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: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its

regulations pertaining to new drug applications (NDA's) to clearly

define in the NDA format and content regulations the requirement to

present effectiveness and safety data for important demographic

subgroups, specifically gender, age, and racial subgroups. FDA

[[Page 6855]]

also is amending its regulations pertaining to investigational new drug

applications (IND's) to require sponsors to tabulate in their annual

reports the numbers of subjects enrolled to date in clinical studies

for drug and biological products according to age group, gender, and

race. This action is intended to alert sponsors as early as possible to

potential demographic deficiencies in enrollment that could lead to

avoidable deficiencies later in the NDA submission. This rule does not

address the requirements for the conduct of clinical studies and does

not require sponsors to conduct additional studies or collect

additional data. It also does not require the inclusion of a particular

number of individuals from specific subgroups in any study or overall.

The rule refers only to the presentation of data already collected.

DATES: Effective August 10, 1998. Submit written comments on the

information collection provisions of this final rule by April 13, 1998.

ADDRESSES: Submit written comments on the information collection

provisions of this final rule to the Dockets Management Branch (HFA-

305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Nancy E. Derr, Center for Drug

Evaluation and Research (HFD-5), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-594-5400, FAX 301-827-6197.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of September 8, 1995 (60 FR 46794), FDA

proposed to amend its NDA regulations at Sec. 314.50(d)(5) (21 CFR

314.50(d)(5)) to require sponsors of NDA's to include in their

applications analyses of effectiveness and safety data for important

demographic subgroups, specifically gender, age, and racial subgroups

and, as appropriate, other subgroups of the population of patients

being treated, such as patients with renal failure or patients with

different severity levels of the disease. This action codifies

expectations that FDA has described in previous guidance. FDA also

proposed to amend its IND regulations at Sec. 312.33(a)(2) (21 CFR

312.33(a)(2)) to require IND sponsors to characterize in their annual

reports the numbers of subjects enrolled in a clinical study for a drug

or biological product according to age group, gender, and race.

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 also is 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 (e.g., pediatrics, geriatrics, patients with renal

failure) * * * [and] an integrated summary of all available information

about the safety of the drug product * * *. However, as discussed in

section I of this document, a review of various agency studies and

examinations of NDA data bases has revealed that in many cases (about

half) data collected and submitted as part of an NDA still are not

being analyzed consistently to look for differences in response to

drugs among various population subgroups.

This final rule reflects the growing recognition within the agency

and the health community that: (1) Different subgroups of the

population may respond differently to a specific drug product and (2)

although the effort should be made to look for differences in

effectiveness and adverse reactions among such subgroups that effort is

not being made consistently.

Since the early 1980's, FDA has been concerned about possible

differences in response to drugs among subsets of the overall

population, such as age, gender, or racial subsets. The agency has

addressed in various ways the question of how to obtain information

that would permit individualization of therapy. Evaluation of potential

differences among demographic subsets requires that individuals from

these subsets be included in studies and that analyses to seek

differences in response be carried out. During the past decade, FDA has

encouraged demographic subgroup analyses in various guidance documents

and other regulatory actions. FDA also has examined the extent of

participation of patient subgroups in drug development programs.

In 1983 and again in 1989, FDA examined the relative numbers of

individuals in NDA data bases from two important demographic subgroups,

women and the elderly (58 FR 39406 at 39412, July 22, 1993). 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 agency

also found that, in general, the elderly were reasonably well

represented in clinical trials.

In a study of drugs approved during the period 1988 through 1991,

conducted by the General Accounting Office (GAO) entitled ``FDA Needs

to Ensure More Study of Gender Differences in Prescription Drug

Testing,'' GAO/HRD-93-17, 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. Analysis also showed that, even when enough women

are included in testing, trial data often are not analyzed to determine

if women's responses to a drug differed from those of men. The study

also showed that the participation of women took place primarily during

the later phases of drug development.

FDA's first formal encouragement to analyze population subsets

appeared in the 1985 version of Sec. 314.50, in which paragraph

(d)(5)(v) (integrated summary of effectiveness) called for evidence to

support modifications of dosage for specific subgroups, e.g.,

pediatrics, geriatrics, patients with renal failure. In 1988, the

agency developed the ``Guideline for the Format and Content of the

Clinical and Statistical Sections of New Drug Applications'' to explain

aspects of the 1985 revision of Sec. 314.50. In that guidance, FDA

discussed the importance of analyzing data from population subsets

within NDA data bases to look for differences in effectiveness and

adverse reactions to drugs. The guidance addressed the importance of

subgroup analyses of both safety and effectiveness and of analyses in

subgroups other than those mentioned in the regulations.

