Federal Register, Volume 63 Issue 28 (Wednesday, February 11, 1998)

[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 Burden^{1
----------------------------------------------------------------------------------------------------------------
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}