United States Government Accountability Office

Washington, DC 20548 

September 28, 2007 

The Honorable Edward M. Kennedy 

Chairman 

Committee on Health, Education, Labor, and Pensions 

United States Senate 

The Honorable Henry A. Waxman 

Chairman 

Committee on Oversight and Government Reform 

House of Representatives 

Subject: Prescription Drugs: FDA Guidance and Regulations Related to Data on Elderly 

Persons in Clinical Drug Trials

Elderly persons use drugs at a higher rate than younger persons,1

 in part because elderly 

persons experience higher rates of certain diseases—such as cancer, Parkinson’s disease, 

and heart disorders. Elderly persons—those age 65 and older—are also more likely than 

younger adults to experience complications when taking some prescription drugs.2

 For 

example, because of their decreased liver and kidney functions, elderly persons often lack 

the ability to eliminate drugs from their bodies as efficiently as younger adults, making 

elderly persons more likely to experience side effects associated with drugs. As a result, the 

Food and Drug Administration (FDA) has noted that it is important that drugs be studied for 

use by elderly persons during the clinical drug trials3

—that is, those drug studies conducted 

by drug sponsors before they submit an application to have a drug approved for marketing.4

 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. 

 GAO-07-47R Elderly Persons in Clinical Drug Trials 
FDA is responsible for oversight of clinical drug trials and deciding whether to approve new 

drugs for marketing in the United States. This responsibility includes determining if drugs are 

safe and effective for the people expected to use them, including elderly persons. To 

implement its responsibilities, FDA issues guidance and regulations for drug sponsors on 

conducting clinical drug trials and submitting new drug applications (NDA) to FDA to seek 

drug approval based in part on the results of those clinical drug trials.5

 NDAs include data on 

both the safety and effectiveness of the drug being studied. FDA guidance describes the 

process FDA medical officers (typically doctors) are to follow in reviewing those NDAs as 

part of the NDA review process and recommending whether to approve a new drug for 

marketing in the United States.6

 As part of the process by which drugs are considered for 

approval, medical officers also meet in teams with supervisors and other experts, including 

biochemists and statisticians, to discuss the merits of the NDA. 

Concerns have been raised about the inclusion of elderly persons in clinical drug trials.

7

 You 

asked us to examine FDA’s activities related to data reported about elderly persons in the 

study of new drugs. In this report, we examine FDA’s guidance and regulations related to 

(1) drug sponsors’ reporting of data to FDA to describe the effects of a proposed drug on 

elderly persons and (2) FDA medical officers’ review of safety and effectiveness data that 

drug sponsors provided for elderly persons. 

To examine guidance and regulations on drug sponsors’ reporting of data related to elderly 

persons, we reviewed FDA guidance related to the study of drugs and the format and content 

of an NDA. We also examined FDA regulations on reporting drug safety and effectiveness 

data by age in the NDA and reporting data on elderly persons on the drug labeling.8

 To 

determine how drug sponsors have reported data related to the guidance and regulations, we 

reviewed all 36 NDAs submitted to FDA from January 1, 2001, through June 30, 2004, that 

FDA had reviewed and were for drugs that are proposed to treat diseases that we determined 

affect elderly persons with a disproportionately greater frequency compared to younger 

 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. 

 2 GAO-07-47R Elderly Persons in Clinical Drug Trials
persons.9

 To determine the number of elderly participants associated with each NDA, we 

reviewed the overall descriptions of the clinical drug trials. To determine how drug sponsors 

reported safety and effectiveness data by age, we reviewed other sections of NDA summary 

documents that reported the relevant analyses.10

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 onequarter 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 

 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. 

10A drug sponsor sometimes used different age categories to report summary information about 

participants, comparisons of safety by age, and comparisons of effectiveness by age.

