[Federal Register: September 8, 1995 (Volume 60, Number 174)]
[Proposed Rules]
[Page 46794-46797]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr08se95-24]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 312 and 314
[Docket No. 95N-0010]
Investigational New Drug Applications and New Drug Applications
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations pertaining to investigational new drug applications
(IND's) and new drug applications (NDA's). The proposed rule would
clearly define in the NDA format and content requirements the need to
present effectiveness and safety data for important demographic
subgroups, specifically gender, age, and racial subgroups. The rule
would codify expectations that FDA has previously described in
guidance. The proposed amendments would also require IND sponsors of
drugs, including biological products, to characterize, in their annual
reports, the number of subjects in a clinical study according to age
group, gender, and race. The proposed rule does not address the
requirements for the conduct of clinical studies and would not require
sponsors to conduct any more studies than they have already conducted.
It also would not require the inclusion of particular numbers of
individuals from specific subgroups in any study or overall. The rule
refers only to the presentation of data already collected. The scope of
this proposal does not extend to requiring additional studies or data.
DATES: Written comments by December 7, 1995.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: Deborah A. Wolf, Center for Drug
Evaluation and Research (HFD-362), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-594-1046.
SUPPLEMENTARY INFORMATION: The proposed rule would amend the NDA
content and format regulations at 21 CFR 314.50 to explicitly require
that sponsors submit effectiveness and safety data by gender, age, and
racial subgroups and other subgroups of the population of patients
treated, as appropriate, such as patients with renal failure or
patients with different levels of severity of disease. In the Federal
Register of July 22, 1993 (58 FR 39406), FDA published a guideline
entitled ``Guideline for the Study and Evaluation of Gender Differences
in the Clinical Evaluation of Drugs.'' The guideline provided guidance
on FDA's expectations regarding inclusion of both men and women in drug
development, analyses of clinical data by gender, assessment of
potential pharmacokinetic differences between genders, and conduct of
specific additional studies in women, where indicated. The preamble to
the guideline described the development of the agency's policy
regarding the evaluation of clinical data by gender. The guideline
noted that over the preceding decade there had been growing concern
that the drug development process did not produce adequate information
about the effects of drugs in women (58 FR 39406). Analyses of
published clinical trials in certain therapeutic areas had indicated
that there had been little or no participation by women in many of the
studies. There had also been little study of the effects of such
aspects of female
[[Page 46795]]
physiology as the menstrual cycle and menopause or of the effects of
oral contraceptives and systemic progestins and estrogens on drug
action and pharmacokinetics.
The guideline also explained that concerns about the adequacy of
data on the effects of drugs in women have arisen in the context of an
increasing awareness of the need to individualize treatment in the face
of the wide variety of demographic, disease-related, and individual
patient-related factors that can lead to different responses in subsets
of the population. Optimal use of drugs requires identification of
these factors so that appropriate adjustments in dose, concomitant
therapy, or monitoring can be made. The guideline was part of FDA's
effort to address the need to gather and evaluate data from various
subpopulations in clinical drug trials. The agency had previously
addressed the need to develop information on the elderly in the 1989
guideline entitled, ``Guideline for the Study of Drugs Likely to be
Used in the Elderly.'' That guideline provided similar guidance
regarding inclusion of elderly patients in clinical trials and
assessment of clinical and pharmacokinetic differences between older
and younger patients.
In 1983 and 1989, FDA examined the relative numbers of individuals
from two important demographic subgroups, women and the elderly, in the
data bases of NDA's. The agency found that, in general, the proportions
of women and men included in the clinical trials were similar to the
respective proportions of women and men who had the diseases for which
the drugs were being studied, taking into account the age range of the
population studied. The General Accounting Office (GAO) conducted a
larger study of drugs approved during the period 1988 through 1991, and
found similar proportions. Women were found to typically represent a
majority of patients in NDA data bases of drugs used to treat
conditions more common, or more commonly treated, in women, and a
minority, generally a sizable one, in tests of drugs for conditions
that occur predominantly in males in the age range usually included in
the clinical trials.
