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Executive Summary

FDA is initiating proceedings to withdraw approval of 25 Quantum ANDAs. The list of Quantum drugs for which FDA will seek ANDA withdrawal includes triamterene/hydrochlorothiazide (the equivalent of Maxzide), clorazepate (Tranxene), diazepam (Valium) and trazodone (Desyrel). FDA also intends to change the therapeutic equivalence evaluation rating for the 25 products from "AB" (therapeutically equivalent) to "BX" (assumed therapeutically inequivalent pending further evaluation). In a Nov. 15 letter to Quantum, FDA Office of Compliance Director Daniel Michels informed the firm that the agency would be taking the actions based on its determination "that untrue statements, discrepancies, and omissions exist concerning the production and testing of lots used to support approval of the applications." Quantum was included among the group of 20 large generic firms inspected as part of the agency's industry review. An FD-483 adverse inspection observations report issued to Quantum on October 20 at the completion of the inspection details the specific recordkeeping and filing problems found by the agency. The FDA findings, Michels contends in the Nov. 15 letter to Quantum, raise "serious" questions about the reliability of the application data and the bioequivalence of the products, and mandate that the agency "change its advice to the public regarding the therapeutic equivalence of the products." The letter notes that a "formal" description of, and the "specific grounds for," the agency's proposal to withdraw approval of the ANDA's will be published "shortly" in the Federal Register. Quantum will have 30 days after the notice is published to request a hearing. Quantum also recently received a regulatory letter from FDA addressing results of microbiological assays by FDA on samples of the firm's product, nystatin. The reg letter, issued Oct. 25, states that samples from two lots of oral and two lots of vaginal nystatin tablets "failed to meet established standards of potency . . . in that they contain less than 90% of the Nystatin units which they are labeled to contain." Quantum recalled the nystatin lots cited on Nov. 8 along with four other products found by FDA to contain false ANDA data. Nystatin was not included in the list of products for which FDA is proposing ANDA withdrawal based on fraudulent findings. The other Quantum products included on FDA's ANDA withdrawal list are fenoprofen (the generic equivalent of Nalfon), oxazepam (Serax), timolol maleate (Blocadren), meclofenamate (Meclomen), and doxepin (Sinequan). FDA Commissioner Young reported on the Quantum situation during an update on generic inspections presented to Chairman Dingell's (D-Mich.) House Energy & Commerce Oversight Subcommittee on Nov. 17. Young said that of the 11 "suspect" firms originally targeted for special FDA inspections, four were found to have "engaged in fraud and misrepresentation of information submitted to FDA in their ANDAs. Other problems, such as good manufacturing practice (GMP) violations and unauthorized deviations from approved manufacturing procedures, were found in eight of the 11 firms surveyed. Thus far, Young reported, "the violations have resulted in 54 product recalls, three ANDA withdrawal actions covering 29 products, one voluntary product withdrawal, and some referrals for criminal prosecution to the Department of Justice." Among the additional 20 firms selected for review based on their number of ANDAs, Quantum is the only firm cited to date by FDA for fraudulent filings; two other firms, Watson Labs and Pharmaceutical Basics, were found to have GMP problems serious enough to warrant regulatory letters. "These findings, along with other manufacturing deficiencies discovered by FDA investigators and the firms themselves," Young reported, "have led to an additional 35 product recalls." A key component of these special inspections was the cross-checking of plant records with product data and manufacturing information provided to FDA in the firm's ANDAs, a selection of which were brought by the FDA investigators to the plants for this purpose. Young reported that "in all, approximately 380 ANDAs, or nearly 12% of the total number of ANDAs held by all of the companies surveyed, were audited in conjunction with these specialized inspections." The FDA management at the hearing indicated that this type of in-plant ANDA review would become a part of FDA's normal inspection routine. FDA labs have now completed analysis of about 2,500 samples from the top 30 generic drugs. The analysis found that 27 samples, or about 1.1% of those analyzed, did not meet product specifications -- "a rate approximating that found in other FDA brandname and generic drug sampling surveys over the last five years," Young pointed out. The sampling effort has resulted in the recall of multiple strengths of four products, including Quantum's nystatin. Reporting on the agency's review of bioequivalence testing samples, Young noted that the agency has now obtained "over 1,500 product samples from three major contract labs in the U.S. and Canada for visual and chemical analysis to assess the adequacy of bioequivalency testing and to determine if such testing was performed using fraudulent samples." In addition to the analysis of samples collected from the 30 plus firms included in the inspection review, Young noted that FDA has recently broadened its bioequivalence sampling review "by embarking upon a review of eight domestic and three foreign laboratories that perform premarket product testing services."

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