In 1989, after several years of public discussion, the agency

addressed the need to develop information on the elderly in a guideline

entitled ``Guideline for the Study of Drugs Likely to be Used in the

Elderly.'' The guideline provides guidance regarding the inclusion of

elderly patients in clinical trials and the assessment of clinical and

pharmacokinetic differences between older and younger patients. In

addition, the agency issued a final rule in the Federal Register of

August 27, 1997 (62 FR 45313), entitled ``Specific Requirements on

Content and Format of Labeling for Human Prescription Drugs; Addition

of `Geriatric Use' Subsection in the Labeling,'' which, among other

things, requires the inclusion of a subsection on geriatric use in the

labeling of drugs.

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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 provides guidance on FDA's expectations regarding including

both men and women in drug development, the need to analyze clinical

data by gender, the assessment of potential pharmacokinetic differences

between genders, and the conduct of specific additional studies in

women, where indicated. The 1993 guideline also describes how concerns

about the adequacy of data on the effects of drugs in women have arisen

within 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.

In 1993, FDA also published guidance on the agency's use of the

refusal-to-file (RTF) option. The guidance states that the agency

generally can exercise its RTF authority under 21 CFR 314.101(d)(3) if

there is ``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 * * *.''

Despite repeated agency encouragement in both regulations and

guidance, FDA and GAO have found that the analysis of effectiveness and

safety data in relevant population subgroups, including age, gender,

and racial subgroups, is not being carried out consistently. This rule

makes the need for these subgroup analyses completely clear.

II. Highlights of the Final Rule

This final rule revises current IND annual report regulations at

Sec. 312.33(a)(2) to require that the number of subjects entered to

date into a clinical study for drug or biological products be tabulated

by age group, gender, and race. This action is intended to alert

sponsors and the FDA as early as possible to potential demographic

deficiencies in enrollment that could lead to avoidable deficiencies in

the NDA submission.

The current wording of NDA content and format regulations at

Sec. 314.50(d)(5) does not fully reflect the need to present in the NDA

the safety and effectiveness data by subgroup. It also omits specific

mention of some important subgroups, including those of gender and

race. Therefore, this final rule also revises NDA content and format

regulations at Sec. 314.50(d)(5) to require that effectiveness and

safety data be presented for demographic subgroups including age group,

gender, and race and, when appropriate, other subgroups of the

population of patients treated, such as patients with renal failure, or

patients with different severity levels of the disease.

In response to comments received on the proposed rule, the agency

is making minor changes to the wording to clarify the intent of the

rule. In Sec. 312.33(a)(2), ``characterized'' has been changed to

``tabulated'' to make clear that the numbers of the subjects enrolled

to date in clinical studies need only be counted and listed in tabular

form in annual reports according to age group, gender, and race. No

analysis of data is being required for annual reports. Some comments

asked for clarification of the phrase, ``as appropriate'' in

Sec. 314.50(d)(5)(v) and (d)(5)(vi). When data suggest a different

response to a drug product in a subgroup other than age group, gender,

or race, it is appropriate to present the data for such a subgroup in

the NDA. Examples of such subgroups include subjects who seem to

respond differently because of a concomitant disease, renal failure, or

different severity level of the disease. The agency is changing the

phrase ``as appropriate'' to ``when appropriate.'' The phrase ``and

shall identify any modifications of dose or dose interval needed for

specific subgroups'' has been added to the end of the second sentence

in Sec. 314.50(d)(5)(v) to restore wording that was removed in the

proposal. The agency believes that the reinsertion of this wording

makes the intent of the rule clearer than the proposed wording.

FDA believes this final rule will help focus drug sponsors'

attention throughout the drug development process on the enrollment in

clinical drug trials of subjects representing the various subgroups of

the population expected to use the drug being tested once it is

approved and marketed. Although enrollment generally is broad and

reflects the population with the disease, this is not always the case.

The rule also will help sponsors better evaluate in their NDA's the

safety and efficacy profiles of drugs for various subgroups. Because

this rule clarifies agency expectations about the analysis of data that

should be included in the NDA to evaluate possible differences in

response among gender, age, and racial subgroups, an RTF action based

on failure to carry out such critical analyses will be less likely.

III. Comments on the Proposed Rule

FDA received 13 comments on the proposed rule, 8 from

representatives of pharmaceutical companies and 5 from health

professional, pharmaceutical, and special interest associations. Most

comments supported FDA's proposal. One comment called it ``a major step

forward.'' Another called it ``a catalyst to uncover potential gender-

related differences in drug response.'' Others commended the agency for

efforts to safeguard public safety by codifying previously announced

FDA policy regarding demographic subgroup analyses.

Two comments were less supportive. One comment said that the

proposal ``is premature and substitutes the real risk of false

positives for the largely theoretical risks of false negatives.'' This

comment recommended that the conduct of subgroup analyses be addressed

``in a scientifically driven manner to avoid increasing the expenditure

of resources without a clear or likely benefit.'' The other comment

said that the proposal is ``relatively meaningless'' as it requires

only the reporting of data already collected; if the sponsor has not

collected any data relevant to subgroup analysis, the proposed rule

will not cure the deficiency. Several comments also raised specific

issues for consideration by the agency. The specific issues raised in

the public comments are discussed in sections III.A, B, and C of this

document.

