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). INTERPRETATION: 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.
RCT Entities:
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). INTERPRETATION: 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.
Authors: Michael F Drummond; David A Wilson; Panos Kanavos; Peter Ubel; Joan Rovira Journal: Int J Technol Assess Health Care Date: 2007 Impact factor: 2.188
Authors: L Lacomblez; G Bensimon; P N Leigh; P Guillet; L Powe; S Durrleman; J C Delumeau; V Meininger Journal: Neurology Date: 1996-12 Impact factor: 9.910
Authors: K P Johnson; B R Brooks; J A Cohen; C C Ford; J Goldstein; R P Lisak; L W Myers; H S Panitch; J W Rose; R B Schiffer Journal: Neurology Date: 1995-07 Impact factor: 9.910
Authors: Robert C Griggs; Mark Batshaw; Mary Dunkle; Rashmi Gopal-Srivastava; Edward Kaye; Jeffrey Krischer; Tan Nguyen; Kathleen Paulus; Peter A Merkel Journal: Mol Genet Metab Date: 2008-11-13 Impact factor: 4.797
Authors: Wendy R Galpern; Christopher S Coffey; Alberto Albanese; Ken Cheung; Cynthia L Comella; Dixie J Ecklund; Stanley Fahn; Joseph Jankovic; Karl Kieburtz; Anthony E Lang; Michael P McDermott; Jeremy M Shefner; Jan K Teller; John L P Thompson; Sharon D Yeatts; H A Jinnah Journal: Neurotherapeutics Date: 2014-01 Impact factor: 7.620
Authors: H A Jinnah; Alberto Albanese; Kailash P Bhatia; Francisco Cardoso; Gustavo Da Prat; Tom J de Koning; Alberto J Espay; Victor Fung; Pedro J Garcia-Ruiz; Oscar Gershanik; Joseph Jankovic; Ryuji Kaji; Katya Kotschet; Connie Marras; Janis M Miyasaki; Francesca Morgante; Alexander Munchau; Pramod Kumar Pal; Maria C Rodriguez Oroz; Mayela Rodríguez-Violante; Ludger Schöls; Maria Stamelou; Marina Tijssen; Claudia Uribe Roca; Andres de la Cerda; Emilia M Gatto Journal: Mov Disord Date: 2017-09-01 Impact factor: 10.338