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Executive Summary

FDA bioequivalence determinations for generic versions of post-1962 drugs can be based on the same methodology used to determine bioequivalence of pre-1962 products, FDA Bioequivalence Div. Director Shrikant Dighe, PhD, said at a June 25-26 seminar on the patent restoration/ANDA law. During his presentation at the seminar, sponsored by the Natl. Assn. of Pharmaceutical Mfrs. (NAPM), Dighe said: "I don't see any reason why" bioequivalence for a generic version of a post-1962 drug should be determined by different methods than those applied to pre-1962 drugs. "I haven't seen any evidence so far why the classical methods of measuring the blood concentrations or urinary concentration of drugs cannot be used to determine the extent and rate of a generic drug's bioavailability in a bioequivalency study," he declared. Several brandname drug mfrs. have maintained in petitions to the agency that differences in bioavailability exist between some pioneer and generic products, and that these differences can result in clinical differences. The brandname firms have asked FDA to require additional tests of the generic versions to ensure therapeutic equivalence. In February Roche maintained that bioequivalence requirements for any generic version of Valium (diazepam) should include pharmacodynamic measurements of the drug's availability at the site of action. Similarly, in a May petition McNeil proposed requirements for generic versions of Haldol (haloperidol) that would include multiple-dose, two-way crossover studies in schizophrenic patients ("The Pink Sheet" March 4, p. 3 and June 10, T&G-3). Generic Firms Will Become Research-Based Enterprises -- Zenith's Reese On the other hand, Dighe said that generic applicants should consider doing clinical studies for generic products which have a higher rate of bioavailability than their reference drugs. For example, he said, a limited clinical trial conducted as a triple crossover with the generic drug, the reference drug, and solution, could demonstrate the higher bioavailability of the generic product. Such information could be included in an approval application. For example, a 25 mg generic that achieves blood levels equivalent to a 50 mg reference drug would be a candidate for such testing, Dighe said. Dighe suggested generic firms might want to "educate" MDs and pharmacists about the superior bioavailability of their products, and the brandname mfr. might want to reformulate in order to copy the generic product's bioavailability. "I know there are a lot of questions that if" a generic is not approved as exactly bioequivalent to the listed drug, "what good is it?" the FDAer said. "The next thing you would have to do is to go to the physicians, go to the pharmacists, and you have to educate them. . .about the better performance of your product," Dighe stated. "And I think that the message will go to the brandname product; the message will also go across to the pharmacists and to the physicians, and perhaps -- - and I think this most likely -- - the brandname product will follow." Dighe added that there are currently "three or four" brandname products that are on the market with bioavailability profiles that are likely to be surpassed by generic versions. One is SK&F's Dyazide, a diuretic taken up to four times daily for hypertension; Mylan/Lederle's Maxizide, which contains the same active ingredients (hydrochlorothiazide with triamterene) but is taken once daily, is more fully bioavailable. Maxzide was approved under a full NDA. Zenith Scientific Director Robert Reese, MD, suggested that the brandname/generic distinction might be further blurred because "generic mfrs. may seek entry into the research-based pharmaceutical business." Reese cited a recent report by SRI, Inc. that maintains some generic houses, for example, Rugby, might be planning for the development of exclusive products through their own research facilities ("The Pink Sheet" June 18, T&G-I). Reese said: "It's pure speculation on my part, but I feel strongly there must be more and more of it [innovation] as the individual generic companies increase in size and as the list of drugs going off patent begins to diminish. It's just natural that they'll go into the development of more proprietary products," including new compounds as well as new formulations and delivery mechanisms. PMA Associate General Counsel Edwin Mulcahy maintained that when brandname products receive new indications, generic counterparts should "not be considered therapeutically equivalent for purposes of" the MAC program, substitution, and drug formularies. Mulcahy said PMA is concerned about how the exclusivity provisions of the Waxman/Hatch law will be implemented in the marketplace. If "two companies market a product and one can make only two of the [labeling] claims but the other company, because of the exclusivity provision, can make a third claim, the product should not be considered multisource under the MAC program," he maintained, "and there [should] be an appropriate listing in the FDA Orange Book [the Therapeutic Equivalence List] that certain products have not been approved for all uses." The assn. is further concerned that FDA grant exclusivity for new indications and formulations requiring clinicals for approval and that, in cases where exclusivity is denied because clinicals are not considered "essential" to approval under the law, the agency at least notify the sponsor early in the approval process. Generic Industry Should Take Lead In Consumer-Oriented Health Issues -- HRG's Schultz The three-year exclusivity rule was "included in the law as an incentive for post-approval research," he argued. When a company submits a protocol for clinical testing in support of a new indication, "FDA, say within 30 days, should determine" whether the proposed testing is "essential," Mulcahy said. "It is crucial that the company doing the testing find out early on whether the testing would be considered essential and the exclusivity would be attached when the testing is completed" and the indication is approved. Health Research Group Counsel William Schultz contended that special notations in the Orange Book are not needed to distinguish products with exclusively added indications from their generic counterparts. The innovator company can distinguish its product through advertising and detailing, Schultz noted. But "it seems to me to be kind of absurd to say that the generic drug is not therapeutically equivalent when it really is." Schultz added that the generic industry is in a position to foster a consumer-oriented image for itself. Because generic companies are doing business by selling less expensive products, they "can say they're riding a white horse; they're really doing something that is useful," he maintained. "I would hope that generic companies would take this on as their theme and look for other ways that they can step out and really take a lead in health care issues," he said. For example, Schultz suggested that generic firms "think seriously about using the label that FDA originally proposed" for aspirincontaining products regarding the association to Reye's Syndrome.

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