA does not intend to change, in any way, the IND or IDE 
regulations, including the timeframes. If an IND or IDE is submitted 
and a clinical hold is not issued within 30 days, the manufacturer can 
commence the study or studies. However, the fact that FDA does not 
issue a clinical hold within 30 days, does not prevent FDA from 
determining, within 60 days, that a protocol is inadequate. FDA can 
issue a clinical hold at any time after the 30-day period if the 
requirements for issuing a clinical hold are met. If the protocol is 
put on clinical hold within 30 days, it may not be dispositive of the 
issue because the sponsor may remedy the reason for the clinical hold 
within the 60-day period. However, if the reason for issuing the 
clinical hold is not resolved, it will be dispositive of the issue. 
Finally, FDA is declining to revise the rule to provide that if the 
agency finds that the protocols are adequate, it will be bound by this 
decision. FDAMA addressed the issue of agreements regarding the 
parameters of the design and size of clinical trials. (See, e.g., 
section 505(b)(4)(C) or section 520(g)(7)(A) through (g)(7)(C) of the 
act (21 U.S.C. 360j(g)(7)(A) through (g)(7)(C)).) FDA will abide by 
these statutory directives.
    54. Proposed Sec. 99.201(a)(4)(ii) required a manufacturer that has 
planned studies that will be needed for the submission of a 
supplemental application for the new use to certify that it will 
exercise due diligence to complete such studies and submit a supplement 
within 36 months of dissemination. FDA has revised this section to 
reflect the possibility that FDA may determine, before the 
certification is submitted, that the studies needed to submit a 
supplemental application cannot be completed and submitted within 36 
months. This change is further reflected in Sec. 99.203.
    55. One comment requested that the 36-month timeframe for 
submitting a supplement not override the time limits created under 
separate regulatory or statutory authority. This comment was concerned 
that if FDA finalizes its proposed 1997 regulation on pediatric 
research and it includes compliance dates for completing the pediatric 
studies that are less than 36 months, the 36-month period in this part 
not override that shorter timeframe.
    As FDA has stated elsewhere in this document, nothing in this 
regulation is meant to change or supersede other regulatory 
requirements.
    56. One comment asked FDA to clarify the submission requirements 
and FDA action requirements with respect to nonsignificant risk 
devices.
    Protocols submitted for studies for devices considered to be 
nonsignificant will be reviewed by FDA only to ensure that the protocol 
for the study is consistent with the new use information to be 
disseminated. Manufacturers must present the protocol for the 
nonsignificant risk device study to an institutional review board (IRB) 
for approval before starting the study. (See 21 CFR 812.1(b)(1).) 
However, all reporting requirements under this part will apply to 
nonsignificant risk device studies.
    57. One comment requested that the agency provide the sponsor an 
opportunity to meet with FDA promptly to review what changes can be 
made to the protocol to ensure that it meets requisite standards.
    Sections 505(b)(4)(B) and 520(g)(7)(A) and (g)(7)(C) of the act 
provide sponsors with an opportunity to meet regarding their proposed 
protocols. Therefore, no changes to this rule are necessary.
    58. One comment recommended that all statements submitted under 
this part be certified by an officer from the manufacturer's executive 
committee. Another comment recommended that the language in the 
certification should include ``to the best of my knowledge'' to reduce 
the risk that a certifying official could be penalized for an 
inadvertent mistake not within his/her knowledge.
    The final rule requires that the manufacturer's attorney, agent, or 
other authorized official sign the submission. Although an officer from 
the manufacturer's executive committee may be an authorized official, 
FDA does not think it is necessary for the submission to be signed by 
such an officer. FDA also does not agree that it would be appropriate 
to include the words ``to the best of my knowledge'' in the 
certification. The attorney, agent, or other authorized official who 
signs the submission and certification on behalf of the manufacturer, 
and ultimately the manufacturer itself, is responsible for what is 
submitted to the agency under this part.
    59. Proposed Sec. 99.201(c) described the component in each FDA 
center that will receive a submission under this part. Several comments 
noted that it would be appropriate for the review divisions in the 
centers to also receive copies of the information submitted under this 
part.
    In the final rule, FDA is retaining the requirement that the 
submissions go to a single office within each center. Those offices 
will forward the information to the appropriate review divisions within 
the agency. The regulation need not spell out all of FDA's internal 
procedures for processing these submissions.
    60. One comment stated that FDA needs to clarify the required 
physical organization of the documents submitted under this part.
    FDA does not think it is appropriate to include that kind of detail 
in this regulation. Nevertheless, FDA expects that materials in a 
submission will be organized and labeled in accordance with the 
submission requirements described in this part. If FDA subsequently 
determines that manufacturers need more guidance in this area, it will 
issue a guidance document.
    61. A number of comments objected to proposed Sec. 99.201(d), which 
provided that the 60-day (post submission) period shall begin to run 
when FDA receives a complete submission and that a submission shall be 
considered complete if FDA determines that it is sufficiently complete 
to permit a substantive review. These comments argued that FDA would 
use this provision to extend the 60-day time period. The concern was 
that FDA would, on day 59, advise a manufacturer that their submission 
was not complete and therefore the 60-day time period had not begun. 
The comments said that Congress meant for FDA to give a final answer 
within the 60-day time period.
    As further described below, FDA is committing to give manufacturers 
a final decision within 60 days. FDA has revised Sec. 99.201(d) to 
provide that the 60-day period shall begin when FDA receives a 
manufacturer's submission, including, where applicable, a

[[Page 64568]]

certification statement or an application for an exemption.
    62. A number of comments were made regarding the appropriateness of 
public disclosure of information submitted under this part. Some 
comments argued that both the fact of the submission and all 
information in the submission is confidential and should not be 
released. Other comments argued that all of the previous information 
should be public because the public, including the patient community, 
wants to be involved and has a right to know about a submission, the 
data in such submission, FDA action on the submission, what studies are 
being conducted, and the status of those studies. Several comments 
argued that upon receiving a submission, FDA should publish in the 
Federal Register, the citation for the article and the bibliography, 
and solicit additional published information that might be appropriate 
for dissemination. One comment argued that the public should have an 
opportunity to comment prior to FDA's granting approval for 
dissemination of information and that FDA should hold an advisory 
committee meeting and let the public participate in its decision on 
whether an exemption from the requirement to submit a supplement should 
be granted.
    FDA declines to amend the rule to require a notice and comment 
process before permitting dissemination to proceed or before granting 
an exemption. However, the Freedom of Information Act (FOIA) and FDA's 
regulations will dictate what information submitted under this 
provision can be disclosed. Because the agency was required to issue 
this regulation within such a short period of time, it has been unable 
to fully examine all issues of disclosability. However, the agency will 
continue to examine these issues separately.
    b. Request to extend the time for completing planned studies 
(Sec. 99.203).   Section 554(c)(3) of the act (21 U.S.C. 360aaa-3) 
describes two types of extensions of time regarding planned studies. 
Section 554(c)(3)(A) of the act provides that the 36 month period for 
completing planned studies and submitting a supplemental application 
may be extended by the Secretary of Health and Human Services (the 
Secretary) if the Secretary determines that the studies needed to 
submit such application cannot be completed and submitted within 36 
months. This type of extension would be granted before such studies are 
begun. Section 554(c)(3)(B) of the act provides that the period for 
completing planned studies and submitting a supplemental application 
may be extended by the Secretary if the manufacturer submits a written 
request for the extension and the Secretary determines that the 
manufacturer has acted with due diligence to conduct the studies in a 
timely manner. The latter extension cannot exceed 24 months. Proposed 
Sec.  99.203 set forth the procedures that a manufacturer must follow 
to request an extension of time for submitting a supplemental 
application and the content of a request for an extension. The 
provision covered only the extension in section 554(c)(3)(B) of the 
act.
    63. The comments to this provision indicated that there was some 
confusion regarding the two different statutory procedures. Several 
comments asked FDA to more clearly set out the two procedures 
contemplated by the statute.
    Although the statute specifically refers to a manufacturer request 
in connection only with the procedure described in section 554(c)(3)(B) 
of the act and FDA agrees that the agency can, under section 
554(c)(3)(A), on its own initiative determine before the studies have 
begun that more than 36 months is needed, FDA believes that 
manufacturers will come to FDA and ask FDA to make a determination 
under section 554(c)(3)(A) of the act. Therefore, FDA has revised 
Sec. 99.203 to establish procedures for the two different types of 
extensions. The first extension, set forth in Sec. 99.203(a), relates 
to a request for an extension by the manufacturer at or before the time 
it submits its dissemination package to FDA because the 36-month period 
is not enough time to complete a study or studies of the new use and 
submit a supplemental application. Revised Sec. 99.203(b) sets forth 
the procedures that a manufacturer must follow to request an extension 
of time for submitting a supplemental application after a study has 
begun and the content of a request for an extension.
    c. Application for exemption from the requirement to file a 
supplemental application (Sec. 99.205). Proposed Sec. 99.205 set forth 
what a manufacturer must submit when seeking an exemption from the 
requirement to file a supplemental application for a new use for 
purposes of disseminating information on that new use. It required the 
manufacturer to include an explanation as to why an exemption is sought 
and to include materials demonstrating that it would be economically 
prohibitive or unethical to conduct the studies needed to submit a 
supplemental application for the new use.
    64. A number of comments supported the standards that FDA proposed 
to determine whether it would be economically prohibitive or unethical 
to conduct the studies needed to submit a supplemental application. 
Some noted that FDA's standards are consistent with congressional 
intent that exemptions be limited in scope and infrequent or rare. One 
comment argued that pediatric exemptions should be extremely rare. One 
comment stated that exemptions should never be granted.
    FDA agrees that Congress intended that exemptions from the 
requirement to file a supplemental application for a new use be granted 
in limited circumstances (see H. Conf. Rept. No. 399, 105th Cong., 1st 
sess. at 100 (1997); 143 Congressional Record S9,837 (daily ed. Sept. 
24, 1997) (Statement of the Managers)). There is nothing in the statute 
or legislative history that gives FDA authority to apply a different 
standard in the case of pediatric exemptions. Moreover, the act 
provides for exemptions, so FDA does not agree that such exemptions 
should never be granted. In light of the comments received to the 
standards set forth in its proposal (discussed in more detail below), 
FDA is adopting a different standard for the economically prohibitive 
exemption. Although, FDA is not changing the standard for the unethical 
exemption, it has, as discussed in the following paragraphs, clarified 
how it will apply that exemption.
Economically Prohibitive Exemption
    Under proposed Sec. 99.205(b)(1), a manufacturer seeking an 
exemption from the requirement to file a supplemental application on 
the basis that it would be economically prohibitive to conduct the 
needed studies would have to: (1) Explain why existing data, including 
data from the scientifically sound study described in the information 
to be disseminated, are not adequate to support approval of the new 
use; and (2) show, at a minimum, that the estimated cost of the 
necessary studies would exceed the estimated total revenue from the 
product minus the cost of goods sold and marketing and administrative 
expenses attributable to the product and that there are not less 
expensive ways to obtain the needed information.
    Proposed Sec. 99.205(b)(1) set forth the type of evidence that the 
manufacturer would have to include to meet the requirements for an 
economically prohibitive exemption. These included:
    (1) A description of the current and projected U.S. patient 
population for the product and an estimate of the current and projected 
economic benefit to the

[[Page 64569]]

manufacturer from the use of the drug or device in this population. The 
estimate would assume that the total potential market for the drug or 
device is equal to the prevalence of all of the diseases or conditions 
that the drug or device will be used to treat and involve the following 
considerations: (a) The estimated market share for the drug or device 
during any exclusive market period, a summary of the exclusive market 
period for the product, and an explanation of the basis for the 
estimate; (b) a projection of and justification for the price at which 
the drug or device will be sold; and (c) comparisons with sales of 
similarly situated drugs or devices, where available.
    (2) A description of the additional studies that the manufacturer 
believes are necessary to support the submission of a supplemental 
application for the new use and an estimate of the projected costs for 
such studies; and
    (3) An attestation by a responsible individual of the manufacturer 
verifying that the estimates included with the submission are accurate 
and were prepared in accordance with generally accepted accounting 
procedures. The data underlying and supporting the estimates shall be 
made available to FDA upon request.
    65. As set forth previously, some of the comments agreed with FDA's 
construction of ``economically prohibitive'' These comments argued that 
such exemptions should be granted rarely and that the criteria for such 
an exemption should be rigorous. One comment argued that the cost for 
the studies should substantially exceed revenues to qualify for the 
exemption. Several comments opposed such an equation.
    FDA agrees that exemptions should be granted only in limited 
circumstances. As set forth below, however, FDA was convinced by the 
comments that the standard set forth in its proposal was inappropriate 
and has revised the standard.
    66. A number of comments objected to how the agency proposed to 
determine what is economically prohibitive. First, they objected to the 
agency's use of the term ``rare'' in describing when such exemptions 
would be granted. One comment opined that Congress meant for the 
exemption to arise in a ``fair number of circumstances.'' Second, they 
objected to the absence of the criteria listed in the statute and 
report language from the standard set forth in the codified regulation. 
Third, they claimed that the proposed rule's standard for determining 
what is economically prohibitive is too high.
    One comment argued that the exemption should be granted if it does 
not make economic sense to pursue a supplement. Others argued that it 
should be based on the revenue from the new use, not all uses of the 
product. Some argued that the standard should be whether the cost of 
the studies would exceed the revenues from the new use; others argued 
that it should be whether the cost of the studies exceeds the new use 
revenues that resulted from approval of the supplement (i.e., the 
increase in revenues from the new use that result from submission of 
the supplement). Several comments argued that FDA should automatically 
grant an exemption if the new use is for a rare disease or condition 
because for such use there is no reasonable expectation that the cost 
of developing and making available a drug for such disease will be 
recovered from sales in the United States of such drug. Several 
comments argued that the economically prohibitive exemption should 
automatically be granted if: (1) There is no market exclusivity for the 
product (from patent, orphan drug status, or Waxman-Hatch); or (2) the 
patient population likely to be served by the new indication will not 
exceed an established number (e.g., 1,000). One comment opined that 
interpreting ``prohibitive'' to mean anything other than the point at 
which an economically rational company will not pursue research ignores 
the needs of patients with rare disorders.
    FDA agrees that Congress did not use the term ``rare'' in the 
legislative history. Nevertheless, Congress did state that exemptions 
to the requirement to submit a supplement would be appropriate only in 
``limited circumstances,'' which in FDA's view implies fewer than in a 
``fair number of circumstances.'' Moreover, Congress strongly 
emphasized the critical importance of getting information about new 
uses onto the label. Although FDA did not include the criteria listed 
in the statute and the legislative history in the standard for 
economically prohibitive, they were included as types of evidence that 
would be required to support the exemption.
    FDA's proposed criterion did not focus solely on sales from the new 
use because the agency believed that there might be many circumstances 
where the cost of the study requirements would exceed the sales from 
just the new use. The agency explained that in some of these 
situations, even if it were not economically ``wise'' to conduct the 
studies, the cost would not rise to the level of being ``prohibitive.'' 
This view was judged consistent with the legislative history, which 
foresaw the granting of economic exemptions only in limited 
circumstances. The agency noted, however, that defining a practical 
``economically prohibitive'' exemption was particularly troublesome, 
because it would be so difficult for the agency to assess cost and 
income projections. In view of these difficulties, FDA acknowledged 
that it was not certain that the proposed approach was optimal and 
sought comment on other possible ways to define economically 
prohibitive.
    Unfortunately, the agency has received widely conflicting public 
comment on this issue and remains uncertain about the elements of a 
standard that would be most appropriate and effective in achieving the 
statutory goals. An approach that would grant automatic exemptions if: 
(1) The new use were for a rare disease or condition; (2) there was no 
market exclusivity for the product (from patent, orphan drug status, or 
Waxman-Hatch); or (3) the patient population likely to be served by the 
new indication would not exceed an established number (e.g., 1,000) 
would be inappropriate. Neither the statute nor the legislative history 
provide for automatic exemptions in these circumstances. Rather, they 
direct FDA to take both market exclusivity and population size into 
account. The legislative history made clear that the size of the 
patient population would not necessarily justify an exemption. In fact, 
the legislative history stated that an exemption based on the size of 
the patient population was intended to be the exception rather than the 
rule in cases of populations suffering from orphan or rare diseases or 
conditions. The legislative history made clear that FDA should consider 
the importance of getting products for these diseases or conditions 
approved. It noted that for many years, Congress has sought to 
encourage research into orphan diseases and support the approval of 
innovative drugs for their treatment. Congress, therefore, has directed 
FDA to recognize the vital importance of encouraging applications for 
new products intended to treat rare diseases and to examine very 
carefully whether an exemption from filing a supplemental application 
might hinder such research (see H. Conf. Rept. No. 399, 105th Cong., 
1st sess. at 100 (1997); H. Rept. No. 310, 105th Cong. 1st. sess. at 62 
(1997)).
    Because the agency remains uncertain about the elements of a 
standard that would be most appropriate and effective, FDA plans to 
continue its search for a policy that would satisfy the congressional 
expectation of approving exemptions in only limited

