On March 8, 2002, the FDA announced the approval of interferon beta-1a (Rebif, Serono) for the treatment of relapsing forms of MS. The FDA based its approval on the results of two trials.
Patients with relapsing forms of multiple sclerosis now have an additional treatment option. Last month, the Food & Drug Administration announced the approval of interferon beta-1a (Rebif, Serono) for the treatment of relapsing forms of MS. The FDA based its approval on the results of the EVIDENCE (Evidence for Interferon Dose Effect: European North American Comparative Efficacy) study and the PRISMS (Prevention of Relapses and Disability by Interferon Beta-1a, Rebif Subcutaneously in MS) study. Rebif was found to delay the agglomeration of physical challenges and decrease the frequency of clinical complications in those with relapsing MS.
The drug could not previously be marketed in the United States because Avonex (another formulation of interferon beta-1a made by Biogen) was protected under the Orphan Drug Act. However, the FDA felt that the results of the EVIDENCE study at 24 weeks demonstrated clinical superiority for Rebif as compared with Avonex, and the agency granted marketing approval for the drug.
Opponents of this decision feel that the design of the EVIDENCE study is flawed. According to Jeffrey Greenstein, M.D., professor of neurology and director of the MS Center, Temple University, 24 weeks is too short a time frame to assess the differences in efficacy between Rebif and Avonex. In order to accurately evaluate the progression of the disease, he said, it would be necessary to treat patients for two to three years.
In addition, Greenstein continued, only the evaluating investigators were blinded. This open-label design had the potential to bias the results. He also feels that the results of MRI testing could introduce bias, even though it was believed to be completely objective. Another mistake, he said, was to assess the number of relapses as an odds ratio, not as a relapse rate, because odds ratios can overinflate differences between study groups.
A memo posted by the FDA on its Web site (www.fda.gov) describing and summarizing the agency's analyses of the EVIDENCE trial could address concerns about the study design. According to the document, the FDA has a precedent of accepting an effect on exacerbation alone as clinically meaningful. Complete remission may take weeks or even months and may not be complete. The agency concluded that exacerbations were an aspect of MS relevant for evaluation.
The study was designed to gain marketing approval by addressing requirements of the orphan drug regulations. The FDA deemed demonstration of clinical effectiveness on a single clinical endpoint sufficient for this purpose. The agency concluded that the occurrence of clinical exacerbations was compliant with the intent of orphan drug regulations.
The FDA document also enu- merated how the manufacturer addressed the issue of study bias. Frequent contact occurred between the study participants and the trial investigators. Separate investigators were used for treatment and evaluation, and the evaluating clinician was blinded as to the assigned treatment.
The FDA did not have concerns about study duration, because prior experience had shown persistence for the beneficial effects of interferons. Its memo stated that no indication of diminishing efficacy for Rebif was noted.
Those diagnosed with a rapidly progressing form of MS are not candidates for Rebif therapy, said Jim Garnick, Pharm.D., BCPS, clinical instructor, University of Michigan College of Pharmacy. Rebif should be used with caution in those with preexisting seizure disorders and a history of depression, he continued. It is contraindicated in those with a history of hypersensitivity to natural or recombinant interferon or human albumin. The drug is administered subcutaneously at a dosage of 44 mcg three times a week. Common side effects include injection-site reaction and flu-like symptoms; the most serious adverse effects are psychiatric disorders, including severe depression and suicidal ideation.
Charlotte LoBuono. A new drug for treating relapsing MS gains approval.
Apr. 1, 2002;146:21.