EPO LABELING SHOULD BE FOR CHRONIC RENAL FAILURE USE -- FDA ADVISORY COMMITTEE RECOMMENDS; BROAD INDICATION MAY ELIMINATE ORPHAN EXCLUSIVITY

Erythropoietin should be approved for treatment of chronic renal failure patients, instead of the more restrictive use in end stage renal disease sought by both Amgen and Chugai, FDA recommended to FDA's Blood Products Advisory Committee on May 11. "FDA believes that approval of EPO with a label indication for all CRF [chronic renal failure] is preferable to a restricted label indication," FDA Center for Biologics Evaluation and Research Review Committee Chairman Joseph Fratantoni, MD, told the panel. The committee generally agreed with the agency's recommendation that EPO be approved for chronic renal failure, although some committee members expressed reservations about the limited data on predialysis patients. "We are not going to hold up the licensing [of EPO] just because there is not enough data for chronic renal failure," said committee chairman Louise Keating, Director of Northern Ohio Red Cross Blood Services. The committee's agreement with FDA means that EPO could be approved in the short term for both the indications sought by Amgen and the biotech company's co-marketing partner, Ortho. The decision to broaden the use may also make it possible for Chugai-Upjohn to come on the market with their EPO product, once approved, since the broader label could expand the potential patient population beyond the limits set for orphan exclusivity. The question of a simultaneous approval for Amgen and Ortho remains unclear. Fratantoni maintained that "FDA has reviewed and will continue to review each submitted erythropoietin product [and] review them as separate entities." To distinguish between the various products, FDA has assigned recombinant erythropoietin "an official name of epoietin intended to be used with a suffix that will be specific for each manufacturer," Fratantoni told the committee. Amgen's Epogen has been given the generic name of epoietin [alpha]. Amgen CEO George Rathmann balked at the FDA suggestion of a broader indication for EPO. Noting that "95% of all data filed with the FDA to date is from dialysis end stage renal disease patients," Rathmann suggested that there is not enough proof of efficacy to approve EPO in predialysis treatment. Rathmann emphatically recommended that EPO approval be "restricted to endstage renal disease patients and with the labeled precaution that it is not indicated for use in non-dialysis patients since the safety and efficacy of epoietin [alpha] has not been established for these patients." Amgen's concerns may be two-fold. One is that the additional review of predialysis data will further delay the approval of EPO or, at a minimum, require Amgen to amend its labeling, which has already been formalized in an insert. The other obvious concern is that inclusion of predialysis patients may increase the treatment population to more than 200,000, thereby disqualifying EPO from orphan exclusivity. Despite numerous discussions with FDA's Orphan Products Division on the matter, CBER reportedly has not yet decided how the broadening of the indication will affect EPO's orphan status. The issue of orphan exclusivity was not addressed at the committee meeting. "Orphan . . . issues will be dealt with by the agency at a later time," FDA Division of Blood and Blood Products Director Joel Solomon, MD, said. Asked by the committee whether the additional predialysis data would hold up the approval of EPO, which had been ready for approval for the dialysis-only indication in March, Fratantoni responded that "from now [on], whether predialysis data are included or not there should be no difference in time to approval." However, the committee agreed that there should be some "additional information or guidance in the labeling to make it known that [dialysis and predialysis] are different [populations]." Keating also pointed out that "there are not the same disease data available." An Ortho open label efficacy study involving 117 predialysis patients showed that patients had a corresponding rise in hematocrit when given Eprex at doses of 50 U/kg three times a week (T.I.W.) (up 0.13% points/day), 100 U/kg T.I.W. (up 0.20% pts./day), and 150 U/kg T.I.W. (up 0.26% pts./day). Ortho also presented data on subcutaneous administration of Eprex at a dose of 100 U/kg T.I.W., which found that "EPO can be given by the intravenous or subcutaneous routes with equal effectiveness," Ortho's Robert Abels told the committee. Amgen and Ortho reached an agreement in 1985 to develop erythropoietin for the two separate indications. Under the agreement, Amgen was to have the U.S. dialysis market for its product Epogen and Ortho was to have marketing rights for pre-dialysis in the U.S. and both indications in the rest of the world for its product Eprex. Differences between the two companies led to an Ortho lawsuit against Amgen earlier this year. A March decision in Delaware federal court forced Amgen, which had filed a PLA for chronic renal disease without Ortho's predialysis data, to include Ortho's data in its PLA ("The Pink Sheet" March 27, p. 3). The Amgen/Ortho dispute is currently in arbitration in Chicago, with hearings scheduled for August. The committee did not distinguish between Amgen and Chugai, which also presented data to the panel, in its discussion of the approval issues for EPO. However, Amgen's leadership position for first approval has not been substantially changed by the consideration of Chugai's data. Amgen submitted its PLA in October 1987 and Chugai in July 1988. Furthermore, Chugai's submission only includes dialysis data, which may not support the broader indication of chronic renal disease. In addition, Amgen's EPO plant has already been inspected by FDA, while Chugai's plant in Japan has not yet been cleared. Chugai presented data from an open label dose response study, conducted by G. H. Besselaar Associates, in dialysis patients who were treated three times weekly with 25 U/kg, 100 U/kg, and 200 U/kg of Marogen. At eight weeks hemoglobin measurements had changed from the baseline 8.5 gm to 8 gm for the 25 U/kg dose, to 10 gm for the 100 U/kg, and to 11 gm for the 200 U/kg. By 32 weeks all three doses maintained hemoglobin measurements of 10 to 11 gms. Recommended dosing for erythropoietin was also addressed by the committee. A majority of committee members found the FDA-proposed initial dose of 50 units/kg three times a week to be "too conservative." In its recommendation, the committee expanded the initial dose to range from 50 to 100 U/kg T.I.W, which his still less than the 50 to 150 U/kg T.I.W. proposed by Amgen. The committee agreed with FDA that the target red blood cell level should be a limited to a hematocrit of 30 to 33%, with a maximum of 36%.