Although women have been included in the later phases of clinical
trials, the agency believes that inclusion alone is not sufficient for
adequate assessment of potential gender differences. There must be an
effort to use the data to discover such differences, and the agency
found that this effort was not made. Various documents published by the
agency have reflected the need to examine gender as well as other
characteristics for their effects on drug response. FDA's regulations
on NDA content and format require the clinical data section of the NDA
to include, among other things, ``An integrated summary of the data
demonstrating substantial evidence of effectiveness for the claimed
indications. Evidence is also required to support the dosage and
administration section of the labeling, including support for the
dosage and dose interval recommended, and modifications for specific
subgroups (for example, pediatrics, geriatrics, patients with renal
failure)'' and an integrated summary of safety. (See 21 CFR
314.50(d)(5)(v) and (d)(5)(vi)(a)). The examples of subgroups listed in
Sec. 314.50(d)(5)(v) were not intended to be a complete list or to
limit the subgroups for which data should be submitted. In 1988, in a
guideline entitled, ``Guideline for the Format and Content of the
Clinical and Statistical Sections of New Drug Applications,'' FDA
discussed analyses of population subsets within NDA data bases to look
for differences in effectiveness and adverse reactions to drugs. The
guideline describes the population subsets to include subsets such as
different genders, age groups, and races, and other subsets such as
people receiving other drug therapy and people with concurrent
illnesses. See, ``Guideline for the Format and Content of the Clinical
and Statistical Sections of New Drug Applications'' at pages 32 and 40.
The guideline describes the need for clinical data beyond the specific
subgroups and categories of information set forth in the current
regulations.
The current wording of Sec. 314.50, while not intended to limit the
analyses to be carried out does not fully reflect the need to present
the safety and effectiveness data by subgroup and omits important
subgroups, including gender and racial groups. The proposal would make
explicit the agency's requirements concerning the data that are
presented in NDA's. It would make clear the need to present safety and
effectiveness data by gender, age, and racial subgroups to allow a
determination, to the extent the data permit, of whether these factors
affect results of treatment or alter dosing requirements.
FDA believes that it is important to make such an explicit
requirement. After the publication of the 1988 guideline, FDA and GAO
examined data bases for NDA's to see whether the analyses to which the
guideline refers were being conducted and submitted. Both of the
examinations found that in about half of the cases the data bases were
not being analyzed to determine whether there were differences in
response to drugs between the two genders or among different racial
groups and age groups. Thus, changes that the proposal would make to
Sec. 314.50 would codify what the agency has already identified as
important elements of clinical data.
FDA also believes that to codify the need for presentations of data
by subgroups will provide industry with clear information regarding
potential consequences of the absence of subgroup data. The agency's
regulation governing the filing of an application, which is set forth
in 21 CFR 314.101, provides that the Center for Drug Evaluation and
Research may refuse to file an NDA that, among other things, is not
submitted in the form required under Sec. 314.50 or that is incomplete
because it does not on its face contain information required under
section 505(b) of the Federal Food, Drug and Cosmetic Act. 21 CFR
314.101(d)(3). The refusal to file policy attempts to direct FDA's
resources to applications complete enough for review. The agency's
``New Drug Evaluation Guidance Document: Refusal to File'' describes
situations in which FDA applies the provision in Sec. 314.101(d)(3) to
make refusal to file decisions. In particular, the document explains
that omission of critical data, information or analyses needed to
evaluate effectiveness and safety or provide adequate directions for
use is an appropriate basis for a refusal to file. Among the particular
considerations in refusal to file decisions is a ``clearly inadequate
evaluation for safety and/or effectiveness of the population intended
to use the drug, including pertinent subsets, such as gender, age, and
racial subsets.'' Thus, the proposal would allow sponsors to know from
the beginning that data that are not presented with regard to gender,
age, and racial groups are grounds for a refusal to file.
It is important to note that the rule does not address the
requirements for the conduct of clinical studies and that this proposal
would not require sponsors to conduct any more studies than they have
already conducted. It also does not require the inclusion of particular
numbers of individuals from specific subgroups in any study or overall.
The rule refers only to the presentation of data already collected. The
scope of this proposal does not extend to requiring additional studies
or data.
Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) that this action
is of a
[[Page 46796]]
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.
Paperwork Reduction Act of 1980
This proposed rule contains information collections which are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1980. The title, description, and
respondent description of the information collection are shown below
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 the collection of information.
Title: Investigational New Drug Applications and New Drug
Applications.
Description: The information submitted by respondents pursuant to
the proposed regulatory revisions would assist the agency in monitoring
the success of drug companies in enrolling in clinical drug trials
subjects representing various subgroups of the population expected to
use the drug being tested once it is approved and marketed and in
better evaluating the safety and efficacy profiles of drugs for various
subgroups.
