[Federal Register Volume 63, Number 109 (Monday, June 8, 1998)]
[Proposed Rules]
[Pages 31143-31161]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-14918]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 16 and 99

[Docket No. 98N-0222]


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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[[Page 31144]]

SUMMARY: The Food and Drug Administration (FDA) is proposing to issue 
new 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 
proposal, which would implement the dissemination provisions of the 
Food and Drug Administration Modernization Act of 1997 (FDAMA), would 
describe the new use information that a manufacturer may disseminate 
and describe the content of and establish procedures for a 
manufacturer's submissions to FDA before it may begin disseminating 
information on the new use. The proposal also would describe how 
manufacturers seeking to disseminate new use information must agree to 
submit a supplement 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 proposal also would provide for requests to extend the time period 
for submitting a supplement for a new use, and it would describe how a 
manufacturer can seek an exemption from the requirement to submit a 
supplement. Additionally, the proposal would discuss FDA actions in 
response to manufacturers' submissions, corrective actions that FDA may 
take, and recordkeeping and reporting requirements.

DATES: Written comments by July 23, 1998.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. Submit written comments on the information 
collection requirements to the Office of Information and Regulatory 
Affairs, Office of Management and Budget (OMB), New Executive Office 
Bldg., 725 17th St. NW., Washington, DC 20503, Attn: Desk Officer for 
FDA.

FOR FURTHER INFORMATION CONTACT:
    Regarding general questions: Margaret M. Dotzel, Office of Policy 
(HF-22), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, 301-827-5321.
    Regarding biological products and devices regulated by the Center 
for Biologics Evaluation and Research: Toni M. Stifano, Center for 
Biologics Evaluation and Research (HFM-200), 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/Summary of Legislation

    On November 21, 1997, the President signed into law FDAMA (Pub. L. 
105-115). Section 401 of FDAMA amended the Federal Food, Drug, and 
Cosmetic Act (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:
    1. The information is about a drug or device that is being legally 
marketed;
    2. The information is not derived from another manufacturer's 
clinical research, unless that other manufacturer has given its 
permission for the dissemination;
    3. Sixty days prior to the dissemination, the manufacturer submits 
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;
    4. The information is not false or misleading and does not pose a 
significant risk to public health;
    5. The information is in the form of unabridged reprints or copies 
of peer reviewed articles about scientifically sound clinical 
investigations published in scientific or medical journals or in the 
form of unabridged reference publications that include information 
about scientifically sound clinical investigations;
    6. The manufacturer includes with such information a prominently 
displayed statement disclosing: That the use is not approved or cleared 
by FDA; if applicable, that the information is being disseminated at 
the manufacturer's expense; if applicable, the names of any authors of 
the information who are employees of or consultants to the manufacturer 
or have received compensation or have a significant financial interest 
in the manufacturer; 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; and the identification of any person 
that has provided funding for the study related to the new use for 
which such information is being disseminated;
    7. The manufacturer includes the official labeling and a 
bibliography of other articles from scientific reference publications 
or journals relating to the new use;
    8. If FDA determines that the information fails to provide data, 
analyses, or other written matter that is objective and balanced, the 
manufacturer includes additional objective and scientifically sound 
information that pertains to the safety or effectiveness of the new use 
and/or an objective statement prepared by FDA that bears on the safety 
or effectiveness of the new use; and
    9. The manufacturer has: (a) Submitted a supplemental application 
for the new use; (b) completed the studies needed for a supplemental 
application for the new use and certified that such studies are 
completed and that a supplemental application will be submitted within 
6 months of the initial dissemination; (c) provided a proposed protocol 
and schedule for conducting the studies needed for a supplemental 
application for the new use, which FDA has found to be adequate and 
reasonable (respectively) and certified that such application will be 
submitted no later than 36 months after the initial dissemination; or 
(d) received an exemption from the requirement to file a supplemental 
application on the grounds that conducting the studies needed for a 
supplemental application would be unethical or economically 
prohibitive.
    Under the new law, if FDA fails to act on a request for an 
exemption within 60 days, the exemption is deemed approved, and a 
manufacturer who meets all other requirements may begin to disseminate 
the written information. FDA may, however, subsequently terminate the 
deemed approval and order a manufacturer to cease dissemination. FDA 
can also order the manufacturer to take corrective action if the new 
use would pose a significant risk to public health.
    Manufacturers have an ongoing responsibility to provide FDA with 
additional information about the new uses that are the subject of 
dissemination under these provisions, and, if this information 
indicates that the new use may not be effective or may

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present a significant risk to public health, FDA may order the 
cessation of the dissemination about the new use. FDA may also order 
cessation of dissemination if the manufacturer fails to comply with any 
requirement for dissemination, including the requirements relating to 
the completion of studies and/or the submission of a supplemental 
application.
    Every 6 months, manufacturers that disseminate information under 
these provisions are required to prepare and submit to FDA lists of the 
titles of articles and reference publications that have been 
disseminated during the previous 6-month period and the categories of 
providers who have received the materials. In addition, manufacturers 
must keep records that can be used by the manufacturer or FDA to take 
corrective action. Such records may, at FDA's discretion, identify 
either the recipient of the information or the categories of such 
recipients. Manufacturers that have committed to doing the studies 
needed for submission of a supplement on a new use must also submit 
periodic reports to FDA that describe the status of the studies.
    The dissemination of information in accordance with new section 551 
of the act (21 U.S.C. 360aaa) is not construed as evidence of a new 
intended use of the drug or device, and it is not considered to be 
labeling, adulteration, or misbranding. This rule of construction 
applies, however, only to the dissemination of information in 
compliance with the statutory requirements. Moreover, disseminating 
information in violation of the requirements of section 551 of the act 
is prohibited.
    Section 401(c) of FDAMA directs FDA to issue regulations to 
implement the new statutory provisions within 1 year of enactment (by 
November 21, 1998). Accordingly, the agency must solicit public comment 
on this proposal, consider the comments submitted, and prepare and 
publish a final implementing regulation by November 21, 1998. In light 
of this limited timeframe, the Commissioner finds good cause under 21 
CFR 10.40(b)(2) for providing a shortened comment period of 45 days.
    Section 401(d) of FDAMA provides that the new provisions will take 
effect 1 year after the date of enactment (November 21, 1998) or upon 
FDA's issuance of final regulations, whichever is sooner. According to 
section 401(e) of FDAMA, the provisions will sunset on September 30, 
2006, or 7 years after the date on which the agency issues its 
regulations, whichever is later.

II. Description of the Proposed Rule

    The proposed rule would create a new part 99 entitled 
``Dissemination of Information on Unapproved/New Uses for Marketed 
Drugs, Biologics, and Devices.''

