[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 Burden1
----------------------------------------------------------------------------------------------------------------
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 Burden1
----------------------------------------------------------------------------------------------------------------
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
