Although the FDA has measures in place to mitigate safety risks and reduce the off-label promotion of drugs, public health emergencies like the COVID-19 pandemic can put pressure on the agency to hasten the approval process and relax advertising standards. However, even before this pandemic, physicians have raised concerns regarding the approval process, as in a 2019 report in JAMA.
The JAMA report raises two main concerns. First, many doctors believe that expedited approval can cause drugs or devices to come to market before all safety issues have been addressed. Second, physicians perceive the FDA’s leniency on the illegal promotion of drug use for off-label indications (not to be confused with the perfectly legal practice of off-label prescription) as harmful to patients. This is because it permits manufacturers to encourage the use of those medications for indications for which the drugs are inadequately vetted.
Existing criticism of the FDA
To meet increasing market demands, the FDA has implemented measures to speed up the drug approval process, like fast track and breakthrough therapy designations, priority reviews, and accelerated approvals.
“Accelerated approval can be applied to promising therapies that treat a serious or life-threatening condition and provide therapeutic benefit over available therapies,” according to the FDA.
But, researchers have shown an association between the uptick in the number of novel therapeutic approvals and an increased incidence of black box warning labels. The black box warnings are the FDA’s most stringent safety labeling requirements for prescription drugs that are used to inform prescribers and patients about the serious health risks associated with a drug’s use. Experts have also shown that drugs approved through the FDA’s fast track programs often require boxed warnings shortly after hitting the market.
For instance, in two 2017 studies published in JAMA and Expert Opinions on Drug Safety, researchers investigated the incidence of new FDA black box warning requirements from 2001 to 2010 and 2008 to 2015, respectively. In both studies, roughly one-third of all FDA-approved novel therapeutics (27% and 29%) required new post-market boxed warnings. While getting new drugs on the market as quickly as possible is important, it’s clear that some important safety measures do tend to fall by the wayside. And it might have to do with the FDA’s pivotal trial measure for drug approval. (More on that later.)
There’s also been some disapproval in the medical community when it comes to the FDA’s lax attitude on off-label drug promotion. Healthcare providers have the authority to prescribe FDA-approved drugs for any reason they believe will benefit a patient—regardless of whether the drug is being used on- or off-label. Off-label prescription is both entirely ethical and legal. Off-label promotion is not. The FDA does have limited authority to pursue criminal charges against manufacturers or other entities that push their drugs for off-label use. The agency, however, has come under fire for not cracking down more. Health experts and healthcare providers are concerned that the FDA’s restrictions on off-label drug promotion have become too lax, and that off-label promotion could be encouraging drug abuse among patients.
“Last year alone, doctors filled out over 4 billion drug prescriptions in the United States. But according to some estimates, Americans used nearly one-fifth of these prescriptions for uses unauthorized by the US Food and Drug Administration—uses that ultimately come with a much greater risk of harm,” according to the Regulatory Review.
What physicians think
Authors of the JAMA report sought to understand physicians’ attitudes towards the FDA and its processes. Led by Aaron S. Kesselheim, MD, JD, MPH, Harvard Medical School, Boston, MA, the researchers surveyed a random, national sample of primary care internists and medical specialists (n = 1,500) to better understand their attitudes toward the FDA’s drug-approval standards and off-label promotion policies. Surveyed physicians were all from the American Board of Internal Medicine Diplomate list.
Each physician (500 clinically active internists, 500 endocrinologists, and 500 cardiologists) was given a 25-question survey that assessed their perspectives about off-label drug promotion, FDA approval standards, and connections between drug evaluation and pricing. A total of 686 physicians responded, the majority of whom were men (59%) and about 18 years removed from medical school, on average.
While most survey respondents (80%) reported that they “were in favor” of the current FDA drug approval process—agreeing that it “protect[s] the public from ineffective or dangerous drugs”—that is not to say that they saw no faults with the process. In fact, the majority of respondents (78%) called for a more rigorous review of each drug in the approval pipeline. Furthermore, more than half of respondents (60%) also believe that a reduction of off-label drug promotion would be beneficial.
“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,” wrote Dr. Kesselheim and coauthors. But, a majority of the survey respondents cited a preference for drugs to instead be tested in 2 prospective randomized trials prior to the agency’s approval.
Unfortunately, a recent study from Harvard shows that trends among new drug approvals are in contradiction with what the physician respondents from the JAMA report deem to be sufficient evidence for new drug approvals. In fact, the Harvard researchers report that the proportion of new drugs supported by at least 2 pivotal trials decreased from 80.6% in 1995-1997 to just 52.8% in 2015-2017.
Besides insufficient clinical data to support drugs for approval, the JAMA survey respondents were also in criticism of current off-label drug promotion. Although federal law doesn’t explicitly permit the FDA to regulate manufacturers’ promotion of off-label uses of drugs, there are certain statutes in place that grant the agency limited authority to ban off-label promotion and pursue criminal charges against perpetrators.
However, physicians took issue with how the rules aimed at blocking off-label promotion of non–FDA-approved indications have become too lax. In the JAMA report, 60% of respondents felt that the FDA should “definitely not” or “probably not” allow off-label promotion directly to physicians. Additionally, most respondents felt it would be a “bad idea” or “terrible idea” to allow off-label promotion in doctors’ offices (71%) or in medical journals (68%), arguing that it may “increase prescriptions for drugs without meaningful benefits (61%; n = 416) and for diseases not previously considered medical problems (84%; n = 568).” Only 30% of respondents felt that off-label promotion could improve clinical decisions, while 42% felt that off-label promotion might actually worsen clinical decisions.
The JAMA report researchers noted that their findings are nothing new. In fact, they state that physician respondents’ desire for a new, higher bar for the drug-approval process is “a close match for known physician statistics.” Moving forward, they believe that “the views of practicing clinicians should inform evolving FDA policies about drug approval standards and off-label promotion.”