A. IND Annual Reports

Current IND annual report regulations, at Sec. 312.33(a)(2),

require sponsors to include in annual reports 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. FDA proposed to amend Sec. 312.33(a)(2) to

require sponsors to characterize the number of subjects entered into

the study to date by age group, gender, and race.

1. Three comments opposed the proposal because they felt that

presentation of demographic information in IND annual reports would

provide little or no useful information and would add an unnecessary

layer of bureaucracy and cost to drug development at a time when

pending proposals for FDA reform seek to reduce these costs. One

comment said that the agency's expectations and policy in this area are

well known through guidelines and

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would be made more explicit through codification of the proposed

amendments to Sec. 314.50(d)(5), but that the proposal to change

reporting requirements in IND's would not provide additional assurance

that these expectations would be met.

2. Two comments stated that the proposed change to the IND

regulations was redundant because of the proposal to evaluate subgroup

information in NDA applications. One of the comments requested that FDA

limit subgroup reporting to NDA's.

3. Two comments noted that reporting demographic information in IND

annual reports would not provide accurate information and could be

misleading because early studies would have small numbers of subjects

and may not necessarily be representative of the final study

population. One of the comments stated that recruitment of sufficient

numbers of patients distributed across subgroups is the responsibility

of the sponsor and, if necessary, enrollment demographics could be

discussed with the FDA at the appropriate stages of development.

Another comment said that current regulations require IND sponsors to

submit a clinical plan that would inform the agency of the sponsor's

intentions regarding the inclusion of various subgroups in clinical

trials. The comment noted that the agency would not be provided with a

complete picture of the overall clinical trial program because many

drug development programs include substantial amounts of clinical data

from studies conducted outside the United States, which are not

necessarily conducted under the IND.

FDA believes that all of these comments reflect a misunderstanding

of the intent and scope of the proposed IND amendment. This rulemaking

only requires drug sponsors to tabulate the number of subjects enrolled

to date in clinical drug trials by demographic subgroup, including age

group, gender, and race, to enable sponsors and FDA to track enrollment

in clinical trials of members of the various subgroups of the

population expected to use the drug once it is marketed. FDA believes

that the effort and cost imposed by this requirement will be negligible

and that the requirement is important for IND submissions because it

will give sponsors an early warning of a possible significant

deficiency in the developing data base that could lead to avoidable

deficiencies in the NDA submission.

4. One comment requested that FDA only require inclusion of

demographic data in IND annual reports after it is available in the

clinical data base. The comment noted that, when patient case records

are still in the field, demographic information would not be available

in a ``verifiable'' form.

FDA declines to revise the proposed amendment to limit the

submission of demographic information in IND annual reports to data in

clinical data bases because, in most cases, much of the required

demographic data already will be available upon subject enrollment. The

amendment does not require that the data be absolutely verifiable prior

to reporting. The agency emphasizes that this amendment is not intended

to change information-gathering methods. It only requires the

tabulation of available demographic data on the participants enrolled

in clinical drug trials.

5. Four comments addressed the conduct of subgroup analyses in IND

annual reports even though FDA had not proposed to require such

analyses. One comment said that it would be unproductive and burdensome

to split summarized data in IND annual reports into subgroups because

data in these reports already have little power. Another comment

assumed that safety and efficacy of individual subgroups need not be

demonstrated while one other comment requested that FDA clearly state

that this assumption is true. These comments requested that FDA state

that statistical demonstration of subgroup safety and efficacy would be

required only if a claim is being made relative to the subgroup. One of

the comments also requested that FDA state that a lack of significant

findings in a subgroup would not be adversely reflected in the

labeling. Another comment said that subgroup analyses may pose special

problems because IND annual reports are sometimes prepared using

interim data bases that contain data intended for a variety of purposes

that may, or may not, include those identified in the proposal.

FDA emphasizes that this rule only requires the tabulation in IND

annual reports of the numbers of subjects enrolled to date by

demographic subgroups, including age group, gender, and race. FDA

believes that it is important to tabulate demographic information in

IND annual reports to track the enrollment of subjects representing

those who are expected to use the drug product. 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. As a result, this rule does not require analysis of

subgroup data in IND annual reports.

6. One comment requested that FDA require a sponsor to file gender

accrual data and analyze the data in IND annual reports. The comment

noted that on January 19, 1995, the National Task Force on AIDS Drug

Development recommended conducting gender accrual analysis in IND

annual reports. The comment pointed out that under the proposal such an

analysis would not be required if subgroup data did not exist and, if

available, would yield a very limited and inaccurate gender accrual

analysis. The comment also noted that, from a scientific perspective,

use of the data thus far collected would most likely result in a

statistically skewed by-gender analysis.

