[Federal Register Volume 63, Number 28 (Wednesday, February 11, 1998)]
[Rules and Regulations]
[Pages 6854-6862]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-3422]


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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: 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.

[[Page 6856]]

    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

[[Page 6857]]

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

[[Page 6858]]

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.''

[[Page 6859]]

    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