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Executive Summary

Amgen is seeking to delay the approval of Chugai/Upjohn's Marogen brand of erythropoietin until FDA issues regulations implementing the Orphan Drug Act and defines more precisely the distinction between different recombinant products. In an Oct. 16 citizens petition to FDA, Amgen expressed its concern about an imminent Marogen approval. The company reports that it has information that FDA is "poised to approve" the Upjohn/Chugai product. A product license application (PLA) for the Upjohn/Chugai erythropoietin has been pending at FDA since Sept. 21, 1988. It reached one benchmark in the PLA approval process in late May ("The Pink Sheet" May 29, p. 15). The product is licensed to Upjohn/Chugai from Genetics Institute. While Amgen's filing is not an ironclad indicator of a pending decision on Marogen by FDA, eleventh-hour challenges can correlate with imminent approvals. In a similar situation during FDA's consideration of Lilly's Humatrope, Genentech filed suit on March 6, 1987 to block the Lilly application. Lilly's product was approved two days later. Amgen is asking that FDA "stay any administrative action to approve another sponsor's epoetin for the same indication as epoetin alfa [Amgen's Epogen] until 1) the Commissioner has issued final rules implementing the Orphan Drug Act . . . and 2) Amgen has had notice and an opportunity to respond to any evidence proffered by a subsequent sponsor that its epoetin is a different or clinically superior 'drug' for purposes of" orphan drug exclusivity. * FDA's orphan drug regs were originally expected in the autumn of 1988 ("The Pink Sheet" Oct. 10, 1988, p. 12). The regs, however, have reportedly been delayed by on Office of Management & Budget request for redrafting. FDA's most recent estimate, in its April agenda for pending regulations, was for a July 1989 release ("The Pink Sheet" May 1, T&G-4). Amgen's Epogen was approved June 1 for the treatment of anemia associated with chronic renal failure and granted seven years marketing exclusivity for that indication under the Orphan Drug Act. The act prohibits FDA from approving a product for the same indication unless it is deemed to be a different drug or clinically superior to the drug holding exclusivity. Although FDA has not made an official pronouncement that Chugai/Upjohn's erythropoietin is different, FDA, at the time of Epogen's approval, said that the product "may" be different. Chugai/Upjohn maintains that Marogen would not violate orphan drug exclusivity because of differences in glycosylation. Available information, the Amgen petition notes, "suggests that the FDA intends to use differences in glycosylation as a basis for distinguishing Amgen's recombinant EPO from Chugai/Upjohn's product." The Amgen petition charges that FDA's failure to promulgate orphan drug regulations violates the Administrative Procedures Act. Amgen is suggesting a proposed 30-day deadline for issuance of the regs. FDA should include procedures for allowing exclusivity holders "to respond to any evidence which suggests that a subsequent sponsor's drug . . . is a different or 'clinically superior' drug," Amgen said. The burden of demonstrating that a product is different should fall on the sponsor of the subsequent product, Amgen contends. "The absence of implementing rules to define a 'drug' for purposes of this market exclusivity provision, and to afford holders of market exclusivity appropriate notice and an opportunity for submission of views on any action which threatens to diminish that market exclusivity, violates the Secretary's statutory duty to promulgate rules and directly conflicts with Congress' intent in enacting the Orphan Drug Act," the petition maintains. "Moreover, the Secretary's failure to issue proposed rules is unlawful under the Administrative Procedure Act, and the failure to afford minimum due process protections is unlawful under the United States Constitution." Amgen included proposed orphan regulations in its petition. Under the company's proposal, "a subsequent drug shall be deemed to be the same as the pioneer drug if 1) in the case of a synthetic drug, the subsequent drug has the same three-dimensional chemical structure as the pioneer drug; 2) in the case of a biological product, the subsequent drug has the same amino acid sequence as the pioneer drug or a sequence sufficiently duplicative of the pioneer drug to yield the same biological activity." Amgen's suggested definition would jibe with the human growth hormone decision that found a distinction between the Genentech and Lilly orphan applications based on a difference in amino acid chains. The importance of the definition for the biotech industry is illustrated by the fact that the Amgen definition might not protect an orphan product such as Genzyme's Ceredase (glucocerebrosidase) which is under review at FDA for treatment of Gaucher's Disease ("The Pink Sheet" May 29, p. 13). Ceredase is a remodeled glycoprotein version of a naturally occurring enzyme. The petition suggests that sponsors of subsequent drug products be required to submit to FDA within 30 days of their NDA or PLA filing a sample of their drug product and an explanation of the rationale for believing the product is different from the product with exclusivity. Under Amgen's proposal, FDA would then provide the sample and rationale to the innovator firm, which would have 120 days to submit a response and request a regulatory hearing. In support of its position that glycosylation differences would not render a product a new drug, Amgen pointed to FDA's determination that Serono's human growth hormone (Saizen) is not different from Lilly's Humatrope. Noting that FDA denied Serono's Saizen NDA despite the fact that the firm's human growth hormone is produced in mammalian cells while Lilly's is produced in bacterial (E. coli) cells, Amgen said: "To now hold that [Epogen and Marogen, which are] both produced in the same mammalian cells (i.e., Chinese hamster ovary cells), are different due to purported differences in glycosylation is patently inconsistent with this prior ruling." The petition also points out that FDA has used different criteria in determining new drug status of products in implementing other portions of the FD&C Act. For example, Amgen cites FDA's provisions for five-year marketing exclusivity. For that decision, FDA requires that a product be an active moiety which has never before been approved. "In this case," the petition states, "FDA has provided no evidence to indicate that the active moiety of Upjohn-Chugai's recombinant-EPO is any different from Amgen's recombinant-EPO product." Amgen's petition was prepared by counsel Stephan Lawton (Pierson, Ball & Dowd). Amgen is still embroiled in patent litigation with Genetics Institute. Final oral arguments in the Massachusetts federal court case are scheduled for Nov. 9 and a final decision is supposed to be issued on or before Dec. 13.

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