Pivotal studies of orphan drugs approved for neurological diseases.
OBJECTIVE
To identify design elements of clinical trials leading to US Food and Drug Administration approval of drugs for neurological diseases with and without orphan indications.


METHODS
We used publicly available information to identify approvals for drugs for neurological diseases with an orphan indication (n = 19) and compared them with recent approvals for drugs for neurological diseases without an orphan indication (n = 20). We identified "pivotal trials" from drug labels and drug approval packages, and assessed them on four elements of clinical trial design: control, blinding, randomization, and size.


RESULTS
All drugs for neurological diseases (100%) approved without an orphan indication included at least two randomized, double-blind, placebo-controlled trials. In comparison, 32% of drugs with an orphan indication had at least two such trials (p < 0.001) and 74% had at least one (p = 0.02). Thirty-three pivotal trials were conducted for the 19 drugs approved with an orphan indication. Of the 33 trials, 11 (33%) did not use a placebo control, 9 (27%) were not double blind, and 4 (12%) were not randomized. Drugs approved without an orphan indication had more pivotal trials per drug (3.8 vs 1.7 trials; p < 0.001) and a larger mean trial size (506 vs 164 trial participants; p < 0.001).


CONCLUSIONS
The US Food and Drug Administration has approved orphan drugs for neurological diseases without randomized, doubled-blind, placebo-controlled pivotal trials. As orphan drug development grows, demand will likely increase for alternative designs for conducting adequate and well-controlled studies to demonstrate drug efficacy.
Mitsumoto
Jun
J
College of Physicians and Surgeons, Columbia University, New York, NY, USA. jmm2174@columbia.edu
Dorsey
E Ray
ER
Beck
Christopher A
CA
Kieburtz
Karl
K
Griggs
Robert C
RC
D017277:Drug Approval; D006801:Humans; D009422:Nervous System Diseases / Q000188:drug therapy*; D009965:Orphan Drug Production; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D014481:United States; D014486:United States Food and Drug Administration