Prescription Drugs: FDA Guidance and Regulations Related to Data 
on Elderly Persons in Clinical Drug Trials (28-SEP-07,		 
GAO-07-47R).							 3
                                                                 
Elderly persons use drugs at a higher rate than younger persons, 
in part because elderly persons experience higher rates of	 
certain diseases--such as cancer, Parkinson's disease, and heart 
disorders. Elderly persons--those age 65 and older--are also more
likely than younger adults to experience complications when	 
taking some prescription drugs. For example, because of their	 
decreased liver and kidney functions, elderly persons often lack 
the ability to eliminate drugs from their bodies as efficiently  
as younger adults, making elderly persons more likely to	 
experience side effects associated with drugs. As a result, the  
Food and Drug Administration (FDA) has noted that it is important
that drugs be studied for use by elderly persons during the	 
clinical drug trials--that is, those drug studies conducted by	 
drug sponsors before they submit an application to have a drug	 
approved for marketing. FDA is responsible for oversight of	 
clinical drug trials and deciding whether to approve new drugs	 
for marketing in the United States. This responsibility includes 
determining if drugs are safe and effective for the people	 
expected to use them, including elderly persons. To implement its
responsibilities, FDA issues guidance and regulations for drug	 
sponsors on conducting clinical drug trials and submitting new	 
drug applications (NDA) to FDA to seek drug approval based in	 
part on the results of those clinical drug trials. NDAs include  
data on both the safety and effectiveness of the drug being	 
studied. FDA guidance describes the process FDA medical officers 
(typically doctors) are to follow in reviewing those NDAs as part
of the NDA review process and recommending whether to approve a  
new drug for marketing in the United States. As part of the	 
process by which drugs are considered for approval, medical	 
officers also meet in teams with supervisors and other experts,  
including biochemists and statisticians, to discuss the merits of
the NDA. Concerns have been raised about the inclusion of elderly
persons in clinical drug trials.7 You asked us to examine FDA's  
activities related to data reported about elderly persons in the 
study of new drugs. In this report, we examine FDA's guidance and
regulations related to (1) drug sponsors' reporting of data to	 
FDA to describe the effects of a proposed drug on elderly persons
and (2) FDA medical officers' review of safety and effectiveness 
data that drug sponsors provided for elderly persons. Assessing  
whether a drug is safe and effective for use by elderly persons  
requires that a sufficient number of elderly persons be included 
in clinical drug trials. As the number of elderly participants in
clinical drug trials increases, the ability of drug sponsors to  
detect responses unique to elderly persons for a given safety or 
effectiveness outcome also increases. Failing to include	 
sufficient numbers of elderly persons in clinical drug trials may
make it less likely that safety concerns and effectiveness	 
outcomes unique to elderly persons will be detected during the	 
clinical drug trials. FDA's guidance recommends that drug	 
sponsors not exclude elderly persons from clinical drug trials on
the basis of their age alone because such exclusions might	 
prevent drug sponsors from collecting sufficient information	 
about the effects of drugs in elderly persons.20 Instead, the	 
guidance suggests that, when necessary, exclusion criteria should
focus on more relevant issues, such as either the presence of an 
illness that could make participation in the clinical drug trial 
dangerous or the person's inability to provide informed consent. 
-------------------------Indexing Terms------------------------- 
REPORTNUM:   GAO-07-47R 					        
    ACCNO:   A76812						        
  TITLE:     Prescription Drugs: FDA Guidance and Regulations Related 
to Data on Elderly Persons in Clinical Drug Trials		 
     DATE:   09/28/2007 
  SUBJECT:   Data collection					 
	     Drug treatment					 
	     Drugs						 
	     Elderly persons					 
	     Federal agencies					 
	     Pharmacological research				 
	     Physicians 					 
	     Product safety					 
	     Regulatory agencies				 
	     Reporting requirements				 
	     Safety regulation					 
	     Trials						 

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GAO-07-47R

   

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September 28, 2007

The Honorable Edward M. Kennedy
Chairman
Committee on Health, Education, Labor, and Pensions
United States Senate

The Honorable Henry A. Waxman
Chairman
Committee on Oversight and Government Reform
House of Representatives

Subject: Prescription Drugs: FDA Guidance and Regulations Related to Data
on Elderly Persons in Clinical Drug Trials

Elderly persons use drugs at a higher rate than younger persons,^1 in part
because elderly persons experience higher rates of certain diseases--such
as cancer, Parkinson's disease, and heart disorders. Elderly
persons--those age 65 and older--are also more likely than younger adults
to experience complications when taking some prescription drugs.^2 For
example, because of their decreased liver and kidney functions, elderly
persons often lack the ability to eliminate drugs from their bodies as
efficiently as younger adults, making elderly persons more likely to
experience side effects associated with drugs. As a result, the Food and
Drug Administration (FDA) has noted that it is important that drugs be
studied for use by elderly persons during the clinical drug trials^3--that
is, those drug studies conducted by drug sponsors before they submit an
application to have a drug approved for marketing.^4

^1National Center for Health Statistics, Health, United States, 2006 With
Chartbook on Trends in the Health of Americans (Hyattsville, Md.: 2006).

^2For purposes of geriatric drug labeling, the Food and Drug
Administration has defined the geriatric or elderly population as persons
age 65 and older. 62 Fed. Reg. 45313, 45316, 45325 (Aug. 27, 1997)
(codified at 21 C.F.R. S 201.57(c)(9)(v) (2007)).