 3 GAO-07-47R Elderly Persons in Clinical Drug Trials
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,11

and monitoring the safety and effectiveness of drugs after they are marketed. Before any new 

drug can be tested on people, the drug sponsor generally must submit to FDA a proposal that, 

among other things, lays out a plan for how the drug will be tested and outlines the measures 

that will be taken to protect clinical drug trial participants.12 This proposal is also required to 

 11In response to concerns associated with the use of drugs by elderly persons, FDA began requiring a 

“geriatric use” subsection to a drug’s labeling in 1998 (62 Fed. Reg. 45313, 4325 (Aug. 27, 1997)) 

(codified at 21 C.F.R. § 201.57(c)(9)(v) (2007)). This subsection of the drug labeling is where 

information related to a drug’s safety and effectiveness for elderly persons is included by the drug

sponsor. 

12A narrow category of clinical drug trials in humans can be exempt from this requirement. See 

21 C.F.R. § 312.2(b) (2007).

 4 GAO-07-47R Elderly Persons in Clinical Drug Trials
specify criteria that will be used to exclude persons from participating in clinical drug trials.13

For example, participants with other diseases or those taking certain other medications 

might be excluded from a clinical drug trial. Typically, a drug sponsor and FDA officials will 

have discussions about the design of the clinical drug trials before the drug sponsor submits 

this proposal. 

To obtain approval for marketing a drug in the United States, drug sponsors must then submit 

information to FDA about the completed clinical drug trials—along with pharmacology and 

toxicology data, chemistry and manufacturing data, and proposed labeling language—in the 

form of an NDA. NDAs include sections summarizing safety and effectiveness data. FDA 

regulations require that these sections include background information about the clinical 

drug trials and summary information about their participants—including exclusion criteria 

used in the clinical drug trials—as well as evidence from clinical drug trials demonstrating 

that the proposed drug is safe and effective for its intended use.14 The NDAs are reviewed by 

FDA medical officers, typically doctors, who then discuss their reviews in teams with 

supervisors and other experts to help FDA determine whether to approve a drug for 

marketing. 

Elderly Persons in Clinical Drug Trials

Assessing whether a drug is safe and effective for use by elderly persons requires that a 

sufficient number of elderly persons be included in clinical drug trials. As the number of 

elderly participants in clinical drug trials increases, the ability of drug sponsors to detect 

responses unique to elderly persons for a given safety or effectiveness outcome also 

increases. Failing to include sufficient numbers of elderly persons in clinical drug trials may 

make it less likely that safety concerns and effectiveness outcomes unique to elderly persons 

will be detected during the clinical drug trials. 

A variety of factors make it difficult to include elderly persons in clinical drug trials. For 

example, elderly persons are more likely than younger persons to use multiple medications 

or have multiple diseases, which might preclude their participation in a clinical drug trial 

because these factors can confound the interpretation of the clinical drug trial results.15

Another challenge to including elderly persons in clinical drug trials is that some physicians 

might not refer elderly persons to clinical drug trials because they believe that elderly

persons may be less likely than younger adults to tolerate or benefit from new drug 

therapies.16 Elderly persons might also avoid clinical drug trials if they believe the treatment 

would not benefit them or if they are concerned about the toxicity of the treatment.17

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

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

15Institute of Medicine, Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in 

Elderly African-American Populations (Washington, D.C.: 1997). 

16Edward L. Trimble et al., “Representation of Older Patients in Cancer Treatment Trials,” Cancer 

Supplement, vol. 74, no. 7 (1994). 

17Joy H. Lewis et al., “Participation of Patients 65 Years of Age or Older in Cancer Clinical Trials,” 

Journal of Clinical Oncology, vol. 21, no. 7 (2003), and Trimble et al., “Representation of Older 

Patients in Cancer Treatment Trials.” 

 5 GAO-07-47R Elderly Persons in Clinical Drug Trials
Elderly persons may also have difficulty accessing clinical drug trials. For example, elderly 

persons are more likely than younger adults to be affected by dementia and other cognitive 

impairments that can impede drug sponsors’ ability to obtain their informed consent, which 

is necessary for participation in clinical drug trials.

18 Elderly persons also may not want to or 

be able to participate in clinical drug trials. For example, participants in clinical drug trials 

may have to visit the doctor more often than they otherwise would, and elderly persons may 

have difficulty traveling to clinic appointments or may not be able to afford the necessary 

transportation costs.19

FDA’s guidance recommends that drug sponsors not exclude elderly persons from clinical 

drug trials on the basis of their age alone because such exclusions might prevent drug 

sponsors from collecting sufficient information about the effects of drugs in elderly persons.20

Instead, the guidance suggests that, when necessary, exclusion criteria should focus on more 

relevant issues, such as either the presence of an illness that could make participation in the 

clinical drug trial dangerous or the person’s inability to provide informed consent. 

