Prescription Drugs
FDA Guidance and Regulations Related to Data on Elderly Persons in Clinical Drug Trials Gao ID: GAO-07-47R September 28, 2007Elderly 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.
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.
GAO-07-47R, Prescription Drugs: FDA Guidance and Regulations Related to Data on Elderly Persons in Clinical Drug Trials
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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,[Footnote 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.[Footnote 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[Footnote 3]--that is,
those drug studies conducted by drug sponsors before they submit an
application to have a drug approved for marketing.[Footnote 4]
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.[Footnote 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.[Footnote 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.[Footnote 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.[Footnote 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.[Footnote 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.[Footnote 10]
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.
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,[Footnote 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.[Footnote 12] This
proposal is also required to specify criteria that will be used to
exclude persons from participating in clinical drug trials.[Footnote
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.
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.[Footnote 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.[Footnote 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.[Footnote 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.[Footnote 17]
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.[Footnote
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.[Footnote
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.[Footnote 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.[Footnote 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.
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.[Footnote 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.[Footnote 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.[Footnote 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).[Footnote 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.[Footnote 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.[Footnote 27]
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.
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.
As arranged with your offices, unless you publicly announce the
contents of this report earlier, we plan no further distribution of it
until 30 days after its issue date. At that time we will send copies of
this report to the Commissioner of the Food and Drug Administration and
other interested parties. We will also provide copies to others upon
request. In addition, the report will be available at no charge on
GAO's Web site at [hyperlink, http://www.gao.gov].
If you or your staffs have any questions about this report, please
contact me at (202) 512-7114 or crossem@gao.gov. Contact points for our
Offices of Congressional Relations and Public Affairs may be found on
the last page of this report. GAO staff who made major contributions to
this report are listed in enclosure V.
Signed by:
Marcia Crosse Director, Health Care:
Enclosures - 5:
[End of section]
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.[Footnote 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.[Footnote 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.[Footnote 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.[Footnote 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.
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.
[End of section]
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.[Footnote 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.[Footnote 33]
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:
NDA, by disease category[A]: Cancer: 1;
Total persons in clinical drug trials, regardless of age[B]: 4,493;
Persons younger than age 65: 3,649;
Persons younger than age 65: 81;
Persons age 65 and older: 844;
Persons age 65 and older: 19;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Cancer: 2;
Total persons in clinical drug trials, regardless of age[B]: 2,881;
Persons younger than age 65: 2,347;
Persons younger than age 65: 81;
Persons age 65 and older: 534;
Persons age 65 and older: 19;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Cancer: 3;
Total persons in clinical drug trials, regardless of age[B]: 1,468;
Persons younger than age 65: 869;
Persons younger than age 65: 59;
Persons age 65 and older: 394;
Persons age 65 and older: 27;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 205;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 14.
NDA, by disease category[A]: Cancer: 4;
Total persons in clinical drug trials, regardless of age[B]: 1,465;
Persons younger than age 65: 0;
Persons younger than age 65: 0;
Persons age 65 and older: 0;
Persons age 65 and older: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 1,465;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 100.
NDA, by disease category[A]: Cancer: 5;
Total persons in clinical drug trials, regardless of age[B]: 1,249;
Persons younger than age 65: 708;
Persons younger than age 65: 57;
Persons age 65 and older: 541;
Persons age 65 and older: 43;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Cancer: 6;
Total persons in clinical drug trials, regardless of age[B]: 1,052;
Persons younger than age 65: 628;
Persons younger than age 65: 60;
Persons age 65 and older: 424;
Persons age 65 and older: 40;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Cancer: 7;
Total persons in clinical drug trials, regardless of age[B]: 936;
Persons younger than age 65: 572;
Persons younger than age 65: 61;
Persons age 65 and older: 364;
Persons age 65 and older: 39;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Cancer: 8;
Total persons in clinical drug trials, regardless of age[B]: 928;
Persons younger than age 65: 610;
Persons younger than age 65: 66;
Persons age 65 and older: 218;
Persons age 65 and older: 23;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 100;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 11.
NDA, by disease category[A]: Cancer: 9;
Total persons in clinical drug trials, regardless of age[B]: 426;
Persons younger than age 65: 276;
Persons younger than age 65: 65;
Persons age 65 and older: 150;
Persons age 65 and older: 35;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Cancer: 10;
Total persons in clinical drug trials, regardless of age[B]: 361;
Persons younger than age 65: 133;
Persons younger than age 65: 37;
Persons age 65 and older: 222;
Persons age 65 and older: 61;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 6;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 2.
