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Data on Elderly Persons in Clinical Drug Trials' which was released on 
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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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