FDA Guidance Encourages Inclusion of Elderly Persons, and Regulations Require 

That Drug Sponsors Report Clinical Drug Trial Data by Age 

FDA guidance recommends that drug sponsors include elderly persons in clinical drug trials, 

and FDA regulations require that the drug sponsors report clinical drug trial data by age. 

Agency guidance recommends that drug sponsors avoid excluding persons on the basis of 

advanced age. To help FDA determine the number of elderly persons in clinical drug trials, 

agency guidance also recommends how drug sponsors should report the age of clinical drug 

trial participants in their NDAs and the various formats that drug sponsors can use to report 

this information. For example, FDA recommended in its current guidance on the format of a 

drug application, issued in 1988, various ways that drug sponsors could report the age of 

participants, including the average age, the ages of the youngest and oldest participants (the 

age range), and the number of participants who fall into specific age categories.21 In addition, 

FDA encourages meetings between drug sponsors and FDA officials prior to the submission 

of an NDA that may include discussions of the best approach for presenting and formatting 

data in the NDA. 

 18Institute of Medicine, Pharmacokinetics and Drug Interactions in the Elderly and Special Issues in 

Elderly African-American Populations. 

19Erin L. Cassidy, E. Baird, and Javaid I. Sheikh, “Recruitment and Retention of Elderly Patients in

Clinical Trials,” American Journal of Geriatric Psychiatry, vol. 9, no. 2 (2001), and M. Margaret

Kemeny et al., “Barriers to Clinical Trial Participation by Older Women With Breast Cancer,” Journal 

of Clinical Oncology, vol. 21, no. 12 (2003). 

20Food and Drug Administration, Guideline for the Study of Drugs Likely to be Used in the Elderly 

(Rockville, Md.: November 1989), and Studies in Support of Special Populations: Geriatrics 

(Rockville, Md.: August 1994). 

21Food and Drug Administration, Guideline for the Format and Content of the Clinical and Statistical 

Sections of an Application (Rockville, Md.: July 1988). 

 6 GAO-07-47R Elderly Persons in Clinical Drug Trials
Based on summary information about the participants, we found that elderly persons were 

included in at least one clinical drug trial supporting each of the 36 NDAs we reviewed.22 For 

28 NDAs, we were able to determine the number of elderly participants in at least one of the 

clinical drug trials. In the remaining 8 NDAs, we could not determine the exact number of 

elderly participants in any of the clinical drug trials because of the way that drug sponsors 

sometimes reported age data in the NDA (see enc. II). For example, an NDA may have 

reported only the age range of participants—such as from 18 through 91—rather than using 

the age category of 65 and older. This would indicate that there was at least one elderly 

person, but precluded us from determining the exact number of elderly participants. 

FDA issued regulations in 1998 to require that drug sponsors report data from clinical drug 

trials that would identify differences in safety and effectiveness associated with age.23 FDA 

has not developed guidance specifically including categories for elderly persons in these age

comparisons, but FDA officials told us that drug sponsors know that age comparisons would 

include elderly persons and that elderly is defined as age 65 and older.24 FDA officials are 

developing guidance that would combine information currently available in multiple guidance 

documents on the format drug sponsors should use for reporting safety data in an NDA, 

including data about age. In our review of 36 NDAs, we found that most drug sponsors used 

the age category of 65 and older when reporting on a drug’s safety and effectiveness by age 

(see enc. III).

25

FDA Expectations That Medical Officers Review Safety and Effectiveness Data 

Related to Elderly Persons Are Not Conveyed in Agency Guidance 

FDA expectations that medical officers review safety and effectiveness data related to elderly 

persons are not conveyed in agency guidance. FDA’s guidance for evaluating safety and 

effectiveness refers to age subgroups broadly.26 For example, FDA guidance states that it may 

be appropriate to examine whether there are differences in the safety and effectiveness of 

drugs between demographic subgroups, such as “old” and “young” participants. Guidance 

also specifies that the medical officers’ clinical review summaries should include an 

examination of safety and effectiveness data among clinical drug trial participants in various 

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

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

(2007)).

