So-called off-label uses of prescription drugs is an enduring controversy – probably because it involves a trade-off of competing value judgments.The FDA is considering loosening its monitoring of off-label prescriptions, but critics are charging that, if anything, regulations should be tightened. Many issues of science-based medicine are at the core of this controversy.
In the US the FDA (Food and Drug Administration) regulates the sale of drugs. In order for a pharmaceutical company to get a drug on the market they must complete FDA monitored clinical trials and demonstrate adequate safety and effectiveness for a specific indication. The specific indication for which a drug is approved is the on-label indication, and all other uses are off-label.
The off-label use of medications is not illegal, nor is it even considered unethical or bad medicine. Rather it is up to the discretion of the prescribing physician. The FDA prohibits pharmaceutical companies from promoting off-label uses of their drugs, but there is no monitoring of physician prescribing.
The core dilemma stems from the conflict between freedom and regulation for quality control. We want to protect the public from the misuse of medications, but at the same time allow physicians to use the best available scientific evidence to make individual medical decisions with their patients.
Off-Label Marketing
At present it is illegal to market drugs for off-label indications. However, the pharmaceutical industry has figured out a number of ways to get around this prohibition through “stealth marketing.” In a recent editorial in PLOS Medicine, Adriane Fugh-Berman and Douglas Melnick spell out a number of these strategies. While I think they ultimately take a rather one-sided view, their insights into the worst behaviors of pharmaceutical companies is enlightening.
For example, they describe various techniques such as decoy indications – a company will research an indication for a new drug that is perceived to be easy to get, and then count on off-label use for harder-to-get indications.
Drug companies also use many venues to disseminate information about off-label uses (legally, if ethically questionable), such as providing information to authors of drug compendiums, ghost writing research, providing favorable articles to physicians, publishing preliminary positive findings from research, then not publishing completed negative results, and sponsoring a variety of educational outlets from speakers to continuing medical education (CME) programs.
Some of this information is monitored by the FDA, but most is not. That is also a current issue, as the FDA is considering reducing its role in monitoring such off-label information.
The concern about such practices is not necessarily that drug companies are providing false information, but that they are distorting the process of information generation and distribution in a way that is systematically and relentlessly biased in favor of their products. This may lead to increased off-label use of drugs.
Does off-label mean not supported by science?
This, of course, is the big question. There is a great deal of high quality scientific research involving the off-label use of drugs that is not FDA monitored. Which indication drug companies go for is (as all sides acknowledge) a marketing decision, not a scientific decision. It is possible, even highly probable, that many drugs are effective for certain off-label indications.
There are many reasons why a physician would prescribe a drug for an off-label indication. It may be indicated for the desired use, but not in the sub-population (i.e. not in children or pregnant women). Off-label use may include use in a closely related disease, or in a milder form of the disease. Sometimes off-label uses are almost identical to on-label uses. For example, one arthritis pain cream is indicated for arthritis of the knee, but not he shoulder.
Off-label use may also include a perceived class effect of the drug. For example, if beta-blockers have been shown to help reduce the risk of heart attacks, a new beta-blocker may be used for this purpose even though it is not indicated for this specific use.
Off label use of drugs gives physicians greater latitude in individualizing treatment for patients, exploring new uses for drugs, and expanding options for individual patients.
The question is – how science-based are most off-label uses of drugs. The study I see most commonly sited is this one by Radley et al, which shows that 21% of drug prescriptions are for off-label use, and that 73% of those uses have little or no scientific backing. However, the methods used to come up with the 73% figure were inadequate and would tend to grossly overestimate this number. As Jennifer Bright pointed out in this letter:
The study used only 1 compendium, the DRUGDEX system (Thomson Micromedex, Greenwood Village, Colo) to define “scientific support,” ignoring evidence in other sources (eg, other compendia and peer-reviewed literature). The lack of additional sources call to question the generalizability of these findings.
I would say not using the peer-reviewed literature is a fatal flaw and renders the findings meaningless. There is a dearth of research on this question otherwise, so I know of no other more reliable figure.
My personal experience certainly does not accord with the 73% figure, probably because I rely on other sources for scientific information, including the peer-reviewed literature. There are also practice guidelines provided by professional organizations and academic institutions, and expert reviews in the published literature. It is, in fact, possible for an off-label use of a drug to become standard of care.