A. Subpart A--General Information

    Proposed subpart A would consist of two provisions. Proposed 
Sec. 99.1 would describe the scope of part 99. Proposed Sec. 99.1(a)(1) 
would explain that the part applies to the dissemination of information 
on human drugs, including biologics, and devices where the information 
to be disseminated concerns 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. 
Proposed Sec. 99.1(a)(2) would provide that 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. This description of the rule's scope would be 
consistent with section 551(a) of the act.
    Proposed Sec. 99.3 would define various terms, such as ``group 
health plan'' (proposed Sec. 99.3(c)), ``health care practitioner'' 
(proposed Sec. 99.3(d)), ``new use'' (proposed Sec. 99.3(g)), and 
``scientific or medical journal'' (proposed Sec. 99.3(i)). In most 
cases, the definitions paraphrase or repeat the statutory definitions 
at section 556 of the act (21 U.S.C. 360aaa-5). However, proposed 
Sec. 99.3(f) would elaborate on the statutory definition of 
``manufacturer'' to include sponsors of marketed drugs or devices. FDA 
is proposing to elaborate in this manner so that sponsors of a drug or 
device who received marketing approval for the product, but do not 
actually manufacture the product, would be able to disseminate 
information under this part.
    The proposed rule would track the statutory definition of ``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. 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. ``New uses'' that would 
require approval of a supplemental application to add the use to the 
labeling of an approved drug or to the labeling of an approved or 
cleared device and that, therefore, would be covered by this part 
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. This illustrative listing 
is consistent with the statutory intent that clearly links the new use 
discussed in the materials to be disseminated to the sponsor's 
submission of a supplemental application in order to add the use to the 
product labeling.
    The proposed rule would also define ``clinical investigation'' and 
``supplemental application,'' which are not defined in the statute. A 
clinical investigation would be defined as an investigation in humans 
that is prospectively planned to test a specific clinical hypothesis. 
The conduct of a clinical investigation according to a preplanned 
protocol generally is a fundamental aspect of hypothesis testing.
    The proposal would define a ``supplemental application'' to mean a 
supplemental new drug application (NDA) for human drugs or a supplement 
to an approved license application for biologics. A supplement to an 
NDA could be a supplement to an application submitted under section 
505(b)(1) of the act (21 U.S.C. 355(b)(1)) or section 505(b)(2) of the 
act. For devices, proposed Sec. 99.3(j)(3) would define a 
``supplemental application'' as a new 510(k) submission, if the device 
is the subject of a cleared 510(k) submission, or a supplement to an 
approved premarket approval application (PMA), if the device is the 
subject of an approved PMA. FDA is proposing to include new 510(k) 
submissions as ``supplemental applications'' because there are no 
``supplements'' for a new use to a 510(k) submission, instead, a new 
use is the subject of a new 510(k) submission. There are instances when 
a new use for a 510(k) device would require the submission of a PMA, 
but this would not be the equivalent of a ``supplement'' and thus, has 
not been included in the definition. Manufacturers that would be 
required to submit a PMA for a new use of a device cleared under 
section 510(k) of the act (21 U.S.C. 360(k)) would not be eligible

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to disseminate materials under the provisions of section 551 of the 
act.

B. Subpart B--Information to be Disseminated

    Proposed subpart B would describe the types of information that 
manufacturers may disseminate under part 99; the information that 
manufacturers must disseminate if they choose to disseminate written 
information about the safety, effectiveness, or benefit of new uses; 
and the persons who may receive the information about new uses.
    Proposed Sec. 99.101 would discuss the types of information 
concerning the safety, effectiveness, or benefit of a new use that a 
manufacturer may disseminate. In brief, the proposal would require that 
the written information to be disseminated:
    1. Concern a drug or device that has been approved, licensed, or 
cleared for marketing by FDA;
    2. Be in the form of an unabridged copy of a peer-reviewed 
scientific or medical journal article or reprint, 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;
    3. Not pose a significant risk to the public health;
    4. Not be false or misleading; and
    5. Not be derived from clinical research conducted by another 
manufacturer, unless the manufacturer disseminating the information has 
permission to make the dissemination.
    Under the proposal, FDA could consider the information to be 
misleading if, among other things, the information includes only 
favorable publications or excludes articles, reference publications, or 
other information concerning risks and adverse effects that are or may 
be associated with the new use. This element is intended to help ensure 
that manufacturers disseminate balanced and objective information. FDA 
also could consider the information to be false or misleading if the 
study design, conduct, data, or analyses do not reasonably support the 
conclusion reached by the authors. In addition, the information would 
be considered misleading if the clinical study utilized a study 
endpoint that is not reasonably well-established as indicative of 
clinical benefit.
    As set forth in the statute and FDA's proposal, the information 
that can be disseminated under part 99 must be in the form of a reprint 
or copy of a journal article or a reference publication. Although the 
requirements set forth in the statute are easily applied to journal 
articles, they are not as easily applied to reference publications. For 
example, the definition of a reference publication indicates that the 
publication may not focus on a particular drug or device of the 
manufacturer that disseminates the information under section 551 of the 
act and may not have a primary focus on new uses of drugs or devices 
that are marketed or under investigation by a manufacturer supporting 
the dissemination of information. This is not altogether consistent 
with the purpose of section 401 of FDAMA, which is to permit the 
dissemination of information about a clinical investigation concerning 
a specific new use if certain criteria are met. In addition, although 
journal articles typically include a detailed description and 
discussion of clinical investigations, reference publications often 
just refer generally to the results of such investigations. Because the 
statute requires the information being disseminated to be about a 
clinical investigation, it seems unlikely that many reference 
publications will meet the requirements for dissemination under this 
provision. Finally, the statute requires that a manufacturer submit (or 
commit to submit) a supplement for each new use discussed in the 
information to be disseminated. This could be construed to mean that a 
manufacturer that disseminates a reference publication that discusses 
many new uses would be required, under the statute, to submit (or 
commit to submit) a supplement for each of the many new uses mentioned.
    Despite these issues, FDA believes that the statutory provisions 
can be interpreted and applied to conform with the text and spirit of 
the legislation. Although the statute does not allow a reference 
publication, as a whole, to focus on the disseminating manufacturer's 
products or new uses, it does not prohibit a manufacturer from citing a 
particular use or uses in a publication that does not have such a focus 
if the manufacturer complies with the requirements set forth in section 
401 of FDAMA. This will, therefore, allow manufacturers to use 
reference publications in the same manner as they would use journal 
articles, i.e., to disseminate information about a specific new use. 
Although a manufacturer must submit (or commit to submit) a 
supplemental application for the new use that it has cited in the 
reference publication, the manufacturer would not have to submit (or 
commit to submit) a supplement for each new use mentioned in the 
publication. Nevertheless, because reference publications rarely 
include detailed discussions of clinical investigations, FDA recognizes 
that the majority of such publications would probably not meet the 
requirements of section 401 of FDAMA and this proposed implementing 
regulation. FDA, therefore, plans to develop draft guidance and solicit 
public comment on reference publications that do not fall within the 
scope of part 99.
    Proposed Sec. 99.101 would also explain that the determination of 
whether a clinical investigation is considered to be scientifically 
sound rests 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. 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. 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. Types of prospectively planned 
investigations include: A clinical trial in which subjects are enrolled 
and assigned to treatment according to a protocol; a meta-analysis of 
published clinical investigations in which there is a planned strategy 
for the inclusion of published articles and for the integrated analysis 
of their results; or a well-documented prospective case series that 
utilizes a predetermined strategy for the inclusion of cases. 
Ordinarily, such a case series would be considered to be a 
scientifically sound clinical investigation for the purposes of 
dissemination only in those circumstances where the disease under study 
had high and predictable mortality and/or morbidity and was not 
expected to improve spontaneously;
    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. An analysis that is based on only a 
portion of all study subjects enrolled should provide information on 
how this population was derived;