24The preamble to the regulation states that, for the purposes of geriatric labeling, FDA has previously 

defined the “elderly” as persons age 65 years and older and recommends that drug sponsors use that 

definition for analysis of safety and effectiveness data for elderly persons (see 63 Fed. Reg. 6854, 6859

(Feb. 11, 1998)). 

25A drug sponsor sometimes used different age categories to report summary information about 

participants, comparisons of safety by age, and comparisons of effectiveness by age. As a result, the 

number of NDAs for which we could determine the number of elderly participants varies according to

the data reported in each NDA. 

26FDA guidance documents for medical officers include a Clinical Review Template, introduced in July

2004, and guidance for reviewing NDA safety data, introduced in 2005. Agency officials told us that 

they intend to develop additional guidance specifically for the review of effectiveness studies. FDA 

guidance also includes Food and Drug Administration, Reviewer Guidance: Conducting a Clinical 

Safety Review of a New Product Application and Preparing a Report on the Review (Rockville, Md.: 

February 2005). 

 7 GAO-07-47R Elderly Persons in Clinical Drug Trials
subgroups—such as age, gender, and race. In contrast, FDA guidance is more specific in its 

references to other demographic subgroups. For example, one guidance document dedicates 

specific subsections to how medical officers should include in their summaries examinations 

of data on the possible effects a drug may have for pregnant women and for children, but 

there is no similar subsection for elderly persons.27

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 longstanding and extensive efforts to assure reasonable representation of elderly persons in 

clinical drug trials. Second, HHS stated that we were incorrect in finding that agency

guidance does not direct medical officers to report whether sufficient numbers of elderly 

persons participated in NDA clinical drug trials. Such information is necessary for FDA to 

assess the safety and effectiveness of the drug for elderly persons. Third, HHS stated that we 

were critical of FDA for not adequately conveying to its reviewers the agency’s expectations 

with regard to the need to review safety and effectiveness data related to elderly persons and 

that they disagreed with this criticism. 

As we noted in the draft report, FDA has made numerous efforts related to the inclusion of 

elderly persons in clinical drug trials and issued many related guidance documents. Providing 

a detailed history of FDA’s work in this area was beyond the scope of this report. 

 27FDA’s guidance includes a subsection where medical officers should report any available information 

on drug exposure to pregnant women and a subsection that should discuss the drug’s effects on 

growth in children, including the measurement of height and weight, the measurement methodology 

used, and adjustments for children’s age and gender, as appropriate. 

 8 GAO-07-47R Elderly Persons in Clinical Drug Trials
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 http://www.gao.gov. 

 9 GAO-07-47R Elderly Persons in Clinical Drug Trials
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. 

Marcia Crosse 

Director, Health Care 

Enclosures – 5 

 10 GAO-07-47R Elderly Persons in Clinical Drug Trials
Enclosure I 

Scope and Methodology 

This report examines the Food and Drug Administration’s (FDA) guidance and regulations 

related to (1) drug sponsors’ reporting of data to describe the effects of a proposed drug on 

elderly persons and (2) FDA medical officers’ review of safety and effectiveness data that 

drug sponsors provided for elderly persons. 

To examine guidance and regulations on drug sponsors’ reporting of data related to elderly 

persons, we examined FDA regulations about the study of the safety and effectiveness of 

drugs by age and about labeling information about the use of a drug by elderly persons. We 

also reviewed FDA guidance related to the study of drugs in general, the study of drugs likely 

to be used by elderly persons, and the format and content of a new drug application (NDA). 

