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Executive Summary

FDA will continue to be flexible in assessing company estimates of patient populations for orphan drug eligibility, FDA's Office of Orphan Products Director Marlene Haffner, MD, told a Food and Drug Law Institute seminar on orphan drug regulations March 20 in Washington, D.C. Companies "can't be held responsible" if they incorrectly estimate fewer than 200,000 patients for a disease "because diagnostic criteria don't exist," because data is lacking for some other reason, or because the disease spreads. Haffner said FDA would revoke orphan exclusivity only if "the information existed [at the time of designation] and we didn't have it available to us." George Stanley, who recently retired from FDA's Office of Orphan Products, said the agency "will be as liberal as it can." Although some companies have sponsored surveys to determine the prevalence of specific diseases, Stanley said, "you can't ask small companies to create [a database] that doesn't exist." In some cases, he noted, "we have actually accepted professional opinions" where no hard data exists. If the population is "less than 1,000," he added, "you're not going to ask for quite as detailed [information] as you would if there were 200,000." The FDLI meeting focused on the recently-proposed orphan drug regulations covering section two of the Orphan Drug Act ("The Pink Sheet" Feb. 4, p. 3). The proposal states that exclusivity "will not be revoked on the ground that the prevalence of the disease or condition (or the target population) becomes more than 200,000 persons." Last year's Orphan Drug Amendments, vetoed by President Bush in November, would have revoked orphan exclusivity once a patient population surpassed 200,000. Haffner also indicated that FDA will adopt a liberal view when companies seek orphan designation for subpopulations of diseases, often referred to as "salami slicing." Haffner said that "in general, if a drug is going to be useful for a specific subset . . . where there's no other drug available for it, and if, on consultation, the [reviewing] division in either drugs or biologics concurs that that's an appropriate indication to study, then we will very likely designate it." While conceding that the use of the Orphan Drug Act to gain exclusivity for drugs under study for other indications is "disturbing" from the point of view of profits generated, Haffner noted that if the drug is first approved for the larger indication it may never ever get studied for the smaller indication." Haffner maintained that FDA's policy is in keeping with "the intent of the Orphan Drug Act, and that was to get drugs appropriately studied and labeled for people with rare diseases." Several FDAers, including Associate Chief Counsel for Enforcement Fletcher Campbell and Chief of Staff Joseph Levitt, used the FDLI forum to solicit comments on several "key" areas in the proposed regulations. Campbell identified six issues that FDA has "struggled with," including: the issue of "sameness versus difference" of drugs and how to deal with clinical superiority for follow-on products; the amendment procedure proposed to handle changing indications; the procedure proposed to determine non-profitability of drugs with more than 200,000 patients; FDA's assumption that it has the authority and the discretion to revoke exclusivity in particular situations; the agency's decision not to establish a challenge procedure for its orphan drug decisions; and the proposal not to apply the new regulations retroactively. Levitt focused on FDA's proposal to allow improved versions of a product with orphan exclusivity onto the market if a company can demonstrate clinical superiority based on the demonstration of a "major contribution to patient care," and not necessarily on improved safety or efficacy. Levitt said that FDA needs "help in figuring out some rational criteria and guidelines so this doesn't become a battleground for everyone deciding they're clinically superior. We want it to be a narrow exception, a safety valve." If "this is opening Pandora's box," Levitt added, "then you ought to write that in also." FDA's proposal specifically excludes consideration of drug cost from the definition of "major contribution to patient care." Levitt admitted that "if I'm a patient I care very much about the price." However, he said, the law should "keep us focused on the scientific and medical issues that we are equipped to deal with," and leave economics out. Campbell pointed out that he believed FDA had no authority to consider cost, nor any mechanisms to ensure that a drug granted shared exclusivity because it was cheaper than an innovator product would maintain its low price after approval. The most-discussed issue at the meeting was FDA's definition of same versus different drugs. Levitt pointed out that the preamble to the proposed regulations includes four options FDA considered before proposing that "two drugs would be considered the same drug if the principal, but not necessarily all, structural features of the two drugs were the same." Levitt said the other three options were listed because "we want to explain our thinking," and because "we'd like the debate to focus on those parameters." The debate at the FDLI meeting contrasted the positions of Genentech Senior Director of Government Affairs Martin Rose, MD, and Ares-Serono VP-Government Affairs Nicholas Ruggieri. Genentech's human growth hormone Protropin has shared exclusivity with Lilly's almost identical Humatrope since 1987, a situation that would apparently only occur under the proposed regulations if Lilly could prove its product superior. Ares-Serono has an NDA pending for its Saizen human growth hormone, which is blocked by the exclusivity provisions. Rose previously had called for a clinical superiority test like the one proposed by FDA ("The Pink Sheet" Dec. 24, T&G-8). He expressed his satisfaction with the proposals as a fair balance between the need to maintain the incentive of exclusivity with the need to ensure that biotechnology products with small but clinically important differences could be marketed. Ruggieri, however, argued that orphan drug exclusivity was not necessary to encourage biotech drug development. "I firmly believe there is no biotech drug in the pipeline or on the market that is there exclusively or mostly because of orphan drug exclusivity," he said. He argued that the orphan drug law had changed from "an incentive to develop drugs to a reward for drug innovation" similar to patents. "FDA ought to regard anything that requires an NDA as a different drug, right down the line," he added. In any event, if a second company is prepared to undertake the expense involved in filing a PLA for a product, "isn't that a bright neon sign that you don't have an orphan in the first place?" Rose responded that the decision on such a policy is "not an argument for FDA, that's an argument for Congress" because it would write the exclusivity incentive "out of the law." Stanley noted that FDA had earlier proposed considering all biologicals as different products under the orphan drug program. In "early 1989," Stanley said, FDA sent a proposal "downtown" to HHS that would have "ended up, in effect, handling all biologics as different." HHS Secretary Sullivan and Assistant Secretary for Health Mason, "to their credit," sent the regulations "back to us to rethink," Stanley said. "We tried [in the proposed regs] to come out with a reasonable compromise between same and different," he added. National Organization for Rare Disorders Executive Director Abbey Meyers warned that "abuses of the intent of the law will continue under these regulations at least until biotech patent laws are changed or the Orphan Drug Act is amended. . . . In the end both consumers and the industry will suffer the consequences because Congress will stop the proverbial goose from laying its golden egg." In a "plea to the industry," Meyers asked orphan sponsors to share your exclusivity voluntarily with your competitors before your orphan drug is approved for marketing. If you can keep these drugs out of the courtroom and reduce the visibility of lobbyists on Capitol Hill, Congress would not be able to interpret these skirmishes as abuses, and the money you save on lawyers and lobbyists would benefit consumers through more affordable orphan drugs."

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