NDA, by disease category[A]: Cancer: 11;
Total persons in clinical drug trials, regardless of age[B]: 256;
Persons younger than age 65: 0;
Persons younger than age 65: 0;
Persons age 65 and older: 0;
Persons age 65 and older: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 256;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 100.
NDA, by disease category[A]: Circulatory system: 12;
Total persons in clinical drug trials, regardless of age[B]: 9,680;
Persons younger than age 65: 3,606;
Persons younger than age 65: 37;
Persons age 65 and older: 6,074;
Persons age 65 and older: 63;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Circulatory system: 13;
Total persons in clinical drug trials, regardless of age[B]: 7,105;
Persons younger than age 65: 3,357;
Persons younger than age 65: 47;
Persons age 65 and older: 3,427;
Persons age 65 and older: 48;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 321;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 5.
NDA, by disease category[A]: Circulatory system: 14;
Total persons in clinical drug trials, regardless of age[B]: 4,226;
Persons younger than age 65: 1,588;
Persons younger than age 65: 38;
Persons age 65 and older: 751;
Persons age 65 and older: 18;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 1,887;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 45.
NDA, by disease category[A]: Circulatory system: 15;
Total persons in clinical drug trials, regardless of age[B]: 3,626;
Persons younger than age 65: 0;
Persons younger than age 65: 0;
Persons age 65 and older: 0;
Persons age 65 and older: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 3,626;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 100.
NDA, by disease category[A]: Circulatory system: 16;
Total persons in clinical drug trials, regardless of age[B]: 1,025;
Persons younger than age 65: 504;
Persons younger than age 65: 49;
Persons age 65 and older: 521;
Persons age 65 and older: 51;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Endocrine, nutritional, metabolic, and
immunity: 17;
Total persons in clinical drug trials, regardless of age[B]: 6,016;
Persons younger than age 65: 4,108;
Persons younger than age 65: 68;
Persons age 65 and older: 1,821;
Persons age 65 and older: 30;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 87;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 1.
NDA, by disease category[A]: Endocrine, nutritional, metabolic, and
immunity: 18;
Total persons in clinical drug trials, regardless of age[B]: 5,056;
Persons younger than age 65: 4,476;
Persons younger than age 65: 89;
Persons age 65 and older: 580;
Persons age 65 and older: 11;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Endocrine, nutritional, metabolic, and
immunity: 19;
Total persons in clinical drug trials, regardless of age[B]: 2,695;
Persons younger than age 65: 2,408;
Persons younger than age 65: 89;
Persons age 65 and older: 287;
Persons age 65 and older: 11;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Endocrine, nutritional, metabolic, and
immunity: 20;
Total persons in clinical drug trials, regardless of age[B]: 1,763;
Persons younger than age 65: 1,175;
Persons younger than age 65: 67;
Persons age 65 and older: 422;
Persons age 65 and older: 24;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 166;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 9.
NDA, by disease category[A]: Endocrine, nutritional, metabolic, and
immunity: 21;
Total persons in clinical drug trials, regardless of age[B]: 612;
Persons younger than age 65: 0;
Persons younger than age 65: 0;
Persons age 65 and older: 0;
Persons age 65 and older: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 612;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 100.
NDA, by disease category[A]: Genitourinary system: 22;
Total persons in clinical drug trials, regardless of age[B]: 8,100;
Persons younger than age 65: 6,158;
Persons younger than age 65: 76;
Persons age 65 and older: 1,942;
Persons age 65 and older: 24;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Genitourinary system: 23;
Total persons in clinical drug trials, regardless of age[B]: 4,042;
Persons younger than age 65: 2,632;
Persons younger than age 65: 65;
Persons age 65 and older: 1,410;
Persons age 65 and older: 35;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Genitourinary system: 24;
Total persons in clinical drug trials, regardless of age[B]: 2,841;
Persons younger than age 65: 1,940;
Persons younger than age 65: 68;
Persons age 65 and older: 901;
Persons age 65 and older: 32;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Genitourinary system: 25;
Total persons in clinical drug trials, regardless of age[B]: 2,146;
Persons younger than age 65: 1,581;
Persons younger than age 65: 74;
Persons age 65 and older: 565;
Persons age 65 and older: 26;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Musculoskeletal system and connective
tissue: 26;
Total persons in clinical drug trials, regardless of age[B]: 14,900;
Persons younger than age 65: 10,904;
Persons younger than age 65: 73;
Persons age 65 and older: 3,996;
Persons age 65 and older: 27;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Musculoskeletal system and connective
tissue: 27;
Total persons in clinical drug trials, regardless of age[B]: 12,911;
Persons younger than age 65: 9,028;
Persons younger than age 65: 70;
Persons age 65 and older: 3,883;
Persons age 65 and older: 30;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Musculoskeletal system and connective
tissue: 28;
Total persons in clinical drug trials, regardless of age[B]: 8,496;
Persons younger than age 65: 0;
Persons younger than age 65: 0;
Persons age 65 and older: 0;
Persons age 65 and older: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 8,496;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 100.
