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Executive Summary

FDA is considering the concept of accepting animal bioequivalence studies for oral generic cytotoxic drugs in place of bio studies in humans. The agency is exploring the idea as a possible solution to the difficult ethical problem of exposing healthy human volunteers to the highly toxic drugs. The issue has come up in the context of approving ANDAs for oral cytotoxic agents. At the National Association of Pharmaceutical Manufacturers annual meeting in late January ("The Pink Sheet" Feb. 1, p. 7), FDA Office of Drug Standards Director Peter Rheinstein, MD, said the agency is "going to be looking at the issue of bioequivalence studies for generic versions of oral anticancer agents." Rheinstein noted that "many of these drugs are themselves carcinogenic, and the idea of using normal volunteers certainly has strong ethical considerations." In addition to the ethical consideration of using healthy volunteers, Rheinstein identified other problems with the design of human bioequivalency trials. "It may be difficult to get a suitable population of people who actually have the disease," he said, noting that the agency planned to look "at a number of alternatives in this regard." FDA met Jan. 29 to discuss possible alternatives to human bioequivalence testing of generic anticancer drugs. Among the FDAers in attendance were Center for Drug Evaluation and Research Director Carl Peck, MD; Office of Drug Review I Director Robert Temple, MD; Office of Drug Review II Director James Bilstadt, MD; Division of Bioequivalence Director Shrikant Dighe, PhD; and Rheinstein. At the meeting, animal bioequivalence studies were offered as one possible alternative for testing of generic oral anticancer drugs that companies might propose to the agency, according to Rheinstein. The FDAer noted, however, that an appropriate animal model would depend on its ability to demonstrate applicability to man. In vitro bioequivalence studies were also discussed as an option. An ANDA currently pending for oral cyclophosphamide is reportedly the catalyst for FDA's recent interest in bioequivalence requirements for oral anticancer products. Rheinstein explained that there are "very few generic versions of any oral anticancer tablets or capsules . . . at the present time." Just recently, Pharmaceutical Basics received approval to market a generic version of Bristol-Myers' Megace (megestrol acetate tablets). Bristol-Myers currently manufactures the only oral cyclophosphamide product, Cytoxan, sold in 25 and 50 mg tablets. Leucovorin and tamoxifen are two other oral anticancer that have been approved via ANDAs. Rheinstein touched on a number of agency activities affecting the generic industry including: FDA regulations implementing Title I of the Waxman/Hatch Patent Term Restoration Act. Rheinstein said that a draft of the regs has been completed, but still faces a lengthy internal clearance process. In addition, the new regs will address the portion of the law relating to what is necessary to break an innovator's exclusivity. Rheinstein explained that the regs will address issues such as: "Does one have to repeat the entire new drug application? Or is there some subset that would suffice to break the exclusivity of Waxman/Hatch?" What happens to generics already on the market when an innovator reformulates, "especially if the innovator does clinical studies to establish his reformulation." This situation will exist when SmithKline's reformulated Dyazide, currently in clinicals, is approved. SmithKline decided to pursue the reformulation after Bolar received ANDA approval for a generic version of the original. Release of FDA's bioequivalence report which will be published shortly. A draft version cleared the Center for Drugs and Biologics last November and the agency now awaits comments from outside consultants. The report "does not find any significant problems with the way FDA has been carrying out its responsibilities to evaluate bioequivalence," Rheinstein said. Therapeutic Inequivalence Action Coordinating Committee, an in-house group established about three months ago to investigate reports of inequivalence. The committee has representation from: the Office of Epidemiology and Biostatistics, the Office of Drug Standards, Office of Compliance, and the Offices of Drug Review I & II. Other issues of current interest to the agency also mentioned by Rheinstein, included the problem of several ANDA applications referring to a single bioequivalence study, and the validity of bioequivalence studies after scale-up production and formulation changes ("The Pink Sheet" Feb. 1, p. 2). Commenting on the dipyridamole DESI situation, the FDAer stated: "I don't think there has been any conscious decision at FDA not to proceed with dipyridamole, with the DESI actions. DESI actions simply take a fairly lengthy period of time. I want to reiterate that what you are seeing is not any conscious decision to favor either the brandname drug or the generic drug." If there is a decline in dipyridamole sales, Rheinstein said, it may not be a result of worry over "the status of generics" but because "reimbursement for all dipyridamole products including Persantine is being severely curtailed." Soon after FDA's publication of the DESI notice, he continued, "Maryland Medicaid sent around a physicians' circular, as well as a pharmacy circular, saying that Medicaid would no longer pay for any generic dipyridamole. It would pay for the brandname only in those cases where the doctor wrote out out the prescription in his own handwriting, and the patient had a heart valve implant and was also on [coumarin]."

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