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Executive Summary

Baxter's Recombinate cleared FDA's Blood Products Advisory Committee on Dec. 12 with the recommendation that the recombinant Factor VIII blood clotting agent be approved for treatment and prophylaxis of hemophilia A. Recombinate readily won a recommendation from the committee in a five-to-zero vote, with two abstentions, for use in hemophiliacs previously treated with plasma-derived Factor VIII products. However, the vote was not as positive as a unanimous vote for approval, in the same patient group, earlier in the day for Miles' KoGENate rFactor VIII (see story p. 13). "I have much more difficulty evaluating the Baxter material than the Miles material," committee consultant Raphael Shulman, MD, National Institute of Diabetes, Digestive and Kidney Diseases, commented. Several committee members agreed that certain information on Recombinate, as well as the presentation by Baxter's Hyland Division, were not as complete as that presented by Miles. Data presented by Hyland Division Medical Director Edward Gomperts, MD, on 109 previously-treated patients from 26 centers in the U.S., Canada and Europe showed that 50 IU/kg Recombinate was equivalent to Hemofil M, Baxter's monoclonally-purified antihemophilc factor, in maintaining hemostasis. The products' half-lives were similar: 14 hours for Hemofil M and 15 hours for Recombinate. No previously treated patients developed inhibitors to the recombinant product. Panel members and consultants were disturbed by the lack of manufacturing data, the inadequate characterization of the product and the incomplete explanation of how assays were performed. The committee had particular difficulty with data on Recombinate's usage in patients previously untreated with plasma- derived Factor VIII. Although the committee agreed that Recombinate is "probably" safe and effective in this group of hemophiliacs, composed usually of neonates, it voted four-to-one, with two abstentions, that the data were inconclusive with regard to the product's safety in previously untreated patients (PUPs). With some caveats, Miles' KoGENate received a unanimous recommendation for use in this patient group. The essential problem with Baxter's data was discussed by FDA's William Fricke, MD, chief of the Laboratory of Hemostasis and Thrombosis. "Our interpretation of the Baxter data on previously untreated patients is more difficult than that of Miles' data because of the short length of followup and minimal treatment most of the patients have received. . . . The vast majority of patients have less than 10 exposure days," Fricke said. Baxter recently completed enrollment of 75 previously untreated patients in a 32-center study that will follow patients up to 24 months or 50 exposures to Recombinate, whichever is longer. However, the company presented data only on 42 PUPs who had been exposed to the recombinant Factor VIII an average of six days. Recombinate effectively produced hemostasis in the patients evaluated, Gomperts said. Inhibitors to Recombinate formed in three of 27 PUPs tested, less than 10%. The inhibitor formation was less than that observed in Miles' studies in PUPs. Miles' data showed that inhibitors appeared in about 16% of the 72 PUPs studied, and KoGENate had a 37% rate of inhibitor formation in severely hemophilic PUPs (defined as having less than 2% endogenous Factor VIII). FDA's Fricke noted, however, that for Recombinate, "there is really too little data on the previously untreated patients to make even an estimate of the rate of inhibitor development." He added: "As with the Miles product, I think caution certainly needs to be exercised with regard to the licensure until enough data is collected such that a reliable estimate can be made of what the risk for antibody development is." Committee member Barbara Alving, MD, Walter Reed Medical Institute of Research, agreed with Fricke, saying: "This [product] appears to be relatively safe and efficacious, but we need more data, just as with Miles. Miles' [data on inhibitors] has made us worry. This has made us worry less perhaps because we know less." Recombinate researcher Gilbert White, MD, University of North Carolina, said that because the Miles' study has been going on longer "there are probably four times the number of exposure days but there are also four times the number of inhibitors." White, a committee member, did not sit on the panel during the meeting due to conflict of interest. Both Baxter and Miles should be required to conduct Phase IV studies to determine the incidence and prevalence of inhibitors to their respective products, the committee agreed. The panel also recommended that companies attempt to characterize the specific inhibitors to recombinant Factor VIII and determine whether they might have the potential to diminish the efficacy of Factor VIII products. The committee also expressed interest in assays for the presence of foreign proteins in the products, in particular hamster proteins, since both recombinant agents are produced in hamster cell lines. Fricke said that there are a number of issues that remain to be resolved by both Miles and Baxter. One of the issues is "the assignment of a reliable and accurate potency to each vial of lot" of the recombinant products, Fricke said. Only Miles applied for orphan designation for its recombinant Factor VIII product. The U.S. population of people with hemophilia A is estimated at 15,000-20,000. However, even if Miles' KoGENate is approved first, Recombinate will not be excluded from the market for a seven-year period because of an agreement struck between the companies. Baxter and its Recombinate licensor Genetics Institute entered into a cross-licensing agreement with Miles and its licensor Genentech in August 1990 to avoid a court battle over the patent to the blood clotting factor.

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