[Federal Register Volume 60, Number 174 (Friday, September 8, 1995)]
[Proposed Rules]
[Pages 46794-46797]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-22297]



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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