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. 2023 Feb 27;8(2):224–233. doi: 10.1016/j.jacbts.2022.12.011

Off-Label Use vs Off-Label Marketing of Drugs

Part 1: Off-Label Use—Patient Harms and Prescriber Responsibilities

Gail A Van Norman 1,∗
PMCID: PMC9998554  PMID: 36908673

Central Illustration

graphic file with name fx1.jpg

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Key Words: drugs and device marketing, ethics, off label marketing, off label use

Abbreviations and Acronyms: FDA, Food and Drug Administration

Summary

Once medical drugs and devices are approved for marketing by the FDA they can legally be used for purposes and in ways other than the ones for which they have been tested and approved. However, it is illegal for manufacturers to advertise or promote such unapproved uses of the drugs and devices. Part 1 of this review focuses on off-label use of FDA-approved therapies. Part 2 addresses illegal off-label marketing of drugs and devices. While off-label use can be beneficial to patients, unless carefully undertaken off label use may undermine the important safety mission of the FDA, can expose patients to elevated risks without proven benefits (or possibly no benefit), and can reduce motivation of companies to study the safety and risks of off-label use of therapies. These problems are further amplified when off-label use occurs among very vulnerable patient populations such as the elderly, patients with mental health disorders, pregnant women and pediatric patients. This review considers ethical issues in off-label use, as well as important steps for physicians considering an off-label prescription of a drug or device.

The clinical and commercial lives of drugs and medical devices continue to evolve after marketing approval is granted by the U.S. Food and Drug Administration (FDA). Clinicians produce clinical comparison studies regarding benefits and risks, find new uses, apply the drug or device to new patient populations, and modify dosing regimens from those approved by the FDA in so-called “off-label use.”1 Such clinical innovations can be beneficial to patients by providing new therapies, or expanding therapy to underserved patients. Drug and device companies can approach the FDA with new studies to obtain marketing approval for new indications, expanded patient groups, and recommendations regarding dosing and administration. But in the majority of cases, variations in clinical use precede official approval, and in many others, such approval is never obtained. Off-label use may even discourage companies from undertaking the expense of additional clinical studies to obtain full approval for a new use. Motivated to increase sales and prescriptions, and subsequent profits, manufacturing companies frequently encourage expanded use through marketing activities (deemed “off-label marketing”). Off-label use and marketing of drugs is better studied than off-label use and marketing of medical devices. However, off-label use and marketing of devices is coming under increasing scrutiny and raises similar concerns for patients, clinicians, and regulators.

This 2-part review covers important aspects of off-label use and off-label marketing, which can pose serious risks to patients and inappropriately involve researchers and clinicians in potentially illegal marketing schemes. To better understand off-label commercialization, Part 1 of this review discusses off-label use, ethical and regulatory obligations of clinicians, and suggestions for safer and more ethical off-label prescribing (Central Illustration). Part 2 focuses on off-label marketing, regulatory limitations on companies with regard to promotion of off-label use of drugs and devices, strategies used by commercial developers that negatively impact the integrity of the medical literature, and the participation of clinicians and researchers in activities that may represent illegal and/or unethical promotion in disguise.

Central Illustration.

Central Illustration

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Off-Label Drug Use: Prevalence, Ethical and Professional Considerations, and Regulation

Prevalence of Off-Label Use

The FDA is responsible for the approval of drugs and medical devices for commercial marketing and distribution in the United States, performing as 1 of the largest consumer safety organizations in the world. Once scientific studies have been carried out that demonstrate that the drug or device works as intended and is safe, the FDA issues a “marketing approval” that allows the manufacturer to market it, but only for the purposes and manners of use that were studied, because safety and efficacy for any other uses or methods have not been shown (Box 1).

Box 1. Manufacturer Responsibilities to Obtain FDA Approval for Drugs.

  • •

    The manufacturer must identify the purpose and intended use of the drug.

  • •

    The manufacturer must create instructions for the intended user reflecting how the drug should be administered.