^3Clinical drug trials are the studies conducted to demonstrate the safety
and effectiveness of drugs in humans. Clinical drug trials generally
include persons being treated with the drug against a comparison group. A
comparison group may include participants who receive a placebo or
nontherapeutic treatment or participants who receive an alternative
therapy.

^4Drug sponsors are usually pharmaceutical companies. In addition to
pharmaceutical companies, other entities sponsoring drug development
include government agencies, health care institutions, and individual
physician investigators.

FDA is responsible for oversight of clinical drug trials and deciding
whether to approve new drugs for marketing in the United States. This
responsibility includes determining if drugs are safe and effective for
the people expected to use them, including elderly persons. To implement
its responsibilities, FDA issues guidance and regulations for drug
sponsors on conducting clinical drug trials and submitting new drug
applications (NDA) to FDA to seek drug approval based in part on the
results of those clinical drug trials.^5 NDAs include data on both the
safety and effectiveness of the drug being studied. FDA guidance describes
the process FDA medical officers (typically doctors) are to follow in
reviewing those NDAs as part of the NDA review process and recommending
whether to approve a new drug for marketing in the United States.^6 As
part of the process by which drugs are considered for approval, medical
officers also meet in teams with supervisors and other experts, including
biochemists and statisticians, to discuss the merits of the NDA.

Concerns have been raised about the inclusion of elderly persons in
clinical drug trials.^7 You asked us to examine FDA's activities related
to data reported about elderly persons in the study of new drugs. In this
report, we examine FDA's guidance and regulations related to (1) drug
sponsors' reporting of data to FDA to describe the effects of a proposed
drug on elderly persons and (2) FDA medical officers' review of safety and
effectiveness data that drug sponsors provided for elderly persons.

To examine guidance and regulations on drug sponsors' reporting of data
related to elderly persons, we reviewed FDA guidance related to the study
of drugs and the format and content of an NDA. We also examined FDA
regulations on reporting drug safety and effectiveness data by age in the
NDA and reporting data on elderly persons on the drug labeling.^8 To
determine how drug sponsors have reported data related to the guidance and
regulations, we reviewed all 36 NDAs submitted to FDA from January 1,
2001, through June 30, 2004, that FDA had reviewed and were for drugs that
are proposed to treat diseases that we determined affect elderly persons
with a disproportionately greater frequency compared to younger persons.^9
To determine the number of elderly participants associated with each NDA,
we reviewed the overall descriptions of the clinical drug trials. To
determine how drug sponsors reported safety and effectiveness data by age,
we reviewed other sections of NDA summary documents that reported the
relevant analyses.^10

^5FDA issues both guidance and regulations relevant to the study of new
drugs. Guidance describes the agency's policy on regulatory issues,
thereby suggesting ways that drug sponsors or agency officials might meet
those requirements that are specified in regulations.

^6In this report, we use the term "guidance" to mean those FDA documents
which outline procedures medical officers are to follow in their review.

^7For example, see Lilia Talarico et al., "Enrollment of Elderly Patients
in Clinical Trials for Cancer Drug Registration: A 7-Year Experience by
the US Food and Drug Administration," Journal of Clinical Oncology, vol.
22, no. 22 (2004); Susan L. Mitchell et al., "Exclusion of Elderly
Subjects from Clinical Trials for Parkinson Disease," Archives of
Neurology, vol. 54, no. 11 (1997); and Patrick Y. Lee et al.,
"Representation of Elderly Persons and Women in Published Randomized
Trials of Acute Coronary Syndromes," Journal of the American Medical
Association, vol. 286, no. 6 (2001).

^8The drug labeling includes the physician package insert, which is
designed for and directed to physicians and other health care
professionals and provides information under which practitioners licensed
by law to administer the drug can use the drug safely and for the purposes
for which it is intended (21 C.F.R. S 201.100(c)(1) (2007)). Among other
things, drug labeling also includes the label--the printed information on
the immediate container of the drug product--and the patient package
inserts, which FDA also approves, designed to instruct patients about the
safe and effective use of a drug.

To examine the guidance for medical officers' review of data on elderly
persons, we reviewed the most recent guidance (issued in 2004 and 2005)
specifically for FDA medical officers and interviewed FDA officials
responsible for overseeing the NDA review process to obtain information on
how this guidance relates to the larger NDA review process. We also
examined the FDA medical officer reviews completed for the 36 NDAs in our
sample to obtain examples of examinations related to elderly persons. (See
enc. I for a more detailed discussion of our scope and methodology.) We
conducted our work from August 2004 through September 2005, in April 2006,
and from April 2007 through September 2007, in accordance with generally
accepted government auditing standards.

Results in Brief

FDA guidance recommends that drug sponsors include elderly persons in
clinical drug trials, and FDA regulations require that the drug sponsors
report clinical drug trial data by age. The agency guidance recommends
that drug sponsors avoid excluding persons from clinical drug trials on
the basis of advanced age and offers various suggestions on how drug
sponsors should report the age of clinical drug trial participants to help
FDA determine the number of elderly participants. To identify differences
in the safety and effectiveness of a drug associated with age, FDA
regulations require that drug sponsors report clinical drug trial data by
age. For the 36 NDAs we reviewed, drug sponsors generally included elderly
persons and reported safety and effectiveness data for elderly persons in
clinical drug trials. FDA officials are developing guidance that would
combine information currently available in multiple guidance documents on
the format drug sponsors should use for reporting safety data in an NDA,
including data about age.