[[Page 64570]]

circumstances, without foreclosing the dissemination of useful 
information by firms that could not otherwise conduct the needed 
studies. In the meantime, FDA will implement the statute by basing its 
evaluation of each exemption on a case-by-case determination of whether 
the cost of the study for the new use reasonably exceeds the total 
expected revenue from the new use minus the cost of goods sold and 
marketing and administrative expenses attributable to the new use of 
the product. This standard may not always meet a strict profitability 
criterion because it considers all new use revenues, rather than just 
the new use revenues that would result from approval of the supplement. 
Nevertheless, it is consistent with most of the comments submitted by 
the affected industry on this issue, it is consistent with the 
statutory directive, and it attempts to strike a fair balance between 
assuring the widest possible information dissemination while granting 
economic exemptions only in ``limited circumstances.''
    The final rule sets forth the statutory standard and the 
information that FDA would need to make this case-by-case 
determination. This will include information about: (1) The cost of the 
study for the new use; (2) the expected patient population for the new 
use; (3) the expected total revenue for the new use minus the cost of 
goods sold and marketing and administrative expenses attributable to 
the new use of the product; (4) the amount of exclusivity for the drug 
or new use; and (5) other information that the manufacturer believes 
demonstrates that conducting the studies on the new use would be 
economically prohibitive.
    As this revised criterion may significantly expand the number of 
exemption applications beyond that anticipated by the Congress, the 
agency is determined to review its experience with these requests as 
they are submitted and, if necessary, to contract with outside economic 
experts to help develop an approach that most appropriate and effective 
and workable for the agency.
    67. A number of comments objected to the requirement to submit 
detailed financial data. These comments argued that manufacturers 
should be not required to submit highly sensitive and proprietary 
information. Others felt that FDA is not qualified to review and 
evaluate this data.
    Congress directed FDA to grant an economic exemption only upon 
making a determination that conducting the studies and submitting a 
supplement would be economically prohibitive. FDA cannot make this 
determination without examining the relevant company data. Therefore, 
the final rule retains these requirements.
    68. Several comments regarding FDA's approach to economic 
exemptions recommended that FDA require a manufacturer to submit a 
certified public accountant's (CPA's) opinion on the economic 
feasibility of filing a supplemental NDA. FDA could contest the claim 
by providing a CPA's statement to the contrary.
    FDA declines to adopt this approach because it removes the agency 
from the statutorily-specified role of determining whether it would be 
economically prohibitive to conduct the studies.
    69. One comment recommended that manufacturers be given the 
flexibility to present whatever information they determine is relevant 
to the ``economically prohibitive'' factor, that the manufacturer be 
able to use its own assumptions, and that each situation be evaluated 
on a case-by-case basis.
    As set forth previously, FDA is adopting a case-by-case 
determination and has specified the information that is essential for 
this determination. Nevertheless, manufacturers are free to provide 
whatever additional information they think is relevant to the 
determination. This could include information that would explain why a 
study is so expensive to conduct. For example, one factor might be the 
difficulty of enrolling patients in a clinical investigation if the new 
use has become the standard of care.
    70. Proposed Sec. 99.205(b)(1)(ii)(A) stated that the estimated 
economic benefit for a drug or device shall assume that the total 
potential market is equal to the prevalence of the disease(s) or 
condition(s) that such product will be used to treat. Several comments 
argued that this assumption should be deleted because the potential 
market for the drug or device may be less than the prevalence of the 
disease in question if other therapies are likely to be used in some 
portion of the total patient population.
    FDA agrees that this assumption should be deleted and has done so 
in the final rule.
    71. One comment argued that the manufacturer should not be required 
to provide a ``justification'' of the price at which the drug will be 
sold. According to this manufacturer, only a projection is relevant.
    FDA has to be able to determine whether the manufacturer's proposed 
price is reasonable. It may be that ``justification'' for the price is 
not appropriate. Therefore, in Sec. 99.205(b)(ii)(C) of the final rule, 
FDA will seek an explanation of the price at which the drug or device 
will be sold.
    72. One comment opined that permitting an exemption because of cost 
is an ethical decision because it is placing a monetary value on 
people's lives and safety.
    FDA does not agree that an economically prohibitive exemption is 
placing a monetary value on people's lives and safety. The standard in 
FDA's regulation is intended to best effectuate the goals of the 
statute.
    73. Proposed Sec. 99.205(b)(1)(ii)(C) required a manufacturer to 
provide an attestation by a responsible individual of the manufacturer 
verifying that the estimates included with a submission are accurate 
and were prepared in accordance with generally accepted accounting 
procedures. In addition, the data underlying and supporting the 
estimates would have to be made available to FDA upon request. In the 
preamble to the proposed rule, FDA noted that it had considered 
requiring a report of an independent CPA with respect to the estimates 
and FDA solicited comment on whether such a report should be required 
in lieu of, or as an alternative to, the attestation that would be 
required by the proposal.
    Some comments supported the submission of the CPA report discussed 
previously, others felt that such a report should not be required. 
Still other comments stated that the CPA report should be submitted in 
lieu of the underlying data or that the CPA should make the 
determination of economic feasibility instead of FDA.
    As stated previously, FDA refuses to adopt a procedure by which it 
surrenders decision making to a CPA. However, FDA is not convinced that 
it is necessary to require a report of an independent CPA with respect 
to the estimates. Under Sec. 99.205(b)(1)(iii), therefore, FDA will 
accept either an attestation by a responsible individual of the 
manufacturer or by a CPA verifying that the estimates included with a 
submission are accurate and were prepared in accordance with generally 
accepted accounting procedures.
Unethical Exemption
    Proposed Sec. 99.205(b)(2) required a manufacturer seeking an 
exemption on the basis that it would be unethical to conduct the 
studies needed to submit a supplement, to: (1) Explain why existing 
data, including data from the scientifically sound study described in 
the information to be disseminated, are not adequate to support 
approval of the new use; and (2) show that, notwithstanding the 
insufficiency of existing data to support the submission of a 
supplemental application for the

[[Page 64571]]

new use, the data are persuasive to the extent that withholding the 
drug or device in the course of conducting a controlled study would 
pose an unreasonable risk of harm to human subjects.
    The proposed codified language provided that an unreasonable risk 
of harm would ordinarily arise only in situations in which the new use 
of the drug or device appears to affect mortality or irreversible 
morbidity. Evidence suggesting that the drug or device is the standard 
of care for the new use can add weight to an argument that conduct of a 
needed study or studies would be unethical.
    To support its argument that the conduct of a needed study or 
studies would be unethical, the proposal provided that a manufacturer 
would need to address the possibility of conducting studies in 
different populations or of modified design (e.g., adding the new 
therapy to existing treatments or using an alternative dose if 
monotherapy studies could not be conducted).
    The proposal further provided that in assessing the appropriateness 
of conducting studies to support the new use, the manufacturer may 
provide evidence that the new use represents standard medical treatment 
or therapy. Evidence that the new use represents standard medical 
therapy can be one element of an argument that studies cannot ethically 
be conducted, but the persuasiveness of available data is equally 
important. Evidence that the new use represents standard medical 
therapy might be obtained from a number of different sources. The 
preamble to the proposal set forth the following possible 
considerations: (1) Whether the new use meets the requirements of 
section 1861(t)(2)(B) of the Social Security Act, which defines 
``medically accepted indications'' with respect to the use of a drug; 
(2)  Whether a medical specialty society that is represented in or 
recognized by the Council of Medical Specialty Societies (or is a 
subspecialty of such society) or is recognized by the American 
Osteopathic Association has found that the new use is consistent with 
sound medical practice; (3)  Whether the new use is described in a 
recommendation or medical practice guideline of a Federal health 
agency, including the National Institutes of Health, the Agency for 
Health Care Policy and Research, and the Centers for Disease Control 
and Prevention of the Department of Health and Human Services; and (4)  
Whether the new use is described in a current compendia such as the 
United States Pharmacopoeia Drug Information for the Health Care 
Professional, the American Medical Association Drug Evaluations, or the 
American Hospital Formulary Service (see 63 FR 31143 at 31150).
    74. A number of comments objected to FDA's proposed criteria for 
the unethical exemption--particularly the emphasis on the requirement 
that it ordinarily would arise only in situations in which the new use 
appears to affect mortality or irreversible morbidity. Some comments 
believed that the criteria set forth in the legislative history (that 
are discussed in the preamble) should be in the codified language. 
Finally, a number of comments argued that if the new use is the 
standard of medical care, FDA must automatically grant an exemption.
    The act clearly does not require FDA to automatically grant an 
exemption if a new use is the standard of medical care. The act says 
that FDA must consider (among other considerations that the Secretary 
finds appropriate) whether the new use is the standard of medical care, 
and that is what FDA proposed to do. Moreover, an automatic exemption 
would not be reasonable from a scientific standpoint because there are 
many instances in which the results of a controlled clinical trial have 
demonstrated that a drug or device is unsafe or ineffective for a new 
use for which it is considered to be the standard of care.
    The standard set forth in Sec. 99.205 is consistent with how FDA 
determines what studies are unethical in other contexts (i.e., when a 
manufacturer argues that it would be unethical to conduct a study). 
Moreover, the standard is consistent with the legislative history, 
which provides that such exemptions should be granted in limited 
circumstances. Therefore, FDA is retaining the proposed basic standard 
for the unethical exemption in the final rule (i.e., the data are 
persuasive to the extent that withholding the drug or device in the 
course of conducting a controlled study would pose an unreasonable risk 
of harm to human subjects). FDA continues to believe an effect on 
irreversible morbidity or mortality is what ordinarily would be 
required to show an unreasonable risk of harm. Nevertheless, there 
could be other circumstances in which the agency would find that it 
would be unethical to do the study, i.e., because there would be an 
unreasonable risk of harm even though the new use does not affect 
irreversible morbidity or mortality. In making a determination that it 
would be unethical to conduct a study, the agency must consider whether 
informed consent and proper IRB review would address the concerns 
raised by questions about whether it is appropriate to conduct a study.
    FDA rejects the suggestion that the factors set forth in the 
legislative history that FDA may consider in deciding whether to grant 
an exemption be included as requirements in the codified language. FDA 
has included the statutory factors in the codified language. The 
legislative history provides that FDA may consider those factors among 
other factors, and thus, consideration of these factors is neither 
mandatory nor is it exclusive.
    75. One comment argued that the standard needs to take into account 
the difficulty of enrolling patients in a study in which some subjects 
will receive a placebo when a patient can go to a doctor and receive a 
prescription for the drug. The comment further noted that physicians 
refuse to participate in placebo controlled studies of therapies they 
already believe to be effective.
    FDA agrees that it can be difficult to enroll patients in placebo 
controlled trials and that this could be a relevant consideration. 
Moreover, not all controlled studies are placebo controlled. Companies 
may be able to conduct studies of a different design, depending on the 
situation. For example, a company may be able to compare the new use to 
another therapy that is known to work or may be able to rely on 
historical controls. In some cases, the new use could be added to 
existing therapy and compared with placebo added to existing therapy. 
If these alternate study designs mean that the study or studies will 
take longer, FDA can consider whether to extend the time to conduct the 
studies and submit a supplemental application.
    76. One comment suggested that FDA should grant an exemption if the 
new use is listed in the USP DI or Hospital Formulary. Another comment 
suggested that an unethical exemption should be granted if the 
unapproved use: (1) Is accepted in a monograph of the USP; (2) is 
approved by another ``first world'' country; or (3) is approved by a 
state FDA. Finally, one comment suggested that FDA should automatically 
grant an unethical exemption if the new use: (1) Represents the 
standard of care, as represented by inclusion in specified compendia or 
practice guidelines, or (2) involves a combination of products or more 
than one sponsor and should grant other exemptions on a case-by-case 
basis.
     FDA does not agree that any of these individual factors is enough 
to show that studying a new use would be unethical. Moreover, there is 
nothing in the statute or legislative history to