  • •

    The manufacturer must demonstrate that if the product is used for its specified purpose and according to instructions, it is effective.

  • •

    The manufacturer must demonstrate that if the product is used for its specified purpose and according to instructions it is safe.

Although the FDA regulates the marketing and safety of drugs and devices, it does not regulate the practice of medicine,1 and physicians are legally free to use them for purposes other than that for which they were approved, so long as the use is based in “firm scientific rationale and on sound medical evidence” and as long as they “maintain records of the product’s uses and effects.”2 Such “off-label” use includes (but is not limited to) prescribing a drug or device for a different purpose than the one approved by the FDA, administering a drug in a dose or route of administration not formally tested during the FDA approval process, or use of a drug or device in a patient population not tested during clinical phase trials. Off-label use does not imply a contraindicated or illegal use.

Off-label prescriptions for drugs are common, occurring overall in 21%3 to 32.3%4 of prescriptions overall. Prevalence of off-label prescribing varies widely with the class of drugs: in 1 review, off-label use was highest among cardiovascular medications (excluding antihyperlipidemic and antihypertensive medications), constituting 46% of prescriptions, and was lowest among diabetes therapies (1%)3 (Figure 1).

Figure 1.

Figure 1

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Estimated Numbers of Off-Label Use by Class of Drug During a 1-Year Period

(A) Absolute number of prescriptions (in millions) during a 1-year period. (B) Percentage of off-label prescriptions per drug class during a 1-year period. (C) Percentage of prescriptions per drug class during the period with strong scientific vs little or no scientific support during the 1-year period. Adapted from Radley et al.3

In more recent years, off-label use of medical devices has become more common,5 although its overall prevalence has not been well studied. Some examples of off-label use of devices in cardiovascular medicine include off-label placement of expandable biliary stents in the vasculature,6 off-label use of pulmonary vasodilators,7 off-label expansion of transcatheter heart valves based on patient-specific anatomical considerations (constituting up to 20% of all procedures),8 and off-label use of drug-eluting cardiac stents (comprising 60% of all implantations according to 1 study).9

Despite its frequency, or perhaps even because of it, off-label use is fraught with problems. Unmanaged off-label use can compromise sound medical practice, and it undermines the important safety mission of the FDA.10 Although off-label use is touted as being beneficial to patients, it discourages manufacturers from investing in clinical studies that help assure efficacy and safety in expanded uses. It also facilitates patient exposure to treatments that are of unproven and possibly no benefit, while elevating the risks of unknown adverse consequences of the off-label uses when underlying medical evidence supporting the use is scant. In 1 study, off-label use of drugs was associated with a 44% overall higher likelihood of adverse effects in adults.11 In children, the relative risk of adverse events for off-label vs on-label prescribing is reported to be as high as 3.44.12 A recent report found that 100% of deaths and 54.2% of injuries associated with expandable biliary stents that were reported to the Medical Device Reporting data of the FDA involved the planned, off-label placement of the device in the vasculature rather than the biliary tree.6

Of grave concern is the fact that off-label use of drugs often occurs among very vulnerable patient groups, such as patients with mental health disorders, the elderly, and pregnant women and children who are historically under-represented among subjects of clinical research. Off-label use of antipsychotic drugs in adult patients, for example, approaches 75%, and in pediatric patients, off-label use of these drugs approaches a whopping 93%.13 A recent review found that up to 97% of pediatric inpatients are exposed to at least 1 off-label prescription.14 In other studies, 84% of a cohort of elderly European patients had been prescribed off-label drugs,15 and over 80% of pregnant women are regularly prescribed off-label therapies that have been untested in pregnant populations.16,17 Some authors use the term “therapeutic orphan” to describe infants, children, and pregnant women for whom there is a lack of research on treatment efficacy and safety, because these patients are commonly excluded from clinical research over ethical, legal, and safety concerns.13,18 Even when these groups are included in randomized controlled trials, sample sizes are often too small to detect rare medical events, and therefore the safety of such uses is often inadequately studied.