FDA guidance recommends that medical officers determine whether the
proposed drugs are safe and effective for the populations expected to use
them, but the guidance does not mention elderly persons specifically. FDA
officials told us that the agency expects that medical officers will
assess the safety and effectiveness of a drug for elderly persons when
they review data in an NDA; however, these expectations are not conveyed
in agency guidance. We found that about two-thirds of the medical officer
reviews we examined included a discussion by the medical officer of the
safety and effectiveness of the drug for elderly persons. However, agency
guidance does not direct medical officers to report whether sufficient
numbers of elderly persons participated in NDA clinical drug trials to
assess the safety and effectiveness of a drug for elderly persons. We
found that about one-quarter of the medical officer clinical review
summaries that we reviewed documented the medical officer's review of the
sufficiency of representation of elderly persons. FDA officials told us
that the agency's reviewers understand that the request in agency guidance
for an analysis of a drug's effects by age includes an analysis of the
drug's effects upon elderly persons. They also said that age differences
are almost always discussed during team meetings. FDA officials added that
approval recommendations are not made independently by one medical
officer, but rather result from discussions among medical officers and
others on a review team.

^9Based on information provided by FDA officials in April 2007 that
guidance and regulations related to elderly persons in clinical drug
trials had not changed since the beginning of our review, we determined
that these data were relevant for our purposes.

^10A drug sponsor sometimes used different age categories to report
summary information about participants, comparisons of safety by age, and
comparisons of effectiveness by age.

In commenting on a draft of this report, the Department of Health and
Human Services (HHS) raised three main concerns. First, HHS stated that
the draft did not completely summarize FDA's long-standing and extensive
efforts to assure reasonable representation of elderly persons in clinical
drug trials. As we noted in the draft report, FDA has made numerous
efforts related to the inclusion of elderly persons in clinical drug
trials and issued many related guidance documents. Further discussion of
these issues was beyond the scope of this report. Second, HHS stated that
we were incorrect in finding that agency guidance does not direct medical
officers to report whether sufficient numbers of elderly persons are
represented in NDA clinical drug trials. Such information is necessary for
FDA to assess the safety and effectiveness of the drug for elderly
persons. However, as we stated in the draft report and HHS noted in its
comments, sufficiency of representation is referred to in FDA guidance
using broad terms, such as "age" or "demographic subgroups," rather than
using specific ages or terms such as "elderly." Only about one-quarter of
the medical officer's clinical review summaries that we examined
documented the medical officer's review of the sufficiency of
representation of elderly persons. Third, HHS stated that we were critical
of FDA for not adequately conveying to its reviewers the agency's
expectations with regard to the need to review safety and effectiveness
data related to elderly persons. However, we found that analyses of safety
and effectiveness for elderly persons were documented in only about
two-thirds of the medical officer reviews that we examined.

Background

FDA approves prescription drugs for marketing in part based on its
determination that they are safe and effective for their intended use.
Elderly persons sometimes react to drugs differently than younger persons.
Determining safety and effectiveness for elderly persons requires that
sufficient numbers of such participants be included in clinical drug
trials. However, including elderly persons in clinical drug trials can
sometimes be challenging.

The Drug Development and Approval Process

FDA helps to ensure the safety and effectiveness of marketed drugs by
reviewing proposals for conducting clinical drug trials, reviewing drug
applications and proposed drug labeling,^11 and monitoring the safety and
effectiveness of drugs after they are marketed. Before any new drug can be
tested on people, the drug sponsor generally must submit to FDA a proposal
that, among other things, lays out a plan for how the drug will be tested
and outlines the measures that will be taken to protect clinical drug
trial participants.^12 This proposal is also required to specify criteria
that will be used to exclude persons from participating in clinical drug
trials.^13 For example, participants with other diseases or those taking
certain other medications might be excluded from a clinical drug trial.
Typically, a drug sponsor and FDA officials will have discussions about
the design of the clinical drug trials before the drug sponsor submits
this proposal.

^11In response to concerns associated with the use of drugs by elderly
persons, FDA began requiring a "geriatric use" subsection to a drug's
labeling in 1998 (62 Fed. Reg. 45313, 4325 (Aug. 27, 1997)) (codified at
21 C.F.R. S 201.57(c)(9)(v) (2007)). This subsection of the drug labeling
is where information related to a drug's safety and effectiveness for
elderly persons is included by the drug sponsor.

^12A narrow category of clinical drug trials in humans can be exempt from
this requirement. See 21 C.F.R. S 312.2(b) (2007).

To obtain approval for marketing a drug in the United States, drug
sponsors must then submit information to FDA about the completed clinical
drug trials--along with pharmacology and toxicology data, chemistry and
manufacturing data, and proposed labeling language--in the form of an NDA.
NDAs include sections summarizing safety and effectiveness data. FDA
regulations require that these sections include background information
about the clinical drug trials and summary information about their
participants--including exclusion criteria used in the clinical drug
trials--as well as evidence from clinical drug trials demonstrating that
the proposed drug is safe and effective for its intended use.^14 The NDAs
are reviewed by FDA medical officers, typically doctors, who then discuss
their reviews in teams with supervisors and other experts to help FDA
determine whether to approve a drug for marketing.

Elderly Persons in Clinical Drug Trials

Assessing whether a drug is safe and effective for use by elderly persons
requires that a sufficient number of elderly persons be included in
clinical drug trials. As the number of elderly participants in clinical
drug trials increases, the ability of drug sponsors to detect responses
unique to elderly persons for a given safety or effectiveness outcome also
increases. Failing to include sufficient numbers of elderly persons in
clinical drug trials may make it less likely that safety concerns and
effectiveness outcomes unique to elderly persons will be detected during
the clinical drug trials.

