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PHARMACEUTICAL BASICS, INC. PLANS TO WITHDRAW 47 ANDAs OUT OF 62 ANDA WITHDRAWALS SOUGHT BY FDA; FIRM QUESTIONS NEED FOR CLASS II RECALLS

Executive Summary

Pharmaceutical Basics, Inc. has agreed to withdraw 47 ANDAs due to discrepancies in the applications regarding pre-production batch sizes. In a June 6 letter to FDA, PBI said it intends to "prepare formal letters of withdrawal for each of these applications, which will be submitted to the Office of Generic Drugs in short order," the letter says. FDA notified PBI on May 1 that it "intends to downgrade the therapeutic equivalence codes and initiate withdrawal of ANDA approval" for 62 products "because of untrue statements, discrepancies and omissions concerning the manufacturing and control of batches used to support approval of the applications." PBI maintains that, for 15 of the ANDAs withdrawal is not appropriate. The number of ANDAs FDA intends to downgrade has grown from earlier reports. FDA officials testified before Rep. Dingell's (D- Mich.) House Oversight Subcommittee March 7 that the agency intended to downgrade the bioequivalence of 23 of PBI's ANDAs because of false statements ("The Pink Sheet" March 18, p. 11). PBI shut down its Denver facility on Jan. 16 following the discovery of "apparent discrepancies relating to the reported size of certain pre-production pilot batches" ("The Pink Sheet" Jan. 21, T&G-11). The company reminded FDA in the June 6 letter that it inherited the problem ANDAs from former owner Colmed Labs. The agency's May 1 letter also requested that PBI initiate a recall of all 62 products. PBI opposes a recall based on the findings of its auditors that there is "no reasonable concern on the basis of which they would counsel PBI to recall any of the reviewed products," or "at a minimum" opposes the classification of the recall as Class II, which indicates a potential safety hazard. PBI also reportedly has determined that very little of the products in question remain on the market. In addition to the conclusions of its own auditors, the company noted that the agency evaluated several PBI drugs as part of its nationwide sampling of generic drugs undertaken in 1989 and 1990. Carbamazepine tablets, metaproterenol sulfate tablets, valproic acid capsules, valproic acid syrup, and warfarin sodium tablets were tested, PBI said. "All batches of all tested PBI drugs met all assayed USP and/or ANDA specifications." Representatives of FDA's Center for Drug Evaluation and Research, Office of Compliance, and Office of Regulatory Affairs are expected to meet early in the week of June 24 to determine what actions to take if PBI refuses a recall. A seizure action reportedly may be threatened. FDA's position remains that, in the face of false statements in a submission, there can be no certainty that there is not a safety hazard in products involved. The agency also reportedly is concerned with applying a consistent standard across the industry: the policy has been that false statements merit a Class II recall. That stance could also indicate that other firms, such as Chelsea, which have withdrawn ANDAs without initiating recalls, may be facing increased pressure or stronger agency actions. PBI also suggested in the letter "alternatives" to the withdrawals of two products involving four ANDAs: megestrol acetate 20 and 40 mg and metaproterenol sulfate tablets 10 and 20 mg. For these two products, "despite the general agreement of our auditors with the FDA investigators' findings, we would nevertheless propose an alternative to withdrawal of the approved ANDAs," PBI said. "Post-ANDA, in vivo biostudies are available for each of these products, which provide untainted, independent bases for assurance of the safety, efficacy and bioequivalence of the drugs," PBI maintained in the letter. The company proposed submitting supplements containing accurate batch records and stability studies "within the next 30 to 60 days" as an alternative to withdrawal and resubmission of the ANDAs. For the remainder of the 62 ANDAs in question, PBI contended that it "is of the view that non-material discrepancies do not warrant withdrawal of approval." The letter cites "inconsequential inconsistencies" relating generally "to the dates on which batches may have been made and submitted records prepared." PBI told FDA that it wants "to share with you" its auditors' reports about these ANDAs "as a basis for establishing a mechanism to cure the non-material 'defects'" in the ANDAs. "Reliable pre- and post- approval data exist which confirm the adequacy of the projected smaller batch sizes to demonstrate bioequivalence," PBI maintained. "In our view, the true test of FDA's discretionary enforcement authority is the agency's ability and willingness to impose penalties commensurate to a violative act, as tempered by the responsiveness and cooperation of a 'responsible' party who brings the act to light," the letter says. "Many others in the pharmaceutical industry are paying close attention to our situation hoping to observe (we believe) that government authorities can and will reasonably moderate their enforcement penalties when a company has voluntarily come forward openly and ethically once problems are identified."
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