An injunction barring further marketing of the generic drug Repronex, recently approved by the Food and Drug Administration, was issued by a U.S. District Court July 25. Although this is the first time that a court has ruled against an FDA determination of generic equivalence in numerous lawsuits brought by manufacturers of reference brand products, it is not the first time that Sporkin has decided against a federal agency. Sporkin wrote, "the FDA cannot selectively choose to reinterpret the FFDCA (Federal Food Drug and Cosmetic Act) and its own implementing regulations in such an arbitrary manner. 'Same' means 'identical,' just as the agency's own regulation say and an agency must follow its own regulations and not arbitrarily reinterpret those regulations."
An injunction barring further marketing of the generic drug Repronex, recently approved by the Food and Drug Administration, was issued by a U.S. District Court July 25. The injunction was sought in a complaint against the FDA brought by Serono Laboratories, manufacturer of Pergonal, the reference brand menotropin prescribed to enhance fertility. In granting the preliminary injunction that prevents Ferring Pharmaceuticals from marketing Repronex in the United States, pending a trial for permanent injunction, Judge Stanley Sporkin found that the FDA had not complied with its own criteria and regulatory mandate to find the ingredients of the generic product to be identical to those of the reference brand.
Although this is the first time that a court has ruled against an FDA determination of generic equivalence in numerous lawsuits brought by manufacturers of reference brand products, it is not the first time that Sporkin has decided against a federal agency. In 1995, for example, he overturned the Justice Department's antitrust settlement with Microsoft; albeit in a decision that was, itself, subsequently overruled.
In finding for the Serono Laboratories complaint against the FDA, Sporkin wrote, "the FDA cannot selectively choose to reinterpret the FFDCA (Federal Food Drug and Cosmetic Act) and its own implementing regulations in such an arbitrary manner. 'Same' means 'identical,' just as the agency's own regulation say and an agency must follow its own regulations and not arbitrarily reinterpret those regulations."
The judgment was based on the FDA determining product equivalency despite uncovering such differences as a "microheterogeneity" in isoform composition of follicle stimulating hormone (FSH) and luteinizing hormone (LH), which could occur from the manufacturers' different means of extracting and purifying these active ingredients from the urine of postmenopausal women. In addition, the agency had distinguished between the products in the amounts of urinary protein and lactose, which the court found to conflict with the standard for identical "inactive ingredients" but which the FDA appeared to have accepted within less specific criteria for "impurities."
Douglas Sporn, director of the FDA office of generic drugs, told Psychiatric Times, "I still believe we did the right thing by approving the product. We found it to be pharmaceutically identical, otherwise we would not have approved it."
This assessment by the agency is consistent with a study of menotropins, conducted before the availability of Repronex, by Swedish researchers who reported, "the pharmacokinetic and pharmacodynamic properties of the urinary gonadotrophin preparations studied are very similar if not identical, and are not influenced by differences in their microhet-erogeneity" (Diczfalusy and Harlin).
The scientific judgment of the FDA that the reference and generic applicant products are pharmaceutically equivalent did not, however, satisfy the court's requirement for the application of regulations that mandate identical composition. In addition, Serono Laboratories successfully showed that differences found by the FDA in the products' inactive ingredients were associated with different antigenic potential, and therefore represented different levels of safety.
The agency was judged by the court to have arbitrarily chosen measures to assess the inactive ingredients. The FDA appeared to have chosen criteria from the 1984 Drug Price Competition and Patent Term Restoration Act (the Hatch-Waxman Amendments that established the current program of Abbreviated New Drug Applications [ANDA] for generic drugs), which require that inactive ingredients are safe, rather than the 1992 implementing regulations that require the inactive ingredients to also be identical and occur in the same concentration as those in the innovator drug.
The agency's argument that only the earlier criteria applied to the Repronex application because it was submitted in 1990, prior to the 1992 implementing regulations, prompted a caustic opinion from Sporkin. "This contention dumbfounds the court," he wrote. "It was the impression that the FDA's role was to protect the public. How is the public protected by allowing a new drug to come to market on a more lenient basis than required by existing law?"
The Serono Laboratories complaint had also described the application of standards by the agency as "arbitrary" (as well as "capricious" and "inequitable") because another menotropin approved after Pergonal, Organon's Humegon, had been reviewed as a New Drug Application (NDA) distinct reference brand, rather than as an ANDA generic based upon the Pergonal reference. This was not found to be material by the Court, however, as the ANDA application for Repronex had actually been submitted by the original patent holder, Lederle Laboratories, prior to the NDA application for Humegon; and Humegon had already gained new drug approval in several countries.
