Pivotal trials for orphan cancer drugs often have fewer patients and lower standards than trials for more prevalent cancers, raising concerns about the safety and efficacy of some drugs approved to treat rare medical conditions, according to a new study published in the Journal of the American Medical Association (JAMA).

The study authors, who are affiliated with Brigham and Women’s Hospital and Harvard Medical School in Boston, argued that while the FDA must approve prescription drugs on the basis of adequate studies, the FDA often will “relax” the requirements for drugs to treat rare medical conditions.

“Orphan drugs are likely to qualify for lower approval standards because they are designed for small populations in which organization of controlled trials may be difficult,” according to the study analysis, written by Aaron Kesselheim, M.D., Jessica Myers, Ph.D., and Jerry Avorn, M.D.

The researchers called for the FDA to consider adopting new requirements to ensure orphan drugs are rigorously evaluated and closely followed once they are approved. Through 2010, The FDA has approved 362 orphan drugs, with oncology representing the largest clinical subcategory.

The JAMA study, which reviewed all new cancer drug approvals from 2004 to 2010, found several significant differences in the pre-approval evaluation of orphan versus non-orphan drugs. Specifically, the researchers found the FDA approved alternative trial designs that allowed most orphan cancer drugs to be approved on the basis of single-group, nonrandomized trials that enrolled comparatively small numbers of patients, and that the trials relied on surrogate markers of disease response to assess efficacy. In addition, the study found orphan drugs had shorter clinical testing phases than non-orphan products.

“The higher frequency of non-blinded, nonrandomized trials of orphan drugs raises concerns about the robustness of the findings of such trials,” the study stated. “While the complexity of performing clinical trials in orphan populations should be acknowledged, methodological designs should still strive to include blinding and randomization, which are among the hallmarks of high-quality clinical trial design.”

Given the limited basis on which orphan cancer drugs are approved, the researchers said they found “a suggestion of safety concerns” associated with the orphan treatments. The study noted that an orphan drug approved in 2000 for acute myeloid leukemia was removed from the market in 2010 for safety reasons while two orphan drugs are not being reimbursed in the United Kingdom due to concerns about their efficacy and high cost.

However, Peter L. Saltonstall, president and CEO of the National Organization for Rare Disorders, said his organization is not aware of a higher rate of safety and efficacy questions for orphan products than for drugs for more common diseases, and pointed out that the JAMA article “offers no support for questioning the safety or effectiveness record” of orphan drugs. “FDA has shown flexibility in accepting protocols for pivotal trials of orphan drugs while maintaining its traditionally high standard that all drugs must be proven safe and effective for their intended populations,” Saltonstall said in a statement issued in response to the JAMA article. “Furthermore, the law places responsibility on manufacturers to report signals of risk associated with all approved drugs; manufacturers of orphan drugs are required to abide by that requirement just like manufacturers of other drugs.”

The JAMA study also raised questions about how incentives are applied under the Orphan Drug Act, which provides manufacturers that develop drugs to treat rare diseases tax breaks, additional market exclusivity and research grants. While there are about 6,000 rare diseases affecting about 25 million Americans, the study found that most new orphan drugs are for a limited number of diseases and drug classes. This suggests, according to the authors, that the law might not encourage drug innovation for a diverse range of rare conditions.

Karyn Korieth