FDA declines to revise the proposed amendment to require the

analysis of subgroup data in IND annual reports. The final rule

requires only that the number of subjects be tabulated by age group,

gender, and race in annual reports to alert drug sponsors to potential

demographic deficiencies in their enrollment. The rule does not require

an analysis of such data at this stage in drug development.

B. NDA Content and Format

FDA proposed to revise the requirements for the content and format

of NDA's, under Sec. 314.50, to require sponsors to submit

effectiveness (Sec. 314.50(d)(5)(v)) and safety

(Sec. 314.50(d)(5)(vi)(a)) data by gender, age, and racial subgroups

and, as appropriate, other subgroups of the population of patients to

be treated, such as patients with renal failure or patients with

different severity levels of the disease.

7. Two comments supported these amendments when they pertained to

NDA integrated summaries of efficacy and safety, but did not support

their inclusion in individual study reports. The comments noted that

the integrated summaries of safety and efficacy are the most

appropriate place for subgroup analyses because the full NDA data base

provides sample sizes that can more likely withstand such analyses and

also allows an evaluation of consistency of effects across studies. One

of the comments said that subgroup analyses in individual study reports

would increase bulk and add nothing to the evaluation of either safety

or efficacy because, in isolation, these analyses can be misleading at

worst and at best amount to needless replication of results that still

need to be presented in context, i.e., in light of other relevant

studies. The comment requested that FDA revise proposed

Sec. 314.50(d)(5)(v) by adding the following sentences: ``These gender,

age, and racial subgroup summaries (and, when appropriate, other

subgroup summaries) should be

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based on all parts of the NDA database that are relevant to the

efficacy of the drug product in those subgroups. Therefore, in general,

the appropriate place for these subgroup analyses will [be] in the

Integrated Summary of Efficacy (rather than in individual study

reports).'' The comment proposed similar language for safety data,

under proposed Sec. 314.50(d)(5)(vi)(a).

FDA agrees that the most appropriate place for the conduct of

subgroup analyses in an NDA is in the integrated summaries of

effectiveness and safety. This is why the agency is codifying the

requirement for subgroup summaries under the paragraphs of the clinical

data section of the format and content requirements that pertain to the

integrated summary of effectiveness (Sec. 314.50(d)(5)(v)) and safety

(Sec. 314.50(d)(5)(vi)(a)).

FDA declines, however, to add language saying that, in general, it

is inappropriate for sponsors to conduct subgroup analyses in

individual study reports because sometimes it is useful to conduct such

analyses. The 1988 ``Guideline for the Format and Content of the

Clinical and Statistical Sections of New Drug Applications,'' the 1989

``Guideline for the Study of Drugs Likely to be Used in the Elderly,''

and the 1993 ``Guideline for the Study and Evaluation of Gender

Differences in the Clinical Evaluation of Drugs'' advise sponsors to

carry out subset analyses that consider the entire efficacy and safety

data bases (i.e., in integrated summaries), but also suggest that, if

individual studies are large enough, it may be useful to consider

subsets in individual studies. Even in integrated summaries, subset

analyses may be based on pooled data or may examine subset results by

looking at the range of results in individual studies. FDA recognizes

that although the analysis of subsets with particular characteristics

in individual studies often detects only relatively large differences,

such differences could be useful in suggesting hypotheses worth

examining in other studies and help refine labeling information,

patient selection, dose selection, and other information.

To better clarify the requirement for subgroup summaries for

effectiveness data, FDA changed proposed Sec. 314.50(d)(5)(v) by adding

a phrase, ``and shall identify any modifications of dose or dose

interval needed for specific subgroups,'' to the end of the second

sentence in paragraph (v). The phrase ``and modifications for specific

subgroups'' had been removed in the proposed amendment. The reinsertion

of similar wording makes it clear that one important reason for

presenting effectiveness data by age group, gender, and race is to

identify any modifications of dose or dose interval that might be

needed for those subgroups.

8. One comment contended that the proposal requires data to be

presented by subgroups without a clear rationale. The comment suggested

that sponsors use a screening hypothesis test in the integrated

summaries to see if groups are behaving differently or provide summary

information by appropriate subgroups to look for trends. The comment

requested that FDA require sponsors to perform subgroup analyses only

when there is a biologically plausible, data-driven reason for concern.

The comment indicated that such a scientific approach would result in

more appropriate labeling and avoid drawing conclusions from poorly

powered data. Another comment asked whether interaction tests (e.g.,

by-gender treatment) would be acceptable for purposes of exploring

whether there are differences among subgroups.

Another comment noted that regulatory misinterpretations regarding

compliance could result because some indications are specific to one or

more subgroups and FDA personnel, who will be deciding on the

appropriate type of analysis, may not be familiar with all indications

of the group and subgroup.

