46794 Federal Register / Vol. 60, No. 174 / Friday, September 8, 1995 / Proposed Rules
43025, August 22, 1994), and by adding
a new airworthiness directive (AD), to
read as follows:
Jetstream Aircraft, Limited: Docket 94–
NM–237–AD. Supersedes AD 94–17–12,
Amendment 39–9007.
Applicability: Model 4101 airplanes;
having constructors numbers 41004 through
41015 inclusive, 41018 through 41026
inclusive, 41028 through 41030 inclusive,
and 41032; certificated in any category.
Note 1: This AD applies to each airplane
identified in the preceding applicability
provision, regardless of whether it has been
modified, altered, or repaired in the area
subject to the requirements of this AD. For
airplanes that have been modified, altered, or
repaired so that the performance of the
requirements of this AD is affected, the
owner/operator must use the authority
provided in paragraph (d) of this AD to
request approval from the FAA. This
approval may address either no action, if the
current configuration eliminates the unsafe
condition; or different actions necessary to
address the unsafe condition described in
this AD. Such a request should include an
assessment of the effect of the changed
configuration on the unsafe condition
addressed by this AD. In no case does the
presence of any modification, alteration, or
repair remove any airplane from the
applicability of this AD.
Compliance: Required as indicated, unless
accomplished previously.
To prevent uncommanded extension of the
lift spoiler in the event of loss of hydraulic
pressure in the spoiler actuator, accomplish
the following:
(a) Within 21 days after September 6, 1994
(the effective date of AD 94–17–12,
amendment 39–9007), remove the spoiler
actuators in accordance with Jetstream Alert
Service Bulletin J41–A27–034, dated June 9,
1994, or Revision 1, dated October 28, 1994.
Following removal of the actuators,
accomplish the requirements of paragraphs
(a)(1) and (a)(2) of this AD, in accordance
with the service bulletin. Thereafter, repeat
the requirements of this paragraph at
intervals not to exceed 500 landings.
(1) Prior to further flight, purge the
hydraulic system to ensure that there is no
contamination.
(2) Prior to further flight, install a spoiler
actuator that has been previously certified
and marked with an ‘‘R’’ after the serial
number on the nameplate of the actuator.
(b) For spoiler actuators having Lucas
Aerospace part number (P/N) TY1763–01A or
P/N TY1763–01B: Prior to the accumulation
of 5,000 total hours time-in-service on the
spoiler actuator, or within 30 days after the
effective date of this AD, whichever occurs
later, replace the actuator with a new or
serviceable part, in accordance with
Jetstream Service Bulletin J41–A27–034,
Revision 1, dated October 28, 1994.
Thereafter, prior to the accumulation of 5,000
hours time-in-service on the spoiler actuator,
replace the actuator with a new or
serviceable part, in accordance with the
service bulletin. Such replacement
constitutes terminating action for the
repetitive purging and repetitive installation
requirements of paragraph (a) of this AD.
(c) Installation of improved spoiler
actuators (Modification JM 41381) on the left
and right wings, in accordance with Jetstream
Service Bulletin J41–27–037, dated
November 7, 1994, constitutes terminating
action for the requirements of paragraphs (a)
and (b) of this AD.
(d) An alternative method of compliance or
adjustment of the compliance time that
provides an acceptable level of safety may be
used if approved by the Manager,
Standardization Branch, ANM–113, FAA,
Transport Airplane Directorate. Operators
shall submit their requests through an
appropriate FAA Principal Maintenance
Inspector, who may add comments and then
send it to the Manager, Standardization
Branch, ANM–113.
Note 2: Information concerning the
existence of approved alternative methods of
compliance with this AD, if any, may be
obtained from the Standardization Branch,
ANM–113.
(e) Special flight permits may be issued in
accordance with sections 21.197 and 21.199
of the Federal Aviation Regulations (14 CFR
21.197 and 21.199) to operate the airplane to
a location where the requirements of this AD
can be accomplished.
Issued in Renton, Washington, on
September 1, 1995.
Darrell M. Pederson,
Acting Manager, Transport Airplane
Directorate, Aircraft Certification Service.