A variety of factors make it difficult to include elderly persons in
clinical drug trials. For example, elderly persons are more likely than
younger persons to use multiple medications or have multiple diseases,
which might preclude their participation in a clinical drug trial because
these factors can confound the interpretation of the clinical drug trial
results.^15 Another challenge to including elderly persons in clinical
drug trials is that some physicians might not refer elderly persons to
clinical drug trials because they believe that elderly persons may be less
likely than younger adults to tolerate or benefit from new drug
therapies.^16 Elderly persons might also avoid clinical drug trials if
they believe the treatment would not benefit them or if they are concerned
about the toxicity of the treatment.^17

^1321 C.F.R. S 312.23(a)(6)(iii)(c) (2007).

^14See for example, 21 C.F.R. S 314.50(d)(5) (2007).

^15Institute of Medicine, Pharmacokinetics and Drug Interactions in the
Elderly and Special Issues in Elderly African-American Populations
(Washington, D.C.: 1997).

^16Edward L. Trimble et al., "Representation of Older Patients in Cancer
Treatment Trials," Cancer Supplement, vol. 74, no. 7 (1994).

^17Joy H. Lewis et al., "Participation of Patients 65 Years of Age or
Older in Cancer Clinical Trials," Journal of Clinical Oncology, vol. 21,
no. 7 (2003), and Trimble et al., "Representation of Older Patients in
Cancer Treatment Trials."

Elderly persons may also have difficulty accessing clinical drug trials.
For example, elderly persons are more likely than younger adults to be
affected by dementia and other cognitive impairments that can impede drug
sponsors' ability to obtain their informed consent, which is necessary for
participation in clinical drug trials.^18 Elderly persons also may not
want to or be able to participate in clinical drug trials. For example,
participants in clinical drug trials may have to visit the doctor more
often than they otherwise would, and elderly persons may have difficulty
traveling to clinic appointments or may not be able to afford the
necessary transportation costs.^19

FDA's guidance recommends that drug sponsors not exclude elderly persons
from clinical drug trials on the basis of their age alone because such
exclusions might prevent drug sponsors from collecting sufficient
information about the effects of drugs in elderly persons.^20 Instead, the
guidance suggests that, when necessary, exclusion criteria should focus on
more relevant issues, such as either the presence of an illness that could
make participation in the clinical drug trial dangerous or the person's
inability to provide informed consent.

FDA Guidance Encourages Inclusion of Elderly Persons, and Regulations
Require That Drug Sponsors Report Clinical Drug Trial Data by Age

FDA guidance recommends that drug sponsors include elderly persons in
clinical drug trials, and FDA regulations require that the drug sponsors
report clinical drug trial data by age. Agency guidance recommends that
drug sponsors avoid excluding persons on the basis of advanced age. To
help FDA determine the number of elderly persons in clinical drug trials,
agency guidance also recommends how drug sponsors should report the age of
clinical drug trial participants in their NDAs and the various formats
that drug sponsors can use to report this information. For example, FDA
recommended in its current guidance on the format of a drug application,
issued in 1988, various ways that drug sponsors could report the age of
participants, including the average age, the ages of the youngest and
oldest participants (the age range), and the number of participants who
fall into specific age categories.^21 In addition, FDA encourages meetings
between drug sponsors and FDA officials prior to the submission of an NDA
that may include discussions of the best approach for presenting and
formatting data in the NDA.

^18Institute of Medicine, Pharmacokinetics and Drug Interactions in the
Elderly and Special Issues in Elderly African-American Populations.

^19Erin L. Cassidy, E. Baird, and Javaid I. Sheikh, "Recruitment and
Retention of Elderly Patients in Clinical Trials," American Journal of
Geriatric Psychiatry, vol. 9, no. 2 (2001), and M. Margaret Kemeny et al.,
"Barriers to Clinical Trial Participation by Older Women With Breast
Cancer," Journal of Clinical Oncology, vol. 21, no. 12 (2003).

^20Food and Drug Administration, Guideline for the Study of Drugs Likely
to be Used in the Elderly (Rockville, Md.: November 1989), and Studies in
Support of Special Populations: Geriatrics (Rockville, Md.: August 1994).

^21Food and Drug Administration, Guideline for the Format and Content of
the Clinical and Statistical Sections of an Application (Rockville, Md.:
July 1988).

Based on summary information about the participants, we found that elderly
persons were included in at least one clinical drug trial supporting each
of the 36 NDAs we reviewed.^22 For 28 NDAs, we were able to determine the
number of elderly participants in at least one of the clinical drug
trials. In the remaining 8 NDAs, we could not determine the exact number
of elderly participants in any of the clinical drug trials because of the
way that drug sponsors sometimes reported age data in the NDA (see enc.
II). For example, an NDA may have reported only the age range of
participants--such as from 18 through 91--rather than using the age
category of 65 and older. This would indicate that there was at least one
elderly person, but precluded us from determining the exact number of
elderly participants.