[[Page 64572]]

suggest that any of the single factors should be sufficient to meet the 
unethical exemption. FDA will, however, consider these factors in 
making its determination of when it would be unethical to conduct a 
study.
    77. One comment noted that, although it supported the list of 
sources to be used to provide evidence that a new use represents 
standard medical therapy, after 1998, the American Medical 
Association's (AMA's) Drug Evaluation and the USP DI may no longer be 
available.
    If the AMA's Drug Evaluation and/or the USP DI become unavailable, 
FDA will stop using them as evidence that a new use is the standard of 
care.
    78. One comment noted that there are diverse opinions in the 
medical community about what standard of care means. Another noted that 
``consistent with sound medical practice'' is not the same as 
``standard of care'' and that an unapproved treatment may be considered 
to be sound medical practice but should still be studied. Several 
comments noted that FDA should take care in how it interprets 
``standard medical treatment or therapy.'' These comments noted that 
manufacturers should not be allowed to take advantage of a situation of 
their own creation. In other words, standard medical treatment should 
not be interpreted as meaning treatment that is regularly used because 
physicians have no other choice because to do so would eliminate the 
requirements for completing any pediatric research.
    FDA agrees that just because a certain treatment is consistent with 
sound medical practice does not mean that it is the standard of care. 
FDA has stated that whether a medical specialty society that is 
represented in or recognized by the Council of Medical Specialty 
Societies (or is a subspecialty of such society) or is recognized by 
the American Osteopathic Association has found that a new use is 
consistent with sound medical practice will be considered as evidence 
that it is the standard of care. Moreover, just because an unapproved 
use of a drug or device is the standard of care, does not mean that it 
is automatically exempt from the requirement to conduct the study 
needed to submit a supplemental application.
    79. Several comments noted that it is almost inconceivable that the 
study of a new use for children could be viewed as unethical.
    FDA will make this determination on a case-by-case basis.
    80. Several comments argued for making the exemption process 
public. One comment said that all information should be made public as 
soon as a manufacturer requests an exemption and that if an exemption 
is granted all information should remain in the public domain so that 
interested parties will be able to play a role in keeping FDA informed 
as to when it should be revoked. Another suggested that prior to 
granting any exemption, FDA should hold a meeting of the appropriate 
advisory committee so that the public has the opportunity to review and 
comment upon the request.
    As set forth previously, FDA declines to adopt a notice and comment 
process for considering exemption requests. The information will be 
made available to the public consistent with FOIA and FDA's 
regulations. FDA has the option of consulting advisory committees about 
exemption requests, when appropriate.
4. Subpart D--FDA Action on Submissions, Requests, and Applications
    a. Agency action on a submission (Sec. 99.301). Proposed 
Sec. 99.301 described the range of FDA's actions when it receives a 
submission. For example, under the proposal, FDA could determine that a 
manufacturer's submission does not comply with the regulatory 
requirements, request additional information or documents to assist the 
agency in determining whether the information to be disseminated 
complies with applicable requirements, or determine that the 
information fails to provide data, analyses, or other written matter 
that is objective and balanced. The proposal also described FDA actions 
in response to a manufacturer's submission when the manufacturer is 
committing to submit a supplement on completed studies or is agreeing 
to conduct the necessary studies and then submit a supplement.
    81. Proposed Sec. 99.301(a) provided that, within 60 days, FDA may 
determine that a submission does not comply with the requirements of 
the proposal or that it needs more information. A number of comments 
objected to the proposal because they believed that FDA would use it to 
extend the 60-day time period. The concern was that FDA would, on day 
59, advise a manufacturer that their submission was not complete and 
therefore the 60-day time period had not begun. The comments said that 
Congress meant for FDA to give a final answer within the 60-day time 
period. Some comments argued that FDA should let manufacturers know if 
their submission is complete within a short period of time, e.g., 
within 15 days of receiving the submission.
    In response to these comments, FDA has eliminated proposed 
Sec. 99.301(a)(2) so that manufacturers will have a final decision 
within 60 days. Within the 60-day period, FDA will either notify a 
manufacturer that it has not met the requirements set forth in the law 
or allow the dissemination to go forward. FDA is not adopting the 
comment's suggestion that it advise sponsors as to whether their 
submissions are complete within a certain number of days (e.g., 15). 
The 60-day statutory timeframe is too short for the agency to make a 
commitment to provide such advice.
    82. One comment stated that FDA should be required to notify the 
manufacturer promptly if it approves a submission in less than 60 days.
    There is no requirement in the statute that FDA notify a 
manufacturer unless it intends to stop the dissemination of information 
under this part. Therefore, FDA is not revising the regulation as 
suggested. The agency will, however, make an effort to notify 
manufacturers promptly if it approves a submission in less than 60 
days.
    83. One comment requested that FDA change the ``may'' in proposed 
Sec. 99.301(a) to ``shall'' and to clarify that a sponsor may begin to 
disseminate material if it has not heard from FDA within 60 days. 
Another comment suggested that FDA clarify Sec. 99.301 to indicate that 
FDA will review an IND or IDE and will notify the manufacturer of the 
IND or IDE approval and that, until such notification, the manufacturer 
cannot disseminate the information.
    FDA declines to change the ``may'' to ``shall'' in Sec. 99.301(a). 
FDA is not required to do any of the things listed in Sec. 99.301(a), 
and so use of the word ``shall'' would be inappropriate. Moreover, it 
is not true that a manufacturer may, in every circumstance, begin 
dissemination if it has not heard from FDA within 60 days. Under 
section 554(c) of the act, a manufacturer that has certified that it 
will conduct the studies needed to submit a supplement and that has 
submitted a proposed protocol and schedule for conducting such studies 
cannot disseminate unless the Secretary has determined that the 
proposed protocol is adequate and that the schedule for completing the 
studies is reasonable. Nevertheless, FDA has revised Sec. 99.301(b) to 
state clearly that the agency will make a positive or negative 
determination on the manufacturer's protocols (and, where appropriate, 
its schedules) within 60 days after receiving a submission under part 
99.
    84. Proposed Sec. 99.301(a)(3) (now redesignated as 
Sec. 99.301(a)(2)) provided

[[Page 64573]]

that FDA shall provide a manufacturer notice and an opportunity for a 
meeting regarding the agency's determination that the information 
submitted is not objective and balanced, and requires additional 
information. One comment suggested that there should be a specific 
timeline for when such a meeting would occur.
    The statute does not require that FDA set a timeline for such a 
meeting. Nevertheless, FDA will provide for such an opportunity as soon 
as is mutually convenient for FDA and the manufacturer. In any event, 
the meeting will take place within the 60-day period. Furthermore, 
should FDA determine that additional articles are necessary to provide 
objectivity and balance, the agency will apply the same standards for 
scientific soundness to those additional articles.
    85. Proposed Sec. 99.301(a)(4) (now redesignated as 
Sec. 99.301(a)(3)) provided that within 60 days of receiving a 
manufacturer's submission, FDA may require the manufacturer to maintain 
records that will identify individual recipients of the information 
that is to be disseminated.
    Some comments supported FDA's not requiring individualized 
recordkeeping in all situations. Others, however, thought it should be 
invoked in all situations and still others thought that ever requiring 
it was too burdensome. One comment argued that the proposed standard 
for individual recordkeeping was too vague and suggested that FDA make 
such a request ``only in rare circumstances, when warranted because of 
special safety considerations associated with a new use.'' One comment 
argued that FDA should provide notice and an opportunity to meet in the 
event that it requires a company to maintain records identifying 
individual recipients.
    Section 553(b) of the act (21 U.S.C. 360aaa-2(b)) expressly 
requires a manufacturer to keep records that the manufacturer may use 
if it is required to take corrective action. Section 553(b) of the act 
also states that, ``Such records, at the Secretary's discretion, may 
identify the recipient of information provided * * * or the categories 
of such recipients.'' FDA does not believe that it would be appropriate 
to require individual recordkeeping in all circumstances. Similarly, 
FDA does not believe that it would be appropriate to require 
recordkeeping of categories of recipients in all circumstances. FDA 
agrees, however, that it should better define the standard for 
individual recordkeeping and will adopt, with slight modifications, the 
standard suggested by the comments. Section 99.301(a)(3) provides for 
individual recordkeeping when warranted because of special safety 
considerations associated with the new use. FDA did not adopt the 
``only in rare circumstances'' language because although it expects to 
require this in limited circumstances, it does not yet have experience 
implementing this provision and nothing in the statute or legislative 
history indicates that Congress intended it to be rare.
    86. One comment was concerned that because the agency has to review 
all submissions within 60 days, sometimes the timeframe will expire and 
allow information dissemination or exemptions to happen without agency 
review and thus patients could be harmed before FDA has time to 
terminate a deemed approval. This comment encouraged the agency to 
provide information to health care providers on the process by which 
the review will occur.
    FDA recognizes that the act would allow information to be 
disseminated without agency review. The agency is committed to 
reviewing all of this information so that inappropriate information 
does not get disseminated.
    87. Proposed Sec. 99.301(b) required FDA to notify the manufacturer 
if the agency determines that its protocol and schedule for conducting 
studies are adequate and reasonable. Until FDA provides such 
notification, dissemination cannot begin. One comment noted that it was 
not the intent of Congress that the 60-day timeframe be delayed as a 
result of ongoing IND/IDE negotiations.
    The statute provides that a manufacturer who submits a protocol and 
proposed schedule for conducting the studies needed to submit a 
supplement, cannot begin to disseminate until FDA determines that they 
are adequate. (See section 554(c)(1) of the act.) However, as stated 
earlier, FDA has revised Sec. 99.301(b) to state that the agency will 
make a positive or negative determination on the manufacturer's 
protocols (and, where appropriate, its schedules) within 60 days after 
receiving a submission under 21 CFR part 99.
    88. Proposed Sec. 99.301(b) described FDA action on a 
manufacturer's proposed protocols and schedules for completing studies. 
One comment said that the rule should clarify which functional groups 
within FDA will be responsible for the review of protocols and studies 
and provide for a timeline for such review.
    FDA has stated previously that clinical information, including 
protocols, that is submitted under this part will be reviewed by the 
appropriate review divisions. It is not necessary for the rule to 
detail FDA's internal procedure. FDA will review such protocols and 
schedules within 60 days. Section 99.301(b) includes that timeframe.
    89. Under proposed Sec. 99.301(b)(2), if a manufacturer has 
completed studies that it believes would be an adequate basis for the 
submission of a supplemental application for the new use and has 
certified that it will submit such supplement within 6 months, FDA 
would conduct a preliminary review of the study reports to determine 
whether the studies are potentially adequate to support the filing of a 
supplemental application for the new use. If FDA determines that the 
study reports are inadequate to support the filing of a supplemental 
application for the new use or are not complete, FDA will notify the 
manufacturer and the manufacturer shall not disseminate the new use 
information under this subpart. One comment argued that FDA should not 
be allowed to take a ``sneak peek'' at preliminary clinical trial data 
prior to its submission in a supplemental application.
    Section 99.201(a)(4)(i) requires manufacturers that have completed 
studies that they believe would be an adequate basis for the submission 
of a supplemental application for the new use and have certified that 
it will submit such supplement within 6 months to submit the protocols 
for those studies. FDA, will, as in the case of the 36-month 
certification, review those protocols to determine whether they are 
adequate. The final rule has been revised to indicate that FDA will 
review the protocols submitted and not the study reports. However, this 
does not in any way affect the agency's ability to determine, based on 
information it has, including information about clinical trials, that 
the information a manufacturer seeks to disseminate is false or 
misleading or would pose a significant risk to public health.
    b. Extension of time for completing planned studies (Sec. 99.303). 
Proposed Sec. 99.303 described FDA's ability to: (1) On its own 
initiative, allow a manufacturer more than 36 months to submit a 
supplemental application, based on the review of the protocols(s) and 
planned schedule; or (2) grant a manufacturer's request to extend the 
36-month period (for up to 24 months). Proposed Sec. 99.303(a) 
described FDA's ability to determine, on its own initiative and before 
any studies have begun, that a manufacturer needs more than 36 months 
to complete the studies needed for submission of a

[[Page 64574]]

supplemental application and to submit such application. Proposed 
Sec. 99.303(b) and (c) described FDA's ability, after such studies have 
begun and the sponsor has submitted a request, to grant an extension of 
the time to submit a supplement by up to 24 months. FDA would grant 
such an extension if the manufacturer makes a request for an extension 
in writing and FDA determines that the manufacturer has acted with due 
diligence to conduct the studies needed for the submission of a 
supplemental application for a new use and to submit such a 
supplemental application, but still needs more time.
    90. The comments to this provision indicated that there was some 
confusion regarding these two different procedures. Several comments 
asked FDA to more clearly set out the two procedures contemplated by 
the statute. Several comments asked FDA to make clear that the 24-month 
limitation applies only to an extension request made after a study has 
begun. One comment suggested that there could be more than one 24-month 
extension.
    FDA has revised this section to make clear that there are two 
different types of extensions. The first extension (in Sec. 99.303 (a)) 
relates to FDA's ability to determine, with or without a request from 
the manufacturer, that 36 months is not enough time to complete a study 
of the new use and submit a supplemental application. This would occur 
before any studies are begun, either before the submission is made or 
at the time of the submission. There is no limit on how much time FDA 
may give a manufacturer under this subsection.
    The second type of extension (described in revised Sec. 99.303(b)) 
relates to FDA's ability to grant a manufacturer's request for an 
extension after a study has begun because, even though it appeared that 
36 months would be sufficient and the manufacturer has acted with due 
diligence, the manufacturer has run into problems and needs more time. 
This type of extension is limited to 24 months and the statute does not 
provide that FDA can give more than one 24-month extension.
    c. Exemption from the requirement to file a supplemental 
application (Sec. 99.305). Proposed Sec. 99.305 described FDA action on 
a request for an exemption from the requirement to submit a 
supplemental application and the criteria to be considered in deciding 
whether to grant a request for an exemption, either because it would be 
economically prohibitive to conduct the studies needed for a 
supplemental application or it would be unethical to conduct the 
clinical studies needed to approve the new use.
    91. Proposed Sec. 99.305(a)(1) states that FDA must act on an 
application for an exemption within 60 days of receipt or it will be 
deemed approved. However, under proposed Sec. 99.305(a)(2), FDA could, 
at any time, terminate such deemed approval if it determines that the 
requirements for granting an exemption have not been met. One comment 
noted that FDA can terminate such deemed approval only if a 
manufacturer is disseminating information under section 551 of the act.
    Section 554(d)(3)(B) of the act provides that if a manufacturer 
disseminates information under section 551 of the act under a deemed 
approval of a request for an exemption, FDA may, at any time, terminate 
a deemed approval and order the manufacturer to cease disseminating the 
information under section 553(b)(3) of the act. FDA does not believe 
that it has to wait for a manufacturer to actually disseminate 
information in order to terminate the deemed approval.
    92. A number of comments suggested that FDA provide a manufacturer 
an opportunity to meet concerning: (1) FDA's determination that the 
manufacturer cannot disseminate information under this part; (2) FDA's 
determination that the manufacturer should maintain records of 
individual recipients; (3) FDA's determination of a company's request 
for an extension of time to complete the necessary studies and submit a 
supplement; (4) FDA's denial of an exemption.
    Section 401 of FDAMA directed FDA to provide manufacturers an 
opportunity to meet regarding a determination that the information to 
be disseminated is not balanced and objective and regarding the 
cessation of information dissemination in certain circumstances. The 
statute does not direct FDA to meet in the circumstances described 
previously. Nevertheless, as always, FDA will honor requests for 
meetings to the fullest extent feasible. Given the short timeframes set 
forth in section 401 of FDAMA, FDA's resource constraints, and the fact 
that FDA does not know how many submissions it will receive under this 
part, FDA is not imposing on itself any additional requirements for 
meetings by making those meetings a part of the regulation.
5. Subpart E--Corrective Actions and Cessation of Dissemination
    Subpart E, as proposed, contained provisions describing the 
corrective actions that FDA could take or order the manufacturer to 
take, termination of approvals of applications for exemption, and the 
applicability of labeling, adulteration, and misbranding authority in 
the event that dissemination failed to comply with section 551 of the 
act.
    93. One comment claimed that proposed subpart E was ``hollow and 
meaningless'' because Congress did not give FDA the authority to seek 
civil money penalties against noncomplying manufacturers.
    FDA disagrees with the comment's characterization of subpart E and 
notes that the agency does, indeed, have the authority to seek civil 
money penalties from any person who violates most requirements of the 
act pertaining to devices (see section 303(f) of the act (21 U.S.C. 
333(f)). Additionally, arguments regarding other civil money penalty 
authority for violations of these regulations are beyond the scope of 
this rulemaking.
    a. Corrective actions and cessation of dissemination of information 
(Sec. 99.401). Proposed Sec. 99.401 authorized FDA to take corrective 
actions and to order a manufacturer to cease dissemination of 
information and take corrective action. In general, the proposal would 
provide for corrective action or an order to cease dissemination of 
information based on post dissemination data, information disseminated 
by the manufacturer, or the manufacturer's supplemental application for 
the new use (or its failure to submit or to complete the studies 
necessary for the supplemental application). Proposed Sec. 99.401 also 
described the procedures to be observed, such as consultation with the 
manufacturer, notice regarding FDA's intent to issue an order to cease 
dissemination, and opportunities for a meeting, and described when a 
manufacturer shall cease disseminating information in the event of its 
noncompliance with the regulations.
    94. Several comments would revise proposed Sec. 99.401 to give 
manufacturers a mechanism for appealing the agency's decision to 
require corrective action. The comments would either amend the rule to 
refer to the dispute resolution provision at section 562 of the act (21 
U.S.C. 360bbb-1), the regulations for internal agency review of 
decisions (Sec. 10.75 (21 CFR 10.75)), or other appeals processes.
    FDA declines to revise the rule to refer to statutory or regulatory 
appeals mechanisms. Such appeals mechanisms are available regardless of 
whether Sec. 99.401 refers to them or not, and it would be both 
impractical and unnecessary to list all possible statutory and 
regulatory appeals mechanisms in Sec. 99.401. Moreover, such a list 
would either become obsolete or useless if any

