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ORPHAN DRUG AVERAGE APPROVAL TIME IS 26 MONTHS V. 34 MONTHS FOR OTHER ORIGINAL NDAs, FDA SAYS; CHEMISTS ARE LOOKING AT "NEW DRUG" DEFINITION

Executive Summary

The average approval time for an orphan drug is approximately 26 months, eight months less than FDA's average approval time for other "original" NDAs, FDA Orphan Product Development Division Director Marlene Haffner, MD, reported at an Oct. 5 Food and Drug Law Institute conference on orphan drugs. Haffner said the speedier approval time is attributable, in part, to the fact that other therapies are often not available to treat the disease for which the orphan is intended. In those cases, she said, "the division has worked very hard to get a product into the marketplace." The majority of orphan products approved have been for products granted either "A" or "B" status (i.e., products representing significant ["A"] or modest ["B"] advantage over existing therapies). To date, 239 products have been granted orphan status enactment of the Orphan Drug Act in 1983, 27 of which have been approved for marketing. Of the 21 approved products for which she had data on therapeutic ratings, Haffner reported that 15 were designated as either "A" or "B" drugs. One of the focal points of the FDLI meeting was the issue of orphan status drug exclusivity. Although simultaneous development situations are relatively rare, the issue has come up with highly visible products, such as human growth hormone, interferon, erythropoietin and aerosol pentamidine. Haffner noted that FDA has administratively addressed the problem of simultaneous development by attempting to assign equally proficient reviewers to competing firms' applications. "We work very hard to assign products to reviewers who are equal, chemists who are equal, and to do the best job we can" to facilitate equivalent reviews, Haffner said. "We work as carefully as possible to assure that things are progressing through the system in the best way possible. But frankly, [simultaneous submissions] don't happen very often." Citing the case of human growth hormone, Metabolism & Endocrine Drug Products Division Solomon Sobel, MD, said that FDA will try complete reviews for pending same-drug orphans near the time expiration of the innovator's exclusivity. Approval, he predicted, will "be relatively close to the time of expiration of exclusivity, but it's not going to be simultaneous." Sobel explained that an exclusivity grant for one firm's product will not affect the review timetable for any "stable" portions of subsequent NDAs. "In my division, I try to get all the reviews complete that are reasonably stable reviews -- that are unlikely to change at the time of expiration of the exclusivity of the innovator," Sobel said. "On the other hand," Sobel continued, "it may not be a correct use of agency resources to have to do two complete reviews" for sections, such as chemistry, which might change during the course of the exclusivity. In the case of human growth hormone, he noted, "I favored clinical evaluation, but my chemist resisted the idea of furnishing a complete review of chemistry for conditions that may not be relevant for the final eventual approval." A second and related exclusivity issue that arose with human growth hormone is FDA's criteria for determining that one product is different from another. Haffner noted that FDA is still planning to issue orphan drug regulations to address the definition of a drug product "for the purposes of determining exclusivity." The regulations, she said, will "attempt to integrate" concepts of differentiation contained in the Waxman/Hatch law, presumably referring to the limitations on ANDA applications. "You will find no surprises," she promised. Haffner predicted that the regs will be out before the end of the calendar year. A draft version has been circulating around the agency for review, and a second revised version incorporating recommended changes is reportedly being printed for a final sign-off by agency topsiders. Although the orphan regs will define what constitutes a new molecular entity, FDA is currently in the process of developing a more complete policy on the issue. The agency has enlisted its chemists to work on a definition along with FDA office heads, including Office of Drug Evaluation I and II Directors Robert Temple, MD, and James Bilstad, MD, respectively. "We are currently working on definitions which clearly indicate when a drug is a new molecular entity and when it is not," Sobel said. "When is a method of producing a peptide, producing a drug with a different spacial configuration . . . or glycosylation of a peptide considered a new molecular entity?" Sobel asked. These are "very difficult questions," he added. Elaine Esber, MD, associate director for research and regulatory condition in the Center for Biologic Evaluation & Research, noted that the issue becomes more complicated with larger molecules. "There are going to be products that are larger in size [where] one will easily be able to substitute an amino acid or change the glycosylation structure or take off a . . . piece of protein." Esber said. She pointed out that such products could arguably be considered NMEs "even though the biological activity might in fact be the same." Regulations on the tax credit for clinical testing of orphans were finalized by the Internal Revenue Service in the Oct. 3 Federal Register. The reg adopts amendments to the Tax Reform Act of 1986, including the provision for coverage of biological products. The final reg also drops the draft's provision for prorating funded amounts between qualified and unqualified clinical testing expenses. Under the final regs, 100% of payments received are treated as funding otherwise qualified clinical testing expenses. FDAers at the FDLI meeting pointed out that the agency is concerned with the use of the orphan drug route to get products out on the market that are likely to be used for non-orphan indications. FDA Orphan Products Division Deputy Director Neil Abel reported that the orphan division "works very closely with the divisions" to identify situations where a sponsor might be trying to get a product approved as an orphan with a much larger patient population use in mind. The review divisions "have always had the [philosophy] that they do not want to approve an indication when they know it's going to be used in a much larger population, and in my experience, they've always used persuasive means to have the organization or firm carry out trials in that larger population." However, Abel added, "if it's really something that is needed for that condition and there is nothing else out there, I don't see any reason why you should designate it [as an orphan]." Sobel noted that written protocol assistance, one of the incentives under the Orphan Drug Act, can be used as a means for identifying the legitimacy of an orphan indication. One "reason for going through the protocol assistance route is to get sponsors' early readings in regard to whether their prevalence estimations are correct or whether they are going for an indication which is not legitimate," Sobel said. Noting that any disease can be divided into subclasses, Sobel observed that some of the subclasses sought in orphan applications "are legitimate" while others "may be artificially created to get under the orphan drug umbrella." FDA reported that the protocol assistance route, which allows a firm to get written agreement on the adequacy of its proposed protocols, has been used by less than 20% of orphan sponsors.
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