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    4. Utilized clinically meaningful endpoints or utilized surrogate 
endpoints that are reasonably likely to predict safety and 
effectiveness. These endpoints should have been assessed using well-
established instruments, and using appropriate measurement frequencies;
    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. In 
circumstances where response to therapy is expected to differ between 
patient subgroups, results should be reported accordingly.
A clinical investigation presented in a format that does not represent 
a reasonably comprehensive presentation of the study design, conduct, 
data, analyses, and conclusions, for example, letters to the editor, 
review abstracts, abstracts of a publication, or other incomplete 
reports, would not qualify for dissemination under this provision. Such 
reports do not provide sufficient information to determine the adequacy 
of the study design and cannot be critically judged by the reader.
    Proposed Sec. 99.101 would further explain what is meant by the 
term ``unabridged,'' i.e., the reprint, article, or reference text must 
retain the same appearance, form, format, content, or configuration as 
the original article or publication. It cannot be accompanied by 
information that is promotional in nature. Because a reference text 
might include a discussion of many new uses and a manufacturer might 
want to disseminate it under part 99 for the purpose of providing 
information on one particular discussion in the book, proposed 
Sec. 99.101(b)(2) would permit the manufacturer to cite a particular 
discussion about a new use in a reference publication in the 
information that is required to be attached to the reference 
publication under proposed Sec. 99.103.
    Proposed Sec. 99.103(a) would, consistent with section 551(b) and 
(c) of the act, describe the information that must accompany the 
journal article or reference publication. Specifically it would 
require:
    1.A prominently displayed statement that discloses 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; if applicable, that the manufacturer is 
disseminating such information at its own expense, the names of authors 
who are employees or consultants to, or have received compensation from 
the manufacturer or who have a significant financial interest in the 
manufacturer, and a statement that there are products or treatments 
approved/cleared for the new use; and the identification of any person 
that has provided funding for the study that is the basis of the 
information for which such information is being disseminated;
    2. The official labeling for the product;
    3. A bibliography of other articles (that concern reports of 
clinical investigations) both supporting and not supporting the new 
use;
    4. 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.
    Proposed Sec. 99.103(c) would describe what is meant by a 
``prominently displayed'' statement by setting forth criteria that are 
consistent with the agency's regulations on prescription drug 
advertising (21 CFR 202.1(e)(7)(viii)) and labeling (21 CFR 
201.10(g)(2)). 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. In addition, 
proposed Sec. 99.103(c) would require such statements to be outlined, 
boxed, highlighted, or otherwise graphically designed and presented on 
the front of the disseminated information in a manner that achieves 
emphasis or notice and is distinct from the other information being 
disseminated.
    For purposes of proposed Sec. 99.103(a)(1)(iii), 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. The concept of relationships that may give rise to conflicts 
of interest has specific and well understood application to medical and 
scientific discourse (e.g., in the publication and peer review 
process). When there is a question as to whether a relationship is 
significant, it should be disclosed. For further guidance and direction 
on the disclosure of significant financial interests, manufacturers 
should refer to FDA's final rule on Financial Disclosure by Clinical 
Investigators (63 FR 5233, February 2, 1998).
    The official labeling that would be required by proposed 
Sec. 99.103(a)(2) would for drugs constitute the current package 
insert. Because devices do not always include a package insert in the 
same form and manner as drugs, 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. The agency expects that this information will be 
found in the information that manufacturers distribute with their 
legally marketed devices.
    The bibliography that would be required by proposed 
Sec. 99.103(a)(3) should appear in the same format used by Index 
Medicus and should include all authors, the full title of the article, 
and complete source information.
    Proposed Sec. 99.103(a)(1)(i) would require the statement that the 
use has not been approved or cleared by FDA and is being disseminated 
under section 551 et seq. of the act to be permanently attached to the 
front of each reprint or copy of an article or reference publication. 
Proposed Sec. 99.103(a)(4) would require any additional information 
required by FDA also to be attached to the front of the disseminated 
information. Under proposed Sec. 99.103(b), all other statements or 
information would have to be attached to the article or reference 
publication.
    Proposed Sec. 99.105 would identify who may receive information 
disseminated under this part. Possible recipients would include health 
care practitioners, pharmacy benefit managers, health insurance 
issuers,

[[Page 31148]]

group health plans, or Federal or State government agencies. This is 
consistent with section 551(a) of the act and is important because it 
is essential that this information be provided only to persons who have 
the education, training, and experience to interpret its meaning and 
relevance.