To determine how drug sponsors have reported data related to the guidance and regulations, 

we reviewed all 36 NDAs submitted to FDA from January 1, 2001, through June 30, 2004, that 

FDA had reviewed and that were for drugs proposed to treat diseases that we determined 

affect elderly persons with a disproportionately greater frequency than younger persons.28

For each of the 36 NDAs in our sample, we reviewed the Integrated Summary of Safety and 

the Integrated Summary of Efficacy that each drug sponsor included in its initial NDA 

submission to FDA. We determined that the data reported in the NDA summary documents 

were sufficiently reliable for the purposes of this report.29 To determine the number of elderly 

participants associated with each NDA, we reviewed the overall descriptions of the clinical 

drug trials. To determine how drug sponsors reported safety and effectiveness data by age, 

we reviewed other sections of NDA summary documents that reported the relevant 

analyses.30 We did not examine other information in the drug application. 

In our review of these summary sections, we collected age of participants and other data 

from each NDA. Where possible, we categorized the participants from each clinical drug trial 

into two age categories—younger than age 65 and age 65 and older. We selected these age 

groups because they are identified in both FDA’s guidance for drug sponsors and the 

preamble to the 1998 regulations.31 If an NDA did not report the number of clinical drug trial 

 28Using data from the National Ambulatory Medical Care Survey (National Center for Health Statistics, 

National Ambulatory Medical Care Survey, 2001), we estimated the proportion of individuals 65 years 

and older in the population with the disease that the drug is proposed to treat. Where the indication

proposed in the NDA was complex, we made our estimate using the primary condition that needs to be

present. For example, if a drug is proposed to treat nausea in persons receiving chemotherapy

treatment for cancer, we would select cancer as our disease of interest. We determined that these data

were sufficiently reliable for the purposes of this report by reviewing relevant technical

documentation, including survey methodology, weighting procedures, and code books describing the 

data elements used in our analyses. Based on information provided by FDA officials in April 2007 that 

guidance and regulations related to elderly persons in clinical drug trials had not changed since the

beginning of our review, we determined that the NDAs we selected were relevant for our purposes. 

29We assessed the reliability of the data reported in the NDA summary documents by reviewing related 

documentation and interviewing agency officials knowledgeable about the data. However, we did not 

confirm the accuracy of the information contained in the summary documents. 

30A drug sponsor sometimes used different age categories to report summary information about 

participants, comparisons of safety by age, and comparisons of effectiveness by age.

31Food and Drug Administration, Studies in Support of Special Populations: Geriatrics (Rockville, 

Md.: August 1994); 63 Fed. Reg. 6859 (1998). 

11 GAO-07-47R Elderly Persons in Clinical Drug Trials
Enclosure I 

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. 

 12 GAO-07-47R Elderly Persons in Clinical Drug Trials
Enclosure II 

Data Provided to FDA by Drug Sponsors on Elderly Persons in Clinical Drug Trials 

for 36 NDAs Submitted to FDA from January 2001 through June 2004 

Elderly persons were included in at least one clinical drug trial supporting each of the 36 

NDAs we reviewed, though some of the trials for these NDAs excluded elderly persons on the 

basis of age alone.32 Drug sponsors reported summary participant data to FDA on the number 

of elderly persons in clinical drug trials supporting 28 of the 36 NDAs we examined. For those 

28 NDAs, we could determine that 33 percent of the participants in the clinical drug trials 

were elderly (age 65 and older) and 65 percent were younger than age 65, according to

summary information provided by drug sponsors in the NDA. Within these 28 NDAs, we were 

unable to determine the age of the remaining 2 percent of participants because drug sponsors 

did not report the age of these participants in a way that allowed us to determine how many 

of them were elderly. For the remaining 8 NDAs, we could not determine the number of 

participants that were elderly for any of the clinical drug trials because the necessary age 

data were not reported in the NDAs. Table 1 presents the number and percentage of clinical 

drug trial participants younger than age 65 and age 65 and older, and the number and 

percentage of those participants for whom drug sponsors did not provide adequate data to 

allow us to classify them into one of these two age categories.33

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

33Within each NDA, we included participants from those clinical drug trials for which the drug sponsor

provided adequate data for us to categorize all participants as being either younger than age 65 or age 

65 and older. We classified the NDAs by disease category, using the disease that the drug is proposed 

to treat, according to the broad categories of disease defined in the International Classification of 

Diseases, Ninth Revision. See Department of Health and Human Services, International 

Classification of Diseases, Ninth Revision, Clinical Modification, 6th ed. (Washington, D.C.: October 

2003). 