FDA issued regulations in 1998 to require that drug sponsors report data
from clinical drug trials that would identify differences in safety and
effectiveness associated with age.^23 FDA has not developed guidance
specifically including categories for elderly persons in these age
comparisons, but FDA officials told us that drug sponsors know that age
comparisons would include elderly persons and that elderly is defined as
age 65 and older.^24 FDA officials are developing guidance that would
combine information currently available in multiple guidance documents on
the format drug sponsors should use for reporting safety data in an NDA,
including data about age. In our review of 36 NDAs, we found that most
drug sponsors used the age category of 65 and older when reporting on a
drug's safety and effectiveness by age (see enc. III).^25

FDA Expectations That Medical Officers Review Safety and Effectiveness
Data Related to Elderly Persons Are Not Conveyed in Agency Guidance

FDA expectations that medical officers review safety and effectiveness
data related to elderly persons are not conveyed in agency guidance. FDA's
guidance for evaluating safety and effectiveness refers to age subgroups
broadly.^26 For example, FDA guidance states that it may be appropriate to
examine whether there are differences in the safety and effectiveness of
drugs between demographic subgroups, such as "old" and "young"
participants. Guidance also specifies that the medical officers' clinical
review summaries should include an examination of safety and effectiveness
data among clinical drug trial participants in various subgroups--such as
age, gender, and race. In contrast, FDA guidance is more specific in its
references to other demographic subgroups. For example, one guidance
document dedicates specific subsections to how medical officers should
include in their summaries examinations of data on the possible effects a
drug may have for pregnant women and for children, but there is no similar
subsection for elderly persons.^27

^22NDAs often include data from more than one clinical drug trial.

^2363 Fed. Reg. 6854, 6862 (Feb. 11, 1998) (codified at 21 C.F.R. S
314.50(d)(5)(v), (vi)(a); S 312.33(a)(2) (2007)).

^24The preamble to the regulation states that, for the purposes of
geriatric labeling, FDA has previously defined the "elderly" as persons
age 65 years and older and recommends that drug sponsors use that
definition for analysis of safety and effectiveness data for elderly
persons (see 63 Fed. Reg. 6854, 6859 (Feb. 11, 1998)).

^25A drug sponsor sometimes used different age categories to report
summary information about participants, comparisons of safety by age, and
comparisons of effectiveness by age. As a result, the number of NDAs for
which we could determine the number of elderly participants varies
according to the data reported in each NDA.

^26FDA guidance documents for medical officers include a Clinical Review
Template, introduced in July 2004, and guidance for reviewing NDA safety
data, introduced in 2005. Agency officials told us that they intend to
develop additional guidance specifically for the review of effectiveness
studies. FDA guidance also includes Food and Drug Administration, Reviewer
Guidance: Conducting a Clinical Safety Review of a New Product Application
and Preparing a Report on the Review (Rockville, Md.: February 2005).

FDA officials responsible for overseeing the NDA review process told us
that they believe that the agency's reviewers understand that FDA guidance
calling for an analysis of age, or information on special populations or
demographic subgroups, also applies to elderly persons. Agency officials
added that age-related differences are almost always part of the team
discussions about NDAs held by medical officers when deciding whether to
recommend a drug for approval. We found that about two-thirds of the
medical officer reviews of the 36 NDAs that we examined included
documentation of the medical officer's review of safety or effectiveness
data for persons age 65 and older.

FDA guidance does not suggest that medical officers determine whether
sufficient numbers of elderly persons participated in NDA clinical drug
trials, in order for FDA to assess the safety and effectiveness of the
drug for elderly persons. Further, FDA guidance does not suggest that they
document in their clinical review summaries the methods they used to
determine whether sufficient numbers of elderly persons participated in
NDA clinical drug trials. We found that about one-quarter of the medical
officer clinical review summaries that we reviewed documented the medical
officer's review of the sufficiency of representation of elderly persons.
None of these medical officer reviews documented the methods used by
medical officers to make a determination of sufficiency. Nevertheless, FDA
officials told us that medical officers routinely make such
determinations. FDA officials told us that medical officers discuss their
reviews in team meetings and that medical officers may conduct additional
meetings to discuss the content of NDAs. Agency officials added that
age-related differences are almost always part of the discussions within
medical review teams that are held as part of the drug approval process.

Agency Comments and Our Evaluation

We provided a draft of this report to HHS for comment. In its comments,
HHS raised three principal concerns. First, HHS stated that the draft did
not completely summarize FDA's long-standing and extensive efforts to
assure reasonable representation of elderly persons in clinical drug
trials. Second, HHS stated that we were incorrect in finding that agency
guidance does not direct medical officers to report whether sufficient
numbers of elderly persons participated in NDA clinical drug trials. Such
information is necessary for FDA to assess the safety and effectiveness of
the drug for elderly persons. Third, HHS stated that we were critical of
FDA for not adequately conveying to its reviewers the agency's
expectations with regard to the need to review safety and effectiveness
data related to elderly persons and that they disagreed with this
criticism.

As we noted in the draft report, FDA has made numerous efforts related to
the inclusion of elderly persons in clinical drug trials and issued many
related guidance documents. Providing a detailed history of FDA's work in
this area was beyond the scope of this report.

^27FDA's guidance includes a subsection where medical officers should
report any available information on drug exposure to pregnant women and a
subsection that should discuss the drug's effects on growth in children,
including the measurement of height and weight, the measurement
methodology used, and adjustments for children's age and gender, as
appropriate.

In its comments, HHS referred to FDA's guidance--the Clinical Review
Template and its 2005 clinical safety review guidance--which HHS stated
directs medical officers to report whether sufficient numbers of elderly
persons participated in NDA clinical drug trials. However, all of the
agency's examples illustrate the broad references found in FDA guidance,
such as "population studied," "special populations," "appropriate
demographic subsets of patients," "various demographic subjects," and
"age." They do not refer specifically to any age group or terms such as
"elderly." FDA officials have told us, and the HHS comments stated, that
medical officers know that all of the references refer to elderly persons
and that age is always considered a pertinent demographic subset and is
explicitly stated in many places in its 2005 clinical safety review
guidance. In our examination of the guidance, however, we found that none
of the references to elderly persons applied specifically to determining
their sufficiency of representation and where sufficiency of
representation is referred to, only the broader terms, such as "age" or
"demographic subgroups" are used. Further, as we stated in the draft
report, only about one-quarter of the medical officer clinical review
summaries that we examined documented the medical officer's review of the
sufficiency of representation of elderly persons. In its comments, HHS
said that FDA guidance on the clinical safety review includes a suggested
table format for medical officers to use in describing the participants in
the clinical drug trials. While this table suggests that the medical
officers report the number of elderly persons included in the clinical
drug trials, it is not a format for reporting a medical officer's findings
related to whether sufficient numbers of elderly persons were included in
the clinical drug trials.

