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."
1. Diczfalusy E, Harlin J. Clinical-pharmacological studies on human menopausal gonadotrophin. Human Reproduction. 1988;3:21-27.