NDA, by disease category[A]: Nervous system and sense organs: 29;
Total persons in clinical drug trials, regardless of age[B]: 2,709;
Persons younger than age 65: 646;
Persons younger than age 65: 24;
Persons age 65 and older: 2,063;
Persons age 65 and older: 76;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: 30;
Total persons in clinical drug trials, regardless of age[B]: 1,229;
Persons younger than age 65: 684;
Persons younger than age 65: 56;
Persons age 65 and older: 485;
Persons age 65 and older: 39;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 60;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 5.
NDA, by disease category[A]: Nervous system and sense organs: 31;
Total persons in clinical drug trials, regardless of age[B]: 290;
Persons younger than age 65: 0;
Persons younger than age 65: 0;
Persons age 65 and older: 0;
Persons age 65 and older: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 290; Persons who could not be categorized as either younger
than age 65 or age 65 and older based on information in the background
of NDA summary documents: 100.
NDA, by disease category[A]: Other: 32;
Total persons in clinical drug trials, regardless of age[B]: 4,870;
Persons younger than age 65: 2,788;
Persons younger than age 65: 57;
Persons age 65 and older: 2,082;
Persons age 65 and older: 43;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Other: 33;
Total persons in clinical drug trials, regardless of age[B]: 3,341;
Persons younger than age 65: 2,575;
Persons younger than age 65: 77;
Persons age 65 and older: 766;
Persons age 65 and older: 23;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Other: 34;
Total persons in clinical drug trials, regardless of age[B]: 2,898;
Persons younger than age 65: 0;
Persons younger than age 65: 0;
Persons age 65 and older: 0;
Persons age 65 and older: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 2,898;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 100.
NDA, by disease category[A]: Other: 35;
Total persons in clinical drug trials, regardless of age[B]: 954;
Persons younger than age 65: 0;
Persons younger than age 65: 0;
Persons age 65 and older: 0;
Persons age 65 and older: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 954;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 100.
NDA, by disease category[A]: Other: 36;
Total persons in clinical drug trials, regardless of age[B]: 774;
Persons younger than age 65: 718;
Persons younger than age 65: 93;
Persons age 65 and older: 56;
Persons age 65 and older: 7;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 0.
NDA, by disease category[A]: Total;
Total persons in clinical drug trials, regardless of age[B]: 127,820;
Persons younger than age 65: 70,668;
Persons younger than age 65: 55;
Persons age 65 and older: 35,723;
Persons age 65 and older: 28;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 21,429;
Persons who could not be categorized as either younger than age 65 or
age 65 and older based on information in the background of NDA summary
documents: 17.
Source: GAO analysis of 36 NDAs submitted to FDA.
[A] GAO 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.
[B] The 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.
[End of table]
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.[Footnote 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.
[End of section]
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.[Footnote 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.[Footnote 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.[Footnote
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.[Footnote 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.
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.
[End of section]
Enclosure IV:
Comments from the Department of Health and Human Services:
Department Of Health & Human Services:
Office of the Assistant Secretary for Legislation:
Washington, D.C. 20201:
September 11, 2007:
Marcia Crosse:
Director, Health Care:
U.S. Government Accountability Office:
Washington, DC 20548:
Dear Ms. Crosse:
Enclosed are the Department's comments on U.S. Government
Accountability Office's (GAO) report entitled: "Prescription Drugs: FDA
Guidance and Regulations Related to Data on Elderly Persons in Clinical
Drug Trials" GAO 07-47R.
The department appreciates the opportunity to review and comment on
this report before its publication.
Sincerely,
Signed by:
R. Hemard for:
Vincent J. Ventimiglia:
Assistant Secretary for Legislation:
Comments Of The Department Of Health And Human Services On The U.S.