[FR Doc. 95–22302 Filed 9–7–95; 8:45 am]
BILLING CODE 4910–13–O
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 312 and 314
[Docket No. 95N–0010]
Investigational New Drug Applications
and New Drug Applications
AGENCY: Food and Drug Administration,
HHS.
ACTION: Proposed rule.
SUMMARY: The Food and Drug
Administration (FDA) is proposing to
amend its regulations pertaining to
investigational new drug applications
(IND’s) and new drug applications
(NDA’s). The proposed rule would
clearly define in the NDA format and
content requirements the need to
present effectiveness and safety data for
important demographic subgroups,
specifically gender, age, and racial
subgroups. The rule would codify
expectations that FDA has previously
described in guidance. The proposed
amendments would also require IND
sponsors of drugs, including biological
products, to characterize, in their
annual reports, the number of subjects
in a clinical study according to age
group, gender, and race. The proposed
rule does not address the requirements
for the conduct of clinical studies and
would not require sponsors to conduct
any more studies than they have already
conducted. It also would not require the
inclusion of particular numbers of
individuals from specific subgroups in
any study or overall. The rule refers
only to the presentation of data already
collected. The scope of this proposal
does not extend to requiring additional
studies or data.
DATES: Written comments by December
7, 1995.
ADDRESSES: Submit written comments
to the Dockets Management Branch
(HFA–305), Food and Drug
Administration, rm. 1–23, 12420
Parklawn Dr., Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT:
Deborah A. Wolf, Center for Drug
Evaluation and Research (HFD–362),
Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301–
594–1046.
SUPPLEMENTARY INFORMATION: The
proposed rule would amend the NDA
content and format regulations at 21
CFR 314.50 to explicitly require that
sponsors submit effectiveness and safety
data by gender, age, and racial
subgroups and other subgroups of the
population of patients treated, as
appropriate, such as patients with renal
failure or patients with different levels
of severity of disease. In the Federal
Register of July 22, 1993 (58 FR 39406),
FDA published a guideline entitled
‘‘Guideline for the Study and Evaluation
of Gender Differences in the Clinical
Evaluation of Drugs.’’ The guideline
provided guidance on FDA’s
expectations regarding inclusion of both
men and women in drug development,
analyses of clinical data by gender,
assessment of potential pharmacokinetic
differences between genders, and
conduct of specific additional studies in
women, where indicated. The preamble
to the guideline described the
development of the agency’s policy
regarding the evaluation of clinical data
by gender. The guideline noted that over
the preceding decade there had been
growing concern that the drug
development process did not produce
adequate information about the effects
of drugs in women (58 FR 39406).
Analyses of published clinical trials in
certain therapeutic areas had indicated
that there had been little or no
participation by women in many of the
studies. There had also been little study
of the effects of such aspects of female
46795Federal Register / Vol. 60, No. 174 / Friday, September 8, 1995 / Proposed Rules
physiology as the menstrual cycle and
menopause or of the effects of oral
contraceptives and systemic progestins
and estrogens on drug action and
pharmacokinetics.
The guideline also explained that
concerns about the adequacy of data on
the effects of drugs in women have
arisen in the context of an increasing
awareness of the need to individualize
treatment in the face of the wide variety
of demographic, disease-related, and
individual patient-related factors that
can lead to different responses in
subsets of the population. Optimal use
of drugs requires identification of these
factors so that appropriate adjustments
in dose, concomitant therapy, or
monitoring can be made. The guideline
was part of FDA’s effort to address the
need to gather and evaluate data from
various subpopulations in clinical drug
trials. The agency had previously
addressed the need to develop
information on the elderly in the 1989
guideline entitled, ‘‘Guideline for the
Study of Drugs Likely to be Used in the
Elderly.’’ That guideline provided
similar guidance regarding inclusion of
elderly patients in clinical trials and
assessment of clinical and
pharmacokinetic differences between
older and younger patients.
In 1983 and 1989, FDA examined the
relative numbers of individuals from
two important demographic subgroups,
women and the elderly, in the data
bases of NDA’s. The agency found that,
in general, the proportions of women
and men included in the clinical trials
were similar to the respective
proportions of women and men who
had the diseases for which the drugs
were being studied, taking into account
the age range of the population studied.
