Physicians’ Perspectives on FDA Approval Standards and Off-label Drug Marketing

Recently, 2 fundamental aspects of the US Food and Drug Administration’s (FDA’s) pharmaceutical market oversight have become controversial. First, the FDA created and increasingly uses expedited development and approval pathways, emphasizing greater reliance on postmarketing drug data.¹ Some argue that approval standards are becoming inappropriately low and postapproval evaluation too lax.²

Second, a court decision and state and federal legislation have chipped away at rules blocking advertising of drugs for non–FDA-approved indications (“off-label promotion”), which leads to patient harm by permitting manufacturers to encourage use of inadequately vetted medications. We surveyed a national sample of primary care internists and medical specialists to characterize physicians’ attitudes on these topics.

We contacted a random sample of 500 clinically active internists, 500 endocrinologists, and 500 cardiologists, all from the American Board of Internal Medicine Diplomate list. From May to December 2017, potential responders were provided online and paper opportunities to respond ($50 honorarium); 84 of these had out-of-date contact information. The project was approved by the Committee for the Protection of Human Subjects at Dartmouth College, with informed consent implied from completing and returning the survey.

We created and pretested a novel 25-question survey assessing perspectives about off-label drug promotion, FDA approval standards, and connections between drug evaluation and pricing. The questions were part of a broader survey about communicating evidence supporting prescription drug use.³ All respondents provided demographic information, primary practice area, and years since medical school or residency graduation.

Among 686 respondents (48% response rate), 385 (59%) were men, 368 (56%) white, 223 (34%) Asian, 18 (3%) African American, and 28 (4%) Hispanic. The mean (SD) age of respondents was 44 (8) years, and they were 18 (8) years removed from medical school.

Most viewed the FDA’s drug approval regulations favorably, with 80% (n = 540) agreeing that its approval process helps “protect the public from ineffective or dangerous drugs.” A majority of respondents (78%; n = 522) preferred that drugs be tested in 2 prospective randomized trials, with the remainder (21%; n = 143) recommending only 1 such trial (very few [1%, n = 8] favored uncontrolled studies and patient experience) (Table 1). At the same time, the majority (65%; n = 438) were satisfied with the FDA’s bar for approving new drugs; only a minority characterized the current FDA standards as “too high” (24%; n = 165) or “much too high” (3%; n = 20).

Most (60%; n = 407) thought that the FDA should “definitely not” or “probably not” allow off-label promotion to physicians and that it would be a “bad idea” or “terrible idea” to allow such promotion by sales representatives in physicians’ offices (71%; n = 479) or in medical journals (68%; n = 458) (Table 2). Many predicted that off-label promotion would increase prescriptions for drugs without meaningful benefits (61%; n = 416) and for diseases not previously considered medical problems (84%; n = 568). Physicians were much more likely to believe that off-label promotion would worsen (rather than improve) clinical decisions (42%; n = 285 vs 30%; n = 198).

More than half of physicians (54%; n = 367) felt that manufacturers need not charge less for drugs used off-label, while 70% (n = 467) supported similar pricing whether FDA approval was based on surrogate or patient outcomes.

Most respondents favored a relatively high bar for new drug approval and preferred that the FDA maintain its current restrictions on off-label marketing. Since the FDA approves about one-third of new drugs on the basis of a single randomized trial and often relies on results from nonrandomized studies,⁴ we thus observed a disconnect between many physicians’ perceptions of the drug approval process and its current reality. Physicians’ views on the dangers of widespread off-label marketing undercut judges’ rationales for permitting off-label marketing; for example, the majority decision in 1 notable case did not recognize that off-label marketing statements, even if not fraudulent, may still fall well short of accurate, unbiased information.⁵

Our results are limited by social desirability and also nonresponse; however, the close match to known physician statistics⁶ is reassuring. The views of practicing clinicians should inform evolving FDA policies about drug approval standards and off-label promotion.

Accepted for Publication: November 30, 2018.

Corresponding Author: Aaron S. Kesselheim, MD, JD, MPH, Department of Medicine, Brigham and Women’s Hospital, 1620 Tremont St, Ste 3030, Boston, MA 02120 (akesselheim@partners.org).

Published Online: January 22, 2019. doi:10.1001/jamainternmed.2018.8121

Author Contributions: Dr Kesselheim had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kesselheim, Woloshin, Schwartz.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kesselheim, Woloshin, Lu, Tessema, Schwartz.

Critical revision of the manuscript for important intellectual content: Kesselheim, Woloshin, Ross, Schwartz.

Statistical analysis: Lu.

Obtained funding: Kesselheim, Schwartz.

Administrative, technical, or material support: Tessema, Ross.

Conflict of Interest Disclosures: Dr Kesselheim reports grants from Consumer Union, the Laura and John Arnold Foundation, the Engelberg Foundation, and from Harvard-MIT Center for Regulatory Science during the conduct of the study. Dr Woloshin reports other support from Consumers Union during the conduct of the study. Drs Woloshin and Schwartz were cofounders of Informulary Inc, a company that provided data on the benefits, harms, and uncertainties of prescription drugs. The company has ceased operations. Drs Woloshin and Schwartz report personal fees from Ross Feller Casey LLP for serving as medical experts in testosterone litigation. Dr Schwartz reports other support from Informulary Inc and from Ross Feller Casey LLP outside the scope of the work. No other disclosures are reported.

Funding/Support: Dr Kesselheim’s work is funded by the Laura and John Arnold Foundation, with additional support from the Harvard Program in Therapeutic Science and the Engelberg Foundation. Survey honoraria provided by Consumer Union.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The authors would like to thank Doris Peter, PhD, Yale School of Medicine for her help in implementing the study. She received no compensation for her contributions.

Additional Information: Dr Schwartz died 1 day before acceptance of this article.