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Executive Summary

Rep. Dingell (D-Mich.) is delving into FDA's handling of generic conjugated estrogens, particularly the agency's treatment of Barr, in a followup to the Energy & Commerce/Oversight Subcommittee's Nov. 17 hearing on the generics investigation. In a Dec. 11 letter to Center for Drug Evaluation and Research Director Carl Peck, Dingell requested clarification of the issue "because of discrepancies or ambiguities involving your testimony on Nov. 17, other record materials, and the [Energy & Commerce/Oversight] Subcommittee's understanding of the history of the conjugated estrogen episode." The letter to Peck includes 48 questions relating to the regulatory history of generic conjugated estrogens and the agency's evolving policy toward bioequivalence requirements for the generic product. Dingell said that Peck's responses to the questions on the "episode" would "be treated as an extention" of Peck's sworn testimony before the subcommittee on Nov. 17. Peck was asked to respond by Dec. 29. Dingell's questions for Peck range from the first USP standards for conjugated estrogens in 1970 to whether FDA still plans to hold another advisory committee meeting on the subject. The subcommittee asked Peck to provide details on past ANDA approvals for conjugated estrogens; the chemical differences between Wyeth-Ayerst's Premarin, which is derived from mare's urine, and the generic synthetic products; changes in Premarin labeling, including potential cancer risks; FDA's conflicting guidances on conjugated estrogens bioequivalence testing requirements; Wyeth-Ayerst's role in influencing FDA's decision to require plasma studies for bioequivalence; Peck's personal understanding of the Fertility & Maternal Health Drugs Advisory Committee recommendations last January; and whether cancer risks were a consideration in rejecting Barr's ANDA applications. The Michigan congressman also asked whether FDA still intends to begin the revocation process for generic conjugated estrogens on the market as the CDER director told the subcommittee in November. Dingell's letter to Peck appears to be an effort to get to the bottom of the agency's decision in October to reject Barr's ANDAs for conjugated estrogens. Barr initially filed ANDAs for conjugated estrogens in 1987 based on urinary excretion studies, which had been recommended by FDA in a 1986 guidance. FDA decided to require blood level studies to determine bioequivalence in June 1988 in response to information provided by Wyeth-Ayerst and rejected Barr's ANDAs. Barr filed a lawsuit against FDA in late 1988 in response to the sudden change in the rules. However, Barr subsequently did a pilot blood level study in an effort to meet the new requirement and submitted the new data in March 1989 and again in June after the first submission was misplaced at FDA; the company's submission was rejected on Oct. 11. Dingell has been concerned that some at FDA may seek retribution against the generic companies that instigated the subcommittee's generics investigation. Barr was one of the three generic firms to go to Dingell with evidence of favoritism in the generic drug approval process. And Barr complained in a recent letter to FDA that the agency's actions toward the company's conjugated estrogens applications was "a retaliatory act" because of "Barr's cooperation with the House Oversight Subcommittee." FDA apparently plans to take the issue to a new generic drugs advisory committee that is now in the process of being established. A notice in the Federal Register is expected to appear before Christmas announcing the establishment of the new advisory committee.

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