The General Accounting Office (GAO)
conducted a larger study of drugs
approved during the period 1988
through 1991, and found similar
proportions. Women were found to
typically represent a majority of patients
in NDA data bases of drugs used to treat
conditions more common, or more
commonly treated, in women, and a
minority, generally a sizable one, in
tests of drugs for conditions that occur
predominantly in males in the age range
usually included in the clinical trials.
Although women have been included
in the later phases of clinical trials, the
agency believes that inclusion alone is
not sufficient for adequate assessment of
potential gender differences. There must
be an effort to use the data to discover
such differences, and the agency found
that this effort was not made. Various
documents published by the agency
have reflected the need to examine
gender as well as other characteristics
for their effects on drug response. FDA’s
regulations on NDA content and format
require the clinical data section of the
NDA to include, among other things,
‘‘An integrated summary of the data
demonstrating substantial evidence of
effectiveness for the claimed
indications. Evidence is also required to
support the dosage and administration
section of the labeling, including
support for the dosage and dose interval
recommended, and modifications for
specific subgroups (for example,
pediatrics, geriatrics, patients with renal
failure)’’ and an integrated summary of
safety. (See 21 CFR 314.50(d)(5)(v) and
(d)(5)(vi)(a)). The examples of
subgroups listed in § 314.50(d)(5)(v)
were not intended to be a complete list
or to limit the subgroups for which data
should be submitted. In 1988, in a
guideline entitled, ‘‘Guideline for the
Format and Content of the Clinical and
Statistical Sections of New Drug
Applications,’’ FDA discussed analyses
of population subsets within NDA data
bases to look for differences in
effectiveness and adverse reactions to
drugs. The guideline describes the
population subsets to include subsets
such as different genders, age groups,
and races, and other subsets such as
people receiving other drug therapy and
people with concurrent illnesses. See,
‘‘Guideline for the Format and Content
of the Clinical and Statistical Sections of
New Drug Applications’’ at pages 32
and 40. The guideline describes the
need for clinical data beyond the
specific subgroups and categories of
information set forth in the current
regulations.
The current wording of § 314.50,
while not intended to limit the analyses
to be carried out does not fully reflect
the need to present the safety and
effectiveness data by subgroup and
omits important subgroups, including
gender and racial groups. The proposal
would make explicit the agency’s
requirements concerning the data that
are presented in NDA’s. It would make
clear the need to present safety and
effectiveness data by gender, age, and
racial subgroups to allow a
determination, to the extent the data
permit, of whether these factors affect
results of treatment or alter dosing
requirements.
FDA believes that it is important to
make such an explicit requirement.
After the publication of the 1988
guideline, FDA and GAO examined data
bases for NDA’s to see whether the
analyses to which the guideline refers
were being conducted and submitted.
Both of the examinations found that in
about half of the cases the data bases
were not being analyzed to determine
whether there were differences in
response to drugs between the two
genders or among different racial groups
and age groups. Thus, changes that the
proposal would make to § 314.50 would
codify what the agency has already
identified as important elements of
clinical data.
FDA also believes that to codify the
need for presentations of data by
subgroups will provide industry with
clear information regarding potential
consequences of the absence of
subgroup data. The agency’s regulation
governing the filing of an application,
which is set forth in 21 CFR 314.101,
provides that the Center for Drug
Evaluation and Research may refuse to
file an NDA that, among other things, is
not submitted in the form required
under § 314.50 or that is incomplete
because it does not on its face contain
information required under section
505(b) of the Federal Food, Drug and
Cosmetic Act. 21 CFR 314.101(d)(3).
The refusal to file policy attempts to
direct FDA’s resources to applications
complete enough for review. The
agency’s ‘‘New Drug Evaluation
Guidance Document: Refusal to File’’
describes situations in which FDA
applies the provision in § 314.101(d)(3)
to make refusal to file decisions. In
particular, the document explains that
omission of critical data, information or
analyses needed to evaluate
effectiveness and safety or provide
adequate directions for use is an
appropriate basis for a refusal to file.
