Off-Label Drug, Medical Device Use Discussed at FDA Hearing

Troy Brown

November 11, 2016

The US Food and Drug Administration (FDA) held a 2-day public hearing this week to solicit input about the marketing and use of medications and medical devices for off-label use. It is fairly common and often works for the patient's benefit, but sometimes the results for the patient can be catastrophic, and even fatal.

Drugs are often used off label when real-world evidence has shown that they work before clinical trial data become available — sometimes during the course of a clinical trial but before the trial has been completed. In some cases, one drug has been shown to work for another similar condition, and in some cases other drugs with similar mechanisms of action have demonstrated effectiveness in the particular condition being treated. Sometimes a new mechanism of action is discovered idiosyncratically while the drug is being used for a different condition.

The fast-paced meeting included speakers from the pharmaceutical, medical device, and insurance industries, as well as physicians, health and safety advocates, patients, and patients' family members. At times the exchanges became heated.

First Amendment

Several speakers weighed in on whether or not, and if so, how, the First Amendment applies to marketing of "off-label" medications. Many speakers said that communications between pharmaceutical companies and healthcare providers should not be restricted as long as they are not misleading. Most agreed that direct-to-consumer marketing of off-label uses is riskier.

But determining whether or not such communications are misleading is not as easy as it may sound, because such marketing might be based on research that is published in a medical journal but does not meet the FDA's rigorous standards. Some less-rigorous studies are ghostwritten, reprinted, and widely disseminated. In addition, communication about off-label use of medications and devices often occurs one-on-one with healthcare providers "behind closed doors," as opposed to at a medical conference where industry claims can be more easily challenged.

Most agreed about the need for physicians and patients to have access to the most current data about the safety and efficacy of new treatments. Insurance companies also need to have the most current economic information about disease burden and overall cost to make coverage decisions.

Strong Evidence Critical

"Off-label promotion undermines public health; industry education is always misleading; and trust in Pharma goes against the evidence," said Adriane Fugh-Berman, MD, a physician and associate professor at Georgetown University Medical Center, Washington, DC. Dr Fugh-Berman is also a paid expert witness at the request of plaintiffs in litigation regarding pharmaceutical marketing practices.

Between 73% and 81% of off-label prescriptions are for conditions for which there is little or no scientific support for efficacy, she said. "We know that promotion increases prescriptions; if the FDA loosens restrictions on off-label promotion, irrational prescriptions and associated harms can be expected to skyrocket," she explained.

Dr Fugh-Berman acknowledged that there are legitimate off-label uses for some medications, but she also said that off-label use increases adverse effects, which are even higher when drugs are used in ways that lack scientific support.

"You've heard from industry that RCTs — randomized controlled trials — don't represent real-world evidence; RCTs represent the only reliable scientific evidence of benefit. Observational studies cannot prove benefit," she added.

"At this hearing, for example, there are several phrases used by industry that we have heard over and over again; what if we reframed some of those phrases? For example, 'unmet medical needs' could be translated as 'untapped profit opportunity'; 'timely' means 'premature,' 'emerging evidence' means 'hope,' 'best evidence available' equals 'rumor,' and 'real-world evidence' means 'not evidence-based,'" Dr Fugh-Berman suggested.

Obtaining FDA Approval "Slow, Cumbersome"

"We believe the FDA's current regulations unnecessarily interfere with the dissemination of scientifically valid information between healthcare professionals and manufacturers," said Doyle Stulting, MD, PhD, American Society of Cataract and Refractive Surgery and the Alliance of Specialty Medicine. Dr Stulting is a past president of the American Society of Cataract and Refractive Surgery; he is also the founder of the Stulting Research Center and professor emeritus at Emory University, both in Atlanta, Georgia.

"This interference ultimately denies physicians access to vital, current, real-world experiences and adversely affects healthcare outcomes. I and my colleagues in the Alliance of Specialty Medicine believe physicians have the ability to assess and interpret clinical data appropriately and that access to those data will result in measurable benefits to patients to improve outcomes and new cures," Dr Stulting said.

"Reasonable restrictions on the communications would include notification that a referenced indication is off label, as well as a requirement that communications be truthful, balanced, and not misleading. Off-label use of drugs and devices is actually very common in my practice and indeed the practice of medicine," Dr Stulting explained. "Off-label use is commonly found in medical textbooks; in fact, failure to prescribe medications or use devices off-label would quickly place many of us, including me, at risk for a malpractice lawsuit.

"Routine use of antibiotics after surgery, like cataract surgery, is off label. The use of antibiotics to treat severe…sight-threatening infections is also off label. Would you like to have surgery without antibiotic coverage?" he asked.

"For certain populations such as children, pregnant women, cancer patients, and patients with rare diseases, FDA-sponsored clinical trials are not feasible or are too costly for any manufacturer to undertake. This is especially true for patients with rare diseases and those with conditions that may exclude them from FDA clinical trials; for patients such as these, off-label use of medical products is our only option, one that may even be vision or life-saving," Dr Stulting explained. "Clinical trials designed for FDA approval is rigorous, well-designed, monitored, appropriately analyzed, and reliable. Obtaining FDA approval for a particular indication is, however, slow, cumbersome, and incredibly expensive."


Off-label use of medications and medical devices in children came up time and again during the meeting. Because children's bodies are smaller, there is less room for error when something goes wrong. And there has often been less clinical research in children compared with adults. Psychiatric drugs are a particular example, because in adults, as well as in children, reaching an accurate diagnosis can be difficult and time-consuming, and requires that a patient try several different drugs before the most effective treatment is found — issues that are magnified with children. At least two speakers described loved ones who committed suicide after being prescribed psychotropic medications either off-label or without proper medical supervision. In both cases, the patients' loved ones said they had been uninformed about the risks.

Written Clarification Forthcoming

Several speakers said they would be submitting additional information between now and January 9, 2017. The public is invited to submit electronic or written comments to or the Division of Dockets Management (9HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD, 20852. All comments must be identified with docket number FDA-2016-N-1149.

Additional information related to this public meeting can be found on the FDA website.

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