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Executive Summary

ICH DRUGS FOR ELDERLY GUIDELINE SUGGESTS PHASE III PHARMACOKINETICS screening method as a viable alternative to formal pharmacokinetic studies to detect differences between older and younger study subjects. "The advantage of a pharmacokinetic screen is that it can assess the effects not only of age itself, but of other factors associated with age (altered body composition, other drugs, concomitant illness) and their interactions," the guideline states. The draft guideline, "Studies in Support of Special Populations: Geriatrics," prepared by the Efficacy Expert Working Group of the International Conference on Harmonization, was published by FDA for comment in the April 16 Federal Register. The working group was established during the first ICH round in Brussels in 1991. Written comments are due by May 17. The agency says it will not extend the comment period because it must respond to the ICH in June. Pharmacokinetic screening may be done in Phase III ("and Phase II if the sponsor wishes"), the guideline says. The procedure involves "obtaining, under steady-state conditions, a small number (one or two) of drug blood level determinations at 'trough' (i.e. just prior to the the next dose) or other defined times from sufficient numbers of Phase II/III clinical trials patients, geriatric and younger," the guideline states. During the process, certain conditions such as time of dosing, relation of dosing to meals, demographic and disease factors, renal and liver function, body size and concomitant illnesses should be noted. "Where the screen detects large differences, formal pharmacokinetic studies may be indicated as a result, unless the screen's results are sufficiently informative," the guidelines state. Formal pharmacokinetic studies can be conducted in healthy geriatric subjects or patient volunteers with the target disease. They may consist of a pilot trial of limited size or a larger single-dose study of sufficient size "to permit statistical comparisons between geriatric and younger subjects." The geriatric guideline also requests pharmacokinetic studies in renally or hepatically impaired patients for drugs that are excreted significantly through the kidney or metabolized primarily in the liver. Drug-drug interaction studies are recommended in cases where the therapeutic range of the drug or likely concomitant drugs is narrow. Drug-drug interaction studies are specifically advised for: digoxin and oral anticoagulants, because many drugs alter their serum concentrations; drugs that undergo extensive hepatic metabolism, because they may be affected by hepatic enzyme inducers like phenobarbital or inhibitors like cimetidine (SmithKline Beecham's Tagamet); and drugs metabolized by cytochrome P-450 enzymes, like terfenadine (Marion Merrell Dow's Seldane), which can be affected by ketoconazole (J&J's Nizoral) and macrolide antibiotics. In addition to the draft geriatric guideline, FDA published in the same Federal Register draft ICH guidelines for stability testing and preclinical reproductive toxicity. Draft guidelines on clinical safety reports and dose response are expected to be published sometime this summer. ICH II is scheduled for Oct. 27-29 in Orlando. One of the recommendations of the draft "Tripartite Guideline for the Stability Testing of New Drug Substances and Products" opposed by FDA is that long-term stability testing take place at a temperature of 25 degrees Celsius. In an introduction to the notice, FDA voiced its opposition to the temperature selection, advocating instead a temperature of 30 C. FDA explained that the ICH selection of 25 C is based on the premise that the tripartite members -- the U.S, Europe and Japan - - are located in (the cooler) climatic zones I and II. However, FDA maintained that "temperatures in regions with significant populations in the U.S., territories of the U.S. and other nations of commerce are defined by [the hotter] climatic zones III and IV." Five other revisions to the current draft stability guideline that FDA is recommending include: "stability test data obtained from laboratory batches would not be acceptable as primary data for determination of an expiration dating period; full stability data should be submitted from three batches, not two, at the time of NDA submission; data from all marketed container/closure systems, not just the 'most sensitive,' should be submitted in an application; formal statistical analysis should be applied to all long-term data; and 'three-month weighted average' under temperature fluctuations should be deleted."

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