Informed Consent
In another PLOS Medicine editorial, Wilkes and Johns argue that physicians should provide informed consent to patients for off-label use of medications. I disagree with their conclusion, however. It is based on the false equation of off-label with experimental. As I stated above, some off-label uses can be established standard of care. It would be confusing and absurd to obtain informed consent from a patient for such a use of a drug as if it were experimental.
Meadows and Hollowell pointed this out as well. They concluded:
Therefore, doctors should not be branded with the additional duty of disclosing non-pertinent information, such as the FDA’s medically irrelevant distinction, to their patients.
There is already an ethical requirement to discuss with patients the potential risks and benefits of any treatment, and this includes discussion of the experimental nature of a treatment. Whether or not a particular use of a drug is off-label is irrelevant, if it is well supported by published evidence. It therefore makes sense to simply focus on the evidence itself, not the regulatory status of the drug.
Further, focusing on FDA labeling rather than the scientific evidence is fodder for lawsuits and insurance companies. The latter now frequently deny reimbursement for off-label uses of drugs on that justification, regardless of the standard of care. In practice, insurance companies can often be convinced that a use is appropriate, but initial denial creates barriers to reimbursement and often physicians and patients do not have the time to fight them.
Also, attorneys are now exploring failure to provide informed consent for off-label uses as a new source of malpractice suits. This could make a practitioner vulnerable to being sued even when they practiced perfect standard-of-care medicine.
Conclusion
In my opinion this focus on off-label use of medications is a counterproductive distraction from the real issue -the scientific basis of treatments. The focus should be on providing high-quality information and unbiased expert review of evidence to determine the best science-based standards of pharmacotherapy.
Whether a treatment is on-label or off label is a matter of FDA regulation only, not best medical practice. This is important for how the pharmaceutical industry is regulated. Many legitimate concerns, as I outlined above, have been raised as to the behavior of pharmaceutical companies and their attempts at managing information regarding their drugs. Tighter oversight and regulation may be necessary to curtail these practices.
For example, I strongly advocate a centralized database of all human trials, with disclosure of the results to regulators and researchers. Drug companies should not be allowed to hide negative or unfavorable results from the public.
I also agree that there needs to be more effective monitoring by the FDA of any information created or disseminated by pharmaceutical companies. Some argue that the FDA is considering pulling back primarily because they do not have the resources, and therefore want to focus their efforts elsewhere. The solution is therefore to provide enough resources to the FDA so that they can fulfill their mandate.
Further – academic and professional organizations need to jealously guard their independence from corporate influence. It is their job to provide unbiased reviews of the scientific evidence and thereby provide guidance to practitioners as to which drug uses are evidence-based, what the standard of care is, and which uses are experimental or not indicated.
A very important point that is never brought up when discussing drug regulation is the outrageous double-standard applied to “supplements.” The editorials calling for higher standards of scientific evidence and regulation to protect the public from ineffective drugs should also apply their principles to the supplement industry – which currently has no effective regulation. I agree with efforts to push the scientific standard of care with drug therapy ever higher, but it is absolute hypocrisy to do this while giving the supplement industry a pass. Let’s apply the same high standards to all medical products on the market.
There may even be a common solution to some of the current issues with off-label use of drugs and the lack of regulation for herbs and supplements. If the FDA had the resources and power to set up independent committees to review the published literature for off-label uses and for the safety and efficacy of supplements, they could provide useful guidance – and even the basis for tighter regulation.
Right now there is only the high bar of FDA drug indication – meaning expensive trials monitored by the FDA. But there is no mechanism to officially review data published in the literature, even high-quality data. This could be a viable mechanism to raise the quality of evidence for both off-label drug uses and the currently unregulated supplements.
In short, both practice and regulation should follow the scientific evidence. Further, the integrity of that evidence needs to be protected from industry tampering. Medical practice, however, should not be subjugated to the currently inadequate regulatory scheme.
There are many good ideas on the table for how we can progress toward a more rational and effective balance of freedom and regulation. Hopefully the political climate will allow that progress to be made, but perhaps that is just wishful thinking.