HHS commented that age references related to the review of the safety and
effectiveness data clearly refer to elderly persons. While we stated in
the draft report that issues pertinent to elderly persons may be discussed
among reviewers, even if they are not mentioned in the written reviews, we
found that analyses of safety and effectiveness for elderly persons were
only documented in about two-thirds of the medical officer reviews that we
examined. Moreover, while FDA developed a regulation requiring that drug
sponsors report safety and effectiveness data by age, we found that drug
sponsors used a variety of age categories to report these data and note
that the agency has not provided guidance to its reviewers regarding their
review of these data.

HHS also noted that not all of the references cited in one footnote
referred to clinical drug trials specifically supporting NDAs. We agree
and deleted the reference to NDAs in the footnoted sentence. Finally, HHS
asserted that the adverse events associated with a nonsteroidal
anti-inflammatory drug referred to in our draft report would not likely
have been revealed during clinical drug trials even if more elderly
persons had been studied. We deleted this example from the report.

HHS's written comments are reprinted in enclosure IV. We incorporated
technical comments as appropriate.

                                   - - - - -

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listed in enclosure V.

Marcia Crosse
Director, Health Care

Enclosures - 5

Enclosure I

                             Scope and Methodology

This report examines the Food and Drug Administration's (FDA) guidance and
regulations related to (1) drug sponsors' reporting of data to describe
the effects of a proposed drug on elderly persons and (2) FDA medical
officers' review of safety and effectiveness data that drug sponsors
provided for elderly persons.

To examine guidance and regulations on drug sponsors' reporting of data
related to elderly persons, we examined FDA regulations about the study of
the safety and effectiveness of drugs by age and about labeling
information about the use of a drug by elderly persons. We also reviewed
FDA guidance related to the study of drugs in general, the study of drugs
likely to be used by elderly persons, and the format and content of a new
drug application (NDA). To determine how drug sponsors have reported data
related to the guidance and regulations, we reviewed all 36 NDAs submitted
to FDA from January 1, 2001, through June 30, 2004, that FDA had reviewed
and that were for drugs proposed to treat diseases that we determined
affect elderly persons with a disproportionately greater frequency than
younger persons.^28 For each of the 36 NDAs in our sample, we reviewed the
Integrated Summary of Safety and the Integrated Summary of Efficacy that
each drug sponsor included in its initial NDA submission to FDA. We
determined that the data reported in the NDA summary documents were
sufficiently reliable for the purposes of this report.^29 To determine the
number of elderly participants associated with each NDA, we reviewed the
overall descriptions of the clinical drug trials. To determine how drug
sponsors reported safety and effectiveness data by age, we reviewed other
sections of NDA summary documents that reported the relevant analyses.^30
We did not examine other information in the drug application.

In our review of these summary sections, we collected age of participants
and other data from each NDA. Where possible, we categorized the
participants from each clinical drug trial into two age
categories--younger than age 65 and age 65 and older. We selected these
age groups because they are identified in both FDA's guidance for drug
sponsors and the preamble to the 1998 regulations.^31 If an NDA did not
report the number of clinical drug trial participants in specific
categories or even these broad age categories, we determined that we were
unable to categorize the age of the participants.

^28Using data from the National Ambulatory Medical Care Survey (National
Center for Health Statistics, National Ambulatory Medical Care Survey,
2001), we estimated the proportion of individuals 65 years and older in
the population with the disease that the drug is proposed to treat. Where
the indication proposed in the NDA was complex, we made our estimate using
the primary condition that needs to be present. For example, if a drug is
proposed to treat nausea in persons receiving chemotherapy treatment for
cancer, we would select cancer as our disease of interest. We determined
that these data were sufficiently reliable for the purposes of this report
by reviewing relevant technical documentation, including survey
methodology, weighting procedures, and code books describing the data
elements used in our analyses. Based on information provided by FDA
officials in April 2007 that guidance and regulations related to elderly
persons in clinical drug trials had not changed since the beginning of our
review, we determined that the NDAs we selected were relevant for our
purposes.

^29We assessed the reliability of the data reported in the NDA summary
documents by reviewing related documentation and interviewing agency
officials knowledgeable about the data. However, we did not confirm the
accuracy of the information contained in the summary documents.

^30A drug sponsor sometimes used different age categories to report
summary information about participants, comparisons of safety by age, and
comparisons of effectiveness by age.

^31Food and Drug Administration, Studies in Support of Special
Populations: Geriatrics (Rockville, Md.: August 1994); 63 Fed. Reg. 6859
(1998).

To examine FDA medical officers' review of data on elderly persons, we
reviewed the most recent guidance (issued in 2004 and 2005) specifically
for medical officers and interviewed FDA officials responsible for
overseeing the NDA review process to obtain information on how this
guidance relates to the larger NDA review process. We also examined the
FDA medical officer reviews completed for the 36 NDAs in our sample to
obtain documentation of examinations conducted by FDA medical officers
related to elderly persons. We did not observe any of the team meetings in
which medical officers and others discussed the merits of each NDA.

We conducted our work from August 2004 through September 2005, in April
2006, and from April 2007 through September 2007, in accordance with
generally accepted government auditing standards.