Description of respondents: Businesses, nonprofit institutions,
small businesses.
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Annual number of Average burden per
Section respondents Annual frequency response Annual burden hours
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312.33(a)(2)......... 1,616 1.................... 2 hours.............. 3,232
(noncommercial).....
..............
312.33(a)(2)......... 362 (commercial)..... 1.................... 8 hours.............. 2,896
314.50............... 50................... 1.................... 40 hours............. 2,000
Total................ ..................... ..................... ..................... 8,128
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The agency has submitted a copy of this proposed rule to OMB for
review of these information collections. Send comments regarding this
burden estimate or any other aspect of this collection of information,
including suggestions for reducing this burden, to FDA's Dockets
Management Branch (address above) and to the Office of Information and
Regulatory Affairs, OMB, Washington, DC 20503.
Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
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; distributive impacts; and equity). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. The proposed rule does
not require any change in the studies a drug manufacturer needs to
conduct or impose any requirements on the conduct of those studies. It
requires only a presentation of data already collected. In addition,
the proposed rule is not a significant regulatory action as defined by
the Executive Order and so is not subject to review under the Executive
Order.
This proposed rule would amend the IND regulations to enable FDA
and sponsors of drugs, including biological products, to monitor the
sponsor's success in studying the populations that are likely to
receive the drug once it is approved. Under the current IND regulations
in Sec. 312.33(a)(2) (21 CFR 312.33(a)(2)), sponsors are required to
submit an annual report that includes for each study, among other
things, ``The total number of subjects initially planned for inclusion
in the study, the number entered into the study to date, the number
whose participation in the study was completed as planned, and the
number who dropped out of the study for any reason.'' The proposed rule
would amend Sec. 312.33(a)(2) to require that the annual report include
the number of subjects entered into the study ``characterized by age
group, gender, and race.'' Reporting and reviewing this information
would not itself represent a need for new studies or patients. The
agency is aware that many clinical trials do not contain enough
patients from various subgroups to perform statistically rigorous
comparisons of outcomes between subgroups. The Regulatory Flexibility
Act requires agencies to analyze regulatory options that would minimize
any significant impact of a rule on small entities. The agency
certifies that the proposed rule will not have a significant economic
impact on a substantial number of small entities. Therefore, under the
Regulatory Flexibility Act, no further analysis is required.
Request for Comments
Interested persons may, on or before December 7, 1995, 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 312
Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.
21 CFR Part 314
Administrative practice and procedure, Confidential business
information, Drugs, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 312
and 314 be amended to read as follows:
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
1. The authority citation for 21 CFR part 312 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351,
352, 353, 355, 356, 357, 371); sec. 351 of the Public Health Service
Act (42 U.S.C. 262).
[[Page 46797]]
2. Section 312.33 is amended by revising paragraph (a)(2) to read
as follows:
Sec. 312.33 Annual reports.
* * * * *
(a) * * *
(2) The total number of subjects initially planned for inclusion in
the study; the number entered into the study to date, characterized by
age group, gender, and race; the number whose participation in the
study was completed as planned; and the number who dropped out of the
study for any reason.
* * * * *
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN
ANTIBIOTIC DRUG
3. The authority citation for 21 CFR part 314 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701,
704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321,
331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).
4. Section 314.50 is amended by revising the second sentence and
adding two new sentences after the second sentence in paragraph
(d)(5)(v) and by adding two new sentences after the first sentence in
paragraph (d)(5)(vi)(a) to read as follows:
Sec. 314.50 Content and format of an application.
* * * * *
(d) * * *
(5) * * *
(v) * * * Evidence is also required to support the dosage and
administration section of the labeling, including support for the
dosage and dose interval recommended. The effectiveness data shall be
presented by gender, age, and racial subgroups. Effectiveness data from
other subgroups of the population of patients treated, as appropriate,
such as patients with renal failure or patients with different levels
of severity of disease, shall also be presented.
(vi) * * *
(a) * * * The safety data shall be presented by gender, age, and
racial subgroups. Safety data from other subgroups of the population of
patients treated, as appropriate, such as patients with renal failure
or patients with different levels of severity of disease, shall also be
presented. * * *
* * * * *
Dated: July 11, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-22297 Filed 9-7-95; 8:45 am]
BILLING CODE 4160-01-F