Two comments requested that FDA only require analyses of primary or

key efficacy and safety variables to allow for a more efficient review

and to avoid drawing inferences that lack a statistical basis. One of

the comments said that it might be appropriate to perform such analyses

only when sample sizes are ``large enough.''

In the ``Guideline for the Format and Content of the Clinical and

Statistical Sections of New Drug Applications,'' FDA indicates that

examination of subsets need not routinely involve formal statistical

analysis. In comparisons of safety and effectiveness results in

subsets, differences of clinically meaningful size are of interest. If

these are not observed, the minor differences that are an expected

consequence of random variation should be displayed, but need not be

analyzed further and would not ordinarily appear in labeling. This

guideline reflects current FDA perspectives on the importance of

subgroup evaluations and should provide the guidance requested by the

comments.

9. One comment requested clarification of the proposed phrase ``as

appropriate.'' The comment asked whether ``other subgroups'' would be

determined by or discussed with the FDA on a case-by-case basis for

each clinical trial or clinical trial setting.

For clarity, FDA has changed the phrase ``as appropriate'' to

``when appropriate.'' FDA advises that the phrase ``when appropriate''

means: When a subset of the population can be identified that might

require a modification of dosing to ensure safe and effective

administration of the drug product, it is appropriate to present an

analysis of data for that subgroup. In particular, sponsors should

consider subgroups for whom the metabolism or excretion of the drug

might be altered, e.g., patients with renal or hepatic, or cardiac

failure, or patients with different severity levels of the disease. The

sponsor may request advice on this matter from the division responsible

for review of their application.

C. General

10. Many comments questioned the extent to which the proposal would

affect clinical trial design because they believed that the proposal

could lead to a request for subgroup sample sizes that are adequate to

interpret results. One comment noted that an RTF action could result if

a clinical trial does not yield sufficient dosing data for each gender,

for every racial subgroup, and for every age group of patient that may

be treated. Another comment asked whether the National Institutes of

Health (NIH) ruling of 1993, which calls for ``sufficient numbers to

allow valid analyses,'' would affect the proposal. The comment asked

whether larger trials would be required to adequately power subgroup

analyses, or, if subgroup differences are shown to be descriptively or

statistically significant, would additional studies be required to

confirm or explain the results. The comment noted that statistically

significant differences found in ad hoc statistical hypothesis testing

could yield a high false-positive rate.

Another comment asked whether subsets were more or less important

than centers because it has been their practice to attempt to achieve

balance in the assignment of treatment arms in clinical trials by

center.

One comment requested clarification of the following phrases

discussed in the preamble to the proposed rule (60 FR 46795): ``There

must be an effort to use the data to discover such [subgroup]

differences'' and ``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.''

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Another comment requested clarification of the phrase ``[the] rule

refers only to the presentation of data already collected.''

Another comment said that the proposed reporting requirement to

``characterize'' the number of subjects in a clinical study according

to age group, gender, and race is inconsistent with the statement in

the proposal that it does ``not require sponsors to conduct any more

studies than they have already conducted.''

One comment requested that FDA revise the statement to clarify that

the rule's criteria can be met by enhanced analysis of existing data.

One comment requested that FDA require sponsors who do not have

data pertaining to the differences of the investigational new drug's

effects by gender to conduct additional studies to obtain such data.

The comment contended that the proposal appears to be an empty gesture

because it requires nothing more than a report of numbers and would not

cure the lack of knowledge about how drugs affect women. The comment

also requested that FDA require sponsors to assess potential

differences between genders including a record of side effects or

treatment response differences and appropriate pharmacokinetic and

pharmacodynamic data as well as a report on hormonal influences. The

comment indicated that, if a sponsor has such data, it can be used to

predict when specific interactions are important.

The agency believes that all of these comments reflect a

misunderstanding of the intent and scope of the proposed amendments.

This rule does not require any change in the number of studies a drug

sponsor needs to conduct, nor does it impose any new requirements on

the conduct of those studies. The rule refers only to the presentation

of data that already have been collected. FDA's expectations for

inclusion of subgroups in clinical trials and analysis of data

generated from such groups are described in FDA guidelines entitled

``Guideline for the Format and Content of the Clinical and Statistical

Sections of New Drug Applications,'' ``Guideline for the Study of Drugs

Likely to be Used in the Elderly,'' and ``Guideline for the Study and

Evaluation of Gender Differences in the Clinical Evaluation of Drugs''.

This rule does not affect those recommendations.