Among the particular considerations in
refusal to file decisions is a ‘‘clearly
inadequate evaluation for safety and/or
effectiveness of the population intended
to use the drug, including pertinent
subsets, such as gender, age, and racial
subsets.’’ Thus, the proposal would
allow sponsors to know from the
beginning that data that are not
presented with regard to gender, age,
and racial groups are grounds for a
refusal to file.
It is important to note that the rule
does not address the requirements for
the conduct of clinical studies and that
this proposal would not require
sponsors to conduct any more studies
than they have already conducted. It
also does not require the inclusion of
particular numbers of individuals from
specific subgroups in any study or
overall. The rule refers only to the
presentation of data already collected.
The scope of this proposal does not
extend to requiring additional studies or
data.
Environmental Impact
The agency has determined under 21
CFR 25.24(a)(8) that this action is of a
46796 Federal Register / Vol. 60, No. 174 / Friday, September 8, 1995 / Proposed Rules
type that does not individually or
cumulatively have a significant effect on
the human environment. Therefore,
neither an environmental assessment
nor an environmental impact statement
is required.
Paperwork Reduction Act of 1980
This proposed rule contains
information collections which are
subject to review by the Office of
Management and Budget (OMB) under
the Paperwork Reduction Act of 1980.
The title, description, and respondent
description of the information collection
are shown below with an estimate of the
annual reporting and recordkeeping
burden. Included in the estimate is the
time for reviewing instructions,
searching existing data sources,
gathering and maintaining the data
needed, and completing and reviewing
the collection of information.
Title: Investigational New Drug
Applications and New Drug
Applications.
Description: The information
submitted by respondents pursuant to
the proposed regulatory revisions would
assist the agency in monitoring the
success of drug companies in enrolling
in clinical drug trials subjects
representing various subgroups of the
population expected to use the drug
being tested once it is approved and
marketed and in better evaluating the
safety and efficacy profiles of drugs for
various subgroups.
Description of respondents:
Businesses, nonprofit institutions, small
businesses.
Section Annual number ofrespondents Annual frequency
Average burden per
response Annual burden hours
312.33(a)(2) ........................................................ 1,616 (noncommer-
cial)...................
1 ................................... 2 hours ................... 3,232
312.33(a)(2) ........................................................ 362 (commercial) .. 1 ................................... 8 hours ................... 2,896
314.50 ................................................................. 50 .......................... 1 ................................... 40 hours ................. 2,000
Total .................................................................... ................................ ...................................... ................................ 8,128
The agency has submitted a copy of
this proposed rule to OMB for review of
these information collections. Send
comments regarding this burden
estimate or any other aspect of this
collection of information, including
suggestions for reducing this burden, to
FDA’s Dockets Management Branch
(address above) and to the Office of
Information and Regulatory Affairs,
OMB, Washington, DC 20503.
Analysis of Impacts
FDA has examined the impacts of the
proposed rule under Executive Order
12866 and the Regulatory Flexibility Act
(Pub. L. 96–354). Executive Order 12866
directs agencies to assess all costs and
benefits of available regulatory
alternatives and, when regulation is
necessary, to select regulatory
approaches that maximize net benefits
(including potential economic,
environmental, public health and safety,
and other advantages; distributive
impacts; and equity). The agency
believes that this proposed rule is
consistent with the regulatory
philosophy and principles identified in
the Executive Order. The proposed rule
does not require any change in the
studies a drug manufacturer needs to
conduct or impose any requirements on
the conduct of those studies. It requires
only a presentation of data already
collected. In addition, the proposed rule
is not a significant regulatory action as
defined by the Executive Order and so
is not subject to review under the
Executive Order.
