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Executive Summary

Generic companies that have submitted fraudulent data will be required by FDA to revalidate bioequivalence studies for generic drugs that are difficult to duplicate, Commissioner Young declared at the Nov. 17 generic drug hearing before the House Commerce/Oversight Subcommittee. Commissioner Young said in written testimony that FDA is "considering whether to require firms that have engaged in fraud to retest the bioequivalence of any of the 'hard-to-copy' products which may still be on the market." When Rep. Lent (R-N.Y.) asked why the agency is only "considering" such action, Young replied: "We hadn't prepared an announcement" when the agency's testimony was prepared. "But let me announce . . . that we have already drawn up a list," Young said. He added that FDA intends "to see whether the companies will voluntarily comply, and if not, we have a few tricks up our sleeve [to] make this revalidation work." Young noted that "some innovator drugs are difficult to copy and, as we have learned, perhaps nearly impossible to replicate honestly." SK&F's Dyazide appears to be one example. The only generic versions were marketed by Vitarine and Bolar, and FDA investigations found evidence that the ANDA sponsors submitted fraudulent data. FDA also announced that it is working with the U.S. Pharmacopeia to tighten specifications for more than 20 critical dose drugs, including phenytoin and conjugated estrogens. The agency is "undertaking an additional program of analyses designed to verify the quality of marketed versions of these drugs with narrow therapeutic ranges," the commissioner testified. FDA has identified more than 20 drugs, "each of which is available in generic form." The drugs are in "important" categories of therapy for epilepsy, asthma, hypertension and heart problems, Young said. "Like our earlier surveys," he said, "we are obtaining product samples from all brandname and generic manufacturers." The review of standards for critical dose products will be prospective, "where appropriate," Young said. The effort is intended to improve the bioequivalence and other quality standards of such drugs. Subcommittee Chairman Dingell (D-Mich.) suggested that sucralfate (Marion's Carafate) is a hard-to-copy drug. Because the drug acts internally as a topical protectant for ulcers, rather than systemically, blood concentration studies cannot be used to demonstrate bioequivalence. However, Stephen Fredd, MD, director of FDA's Gastrointestinal and Coagulation Drug Products Division, testified that the agency does not characterize the required reference-test-placebo studies as clinical trials. The agency calls them "bioequivalence studies with clinical endpoints." Fredd explained that the 1984 ANDA law does not permit FDA to require clinical trials for ANDA approval. Schein-Danbury, Rugby-Darby and Bolar collaborated on a protocol to support an ANDA for generic Carafate, Fredd noted. However, he said the companies proposed conducting the study in Hungary. FDA wanted at least half the study to be performed domestically, so that the study included U.S. patients and clinicians and could be inspected. After the three firms persisted in their plan to conduct the study in Hungary, Fredd said he recommended that a clinical hold be placed on the IND because the protocol would not result in approval. He said he subsequently learned that the firms proceeded with the study despite the clinical hold, presumably in pursuit of Hungarian approval. Dingell said that due to "price levels in the Hungarian market," he had "reason to think that if the study was performed [for marketing] over there they might not be able to recoup the costs of their study." Danbury Vice Chairman William Haddad represented the firms during their negotiations with FDA, Fredd noted.

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