There is virtually no oversight of off-label drug or device use, which bypasses the consumer-safety and efficacy purpose of FDA approval processes and is nearly impossible to track. Problems often only come to notice through industry whistleblowers, or when sufficiently large groups of patients are harmed. An excellent illustration of the dangers of off-label use is Fen-Phen, a combination prescription of fenfluramine hydrocholoride plus phentermine, produced by Wyeth LLC, now a subsidiary of Pfizer. Both drugs were approved by the FDA individually as short-term treatments to assist weight loss in the 1970s, but sales were slow because the drugs individually produced only modest weight loss. After an article was published describing dramatic weight loss if they were used off-label in combination, doctors began prescribing the drugs together, and sales eventually reached over 18 million prescriptions annually in the United States.19 Shortly thereafter, it was discovered that almost one-third of patients who received Fen-Phen suffered significant damage to the lungs and heart.20 A large proportion of them (about 21%) required heart surgery to correct,19 and many experienced disability and/or death. Over 20,000 personal injury lawsuits were filed, and Wyeth Pharmaceuticals set aside over $21 billion for liability claims.21,22 The FDA eventually requested withdrawal of the drugs in 1997.

Other well-known examples of serious harms from off-label use include tiagabine hydrochloride (Gabitril), which was approved for use to prevent partial seizures, but then was used off-label to treat pain, and caused new-onset seizures23; the malaria drug quinine sulfate (Qualaquin), which was used off-label to treat leg cramps, but resulted in life-threatening bleeding24; and use of recombinant activated coagulation factor VII (NovoSeven; Novo Nordisk), which was approved to treat bleeding in certain patients with hemophilia, but was used off-label to treat patients who did not have hemophilia, resulting in devastating thromboembolic problems including acute heart attacks, strokes, paralysis, and death.25

Commercial Efforts to Increase Off-Label Prescribing

Because off-label uses can significantly broaden the target market for a drug or device and therefore its profitability, expansion of off-label use is a significant goal of manufacturers.26

Several characteristics of physicians make them ideal targets for commercial promotion strategies to expand off-label use. For example, most are remarkably ignorant of drug pricing and severely underestimate the effect that increased prescribing can have on medical care costs.27, 28, 29, 30, 31, 32, 33 Most also erroneously believe that they are immune to enticements from manufacturers to prescribe their drugs in preference to lower-cost alternatives.27

Physician surveys and systematic reviews of the literature demonstrate that less than one-half of physicians (in some studies, <25%) are able to estimate within 25% one way or the other the costs of drugs they prescribe. They underestimate the costs of common drugs by as much as 71%, and are most likely to underestimate the costs of brand-name drugs compared with generics. They also underestimate the cost of more expensive drugs compared with inexpensive drugs.28, 29, 30, 31, 32, 33 In other words, prescribers consistently believe that drugs cost their patients far less than they actually do, and the more expensive the drug is, the more mistaken the physician is about that cost. Only 11% of physicians feel that costs to third-party payers are important,34 even though rising drug prices are known to be a significant cause of the rising cost of health care in the United States, increase insurance rates, threaten health care budgets, and raise concerns for the financial solvency of government payer programs.35,36

Prescribers are Strongly Influenced by Marketing

Despite physician beliefs to the contrary, marketing incentives are extremely effective in altering physician prescribing practices in favor of a drug company’s products.37, 38, 39, 40, 41 Although most physicians deny that commercial promotional activities influence their prescribing behavior,42, 43, 44 studies demonstrate that pharmaceutical industry payments are associated with more prescriptions, greater prescription costs, and higher branded drug prescribing38,45, 46, 47—and higher payments to prescribers are directly correlated with more frequent prescribing.38,40,48 A recent systematic review of 36 studies of physician prescribing behavior found that virtually all demonstrated that even brief interactions of physicians with pharmacy representatives increased prescribing behavior and shifted prescribing behavior to more expensive drugs.49 In addition, the more gifts a physician accepts, the more likely it is that they will claim the gifts have no influence over them.42,45, 46, 47