Government Accountability Office's Draft Report Entitled: "FDA Guidance
And Regulations Related To Data On Elderly Persons In Clinical Drug
Trials"(GAO-07-47R):
1. Overall the report acknowledges FDA's extensive efforts to assure
reasonable representation of the elderly in clinical trials and
mentions many guidances, but there is no place in the report where
FDA's long-standing (beginning in 1982) and extensive efforts in this
area are clearly and completely summarized. Such a summary would convey
the scope of FDA's efforts in this regard. It would include FDA's
Guideline for the Study of Drugs Likely to be Used in the Elderly; the
ICH Guidance on the same issue (E7: Studies in Support of Special
Populations: Geriatrics); the extensive emphasis on demographic data in
the 1988 Guideline for the Format and Content of the Clinical and
Statistical Sections of an Application; the 1998 rule requiring
demographic analysis (21 CFR 314.50(d)(v)(vi)); and the emphasis on
demographic analyses in the 2005 Reviewer Guidance: Conducting a
Clinical Safety Review of a New Product Application and Preparing a
Report on the Review, and in the review template used by clinical
reviewers on demographic subgroups, specifically including the elderly.
This summary would be helpful because these cumulative efforts show
clearly that study of the elderly has been a matter of great importance
to FDA for almost 2 decades.
The principal criticism in the report is that FDA does not adequately
convey to its reviewers the agency's expectations with regard to the
need to review safety and effectiveness data related to elderly
persons, apparently because in identifying age as a demographic
characteristic of interest, FDA does not specifically identify the
elderly as an age group of particular interest. As the report points
out, FDA disagrees with this conclusion. The agency specifically asks
reviewers to conduct demographic analyses by gender, race, and age; the
only reason for conducting these analyses is to look for differences in
effectiveness and safety in men versus women, blacks versus whites, and
old versus young, and in the last case the interest is almost always
primarily whether older people respond less well or have more adverse
effects. This interest is recognized by every reviewer and it is not
necessary to state repeatedly that our interest is in the elderly.
Moreover, there are in fact numerous explicit references in the
documents cited above to comparing safety and effectiveness in old and
young. Some of these references are listed in the comments below.
2. The draft report states on page 5 that "agency guidance does not
direct medical officers to report whether sufficient numbers of elderly
persons participated in NDA clinical drug trials." Similar language is
found on page 12.
a. In fact, the Clinical Review Template asks reviewers to consider:
Whether efficacy findings are limited by "limitations of the population
studied";
ii. Adequacy of the assessment in special populations (which always
includes the elderly);
iii. Adequacy of patient exposure in terms of "appropriate demographic
subsets of patients" (see section 7.2);
iv. Whether "adequate numbers of subjects were exposed, including
adequate numbers of various demographic subjects" and "whether patients
excluded from the study (e.g., diabetes, people over 75.) limit the
relevance of safety assessments";
v. "Explorations for drug-demographic interactions";
vi. "Special dosing instructions based on demographics: race, gender,
age for adults".
b. The Safety Review Guidance emphasizes demographic subgroups
repeatedly, e.g. in analyses of deaths (page 14), adverse drop-outs
(page 18), common adverse effects (page 24), laboratory abnormalities
(page 29). Age is always considered to be a demographic subgroup, even
if not explicitly stated as such.
c. The FDA guidance on the Clinical Safety Review (page 36)
specifically calls for showing the numbers of patients by age, gender,
and race and, in table 7.2.1.2.1 specifically shows an age > 65 row. On
page 38 the reviewer is specifically asked to address "whether an
adequate number of subjects were exposed to the drug, including
adequate numbers of various demographic subsets." Again, although GAO
is technically correct that the guidance does not specifically
reference on all occasions that age as a demographic subset, the fact
that age is always considered as a pertinent demographic subset is
entirely obvious to reviewers and is explicitly stated in many places.
3. On page 12, the draft report states that "FDA expectations that
medical officers review safety and effectiveness data related to
elderly persons are not conveyed in agency guidance," apparently
because our guidance refers to age broadly, not specifically to elderly
or "people over 65." The draft asserts that FDA is more specific in its
references to other demographic subgroups. This is incorrect. While
"age" in the abstract could mean 10-20, 20-30, 40-50, etc, it is wholly
clear from the content (described above) of the Clinical Safety Review
guidance, and from FDA's two guidance documents on studies of drugs in
the elderly ("Guideline for the Study of Drugs Likely to be Used in the
Elderly" (1989); ICH E7: Studies in Support of Special Populations:
Geriatrics (1994)), as well as from the fact that the physician package
insert includes a specific section on geriatrics, that references to
"age" are, implicitly, references to the elderly.
The draft report notes (page 13) that FDA told GAO that reviewers all
know that "age" and "demographic analyses" mean elderly, but the draft
report then goes on to suggest that this understanding may not be
complete across all medical officers. In fact, interest in "age" can
have no other meaning. If the interest were in pediatric use, that
terminology would be used; thus, references to analysis by age
implicitly refer to the elderly. And, as noted, this interest has been
signaled repeatedly.
