Characteristics of clinical trials to support approval of orphan vs nonorphan drugs for cancer

JAMA. 2011 Jun 8;305(22):2320-6. doi: 10.1001/jama.2011.769.


Context: The Orphan Drug Act incentivizes medication development for rare diseases, offering substantial financial benefits to the manufacturer. Orphan products constitute most new drug approvals in oncology, but safety and efficacy questions have emerged about some of these agents.

Objectives: To define characteristics of orphan cancer drugs and their pivotal clinical trials and to compare these with nonorphan drugs.

Design and setting: We identified all new orphan and nonorphan drugs approved between 2004 and 2010 to treat cancer. We then collected data on key development variables from publicly available information on the US Food and Drug Administration's Web site and in the Code of Federal Regulations.

Main outcome measures: We assessed clinical testing dates, approved indications, and regulatory characteristics (regular vs accelerated review, advisory committee review, postmarketing commitments). We then compared design features (randomization, blinding, primary end point) of pivotal trials supporting approval of orphan and nonorphan drugs and rates of adverse safety outcomes (deaths not attributed to disease progression, serious adverse events, dropouts) in pivotal trials.

Results: Fifteen orphan and 12 nonorphan drugs were approved between January 1, 2004, and December 31, 2010. Pivotal trials of orphan drugs had smaller participant numbers (median, 96 [interquartile range {IQR}, 66-152] vs 290 [IQR, 185-394] patients exposed to the drug; P < .001) and were less likely to be randomized (30% vs 80%; P = .007). Orphan and nonorphan pivotal trials varied in their blinding (P = .04), with orphan trials less likely to be double-blind (4% vs 33%). Primary study outcomes also varied (P = .04), with orphan trials more likely to assess disease response (68% vs 27%) rather than overall survival (8% vs 27%). More treated patients had serious adverse events in trials of orphan drugs vs trials of nonorphan drugs (48% vs 36%; odds ratio, 1.72; 95% confidence interval, 1.02-2.92; P = .04).

Conclusion: Compared with pivotal trials used to approve nonorphan cancer drugs, pivotal trials for recently approved orphan drugs for cancer were more likely to be smaller and to use nonrandomized, unblinded trial designs and surrogate end points to assess efficacy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers
  • Clinical Trials as Topic*
  • Cohort Studies
  • Double-Blind Method
  • Drug Approval*
  • Endpoint Determination
  • Humans
  • Neoplasms / drug therapy
  • Orphan Drug Production*
  • Randomized Controlled Trials as Topic
  • Research Design
  • Sample Size
  • Treatment Outcome
  • United States
  • United States Food and Drug Administration


  • Antineoplastic Agents
  • Biomarkers