BARR LABS SHUTDOWN SOUGHT BY FDA DUE TO GMP VIOLATIONS UNCOVERED DURING AGENCY INSPECTIONS; FIRM CLAIMS FDA STANCE IS RETALIATION FOR WHISTLEBLOWING

FDA is pressing Barr Labs to shut down its operations in the wake of violations of good manufacturing practice (GMP) regulations uncovered at the firm's Pomona, N.Y. and Northvale, N.J. facilities. During an Oct. 31 meeting involving district and headquarters officials of the agency and representatives of Barr, FDA presented the firm with a draft consent decree calling for a shutdown of operations. Barr refused to sign the consent decree. The company maintained that the violations cited in Sept. 19 and 21 inspection reports are minor and that it is willing to take corrective actions. Barr responded to the report in 10 days and hoped to negotiate corrective actions short of a shutdown; the agency reportedly was only willing to discuss measures to revive operations after a shutdown. The firm is contending that FDA's demand to shut down operations indicates the agency's determination to retaliate against the firm for its whistleblower role in the generic drug scandal. FDA inspected Barr's Northvale, N.J. manufacturing plant and Pomona, N.Y. research facility from April to September. The inspections, which reviewed both pending ANDAs and products currently manufactured by the firm, yielded two FD-483 reports of adverse findings; they were 19 and 32 pages. Barr has said the inspections "uncovered no incidence of fraud, misrepresentation, deception or other similar unlawful acts" ("The Pink Sheet" Oct. 28, T&G-3). The Barr-FDA dispute became public Nov. 6, when Sen. D'Amato (R-N.Y.) declared on the Senate floor that the agency unfairly targeted the firm. "There is a clear appearance that Barr has been singled out for retribution by the bureaucrats" in the FDA's Office of Generic Drugs, D'Amato said. The investigation by the House Oversight Subcommittee into FDA's regulation of the generic drug industry over the past three years was prompted by complaints made by Barr and Mylan. Furthermore, Barr is said to have had a contentious relationship with FDA's New Jersey district office that predates the generic scandal by years. D'Amato told the Senate that "not one of" the firms found by the investigation to have bribed FDA officials or to have submitted fraudulent ANDAs "has been singled out by FDA for any injunction -- much less one that would shut down the companies' operations." The senator said: "It certainly looks like retaliation to me. Why else would the FDA threaten to destroy a company with no record of fraud or abuse while failing to go after any of the dozen or more companies that have committed criminal acts?" However, FDA inspections have been known to result in a shutdown of both brandname and generic firms' operations based on extensive GMP violations. For example, Lilly temporarily closed a sterile processing facility in 1989 after an FDA inspection yielded a 90-page list of GMP violations. Barr is particularly concerned because the inspection issues apparently are delaying approval of at least five ANDAs that FDA has said are otherwise approvable. The firm said its most recent approval was for methotrexate in November 1990. In evaluating Barr's current production, FDA inspectors cited "numerous in-process and finished product failures," leading the agency to conclude that the processes were not validated. The Sept. 19 FD-483 cites several lots of products that "experienced compendial specification failures for either assay, content uniformity or dissolution." The products included tolazamide, propoxyphene, diphenoxylate, dicyclomine and allopurinol. The investigators alleged that the firm had "no documentation of any meaningful investigation to determine the cause or reason" for many of the process failures noted. The report concludes: "Your firm has no meaningful program for process validation since it fails to address many of the critical issues inherent in such a program." FDA said Barr lacked validation protocols for "critical process variables." In a Nov. 1 letter to FDA Commissioner Kessler, MD, House Oversight Subcommittee Chairman Dingell (D-Mich.) noted that Barr is an FDA "critic . . . known for vocally complaining of what it claims are errors and inefficiencies at the agency and for repeatedly demanding accountability on the part of FDA regulators." Dingell also noted that Barr has volunteered to testify against FDA at subcommittee hearings and "has also sued the agency." Therefore, "Barr naturally suspects that the severe punishment being proposed is simply retaliation for Barr's active role" as an FDA critic, Dingell said. The Michigan Democrat reminded Kessler that FDA is obligated "to remain calm, objective and fair -- even in the face of severe provocation" and cautioned that his "subcommittee will act to protect its witnesses from retaliation for their cooperation" in its investigation. On the other hand, the letter notes that cooperation with Congress "does not earn a company any exemption from regulatory requirements, nor any right to special treatment," and Dingell acknowledged that his subcommittee "does not yet have sufficient information to evaluate the truth of Barr's retaliation charge." Dingell noted that "FDA has been reluctant to close down businesses that have been charged, with considerable supporting evidence," with more egregious violations than those of which Barr is accused. Other firms' violations have included "fraud and manufacturing practices that endanger" public safety." Why, he asked, "is the FDA seeking to shut down one firm for good manufacturing practice infractions while others that may threaten the public welfare more directly are allowed to continue operating?" Barr claims that the infractions listed in FDA's inspection reports "are not major problems that have triggered shutdowns in the past," Dingell noted. "Apparently, no criminal violations and no threats to the public health are involved," he said. "Has the FDA ever closed a business' entire manufacturing and shipping operation, even temporarily, for these kinds of infractions, or has Barr been singled out for punishment of unprecedented severity?" he asked. Dingell indicated that the company claims "it has responded in detail to all the allegations and is so anxious to avoid confrontation with the agency that it has offered to conform its behavior to all the agency's demands, even those that the company considers unreasonable." However, the letter states, Barr says its "efforts at accommodation have been either ignored or rebuffed by FDA," whose "officials have apparently been directed not to talk to Barr" about the firm's responses to the inspection reports. Barr already has recalled at least one product as a result of the inspections: 300 mg allopurinol tablets. The firm recalled one lot of the product when a sample failed original and check dissolution analyses by two FDA labs. The firm's records indicated that four finished product lots had failed dissolution testing in 1990, suggesting that the process had not been validated, according to the FDA inspection report. Dingell noted that Barr claimed FDA inspectors "made numerous mistakes in their reports" but "refused to change the reports when the errors were pointed out." For example, the company has said that the inspection report cites Barr for "reworking" products which the firm continually mixed in accordance with ANDA specifications. The letter emphasizes that Dingell "has not prejudged" the merits of Barr's allegations. "The subcommittee understands Barr's compliance history has been problematic," but it "will be following the evolution of this dispute carefully." He added that the allegations "raise issues at the heart of the credibility of the FDA and could threaten the efforts by both [Kessler] and others to strengthen the agency."