Outside the operating room—economic, regulatory, and legal challenges
A regulatory and legal perspective: Issues in off-label device use
By Rebecca Dresser, JD
My comments will focus on off-label use of medical devices, which is a topic rife with ethical questions. I will begin by reviewing recent experience with drug-eluting coronary stents, which are regulated by the FDA as Class III devices, as this experience touches on many of the challenges that arise from off-label product use.
CASE STUDY: DRUG-ELUTING STENTS
The earliest coronary stents were made of bare metal. Over time, arteries treated with these stents tend to become blocked again, requiring patients to return for repeat revascularization. Drug-eluting stents were developed to extend the time that the artery stays open.
Earlier this decade, a couple of device manufacturers sought FDA approval to market their drug-eluting stents. Each manufacturer submitted data from randomized clinical trials in otherwise healthy patients with small, newly diagnosed heart blockages. The trials showed that patients who had received drug-eluting stents had reduced reclogging rates after 9 months compared with those who had received bare metal stents. Risks appeared to be similar between the two types of stents. On the basis of this evidence, the FDA approved the initial drug-eluting stents for marketing in 2003 and 2004.1
Soon after they were approved, drug-eluting stents were being used in about 80% of patients who received coronary stents. However, although these new stents had been tested and approved for use in otherwise healthy patients with small, newly diagnosed heart blockages, about 60% of their real-world use was off label—specifically, in patients with large blockages or additional health problems such as diabetes.
Reports of adverse events with drug-eluting stents began to emerge, so the FDA issued a statement of concern in September 2006 and subsequently convened an advisory panel of outside experts to review the data and make recommendations. In January 2007, that advisory panel concluded that off-label use of drug-eluting stents is associated with an increased risk of thrombosis, death, or myocardial infarction compared with on-label use. The panel noted, however, that data on off-label use were limited and that additional studies were needed to determine optimal treatments for more complex patients.2
So research on the safety of off-label use of drug-eluting stents continues. Recent data—including studies published in the New England Journal of Medicine and JAMA earlier this year3,4—suggest that some off-label uses are safe and effective, but much uncertainty remains.
PHYSICIANS SHOULDER THE ETHICAL BURDEN
The story of drug-eluting stents illustrates some of the issues that can arise with off-label use of devices. Currently, the FDA gives physicians discretion to prescribe approved products for uses that deviate from the products’ FDA-approved package inserts. Although the FDA is imperfect, it provides the most thorough and systematic review we have of medical product safety and efficacy. However, an FDA review typically addresses the risks and benefits of a product in only one context or patient population, which might not apply to another context or population. For instance, children and the elderly are generally not well studied in clinical trials, so off-label use of therapies is particularly common in these populations. Of course, patients can be harmed if off-label use presents unappreciated risks or does not provide an adequate benefit. Even if no adverse effects result from off-label therapy, other harms are possible: an alternative therapy might have been superior or the treatment may simply be a waste of money.
In this absence of regulation, the questions of whether and when to prescribe off label—and what the guiding ethical standards should be—fall to physicians. A few professional groups provide some guidance. The American Medical Association states that off-label use is justified when “based upon sound scientific evidence and sound medical opinion.”5 The American Academy of Pediatrics (AAP) has issued what is perhaps the best statement6 (although it focuses on drugs, its principles can be applied to devices as well). The AAP maintains that off-label use should be based on “sound scientific evidence, expert medical judgment, or published literature” and notes that physicians who prescribe off label have “a public and professional responsibility to assist in the systematic development of the information” about a particular off-label use. The AAP also advocates that prescribers consider discussing with patients (or their parents) the off-label status of a therapy and the degree of the therapy’s acceptance among physicians for the proposed off-label use.
SPECIFIC ETHICAL ISSUES
How to evaluate evidence about off-label use?
The justification for off-label use is not to advance knowledge but to best meet the needs of an individual patient. But how can a physician know that a therapy is best for a proposed use when it has not been through the FDA approval process for that use or for the particular type of patient at hand? Some off-label uses are supported by strong data while others are not. Physicians have the responsibility to evaluate the available evidence with integrity and to promote rigorous research when the available evidence is inadequate.
Healthy skepticism of industry promotion warranted
One problem is that the pharmaceutical and device industries are heavily involved in communicating about off-label uses of products. Since 1997, the FDA has permitted drug and device companies to engage in limited promotion of off-label product uses through distribution of “enduring materials”
such as textbook chapters and peer-reviewed articles. Industry has also been allowed to sponsor education sessions about off-label uses so long as an independent continuing medical education provider is involved in planning the sessions. The authorization for such off-label promotion expired recently, however, and was not renewed in the FDA reauthorization law passed in the fall of 2007. The FDA has since proposed a similar rule regarding off-label promotion,7 but it has been criticized for being a bit more lenient toward such promotion.
Concerns about off-label promotion and communication remain. Manufacturers sometimes violate the spirit of the rules that require independence, for example, through compensating physicians who speak favorably about off-label uses. Similarly, manufacturers sometimes design studies of off-label uses of therapies so that the results are especially likely to turn out favorably.
Data collection: Easier said than done
The aim of promoting information gathering and systematic research on off-label uses may be viewed as a professional duty,6 but in practice this duty is complicated by the question of who will pay for it. Often product manufacturers are already making plenty of money from an off-label use and therefore have little financial incentive to conduct trials to obtain FDA approval to add a new indication or population to the label. At the same time, there is very little money available in the public sector for such studies.
No consensus on patient consent
The principle of informing patients about off-label use is also controversial. Not much litigation has been brought on this issue. The few courts that have addressed it have ruled that no obligation exists to specifically inform patients of off-label status and that physicians are obliged only to inform patients about risks, anticipated benefits, and alternatives to an off-label treatment. Some writers think that most patients do not understand the concept of off-label use and that informing patients will only confuse them. Others argue that off-label uses ought to be disclosed, especially in situations involving very innovative off-label applications or when insurers may not provide coverage. Interestingly, a recent Harris Interactive poll found that about half of the US public feels that doctors should only be allowed to prescribe drugs for diseases for which they are FDA-approved.8
WHAT SHOULD BE DONE?
Some people argue that the regulatory approach to off-label use already works well. Others want more government oversight. Probably no one would argue that every variation from the label should be subjected to the FDA approval process. There is debate over exactly how to define an off-label use—ie, how different it must be from the approved use to legitimately warrant the “off label” title. This is similar to the question of how to define when a change in surgical technique is innovative enough to require formal evaluation.
Some argue that better postmarketing surveillance is needed to assess the effects of off-label device use in patients. Additional help could come from a 2007 amendment to federal law that strengthens requirements to make clinical trial information publicly available through clinical trial registries. This will make it difficult for sponsors to conceal unfavorable data from trials involving off-label uses. More information exchange and independent assessments of off-label uses are also needed to promote better and safer off-label use of medical devices.
