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Executive Summary

Chiron/Berlex' Betaseron (interferon beta) is effective in reducing the frequency of neurological exacerbations in patients with relapsing-remitting multiple sclerosis, FDA's Peripheral and Central Nervous System Drugs Advisory Committee determined at its March 19 meeting. In a seven-to-two vote, the committee members concluded that the sponsor had provided sufficient evidence to support the conclusion that Betaseron is effective in decreasing exacerbations, such as vision problems, lack of motor coordination or tremors, in patients with relapsing-remitting MS. According to a Berlex press release, MS affects "an estimated 250,000 to 350,000 Americans, with approximately half having relapsing- remitting MS." The majority of the committee also agreed that Betaseron is safe for use in treating MS. Committee member Gary Oderda, University of Utah College of Pharmacy, said he "would support [a] motion to recommend approval based on a couple things. One of them," he said, "is the robustness and consistency of the data, both in the clinical endpoints as well as the [magnetic resonance imaging] MRI data, and that I find compelling." The other consideration, Oderda said, is that FDA provided advice to the sponsor about trial requirements and that FDAers had indicated that two clinical trials are not necessarily required for approval. The advisory committee based its conclusion that Betaseron is effective on the results from one Phase III, multicenter trial that was conducted in the U.S. and Canada and involved a total of 338 MS patients. Patients were randomized to self-administer subcutaneous injections of placebo, Betaseron 9 mil. International Units (IU), or Betaseron 45 mil. IU every other day for two years. The primary efficacy endpoints were reduction in exacerbation rates per year and increase in proportion of exacerbation-free patients. Berlex Labs VP-Clinical Research and Development Jeffrey Latts, MD, presented the study results. Betaseron caused a 34% decrease in the rate of exacerbations versus placebo and a 94% higher proportion of patients who were exacerbation-free than placebo. Betaseron administration also resulted in a 93% increase in time to first exacerbation. Latts said that "MS patients receiving Betaseron as a group have fewer moderate and severe exacerbations." Specifically, "over two years, the average patient will experience 26 fewer days of moderate to severe exacerbation." Hospitalizations and corticosteroid administration are also reduced in those patients taking Betaseron, he added. The study results showed that the 45 mil. IU dose of Betaseron is more effective than the 9 mil. IU dose on the exacerbation measures. In addition, Latts said: "There's a dramatic impact of Betaseron treatment on the progression of disease burden measured by magnetic resonance imaging." The lesion area as measured by MRI increased by 19.4% in the placebo group and decreased by 4.2% in the Betaseron patients, Berlex data showed. Most committee members agreed that the MRI data provides support to the clinical data and shows an effect on disease burden. The advisory committee spent a considerable amount of time discussing its concern about the perceived requirement that FDA always wants at least two adequate and well-controlled clinical trials to support approval. FDA Center for Biologics Evaluation and Research Office of Therapeutics Research and Review Director Janet Woodcock, MD, pointed out that CBER has approved "a number of therapeutic biological agents for serious diseases on the basis of a single trial." Committee member Dennis Choi, MD/PhD, Washington University School of Medicine, stated: "I'm beginning to think that the emphasis on two studies as a magic number might be a little misplaced." He added: "I have the discomfort, that I think several people have, that somehow the rules are shifting; perhaps that's the way it should be, because the rule itself is flawed." Choi emphasized that what is important is "the robustness of scientific data." He noted that because the "independent lines of evidence are converging here...[it] gives me a feeling of robustness." However, committee member Richard Penn, MD, Rush- Presbyterian-St. Luke's Medical Center, cautioned: "I don't think our voting to approve this motion should be taken as clear guidance that we will always rely on one study" to approve a therapeutic biological product. Several committee members said they believed that the one trial was not enough to support a recommendation specifically for Betaseron. Committee member Nancy Tempkin, PhD, University of Washington, said that although she "would certainly, at this point, accept this study as showing an effect," she did not think beta interferon "would be approvable based on the one study." Invited committee guest Henry McFarland, MD, National Institute of Neurological Disorders and Stroke, noted: "I think all of us who have been involved in MS trials realize that they have been notoriously difficult." McFarland stated: "I have to say that the evidence here does seem sort of compelling to me as well. I think that this is one of the few trials I've seen where all the trends seem to go in the same direction." He added that "here, even the parts that don't reach statistical significance seem to go in the right direction." McFarland pointed out: "I think with the data that we have right now, we can't say that [Betaseron] changes the course of disease; [however,] I have to say my personal bias is that if you have a treatment that reduces exacerbations, reduces frequency of new lesions on MRI, I would amazed if it didn't change the course of disease." Berlex has an ongoing one-year extension study of Betaseron in patients previously enrolled in the Phase III trial. All the patients who were taking placebo and 9 mil. IU Betaseron were transferred to the 45 mil. IU dose. Berlex' Latts said the data analyzed so far are similar for the same primary efficacy endpoints. Once approved, Betaseron will be the first product available specifically for the treatment of MS. Discussing Betaseron's product license application (92-0495), Andrew Larner, MD/PhD, CBER Division of Cytokine Biology, noted that "this application has been reviewed as a combined effort between CBER and CDER and is the first PLA to be reviewed as a result of this CBER/CDER intercenter agreement." Berlex filed the PLA in the second half of 1992. During the open public hearing, Lawrence Jacobs, MD, University of Buffalo, told the committee there is an ongoing multicenter, placebo-controlled study of another recombinant beta interferon administered intramuscularly as a treatment for multiple sclerosis. Jacobs is the principal investigator of the study, which involves Asta's beta interferon product. The study, which should be completed in a year, uses the primary outcome measure of disability. Jacobs said Biogen has U.S. rights to the product. The study is being supported by the National Institutes of Health and by two grants from the National Multiple Sclerosis Society.

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