In the ``Guideline for the Format and Content of the Clinical and

Statistical Sections of New Drug Applications,'' FDA recommends

analyzing NDA data to identify variations among population subsets in

favorable responses (effectiveness) and unfavorable responses (adverse

reactions) to drugs. The population subsets that should be evaluated

routinely include demographic subsets, such as different age groups,

genders, and races; people receiving other drug therapy; and people

with concomitant illness. The guideline refers only to the analyses

needed. It does not address the question of what the extent of drug

exposure (number of patients) of any particular subset of the

population should be.

The ``Guideline for the Study and Evaluation of Gender Differences

in the Clinical Evaluation of Drugs'' does set forth recommendations

for subgroup enrollment. The guideline states that sponsors are

expected to enroll a full range of patients in their studies; carry out

appropriate analyses to evaluate potential subset differences in the

patients they have studied; study possible pharmacokinetic differences

in patient subsets; and carry out targeted studies to look for subset

pharmacodynamic differences that are especially probable, that are

suggested by existing data, or that would be particularly important if

present. In general, the patients included in clinical studies should

reflect the population that will receive the drug when it is marketed.

Although it may be reasonable to exclude certain patients at early

stages because of characteristics that might make evaluation of therapy

more difficult (e.g., patients on concomitant# therapy), such exclusion

should be abandoned as soon as possible in later development so that

possible drug-drug and drug-disease interactions can be detected. The

guideline also describes specific guidance for gender-related studies.

The ``Guideline for the Study of Drugs Likely to be Used in the

Elderly'' likewise provides specific guidance for age-related studies

in the elderly.

11. A number of comments requested that FDA provide definitions for

subgroups. Two comments requested a definition for the age categories

to avoid the potential need to rework existing data. One of the

comments suggested that FDA consider the following subgroups for the

pediatric population: Newborns (birth to 3 months), infants (3 months

to 2 years), children (2 to 12 years) and adolescents (12 to 18 years).

The comment requested that FDA require that all available safety,

pharmacokinetic, and efficacy data be presented for each of these

subgroups. One comment requested that FDA define subpopulations of

women. The comment indicated that safety, pharmacokinetic, and efficacy

data for pregnant women should be presented separately from data for

women who are not pregnant. Two comments requested that FDA define

categories for race. One of the comments noted that it may be somewhat

problematic to implement the proposal because race descriptions used in

the United States may not be appropriate in other countries.

In its final rule on the revision of the pediatric use subsection

in labeling (59 FR 64240, December 13, 1994), FDA offered the following

guidance for defining the pediatric population: (1) Birth to 1 month

(neonates), (2) 1 month to 2 years of age (infants), (3) 2 years to 12

years (children), and (4) 12 years to 16 years (adolescents). Where

possible, data should be analyzed according to these groups.

Alternatively, it usually would not be necessary to establish a drug

product's effectiveness in each group. On the other hand, it may be

important to have some pharmacokinetic information in each group,

especially the younger age groups, to guide dosing and additional

information, such as a specific study in neonates, to establish safety.

In the final rule on geriatric labeling (62 FR 45313 at 45316,

August 27, 1997), the agency defined ``elderly'' as persons aged 65

years and over. FDA recommends that sponsors use this definition for

analysis of data for the elderly population.

FDA declines to define subpopulations of women because it is not

necessary. Usually, pregnant women would only participate in clinical

trials intended specifically to study drug effects during pregnancy.

The data generated from such trials would, therefore, reflect use in

this subpopulation of women.

FDA also does not believe it necessary to define specific racial

categories in this rule because drug sponsors have been very successful

thus far in identifying the relevant racial categories to help them

examine safety and efficacy profiles of drugs in relation to race and

to identify potential metabolic differences in accordance with race

that could have important biomedical implications. Because of the

diversity of the U.S. population, the changing racial composition of

the population, and the sensitivities of categorizing individuals

according to race, FDA recommends that sponsors use the approach common

in such efforts to capture demographic data, by asking subjects in

clinical trials to identify their racial group. If they desire,

sponsors may use the categories and definitions offered in The Office

of Management and Budget (OMB) Directive No. 15, which currently

identifies the following racial groups:

[[Page 6860]]

American Indian or Alaskan Native: A person having origins in any

of the original peoples of North America.

Asian or Pacific Islander: A person having origins in any of the

original peoples of the Far East, Southeast Asia, the Indian

subcontinent, or the Pacific Islands. This area includes, for example,

China, India, Japan, Korea, the Philippine Islands, and Samoa.

Black: A person having origins in any of the black racial groups of

Africa.

White: A person having origins in any of the original peoples of

Europe, North Africa, or the Middle East.

Many subjects may choose to identify their race as Hispanic, which

can include a person of Mexican, Puerto Rican, Cuban, Central or South

American or other Spanish culture or origin, regardless of race.

Technically, however, the term ``Hispanic'' is used to describe an

ethnic, rather than a racial, group.\1\

---------------------------------------------------------------------------

\1\ OMB has proposed adding the ethnic category ``Hispanic'' to

Directive No. 15 (62 FR 36874, July 9, 1997).

