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Executive Summary

Schering-Plough's Intron A (interferon alpha-2b) for chronic hepatitis B was recommended for approval by a 5-0 vote of FDA's Biological Response Modifiers Advisory Committee on Nov. 25. Schering-Plough presented data from three controlled clinical trials involving over 200 evaluable patients. The trials resulted in response rates of 42% to 54%. Schering VP-Biological Research Jonathan Spicehandler, MD, explained that "the criteria for response in these trials included a hepatitis B e antigen test (HBeAg) being negative during the six-month follow-up period and hepatitis B virus DNA test (HBV DNA) being negative both at the end of treatment and after the follow-up period." In one of the three trials, a U.S. multicenter study, patients confirmed to have chronic hepatitis B were randomized either to control or to 5 mil. units (MU) or 1 MU of Intron A daily for 16 weeks. Spicehandler reported that 16 of 38 patients, or 42% of those receiving 5 MU Intron A, responded to treatment, while six of 38 (16%) of patients treated with 1 MU Intron A responded. By comparison, three of 42 controls (7%) responded. Another study, conducted in Argentina, resulted in a 54% response rate in patients receiving 10 MU of Intron A three times a week for 16 weeks, compared to a 7% response rate for untreated controls. A third study, performed in collaboration with the National Institutes of Health, demonstrated response rates of 42% and 5% in treated and untreated patients, respectively. The committee and its invited consultants agreed that the HBeAg and HBV DNA markers were valid; consultant Alan Schulman, MD, Shady Grove Hospital, concluded that "the disappearance of the viral markers is a valid and very important endpoint." Schering consultant Willis Maddrey, MD, University of Texas, said that elimination of HBeAg is important because "if we turn off the e antigen, we most likely have made the patient non-infectious and . . . have made the patient less likely to have an inflamed liver." Secondary endpoints for the studies included elimination from serum of the hepatitis surface antigen, the results of liver biopsies and the return of ALT liver enzyme levels to "normal or near-normal levels." Maddrey noted that "our evidence for complete ridding of the virus is a loss of hepatitis B surface antigen [HBsAg]." Spicehandler said that in the three trials combined, "the loss of s antigen was achieved in about a third of patients." Spicehandler reported that the correlation between loss of HBeAg and HBV DNA and reduction in ALT levels was 88% in the U.S. multicenter study and 100% in the NIH study. He said the measurements "correlated well" in the Argentine study. Comparison of liver biopsies performed before and after treatment in the U.S. multicenter and Argentine studies showed "a relationship between viral response and histological improvement." Intron A also showed good results in preventing a relapse of hepatitis B. In an "extended follow-up of one-and-a-half to 30 months in 19 patients, none of the patients has relapsed," Spicehandler reported. Schering consultant Maddrey said there are 300 mil. carriers of hepatitis B worldwide, 1 mil. in the U.S., and that "approximately 300,000 cases of this disease are reported annually in the U.S." He noted that current therapy -- steroids and anti- virals -- is "unsatisfactory." Spicehandler presented safety data from over 475 patients. Between 82% and 97% of patients in the three controlled clinical trials experienced flu-like symptoms, notably fatigue and fever, but the side effects were mostly mild to moderate. Severe treatment-related effects were seen in "between 24% and 27%" of patients, the most common being fatigue and fever, Spicehandler said. The study protocols allowed physicians to reduce Intron A doses, to interrupt treatment, or discontinue therapy altogether if patients experienced serious side effects or predefined drops in granulocyte or platelet counts. Under these conditions, "29% to 39% of the patients experienced either reduction or interruption" of therapy, Spicehandler said. An additional 6% discontinued therapy, mostly due to fatigue or depression. Schering VP-Regulatory Affairs Douglass Given, MD/PhD, outlined "the major themes we anticipate getting into the labeling" of Intron A, including a "recommended dose of Intron A for the treatment of chronic hepatitis B in the range of 30 to 35 MU weekly in either of the dosage regimens (5 MU daily or 10 MU TIW) for 16 weeks." He added that "it is very important to have guidance on dose reduction" for patients exhibiting excessive side effects. The committee agreed to Intron A's approval with the understanding that the alpha interferon product will be used "in both chronic active and chronic persistent hepatitis B," although Schering's studies included only nine patients with chronic persistent hepatitis. The committee's decision apparently was based on three factors: lack of clear diagnostic differentiation between the active and persistent versions; the view that patients with CPH may benefit from Intron A; and that CPH can progress to active hepatitis without notice. Committee consultant Robert Carithers, MD, University of Washington, said: "I'd hate to see patients not treated because they are diagnosed [with] CPH. There can be a lot of confusion among pathologists as to where to separate chronic active and chronic persistent." Committee consultant Schulman commented: "If FDA decided to rigidly label this product, patients could be lost to follow up and not treated." Schulman noted that in the U.S., "all pathologists aren't experts in liver histopathology," so the chances of misdiagnosis are increased. As a condition of the committee's approval endorsement, Committee Chairman Jerome Groopman, MD, New England Deaconess Hospitals, said that Schering should conduct studies "to encompass demographic groups that were not contained in the database today" and to "determine better which populations will benefit from therapy." These populations include: patients with CPH; children; people with HIV; Asians; patients with cirrhosis; and patients who do not respond to the initial 16 weeks of Intron A therapy. Schering-Plough VP-Clinical Research Robert Spiegel, MD, responded: "There are a number of studies in the design stage that we are anxious to discuss with the agency . . . and I think we can answer these questions." He noted that Schering is "in discussions with the ACTG [AIDS Clinical Trial Group] to do further studies with HIV-positive patients." Earlier, Schering's Given had remarked: "We feel that the HIV population can respond." Spiegel also outlined a 200-patient "Eurohep" study being conducted by 12 European Community nations. Hepatitis B patients who are not responding to 16 weeks of Intron A therapy will be "randomized to either no further treatment or another 16 weeks of treatment." Spiegel added that "we believe this will answer the questions posed." Some questions were raised concerning the acceptability of the HBV DNA marker. The HBV DNA assay used in the trials is made by Abbott but has not been approved by FDA. Committee consultant Leonard Seeff, MD, V-A Medical Center, Washington, D.C., remarked: "We must recognize that we aren't talking about HBV DNA because the only markers we have are e antigen and surface antigen," and the validity of the HBV DNA test is "unknown." Janice Albrecht, PhD, Schering-Plough's project director, said that Abbott had indicated that "the license application should be ready soon." Schering has provided data from the U.S. multicenter trial to add to the Abbott PLA. Committee Chairman Groopman acknowledged that "the DNA test is not verified. It needs to be rigorously reviewed." FDA approval of Intron A for hepatitis B would be the product's fifth indication in the U.S. Intron A most recently added a hepatitic C treatment indication on Feb. 22. Schering- Plough filed the PLA for the hepatitis B indication in September 1989.

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