Enclosure II

Data Provided to FDA by Drug Sponsors on Elderly Persons in Clinical Drug Trials
        for 36 NDAs Submitted to FDA from January 2001 through June 2004

Elderly persons were included in at least one clinical drug trial
supporting each of the 36 NDAs we reviewed, though some of the trials for
these NDAs excluded elderly persons on the basis of age alone.^32 Drug
sponsors reported summary participant data to FDA on the number of elderly
persons in clinical drug trials supporting 28 of the 36 NDAs we examined.
For those 28 NDAs, we could determine that 33 percent of the participants
in the clinical drug trials were elderly (age 65 and older) and 65 percent
were younger than age 65, according to summary information provided by
drug sponsors in the NDA. Within these 28 NDAs, we were unable to
determine the age of the remaining 2 percent of participants because drug
sponsors did not report the age of these participants in a way that
allowed us to determine how many of them were elderly. For the remaining 8
NDAs, we could not determine the number of participants that were elderly
for any of the clinical drug trials because the necessary age data were
not reported in the NDAs. Table 1 presents the number and percentage of
clinical drug trial participants younger than age 65 and age 65 and older,
and the number and percentage of those participants for whom drug sponsors
did not provide adequate data to allow us to classify them into one of
these two age categories.^33

^32NDAs often include data from more than one clinical drug trial.

^33Within each NDA, we included participants from those clinical drug
trials for which the drug sponsor provided adequate data for us to
categorize all participants as being either younger than age 65 or age 65
and older. We classified the NDAs by disease category, using the disease
that the drug is proposed to treat, according to the broad categories of
disease defined in the International Classification of Diseases, Ninth
Revision. See Department of Health and Human Services, International
Classification of Diseases, Ninth Revision, Clinical Modification, 6th ed.
(Washington, D.C.: October 2003).

Table 1: Number of Persons Reported in NDA Clinical Drug Trials
Categorized by Age (Younger Than Age 65 or Age 65 and Older), by Disease
Category, Based on 36 NDAs Submitted to FDA from January 1, 2001, through
June 30, 2004, for the Treatment of Diseases That GAO Determined
Disproportionately Affected Elderly Persons

                                                               Persons who could
                                                                    not be
                                                                categorized as
                                                                either younger
                                                                than age 65 or
                                                               age 65 and older
                                                                   based on
                                                                information in
                                                               the background of
                          Persons younger    Persons age 65       NDA summary
                            than age 65         and older          documents
                   Total                                                         
              persons in                                                         
                clinical                                                         
                    drug                                                         
NDA, by       trials,                                                         
disease    regardless                                                         
category^a   of age^b Number Percentage  Number Percentage  Number Percentage 
Cancer                                                                        
1               4,493  3,649         81     844         19       0          0 
2               2,881  2,347         81     534         19       0          0 
3               1,468    869         59     394         27     205         14 
4               1,465      0          0       0          0   1,465        100 
5               1,249    708         57     541         43       0          0 
6               1,052    628         60     424         40       0          0 
7                 936    572         61     364         39       0          0 
8                 928    610         66     218         23     100         11 
9                 426    276         65     150         35       0          0 
10                361    133         37     222         61       6          2 
11                256      0          0       0          0     256        100 
Circulatory system                                                            
12              9,680  3,606         37   6,074         63       0          0 
13              7,105  3,357         47   3,427         48     321          5 
14              4,226  1,588         38     751         18   1,887         45 
15              3,626      0          0       0          0   3,626        100 
16              1,025    504         49     521         51       0          0 
Endocrine, nutritional, metabolic, and immunity                               
17              6,016  4,108         68   1,821         30      87          1 
18              5,056  4,476         89     580         11       0          0 
19              2,695  2,408         89     287         11       0          0 
20              1,763  1,175         67     422         24     166          9 
21                612      0          0       0          0     612        100 
Genitourinary system                                                          
22              8,100  6,158         76   1,942         24       0          0 
23              4,042  2,632         65   1,410         35       0          0 
24              2,841  1,940         68     901         32       0          0 
25              2,146  1,581         74     565         26       0          0 
Musculoskeletal system and connective                                         
tissue                                                                        
26             14,900 10,904         73   3,996         27       0          0 
27             12,911  9,028         70   3,883         30       0          0 
28              8,496      0          0       0          0   8,496        100 
Nervous system and sense organs                                               
29              2,709    646         24   2,063         76       0          0 
30              1,229    684         56     485         39      60          5 
31                290      0          0       0          0     290        100 
Other                                                                         
32              4,870  2,788         57   2,082         43       0          0 
33              3,341  2,575         77     766         23       0          0 
34              2,898      0          0       0          0   2,898        100 
35                954      0          0       0          0     954        100 
36                774    718         93      56          7       0          0 
Total         127,820 70,668         55  35,723         28  21,429         17 

Source: GAO analysis of 36 NDAs submitted to FDA.

aGAO classified the NDAs according to broad categories defined in the
International Classification of Diseases, Ninth Revision. The "other"
category combines disease categories that contained two or fewer NDAs.

bThe total number of participants excludes 29 clinical drug trial
participants from four NDAs for which the drug sponsors reported that they
were missing age data.