13 GAO-07-47R Elderly Persons in Clinical Drug Trials 
Enclosure II 

Table 1: Number of Persons Reported in NDA Clinical Drug Trials Categorized by Age (Younger 

Than Age 65 or Age 65 and Older), by Disease Category, Based on 36 NDAs Submitted to FDA from 

January 1, 2001, through June 30, 2004, for the Treatment of Diseases That GAO Determined 

Disproportionately Affected Elderly Persons 

Persons younger than

age 65 

Persons age 65 and

older

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

NDA, by 

disease 

categorya

Total persons

in clinical 

drug trials, 

regardless of

ageb

Number Percentage Number Percentage Number Percentage

Cancer 

1 4,493 3,649 81 844 19 0 0

2 2,881 2,347 81 534 19 0 0

3 1,468 869 59 394 27 205 14

4 1,465 0 0 0 0 1,465 100

5 1,249 708 57 541 43 0 0

6 1,052 628 60 424 40 0 0

7 936 572 61 364 39 0 0

8 928 610 66 218 23 100 11

9 426 276 65 150 35 0 0

10 361 133 37 222 61 6 2

11 256 0 0 0 0 256 100

Circulatory system 

12 9,680 3,606 37 6,074 63 0 0

13 7,105 3,357 47 3,427 48 321 5

14 4,226 1,588 38 751 18 1,887 45

15 3,626 0 0 0 0 3,626 100

16 1,025 504 49 521 51 0 0

Endocrine, nutritional, metabolic, and immunity

17 6,016 4,108 68 1,821 30 87 1

18 5,056 4,476 89 580 11 0 0

19 2,695 2,408 89 287 11 0 0

20 1,763 1,175 67 422 24 166 9

21 612 0 0 0 0 612 100

Genitourinary system

22 8,100 6,158 76 1,942 24 0 0

23 4,042 2,632 65 1,410 35 0 0

24 2,841 1,940 68 901 32 0 0

25 2,146 1,581 74 565 26 0 0

 14 GAO-07-47R Elderly Persons in Clinical Drug Trials
Enclosure II 

Persons younger than

age 65 

Persons age 65 and

older

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

NDA, by 

disease 

categorya

Total persons

in clinical 

drug trials, 

regardless of

ageb

Number Percentage Number Percentage Number Percentage

Musculoskeletal system and connective tissue 

26 14,900 10,904 73 3,996 27 0 0

27 12,911 9,028 70 3,883 30 0 0

28 8,496 0 0 0 0 8,496 100

Nervous system and sense organs

29 2,709 646 24 2,063 76 0 0

30 1,229 684 56 485 39 60 5

31 290 0 0 0 0 290 100

Other

32 4,870 2,788 57 2,082 43 0 0

33 3,341 2,575 77 766 23 0 0

34 2,898 0 0 0 0 2,898 100

35 954 0 0 0 0 954 100

36 774 718 93 56 7 0 0

Total 127,820 70,668 55 35,723 28 21,429 17

Source: GAO analysis of 36 NDAs submitted to FDA. 

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. 

One factor that may have limited the representation of elderly persons in some of the 36 

NDAs we reviewed is that several clinical drug trials had exclusion criteria prohibiting the 

participation of elderly persons on the basis of their age. Clinical drug trials in 13 NDAs had 

exclusion criteria that prohibited the participation of at least some elderly persons on the 

basis of age alone; however, at least one clinical drug trial in all NDAs included some elderly 

participants. Specifically, 3 NDAs had at least one clinical drug trial with a criterion excluding 

all persons older than age 65 from participating. Drug sponsors for the other 10 NDAs had at 

least one clinical drug trial that used criteria excluding a subset of elderly persons—such as 

those older than age 70—from participating in their clinical drug trials.34 FDA officials told us 

that drug sponsors are expected to justify any age cutoff that is used, just as they would any 

other decisions about their research design. 

 34In examining only those clinical drug trials that the drug sponsors designated as most important to

their NDAs, sponsors of seven of these NDAs had criteria that prohibited the participation of some 

older persons based on age alone. 

