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ROFERON-A AND INTRON A ARE SEPARATE BRANDS: LABELING AND STRUCTURES DIFFER; FDA TREATS THEM BOTH AS NATURAL INTERFERONS, SIMULTANEOUS FIRST APPROVALS

Executive Summary

Roche's Roferon-A brand of human alpha interferon carries FDA approved labeling describing a 94% two-year survival rate for hairy cell leukemia patients. Under the clinical pharmacology section of the labeling, the company states: "Of the 75 patients who were evaluable for efficacy following at least 16 weeks of therapy, 46 (61%) achieved complete or partial response. Twenty-one patients (28%) had a minor remission, eight (11%) remained stable, and none had worsening of disease." The Roferon two-year survival rates cited in the labeling surpass the historical control group of hairy cell leukemia patients. The labeling notes that "the probability of survival for two years in patients receiving Roferon-A (94%) was statistically increased compared to a historical control group (75%)." Schering's approved labeling for Intron A is less specific in its statement of the drug's effect of survival and remission results. The Schering interferon brand labeling describes clinical effect by blood cell levels. Intron labeling states that "in clinical trials in patients with hairy cell leukemia, there was depression of criculating red blood cells, white blood cells and platelets during the first one to two months of treatment with Intron A. Subsequently, both splenectomized and non-splenectomized patients with hairy cell leukemia treated with Intron A achieved substantial and sustained improvements in granulocytes, platelets, and hemoglobin levels in 75% of treated patients and at least improvement (minor response) occurred in 90%." In introductory letters to MDs, Schering cites a two-year study with survival rates similar to the Roche labeling. The letters state that "in a 24-month Kaplan-Meier survival analysis, Intron A patients reached an early plateau of 92% probability of survival, while the probability of survival for historical control patients declined to 40% at 24 months." The differences in clinical pharmacology labeling of the first two approved brands of interferon are evidence of the distinctions between the products. The distinctions between the brands were generally downplayed in the simultaneous FDA approvals on June 4. The two alpha interferon products differ in their primary structure by one amino acid. Because of that difference, Intron A is designated as interferon alfa-2b and Roferon is designated as interferon alfa-2a. HHS Secty. Bowen and FDA Com. Young announced the approval of alpha interferon for the treatment of hairy cell leukemia at a press conference June 4. Bowen noted that the approval is for "two brands" which were "developed independently." However, the description of the effectiveness of the ingredient combines information on both products. Bowen commented that "studies show that within months of its application, alpha interferon can provide survival rates of over two years for 92 to 94% in patients with hairy cell leukemia, and can produce remission of the disease in 75 to 90% of them." FDA's press release on the approval points out the independent development work but treats the products as generic versions of the same natural substance. The agency press statement says that the "two companies developed, produced and tested alpha interferon independently, but both biologics are produced by recombinant DNA techniques in which a gene containing the production code for alpha interferon is inserted in a harmless bacteria, which then produced large amounts of the substance identical to that produced by the human body." By approving the Schering and Roche applications simultaneously, the agency showed sensitivity to the public relations impact of the first U.S. approval on the two major pharmaceutical companies most committed to interferon development. Com. Young pointed out that the agency had two licensing review committees involved in the approval decision. FDA's implicit decision to treat both alpha interferons as equivalent products is reminiscent of the decision to approve both OTC applications for ibuprofen simultaneously in 1984. However, in that case, both the American Home Products application and the Upjohn/Bristol-Myers application were for the same ingredient licensed from the same source. If interferon indications are expanded, an important commercial question will be whether FDA continues to treat the products as essentially generic equivalents or distinguishes between the products for other indications. A difference in the purification procedures is addressed in labeling briefly. Roche's purification procedure "includes affinity chromatography using a muring monoclonal antibody," Roferon-A labeling states. The monoclonal antibody was developed by Damon Biotech. Schering uses standard column chromatographic procedures for purification. There may be a difference between the two interferons in their antigenic potential. Schering Director of Oncology Research Robert Spiegel, MD, comments that "to date, there's a suggestion that our product, Intron A, has a very low antigenic potential and there are some reports in the