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

    Proposed subpart C would describe what must be included in the 
different types of submissions that manufacturers would send to FDA in 
order to be able to disseminate information under part 99.
    Proposed Sec. 99.201 would provide that 60 days before 
disseminating information on a new use, a manufacturer must submit to 
FDA:
    1. A copy of all the information to be disseminated (i.e., 
including all attachments) in the form in which the manufacturer plans 
to disseminate it. This will enable FDA to see how the information will 
be presented to its intended audience and to determine whether the 
information is objective and balanced, and meets all of the 
requirements of this part;
    2. 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 a 
summary of such information. For purposes of this section, clinical 
trial information would include, but would not be 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 information and reports required under this 
paragraph would 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 or has no such 
information, it would include a statement to that effect;
    3. An explanation of the search strategy for the bibliography that 
must be included with the disseminated information. The search strategy 
must include the data bases and criteria used to generate the 
bibliography and the time period covered by the bibliography; and
    4. 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. If a supplement for the new use has been submitted, the 
manufacturer would include a cross-reference to that supplemental 
application.
    When the certification provides that the studies have been 
completed, the submission would include the protocols for the studies 
or would cross reference and provide the relevant information on any 
protocols that are already in FDA's files as part of an investigational 
new drug application (IND) or an investigational device exemption 
(IDE). The certification would state that the manufacturer will submit 
a supplemental application within 6 months from the date of initial 
dissemination of information.
    When the certification is that studies will be conducted, proposed 
protocols and a schedule must be submitted. The proposal would require 
that the protocols submitted comply with all applicable requirements in 
21 CFR parts 312 and 812, which relate to investigational new drug 
applications and investigational device exemptions. This means that the 
protocols must be sent to the appropriate review divisions within the 
Center for Drug Evaluation and Research, the Center for Biologics 
Evaluation and Research, or the Center for Devices and Radiological 
Health. The protocols will be reviewed as an original IND or IDE or an 
amendment to an existing IND or IDE. The schedule would include the 
expected dates for principal study events (e.g., initiation and 
completion of patient enrollment, completion of data collection, 
completion of data analysis, and submission of a supplemental 
application). The certification would state that the manufacturer will 
exercise due diligence to complete the clinical studies needed to 
submit a supplemental application for the new use and will submit such 
application to FDA no later than 36 months after the date of the 
initial dissemination of information.
    Proposed Sec. 99.201(b) would describe who should sign a submission 
and certification statement or application for an exemption. In 
general, an authorized official would sign the submission and 
certification statement or application for an exemption. For foreign 
manufacturers, proposed Sec. 99.201(b) would require the signature, 
name, and address of an authorized official residing or maintaining a 
place of business in the United States.
    Proposed Sec. 99.201(c) would provide that manufacturers must 
submit three copies of the submission (including the certification 
statement or application for an exemption) to FDA and would provide the 
appropriate addresses for such submissions. The outside of the shipping 
container of the submission would identify the documents as 
``Submission for the Dissemination of Information on an Unapproved/New 
Use.''
    Proposed Sec. 99.201(d) would provide that the 60-day period begins 
to run when FDA receives a complete submission. The submission would be 
considered complete if FDA determines that it is sufficiently complete 
to permit a substantive review.
    Section 554 of the act (21 U.S.C. 360aaa-3) anticipates that there 
will be times when the 36-month period for filing a supplemental 
application for a new use based on new studies will not be enough time. 
It provides, therefore, that FDA may, on its own initiative at the time 
of initial dissemination, give the manufacturer more than 36 months, or 
that FDA may, upon a manufacturer's request after such studies have 
begun, extend the 36-month period by up to 24 months. Proposed 
Sec. 99.203 would set forth the procedures that a manufacturer must 
follow to request an extension of time for submitting a supplemental 
application. In its request, the manufacturer would: (1) Identify the 
product and new use; (2) describe the study or studies that cannot be 
completed on time; (3) explain why the study or studies cannot be 
completed; (4) describe the current status of the incomplete study or 
studies; (5) summarize the work conducted, including the dates on which 
principal events concerning the study or studies occurred; and (6) 
estimate the additional time needed to complete the study or studies 
and submit a supplemental application. The manufacturer would submit 
three copies of the request to the same address identified for the 
initial submission.
    When Congress passed these provisions of the act, it recognized 
that there may be rare circumstances in which it would be appropriate 
to exempt a manufacturer that seeks to disseminate information about a 
new use from the requirement to submit a supplement for that new use. 
The act sets forth two very narrow exemptions: (1) When, for reasons 
defined by the agency, it would be economically prohibitive to incur 
the costs necessary for the submission of a supplement, and (2) when, 
for reasons defined by the agency, it would be unethical to conduct the 
studies necessary for the supplemental application.
    In making a determination that it would be economically prohibitive 
to conduct the needed studies, section 554 of the act directs FDA to 
consider (in

[[Page 31149]]

addition to any other considerations the agency finds appropriate): (1) 
The lack of the availability under law of any period during which the 
manufacturer would have exclusive marketing rights with respect to the 
new use, and (2) the size of the population expected to benefit from 
approval of the supplemental application. In making a determination 
that it would be unethical to conduct the needed studies, the act 
directs FDA to consider (in addition to any other considerations the 
agency finds appropriate) whether the new use involved is the standard 
of medical care for a health condition.
    Proposed Sec. 99.205 would set forth what a manufacturer must 
submit when seeking an exemption from the requirement to file a 
supplemental application relating to a new use. It would require the 
manufacturer to include an explanation as to why an exemption is sought 
and include materials demonstrating that it would be economically 
prohibitive or unethical to conduct the studies needed to submit a 
supplemental application.
    To obtain either exemption, a manufacturer must first 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. This is a critical element of the 
request because submitting the existing data in a supplement, which may 
require some attempt to retrieve old records, is almost never unethical 
and would almost never be economically prohibitive. The manufacturer 
should make every effort, therefore, to determine whether existing data 
would be adequate, and should include reference to discussions with the 
agency concerning the adequacy of existing data.
    If the manufacturer is seeking an exemption on the grounds that it 
would be economically prohibitive to conduct the study or studies 
needed for approval of the use, it must also 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) would set forth the type of evidence 
that the manufacturer must include to meet the requirements for an 
economically prohibitive exemption. These would include:
    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 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.
    FDA considered requiring a report of an independent certified 
public accountant made in accordance with the Statement on Standards 
for Attestation established by the American Institute of Certified 
Public Accountants with respect to the estimates submitted under this 
section. FDA is soliciting 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.
    Although Congress made it very clear that exemptions from the 
requirement to submit a supplement are to be rare, it left it up to the 
agency to determine when it would grant these exemptions. This was a 
particularly difficult task for the ``economically prohibitive'' 
exemption because it is difficult to assess cost and income 
projections. The agency is proposing to compare the cost of the studies 
needed for a supplement with the total revenue of the product minus the 
cost of goods sold, and marketing and administrative expenses 
attributable to the product. FDA is not focusing only on sales from the 
new use because the agency does not believe that it would be 
``prohibitive'' if the sales from the new use did not cover the cost of 
the studies. In such a situation, it might not be economically wise to 
conduct the studies, but it would not rise to the level of being 
prohibitive. The agency considered whether it should also require that 
the cost of conducting the studies needed for the supplement 
substantially exceed revenues and be unusually great compared to the 
typical costs of developing products for similar uses. Given the 
uncertainty about cost and revenue streams, it is possible that these 
measures would better define what is economically prohibitive. Although 
FDA decided not to include these requirements in the proposal, they are 
still under consideration and, therefore, the agency invites comment on 
whether they are useful in the determination of what is economically 
prohibitive. FDA also is seeking comment on other possible ways to 
define economically prohibitive.
    If the manufacturer is seeking an exemption on the grounds that it 
would be unethical to conduct a needed study or studies, proposed 
Sec. 99.205(b)(2) would require the manufacturer also to show that, 
notwithstanding the insufficiency of existing data to support the 
submission of a supplemental application for the new use, the data are 
persuasive to the extent that withholding the drug in the course of 
conducting a controlled study would pose an unreasonable risk of harm 
to human subjects. For purposes of determining what is unethical under 
this part, an unreasonable risk of harm would ordinarily arise only in 
situations in which the intended 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 intended use can add 
weight to an argument that conduct of a needed study or studies would 
be unethical. To support its conclusion that the conduct of a needed 
study or studies would be unethical, the manufacturer would need to 
provide evidence that it had explored various alternative study designs 
(e.g., active control studies, studies in different populations, 
studies where the product is added to existing treatment), discussed 
these alternatives with the agency, and determined that there were no 
options that were both ethical and capable of generating data adequate 
to support approval. Specifically, the proposal would require the 
manufacturer to provide:
    1. An explanation of why, 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