---------------------------------------------------------------------------

12. One comment requested that FDA ensure that the proposal is

consistent with International Conference on Harmonization of Technical

Requirements for Registration of Pharmaceuticals for Human Use (ICH)

initiatives, in particular, Topic E3: Structure and Content of Clinical

Reports. The comment noted that such consistency is important for

global harmonization.

FDA notes that the final rule is consistent with ICH initiatives.

In the Federal Register of July 17, 1996 (61 FR 37320), FDA issued an

ICH guideline entitled ``E3 Structure and Content of Clinical Study

Reports.'' This guideline recommends that an individual clinical study

report describe demographic characteristics of the study population

and, where the study is large enough to permit this, present data for

demographic and other subgroups (e.g., renal or hepatic function) so

that possible differences in efficacy or safety can be identified. The

guideline also notes that subgroup responses usually should be examined

in the larger data base used in the overall analysis. This is the only

ICH guideline to date that contains information relevant to this final

rule.

13. One comment requested that FDA describe how the proposal will

be implemented. The comment suggested that it be implemented on an

incremental basis, especially with regard to the required changes in

content and format of submissions and the required updates. The comment

noted that it is important to publicize the timing and effective date

of the rule prior to enforcement. Otherwise, the comment contended, it

could cause an enormous burden and expense to sponsors and

manufacturers. The comment also requested that FDA state its position

on the subject of retroactivity, i.e., when the agency would require

reports to be changed and how much advance notice the agency would

give.

FDA is requiring that this final rule become effective on August

10, 1998. All IND annual reports and NDA applications submitted to the

agency on or after the effective date must be in the format specified

in the final rule. FDA believes that this period of time is sufficient

for preparation of these documents because the final rule does not

change information-gathering methods nor does it require sponsors to

conduct additional studies or collect additional data. The final rule

codifies expectations that the agency has described in previous

guidance regarding the presentation of data already collected.

14. One comment suggested that FDA consider sponsorship of an

educational forum such as a workshop or an interactive telecast (e.g.,

FDA/Food and Drug Law Institute telecast) to inform sponsors of the new

regulations.

At present, FDA is not planning a workshop or interactive telecast

on this subject, but may consider sponsoring one if sufficient interest

exists. FDA will make information regarding this rule available on its

World Wide Web site at http://www.fda.gov/cder/guidance.htm. Interested

persons may submit requests for a workshop or interactive telecast to

the Dockets Management Branch (address above) under Docket No. 95N-

0010.

IV. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is

of a type that will not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

V. Paperwork Reduction Act of 1995

This final rule contains information collection provisions that are

subject to review by OMB under the Paperwork Reduction Act of 1995 (the

PRA of 1995) (44 U.S.C. 3501-3520). The title, description, and

respondent description of the information collection provisions are

shown below with an estimate of the annual reporting and recordkeeping

burdens. Included in the estimate is the time required for reviewing

instructions, searching existing data sources, gathering and

maintaining the data needed, and completing and reviewing each

collection of information.

Title: Presentation of Safety and Effectiveness Data for Certain

Subgroups of the Population in Investigational New Drug Application

Reports and New Drug Applications.

Description: This final rule amends the new drug application format

and content regulations to require the presentation of effectiveness

and safety data for important demographic subgroups, specifically

gender, age, and racial subgroups and, when appropriate, other

subgroups of the population of patients being treated, such as patients

with renal failure or patients with different severity levels of the

disease. The final rule also amends FDA's regulations pertaining to

IND's to require sponsors to tabulate in their annual reports the

numbers of subjects enrolled to date in clinical studies for drug and

biological products according to age group, gender, and race. This

action is intended to alert sponsors as early as possible to potential

demographic deficiencies in enrollment that could lead to avoidable

deficiencies later in the NDA submission.

This rule does not address the requirements for the conduct of

clinical studies and does not require sponsors to conduct additional

studies or collect additional data. It also does not require the

inclusion of a particular number of individuals from specific subgroups

in any study or overall. The rule refers only to the presentation of

data already collected.

The data required to be presented under this final rule will assist

the sponsor and the agency in monitoring the enrollment in clinical

drug trials of subjects representing various subgroups of the

population expected to use the drug once it is approved and marketed.

The data also will help the sponsor and the agency to evaluate the

safety and efficacy profiles of drugs for various subgroups.

Description of Respondents: Businesses, nonprofit institutions,

small businesses.

Although the proposed rule of September 8, 1995 (60 FR 46794),

provided a 90-day comment period under the PRA of 1980, FDA is

providing an additional opportunity for public comment under the PRA of

1995, which became effective after the publication of the proposed rule

and applies to this final rule. Therefore, FDA now invites comments on:

(1) Whether the proposed collection of information is necessary for the

proper performance of FDA's functions, including whether

[[Page 6861]]

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. Individuals and organizations may submit comments on the

information collection provisions of this final rule by April 13, 1998.