The immediate effect of the injunction is a halt in sales of Repronex, which entered the market in June, selling at an approximate wholesale cost of $34 per dose, compared to approximately $50 per dose of Pergonal. Joseph Curti, M.D., Ferring Pharmaceuticals Chief Executive Officer told Wall Street Journal correspondent Mark Marmont that the Court's decision was "outrageous," and "is bad for consumers and bad for medicine."
Angry Manufacturers Battle FDA
Manufacturers unsuccessful in arguing to the Food and Drug Administration that a generic drug is not equivalent to their brand product are increasingly carrying their arguments outside the agency. In the suit that preceded the successful outcome for Serono Laboratories, Somerset Pharmaceuticals, failed in court to block a generic selegiline form of Eldepryl and according to a staff person at the FDA generics office, other manufacturers have sued and lost, including Bristol-Myers Squibb over cholestyr-amine (Questran); Glaxo Wellcome over clobetasol (Temovate); Fisons Corporation over cromolyn (Intal); and Schering Corporation, which brought four actions, a separate suit and appeal in each of two districts, over albuterol (Proventil).
In another tack, Coumadin (warfarin) manufacturer Dupont Pharma targeted state legislatures one year before the FDA approved a generic warfarin in July, providing start-up funding for a multisponsored alliance to lobby against substitution without prescriber notification and for increased standards of bioequivalence for products having a narrow therapeutic index (NTI) (Dupont Pharma appears to be closely monitoring the market entry of the generic warfarin product from Barr Laboratories, and in August transmitted an unprecedented fax nationally to practitioners and pharmacies critical of educational materials prepared by Barr Laboratories, to which Barr issued its own nationally distributed fax response-Ed.)
Douglas Sporn, director of the FDA office of generic drugs, related the view of some long-term staffers in his office that this lobbying effort was "an aggressive approach" against generic competition. Roger Williams, Ph.D., Sporn's predecessor as director of the office of generic drugs, recently described this lobbying to Associated Press reporter Jim Drinkard as, "in the class of an economic challenge" rather than a scientific one.
Rick Glaub, of the Washington public relations firm Goddard Claussen, which launched the lobby as the Health Alliance for NTI Patient Safety, dismissed characterizations of the alliance as engaged in a battle between brand and generic drug manufacturers. He explained to Psychiatric Times that the alliance, whose sponsors include the American Psychiatric Association among other medical associations, does not contest the "prescribabilty" of NTI generic drugs as much as their "switchability." The list of approximately 30 generic medications having a narrow therapeutic index was compiled by the FDA and includes warfarin, extended release lithium and clonidine.
Glaub acknowledged that the FDA has been discussing the development of more stringent bioequivalence standards for these drugs within its Medical Policy Coordinating Committee, chaired by Robert Temple, M.D., associate director for medical policy. Glaub commented wryly, however, that the committee progress "has been described as moving with great dispatch, in geological terms."
Each of the manufacturers of reference brand products ("innovator," in the terminology of ANDA [Abbreviated New Drug Applications] approval regulations) that has sought remedies from outside the FDA has been unsuccessful or frustrated in using "citizens petitions," "petitions to stay" or in conferring with FDA staff to criticize ANDA data. In the case of Serono Laboratories, their 1992 citizens petition concerning the 1990 ANDA for Repronex went unanswered for over four years, despite an FDA regulation that requires the Agency to respond within 180 days.
Sporn told Psychiatric Times that the response to Serono Laboratories "was sent after the [Jan. 30, 1997] approval [of Repronex]." He conceded that the mandated response time for citizens' petitions is commonly violated by the agency, remarking that his office is "inundated by citizens' petitions," which he attributes generally to the profit motive of the innovator manufacturer wishing to protect market share rather than to valid concerns about equivalency. "It is fairly common for innovators to try to raise the bar, so to speak," Sporn said, when brand product patents are about to expire.
The protracted period for response is also the result, according to Sporn, of the agency viewing each petition as the basis for a potential lawsuit, and so undertaking extensive deliberations with the agency office of chief counsel. Another reason for delayed response is the lack of manpower, he lamented.
"We are receiving an increased number of [ANDA] applications at the same time as government downsizing, and our priority is review [applications] work before anything else," he went on to say. "It is sapping off resources here to review drug applications. We've had to spend more and more time meeting with attorneys, preparing for lawsuits."
Diczfalusy E, Harlin J. Clinical-pharmacological studies on human menopausal gonadotrophin. Human Reproduction. 1988;3:21-27.