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Executive Summary

Pharmacodynamic studies are a potential replacement for clinical studies currently required to establish equivalence of generic drugs that are not systemically absorbed, FDA Division of Bioequivalence Director Shrikant Dighe, PhD, told the Regulatory Affairs Professionals Society 12th annual meeting Sept. 28. "Pharmacodynamic measurements may be an answer to bioequivalence studies for [drugs] for which there is no absorption in the systemic circulation," Dighe said. "Pharmacodynamic measurements have been demonstrated to be sensitive and reproducible in certain cases, and those could be potential methodologies for the [evaluation] of bioequivalence of these non-absorbing products." If adopted, the use of pharmacodynamic studies could make ANDA submissions for products that are not systemically absorbed easier for generic firms. Presently, the agency requires clinical studies showing therapeutic equivalence for such products, with the number of patients required ranging from 60, for products like cholestyramine and metered-dose inhalers, to 250 for sucralfate. FDA, however, does not appear to be considering use of the studies in the near future. Dighe noted that the pharmacodynamic studies are "fertile territory," but "need to be explored in depth." While discussing agency accomplishments since passage of the Waxman/Hatch law in 1984, Dighe pointed to a number of bioequivalence issues that are still causing problems for FDA, including incorporation of outlier data and specificity of radioimmune assays. The agency is looking at both issues and plans to prepare a guidance document on assay validation and develop a methodology for dealing with outlier data, Dighe said. Addressing the issue of outliers, Dighe explained that "one cannot, without good reason, arbitrarily [delete] values from data because they are too small or too large and somehow to not fit the picture that you want to present." However, he added, "the problem of what to do with outliers is not an easy one." The Division of Biometrics "is looking at this problem very closely," Dighe said, "and will suggest in the near future a possible methodology to evaluate outliers." Submission Of Raw Pharmacokinetic Data On Computer Disks Expedites Reviews, Dighe Says Regarding assay methodologies, Dighe said that radioimmune assays are currently the only type of assay where the agency feels it is not getting sufficient validation information. "Radioimmune assays do present a problem from time to time," he said. "The great difficulty that I find many of the laws have is to show what is the specificity of the radioimmune assay, and that information is sometimes lacking or is not completely adequate." Dighe predicted that a guidance on validation of assay methodologies would be available at the end of November. The Bioequivalence Division is also seeking to increase the amount of pharmacokinetic data submitted on computerized disks. "Our experience to date is that only 15-20% of firms have utilized this medium for submission of raw pharmacokinetic data," Dighe said. FDA published a guidance on computerized submissions of bioequivalence data in December 1987. "If you have the data on computer, especially the raw data, it makes [it] very easy to evaluate the data . . . and these statistical evaluations can be done very quickly," Dighe said. "If we do not have the data on a computer disk, all that raw data has to be entered into the computer [by FDA] and it takes days -- that's going to set you back." Dighe noted that the agency has "no explanation as to why more firms have not taken advantage of the [computerized disk] format, but [is] standing ready with [its] PCs." The Generic Drug Division is increasingly using computers for tracking ANDA submissions. Generic Drug Division Review Support Branch Chief David Rosen reported to RAPS that the division is planning to expand the capabilities of its Management Information System to include, among other things, the capability to access current good manufacturing practice (CGMP) data on companies. Rosen said the agency is "talking about" and has "made headway with" expanding "the system to include interface with the Office of Compliance, and potentially the FDA field offices." FDA "hopes to be able to generate on-line CGMP inspection requests," Rosen said, noting that the division has "had some preliminary discussions with [the Office of Compliance], and they are receptive to the idea." The MIS system includes data on all pending ANDA applications. Rosen noted that the division is currently working on adding data on pending abbreviated antibiotic applications to the system. In addition, the division intends to use the system to track labeling submissions. Summarizing submission and approval statistics during the government fiscal year (Oct. 1-Sept. 30), Rosen noted that only 20 ANDA approvals were recorded in September, well below the monthly approval average of 56.5. Five additional approvals were granted in the last days of September after Rosen's speech. Rosen did not address whether the ongoing Capitol Hill investigations of the division's approval practices had a role in the slowdown of approvals. However, he said that generic dibidion management "attributes this difference [in approval rates] to the simple fact that there were no other applications for which all requirements for approval had been satisfied." Rosen added that "the total number or original applications reviewed during this time remained relatively constant." Generic Not-Approvable Letters Outnumber Approvals By Four-To-One Since Rep. Dingel (of the House Oversight & Investigation Subcommittee) and HHS began the investigation in the early summer ("The Pink Sheet" July 11, p. 3), the number of ANDA approvals, with the exception of September, has not differed significantly from rates in 1987. The division approved 54 ANDAs in July compared to 63 in 1987, and 58 in August of this year, compared to 41 last year. As of Sept. 27, Generic Drugs approved 641 ANDAs and 133 abbreviated antibiotic applications in fiscal 1988. Rosen reported that a total of 829 ANDAs were submitted during the year, 588 of which were for post-1962 drugs. Rosen noted that the division sent out almost 3,000 non-approvable letters during the year, roughly four times more than the number of approvals for ANDA and antibiotics. "It is quite evident from our perspective that there is still substantial room for improvement in the quality of applications made to the division," he commented. During the year, the division also approved approximately 6,000 ANDA supplements. "There has not been any great rise or fall in the division's incoming or outgoing workload when compared to data collected over the previous years that elapsed since the passage of the Drug Price Competition and Patent Restoration Act," Rosen said.

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