[[Page 31150]]

providing no therapy, a placebo, an alternative therapy, or an 
alternative dose) would pose an unreasonable risk of harm to human 
subjects. For purposes of determining what is unethical under this 
part, an unreasonable risk of harm would ordinarily arise only when the 
new use appears to affect mortality or irreversible morbidity; and
    2. A discussion of 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).
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. Some possible considerations might 
include:
    (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 Dispensing Information, the American 
Medical Association Drug Evaluations, or the American Hospital 
Formulary Service.
While these sources would not be definitive evidence of standard 
medical treatment or therapy, they may provide evidence of it in 
certain circumstances.
    FDA has struggled to develop an approach to these exemptions that 
strikes the proper balance. It should be emphasized that Congressional 
intent was clear in expecting exemptions to be rare. Congress 
emphasized the importance of having safe and effective uses of drugs 
and devices reflected in labeling. The agency believes that it has 
struck the proper balance, but it invites comment on the exemption 
criteria it has developed.

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

    Proposed subpart D would describe FDA's actions in response to a 
submission, a request for an extension of the time period to conduct 
studies, and an application for an exemption from the requirement to 
conduct clinical studies and to submit a supplemental application.
    Proposed Sec. 99.301(a) would provide that within 60 days of 
receiving a submission, FDA may:
    1. Determine that the manufacturer does not comply with the 
requirements under this part (e.g., the new use poses a significant 
risk to public health or the clinical investigation described in the 
publication is not scientifically sound) and thus, cannot disseminate 
information about the new use;
    2. Request additional information or documents to assist in 
determining whether the information to be disseminated complies with 
the requirements under this part;
    3. Determine that the information fails to provide data, analyses, 
or other written matter that is objective and balanced. In this case, 
FDA would provide the manufacturer notice and an opportunity for a 
meeting, may require the manufacturer to disseminate additional 
information that is objective and scientifically sound, pertains to the 
safety or effectiveness of the new use, and is necessary to provide 
objectivity and balance, and may 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
    4. Require a manufacturer to maintain records that will identify 
individual recipients of the information that is to be disseminated.
This last provision is tied to the statutory requirement that 
manufacturers keep records of the recipients of the disseminated 
materials so that the manufacturer or FDA can take appropriate 
corrective action, e.g., so that the manufacturer or FDA can notify 
recipients if it is later determined that the new use that is the 
subject of the dissemination may not be effective or may present a 
significant risk to public health. Section 553 of the act (21 U.S.C. 
360aaa-2) provides that such records, at the agency's discretion, may 
identify recipients of the information or the categories of such 
recipients. Although keeping records that identify the individual 
recipients of the information might best ensure that the people who 
have seen and relied on the information will learn of problems or risks 
associated with the use, FDA recognizes that it may not be necessary to 
keep such specific records if the manufacturer is willing to take steps 
to ensure that the individual recipients will see any materials that 
might correct any misperceptions. Under proposed Sec. 99.501, FDA would 
generally permit the manufacturer to decide whether to keep individual 
records or to keep more general records and take more conspicuous 
corrective action. However, there may be instances when it would be in 
the best interest of public health if the manufacturer kept the names 
of the individual recipients. In these cases, proposed 
Sec. 99.301(a)(4) would provide that FDA will generally notify the 
manufacturer in advance, i.e., within the 60-day period for review of 
the submission, that such records must be kept.
    Proposed Sec. 99.301(b) would set forth FDA actions in response to 
a manufacturer's submission when the manufacturer is committing to 
submit a supplement for completed studies or is agreeing to conduct the 
necessary studies and then submit a supplement. If the manufacturer has 
planned studies and submits proposed protocols (either as a new IND or 
IDE or as an amendment to an existing IND or IDE) and a schedule for 
completing such studies, FDA will, within 60 days, review the 
manufacturer's proposed protocol and schedule for completing such 
studies to determine whether the protocols are adequate and the 
schedule for completing the studies is reasonable for purposes of 
disseminating the new use information. The manufacturer cannot 
disseminate the new use information until FDA determines that the 
proposed protocol is adequate and the proposed schedule is reasonable. 
If the manufacturer has completed studies that it believes would be an 
adequate basis for the submission of a supplemental application for the 
new use, FDA will, under the proposal, 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 they are inadequate to support the 
filing of a supplemental application for the new use or are not

[[Page 31151]]

complete, FDA will notify the manufacturer and the manufacturer shall 
not disseminate the new use information under this subpart.
    Proposed Sec. 99.303 would describe FDA's ability to allow a 
manufacturer more than 36 months to submit a supplemental application 
on its own initiative, based on the review of the protocols(s) and 
planned schedule, or to grant a manufacturer's request to extend the 
36-month period (for up to 24 months). Proposed Sec. 99.303(a) would 
describe FDA's ability to determine, on its own initiative, that a 
manufacturer needs more than 36 months to complete the studies needed 
for submission of a supplemental application and to submit such 
application. Proposed Sec. 99.303(b) and (c) would describe FDA's 
ability, after such studies have begun, to grant an extension of the 
time to submit a supplement by up to 24 months. FDA can 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. In this context, 
``due diligence'' refers to a manufacturer's good faith effort to 
develop the data necessary to support a supplemental application for 
the new use and to pursue approval of an application based on those 
data in a timely manner. In its consideration of a request to extend 
the time for completing studies, the agency will look at all relevant 
factors and will focus on the manufacturer's efforts to meet the 
milestones identified in the schedule submitted with the manufacturer's 
certification to complete required studies (i.e., completion of patient 
enrollment in clinical studies, completion of data collection, 
completion of data analysis, and submission of a supplemental 
application). If a manufacturer has failed to meet identified 
milestones despite reasonable efforts to do so and, in the agency's 
judgment, an extension of time to complete the studies will enable a 
manufacturer to complete development of the necessary data and submit a 
supplemental application, the agency may grant an extension of the time 
to complete studies and submit the supplemental application.
    If FDA extends the time period for completing the studies and 
submitting a supplemental application or grants a manufacturer's 
request for an extension, 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.
    Proposed Sec. 99.305 would describe FDA action on an application 
for an exemption from the requirement to submit a supplemental 
application. FDA may grant an application for an exemption if it 
determines that it would be economically prohibitive for the 
manufacturer to conduct the studies needed for a supplemental 
application or it would be unethical to conduct clinical studies needed 
to approve the new use.
    FDA may find that it would be economically prohibitive if, at a 
minimum, existing data characterizing the product's safety and 
effectiveness, 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 the 
estimated cost of the studies needed to support the submission of a 
supplemental application for the new use would exceed the estimated 
total revenue from the product minus the cost of goods sold and the 
marketing and administrative expenses attributable to the product and 
that there are not less expensive ways to obtain the needed 
information. FDA may find that it would be unethical to conduct the 
clinical studies needed to support the submission of a supplemental 
application for the new use when existing data characterizing the 
product's safety and effectiveness, 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 there is sufficiently persuasive evidence 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 will consider, in 
addition to the persuasiveness of available evidence, whether the new 
use of the drug or device is broadly accepted as current standard 
medical treatment or therapy.
    The evidence and factors that FDA will consider in granting an 
exemption were discussed previously. The agency reiterates, however, 
that these exemptions cannot and will not be liberally granted. 
Congress was trying to balance the need to get potentially important 
information on new uses to physicians with the need to get these new 
uses studied, approved, and in the labeling. If FDA were to liberally 
grant exemptions from the requirement to submit a supplemental 
application, the exemptions would undermine Congress's intent to 
ensure, through the review and approval of supplemental applications, 
that the drug or device is safe and effective for the new use.
     Proposed Sec. 99.305(a)(1) would acknowledge 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 may, at 
any time, terminate such deemed approval if it determines that the 
requirements for granting an exemption have not been met.