[[Page 64575]]

statutory or regulatory citations for the appeals mechanisms changed or 
would require FDA to monitor constantly all cross-references without 
any appreciable benefit.
    95. Several comments would amend Sec. 99.401 to permit 
manufacturers to continue disseminating information pending the outcome 
of any appeal except where a significant safety issue or public health 
concern exists. In contrast, one comment said that a manufacturer 
should cease disseminating information while it and FDA are resolving 
any outstanding issues. FDA declines to revise the rule to allow 
manufacturers to continue disseminating information pending the outcome 
of any appeal. In general, section 555 of the act (21 U.S.C. 360aaa-4) 
authorizes the agency to order a manufacturer to cease dissemination of 
information on the unapproved/new use; it does not require the agency 
to stay or defer the effectiveness of such an order pending any appeal 
by the manufacturer. This outcome is consistent with the appeals or 
dispute resolution provisions cited by the comments (section 562 of the 
act and Sec. 10.75), as well as other regulatory mechanisms for 
requesting reconsideration (see, e.g., 21 CFR 10.33 (administrative 
reconsideration of action) and 21 CFR 10.35 (administrative stay of 
action)); none of these mechanisms results in an automatic stay of 
agency action while the agency reconsiders its decision or considers an 
appeal.
    96. One comment suggested that FDA define ``appropriate corrective 
action.'' The comment would amend the rule to give examples of 
corrective action and to describe the circumstances under which 
specific corrective actions might apply.
    By using the term ``appropriate corrective action,'' FDA meant to 
give itself the flexibility to fashion the corrective action to remedy 
the underlying problem or deficiency. As stated in the preamble to the 
proposed rule, these actions include, but are not limited to, ordering 
the manufacturer to send ``Dear Doctor'' letters, to publish corrective 
advertising, to include warning labels on the product, or to include 
warnings or otherwise revise the product labeling (63 FR 31143 at 
31151). FDA declines to define ``appropriate corrective action'' or to 
give examples and to specify when it might order a manufacturer to take 
a particular corrective action. The agency's regulatory experience 
indicates that regulations containing lists or examples often are 
misconstrued as providing an exclusive list (thereby resulting in 
unnecessary disputes as to whether a particular corrective action is 
within the regulation or whether the manufacturer's action is even 
capable of being addressed by the agency) and that regulations that 
describe specific responses to specific situations can deprive the 
agency of the flexibility to tailor a corrective action to fit a 
particular situation. Nevertheless, FDA would note that it expects that 
``Dear Doctor'' letters and/or corrective advertising would be used 
much more often than the addition of warning statements or product 
labeling, which are likely to be used in the more extreme cases.
    97. Proposed Sec. 99.401(a) permitted FDA to take appropriate 
action to protect the public health, including ordering a manufacturer 
to cease dissemination and take corrective action, if FDA determines, 
based on data received after the dissemination has begun, that the new 
use that is the subject of the disseminated information may not be 
effective or may pose a significant risk to public health. The 
provision required FDA to consult with the manufacturer before taking 
any such action.
    One comment disagreed that FDA should have any obligation to 
consult a manufacturer before ordering the manufacturer to cease 
disseminating information on an unapproved/new use.
    Section 555(a)(1) of the act, regarding corrective actions 
following the receipt of data after a manufacturer has begun 
disseminating information, expressly states that the agency, ``after 
consultation with the manufacturer,'' shall take ``such action 
regarding the dissemination of the information as [the agency] 
determines to be appropriate for the protection of the public health, 
which may include ordering that the manufacturer to cease dissemination 
of the information.'' Thus, with respect to corrective actions based on 
post-dissemination data, the act requires FDA to consult the 
manufacturer before taking any action, and Sec. 99.401(a) correctly 
reflects this statutory requirement.
    98. FDA revised Sec. 99.401(c)(3) and (c)(4), by changing the 
references to Sec. 99.303 from paragraphs (a) or (c) to paragraphs (a) 
or (b). This change was needed to correct an error and to reflect the 
changes made to Sec. 99.303, which were previously discussed.
    99. Proposed Sec. 99.401(b) discussed FDA's ability to order 
cessation of dissemination or corrective action because the information 
being disseminated by a manufacturer does not comply with part 99. 
Proposed Sec. 99.401(b)(1) directed FDA to give a manufacturer the 
opportunity to bring itself into compliance if the manufacturer's 
noncompliance constituted a minor violation. Proposed Sec. 99.401(b)(2) 
permitted FDA to order the manufacturer to cease dissemination of 
information after providing notice to the manufacturer and an 
opportunity for a meeting.
    One comment would revise Sec. 99.401(b)(2) to specify a timeframe 
for a meeting, but did not explain why such specificity would be 
beneficial.
    FDA declines to revise the rule as suggested by the comment. 
Because FDA cannot require a manufacturer to cease dissemination until 
it has provided an opportunity for a meeting, it has an incentive to 
schedule such meetings at the earliest possible time, particularly when 
the new use at issue raises significant safety concerns. By not 
specifying a timeframe for a meeting, the regulation provides the 
appropriate flexibility to schedule meetings.
    100. One comment said that FDA should afford manufacturers an 
opportunity to resolve outstanding issues before taking any corrective 
action to avoid burdensome and erroneous corrective action.
    Section 555(b)(1) of the act requires FDA to delay issuing an order 
to provide a manufacturer an opportunity to correct a minor violation 
before ordering such manufacturer to cease dissemination. Section 
99.401(b) provides that opportunity. Moreover, FDA will always consider 
whether and when corrective action is appropriate.
    101. Proposed Sec. 99.401(c) described FDA actions based on a 
manufacturer's supplemental application. For example, under proposed 
Sec. 99.401(c)(1), FDA could order a manufacturer to cease 
dissemination and to take corrective action if the agency determined 
that the supplemental application does not contain adequate information 
for approval of the new use.
    One comment said that FDA should not automatically require a 
manufacturer to cease dissemination if FDA does not approve a 
supplemental application for the unapproved/new use because it fails to 
establish effectiveness. The comment said corrective action should be 
reserved for situations in which ``some significant public health 
concern is identified that would be materially addressed by such 
corrective action.''
    FDA declines to revise Sec. 99.401(c) to limit corrective actions 
as suggested by the comment. If FDA, based on the supplemental 
application submitted by the manufacturer, determines that the drug or 
device is not effective for that use, it could be contrary to the 
interests

[[Page 64576]]

of public health to allow the manufacturer to continue disseminating 
information on that use. Section 555(b)(2) of the act contemplates such 
a result by stating that the agency may order a manufacturer to cease 
dissemination if the agency determines that the supplemental 
application does not contain adequate information for approval of the 
new use.
    Furthermore, one should note that both section 555(b)(2) of the act 
and Sec. 99.401(c) give FDA discretion in issuing an order to cease 
dissemination of information on the unapproved/new use if FDA does not 
approve the supplemental application. Thus, contrary to the comment's 
assertion, an order to cease dissemination under such circumstances is 
not ``automatic.''
    102. One comment said that if FDA does not approve a supplemental 
application because the studies failed to demonstrate efficacy, the 
manufacturer should advise health care practitioners who previously 
received information on the unapproved/new use.
    Requiring a manufacturer to notify recipients or categories of 
recipients that a drug or device is not effective for the unapproved/
new use would be within the range of corrective actions that FDA may 
take. Section 553(b) of the act contemplates such a result by requiring 
manufacturers to keep records of categories of recipients or individual 
recipients of the disseminated information and to use such records if 
the manufacturer is required to take corrective action. Thus, 
corrective actions, in Sec. 99.401, are not confined to orders to cease 
dissemination of information on an unapproved/new use.
    103. One comment sought clarification as to when FDA may determine 
that a supplemental application does not contain adequate information 
for approval of the new use. The comment suggested that proposed 
Sec. 99.401(c)(1) could be interpreted as applying even if FDA 
requested additional information or clarification of a supplemental 
application. The comment stated that dissemination of information on an 
unapproved/new use should cease only when FDA determines that the 
supplemental application is not approvable.
    Section 555(b)(2) of the act permits FDA to order a manufacturer to 
cease dissemination if FDA determines that a supplemental application 
submitted by such manufacturer (for the new use) does not contain 
adequate information for approval of the new use. Section 99.401(c)(1) 
tracks this language. FDA agrees that a decision to seek additional 
data or clarification regarding a supplemental application would 
generally not constitute a determination that the supplement does not 
contain adequate information for approval of the new use. However, 
there may be circumstances in which it is appropriate for the agency to 
order a manufacturer to cease dissemination of information when 
additional data is required. Accordingly, FDA will make these 
determinations on a case-by-case basis.
    104. Proposed Sec. 99.401(c)(2) permitted FDA to order a 
manufacturer to cease dissemination if the manufacturer had certified 
that it would submit a supplemental application within 6 months, and 
the manufacturer failed to submit a supplemental application within 6 
months.
    One comment said FDA should not seek corrective action for a 
manufacturer's failure to submit a supplemental application within 6 
months if there is ``good cause'' for the delay. The comment said that 
FDA should meet with a manufacturer to determine if there is good cause 
for the delay before automatically requiring corrective action and that 
manufacturers should notify FDA as soon as possible if they will not 
meet any deadline.
    FDA declines to revise the rule as requested by the comment. 
Section 99.401(c)(2) does not require any specific corrective action in 
the event that the manufacturer fails to submit a supplemental 
application on time. Instead, it gives FDA the discretion to order the 
manufacturer to cease dissemination of information and to take 
corrective action. FDA will consider, among other things, the reasons 
for a manufacturer's inability to submit a supplemental application on 
time when deciding what type of corrective action to take or whether 
any corrective action is needed.
    Thus, while FDA would appreciate any advance notice from 
manufacturers who believe that they will be unable to submit a 
supplemental application on time and will meet with manufacturers as 
time and resources permit, given the agency's discretion regarding 
corrective actions in Sec. 99.401(c)(2), revising the rule to require 
such meetings is unnecessary.
    105. Proposed Sec. 99.401(d) considered an order to cease 
dissemination of information to be effective upon the date of issuance 
unless otherwise stated by FDA.
    One comment said it would be more efficient if an order to cease 
dissemination of information were effective upon date of receipt by the 
manufacturer. The comment explained that a manufacturer may be unaware 
when FDA issues an order to cease dissemination of information, so the 
order should be effective when the manufacturer receives it. The 
comment also stated that it would be unlikely that a manufacturer could 
stop dissemination of information throughout the United States on the 
same day it receives an order to cease dissemination. Consequently, the 
comment would revise the rule to give manufacturers some time (the 
comment suggested 60 days) in which to comply with the order.
    FDA agrees, in part, with the comment and has revised 
Sec. 99.401(d) to make an order to cease dissemination of information 
effective upon receipt by the manufacturer, unless otherwise indicated 
in the order. The agency does not agree that manufacturers should have 
a specified amount of time after receipt to comply with an order. A 
manufacturer is expected to comply immediately. If the manufacturer is 
unable to comply immediately, it should notify FDA, and FDA will 
evaluate the situation on a case-by-case basis.
    106. Proposed Sec. 99.401(e) required a manufacturer to cease 
dissemination if it fails to comply with the regulations pertaining to 
dissemination of information on unapproved/new uses. This would include 
discontinuation, termination, and a failure to conduct with due 
diligence clinical studies. The proposal also required the manufacturer 
to notify FDA if it ceases dissemination under Sec. 99.401(e).
    One comment would revise the rule to require a manufacturer to 
notify FDA of any failure to comply as soon as the manufacturer 
realizes the failure and ceases dissemination. The comment also would 
require the manufacturer to notify FDA immediately if the manufacturer 
ceases dissemination. Section 99.401(e) already requires a manufacturer 
to notify FDA if it ceases dissemination.
    FDA agrees that the agency should be notified immediately and has 
revised Sec. 99.401(e) accordingly.
    b. Termination of approvals of applications for exemption 
(Sec. 99.403).  Under the act, if FDA fails to act within 60 days on an 
application for an exemption from the requirement to file a 
supplemental application, the application is deemed approved. Proposed 
Sec. 99.403 allowed FDA to terminate the deemed approval of an 
application for an exemption if FDA determines that the manufacturer 
has failed to meet the requirements for granting an exemption. In 
addition, the agency may order the manufacturer to cease disseminating 
information about the new use and, if appropriate, to take corrective 
action.