These changes in prescribing behavior have a lasting, negative impact on patients. Enticements from pharmaceutical companies have been shown to lead to a shift away from prescribing of less-expensive, generic drugs, to more expensive brand-named drugs with no demonstrated clinical advantage over the generics.49,50 In addition, physicians become more likely to prescribe inappropriate, more expensive or invasive therapies for milder forms of disease, increasing the likelihood that any marginal benefit of the drug will be overridden by adverse effects.51 Industry marketing of a drug is associated with an increase in cost of the drug by an average of 60%.52 Attending a single industry-sponsored symposium not only was shown to have hospital-wide effects on drug prescribing and requests for addition of the drug to the hospital formulary (up to 10-fold),53,54 but in 1 study, the changes in prescribing habits after a single interaction lasted for over 2 years.55

Many believe that only substantial gifts and incentives would be capable of inducing a physician to act in self-interest instead of for the patient. But there is irrefutable evidence that even small gifts significantly influence physician prescribing behavior on a broad scale. DeJong et al40 examined the prescribing behavior of 279,699 physicians who received at least a single meal valued at ≤$20 that was provided by the pharmaceutical company promoting 1 of 4 drugs studied. Not only was the physician more than twice as likely to prescribe the advertised drug, but the number of times they prescribed the drug increased in direct proportion to the number of meals provided, up to 8-fold.40 In 2021, pharmaceutical, biotech, and device manufacturers paid 533,056 physicians more than $2 billion in food, beverages, gifts, educational materials, and speaker and consulting services.56 A published analysis from 2021 indicates that the pharmaceutical industry now spends approximately $60 billion annually on marketing and promotion,52,57 and a 2021 report from the National Bureau of Economic Research estimates that more than 85% of drug firms’ marketing expenditures are targeted specifically at influencing physicians to prescribe their drugs.58

Off-Label Prescribing: Ethical and Professional Considerations

Various medical professional organizations agree with the FDA that off-label use should only ethically be entertained when “such use is based on sound scientific evidence and sound medical opinion.”59 These statements are derived from basic tenets that define the practice of medicine: the clinician’s treatment must serve some beneficial medical purpose involving the diagnosis and assessment of health issues, must be based on sound knowledge of the condition at hand, and must be backed by theoretical, clinical, or experimental evidence that leads to a reasonable conclusion that the treatment has a significant chance of altering the course of the disorder in a positive way (or in extreme cases such as terminal illness, simply symptomatic relief of suffering). When off-label prescribing is coupled with sufficient scientific evidence, the adverse event rates are similar to those of FDA-approved drugs and indications.11,60 However, studies show that most off-label drug use occurs without scientific support, defined as documentation of the drug’s effectiveness as an off-label therapy in clinical trials or observational studies3 (Figure 1).

Ethically and professionally, a physician who intends to prescribe a drug or device for off-label use has a responsibility to review the clinical studies and other scientific evidence to justify its use,61 and may face professional sanctions or a malpractice litigation for irrational off-label use, particularly if it results in patient harm.62 Although courts have been reluctant to rule that special informed consent is required for off-label use,63 ethicists agree that the patient must be informed that the drug or device is being prescribed off-label, the potential risks, the fact that the drug or device may not work for the unapproved indication, and other alternative therapies that may be available.64

There are no guidelines for determining which off-label uses are sufficiently supported by medical evidence, and which are not. Largent et al65 identified 4 characteristics of off-label drug use that should raise a red flag for greater scrutiny before prescribing. The first is off-label use of a newly approved drug. New drugs will generally only have efficacy and safety data focused on the approved indication, and clinical experience of <3 to 5 years is insufficient to disclose infrequent, but potentially serious, risks of the drug. The second is new or novel off-label use (ie, a use that is entirely new, rather than use that represents a different dosing regimen, administration route, or patient population for an approved use). New and novel use is unlikely to be supported by strong evidence, because novel therapies will usually not have undergone extensive clinical phase trials that would be required for approval for that use. The third category, therapies with known serious adverse effects, obviously poses greater concern for patient safety, particularly in an unapproved patient group or for an unapproved purpose. Finally, high-cost drugs may not be cost-effective for individual patients, and may represent an undesirable misalignment of drug cost with limited funding resources.