E. Subpart E--Corrective Actions and Cessation of Dissemination

    Proposed subpart E would discuss various actions FDA could take or 
require a manufacturer to take after a manufacturer has begun 
disseminating information on a new use.
    Proposed Sec. 99.401 would pertain to corrective actions and orders 
to cease dissemination of information. These corrective actions and 
orders to cease dissemination of information could apply under three 
different situations, which are set forth in paragraphs (a), (b), and 
(c). Under proposed Sec. 99.401(a), if FDA receives data after a 
manufacturer has begun disseminating information on a new use and the 
agency determines that the new use may not be effective or may present 
a significant risk to public health, FDA would consult the manufacturer 
and, after such consultation, take appropriate action to protect the 
public health. These actions might include ordering the manufacturer to 
cease disseminating information on the new use and to take appropriate 
corrective action. Appropriate corrective action might include, among 
other things, issuing ``Dear Doctor'' letters, publishing corrective 
advertising, including warning labels on the product, or including 
warnings or otherwise revising the product labeling.
    Proposed Sec. 99.401(b) would address FDA actions in response to 
information disseminated by a manufacturer. If the agency determined 
that the disseminated information did not comply with the regulations, 
proposed Sec. 99.401(b) would give FDA two options: (1) If the 
manufacturer's noncompliance constituted a minor violation, provide the 
manufacturer an opportunity to bring itself into compliance; or (2) if 
the manufacturer's noncompliance does not constitute a minor violation, 
order the manufacturer to cease dissemination and to take

[[Page 31152]]

corrective action, such as issuing ``Dear Doctor'' letters, publishing 
corrective advertising, including warning labels on the product, or 
including warnings or otherwise revising the product labeling. These 
orders would be issued only after FDA provided notice of its intent to 
issue an order to cease dissemination and provided an opportunity for a 
meeting to the manufacturer. However, an opportunity for a meeting 
would not be required if the manufacturer's noncompliance was failure 
to submit a supplemental application within 6 months as certified in 
the initial submission.
    Proposed Sec. 99.401(c) would describe when FDA may order a 
manufacturer to cease disseminating information and/or take corrective 
action based on the manufacturer's supplemental application for the new 
use. These orders would be issued when: (1) FDA determines that a 
supplemental application for a new use does not contain adequate 
information for approval of the new use; (2) the manufacturer has 
certified that it will submit a supplemental application within 6 
months or within 36 months and has not done so; (3) the manufacturer 
has certified that it will submit a supplemental application within 36 
months and FDA, after an informal hearing, determines that the 
manufacturer is not acting with due diligence to initiate or complete 
the studies needed to support the submission of the supplemental 
application; or (4) the manufacturer has certified that it will submit 
a supplemental application within 36 months and it has discontinued or 
terminated the studies needed to support such supplemental application. 
The latter provision is intended to deter a manufacturer from 
certifying that it will complete the studies needed to submit a 
supplement so that it can begin disseminating information even though 
it has no intention of completing such studies and submitting a 
supplement.
    The agency's determination of what corrective action would be 
appropriate will be based on a number of factors, including the 
seriousness of any violation of this part, whether there is evidence of 
abuse of this part, and the potential risk to the public health. For 
example, consistent with past agency practice, FDA generally would 
require warnings on the product or in the approved product labeling 
only when there are serious public health concerns.
    Proposed Sec. 99.401(e) provides that a manufacturer must 
immediately (on its own) cease disseminating information under this 
part if it falls out of compliance with the requirements set forth in 
this part.
    As set forth in proposed Sec. 99.305, if FDA fails to act within 60 
days on an application for an exemption from the requirement to file a 
supplemental application, such request shall be deemed approved. 
Proposed Sec. 99.403 would provide, however, that FDA may, at any time, 
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, i.e., the manufacturer has failed to show 
that it would be economically prohibitive or unethical to conduct the 
studies needed to submit a supplemental application. If FDA terminates 
such approval, it may order the manufacturer, within 60 days, to cease 
disseminating the information about the new use and, if the new use 
would pose a significant risk to public health, FDA could order the 
manufacturer to take corrective action. FDA must notify a manufacturer 
if it terminates a deemed approval of an application for an exemption.
    Under proposed Sec. 99.403(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. If FDA terminates an approval of an application for an exemption 
under Sec. 99.403(d), proposed Sec. 99.403(e) would require such 
manufacturer within 60 days of being notified by FDA that its exemption 
approval has been terminated, to 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 information on the new use. FDA may require a 
manufacturer that ceases the dissemination of information on the new 
use to undertake corrective action.
    Proposed Sec. 99.405 would provide 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 such 
dissemination fails to comply with the requirements in section 551 of 
the act and the requirements of this part. A manufacturer who fails to 
act with due diligence to submit a supplement or to begin or complete 
the clinical studies needed to submit a supplement would be deemed to 
be not in compliance with the requirements of this part.