[[Page 64577]]

    107. One comment would revise Sec. 99.403(a)(3) to apply if FDA 
determines that it would be economically and ethically possible to 
conduct the studies needed for a supplement rather than economically or 
ethically possible to conduct such studies.
    FDA agrees and has revised the rule accordingly.
    108. One comment requested that FDA provide notice and an 
opportunity to meet when FDA terminates approval of an application for 
an exemption.
    Section 99.403(c), (d), and (e) provide for notice to the 
manufacturer, and Sec. 99.403(d) also mentions consultation between FDA 
and the manufacturer if FDA determines that the manufacturer no longer 
meets the requirements for an exemption on the basis that it is 
economically prohibitive or unethical to conduct the studies needed to 
support a supplemental application for the new use. Thus, no further 
change to the rule is necessary.
    c. Applicability of labeling, adulteration, and misbranding 
authority (Sec. 99.405). Proposed Sec. 99.405 provided that the 
dissemination of information about a new use could constitute labeling, 
evidence of a new intended use, adulteration or misbranding of the 
product if it fails to comply with the requirements in section 551 of 
the act and the requirements of this part.
    109. One comment claimed that proposed Sec. 99.405 was too broad 
and exceeded the statute by considering a failure to comply with part 
99 to constitute labeling, evidence of a new intended use, 
adulteration, or misbranding of a drug or device. The comment 
acknowledged that labeling that is false or misleading renders a drug 
misbranded and that each introduction of the drug into interstate 
commerce constitutes a separate prohibited act under section 301 of the 
act (21 U.S.C. 331). The comment further acknowledged that FDA can 
pursue various enforcement actions, such as seizures, injunctions, and 
criminal penalties, for each prohibited act. However, the comment 
argued that a failure to comply with part 99 should be a single 
violation rather than a violation for each product sold and that if a 
manufacturer tries to follow part 99, the act prescribes specific 
enforcement consequences, such as corrective action, before FDA resorts 
to other sanctions.
    FDA disagrees with this comment. Although section 401 of FDAMA 
provided FDA additional enforcement tools for violative dissemination 
of off-label information, it did not in any way eliminate or limit 
FDA's ability to use its already existing enforcement mechanisms.
6. Subpart F--Recordkeeping and Reports
    Recordkeeping and reports (Sec. 99.501). Proposed Sec. 99.501 
required a manufacturer that disseminates information under part 99 to 
maintain records sufficient to allow it to take corrective action that 
is required by FDA and described some of the records to be kept. The 
proposal gave manufacturers the option of maintaining records that 
identify recipients of the disseminated information by name or by 
category, but would require manufacturers who choose to identify 
recipients by category to ensure that any corrective action FDA 
requires will be sufficiently conspicuous so as to reach the 
individuals who have received the information about the new use. The 
proposal also permitted FDA to require manufacturers to keep records 
identifying recipients by name and required a manufacturer to keep 
records for 3 years after it has ceased disseminating the information 
on an unapproved or new use and to make the records available to FDA 
for inspection and copying.
    110. One comment suggested that FDA permit manufacturers to submit 
reports via the Internet. The comment said that this would reduce 
paperwork burdens and provide a continuous source of current 
information.
    FDA currently receives certain submissions from industry in 
electronic form and encourages increased utilization of this means. 
Initiatives are underway to formalize a process for electronic 
submission.
    111. Several comments focused on proposed Sec. 99.501(a)(1)(i), 
which required records to identify, by name, the persons receiving the 
disseminated information. This provision would apply if the 
manufacturer did not keep records identifying recipients by category or 
if FDA required the manufacturer to keep records identifying recipients 
by name. One comment supported the provision as written. Several 
comments would amend the rule to require manufacturers to keep records 
identifying recipients by name in all cases. These comments explained 
that requiring manufacturers to maintain records of specific recipients 
would help ensure timely action or notification if the new use is 
ineffective or presents a significant risk to the public health. The 
comments said such records also would help ensure that the manufacturer 
disseminated the information to the appropriate recipients. Two 
comments suggested requiring manufacturers to keep records of health 
professionals by name, health plans, and pharmacies that receive 
information in cases of a recall.
    In contrast, several comments objected to ever requiring 
manufacturers to identify recipients by name. Some comments 
acknowledged that section 553(b) of the act ``technically'' gives FDA 
the discretion to require such records, but nevertheless said the 
provision was ``unnecessary'' or ``unduly burdensome.'' These comments 
would delete the requirement and only require manufacturers to maintain 
records identifying recipients by category.
    FDA declines to revise the rule as suggested by the comments. 
Section 553(b) of the act expressly requires a manufacturer to keep 
records that the manufacturer may use if it is required to take 
corrective action. Section 553(b) of the act also states that, ``Such 
records, at the Secretary's discretion, may identify the recipient of 
the information provided * * * or the categories of such recipients.'' 
To require manufacturers to keep records identifying the recipients in 
all cases, or in no cases, as suggested by the comments, would be 
contrary to the express terms in section 553(b) of the act. As 
previously discussed, however, FDA has better defined the standard for 
individual recordkeeping. Section 99.301(a)(3) of the final rule 
provides for individual recordkeeping when warranted because of special 
safety considerations associated with the new use.
    112. One comment claimed that proposed Sec. 99.501(a)(1)(i) 
exceeded the statutory requirement. The comment said that if FDA 
requires a manufacturer to maintain records identifying recipients by 
category, then if corrective action is later required, FDA should not 
expect manufacturers to generate lists of individual recipients that 
are to receive such corrective action.
    The comment misinterprets the rule. Under Sec. 99.301(a)(3), when 
FDA reviews a manufacturer's submission, the agency would determine 
whether records identifying individual recipients must be kept. FDA 
would impose such a requirement in limited circumstances before the 
manufacturer disseminates any information on the unapproved/new use. 
Section 99.501(a)(1)(i) does not provide a new mechanism for requiring 
manufacturers to keep records identifying individual recipients nor 
does it contemplate requiring manufacturers not previously required to 
identify individual recipients to generate such records if corrective 
action becomes necessary.

[[Page 64578]]

    113. Several comments discussed the semiannual submissions to FDA 
under proposed Sec. 99.501(b). Several comments objected to proposed 
Sec. 99.501(b)(3) and (b)(4), which required a notice and summary of 
any additional clinical research or other data relating to the safety 
or effectiveness of the new use and periodic progress reports on the 
manufacturer's studies. The comments stated that such reporting 
requirements would duplicate information that FDA already receives 
under existing reporting requirements for IND's and NDA's. One comment 
objected to the semiannual frequency of the reports. Another argued 
that FDA failed to set forth ``limits on the responsibilities'' of 
manufacturers ``as the Secretary deems appropriate'' regarding 
additional information that must be submitted. Finally, one comment 
asked FDA to acknowledge that these reports are exempt from disclosure 
under FOIA.
    Section 99.501(b)(3) and (b)(4) reflect the statutory requirement 
at sections 555(a)(2) and 554(c)(2) of the act respectively. Section 
555(a)(2) of the act states that, after a manufacturer disseminates 
information, the manufacturer shall submit ``a notification of any 
additional knowledge of the manufacturer on clinical research or other 
data that relate to the safety or effectiveness of the new use 
involved.'' Section 554(c)(2) of the act requires a manufacturer to 
submit periodic progress reports on its clinical studies. FDA drafted 
the proposed rule to have these periodic progress reports submitted on 
a semiannual basis in order to coincide with the reporting frequency 
for the lists of articles and categories of providers required by 
section 553(a) of the act. This would be more convenient for both 
manufacturers and the agency to have the reports and lists submitted at 
the same time. Thus, FDA did not intend to require duplicate reporting 
of information that is already submitted to the agency under other FDA 
regulations nor did FDA intend to make the submission of such reports 
burdensome.
    To the extent that the information described in Sec. 99.501(b)(3) 
and (b)(4) is already submitted to FDA as part of the routine reporting 
for an application for investigational use or for a marketing 
application, manufacturers may comply with Sec. 99.501(b)(3) and (b)(4) 
by making a cross-reference to the relevant application for 
investigational use or for a marketing application. Thus, a 
manufacturer does not have to duplicate information that it has already 
submitted to FDA. Moreover, FDA did set limits on the manufacturers' 
responsibilities by requiring that the information be reported on a 
semiannual basis. Finally, as stated earlier, public disclosure of 
information submitted under this rule is dictated by the FOIA and FDA's 
regulations.
    114. One comment sought clarification that a manufacturer must 
submit any additional article or publication to FDA before it can be 
disseminated. The concern was that manufacturers would interpret the 
semiannual filing requirement as sufficient once a manufacturer has 
received approval to disseminate information about a particular use.
    The statute and regulation make clear that the manufacturer has to 
come to FDA before beginning to disseminate a journal article or 
reference publication that has not previously been submitted to FDA. In 
other words, once FDA has approved or passed on a specific journal 
article or reference text, the manufacturer can disseminate it to as 
many qualified recipients as it chooses, as long as the manufacturer 
continues to meet the requirements of this part. However, even if FDA 
has approved or passed on one journal article or reference publication 
for a new use, the manufacturer may not disseminate additional/
different journal articles or reference publications for that same use 
without making a separate submission.
    115. If a manufacturer received an exemption from the requirement 
to submit a supplemental application, proposed Sec. 99.501(b)(5) would 
require the manufacturer to submit any new or additional information 
that relates to whether the manufacturer continues to meet the 
requirements for the exemption. One comment objected to this 
requirement, saying that it would need extensive market data to 
continue justifying the need for an exemption on economic grounds and 
that the cost of generating such information would itself be 
economically prohibitive.
    FDA disagrees that it would be economically prohibitive to comply 
with this requirement. The regulation requires manufacturers only to 
provide new or additional information.
    116. Proposed Sec. 99.501(c) required a manufacturer to maintain a 
copy of all information, lists, records, and reports required or 
disseminated under part 99 for 3 years after it has ceased 
dissemination of such information and to make such documents available 
to FDA for inspection and copying. One comment requested clarification 
of this provision. The comment explained that if FDA approves the 
manufacturer's supplemental application, then the manufacturer would no 
longer be disseminating information on an unapproved/new use and would 
not be subject to part 99. Instead, any postapproval dissemination of 
information would be on an approved use and, therefore, would not be 
subject to the recordkeeping requirement in Sec. 99.501(c).
    The comment's interpretation of Sec. 99.501(c) is correct. If FDA 
approves the manufacturer's supplemental application, the use is then 
``approved'' and dissemination of information on the approved use would 
be outside the scope of part 99. However, documents relating to the 
dissemination of information before approval would remain subject to 
Sec. 99.501.
7. Conforming Amendment to 21 CFR Part 16
    The proposed rule would amend 21 CFR 16.1(b)(2) to add the due 
diligence determination under proposed Sec. 99.401(c) to the list of 
regulatory actions that may be the subject of a part 16 hearing.
    FDA received no comments on this provision and has finalized it 
without change.

IV. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages). Under the Regulatory Flexibility Act, unless an agency 
certifies that a rule will not have a significant economic impact on a 
substantial number of small entities, the agency must analyze 
regulatory options that would minimize the impact of the rule on small 
entities. Title II of the Unfunded Mandates Reform Act (Pub. L. 104-4) 
(in section 202) requires that agencies prepare an assessment of 
anticipated costs and benefits before proposing any rule that may 
result in an expenditure in any 1 year by State, local, and tribal 
governments, in the aggregate, or by the private sector, of $100 
million or more (adjusted annually for inflation).
    The agency has reviewed this rule and has determined that it is 
consistent with the regulatory philosophy and principles identified in 
Executive Order 12866, and in these two statutes. Although this rule is 
not an economically significant regulatory action, it is still a 
significant regulatory action as defined by the Executive Order due to 
the novel policy issues it raises.

[[Page 64579]]

 With respect to the Regulatory Flexibility Act, the agency certifies 
that the rule will not have a significant economic impact on a 
substantial number of small entities. Because the final rule does not 
impose any mandates on State, local, or tribal governments, or the 
private sector that will result in a 1-year expenditure of $100 million 
or more, FDA is not required to perform a cost-benefit analysis under 
the Unfunded Mandates Reform Act.
    The rule implements section 401 of FDAMA by describing the new use 
information that a manufacturer may disseminate and by setting forth 
procedures that manufacturers must follow before disseminating 
information on the new use. The benefits of the rule will derive from 
the public health gains associated with the earlier dissemination of 
objective, balanced, and accurate information on important unapproved 
uses of approved products. In addition, the rule may encourage new 
studies or the collection of evidence about these new uses.
    The costs of the rule are modest. A firm would typically conduct 
clinical studies in support of a supplemental application for a new use 
only if the firm believed that the added revenues associated with the 
new indication would exceed the costs of the supporting studies. 
Because this rule will accelerate the receipt of these revenues, it is 
possible that some new use supplemental applications that would not 
have been economically justified in the absence of this rule, will now 
be submitted. No comments on the proposed rule attempted to project the 
magnitude of this incentive and FDA similarly could not estimate the 
number or cost of the additional clinical studies that might accompany 
these applications. The agency notes, however, that they would be 
undertaken voluntarily by the affected firms in the expectation that 
they would increase company profitability.
     Manufacturers choosing not to disseminate new use information will 
incur no costs. Firms voluntarily choosing to disseminate new use 
information will experience added paperwork costs for each submission 
to the agency, but gain sales revenues from the information 
dissemination. FDA cannot make a precise estimate of the number of 
submissions that will be filed, but as explained in section V of this 
document, the agency tentatively forecasts that it will receive 
approximately 300 submissions each year from manufacturers for the 
purpose of disseminating new use information. FDA also estimates that 
the statutory and regulatory paperwork burdens associated with these 
submissions might total almost 52,000 hours, at an average labor cost 
of $35 per hour.\1\ Thus, the total cost of the added paperwork is 
estimated to cost industry approximately $1.8 million per year. FDA 
received no public comments that specifically addressed its paperwork 
estimates.
---------------------------------------------------------------------------

    \1\ Updated from Eastern Research Group, Inc., ``Final Report--
Economic Threshold and Regulatory Flexibility Assessment of Proposed 
Changes to the Current Good Manufacturing Practice Regulations for 
Manufacturing, Processing, Packaging, or Holding Drugs (21 CFR 210 
and 211),'' March 13, 1995. Calculation allocates 50 percent of 
hours to middle management, 25 percent to upper management, and 25 
percent to support staff.
---------------------------------------------------------------------------

    The final rule should not have an adverse impact on any 
manufacturer. One comment asserted that the agency's definition of 
economically prohibitive implies that some manufacturers will 
disseminate information despite a resulting reduction in net income. 
The comment further indicated that this reduction in net income 
requires FDA to undertake additional analysis under the Regulatory 
Flexibility Act. The agency disagrees with this comment, because the 
final rule simply makes the dissemination of unapproved use information 
an option for those firms that find it beneficial to do so. Firms will 
compare the expected sales revenue from the new dissemination activity 
to the associated paperwork cost and disseminate the new information 
only if it increases their profitability. As noted previously, firms 
choosing not to disseminate new use information will face no increased 
costs. Because no firm is likely to experience a reduced net income, 
the rule will not have a significant adverse economic effect on a 
substantial number of small entities and no further analysis is 
required under the Regulatory Flexibility Act.

V. Paperwork Reduction Act of 1995

    This rule contains information collection requirements that are 
subject to public comment and review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520). A description of these provisions is given below in this section 
of the document with an estimate of the annual reporting and 
recordkeeping burden. Included in the estimate is the time for 
reviewing instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    FDA had submitted the information collection requirements for the 
proposed rule to OMB for its review. In its Notice of Office of 
Management and Budget Action, dated July 30, 1998, OMB stated that it 
had concerns regarding the burden and utility of the information 
collection that were to be ``assessed in light of public comments 
received.'' The terms of OMB clearance further stated that OMB:
    is particularly interested in determining whether the public has 
comments on the burden and utility of the information required to be 
included in a submission to FDA, including information submitted to 
meet the economically prohibitive' exception, and the three year 
recordkeeping requirement proposed in the rule. FDA shall 
specifically address any comments received on these and other issues 
related to the information collection requirements * * *.
The proposed rule provided an opportunity for public comment on the 
information collection requirements, but FDA received no comments that 
provided any contrary or different estimates. The agency did receive 
one comment declaring that the estimated information collection burden 
for the proposed rule ``may not be an accurate reflection of the actual 
burden,'' but the comment provided no data or further information that 
would enable FDA to revise the estimated information collection burden 
for the final rule.
    The agency received several comments that questioned the utility of 
the information collection requirements. For example, several comments 
requested changes to the information that would be required to obtain 
an exemption when a manufacturer felt it would be ``economically 
prohibitive'' or ``unethical'' to conduct studies necessary to support 
a supplemental application. These comments generally stated that the 
proposed rule's criteria were too restrictive. The agency revised the 
``economically prohibitive'' criteria in response to the comments and 
modified the language in the ``unethical'' exemption. These issues are 
discussed in more detail in the preamble to the final rule.
    The agency received several comments that questioned the utility of 
the information collection requirements. For example, several comments 
requested changes to the information that would be required to obtain 
an exemption when a manufacturer felt it would be ``economically 
prohibitive'' or ``unethical'' to conduct studies necessary to support 
a supplemental application. These comments generally stated that the 
proposed rule's criteria were too restrictive. The agency revised the 
``economically prohibitive'' criteria in response to the comments and 
modified the language in the ``unethical'' exemption. These issues are

