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Executive Summary

ORPHAN SHARED EXCLUSIVITY: CLINICAL SUPERIORITY should be the criterion for permitting follow-on biologicals to enter the market, Genentech Senior Director of Government Affairs Martin Rose, MD, suggested at a Dec. 12 Food & Drug Law Institute meeting in Washington, D.C. "The follow-on product should offer some significant therapeutic advantage over the pioneer" before receiving shared exclusivity, Rose said, "the kind of difference that would reasonably influence a doctor's or patient's choice between the two agents." Such a policy would promote two objectives, Rose said. First, it would ensure "that the marketing exclusivity provision [will] be preserved for the biotech industry." However, it would also assure that patients would not be denied access to clinically useful follow-on products in cases where apparently minor differences do make a difference in the product's activity. Rose cited HHS Secretary Sullivan's response to a May 3 letter from five senators about the orphan status of Fisons' aerosol pentamidine Pneumopent as evidence that FDA is moving toward clinical superiority as a standard. In an Aug. 30 letter, Sullivan said that "FDA has interpreted the Orphan Drug Act to permit marketing approval for another manufacturer's product even if that drug is essentially the same drug as an approved orphan drug, if the new version provides a significant therapeutic advantage over the first." Sullivan indicated that FDA has not yet decided whether aerosol pentamidine will be granted orphan drug status; however, he reassured the senators that "contrary to what you have heard, FDA has made no determination that the Orphan Drug Act precludes approval of Fisons' regimen for administration of aerosol pentamidine." FDA will not ostensibly consider cost-effectiveness as an advantage, Sullivan said. "While the Administration is concerned about the spiraling costs of health care," Sullivan wrote Capitol Hill, "FDA's mission is to evaluate drug products on the basis of safety and effectiveness, independent of cost considerations." Rose contrasted a policy based on determination of significant therapeutic advantage with the difference standard used in the approval of Lilly's human growth hormone Humatrope. FDA's consideration of the pending PLA for Chugai-Upjohn's Marogen erythropoeitin despite the orphan approval of Amgen's Epogen repeats the difference criterion, Rose maintained. Chugai argues that its product is different than Epogen only because of different patterns of glycosylation (attachment of carbohydrate structures to the basic molecule). Glycosylation, Rose said, varies "under the best manufacturing conditions" and is "easy to manipulate during the manufacturing process." Such variations, he said, "have no predictable effect on activity and often have none at all." "We learned some more," Rose added. FDA "was considering a policy to squarely address 'the same drug issue.' The policy stated that any time the structure of a drug was indeterminate, variable, or heterogeneous [as differently glycosylated drugs are], each manufacturer's version of the drug would be considered different for the purposes of the Orphan Drug Act." Such a policy, he said, "would write most biotechnology products out of the act." Protests from Amgen and Genentech, a Feb. 15 letter from 22 molecular biologists to then FDA Acting Commissioner Benson ("The Pink Sheet" March 5, T&G-3), and a May 24 letter from the Industrial Biotechnology Association ("The Pink Sheet" June 4, T&G-6) caused FDA to reevaluate its position, Rose believes. "Eventually, FDA asked the Institute of Medicine to hold a meeting under the sponsorship of its drug forum to consider this issue," Rose said. The meeting, held Nov. 19-20, "considered heterogeneity in a protein structure in a general way without reference to specific products," Rose said, "Glycosylation was a major agenda item...Most significantly, there was general agreement that the only way to tell whether a change in glycosylation is important is to test the product in the clinic. Several speakers echoed that theme." "Some sort of therapeutic advantage or clinical superiority standard will be adopted for glycosylated drugs and perhaps in other cases of heterogeneity," Rose predicted. "In my view that would be the correct outcome."

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