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Executive Summary

Pharmacokinetic studies are the preferred method for determining whether drugs affect elderly patients differently from the general population. FDA suggests in its just-released Guideline for the Study of Drugs That Are Likely to be Used in the Elderly. The document recommends that "the evaluation of possible differences in response between younger and older people should focus on the evaluation of potential pharmacokinetic differences." The agency identifies several reasons for focusing on pharmacokinetic differences. "Such differences are known to occur and are much more frequent than documented pharmacodynamic differences," the guide states. In addition, pharmacokinetic differences are "relatively easy" to discover and assess, and a pharmacokinetic evaluation is necessary "to allow intelligent assessment of pharmacodynamic differences or relationships." The guideline suggests that sponsors use a "pharmacokinetic screen" to identify potential differences in drug response in the elderly and other subgroups. The screen involves "obtaining, for all or most patients in Phases II and II of a clinical investigation, a small number (one to several) of steady state blood level determinations in order to determine the variability of blood concentrations of a drug under defined conditions of dosing." From the screen data, FDA said, "it should be possible to learn...whether the elderly differ from others in their blood concentrations and whether differences are the result of age alone or other age-associated conditions." The document suggests that if a "screen is not appropriate or not carried out, or if the screen suggests an influence of age, a formal pharmacokinetic study should be performed in the elderly." Patients for such studies, FDA said, "should be in reasonably good health, but should usually have the condition the drug is intended to treat." FDA specifically recommends special pharmacokinetic studies for drugs that are "significantly excreted through renal mechanisms" and for drugs that are subject to "significant hepatic metabolism." The guidelines have been under development for the last seven years and are based on a discussion paper on testing in the elderly that FDA issued in 1983. The long development period for the guideline drew the attention of both the House Aging/Human Services Subcommittee and the Senate Aging Committee last year. The House subcommittee had questioned the delay in producing the guidelines at an April 19, 1989 hearing on drug misuse in the elderly ("The Pink Sheet" April 24, P. 7). The Senate Aging Committee wrote the agency the same month regarding status of the guideline. At the April 1989 hearing, FDA said the guidelines would be available in six to 12 months. The agency had said at a hearing one year earlier that the guideline would be issued in three months. In a March 8 press statement on the guideline, House Aging/Human Services Subcommittee Chairman Downey (D-N.Y.) called the document "long overdue" and urged public comment on the contents. "For years," Downey said, "we have been waiting for this guideline, which seems to have disappeared into a bureaucratic black hole. I welcome the fact that the guideline has emerged at last." Noting that FDA is encouraging comments on the guideline, Downey said he hopes "all interested individuals -- pharmaceutical manufacturers, doctors, pharmacists, service providers to the elderly, advocates, and senior citizens themselves -- will make their views known." * Like the 1983 document, the central theme of the guidelines is that drugs that are likely to be used in the elderly should be tested in a "reasonable number" of elderly patients. FDA's March 5 Federal Register announcement on availability of the guidelines notes that most sponsors currently do include elderly patients in their clinical trials. The agency cites a 1983 survey of recently approved drugs and a study of NDAs approved in 1988 that show that reasonable numbers of older patients have been included in trials. However, NDAs approved in the 1983 period did not usually have information on differing effects in the elderly, while that type of information was included for the 1988-approved drugs. "Almost all of the 1988 cases included analyses of the impact of age on the drug response (effectiveness and/or safety)," FDA said. "Moreover, for the majority of the 1988-approved drugs intended for repeated systemic use, there were pharmacokinetic studies in the elderly and studies in patients with renal or hepatic functional impairment," the agency said. For most drugs, FDA recommends that elderly patients be included in the same study as younger patients. "This permits direct comparisons with younger, but otherwise similar, patients in the same studies," FDA said. However, the agency noted that "in some cases, especially for drugs targeted to older patients or where age-related differences or problems are anticipated, trials might be carried out specifically in the elderly." An alternative to a separate trial, the guideline states, would be to include both old and young patients but "stratify them by age to allow special care or monitoring of the older patients." The document recommends that patients not be excluded from trials on the basis of concomitant illness or medication, unless the "illness or medication will endanger the patient or lead to confusion in interpreting the results of the study. The guideline recommendations are based on four "underlying observations:" that age-related differences in response to drugs can arise from pharmacokinetic differences or pharmacodynamic differences; that most differences seemingly related to age are related to conditions that are common in the elderly, but also occur in other populations; that for a number of practical and theoretical reasons (detailed above), evaluation of different responses to drug should focus on pharmacokinetic differences; and that the pharmacodynamic studies "are warranted only if differences are suspected for some reason, such as clinical trial results, or appear particularly important (e.g., because of a low therapeutic index)." FDA is specifically seeking comment on its proposal that drug sponsors generally bypass pharmacodynamic studies. In its Federal Register announcement on the guideline, FDA noted that the recommendation "generated considerable discussion throughout the development of this guideline." The agency's rationale in not usually requiring pharmacodynamic studies is that "the number of documented age-related pharmacodynamic differences is at this time...small, and the ability to conduct pharmacodynamic studies to detect them in many situations...uncertain," the guideline explains. * In addition to the pharmacokinetic screen, FDA is also recommending that sponsors use an interaction screen to evaluate whether other drugs being used by patients are affecting the kinetics of the test drug. The agency notes that "in some cases, where a concomitant drug is used frequently, formal interaction studies should be carried out." As an example, FDA cites concomitant use of anti-anginal drugs from different pharmacologic classes, which "are commonly combined and should be subject to formal studies of their combined effectiveness and tolerance." The agency also recommends that special interaction studies be done in cases where the therapeutic ratio is low (i.e. ratio of toxic to therapeutic dose) and the likelihood of concomitant therapy or illness is great. FDA cites four specific studies in such cases: an evaluation of digoxin interaction; a study of the effects of hepatic-enzyme inducers (e.g., phenobarbital) and inhibitors (e.g., cimetidine) if the drug under study undergoes extensive hepatic metabolism; in vivo studies to determine whether drugs that are extensively bound to plasma proteins are being displaced by other drugs (e.g., displacement of warfarin by non-steroidal anti-inflammatory drugs); and studies of other drugs likely to be used "unless the pharmacokinetic screen or the interaction screen provides adequate assurance that important interactions do not exist." Copies of the guideline may be obtained by writing FDA's Legislative, Professional, and Consumer Affairs Branch (HFD-365) at 5600 Fishers Lane, Rockville, MD 20857.

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