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Executive Summary

Schering's Intron A should be approved for the treatment of hepatitis C, FDA's Biological Response Modifiers Advisory Committee unanimously recommended at its July 31 meeting. The panel agreed that the recombinant alfa interferon product should be approved "for the therapy of chronic non A, non B hepatitis based on a 24-week course of treatment at a 3 mil. unit dose." The PLA for the Intron A hepatitis C indication was filed in June 1989, and a PLA for hepatitis in September 1989. The committee recommended approval with the provision that Schering conduct post-marketing studies to answer unresolved questions in the company's PLA. There is an "understanding that the recommendation is based on a verification of the data that were not available to read, and that there will be well-constructed Phase IV studies to address issues of long-term treatment and follow-up," said committee chairman Jerome Groopman, MD, New England Deaconess Hospital. Specifically, the committee identified optimum dose and ideal treatment period as issues that could be resolved in post-marketing studies. "The central issue is what is the optimal dose and if it is used on a patient when should we stop," FDA consultant Jay Hoofnagle, National Institute of Diabetes and Digestive and Kidney Diseases, suggested. Schering is currently conducting multidose studies looking at higher doses of Intron A. An approval for Intron A in the treatment of chronic hepatitis C would significantly expand Schering's market for the drug. There are approximately 150,000 cases of non A, non B hepatitis in the U.S. each year, of which 75,000 are considered chronic. Currently, Intron A and Roche's Roferon-A are marketed for the treatment of hairy cell leukemia and Kaposi's sarcoma. The results of a pivotal U.S. study and two European studies, presented by Schering Clinical Research Director Robert Kammer, MD, showed that Intron A elicited a clinical response in 54% of the patients who received 3 mil. units of the drug. Of those patients who responded to Intron A therapy, 77% had a corresponding decrease in liver inflammation. In the U.S. trial, 167 chronic hepatitis C patients, with alanine aminotransferase (ALT) concentrations of at least 1.5 times above the upper limit of what is considered a normal level, received Intron A at doses of 3 mil. units and 1 mil. units, or a control three times a week for 24 weeks. The overall response rate, measured by a decrease in ALT of 50% or more, for patients in the 3 mil. unit dose group was 53% compared to 9% for control, with 23 of the 29 responders achieving a complete response. Results of the U.S. trial were previously published in the Nov. 30 issue of the New England Journal of Medicine ("The Pink Sheet" Dec. 4, p. 14). The response time was "prompt," Kammer noted. "You only had to wait about four weeks in the 3 mil. unit group to see whether you were going to respond for most of these patients." However, at six months following treatment, half of the patients who responded initially to Intron A therapy relapsed in the study. When retreated 10 of the 12 patients, or 83%, responded, Kammer pointed out. There was a corresponding decrease in liver inflammation in the interferon treated patients. The most common adverse reaction associated with Intron A therapy was a mild flu-like symptom, which occurred in a majority of patients. Schering has received 11 reports of thyroid dysfunction from Intron A treatment of hepatitis C patients. "In ongoing studies we are measuring serum [thyroid stimulating hormone] levels," Kammer noted. Long-term effects of Intron A on the thyroid should be monitored as part of Phase IV studies, the committee suggested. Some patients developed anti-interferon antibodies during Intron A treatment; however, the presence of antibody did not seem to have an effect on response to Intron A; nine of the 12 antibody-positive patients responded to treatment. Commenting on the results of the study, Hoofnagle said he felt "strongly that if these serum enzymes fall to normal and stay there that the patient has benefitted. The problem is of course in the studies is the relapse rate over time." Echoing Hoofnagle's concerns, committee member Janice Gabrilove, MD, Memorial Sloan-Kettering Cancer Center, suggested that "additional studies need to be done independent of whether this is good treatment at the present time." Gabrilove commended Schering on the quality-of-life data the company gathered during the trials. She noted that "many" of the committee members were "impressed by the additional information that the patients actually felt better, were able to return to work." Among patients with chronic hepatitis C receiving Intron A, there was a significant improvement in the ability to work, sleep, and rest, according to the Schering data.



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