F. Subpart F--Recordkeeping and Reports

    Subpart F would describe the recordkeeping and reporting 
requirements of a manufacturer that disseminates information under this 
part.
    Proposed Sec. 99.501(a) would require a manufacturer that 
disseminates information under this part to maintain records sufficient 
to allow it to take corrective action that is required by FDA. Under 
the proposal, such records must either identify, by name, those persons 
receiving the disseminated information or identify, by category, the 
recipients of the disseminated information. However, manufacturers who 
choose to identify the recipient by category must be willing 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. Moreover, if FDA determines that, 
because of the nature of the information being disseminated or the 
seriousness of the new use, it is essential to keep records that 
identify the name of the persons receiving the disseminated 
information, it can require a manufacturer to keep such records.
    Proposed Sec. 99.501(a) would also require manufacturers that 
disseminate information under this part to maintain an identical copy 
of any information disseminated under this part and, upon submission of 
a supplemental application to FDA, to notify the appropriate office, 
identified in proposed Sec. 99.201, which is responsible for overseeing 
the implementation of this part.
    Proposed Sec. 99.501(b) would require manufacturers that 
disseminate information under this part to, on a semiannual basis, 
provide FDA:
    1. A list of articles and reference publications disseminated under 
this part during the 6-month period preceding the date on which the 
list is provided;
    2. A list identifying the categories of health care practitioners, 
pharmacy benefit managers, health insurance issuers, group health 
plans, or Federal of State government agencies that received the 
articles and reference publications in the 6-month period described 
above; such list must identify which category received a particular 
article or reference publication;

[[Page 31153]]

    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 data, a copy of 
the research or data. Such other data may include, but is not limited 
to, new articles, reference publications, and summaries of adverse 
events that are or may be associated with the new use; and
    4. If the manufacturer is conducting studies needed for submission 
of a supplemental application, reports that 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, it would, as 
part of this semiannual report, notify FDA of the discontinuation or 
termination of the study and state the reasons for such discontinuation 
or termination.
    Proposed Sec. 99.501(c) would require manufacturers to maintain a 
copy of all information, lists, records, and reports required or 
disseminated under this part for a period of 3 years after it has 
ceased dissemination of the new use information that triggered such 
requirements and make such documents available to FDA for inspection 
and copying.

G. Conforming Amendments

    The proposal would make a conforming amendment to part 16. Part 16 
describes the procedures for regulatory hearings before FDA. Section 
16.1 lists the statutory and regulatory actions that may be the subject 
of a part 16 hearing. The proposal would amend Sec. 16.1(a)(2) to add 
the due diligence determinations under proposed Sec. 99.401(c) to the 
list of regulatory actions that may be the subject of a part 16 
hearing.

III. Analysis of Impacts

    FDA has examined the impacts of the proposed 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 impact on 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. 104-114) (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 proposed rule and has determined that 
it is consistent with the regulatory philosophy and principles 
identified in Executive Order 12866, and these two statutes. Although 
this proposal 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. With respect to the 
Regulatory Flexibility Act, the agency certifies that the rule will not 
have a significant effect on a substantial number of small entities. 
Because the proposed 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 proposed rule implements section 401 of FDAMA by describing the 
new use information that a manufacturer may disseminate and setting 
forth the procedures that manufacturers must follow before 
disseminating information on the new use. FDA has long recognized that 
in certain circumstances, new (off-label) uses of approved products are 
appropriate, rational, and accepted medical practice. There are 
important off-label uses of approved products. The benefits of the rule 
will derive from the public health gains associated with the earlier 
dissemination of objective, balanced, accurate information about such 
important new uses. In addition, the proposed rule may actually 
stimulate new studies or the collection of evidence about these new 
uses.
    The costs of the rule are modest. Firms typically conduct clinical 
studies in support of supplemental applications for new uses only where 
the firm believes that the added revenues associated with the new use 
would exceed the cost 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. FDA cannot 
estimate the number or cost of the additional clinical studies that 
would accompany these applications, but emphasizes that they would be 
undertaken voluntarily by the affected firms in the expectation that 
they would raise company profitability.
    Manufacturers that choose not to disseminate new use information 
will incur no costs. Firms 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 each year, but as explained in section IV of this document, 
the agency preliminarily forecasts that it will receive approximately 
300 submissions from manufacturers for disseminating new use 
information. FDA also estimates that the paperwork associated with 
these submissions might total over 33,000 hours, at an average labor 
cost of $35 per hour. Thus, the total cost of the added paperwork is 
estimated to cost industry approximately $1.2 million per year.
    The proposed rule, however, will not have an adverse impact on any 
manufacturer. 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 
the new use information will face no increased costs due to this rule. 
Firms choosing to disseminate the new use information will do so only 
if the expected increased sales revenues exceed the associated 
regulatory costs. Because no firm will experience a reduced net income, 
the proposed rule will not have a significant adverse effect on a 
substantial number of small entities and no further analysis is 
required under the Regulatory Flexibility Act.

IV. Paperwork Reduction Act of 1995

    This proposed 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 invites comments on: (1) Whether the proposed collection of

[[Page 31154]]

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 proposed 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 Uses 
for Marketed Drugs, Biologics, and Devices.
    Description: The proposed 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 proposed rule sets forth the 
criteria and procedures for making such submissions. Under the proposed 
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 its initial dissemination of 
information. 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 its initial 
dissemination of information. The proposal would also permit 
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 proposal would prescribe the timeframe within which the 
manufacturer shall maintain records that would enable it to take 
corrective action. The proposal would require 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 proposal would require 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 proposed rule is 2,907 hours.
    FDA estimates the burden of this collection of information as 
follows:

                                  Table 1.--Estimated Annual Reporting Burden<SUP>1                                  
----------------------------------------------------------------------------------------------------------------
                                                     Number of                                                  
         21 CFR Section               No. of       Responses per   Total Annual      Hours per      Total Hours 
                                    Respondents     Respondent       Responses       Response                   
----------------------------------------------------------------------------------------------------------------
99.201(a)93)                          172               1.7           297               1             297       
99.201(a)(4)(i)(A)                     57               1.7            98               1              98       
99.201(a)(4)(ii)(a)                    57               1.7            98              10             980       
99.201(a)(5)                           57               1.7            98               1              98       
99.20(c)                              172               1.7           297               0.5           148.5     
99.203(b)                               1               1.7             1              10              10       
99.203(c)                               1               1.7             1               0.5             0.5     
99.205(b)                               2               1.7             3             125             375       
99.301(a)(2)                            2               1.7             3               1               3       
99.501(b)(2)                          172               3.4           594               1             594       
99.501(b)(4)                            2               1.7             3               2               6       
Total                                                                                               2,610       
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of            
  information.                                                                                                  


                                Table 2.--Estimated Annual Recordkeeping Burden<SUP>1                                
----------------------------------------------------------------------------------------------------------------
                                                      Annual                                                    
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours 
                                   Recordkeepers   Recordkeeping      Records      Recordkeeper                 
----------------------------------------------------------------------------------------------------------------
99.501(a)(2)                          172               1.7           297               1             297       
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of            
  information.                                                                                                  

    The above estimates reflect the reporting or recordkeeping burden 
that would be attributable solely to the rule. FDA derived these 
estimates 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.
    The agency has submitted the information collection requirements of 
this proposed rule to OMB for review. Interested persons are requested 
to send comments regarding information collection by July 8, 1998, to 
the Office of Information and Regulatory Affairs, OMB (address above).