Comments should be directed to the Dockets Management Branch (address

above).

At the close of the 60-day comment period, FDA will review the

comments received, revise the information collection provisions as

necessary, and submit these provisions to OMB for review and approval.

FDA will publish a notice in the Federal Register when the information

collection provisions are submitted to OMB, and an opportunity for

public comment to OMB will be provided at that time. Prior to the

effective date of this final rule, FDA will publish a notice in the

Federal Register of OMB's decision to approve, modify, or disapprove

the information collection provisions. An agency may not conduct or

sponsor, and a person is not required to respond to, a collection of

information unless it displays a currently valid OMB control number.

Table 1.--Estimated Additional Annual Reporting Burden1

----------------------------------------------------------------------------------------------------------------

Annual Average Burden per

21 CFR Section Anuual No. of Respondents Frequency Respons Annual Hours

----------------------------------------------------------------------------------------------------------------

312.33(a)(2) 1,616 (noncommercial)\2\ 1 2 hours 3,232

312.33(a)(2) 362 (commercial) 1 8 hours 2,896

314.50(d)(5) 50 1 40 hours 2,000

Total 8,128

----------------------------------------------------------------------------------------------------------------

\1\ There are no capital costs or operating and maintenance costs associated with this collection of

information.

\2\ For purposes of this document, a commercial study under an IND is conducted by a sponsor that is in the

process of developing a drug to the point of commercial marketing. A noncommercial study under an IND is

sponsored, generally, by government agencies or academic institutions for the purpose of gaining knowledge

about the drug. The agency or institution does not own marketing rights for the drug nor is it intended that

the marketing rights holder will submit the results for marketing approval.

For the amendments to Sec. 312.33(a)(2), the estimates are based on

the average number of IND annual reports that FDA receives annually.

For the amendments to Sec. 314.50(d)(5)(v) and (d)(5)(vi)(a), the

estimates are based on the average number of NDA's FDA receives

annually that do not currently include the information that would be

required by the final rule. An average of 100 NDA's are submitted to

FDA annually. As indicated elsewhere in the final rule, in half of the

cases that FDA and GAO examined, the information that would now be

required is currently being presented and analyzed, so the additional

cost imposed by the rule has been calculated only for the 50 remaining

NDA's. In addition, the agency expects that for the most part, a

tabular presentation of descriptive statistics, such as the mean change

in a parameter for a particular subgroup, will be sufficient. Only

occasionally will it be necessary to do more substantive analysis, when

the descriptive statistics suggest a significant difference.

VI. Analysis of Impacts

FDA has examined the impacts of the final 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; distributive impacts; and equity). The agency believes that

this final rule is consistent with the regulatory philosophy and

principles set forth in Executive Order 12866. The final rule does not

require a 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 final

rule is not a significant regulatory action as defined in Executive

Order 12866 and so is not subject to review under the Executive Order.

The final rule amends IND regulations to enable drug sponsors and

FDA to monitor the extent to which patient populations that are likely

to receive the drug once it is approved are being enrolled and studied.

The final rule amends Sec. 312.33(a)(2) to require that the IND annual

report include the number of subjects entered into the study

``tabulated by age group, gender, and race.'' The rule does not require

any analysis of collected data for the IND annual report.

The rule also amends NDA regulations at Sec. 314.50(d)(5)(v) and

(d)(5)(vi) to clearly define in the format and content regulations the

requirement to present effectiveness and safety data for important

demographic subgroups including age group, gender, race, and when

appropriate, other subgroups of the population of patients to be

treated. The rule refers only to the presentation of data already

collected and codifies recommendations that FDA has made in previous

guidance.

The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a rule

on small entities. Since the rule will not impose significant costs on

any affected firm, it will therefore not impose a significant impact on

a substantial number of small entities. The agency certifies that the

final 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.

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, 21 CFR parts 312 and 314 are amended as

follows:

[[Page 6862]]

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

1. The authority citation for 21 CFR part 312 continues to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,

371; 42 U.S.C. 262.

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, tabulated 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: 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 and shall identify any

modifications of dose or dose interval needed for specific subgroups.

Effectiveness data from other subgroups of the population of patients

treated, when appropriate, such as patients with renal failure or

patients with different levels of severity of the disease, also shall

be presented.

(vi) * * *

(a) * * * The safety data shall be presented by gender, age, and

racial subgroups. When appropriate, safety data from other subgroups of

the population of patients treated also shall be presented, such as for

patients with renal failure or patients with different levels of

severity of the disease. * * *

* * * * *

Dated: February 2, 1998.

William B. Schultz,

Deputy Commisioner for Policy.

[FR Doc. 98-3422 Filed 2-10-98; 8:45 am]

BILLING CODE 4160-01-F