 15 GAO-07-47R Elderly Persons in Clinical Drug Trials
Enclosure III 

Data Reported by Drug Sponsors to FDA on the Safety and Effectiveness 

of Drugs for Elderly Persons 

While FDA regulations require that drug sponsors present safety and effectiveness data by 

age, the regulations do not define specific age subgroups to be used, thereby leaving the 

selection of subgroups for analysis to the drug sponsors.35 For example, a drug sponsor may 

compare the effect of the proposed drug on the survival rate of cancer patients age 60 and 

older to its effect on the survival rate of those younger than age 60. According to FDA 

officials, instead of specifying the age categories drug sponsors must use to report data on 

safety and effectiveness outcomes from their clinical drug trials, the regulations FDA issued 

in 1998 were written broadly to allow drug sponsors flexibility to report outcome data in the 

manner they believe to be most appropriate. Agency officials also indicated that specific age 

categories, such as 65 and older, might not be appropriate for comparing safety and 

effectiveness data in all clinical drug trials because a clinical drug trial may have few or no 

participants in a specific age category. FDA officials also told us that drug sponsors know 

that the intent of the regulations is to encourage the examination of how elderly persons 

differ from younger persons in response to the drug and that the agency learns important 

information when an older age category—such as age 70 and older—is used. 

In the 36 NDAs we reviewed, most drug sponsors used the age category of 65 and older when 

reporting data on a drug’s safety and effectiveness by age. Specifically, drug sponsors of 30 

NDAs sometimes used age 65 and older as an age category when reporting data on safety 

outcomes, and drug sponsors of 26 NDAs sometimes used this age category when reporting 

data on effectiveness outcomes.36 The remaining drug sponsors either used a different age 

category or did not report data by age when reporting data on safety or effectiveness.37

Drug sponsors are required to disclose on the drugs’ labeling what they learn from clinical 

drug trials about the safety and effectiveness of a drug for elderly persons. Since 1998, FDA 

has required that drug sponsors include a Geriatric Use subsection in drug labeling that 

conveys the findings from the age comparisons that are reported in the NDAs and the number 

of elderly persons included in that drug’s clinical trials, as appropriate.38 The regulation

provides drug sponsors with a choice of three primary statements to be used in the Geriatric 

Use subsection. First, if there have not been sufficient numbers of elderly participants in 

clinical drug trials to determine whether those age 65 and over respond differently to the 

drug, it should be noted in the labeling along with a statement that dose selection for an

elderly patient proceed with caution, generally starting at the low end of the dosing range. 

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

36A drug sponsor sometimes used different age categories to report summary information about 

participants, comparisons of safety by age, and comparisons of effectiveness by age.

37Three NDAs did not include any effectiveness data by age and one of these NDAs also did not report 

any safety data by age. With regard to the one NDA without any safety or effectiveness data by age, the 

drug did not perform successfully, and FDA did not approve the NDA. FDA officials told us that, for 

the remaining two NDAs, such presentations were either unnecessary or not possible. For one of these 

two, FDA officials stated that it was not necessary for the drug sponsor to report effectiveness data by

age because all of the clinical drug trial participants were between the ages of 55 and 80. For the 

remaining NDA, FDA officials told us that because the drug sponsors studied elderly persons and

younger adults in separate clinical drug trials, the drug sponsors could not provide such comparisons. 

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

16 GAO-07-47R Elderly Persons in Clinical Drug Trials
Enclosure III 

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. 

 17 GAO-07-47R Elderly Persons in Clinical Drug Trials
Enclosure IV 

Comments from the Department of Health and Human Services 

18 GAO-07-47R Elderly Persons in Clinical Drug Trials
Enclosure IV 

 19 GAO-07-47R Elderly Persons in Clinical Drug Trials
Enclosure IV 

 20 GAO-07-47R Elderly Persons in Clinical Drug Trials
Enclosure IV 

 21 GAO-07-47R Elderly Persons in Clinical Drug Trials
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. 

(290383) 

22 GAO-07-47R Elderly Persons in Clinical Drug Trials
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