This proposed rule would amend the
IND regulations to enable FDA and
sponsors of drugs, including biological
products, to monitor the sponsor’s
success in studying the populations that
are likely to receive the drug once it is
approved. Under the current IND
regulations in § 312.33(a)(2) (21 CFR
312.33(a)(2)), sponsors are required to
submit an annual report that includes
for each study, among other things,
‘‘The total number of subjects initially
planned for inclusion in the study, the
number entered into the study to date,
the number whose participation in the
study was completed as planned, and
the number who dropped out of the
study for any reason.’’ The proposed
rule would amend § 312.33(a)(2) to
require that the annual report include
the number of subjects entered into the
study ‘‘characterized by age group,
gender, and race.’’ Reporting and
reviewing this information would not
itself represent a need for new studies
or patients. The agency is aware that
many clinical trials do not contain
enough patients from various subgroups
to perform statistically rigorous
comparisons of outcomes between
subgroups. The Regulatory Flexibility
Act requires agencies to analyze
regulatory options that would minimize
any significant impact of a rule on small
entities. The agency certifies that the
proposed rule will not have a significant
economic impact on a substantial
number of small entities. Therefore,
under the Regulatory Flexibility Act, no
further analysis is required.
Request for Comments
Interested persons may, on or before
December 7, 1995, submit to the Dockets
Management Branch (address above)
written comments regarding this
proposal. Two copies of any comments
are to be submitted, except that
individuals may submit one copy.
Comments are to be identified with the
docket number found in brackets in the
heading of this document. Received
comments may be seen in the office
above between 9 a.m. and 4 p.m.,
Monday through Friday.
List of Subjects
21 CFR Part 312
Drugs, Exports, Imports,
Investigations, Labeling, Medical
research, Reporting and recordkeeping
requirements, Safety.
21 CFR Part 314
Administrative practice and
procedure, Confidential business
information, Drugs, Reporting and
recordkeeping requirements.
Therefore, under the Federal Food,
Drug, and Cosmetic Act, the Public
Health Service Act, and under authority
delegated to the Commissioner of Food
and Drugs, it is proposed that 21 CFR
parts 312 and 314 be amended to read
as follows:
PART 312—INVESTIGATIONAL NEW
DRUG APPLICATION
1. The authority citation for 21 CFR
part 312 continues to read as follows:
Authority: Secs. 201, 301, 501, 502, 503,
505, 506, 507, 701 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321, 331, 351,
352, 353, 355, 356, 357, 371); sec. 351 of the
Public Health Service Act (42 U.S.C. 262).
46797Federal Register / Vol. 60, No. 174 / Friday, September 8, 1995 / Proposed Rules
2. Section 312.33 is amended by
revising paragraph (a)(2) to read as
follows:
§ 312.33 Annual reports.
* * * * *
(a) * * *
(2) The total number of subjects
initially planned for inclusion in the
study; the number entered into the
study to date, characterized by age
group, gender, and race; the number
whose participation in the study was
completed as planned; and the number
who dropped out of the study for any
reason.
* * * * *
PART 314—APPLICATIONS FOR FDA
APPROVAL TO MARKET A NEW DRUG
OR AN ANTIBIOTIC DRUG
3. The authority citation for 21 CFR
part 314 continues to read as follows:
Authority: Secs. 201, 301, 501, 502, 503,
505, 506, 507, 701, 704, 721 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321,
331, 351, 352, 353, 355, 356, 357, 371, 374,
379e).
4. Section 314.50 is amended by
revising the second sentence and adding
two new sentences after the second
sentence in paragraph (d)(5)(v) and by
adding two new sentences after the first
sentence in paragraph (d)(5)(vi)(a) to
read as follows:
§ 314.50 Content and format of an
application.
* * * * *
(d) * * *
(5) * * *
(v) * * * Evidence is also required to
support the dosage and administration
section of the labeling, including
support for the dosage and dose interval
recommended. The effectiveness data
shall be presented by gender, age, and
racial subgroups. Effectiveness data
from other subgroups of the population
of patients treated, as appropriate, such
as patients with renal failure or patients
with different levels of severity of
disease, shall also be presented.
(vi) * * *
(a) * * * The safety data shall be
presented by gender, age, and racial
subgroups. Safety data from other
subgroups of the population of patients
treated, as appropriate, such as patients
with renal failure or patients with
different levels of severity of disease,
shall also be presented. * * *
* * * * *
Dated: July 11, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95–22297 Filed 9–7–95; 8:45 am]
BILLING CODE 4160–01–F
DEPARTMENT OF LABOR
Wage and Hour Division
29 CFR Part 552
RIN 1215–AA82
Application of the Fair Labor
Standards Act to Domestic Service
AGENCY: Wage and Hour Division,
Employment Standards Administration,
Labor.