Whether off-label use of drugs in 1 of these 4 categories of concern should be undertaken depends in large part on the level of evidence supporting the use. Largent et al65 propose 3 categories of evidence that should be applied when considering use of 1 of the 4 red flag categories: supported use, suppositional use, and investigational use. Each category is defined by the level of certainty of the medical evidence that the use will result in a net health benefit, in accordance with the US Preventative Services Task Force proposed criteria for assessing the certainty of health benefit indicated from medical evidence66 (Table 1).

Table 1.

USPSTF Level of Certainty That a Therapy Will Provide Net Health Benefit in a Primary Care Patient Population

Level of Certainty Characteristics of Available Evidence
High
  • •

    Consistent results from well-designed, well-conducted studies in a representative patient population

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    The conclusion is unlikely to be strongly affected by future studies
Moderate
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    Available evidence is sufficient to suggest benefit, but the reliability of the estimate of benefit is limited due to number, size, or quality of existing studies, lack of consistency of findings across clinical studies, limited generalizability of findings

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    More studies may alter the assessment of benefit depending on the magnitude of change
Low
  • •

    Available evidence is insufficient to assess effects on health outcomes. This could be because of limited study size or number, flaws in existing study designs, inconsistency of findings across studies, gaps in the chain of evidence, findings that are not generalizable, lack of information on health outcomes

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    More information is needed
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Adapted from Sawaya et al.66

USPSTF = US Preventative Services Task Force.

“Supported use” is associated with a moderate-to-high level of certainty of benefit. In supported use, drugs might generally be prescribed in much the same way that drugs are used on-label. Patients should be advised about treatment in a similar manner to on-label use. “Suppositional use” is associated with a low level of certainty due to less or lower quality medical evidence. Physicians should consider whether the risks of treatment based on weak evidence is actually sufficiently better than the risks of no treatment. If suppositional treatment is undertaken, patients should be clearly advised that the level of evidence for off-label use is weak, and that the risks of treatment may outweigh no treatment at all. Largent et al65 suggest that suppositional use should always be linked to data collection and reporting to MedWatch, the FDA safety information and adverse event reporting site.67 “Investigational off-label use” is associated with lack of sufficient medical evidence to estimate a benefit and should generally be limited to research protocols (and compassionate use events), requiring a formal and detailed discussion about the lack of data regarding the off-label use. In investigational use, the patient should be told that the purpose of providing the treatment is to gather data to improve medical care for future patients, and that use of the drug is not medically indicated treatment, although the current patient might benefit. Obviously, in such cases an institutional review board should be involved.

Van der Zanden et al60 describe BRAvO (the benefit and risk assessment for off-label use), another practical framework for clinicians in evaluating off-label use of drugs in pediatric patients. BRAvO takes into account problem, objectives, alternatives, consequences, tradeoffs, uncertainty, risk attitudes, and linked decisions (PrOACT-URL) in decision-making60 (Table 2). Their framework provides good questions to ask when the issue of off-label use primarily concerns translation of use in an approved patient population (eg, use in adults) to an unapproved patient population (children).

Table 2.

BRAvO Using PrOACT-URL: A Sample of Proposed Questions to Ask Before Prescribing

Problem and alternatives
  • •

    Define the unmet medical need and intended use

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    Assess licensing status of the drug

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    What are alternative treatments, and why are they less suitable?

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    Do peer-reviewed clinical guidelines or referenced drug handbooks recommend the off-label use?
Objectives: efficacy
  • •

    What clinical parameters define sufficient efficacy?

