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Executive Summary

The anemic chronic renal failure patient population for erythropoietin exceeds 600,000, Chugai-Upjohn maintained in a recent citizens petition requesting that FDA withdraw orphan exclusivity for Amgen's Epogen and issue a license for Chugai-Upjohn's Marogen brand of EPO for the treatment of anemia associated with chronic renal failure. The petition cites a study completed in December by the company that "shows that well over 600,000 Americans appear to suffer from this disease." The Chugai-Upjohn figures are based on a study of chronic renal failure conducted for the company by the Arlington, Virginia-based Degge Group Ltd. (founded by former FDA Division of Drug Experience Director Judith Jones, MD/PhD) and published reports of the incidence of anemia among subcategories of CRF patients, the petition states. In an earlier 1989 study, Upjohn staff analysts estimated the predialysis anemia CRF population alone at 870,000. The Degge Group study estimates that there are 17 mil. CRF patients in the U.S., which can be broken down into: asymptomatic or pre-disease (15 mil.); symptomatic (2.1 mil.); and end-stage renal disease (109,730). The symptomatic CRF group with serum creatinine levels of 4-8 mg/dl, considered by Chugai-Upjohn to be the "predialysis" group, includes patients with chronic glomerulonephritis, diabetic nephropathy, chronic pyelonephritis, hypertensive nephropathy, polycystic kidney disease, and drug-induced chronic toxic nephritis. From studies in the literature, Chugai-Upjohn said it calculated that approximately 25% of patients, or about 530,000, in the symptomatic group could be considered anemic, with a hemoglobin of 10 g/dl or less. Similarly, the company found that 98% of the end-stage renal disease patients, or 107,535, with serum creatinine levels greater than 8 g/dl, are anemic. As a result, the company estimates a total of 637,000 CRF patients with pre-dialysis and dialysis anemia who could benefit from treatment with erythropoietin. Chugai-Upjohn estimates that 20% of the 15 mil. asymptomatic CRF or proteinuric patients with serum creatinine levels between 2 and 4 gdl, suffer from anemia. Therefore, the potential EPO use in that population alone could number three million. "Given the enormous margin by which these CRF anemia figures exceed 200,000," Chugai-Upjohn maintained, "it is impossible for the FDA to find that the CRF population falls below the Section 526(a) orphan drug population ceiling." The company noted that "FDA's conclusion that CRF anemia affects fewer than 200,000 persons is based on data presented to the agency by Amgen." Chugai-Upjohn met with FDA Office of Orphan Products Director Marlene Haffner, MD, in November to discuss preliminary analyses of the study. As a result of the meeting, Chugai-Upjohn adjusted the hematocrit level used in the study to measure the onset of CRF anemia from 12 g/dl to 10 g/dl. Despite this adjustment, the company noted, "the prevalence figures still far exceed 200,000." Arguing further against orphan status for EPO, the Chugai-Upjohn noted that "Amgen sales for EPO for CRF anemia, since the drug went on the market June 1, 1989, already total approximately $100 mil. -- a significant amount for the first seven months sales of any drug, much less a supposed 'orphan' drug." The company maintained that the Orphan Drug Act is intended to promote development of drugs with "little or no commercial value," and allow a company to recover development and marketing costs. "Amgen cannot, in the face of this experience, claim that it is reasonable to expect that Amgen will not recover its EPO development and marketing costs," Genetics Institute declared. The citizen petition supplements a petition filed by the company in November that requests an agency stay in conferring orphan exclusivity to Amgen's Epogen ("The Pink Sheet" Nov. 27, T&G-7). FDA had notified Amgen in an Oct. 6 letter, four months after the approval of Epogen, that Epogen had received orphan exclusivity for the treatment of CRF anemia. Both Epogen and Marogen originally received orphan designation for anemia associated with end-stage renal disease (ESRD) and Chugai-Upjohn has maintained that FDA violated the Orphan Act when it retroactively granted Amgen seven years of exclusive marketing rights for the broader indication of CRF anemia. Chugai-Upjohn has argued that ESRD itself is not an orphan disease but a phase in renal impairment at which the physician decides dialysis is necessary. The company contended in the petition that "FDA itself recognized that ESRD is not a separate medically or scientifically cognizable disease or condition when, in 1987, the agency dissuaded Amgen and its EPO marketing partner, Ortho, from filing separate PLAs for ESRD and non-ESRD CRF anemia." In fact, FDA indicated to Chugai-Upjohn at a July 5, 1989 meeting that the agency preferred the indication for anemia associated with CRF indication for Marogen as well, even though the company had filed data on a small number of non-dialysis patients. A company memo on the meeting states: "No requests for additional pre-dialysis clinical studies were made with the FDA's full knowledge of our thirtysome patient group although a request for future studies was not ruled out." However, the memo notes that "Marogen approval for that indication will include restrictive labeling such as a prohibition to use the present Marogen formulation for subcutaneous administration." Epogen labeling contains both I.V. and subcutaneous administration.

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