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FDA Guidance and Regulations Related to Data on Elderly Persons in Clinical Drug Trials, Jan 2008

January 10, 2008

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

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

Dear Chairman Kennedy and Chairman Waxman:

The American Association for Geriatric Psychiatry (AAGP) appreciates the report that you requested from the General Accountability Office (GAO) on data on elderly persons in clinical drug trials. The report, entitled FDA Guidance and Regulations Related to Data on Elderly Persons in Clinical Drug Trials (GAO-07-47R), was issued on September 28, 2007.

AAGP is a professional membership organization dedicated to promoting the mental health and well-being of older people and improving the care of those with late-life mental disorders. AAGP’s membership consists of 2,000 geriatric psychiatrists, as well as other health professionals who focus on the mental health problems faced by senior citizens.

This GAO report notes that the guidance issued by Food and Drug Administration (FDA) has failed to provide the needed assurance that drugs are safe and effective for older adults. This problem has been evident for years to geriatric psychiatrists, both researchers and clinicians, and we welcome the attention that is now being focused on it.

Our members have reviewed the GAO report and have a number of comments and recommendations to offer that we believe would be helpful in developing regulations that would help to ensure that clinical trials give practitioners and patients useful guidance in prescribing for older adults.

The report points out that FDA's intention has been to prevent sponsors from excluding persons of "advanced age," but for these purposes FDA defines elderly as 65 and over. Thus, the current guidance allows drug companies to satisfy the requirement primarily with younger, healthier elderly subjects in the 65-74 age range and continue to exclude old-old (ages 75 to 84) and oldest-old (ages 85 and older), the groups of frail patients who are most vulnerable to adverse effects. The report comments that, if trials contained sufficient numbers of elderly subjects, then the percentages over ages 65 and 75 should be reported.

A quick survey of the prescribing information for Aricept, Exelon, and Namenda, medications approved for the treatment of Alzheimer’s Disease, demonstrates the difference stronger reporting can make in addressing this problem. Neither Exelon nor Namenda have a geriatric use section (understandably) but both have a pediatric use section. Exelon reports the mean age of subjects as 73 with a range of 41-95, but with no report on how many of the subjects were over 75, nor the mean age of this group. The report for Namenda is similar. Aricept reports a mean age of 73 and reports that 80% were between 65 and 84 and 49% were over 75 years old. Aricept also does have a geriatric use section. Thus, from the prescribing information for these products, it is difficult to ascertain the number and percentage of patients in studies who actually were over 75 and the mean age of this older-old cohort (i.e., was their mean age 76 or 84?). These medications are examples of drugs intended for treatment of an old-age disease, and it is difficult to glean detailed descriptive information about the ages of the patients studied. This pattern represents the rule rather than the exception for all types of medications that frail, elderly patients receive.

Supporting the need for inclusion (and at least reporting) of those older than 74, an analysis a total of 9664 subjects who were enrolled in trials studying osteoarthritis and rheumatoid arthritis found that although more than half of the studies reviewed included patients over 65 years of age, there were only 207 (2.1%) patients in this age group and, only 14 of the 9664 patients studied were between 75 and 84 years of age, with none representing those aged over 85 years (Rochon PA, et al, Reporting of age data in clinical trials of arthritis. Deficiencies and solutions. Arch Intern Med 1993; 153: 243-8).

Similarly, with respect to cognitive enhancers, exclusion criteria for two regulatory trials for Cholinesterase Inhibitors (ChEI) were found to eliminate more than 90% of a community sample of 3470 subjects with possible or probable Alzheimer’s Disease; overall, only 4.4% or 7.9% would have been provisionally eligible for each of two trials. Patients provisionally eligible were younger, relatively underrepresented by women, better educated, wealthier, and more likely to be white than ineligible patients. (Schneider LS. et al. Eligibility of Alzheimer's disease clinic patients for clinical trials. J Am Geriatrics Soc. 45:923-8, 1997).

We suggest also that consideration should be given to reporting not only “mean” age, but also the “median” age. By reporting "mean" age, the sample may seem to contain a greater number of oldest individuals but in reality have very few. For example, the mean age of a sample containing 3 persons aged 60, 65, and 90 is 71.6 yeas of age. On the other hand, the "median" is the age at which half the sample is younger and half older is 65. The mean is more informative when the distribution is normal. But when there are outliers the median is better. Because of age related comorbid conditions the risk-benefit ratio becomes less favorable with advanced age. Data generated from oversampling of persons of advanced age would reduce adverse reactions as well as avoid costly therapeutic failures. We believe the FDA should give careful consideration to this point, since it is properly the focus of the report.

AAGP recommends that the law be strengthened to require FDA to mandate more stringent reporting and prescribing information with respect to geriatric participations in clinical trials. Specifically:

1. The prescribing information for all medications should have a geriatric use section, including drugs intended to be used primarily in the elderly.

2. The FDA should institute uniform reporting requirements for products' geriatric use sections to include the numbers, mean and median ages, and percentages of patients 65 and over and 75 and over, and, if there were sufficient numbers above 75, separate listing of side effects/adverse effects for the categories under 65, 65-74, and 75 and over.

3. Consideration should be given to redefining the definition of “elderly” so that it begins at age 70, at least, and perhaps even 75. The real issue is frailty, not age; adults through their 60s generally do not face issues of frailty in large numbers.

The crucial concern raised by the GAO report is that there is no data to support that this situation with respect to data on older adults has changed since the FDA instituted guidance on the issue. While we appreciate that aging represents a very heterogeneous process, as a general surrogate we know that those over the age of 74 are more likely to be fragile, have medical co-morbidity and take more medications than younger persons. As noted by the report, elders are disproportionately the greatest consumers of prescription medications, and it is vital that they be adequately represented in regulatory trials and that data obtained in those older than age 74 be reported.

We appreciate your leadership in exploring this important issue and would welcome the opportunity to work with you and members of your staffs in finding ways to address the problem.

Sincerely,

Gary S. Moak, MD
President

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