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Executive Summary

INWOOD PROPRANOLOL SR BIOEQUIVALENCE TO INDERAL LA is supported by bio studies analyzed using the method of statistical evaluation recommended by FDA, Inwood Labs' parent Forest maintained in a March 9 submission to FDA. The submission responds to a Feb. 13 petition from Wyeth-Ayerst that asked FDA to withdraw Inwood's ANDA for sustained release propranolol based on alleged bioinequivalence to the innovator product ("The Pink Sheet" Feb. 26, T&G-1). Wyeth-Ayerst argued, among other things, that Inwood improperly had excluded a patient with high propranolol-free plasma levels in its submission to FDA. In addition, Wyeth-Ayerst's own statistical analysis of Inwood's ANDA studies found that the product was not bioequivalent to Inderal LA. In response, Forest reported that it hired two statisticians -- Sanford Bolton, PhD, St. John's University, and J. Richard Trout, PhD, Rutgers University -- to evaluate the ANDA studies. The two statisticians, Forest said, "concluded that the exclusion of [the] subject from the analysis was statistically justified, and that the methodology utilized to test for bioequivalence, namely, the two one-sided t-test, was appropriate." The methodology used by the statisticians, Forest argued, is the approach "currently recommended by FDA" and reflects recommendations made by the agency's Bioequivalence Task Force after FDA's September 1986 hearing on bioequivalence. The statistical methodology applied by Wyeth-Ayerst, Forest contended, is "not conventional," is "untested," and was "applied in an arbitrary and capricious manner." * Inwood's sustained release propranolol is currently the only generic version of Inderal LA on the market. Wyeth-Ayerst has attacked the bioequivalence of the "AB"-rated generic at the state level, also arguing that the product should not be accepted by the New Jersey formulary. The state formulary accepted Inwood's product after a Feb. 13 hearing where it heard arguments from both sides. In addition to the statistical bioequivalence issue, Wyeth-Ayerst had told FDA that independent studies of certain lots of Inwood's propranolol found that dissolution limits did not conform to Inwood's ANDA specifications. Addressing that argument, Forest pointed out that the "validated analytical method and composition of the product are proprietary and not available in FDA's summary basis of approval." Without that information, Forest maintained, "it would be impossible for Wyeth-Ayerst to assure the validity of their dissolution data because they could not have utilized a properly validated analytical method. Accordingly, their dissolution data are not to be believed and should be rejected outright." Inwood's sustained release propranolol was the subject of an inspection conducted by FDA in November. The 12-item FD-483 issued by the agency focused primarily on recordkeeping violations and deviations from ANDA manufacturing specifications. For example, FDA cited the firm for: using an encapsulation procedure that was not documented or validated; not including specific dissolution equipment used in lab data; lack of in-process assays on seed bleeds, which are specified in the ANDA; and using different mixing procedures and propranolol seeds than specified in the ANDA. The FD-483 also cites the firm for a batch record FDA says was "reconstructed." Entries on the record, the agency reported, "were not made concurrently with the operations and the signatures/initials of persons performing the operations are not authentic." In a March 2 release, Forest said it believes it "adequately addressed" issues raised by FDA in the FD-483. The company said it responded to the inspection report in December, but has not yet heard back from FDA. Forest issued the release, which addresses Wyeth-Ayerst's petition as well as the propranolol inspection and an earlier inspection on controlled release theophylline, following what the company described as "an unusual amount of trading in Forest stock yesterday, perhaps based on some confusion regarding its Inwood Laboratories subsidiary's generic products." Forest reported that its responses to the FD-483 issued after the September theophylline inspection "have been accepted by FDA." The inspection report includes citations for changes in material specifications and analytical procedures that were not documented in annual reports; changes in material specifications for "active ingredient and time release agent" not listed in annual reports; and "two instances where dilutions for dissolution tests were reported not according to procedure." The report states that "no evidence of submission batch size, formulation, analytical data or biostudy sample falsification or misrepresentation was noted."

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