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Executive Summary

SUPERPHARM DIAZEPAM ANDAs WILL BE WITHDRAWN due to "untrue statements of material fact" and "lack of substantial evidence" to support the approvals, under an FDA action proposed May 22. Superpharm holds three ANDAs for 2, 5 and 10 mg strengths of its generic version of Roche's Valium. Superpharm suspended distribution of its diazepam products last August and recalled products Dec. 5. FDA said it is proposing to withdraw the ANDAs because "the applications contain untrue statements of material fact, and (2) based on new information, evaluated together with the evidence available when the applications were approved, there is a lack of substantial evidence" that the drugs will have their intended effect. FDA announced that it would pursue ANDA withdrawal proceedings against Superpharm's diazepam products last December ("The Pink Sheet" Dec. 18, p. 2), when the agency downgraded the drugs' bioequivalence ratings from AB to BX. Superpharm has until June 19 to request a hearing on the proposed ANDA withdrawals. Superpharm is considering whether to request a hearing on the proposed ANDA withdrawal or to challenge FDA's action. A spokesperson for the manufacturer said Superpharm is "looking at various ways of bringing our products back to the marketplace." During testimony one year ago before Rep. Dingell's (D-Mich.) House Oversight Subcommittee, FDA former Generic Drugs Division Director Marvin Seife, MD, suggested that Superpharm's diazepam was a suspicious drug approval. Seife noted that it "was reviewed in a record four and one-half months." The proposal notes that during an inspection of Superpharm conducted from July 11 to Aug. 1, 1989, "FDA investigators identified false statements and other significant discrepancies concerning the production and testing of batches used to support approval" of the three applications. "The untrue statements and discrepancies identified" in the ANDAs "constitute new information that raises serious questions about the identity and characteristics of the batches that were used to demonstrate the bioequivalence of Superpharm's products and, thus, raises concerns about the actual bioequivalence of Superpharm's marketed products to Valium tablets," the agency said. Furthermore, the proposal asserts, "the scope and significance of the untrue statements and discrepancies call into question the reliability of all data submitted to FDA to support approval of Superpharm's ANDAs for diazepam." The ANDA withdrawal proposal explains that FDA granted a waiver on in vivo bioequivalence study requirements for the 2 mg and 5 mg products "because of the similarity of these two strengths to the 10 mg product." FDA noted that "comparative in vitro dissolution studies were required instead." One discrepancy involves batch records for the 2 mg product. Superpharm's July 1, 1985 ANDA cites a 20,000-tablet batch, while the company's response to an FDA deficiency letter - which indicated the batch "was inadequate for the purpose of stability testing" - cites a 60,000-tablet batch. The proposal notes that FDA's reevaluation of the ANDA and inspection of the firm "have revealed a number of discrepancies" regarding the batch. Not only do different batch records indicate different batch sizes, but the records "also show that the two different sizes were manufactured in the same equipment at the same time, a physical impossibility." Furthermore, "discrepancies also exist concerning the raw material and manufacturing steps used in the manufacture" of the batch, according to the agency. Two batch production records were also submitted for the 5 mg product. One, indicating a 20,000-tablet batch, was submitted with the ANDA and the second, indicating a 60,000-tablet batch, was submitted in response to a deficiency letter. In addition, batch records filed with FDA indicate that the batch was manufactured on March 1, 1985, but a Superpharm facility notebook indicates manufacture on March 28, 1985. Furthermore, FDA said it found discrepancies "concerning the raw materials used in the batch." Regarding the 10 mg product, FDA said its inspection "revealed several discrepancies regarding the manufacture of" two stability batches. "First, inconsistencies exist between the amount of product produced according to the batch records, the amount of product destroyed according to destruction records and the amount of product necessary to perform the required stability studies on these batches," the agency said. Furthermore, "although the batch records show the use of multiple excipients, the raw material inventory records corresponding to the lots of excipient ingredients on the batch records do not show use of any excipients" in one 10 mg batch " and show use of only one excipient in" another. Plant records also differed from the ANDA regarding the manufacturer and supplier of the diazepam raw material.

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