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LILLY INSPECTION REPORTS FOR FOUR YEARS REQUESTED BY DINGELL; GPIA WANTS CONGRESSIONAL SCRUTINY OF BRAND FIRMS, ASKS FDA TO FORWARD INSPECTION INFO

Executive Summary

House Energy & Commerce/Oversight Subcommittee Chairman Dingell (D-Mich.) is asking FDA for all FDA inspection reports and adverse observations on Lilly pharmaceutical manufacturing facilities since the beginning of 1985. The request for the four-and-a-half years of records is a follow-up to the recently completed inspection of a Lilly solid drug manufacturing facility and the company's subsequent recall of 10 products made at that facility. Based on the publicity Lilly's recall generated in the lay press and the ongoing attention to drug manufacturing issues, the congressional request for Lilly documents is a natural response. Dingell's staff contacted Lilly directly about the inspection during the first week in September. The recall and congressional interest in inspection documents, however, put Lilly on the hot seat -- not only for the company's own reputation but also for the rest of the brandname industry. The Dingell subcommittee's reaction to the Lilly regulatory record and the company's response to the recent findings may determine the extent to which congressional inquiry into manufacturing and approval practices in the generic industry spill over to the brandname part of the industry. Lilly's initial reaction to the adverse inspection findings was forceful and rapid. The firm discontinued production at the inspected facility, elevated three execs to new positions to revamp quality control procedures and began a product-by-product review of the products manufactured at the inspected facility to check FDA allegations. Within two weeks, Lilly responded to FDA and initiated the recall (see related story). That response, plus a commitment by the firm to review its manufacturing procedures for all of its pharmaceutical products, appears well designed to reassure congressional oversight. There are a number of figures, however, who would welcome a chance to pull Lilly and other brand firms into the limelight about manufacturing practices. Lilly openly denigrated the generic drug business in the late 1970s and carried on a protracted public argument with then-FDA Commissioner Donald Kennedy over the comparable recall records of the brand and generic sectors. One request for more attention to the inspection records and manufacturing practices of the brandname companies was sent to FDA Sept. 12 from Danbury Pharmacal's William Haddad. Writing as chairman of the Generic Pharmaceutical Industry Association (GPIA), Haddad requested "that FDA forward to the Dingell committee the last 24 months of records of the brandname inspections, including reports of GMP ]good manufacturing practices regs[, recalls labeling, paperwork, etc." Noting that the generic drug crisis has publicized problems involving either corruption or "the manufacturing practices of certain companies," Haddad contended that the GMP problems, labeling and stability issues, paperwork deficiencies, recalls and "other problems" have been "presented in a vacuum." Such violations "are problems of the pharmaceutical industry, not just of generic companies," he maintained. "I don't want to minimize the misconduct of some companies, nor do I want to diminish the concern of the FDA or the committee about the practices outlined," Haddad said. However, "I would dearly like to have them considered in context." Commissioner Young provided what he called "a sense of perspective" regarding the generic crisis at a Sept. 14 meeting of the American Pharmaceutical Association's Academy of Pharmaceutical Research & Science. From October 1985 through June 1989, Young said, there have been 25 Class I recalls of drug products, of which 16 involved generic drugs. Problems with consistency in product bioavailability also are not restricted to the generic industry. According to FDA "Enforcement Report" records, 17 drugs were recalled in 1988 due to batch-to-batch dissolution failures. Eight of those 1988 dissolution recalls were conducted by brandname firms (Abbott, two by Lilly, Sterling, Carter-Wallace, Sandoz, and two by Smith Kline & French). Eight products were recalled by generic firms (two by Pharmaceutical Basics, Sidmak, Pioneer Pharmaceuticals, Kalipharma, Zenith, Lemmon, and Rondex/UDL). An additional product was recalled by the Cord generic arm of Ciba-Geigy. Commissioner Young continues to stand by his assessment that FDA has received no "unusual" generic drug safety and efficacy reports to date. At the opening session of the Sept. 14-15 meeting of the American Pharmaceutical Association's Academy of Pharmaceutical Research & Science, Young predicted that the "recalls and suspensions" associated with the generic inspections "may be temporary." Young said "many of the products may well reappear on the market if technical questions about them can be cleared up." FDA investigators have uncovered four kinds of problems during for-cause inspections of generic drug firms, Young said. They relate to bioequivalence studies, stability data, manufacturing specifications listed in individual ANDAs, and GMP (good manufacturing practice) requirements. Young said inspectors found evidence that two firms submitted fraudulent bioequivalence data based on tests in which the innovator product was disguised as the test generic drug. "So far, this represents a very small number of products, none of which are currently being marketed," he added. The inspections also indicate that three firms have falsified records on production runs used to support ANDA approvals, Young continued. "Samples from these production runs were used in bioequivalence studies to validate the therapeutic equivalence of the generic drug" to the reference product, he explained. The falsification involved either overstating the size of the production run or manufacturing the samples at the companies' research lab rather than the production department. Among manufacturing problems, inspectors "have discovered that some firms, in 'scaling up' from relatively small batches of drugs submitted for approval to the full production runs, have not demonstrated that the product continues to meet all specifications," Young said. Other manufacturing problems involve unapproved changes made in the manufacturing processes, inadequate records, and GMP violations. GMP problems "are not confined to this particular group of recently inspected firms, or for that matter, the generic drug industry," the commissioner pointed out. The inspection has resulted in 29 Class II recalls by 13 generic drug firms but no Class I recalls, he said.
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