[[Page 64580]]

discussed in more detail in the preamble to the final rule.
    The agency did not receive any comments that questioned the utility 
of the 3-year recordkeeping requirement. One comment sought 
clarification as to whether the recordkeeping requirement would still 
apply if FDA approved the supplemental application for the new use, and 
FDA has addressed that comment in its discussion of the recordkeeping 
provision.
    FDA did, however, simplify the provision concerning the 
``economically prohibitive'' exception in response to comments it 
received. FDA discusses the impact of this revision on the estimated 
annual reporting burden later in this section.
    FDA requested emergency processing of the information collection 
requirements for this final rule. OMB granted approval to the 
collection of information and assigned a control number (OMB 0910-
0390). The final rule's information collection requirements, therefore, 
are effective upon November 20, 1998. However, the agency is also 
submitting the information collection requirements for the final rule 
to OMB for routine processing. Consequently, FDA is providing an 
opportunity for public comment on the final rule's information 
collection requirements.
    FDA invites comments on: (1) Whether the collection of information 
is necessary for the proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the collection of information, 
including the validity of the methodology and assumptions used; (3) 
ways to enhance the quality, utility, and clarity of the information to 
be collected; and (4) ways to minimize the burden of the collection of 
information on respondents, including through the use of automated 
collection techniques, when appropriate, and other forms of information 
technology.
    Title: Dissemination of Treatment Information on Unapproved/New 
Uses for Marketed Drugs, Biologics, and Devices.
    Description: The rule implements sections 551 through 557 of the 
act (21 U.S.C. 360aaa-360aaa-6) as amended by FDAMA, which requires a 
manufacturer that intends to disseminate certain treatment information 
on unapproved uses for a marketed drug, biologic, or device to submit 
that information to FDA. The rule sets forth the criteria and 
procedures for making such submissions. Under the rule, a submission 
would include a certification that the manufacturer has completed 
clinical studies necessary to submit a supplemental application to FDA 
for the new use and will submit the supplemental application within 6 
months after dissemination of information can begin. If the 
manufacturer has planned, but not completed, such studies, the 
submission would include proposed protocols and a schedule for 
conducting the studies, as well as a certification that the 
manufacturer will complete the clinical studies and submit a 
supplemental application no later than 36 months after dissemination of 
information can begin. The rule also permits manufacturers to request 
extensions of the time period for completing a study and submitting a 
supplemental application and to request an exemption from the 
requirement to submit a supplemental application. The rule prescribes 
the timeframe within which the manufacturer shall maintain records that 
would enable it to take corrective action. The rule requires the 
manufacturer to submit lists pertaining to the disseminated articles 
and reference publications and the categories of persons (or 
individuals) receiving the information and to submit a notice and 
summary of any additional research or data (and a copy of the data) 
relating to the product's safety or effectiveness for the new use. The 
rule requires the manufacturer to maintain a copy of the information, 
lists, records, and reports for 3 years after it has ceased 
dissemination of the information and to make the documents available to 
FDA for inspection and copying.
    Description of Respondents: All manufacturers (persons and 
businesses, including small businesses) of drugs, biologics, and device 
products.
    The estimated burden associated with the information collection 
requirements for this rule is 52,208 hours.
    FDA estimates the burden of this collection of information as 
follows:

                                  Table 1.--Estimated Annual Reporting Burden1
----------------------------------------------------------------------------------------------------------------
                                                      Annual
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                    Respondents      Response        Responses       Response
----------------------------------------------------------------------------------------------------------------
99.201(a)(1)                          172               1.7           297              40          11,880
99.201(a)(2)                          172               1.7           297              24           7,128
99.201(a)(3)                          172               1.7           297               1             297
99.201(a)(4)(i)(A)                     52               1.7            89              30           2,670
99.201(a)(4)(ii)(A)                    52               1.7            89              60           5,340
99.201(a)(5)                           52               1.7            89               1              89
99.201(b)                             172               1.7           297               0.5           148.5
99.201(c)                             172               1.7           297               0.5           148.5
99.203(a)                               1               1.7             1              10              10
99.203(b)                               1               1.7             1              10              10
99.203(c)                               2               1               2               0.5             1
99.205(b)                              17               1.8            30              82           2,460
99.501(b)(1)                          172               3.4           594               8           4,752
99.501(b)(2)                          172               3.4           594               1             594
99.501(b)(3)                          172               3.4           594              20          11,880
99.501(b)(4)                            2               1.7             3               2               6
99.501(b)(5)                           17               1.8            30              41           1,230
Total Hours                                                                                        48,644
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


[[Page 64581]]


                                Table 2.--Estimated Annual Recordkeeping Burden1
----------------------------------------------------------------------------------------------------------------
                                                      Annual
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                   Recordkeepers   Recordkeeping      Records      Recordkeeper
----------------------------------------------------------------------------------------------------------------
99.501(a)(1)                          172               1.7           297              10           2,970
99.501(a)(2)                          172               1.7           297               1             297
99.501(c)                             172               1.7           297               1             297
Total Hours                                                                                         3,564
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    FDA derived these estimates primarily from existing data on 
submissions made under supplemental applications and other submissions 
to the agency, as well as information from industry sources regarding 
similar or related reporting and recordkeeping burdens.
    However, because the final rule revises the ``economically 
prohibitive'' exception requirement, FDA has decreased the estimated 
burden associated with an exemption request under Sec. 99.205(b) and 
has increased the number of annual responses seeking an exemption. In 
the preamble to the proposed rule, FDA estimated that 1 percent or 
approximately 2 of the 172 manufacturers would submit an exemption 
request. The estimated reporting burden for Sec. 99.205(b), as 
originally proposed, was 125 hours per response. This was based on a 
similar reporting burden for certain submissions under (Sec. 316.20 (21 
CFR 316.20)) even though FDA stated that the actual reporting burden 
would probably be less because proposed Sec. 99.205(b) was not as 
extensive as Sec. 316.20. For the final rule, FDA has reduced the 
estimated reporting burden per response to 82 hours because the revised 
requirements are not as extensive as those in the proposal and has 
increased the total number of respondents and annual responses to 17 
and 30 respectively (or approximately 10 percent of all respondents and 
submissions). This results in a total hour burden of 2,460 hours for 
Sec. 99.205(b). Additionally, FDA has revised Sec. 99.203 to permit 
manufacturers to request an extension of the 36-month time period for 
conducting studies and submitting a supplemental application before it 
makes a submission to FDA. FDA, therefore, has adjusted the information 
collection tables to reflect this revision.
    The estimated increase in the number of exemption requests results 
in a corresponding decrease in the remaining number of submissions 
under Sec. 99.201(a)(4)(i)(A), (a)(4)(ii)(A), and (a)(5). FDA assumes 
that the remaining 267 submissions will be divided equally among 
Sec. 99.201(a)(4)(i)(A), (a)(4)(ii)(A), and (a)(5) resulting in 89 
responses in each provision and approximately 52 respondents per 
provision. Although FDA has not altered the estimated burden hours per 
response for Sec. 99.201(a)(4)(i)(A), (a)(4)(ii)(A), and (a)(5), the 
total burden hours for each of these provisions is reduced due to the 
smaller number of annual responses.
    Additionally, the final rule accounts for the estimated annual 
reporting and recordkeeping burdens for several provisions 
(Secs. 99.201(a)(1), 99.201(a)(2), 99.203(a), 99.501(a)(1), 
99.501(b)(1), 99.501(b)(3), 99.501(b)(5), and 99.501(c)). These 
provisions were omitted from the Paperwork Reduction Act discussion in 
the preamble to the proposed rule. The final rule also accounts for the 
statutory reporting burden associated with Sec. 99.201(a)(4).
    The agency has submitted the information collection requirements of 
this rule to OMB for review. Interested persons are requested to send 
comments regarding information collection by January 19, 1999, to the 
Dockets Management Branch (address above).

VI. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

List of Subjects

21 CFR Part 16

     Administrative practice and procedure.

21 CFR Part 99

    Administrative practice and procedure, Biologics, Devices, Drugs, 
Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Acting Commissioner of Food and Drugs, 21 
CFR chapter I is amended to read as follows:

PART 16--REGULATORY HEARING BEFORE THE FOOD AND DRUG ADMINISTRATION

    1. The authority citation for 21 CFR part 16 is revised to read as 
follows:

     Authority: 15 U.S.C. 1451-1461; 21 U.S.C. 141-149, 321-394, 
467f, 679, 821, 1034; 28 U.S.C. 2112; 42 U.S.C. 201-262, 263b, 364.
    2. Section 16.1 is amended in paragraph (b)(2) by numerically 
adding an entry for Sec. 99.401(c) to read as follows:


Sec. 16.1  Scope.

 * * * * *
    (b) *   *   *
    (2) Regulatory provisions:
 * * * * *
    Sec. 99.401(c), relating to a due diligence determination 
concerning the conduct of studies necessary for a supplemental 
application for a new use of a drug or device.
 * * * * *
    3. Part 99 is added to read as follows:

PART 99--DISSEMINATION OF INFORMATION ON UNAPPROVED/NEW USES FOR 
MARKETED DRUGS, BIOLOGICS, AND DEVICES

Subpart A--General Information

Sec.
99.1   Scope.
99.3    Definitions.

Subpart B--Information to be Disseminated

99.101   Information that may be disseminated.
99.103    Mandatory statements and information.
99.105   Recipients of information.

Subpart C--Manufacturer's Submissions, Requests, and Applications

99.201    Manufacturer's submission to the agency.
99.203   Request to extend the time for completing planned studies.
99.205   Application for exemption from the requirement to file a 
supplemental application.

[[Page 64582]]

Subpart D--FDA Action on Submissions, Requests, and Applications

99.301   Agency action on a submission.
99.303   Extension of time for completing planned studies.
99.305    Exemption from the requirement to file a supplemental 
application.

Subpart E--Corrective Actions and Cessation of Dissemination

99.401   Corrective actions and cessation of dissemination of 
information.
99.403   Termination of approvals of applications for exemption.
99.405   Applicability of labeling, adulteration, and misbranding 
authority.

Subpart F--Recordkeeping and Reports

99.501   Recordkeeping and reports.
    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360c, 360e, 
360aa-360aaa-6, 371, and 374; 42 U.S.C. 262.

Subpart A--General Information


Sec. 99.1  Scope.

    (a) This part applies to the dissemination of information on human 
drugs, including biologics, and devices where the information to be 
disseminated:
    (1) Concerns the safety, effectiveness, or benefit of a use that is 
not included in the approved labeling for a drug or device approved by 
the Food and Drug Administration for marketing or in the statement of 
intended use for a device cleared by the Food and Drug Administration 
for marketing; and
    (2) Will be disseminated to a health care practitioner, pharmacy 
benefit manager, health insurance issuer, group health plan, or Federal 
or State Government agency.
    (b) This part does not apply to a manufacturer's dissemination of 
information that responds to a health care practitioner's unsolicited 
request.


Sec. 99.3   Definitions.

    (a) Agency or FDA means the Food and Drug Administration.
    (b) For purposes of this part, a clinical investigation is an 
investigation in humans that tests a specific clinical hypothesis.
    (c) Group health plan means an employee welfare benefit plan (as 
defined in section 3(1) of the Employee Retirement Income Security Act 
of 1974 (29 U.S.C. 1002(1))) to the extent that the plan provides 
medical care (as defined in paragraphs (c)(1) through (c)(3) of this 
section and including items and services paid for as medical care) to 
employees or their dependents (as defined under the terms of the plan) 
directly or through insurance, reimbursement, or otherwise. For 
purposes of this part, the term medical care means:
    (1) Amounts paid for the diagnosis, cure, mitigation, treatment, or 
prevention of disease, or amounts paid for the purpose of affecting any 
structure or function of the body;
    (2) Amounts paid for transportation primarily for and essential to 
medical care referred to in paragraph (c)(1) of this section; and
    (3) Amounts paid for insurance covering medical care referred to in 
paragraphs (c)(1) and (c)(2) of this section.
    (d) Health care practitioner means a physician or other individual 
who is a health care provider and licensed under State law to prescribe 
drugs or devices.
    (e) Health insurance issuer means an insurance company, insurance 
service, or insurance organization (including a health maintenance 
organization, as defined in paragraph (e)(2) of this section) which is 
licensed to engage in the business of insurance in a State and which is 
subject to State law which regulates insurance (within the meaning of 
section 514(b)(2) of the Employee Retirement Income Security Act of 
1974 (29 U.S.C. 1144(b)(2))).
    (1) Such term does not include a group health plan.
    (2) For purposes of this part, the term health maintenance 
organization means:
    (i) A Federally qualified health maintenance organization (as 
defined in section 1301(a) of the Public Health Service Act (42 U.S.C. 
300e(a)));
    (ii) An organization recognized under State law as a health 
maintenance organization; or
    (iii) A similar organization regulated under State law for solvency 
in the same manner and to the same extent as such a health maintenance 
organization.
    (f) Manufacturer means a person who manufactures a drug or device 
or who is licensed by such person to distribute or market the drug or 
device. For purposes of this part, the term may also include the 
sponsor of the approved, licensed, or cleared drug or device.
    (g) New use means a use that is not included in the approved 
labeling of an approved drug or device, or a use that is not included 
in the statement of intended use for a cleared device.
    (h) Pharmacy benefit manager means a person or entity that has, as 
its principal focus, the implementation of one or more device and/or 
prescription drug benefit programs.
    (i) A reference publication is a publication that:
    (1) Has not been written, edited, excerpted, or published 
specifically for, or at the request of, a drug or device manufacturer;
    (2) Has not been edited or significantly influenced by such a 
manufacturer;
    (3) Is not solely distributed through such a manufacturer, but is 
generally available in bookstores or other distribution channels where 
medical textbooks are sold;
    (4) Does not focus on any particular drug or device of a 
manufacturer that disseminates information under this part and does not 
have a primary focus on new uses of drugs or devices that are marketed 
or are under investigation by a manufacturer supporting the 
dissemination of information; and
    (5) Does not present materials that are false or misleading.
    (j) Scientific or medical journal means a scientific or medical 
publication:
    (1) That is published by an organization that has an editorial 
board, that uses experts who have demonstrated expertise in the subject 
of an article under review by the organization and who are independent 
of the organization, to review and objectively select, reject, or 
provide comments about proposed articles, and that has a publicly 
stated policy, to which the organization adheres, of full disclosure of 
any conflict of interest or biases for all authors or contributors 
involved with the journal or organization;
    (2) Whose articles are peer-reviewed and published in accordance 
with the regular peer-review procedures of the organization;
    (3) That is generally recognized to be of national scope and 
reputation;
    (4) That is indexed in the Index Medicus of the National Library of 
Medicine of the National Institutes of Health; and
    (5) That is not in the form of a special supplement that has been 
funded in whole or in part by one or more manufacturers.
    (k) Supplemental application means:
    (1) For drugs, a supplement to support a new use to an approved new 
drug application;
    (2) For biologics, a supplement to an approved license application;
    (3) For devices that are the subject of a cleared 510(k) submission 
and devices that are exempt from the 510(k) process, a new 510(k) 
submission to support a new use or, for devices that are the subject of 
an approved premarket approval application, a supplement to support a 
new use to an approved premarket approval application.

[[Page 64583]]

Subpart B--Information to be Disseminated


Sec. 99.101  Information that may be disseminated.

