Investigational New Drug Applications and New Drug Applications

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

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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).

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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