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