    (a) A manufacturer may disseminate written information concerning 
the safety, effectiveness, or benefit of a use not described in the 
approved labeling for an approved drug or device or in the statement of 
intended use for a cleared device, provided that the manufacturer 
complies with all other relevant requirements under this part. Such 
information shall:
    (1) Be about a drug or device that has been approved, licensed, or 
cleared for marketing by FDA;
    (2) Be in the form of:
    (i) An unabridged reprint or copy of an article, peer-reviewed by 
experts qualified by scientific training or experience to evaluate the 
safety or effectiveness of the drug or device involved, which was 
published in a scientific or medical journal. In addition, the article 
must be about a clinical investigation with respect to the drug or 
device and must be considered to be scientifically sound by the experts 
described in this paragraph; or
    (ii) An unabridged reference publication that includes information 
about a clinical investigation with respect to the drug or device, 
which experts qualified by scientific training or experience to 
evaluate the safety or effectiveness of the drug or device that is the 
subject of the clinical investigation would consider to be 
scientifically sound;
    (3) Not pose a significant risk to the public health;
    (4) Not be false or misleading. FDA may consider information 
disseminated under this part to be false or misleading if, among other 
things, the information includes only favorable publications when 
unfavorable publications exist or excludes articles, reference 
publications, or other information required under Sec. 99.103(a)(4) or 
the information presents conclusions that clearly cannot be supported 
by the results of the study; and
    (5) Not be derived from clinical research conducted by another 
manufacturer unless the manufacturer disseminating the information has 
the permission of such other manufacturer to make the dissemination.
    (b) For purposes of this part:
    (1) FDA will find that all journal articles and reference 
publications (as those terms are defined in Sec. 99.3) are 
scientifically sound except:
    (i) Letters to the editor;
    (ii) Abstracts of a publication;
    (iii) Those regarding Phase 1 trials in healthy people;
    (iv) Flagged reference publications that contain little or no 
substantive discussion of the relevant clinical investigation; and
    (v) Those regarding observations in four or fewer people that do 
not reflect any systematic attempt to collect data, unless the 
manufacturer demonstrates to FDA that such reports could help guide a 
physician in his/her medical practice.
    (2) A reprint or copy of an article or reference publication is 
``unabridged'' only if it retains the same appearance, form, format, 
content, or configuration as the original article or publication. Such 
reprint, copy of an article, or reference publication shall not be 
disseminated with any information that is promotional in nature. A 
manufacturer may cite a particular discussion about a new use in a 
reference publication in the explanatory or other information attached 
to or otherwise accompanying the reference publication under 
Sec. 99.103.


Sec. 99.103  Mandatory statements and information.

    (a) Any information disseminated under this part shall include:
    (1) A prominently displayed statement disclosing:
    (i) For a drug, ``This information concerns a use that has not been 
approved by the Food and Drug Administration.'' For devices, the 
statement shall read, ``This information concerns a use that has not 
been approved or cleared by the Food and Drug Administration.'' If the 
information to be disseminated includes both an approved and unapproved 
use or uses or a cleared and uncleared use or uses, the manufacturer 
shall modify the statement to identify the unapproved or uncleared new 
use or uses. The manufacturer shall permanently affix the statement to 
the front of each reprint or copy of an article from a scientific or 
medical journal and to the front of each reference publication 
disseminated under this part;
    (ii) If applicable, the information is being disseminated at the 
expense of the manufacturer;
    (iii) If applicable, the names of any authors of the information 
who were employees of, or consultants to, or received compensation from 
the manufacturer, or who had a significant financial interest in the 
manufacturer during the time that the study that is the subject of the 
dissemination was conducted up through 1 year after the time the 
article/reference publication was written and published;
    (iv) If applicable, a statement that there are products or 
treatments that have been approved or cleared for the use that is the 
subject of the information being disseminated; and
    (v) The identification of any person that has provided funding for 
the conduct of a study relating to the new use of a drug or device for 
which such information is being disseminated; and
    (2) The official labeling for the drug or device;
    (3) A bibliography of other articles (that concern reports of 
clinical investigations both supporting and not supporting the new use) 
from a scientific reference publication or scientific or medical 
journal that have been previously published about the new use of the 
drug or device covered by the information that is being disseminated, 
unless the disseminated information already includes such a 
bibliography; and
    (4) Any additional information required by FDA under 
Sec. 99.301(a)(2). Such information shall be attached to the front of 
the disseminated information or, if attached to the back of the 
disseminated information, its presence shall be made known to the 
reader by a sticker or notation on the front of the disseminated 
information and may consist of:
    (i) Objective and scientifically sound information pertaining to 
the safety or effectiveness of the new use of the drug or device and 
which FDA determines is necessary to provide objectivity and balance. 
This may include information that the manufacturer has submitted to FDA 
or, where appropriate, a summary of such information and any other 
information that can be made publicly available; and
    (ii) An objective statement prepared by FDA, based on data or other 
scientifically sound information, bearing on the safety or 
effectiveness of the new use of the drug or device.
    (b) Except as provided in paragraphs (a)(1)(i) and (a)(4) of this 
section, the statements, bibliography, and other information required 
by this section shall be attached to such disseminated information.
    (c) For purposes of this section, factors to be considered in 
determining whether a statement is ``prominently displayed'' may 
include, but are not limited to, type size, font, layout, contrast, 
graphic design, headlines, spacing, and any other technique to achieve 
emphasis or notice. The required statements shall be outlined, boxed, 
highlighted, or otherwise graphically designed and presented in a 
manner that achieves emphasis or notice and is distinct from the other 
information being disseminated.

[[Page 64584]]

Sec. 99.105  Recipients of information.

    A manufacturer disseminating information on a new use under this 
part may only disseminate that information to a health care 
practitioner, a pharmacy benefit manager, a health insurance issuer, a 
group health plan, or a Federal or State Government agency.

Subpart C--Manufacturer's Submissions, Requests, and Applications


Sec. 99.201  Manufacturer's submission to the agency.

    (a) Sixty days before disseminating any written information 
concerning the safety, effectiveness, or benefit of a new use for a 
drug or device, a manufacturer shall submit to the agency:
    (1) An identical copy of the information to be disseminated, 
including any information (e.g., the bibliography) and statements 
required under Sec. 99.103;
    (2) Any other clinical trial information which the manufacturer has 
relating to the effectiveness of the new use, any other clinical trial 
information that the manufacturer has relating to the safety of the new 
use, any reports of clinical experience pertinent to the safety of the 
new use, and a summary of such information. For purposes of this part, 
clinical trial information includes, but is not limited to, published 
papers and abstracts, even if not intended for dissemination, and 
unpublished manuscripts, abstracts, and data analyses from completed or 
ongoing investigations. The reports of clinical experience required 
under this paragraph shall include case studies, retrospective reviews, 
epidemiological studies, adverse event reports, and any other material 
concerning adverse effects or risks reported for or associated with the 
new use. If the manufacturer has no knowledge of clinical trial 
information relating to the safety or effectiveness of the new use or 
reports of clinical experience pertaining to the safety of the new use, 
the manufacturer shall provide a statement to that effect;
    (3) An explanation of the manufacturer's method of selecting the 
articles for the bibliography (e.g., the databases or sources and 
criteria (i.e., subject headings/keywords) used to generate the 
bibliography and the time period covered by the bibliography); and
    (4) If the manufacturer has not submitted a supplemental 
application for the new use, one of the following:
    (i) If the manufacturer has completed studies needed for the 
submission of a supplemental application for the new use:
    (A) A copy of the protocol for each completed study or, if such 
protocol was submitted to an investigational new drug application or an 
investigational device exemption, the number(s) for the investigational 
new drug application or investigational device exemption covering the 
new use, the date of submission of the protocol(s), the protocol 
number(s), and the date of any amendments to the protocol(s); and
    (B) A certification stating that, ``On behalf of [insert 
manufacturer's name], I certify that [insert manufacturer's name] has 
completed the studies needed for the submission of a supplemental 
application for [insert new use] and will submit a supplemental 
application for such new use to the Food and Drug Administration no 
later than [insert date no later than 6 months from date that 
dissemination of information under this part can begin]''; or
    (ii) If the manufacturer has planned studies that will be needed 
for the submission of a supplemental application for the new use:
    (A) The proposed protocols and schedule for conducting the studies 
needed for the submission of a supplemental application for the new 
use. The protocols shall comply with all applicable requirements in 
parts 312 of this chapter (investigational new drug applications) and 
812 of this chapter (investigational device exemptions). The schedule 
shall include the projected dates on which the manufacturer expects the 
principal study events to occur (e.g., initiation and completion of 
patient enrollment, completion of data collection, completion of data 
analysis, and submission of the supplemental application); and
    (B) A certification stating that, ``On behalf of [insert 
manufacturer's name], I certify that [insert manufacturer's name] will 
exercise due diligence to complete the clinical studies necessary to 
submit a supplemental application for [insert new use] and will submit 
a supplemental application for such new use to the Food and Drug 
Administration no later than [insert date no later than 36 months from 
date that dissemination of information under this part can begin or no 
later than such time period as FDA may specify pursuant to an extension 
granted under Sec. 99.303(a)];'' or
    (iii) An application for exemption from the requirement of a 
supplemental application; or
    (5) If the manufacturer has submitted a supplemental application 
for the new use, a cross-reference to that supplemental application.
    (b) The manufacturer's attorney, agent, or other authorized 
official shall sign the submission and certification statement or 
application for exemption. If the manufacturer does not have a place of 
business in the United States, the submission and certification 
statement or application for exemption shall contain the signature, 
name, and address of the manufacturer's attorney, agent, or other 
authorized official who resides or maintains a place of business in the 
United States.
    (c) The manufacturer shall send three copies of the submission and 
certification statement or application for exemption to FDA. The 
outside of the shipping container shall be marked as ``Submission for 
the Dissemination of Information on an Unapproved/New Use.'' The 
manufacturer shall send the submission and certification statement or 
application for exemption to the appropriate FDA component listed in 
paragraphs (c)(1) through (c)(3) of this section.
    (1) For biological products and devices regulated by the Center for 
Biologics Evaluation and Research, the Advertising and Promotional 
Labeling Staff (HFM-602), Center for Biologics Evaluation and Research, 
Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852;
    (2) For human drug products, the Division of Drug Marketing, 
Advertising, and Communications (HFD-40), Center for Drug Evaluation 
and Research, Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857; or
    (3) For medical devices, the Promotion and Advertising Policy Staff 
(HFZ-302), Office of Compliance, Center for Devices and Radiological 
Health, Food and Drug Administration, 2098 Gaither Rd., Rockville, MD 
20850.
    (d) The 60-day period shall begin when FDA receives a 
manufacturer's submission, including, where applicable, a certification 
statement or an application for an exemption.


Sec. 99.203  Request to extend the time for completing planned studies.

    (a) A manufacturer may request, prior to or at the time of making a 
submission to FDA under Sec. 99.201, that FDA extend the 36-month time 
period for completing the studies and submitting a supplemental 
application for the new use that is the subject of the information to 
be disseminated. Such request must set forth the reasons that such 
studies cannot be completed and submitted in a supplemental application 
within 36 months.
    (b) A manufacturer who has certified that it will complete the 
studies necessary to submit a supplemental application for a new use 
within a

[[Page 64585]]

specified period of time from the date that dissemination of 
information under this part can begin under Sec. 99.201(a)(4)(ii), but 
later finds that it will be unable to complete such studies and submit 
a supplemental application within that time period may request an 
extension of time from FDA. The manufacturer, in its request for 
extension, shall identify the product, the new use, and shall:
    (1) Describe the study or studies that cannot be completed on time 
and explain why the study or studies cannot be completed on time;
    (2) Describe the current status of the incomplete study or studies 
and summarize the work conducted, including the dates on which 
principal events concerning the study or studies occurred; and
    (3) Estimate the additional time needed to complete the studies and 
submit a supplemental application. The requested extension shall not 
exceed an additional 24 months.
    (c) The manufacturer shall send three copies of the request for 
extension to the same FDA office that received the manufacturer's 
initial submission and certification statement. The outside of the 
envelope shall be marked as ``Request for Time Extension--Dissemination 
of Information on an Unapproved Use.''


Sec. 99.205  Application for exemption from the requirement to file a 
supplemental application.

    (a) In certain circumstances, described in paragraph (b) of this 
section, a manufacturer may submit an application for an exemption from 
the requirement to submit a supplemental application for a new use for 
purposes of disseminating information on that use.
    (b) The manufacturer's application for an exemption shall identify 
the basis for the proposed exemption and shall include materials 
demonstrating that it would be economically prohibitive or that it 
would be unethical to conduct the studies necessary to submit a 
supplemental application for the new use.
    (1) If the basis for the manufacturer's application for exemption 
is that it would be economically prohibitive to incur the costs 
necessary to submit a supplemental application for a new use, the 
manufacturer shall, at a minimum, provide:
    (i) Evidence explaining why existing data characterizing the safety 
and effectiveness of the drug or device, including data from the study 
described in the information to be disseminated, are not adequate to 
support the submission of a supplemental application for the new use. 
Such evidence shall include an analysis of all data relevant to the 
safety and effectiveness of the use, a summary of those data, and any 
documentation resulting from prior discussions with the agency 
concerning the adequacy of the existing data; and
    (ii) Evidence demonstrating that the cost of the study or studies 
for the new use reasonably exceeds the expected revenue from the new 
use minus the costs of goods sold and marketing and administrative 
expenses attributable to the new use of the product. Such evidence 
shall include:
    (A) A description of the additional studies that the manufacturer 
believes are necessary to support the submission of a supplemental 
application for the new use, including documentation from prior 
discussions, if any, with the agency concerning the studies that would 
be needed, and an estimate of the projected costs for such studies;
    (B) The expected patient population for the new use;
    (C) The expected revenue for the new use, including an explanation 
of the price at which the drug or device will be sold;
    (D) Any exclusivity for the drug or device for the new use; and
    (E) Any other information that the manufacturer has showing that 
conducting the studies on the new use would be economically 
prohibitive; and
    (iii) An attestation by a responsible individual of the 
manufacturer or an individual acting on the manufacturer's behalf 
verifying that the estimates included with the submission are accurate 
and were prepared in accordance with generally accepted accounting 
procedures. The data underlying and supporting the estimates shall be 
made available to FDA upon request. Alternatively, a manufacturer may 
submit a report of an independent certified public accountant in 
accordance with the Statement of Standards for Attestation established 
by the American Institute of Certified Public Accountants and agreed 
upon procedures performed with respect to the estimates submitted under 
this section.
    (2) If the basis for the manufacturer's application for exemption 
is that it would be unethical to conduct the studies necessary for the 
supplemental application for a new use, the manufacturer shall provide 
evidence:
    (i) Explaining why existing data characterizing the safety and 
effectiveness of the drug or device, including data from the study 
described in the information to be disseminated, are not adequate to 
support the submission of a supplemental application for the new use. 
Such evidence shall include an analysis of all data relevant to the 
safety and effectiveness of the new use, a summary of those data, and 
any documentation resulting from prior discussions with the agency 
concerning the adequacy of the existing data; and
    (ii) Explaining why it would be unethical to conduct the further 
studies that would be necessary for the approval of the new use. Such 
evidence shall establish that, notwithstanding the insufficiency of 
available data to support the submission of a supplemental application 
for the new use, the data are persuasive to the extent that withholding 
the drug or device in a controlled study (e.g., by providing no 
therapy, a placebo, an alternative therapy, or an alternative dose) 
would pose an unreasonable risk of harm to human subjects. In assessing 
the appropriateness of conducting studies to support the new use, the 
manufacturer may provide evidence showing that the new use is broadly 
accepted as current standard medical treatment or therapy. The 
manufacturer shall also address the possibility of conducting studies 
in different populations or of modified design (e.g., adding the new 
therapy to existing treatments or using an alternative dose if 
monotherapy studies could not be conducted).