V. 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.

[[Page 31155]]

VI. Request for Comments

    Interested persons may, on or before July 23, 1998, submit to the 
Dockets Management Branch (address above) written comments regarding 
this proposal. Two copies of any comments are to be submitted, except 
that individuals may submit one copy. Comments are to be identified 
with the docket number found in brackets in the heading of this 
document. Received comments may be seen in the office above between 9 
a.m. and 4 p.m., Monday through Friday.

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 Commissioner of Food and Drugs, it is 
proposed that 21 CFR chapter I be 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:  21 U.S.C. 141-149, 321-394, 467f, 679, 821, 1034; 42 
U.S.C. 201-262, 263b, 364; 15 U.S.C. 1451-1461; 28 U.S.C. 2112.

    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.

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 is prospectively planned to test 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

[[Page 31156]]

approved drug or device, or a use that is not included in the statement 
of intended use for a cleared device.
     (h) 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.
     (i) 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.
     (j) 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, 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.

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 above; 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 or 
excludes articles, reference publications, or other information 
concerning risks and adverse effects that are or may be associated with 
the new use; 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) 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. 
Accordingly, a clinical investigation described or discussed in a 
reprint or copy of an article or in a 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. 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, or abstracts of publications) 
does not qualify for dissemination under this part; and
     (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 and is being 
disseminated under section 551 et seq. of the Federal Food, Drug, and 
Cosmetic Act.'' For devices, the statement shall read, ``This 
information concerns a use that has not been approved or cleared by the 
Food and Drug Administration and is being disseminated under section 
551 et seq. of the Federal Food, Drug, and Cosmetic Act.'' If the 
information to be disseminated includes both approved and unapproved 
uses or cleared and uncleared uses, the manufacturer shall modify the 
statement to identify the unapproved or uncleared new use. 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 are

[[Page 31157]]

employees of, or consultants to, or have received compensation from the 
manufacturer, or who have a significant financial interest in the 
manufacturer;
     (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. Such information, 
which shall be attached to the front of the disseminated information, 
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.


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 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. 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 information and reports 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 search strategy in 
selecting the articles for the bibliography (e.g., the databases and 
criteria 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 of the initial 
dissemination of information under this part];'' 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 of the initial dissemination of information under this part];'' 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,

[[Page 31158]]

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 
below:
     (1) For biological products and devices regulated by the Center 
for Biologics Evaluation and Research, the Advertising and Promotional 
Labeling Staff (HFM-202), 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 complete 
submission, including, where applicable, a certification statement or 
application for exemption. For purposes of this part, a submission 
shall be considered to be complete if FDA determines that it is 
sufficiently complete to permit a substantive review.


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

     (a) A manufacturer who has certified that it will complete the 
studies necessary to submit a supplemental application for a new use 
within 36 months from the date of initial dissemination of information 
under this part, 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.
     (b) 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 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 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) Demonstrating that the estimated cost of the studies needed 
for the approval of the new use would exceed the estimated total 
revenue from the drug or device less 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. Such evidence shall include:
     (A) 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 manufacturer from its use. Such estimate shall 
assume that the total potential market for the drug or device is equal 
to the prevalence of the disease(s) or condition(s) that the drug or 
device will be used to treat and involve the following considerations:
     (1) The estimated market share for the drug or device during any 
exclusive market period, a summary of any exclusive market period for 
the product, and an explanation of the basis for the estimate;
     (2) A projection of and justification for the price at which the 
drug or device will be sold; and
     (3) Comparisons with sales of similarly situated drugs or devices, 
where available.
     (B) 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;
     (C) 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.
     (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

[[Page 31159]]

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. For purposes of determining what is unethical under this part 
an unreasonable risk of harm would ordinarily arise only when the new 
use appears to affect mortality or irreversible morbidity. 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) Request additional information or documents to assist the 
agency in determining whether the information to be disseminated 
complies with the requirements under this part. This may include, but 
is not limited to, copies of articles listed by the manufacturer in its 
bibliography;
     (3) Determine that the information submitted regarding a new use 
fails to provide data, analyses, or other written matter that is 
objective and balanced. If FDA makes such a determination, the agency:
     (i) Shall provide to the manufacturer notice and an opportunity 
for a meeting regarding the agency's determination;
     (ii) May require the manufacturer to disseminate additional 
information, including information which 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;
     (B) Pertains to the safety or effectiveness of the new use; and
     (C) Is necessary to provide objectivity and balance; and
     (iii) May 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
     (4) Require the manufacturer to maintain records that will 
identify individual recipients of the information that is to be 
disseminated.
     (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 if it 
determines that the proposed protocols are adequate and the proposed 
schedule for completing the studies is reasonable. Until such 
notification, the manufacturer shall not disseminate any information 
under this part; 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 preliminary 
review of the completed study reports to determine whether they are 
potentially adequate to support the filing of a supplemental 
application for the new use. FDA shall notify the manufacturer if it 
determines that the completed studies are inadequate, based on a 
preliminary review, to support the filing of a supplemental application 
for the new use or are not complete. Upon such notification, the 
manufacturer shall not disseminate any information under this part.


Sec. 99.303  Extension of time for completing planned studies.

     (a) Upon review of a drug or device manufacturer's proposed 
protocol and schedule for conducting studies needed for the submission 
of a supplemental application for a new use, FDA may 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.
     (b) The manufacturer may, in writing, request 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. Extensions under this paragraph shall 
not exceed 24 months.
     (c) 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.
     (d) If FDA extends the time period for completing the studies and 
submitting a supplemental application under paragraph (a) of this 
section or grants a manufacturer's request for an extension under 
paragraph (c) 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

[[Page 31160]]

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 estimated cost of the studies needed to support the 
submission of a supplemental application for the new use exceed the 
estimated total revenue from the drug or device less the cost of goods 
sold and marketing and administrative expenses attributable to 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 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 shall 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 initial dissemination 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 (c), 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 (c), 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 
issuance by FDA, 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 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 or 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

[[Page 31161]]

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 information on the new use. FDA may require a 
manufacturer that ceases the 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) 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:
     (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, periodic progress reports on 
these studies. 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 
requirement 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: May 29, 1998.
Michael A. Friedman,
Lead Deputy Commissioner for the Food and Drug Administration.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 98-14918 Filed 6-4-98; 4:30 pm]
BILLING CODE 4160-01-F