After an investigational medication is subject to clinical trials but before it is permitted to be used widely in patients, the FDA reviews the clinical trial results to ensure that the drug’s potential benefits outweigh possible harms for its proposed specific indication. Many FDA approvals are based on trials comparing drugs with placebo rather than active comparators or standards of care. The FDA also allows for expedited drug development and approvals for serious or life-threatening conditions. Such drugs may be studied in single-arm studies with no comparator.

“Since 2012, drugs can be designed as a ‘breakthrough therapy’ if preliminary clinical evidence suggests that they offer an advantage over existing options,” explains Aaron S. Kesselheim, MD, JD, MPH. “This designation is increasingly being used in press releases and prescribing resources when drugs are approved, but the term ‘breakthrough’ may lead physicians and patients to become overly optimistic about a medication’s effectiveness.”

Through April 2015, the FDA designated 76 drugs as breakthrough therapies. Few investigations, however, have explored how physicians interpret the term “breakthrough therapy” or their understanding of what level of clinical testing can lead to FDA approval.

Surveying the Scene

Dr. Kesselheim and colleagues recently surveyed clinically active internists and specialists in endocrinology, hematology, and infectious diseases from the American Board of Internal Medicine’s diplomate list. The authors posed three questions about FDA approval and five about breakthrough therapies. About 60% of the 1,148 physicians who were contacted responded to the survey. The average age of respondents was 46, and more than half (55%) were men. In total, about 79% of specialists responded to the survey.

The results, published in JAMA, “showed that physician knowledge about FDA approvals appears to be limited,” Dr. Kesselheim says. About 73% incorrectly believed that an FDA approval meant a drug had comparable effectiveness with that of other approved medications. Another 70% incorrectly believed than an approval required both a statistically significant and clinically important effect. In fact, drugs can be approved without showing a classically statistically significant effect, and many drugs are approved based on their effects on biomarkers that may not necessarily translate to a clinically important effect. Among the three breakthrough knowledge questions, 52% incorrectly believed that strong evidence, such as data from randomized trials, is needed to earn such a designation.

The investigation also asked respondents to consider a hypothetical scenario in which they had a patient with a serious medical condition for which there has been no effective treatment. Respondents were informed that the FDA recently approved two otherwise equivalent new drugs for this condition, except one was labeled as a “breakthrough therapy” and one was defined as having early promising clinical results (the statutory definition of a breakthrough therapy). Nearly 95% of physicians preferred the drug labeled as a breakthrough over the medication that had no breakthrough designation.

Looking Ahead

“Our data show that many internists and specialists have substantial deficits in the implications of a drug being FDA approved,” Dr. Kesselheim says. “Many physicians also misinterpreted the term ‘breakthrough,’ believing that these drugs were supported by stronger evidence than what is required by statute. It’s critical to recognize these misconceptions because it may lead physicians to overprescribe newly approved drugs. Physicians need to scrutinize the data on the efficacy of new medicines. We can’t allow ourselves to be misled by simple monikers like ‘breakthrough therapy.’”

Dr. Kesselheim adds that educational efforts are needed for both physicians and patients on the FDA approval process. “We need to close the gaps on perception and reality of what it means for a drug to be a true breakthrough,” he says. “Policymakers should also reexamine the designation of such therapies to improve communication with doctors and patients regarding how well these drugs work and what patients can expect when using them.”


Kesselheim AS, Woloshin S, Eddings W, Franklin JM, Ross KM, Schwartz LM. Physicians’ knowledge about FDA approval standards and perceptions of the “breakthrough therapy” designation. JAMA. 2016;315:1516-1518. Available at: