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Executive Summary

FDA is initiating withdrawal proceedings for Bolar's ANDAs for its nitrofurantoin macrocrystals 50 and 100 mg caps, based on information from sample analyses that raise questions about the validity of bioequivalence testing for the products. The agency also intends to downgrade the therapeutic equivalence code of the products from "AB" (equivalent) to "BX" (inequivalent) in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (the "Orange Book"). FDA informed Bolar of its intended actions in an Oct. 13 letter. Lab results from bioequivalence samples, FDA said, "show that the product tested to demonstrate bioequivalence is not representative of the nitrofurantoin products manufactured by Bolar" and "strongly suggest that Norwich Eaton's Macrodantin product was substituted for Bolar's product in the bioequivalence test." FDA explained that it compared a sample obtained from Bolar's contract testing lab PharmaKinetics with a sample of the innovator product, Macrodantin. Those tests, FDA said, "revealed that the sample of Bolar's [bioequivalence lot] is analytically indistinguishable from the sample of Norwich Eaton's [Macrodantin] reference lot." The agency also evaluated a sample from Bolar's current production lot, which showed the product to be "substantially different" from the samples of Macrodantin and Bolar's bioequivalence lot, FDA said. The agency further noted that analysis of a sample submitted by Bolar during the ANDA "approval process revealed a product substantially different" from the sample of the bio lot collected at PharmaKinetics. Earlier questioning by FDA about the validity of the bio samples resulted in an Oct. 9 recall of Bolar's nitrofurantoin to the wholesale level. FDA asked the firm on Oct. 12 to extend the recall to the retail level. Bolar denied that request on Oct. 13, and the agency is now considering legal action to force the extension. In an Oct. 6 release, FDA said that it presented to Bolar "evidence . . . indicating that the company substituted the innovator product for its own during bioequivalency testing." According to Bolar, FDA showed company representatives a photograph of a plain, unmarked capsule that the agency identified as Bolar's bioequivalence sample. At the time, FDA requested that the company begin a recall, because it cannot "assure whether the Bolar product is therapeutically equivalent to the brandname product." Bolar maintains that it did not submit the bio sample tested and photographed by FDA. Bolar "believes that the product tested by the FDA was not the same product it provided to the testing laboratory," the firm said in an Oct. 8 release. The company explained that its bio samples are always "dressed up" with the Bolar logo, unlike the sample tested and photographed by FDA. Bolar said that it has hired an outside firm to conduct an investigation to determine the origins of the bio sample. However, Bolar's argument is at odds with PharmaKinetics' views on the origin of the sample. PharmaKinetics' outside counsel (Laxalt, Washington, Perito & Dubuc) maintains that the material that the FDA obtained from PharmaKinetics was a sample retained from the lot submitted by Bolar for testing several years ago. The firm noted that PharmaKinetics' records on the bio sample describe the product as yellow capsules with no markings. Laxalt et al. says that it was not unusual for Bolar to submit test material in unmarked capsules and tablets. Nitrofurantoin "accounts for almost 10% of Bolar sales as of Sept. 30," Bolar said. The firm's product, approved on June 24, 1988, is the only generic nitrofurantoin macrocrystals on the market. According to FDA, nitrofurantoin macrocrystals are a very difficult product to replicate, and several companies that filed ANDA applications failed at their attempts. HHS' Office of the Inspector General also attended the Oct. 6 meeting between FDA and Bolar. The IG's office initiated a criminal investigation of Bolar a couple of months ago. Reportedly, the Justice Department has not yet decided whether to prosecute Bolar. Other firms under criminal investigation by the IG include Vitarine, Par and Quad. Nitrofurantoin represents the third incidence of an alleged switching of an innovator product for a generic version of a Bolar drug during bioequivalence testing. Previously, FDA discovered that innovator products may have been switched for Bolar's generic Dyazide and Mellaril in bio samples. As with nitrofurantoin, Bolar maintains that allegations of switches for Mellaril and Dyazide involve sample confusions or mix ups. In the case of Dyazide, the company submitted two lots for testing to PharmaKinetics, only one of which passed bioequivalence testing. The firm subsequently notified PharmaKinetics that the lot numbers of the two samples were inadvertently switched. With Mellaril, FDA found that bio samples contained Sandoz' product. Bolar said that Sandoz tablets fell into a coating machine that covered the Sandoz logo, and that those tablets were mistakenly mixed in with Bolar's tablets. Bolar is one of the 13 generic drug companies that have been subjects of FDA's forcause inspections of manufacturing and bio testing practices. In its Oct. 6 release, FDA noted that it "has been systematically evaluating samples of Bolar's products."

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