medical literature now that higher levels of what's been called serum neutralizing activity have been found after treatment with Roferon." A published report earlier this year, Spiegel told "The Pink Sheet," stated that in over 500 patients tested with Intron A "less than 3% showed any sign of this type of activity in the blood that would be able to neutralize interferon as if an antibody was being produced against interferon." Roferon-A labeling states that "neutralizing antibodies to Roferon-A were detected in approximately 27% of all patients (3.4% for patients with hairy cell leukemia). No clinical sequelae of their presence have been documented thus far." Labeling for Intron notes: "In a multicenter controlled clinical trial involving 145 hairy cell leukemia patients, no serum neutralizing activity was detected in the 87 patients evaluated. Serum neutralizing activity was detected in some patients treated with higher doses of Intron A in malignancies other than hairy cell leukemia. The clinical significance of these findings is unknown." Alpha interferon license applications have been pending at FDA since 1983, when Schering, who licensed the interferon from Biogen, submitted applications for treatment of Kaposi's sarcoma and multiple myeloma. The firm also has applications pending for malignant melanoma, venereal warts, and prevention of the common cold. Roche, a Genentech licensee, has applications pending for cancer indications, including Kaposi's sarcoma. FDA acted quickly in approving the application for treatment of hairy cell leukemia. Schering submitted an application June 28, 1985; and Roche filed a license application in August 1985. Bowen noted that 2,000 to 3,000 people in the U.S. suffer from hairy cell leukemia. In response to a question at the June 4 press conference, Young said other indications for alpha interferon would be approved by FDA "possibly within this year" or next year. Roche predicts the next indication will be for Kaposi's sarcoma. Young praised the agency staff for their efforts in approving alpha interferon. He commented that "in addition to basic and clinical research -- supported by Natl. Cancer Institute, Natl. Institutes of Health, Natl. Science Foundation and universities -- and the developmental research in the two companies that developed this treatment, credit should go to FDA's Div. of Virology for the tremendous job they did in coordinating and expenditing the review and approval processes for alpha interferon." Young added that "in the most rapidly advancing technology, it is imperative that 'bench scientists' participate in the review to add a layer of safety to the process." Bowen highlighted the breakthrough treatment alpha interferon represents for hairy cell leukemia patients. "Until alpha interferon, treatment methods were limited to surgical removal of patients' spleen, partially suppressive chemotherapy, and blood transfusions," Bowen stated. "Even with these treatments, 7 to 20% of hairy cell leukemia patients died each year." Schering launched Intron A immediately upon approval and Roche said it expects to ship its interferon very soon. Roche's price to whslrs. for Roferon-A is $20 per vial of 3 million or 18 million internatl. units (IU) of alpha-2 interferon. Schering said the average whsle. price for Intron A is $24.48 for 3 million units of the product. Each vial of Intron A contains either 3 million, 5 million, 10 million, or 25 million IU of alpha interferon. Roferon-A is marketed in a solution while Intron A is marketed as a lyophilized product for reconstitution. For Roferon-A, the induction dose is 3 million IU daily for 16 to 24 weeks, administered subcutaneously or intramuscularly. The recommended maintenance dose is 3 million IU, three times per week. Intron A labeling notes that the recommended dosage is 2 million IU/m2 administered intramuscularly or subcutaneously three times a week. Labeling for the two products states that "patients should be cautioned not to change brands of interferon without medical consultation, because a change in dosage may result." The two firms have also produced patient information sheets for home use of alpha interferon. The sheets give step-by-step instructions on how to reconstitute and administer the interferon. Unlike traditional patient package inserts, they do not specify adverse reactions associated with the drug. Schering's labeling cautions that the information "is intended to aid in the safe and effective use" of interferon, but "is not a disclosure of all possible adverse or intended effects." Roche's information sheet contains a summary of side effects. Intron A is currently marketed in Canada, the U.K., Ireland and the Philippines for hairy cell leukemia. It is also marketed in Ireland and the Philippines for multiple myeloma, malignant melanoma, Kaposi's sarcoma and venereal warts. Although not marketed, the product is approved for one or more of these indications in Colombia, Chile, Belgium and Luxembourg. Roferon-A has not been approved outside the U.S., but applications are pending in Italy, France, Germany, Japan, Great Britain, Sweden, Switzerland, the Republic of Ireland and the Netherlands.

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