4. On page 13, the draft report says that medical officers are not
asked to "determine whether sufficient numbers of elderly persons
participated in NDA clinical drug trials." As the quote from page 38 of
the Clinical Safety Review guidance above makes clear, they are in fact
asked that very thing.
Specific General Comments:
1. p 3: Footnote 6 is to support the contention that there is concern
about inclusion of elderly persons in clinical drug trials supporting
NDAs. That concern has certainly been expressed but note that the Lee,
et al reference does not refer to trials supporting NDAs but rather to
trials of acute coronary syndromes generally. We are not sure what the
Mitchell reference refers to, and therefore suggest that GAO confirm
that it pertains to trials supporting NDAs. Talarico, et al concluded
that the elderly were under-represented compared to disease prevalence,
but that does not necessarily mean there were not sufficient elderly
patients for analysis. No one has argued that clinical trials must
contain age representation proportional to demographic prevalence; what
is necessary is to include sufficient numbers of elderly to provide
sufficient exposure (something that is admittedly a judgment call).
Talarico, et al do not address that issue, although they certainly
raise the concern, especially for the very old, that representation
might be inadequate and that responses could well differ by age.
2. p 8: Footnote 13 presumably refers to Oraflex (benoxaprofen). It is
not likely that the rare late-developing serious liver injury that led
to withdrawal of the drug was common enough to have shown up in
clinical trials; thus, the fact that the trials did not include
extensive numbers of elderly persons in all likelihood did not affect
the situation with regard to the adverse event at issue.
[End of section]
Enclosure V:
GAO Contact and Staff Acknowledgments:
GAO Contact:
Marcia Crosse, (202) 512-7114 or crossem@gao.gov:
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.
[End of section]
Footnotes:
[1] National Center for Health Statistics, Health, United States, 2006
With Chartbook on Trends in the Health of Americans (Hyattsville, Md.:
2006).
[2] For 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. § 201.57(c)(9)(v) (2007)).
[3] Clinical 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.
[4] Drug 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.
[5] FDA 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.
[6] In this report, we use the term "guidance" to mean those FDA
documents which outline procedures medical officers are to follow in
their review.
[7] For 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).
[8] The 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. § 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.
[9] 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 these data were relevant for our purposes.
[10] A drug sponsor sometimes used different age categories to report
summary information about participants, comparisons of safety by age,
and comparisons of effectiveness by age.
[11] In 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. § 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.
[12] A narrow category of clinical drug trials in humans can be exempt
from this requirement. See 21 C.F.R. § 312.2(b) (2007).
[13] 21 C.F.R. § 312.23(a)(6)(iii)(c) (2007).
[14] See for example, 21 C.F.R. § 314.50(d)(5) (2007).
[15] Institute of Medicine, Pharmacokinetics and Drug Interactions in
the Elderly and Special Issues in Elderly African-American Populations
(Washington, D.C.: 1997).
[16] Edward L. Trimble et al., "Representation of Older Patients in
Cancer Treatment Trials," Cancer Supplement, vol. 74, no. 7 (1994).
[17] Joy 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."
[18] Institute of Medicine, Pharmacokinetics and Drug Interactions in
the Elderly and Special Issues in Elderly African-American Populations.
[19] Erin 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).
[20] Food 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).
[21] Food and Drug Administration, Guideline for the Format and Content
of the Clinical and Statistical Sections of an Application (Rockville,
Md.: July 1988).
[22] NDAs often include data from more than one clinical drug trial.
[23] 63 Fed. Reg. 6854, 6862 (Feb. 11, 1998) (codified at 21 C.F.R. §
314.50(d)(5)(v), (vi)(a); § 312.33(a)(2) (2007)).
[24] The 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)).
[25] A 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.
[26] FDA 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).
[27] FDA'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.
[28] Using 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.
[29] We 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.
[30] A drug sponsor sometimes used different age categories to report
summary information about participants, comparisons of safety by age,
and comparisons of effectiveness by age.
[31] Food and Drug Administration, Studies in Support of Special
Populations: Geriatrics (Rockville, Md.: August 1994); 63 Fed. Reg.
6859 (1998).
[32] NDAs often include data from more than one clinical drug trial.
[33] Within 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).
[34] In 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.
[35] See 21 C.F.R. § 314.50(d)(5)(v), (vi)(a); § 312.33(a)(2) (2007).
[36] A drug sponsor sometimes used different age categories to report
summary information about participants, comparisons of safety by age,
and comparisons of effectiveness by age.
[37] Three 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.
[38] 62 Fed. Reg. 45313, 45325 (Aug. 27, 1997) (codified at 21 C.F.R. §
201.57(c)(9)(v) (2007)).
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