Subpart D--FDA Action on Submissions, Requests, and Applications


Sec. 99.301  Agency action on a submission.

    (a) Submissions. Within 60 days after receiving a submission under 
this part, FDA may:
    (1) Determine that the manufacturer does not comply with the 
requirements under this part and that, as a result, the manufacturer 
shall not disseminate any information under this part;
    (2) After providing the manufacturer notice and an opportunity for 
a meeting, determine that the information submitted regarding a new use 
fails to provide data, analyses, or other written matter that is 
objective and balanced and:
    (i) Require the manufacturer to disseminate additional information, 
including information that the manufacturer has submitted to FDA or, 
where appropriate, a summary of such information or any other 
information that can be made publicly available, which, in the agency's 
opinion:
    (A) Is objective and scientifically sound;

[[Page 64586]]

    (B) Pertains to the safety or effectiveness of the new use; and
    (C) Is necessary to provide objectivity and balance; and
    (ii) Require the manufacturer to disseminate an objective statement 
prepared by FDA that is based on data or other scientifically sound 
information available to the agency and bears on the safety or 
effectiveness of the drug or device for the new use; and
    (3) Require the manufacturer to maintain records that will identify 
individual recipients of the information that is to be disseminated 
when such individual records are warranted due to special safety 
considerations associated with the new use.
    (b) Protocols/Studies. Within 60 days after receiving a submission 
under this part, FDA shall:
    (1) If the manufacturer has planned studies that will be needed for 
the submission of a supplemental application for the new use, review 
the manufacturer's proposed protocols and schedule for completing such 
studies and determine whether the proposed protocols are adequate and 
whether the proposed schedule for completing the studies is reasonable. 
FDA shall notify the manufacturer of its determination; or
    (2) If the manufacturer has completed studies that the manufacturer 
believes would be an adequate basis for the submission of a 
supplemental application for the new use, conduct a review of the 
protocols submitted for such studies to determine whether they are 
adequate. FDA shall notify the manufacturer of its determination.


Sec. 99.303  Extension of time for completing planned studies.

    (a) Upon review of a drug or device manufacturer's proposed 
protocols and schedules for conducting studies needed for the 
submission of a supplemental application for a new use, FDA may, with 
or without a request for an extension from the manufacturer, determine 
that such studies cannot be completed and submitted within 36 months. 
The agency may exercise its discretion in extending the time period for 
completing the studies and submitting a supplemental application. 
Extensions under this paragraph are not subject to any time limit, but 
shall be made before the manufacturer begins the studies needed for the 
submission of a supplemental application for the new use.
    (b) The manufacturer may, after beginning the studies needed for 
the submission of a supplemental application for a new use, request in 
writing that FDA extend the time period for conducting studies needed 
for the submission of a supplemental application for a new use and 
submitting a supplemental application to FDA. FDA may grant or deny the 
request or, after consulting the manufacturer, grant an extension 
different from that requested by the manufacturer. FDA may grant a 
manufacturer's request for an extension if FDA determines that the 
manufacturer has acted with due diligence to conduct the studies needed 
for the submission of a supplemental application for a new use and to 
submit such a supplemental application to FDA in a timely manner and 
that, despite such actions, the manufacturer needs additional time to 
complete the studies and submit the supplemental application. 
Extensions under this paragraph shall not exceed 24 months.
    (c) If FDA extends the time period for completing the studies and 
submitting a supplemental application under paragraph (a) of this 
section after the manufacturer has submitted a certification under 
Sec. 99.201(a)(4)(ii)(B), or if FDA grants a manufacturer's request for 
an extension under paragraph (b) of this section, the manufacturer 
shall submit a new certification under Sec. 99.201(a)(4)(ii)(B) that 
sets forth the timeframe within which clinical studies will be 
completed and a supplemental application will be submitted to FDA.


Sec. 99.305  Exemption from the requirement to file a supplemental 
application.

    (a) Within 60 days after receipt of an application for an exemption 
from the requirement of a supplemental application, FDA shall approve 
or deny the application.
    (1) If FDA does not act on the application for an exemption within 
the 60-day period, the application for an exemption shall be deemed to 
be approved.
    (2) If an application for an exemption is deemed to be approved, 
FDA may, at any time, terminate such approval if it determines that the 
requirements for granting an exemption have not been met. FDA shall 
notify the manufacturer if the approval is terminated.
    (b) In reviewing an application for an exemption, FDA shall 
consider the materials submitted by the manufacturer and may consider 
any other appropriate information, including, but not limited to, any 
pending or previously approved applications for exemption submitted by 
the manufacturer.
    (c) FDA may grant an application for an exemption if FDA determines 
that:
    (1) It would be economically prohibitive for the manufacturer to 
incur the costs necessary to submit a supplemental application for a 
new use, which at a minimum requires:
    (i) That existing data characterizing the safety and effectiveness 
of the drug or device, including data from the study described in the 
information to be disseminated are not adequate to support the 
submission of a supplemental application for the new use; and
    (ii) That the cost of the study or studies for the new use 
reasonably exceeds the expected revenue from the new use minus the cost 
of goods sold and marketing and administrative expenses attributable to 
the new use of the product, and there are not less expensive ways to 
obtain the needed information; or
    (2) It would be unethical to conduct clinical studies needed to 
support the submission of a supplemental application for the new use 
because:
    (i) Existing data characterizing the safety and effectiveness of 
the drug or device, including data from the study described in the 
information to be disseminated are not adequate to support the 
submission of a supplemental application for the new use; and
    (ii) Although available evidence would not support the submission 
of a supplemental application for the new use, the data are persuasive 
to the extent that withholding the drug or device in a controlled study 
would pose an unreasonable risk of harm to human subjects and no 
studies in different populations or of modified design can be utilized. 
In determining whether it would be unethical to conduct clinical 
studies, the agency shall consider, in addition to the persuasiveness 
of available evidence of effectiveness, whether the new use of the drug 
or device is broadly accepted as current standard medical treatment or 
therapy.

Subpart E--Corrective Actions and Cessation of Dissemination


Sec. 99.401  Corrective actions and cessation of dissemination of 
information.

    (a) FDA actions based on post dissemination data. If FDA receives 
data after a manufacturer has begun disseminating information on a new 
use and, based on that data, determines that the new use that is the 
subject of information disseminated under this part may not be 
effective or may present a significant risk to public health, FDA shall 
consult the manufacturer and, after such consultation, take appropriate 
action to protect the public health. Such action may include ordering 
the manufacturer to cease disseminating

[[Page 64587]]

information on the new use and to take appropriate corrective action.
    (b) FDA actions based on information disseminated by a 
manufacturer. If FDA determines that a manufacturer is disseminating 
information that does not comply with the requirements under this part, 
FDA may:
    (1) Provide to the manufacturer an opportunity to bring itself into 
compliance with the requirements under this part if the manufacturer's 
noncompliance constitutes a minor violation of these requirements; or
    (2) Order the manufacturer to cease dissemination of information 
and to take corrective action. FDA shall issue such an order only after 
it has:
    (i) Provided notice to the manufacturer regarding FDA's intent to 
issue an order to cease dissemination; and
    (ii) Provided to the manufacturer an opportunity for a meeting. FDA 
need not provide an opportunity for a meeting if the manufacturer 
certified that it will submit a supplemental application for the new 
use within 6 months of the date that dissemination can begin and the 
noncompliance involves a failure to submit such supplemental 
application.
    (c) FDA actions based on a manufacturer's supplemental application. 
FDA may order a manufacturer to cease disseminating information under 
this part and to take corrective action if:
    (1) In the case of a manufacturer that has submitted a supplemental 
application for the new use, FDA determines that the supplemental 
application does not contain adequate information for approval of the 
new use;
    (2) In the case of a manufacturer that has certified that it will 
submit a supplemental application for the new use within 6 months, the 
manufacturer has not, within the 6-month period, submitted a 
supplemental application for the new use;
    (3) In the case of a manufacturer that has certified that it will 
submit a supplemental application for the new use within 36 months or 
within such time as FDA has determined to be appropriate under 
Sec. 99.303(a) or (b), such manufacturer has not submitted the 
supplemental application within the certified time, or FDA, after an 
informal hearing, has determined that the manufacturer is not acting 
with due diligence to initiate or complete the studies necessary to 
support a supplemental application for the new use; or
    (4) In the case of a manufacturer that has certified that it will 
submit a supplemental application for the new use within 36 months or 
within such time as FDA has determined to be appropriate under 
Sec. 99.303(a) or (b), the manufacturer has discontinued or terminated 
the clinical studies that would be necessary to support a supplemental 
application for a new use.
    (d) Effective date of orders to cease dissemination. An order to 
cease dissemination of information shall be effective upon date of 
receipt by the manufacturer, unless otherwise stated in such order.
    (e) Cessation of dissemination by a noncomplying manufacturer. A 
manufacturer that begins to disseminate information in compliance with 
this part, but subsequently fails to comply with this part, shall 
immediately cease disseminating information under this part. A 
manufacturer that discontinues, terminates, or fails to conduct with 
due diligence clinical studies that it certified it would complete 
under Sec. 99.201(a)(4)(ii) shall be deemed not in compliance with this 
part. A manufacturer shall notify FDA immediately if it ceases 
dissemination under this paragraph.


Sec. 99.403  Termination of approvals of applications for exemption.

    (a) FDA may, at any time, terminate the approval of an application 
for an exemption from the requirement to file a supplemental 
application if:
    (1) The application for an exemption had been deemed to be approved 
because the agency had not acted on the application within 60 days 
after its receipt by FDA;
    (2) The manufacturer is disseminating written information on the 
new use; and
    (3) FDA determines that it would be economically and ethically 
possible for the manufacturer to conduct the clinical studies needed to 
submit a supplemental application for the new use.
    (b) If FDA terminates a deemed approval of an application for an 
exemption under paragraph (a) of this section, FDA also may:
    (1) Order the manufacturer to cease disseminating information; and
    (2) Order the manufacturer to take action to correct the 
information that has been disseminated if FDA determines that the new 
use described in the disseminated information would pose a significant 
risk to public health.
    (c) FDA shall notify the manufacturer if it terminates the deemed 
approval of an application for an exemption under paragraph (a) of this 
section. If FDA also issues an order to cease dissemination of 
information, the manufacturer shall comply with the order no later than 
60 days after its receipt.
    (d) FDA may, at any time, terminate the approval of an application 
for an exemption from the requirement to file a supplemental 
application for a new use if, after consulting with the manufacturer 
that was granted such exemption, FDA determines that the manufacturer 
no longer meets the requirements for an exemption on the basis that it 
is economically prohibitive or unethical to conduct the studies needed 
to submit a supplemental application for the new use.
    (e) If FDA terminates an approval of an application for an 
exemption under paragraph (d) of this section, the manufacturer must, 
within 60 days of being notified by FDA that its exemption approval has 
been terminated, file a supplemental application for the new use that 
is the subject of the information being disseminated under the 
exemption, certify, under Sec. 99.201(a)(4)(i) or (a)(4)(ii) that it 
will file a supplemental application for the new use, or cease 
disseminating the information on the new use. FDA may require a 
manufacturer that ceases dissemination of information on the new use to 
undertake corrective action.


Sec. 99.405  Applicability of labeling, adulteration, and misbranding 
authority.

    The dissemination of information relating to a new use for a drug 
or device may constitute labeling, evidence of a new intended use, 
adulteration, or misbranding of the drug or device if such 
dissemination fails to comply with section 551 of the Federal Food, 
Drug, and Cosmetic Act (the act) (21 U.S.C. 360aaa) and the 
requirements of this part. A manufacturer's failure to exercise due 
diligence in submitting the clinical studies that are necessary for the 
approval of a new use that is the subject of information disseminated 
under this part or in beginning or completing such clinical studies 
shall be deemed a failure to comply with section 551 of the act and the 
requirements of this part.

Subpart F--Recordkeeping and Reports


Sec. 99.501  Recordkeeping and reports.

    (a) A manufacturer disseminating information under this part shall:
     (1) Maintain records sufficient to allow the manufacturer to take 
corrective action as required by FDA. The manufacturer shall make such 
records available to FDA, upon request, for inspection and copying. 
Such records shall either:

[[Page 64588]]

     (i) Identify, by name, those persons receiving the disseminated 
information; or
    (ii) Identify, by category, the recipients of the disseminated 
information, unless FDA requires the manufacturer to retain records 
identifying individual recipients of the disseminated information. 
Manufacturers whose records identify recipients by category only shall:
    (A) Identify subcategories of recipients where appropriate (e.g., 
oncologists, pediatricians, obstetricians, etc.); and
    (B) Ensure that any corrective action to be taken will be 
sufficiently conspicuous to individuals within that category of 
recipients;
    (2) Maintain an identical copy of the information disseminated 
under this part; and
    (3) Upon the submission of a supplemental application to FDA, 
notify the appropriate office identified in Sec. 99.201(c) of this 
part.
    (b) A manufacturer disseminating information on a new use for a 
drug or device shall, on a semiannual basis, submit to the FDA office 
identified in Sec. 99.201(c) of this part:
    (1) A list containing the titles of articles and reference 
publications relating to the new use of drugs or devices that the 
manufacturer disseminated to a health care practitioner, pharmacy 
benefit manager, health insurance issuer, group health plan, or Federal 
or State Government agency. The list shall cover articles and reference 
publications disseminated in the 6-month period preceding the date on 
which the manufacturer provides the list to FDA;
    (2) A list identifying the categories of health care practitioners, 
pharmacy benefit managers, health insurance issuers, group health 
plans, or Federal or State Government agencies that received the 
articles and reference publications in the 6-month period described in 
paragraph (b)(1) of this section. The list shall also identify which 
category of recipients received a particular article or reference 
publication;
     (3) A notice and summary of any additional clinical research or 
other data relating to the safety or effectiveness of the new use, and, 
if the manufacturer possesses such clinical research or other data, a 
copy of the research or data. Such other data may include, but is not 
limited to, new articles published in scientific or medical journals, 
reference publications, and summaries of adverse effects that are or 
may be associated with the new use;
    (4) If the manufacturer is conducting studies necessary for the 
submission of a supplemental application, the manufacturer shall submit 
periodic progress reports on these studies to FDA. Such reports shall 
describe the studies' current status (i.e., progress on patient 
enrollment, any significant problems that could affect the 
manufacturer's ability to complete the studies, and expected completion 
dates). If the manufacturer discontinues or terminates a study before 
completing it, the manufacturer shall, as part of the next periodic 
progress report, state the reasons for such discontinuation or 
termination; and
    (5) If the manufacturer was granted an exemption from the 
requirements to submit a supplemental application for the new use, any 
new or additional information that relates to whether the manufacturer 
continues to meet the requirements for such exemption. This information 
may include, but is not limited to, new or additional information 
regarding revenues from the product that is the subject of the 
dissemination and new or additional information regarding the 
persuasiveness of the data on the new use, including information 
regarding whether the new use is broadly accepted as current standard 
medical treatment or therapy.
    (c) A manufacturer shall maintain a copy of all information, lists, 
records, and reports required or disseminated under this part for 3 
years after it has ceased dissemination of such information and make 
such documents available to FDA for inspection and copying.

    Dated: November 17, 1998.
Michael A. Friedman,
Acting Commissioner for Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 98-31242 Filed 11-19-98; 8:45 am]
BILLING CODE 4160-01-F