ACTION: Proposed rule; reopening and
extension of comment period.
SUMMARY: This document reopens and
extends the period for filing written
comments on a proposed revision to
§ 552.109 of Regulations, 29 CFR part
552, which was published in the
Federal Register on December 30, 1993
(58 FR 69310), to clarify the minimum
wage and overtime exemption under the
Fair Labor Standards Act (FLSA) for
certain employees of third-party
employers who provide domestic
companionship services. The
Department is continuing to consider
this particular proposal, and this action
is taken in order to obtain additional
comments from interested parties. A
separate final rule published elsewhere
in this issue amends 29 CFR part 552 to
incorporate changes necessitated by
amendments to Title II of the Social
Security Act, which were enacted
October 22, 1994, as Pub. L. 103–387
(Social Security Domestic Employment
Reform Act), and makes other updating
and technical revisions as proposed in
the notice of December 30, 1993.
DATES: Comments are due on or before
November 7, 1995.
FOR FURTHER INFORMATION CONTACT:
Richard M. Brennan, Acting Director,
Division of Policy and Analysis, Wage
and Hour Division, Employment
Standards Administration, U.S.
Department of Labor, Room S–3506, 200
Constitution Avenue NW., Washington,
DC 20210, (202) 219–8412. This is not
a toll-free number.
SUPPLEMENTARY INFORMATION: The Fair
Labor Standards Act of 1938 (52 Stat.
1060, as amended; 29 U.S.C. 201 et
seq.), as amended by the Fair Labor
Standards Amendments of 1974 (Pub. L.
93–259, 88 Stat. 55), extended with
certain exceptions the FLSA’s minimum
wage, overtime pay, and recordkeeping
provisions to domestic service
employees whose compensation for
services would constitute wages under
section 209(g) of Title II of the Social
Security Act, or who are employed by
one or more employers for more than 8
hours in the aggregate in any workweek.
Section 13(a)(15) of the FLSA provides
an exemption from the minimum wage
and overtime pay requirements of the
Act for ‘‘employees employed on a
casual basis in domestic service
employment to provide babysitting
services,’’ and for domestic service
employees employed ‘‘to provide
companionship services for individuals
who * * * are unable to care for
themselves.’’ Section 13(b)(21) provides
an overtime exemption for domestic
service employees who reside in the
household in which they are employed.
On February 20, 1975, regulations and
interpretations implementing the
domestic service employment
provisions of the FLSA were published
in the Federal Register (40 FR 7405) at
29 CFR part 552.
The Department published a notice of
proposed rulemaking in the Federal
Register on December 30, 1993 (58 FR
69310), inviting public comments until
February 28, 1994, which, among other
things, would revise § 552.109 to clarify
that, in order for the exemptions in
FLSA sections 13(a)(15) and 13(b)(21) to
apply, employees engaged in providing
companionship services and live-in
domestic service employees who are
employed by a third-party employer or
agency must also be ‘‘jointly’’ employed
by the family or household using their
services. In addition, the Department
invited public comments on certain
updating and technical changes to 29
CFR part 552.
The Department proposed to revise
§ 552.109 to provide, consistent with
rulings of the Wage-Hour Administrator,
that companions and live-in domestics
employed by third-party employers are
eligible for the exemptions in FLSA
sections 13(a)(15) and 13(b)(21) only
where the individuals are also
employed by the family or household
using their services. This clarification
was considered necessary in order to
make the underlying definition of
‘‘domestic service employees’’ (i.e.,
someone who performs services of a
household nature ‘‘in or about a private
home * * * of the person by whom he
or she is employed * * *’’) at § 552.101
internally consistent with § 552.109,
applicable to domestic service
employees who provide
‘‘companionship services.’’
A total of 7 comments were received
in response to the notice. All focused
their remarks on the proposed revision