One factor that may have limited the representation of elderly persons in
some of the 36 NDAs we reviewed is that several clinical drug trials had
exclusion criteria prohibiting the participation of elderly persons on the
basis of their age. Clinical drug trials in 13 NDAs had exclusion criteria
that prohibited the participation of at least some elderly persons on the
basis of age alone; however, at least one clinical drug trial in all NDAs
included some elderly participants. Specifically, 3 NDAs had at least one
clinical drug trial with a criterion excluding all persons older than age
65 from participating. Drug sponsors for the other 10 NDAs had at least
one clinical drug trial that used criteria excluding a subset of elderly
persons--such as those older than age 70--from participating in their
clinical drug trials.^34 FDA officials told us that drug sponsors are
expected to justify any age cutoff that is used, just as they would any
other decisions about their research design.

^34In examining only those clinical drug trials that the drug sponsors
designated as most important to their NDAs, sponsors of seven of these
NDAs had criteria that prohibited the participation of some older persons
based on age alone.

Enclosure III

 Data Reported by Drug Sponsors to FDA on the Safety and Effectiveness of Drugs
                              for Elderly Persons

While FDA regulations require that drug sponsors present safety and
effectiveness data by age, the regulations do not define specific age
subgroups to be used, thereby leaving the selection of subgroups for
analysis to the drug sponsors.^35 For example, a drug sponsor may compare
the effect of the proposed drug on the survival rate of cancer patients
age 60 and older to its effect on the survival rate of those younger than
age 60. According to FDA officials, instead of specifying the age
categories drug sponsors must use to report data on safety and
effectiveness outcomes from their clinical drug trials, the regulations
FDA issued in 1998 were written broadly to allow drug sponsors flexibility
to report outcome data in the manner they believe to be most appropriate.
Agency officials also indicated that specific age categories, such as 65
and older, might not be appropriate for comparing safety and effectiveness
data in all clinical drug trials because a clinical drug trial may have
few or no participants in a specific age category. FDA officials also told
us that drug sponsors know that the intent of the regulations is to
encourage the examination of how elderly persons differ from younger
persons in response to the drug and that the agency learns important
information when an older age category--such as age 70 and older--is used.

In the 36 NDAs we reviewed, most drug sponsors used the age category of 65
and older when reporting data on a drug's safety and effectiveness by age.
Specifically, drug sponsors of 30 NDAs sometimes used age 65 and older as
an age category when reporting data on safety outcomes, and drug sponsors
of 26 NDAs sometimes used this age category when reporting data on
effectiveness outcomes.^36 The remaining drug sponsors either used a
different age category or did not report data by age when reporting data
on safety or effectiveness.^37

Drug sponsors are required to disclose on the drugs' labeling what they
learn from clinical drug trials about the safety and effectiveness of a
drug for elderly persons. Since 1998, FDA has required that drug sponsors
include a Geriatric Use subsection in drug labeling that conveys the
findings from the age comparisons that are reported in the NDAs and the
number of elderly persons included in that drug's clinical trials, as
appropriate.^38 The regulation provides drug sponsors with a choice of
three primary statements to be used in the Geriatric Use subsection.
First, if there have not been sufficient numbers of elderly participants
in clinical drug trials to determine whether those age 65 and over respond
differently to the drug, it should be noted in the labeling along with a
statement that dose selection for an elderly patient proceed with caution,
generally starting at the low end of the dosing range. Second, if there
have been sufficient numbers of elderly participants in clinical drug
trials to make it likely that differences in safety and effectiveness
between older and younger participants would have been detected, but no
such differences were found, it should be noted in the labeling. The
labeling should also note the percentage or total number of trial
participants who were 65 years of age and older and 75 years of age and
older. Third, if there is evidence that there are differences in safety or
effectiveness between elderly and younger participants or that elderly
persons require dosage adjustments or monitoring, it should be noted in
the labeling along with a description of these differences.

^35See 21 C.F.R. S 314.50(d)(5)(v), (vi)(a); S 312.33(a)(2) (2007).

^36A drug sponsor sometimes used different age categories to report
summary information about participants, comparisons of safety by age, and
comparisons of effectiveness by age.

^37Three NDAs did not include any effectiveness data by age and one of
these NDAs also did not report any safety data by age. With regard to the
one NDA without any safety or effectiveness data by age, the drug did not
perform successfully, and FDA did not approve the NDA. FDA officials told
us that, for the remaining two NDAs, such presentations were either
unnecessary or not possible. For one of these two, FDA officials stated
that it was not necessary for the drug sponsor to report effectiveness
data by age because all of the clinical drug trial participants were
between the ages of 55 and 80. For the remaining NDA, FDA officials told
us that because the drug sponsors studied elderly persons and younger
adults in separate clinical drug trials, the drug sponsors could not
provide such comparisons.

^3862 Fed. Reg. 45313, 45325 (Aug. 27, 1997) (codified at 21 C.F.R. S
201.57(c)(9)(v) (2007)).

In addition to the three statements provided by FDA, the regulation also
allows drug sponsors to suggest alternative statements that FDA may
approve if it determines them to be accurate and appropriate. Further, FDA
may permit omission of a Geriatric Use statement if the agency determines
that none of the statements are appropriate or relevant to a drug's
labeling. Of the 21 drug labels that had been approved through June 2004,
from our sample of 36 NDAs, we found that 15 used one of the types of
labeling statements above, while 5 used alternative statements approved by
FDA. One drug label omitted the Geriatric Use subsection.

Enclosure IV

           Comments from the Department of Health and Human Services
			  
Enclosure V			  

                     GAO Contact and Staff Acknowledgments

GAO Contact

Marcia Crosse, (202) 512-7114 or [4][email protected]

Acknowledgments

In addition to the contact named above, Thomas Conahan, Assistant
Director; George Bogart; William Hadley; Cathy Hamann; Carolyn Feis
Korman; and Gloria Taylor made key contributions to this report.

(290383)

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