evidence of efficacy. They included 30 phase III studies, 17 phase II studies, 1 phase I study, and 4 phase IV studies (which were conducted following FDA approval of the drug for a different indication).

In this sample, 13 of the 30 orphan drugs were approved based on a single efficacy trial, including 8 based on a single phase III trial; 4 based on a single phase II trial; and 1 based on a single phase I trial. Among the 55 pivotal trials, 27 had a double-blind design, 5 were single-blind, and the remaining 23 did not have blinding. Twenty-six trials used placebo controls, and 11 used active comparators. Thirty-eight studies were randomized. Thirteen were single-arm studies.

Box 3-3 presents examples of the different kinds of efficacy studies that FDA has accepted in approving orphan drugs. The examples suggest considerable variability and flexibility in the evidence that FDA has

BOX 3-3

Examples of Variations in Types of Efficacy Studies Accepted by FDA in Orphan Drug Approvals

In 2010, FDA approved carglumic acid (Carbaglu) for the treatment of acute hyperammonemia resulting from a deficiency of the enzyme N-acetylglutamate synthase (NAGS). NAGS deficiency is an extremely rare condition that can be fatal without treatment. The sponsor submitted data from a retrospective, unblinded, controlled case series for 23 patients who were treated for a median of 7.9 years (range 0.6 to 20.8 years). Complete data were available for 13 patients. The summary review stated that “although the retrospective case series data … are not derived from traditionally defined adequate and well controlled investigations, the plasma ammonia level data submitted for review do stand as evidence ‘on the basis of which it could fairly and responsibly be concluded by experts that the drug will have the effect it purports or is represented to have’” (Greibel, 2010, p. 1 quoting Section 505(d) of the Food, Drug, and Cosmetic Act). The approval letter from FDA specified a number of postmarket study requirements, including a registry to obtain long-term safety information over a 15-year period (Beitz, 2010).


Alglucosidase alfa (Myozyme) was approved in April 2006 as enzyme replacement therapy for Pompe disease, a rare autosomal recessive lysosomal storage disease. Without treatment, infants with the disease usually die by 18 months of age from respiratory and heart failure. Myozyme was approved based primarily on the results of a randomized, open-label, historically controlled study in 18 infantile-onset patients. The ventilator-free survival rate for the treated infants was 83 percent at 18 months of age compared to 2 percent survival in the age-matched historical comparison groups of 61 patients. Among other postmarket studies, the sponsor agreed to two long-term studies to collect additional clinical data, including growth and development information (Beitz, 2006).


Before colchicine (Colcrys) received orphan drug approval in 2009 for familial



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