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    Is the drug used in another patient population for a similar indication?

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    Do the label and off-label patient populations have similar disease pathophysiology, response to drug intervention, and exposure–response relationships>

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    Based on mechanism of action, is the drug likely to be affective in the new use/patient population>
Objectives: safety
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    Define unacceptable risk, toxic properties of the drug, main adverse events reported in the on-label patient groups

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    Adverse events: have they been reported in the unapproved patient population?

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    How can risks be mitigated?

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    What risks cannot be mitigated?
Objectives: dosing
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    Can clinical response be predicted or monitored?

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    What dosages were used in clinical studies?

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    Can the new dose be simulated using existing data?
Consequences
  • •

    What are the potential treatment benefits and risks?
Tradeoffs
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    Are the benefits clinically relevant?

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    Are the risks acceptable?

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    What are the risks/benefits of alternative treatments?
Uncertainties
  • •

    What is the uncertainty of available evidence?
Risk tolerance
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    Is there bias among the treating health care team?

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    How does risk tolerance of the treatment team members affect the decision?
Linked decisions
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    Is the decision to treat off-label consistent with similar previous decisions?

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    Is explicit informed consent needed?

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    Will publication be considered to allow other health care teams to learn from the clinical experience?
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Adapted from Van der Zanden et al.60

BRAvO = benefit and risk assessment for off-label use; PrOACT-URL = problem, objectives, alternatives, consequences, tradeoffs, uncertainty, risk attitudes and linked decisions.

More simply, other authors suggest that physicians considering off-label prescribing ask themselves the following questions: 1) does the drug have FDA approval for another use; 2) has the off-label use been subject to substantial peer review; 3) is the off-label use medically necessary; and 4) is the use of the medication nonexperimental?62

Likewise, physicians should incorporate systematic considerations before prescribing an off-label use for a medical device. Yadin et al5 have proposed a framework that parallels the considerations in off-label prescribing of drugs (Table 3).

Table 3.

Considerations for Off-Label Use of a Medical Device

Clinical concerns
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    Is the physician familiar with indicated uses, contraindications, and warnings?

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    Does the patient condition warrant off-label use?

  • •

    Does peer-reviewed literature support the off-label use? What is the quality of the literature? Has it been reviewed, and is the review up-to-date?

  • •

    Is there other support for the proposed, off-label use (eg, case reports or series)?

  • •

    Is the provider qualified to use the device: that is, had attended educational seminars and received training?

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    Is there a local protocol for the off-label procedure that is at least as detailed as the labeled directions for use?
Risk concerns
  • •

    Is there an approved alternative device for the proposed purpose?

  • •

    Does the manufacturer support this off-label use?

  • •

    What is known about the relative risk of harm compared with labeled use of the device?

  • •

    Are privileges associated with off-label use handled consistently with privileges for labeled use?

  • •

    Is the off-label use appropriately tracked, with recording and preservation of outcomes, including devices failure?

  • •

    What is the liability of the off-label use for the user, hospital, and manufacturer?

  • •

    What impact will an adverse event potentially have on public relations?
Regulatory concerns
  • •

    Is there a local/hospital policy concerning off-label use?

  • •

    Does the device label contraindicate the proposed off-label use?

  • •

    Is the off-label use experimental? Should an IRB be consulted?

  • •

    Does the off-label use fall under an FDA compassionate use exemption? And if so, have the appropriate contacts with the FDA been made?

  • •

    Have the patient/family been presented with appropriate information, including the fact that the proposed use is not approved by the FDA, and have they given consent to the off-label use?
Documentation
  • •

    Have all policies, supporting evidence, privileges, and user qualifications for the off-label use been documented?

  • •

    Is there a system for maintaining documentation of the off-label use and outcomes, and for reporting adverse outcomes to the manufacturer and the FDA?

  • •

    Has an IRB application been made and documented if appropriate?

  • •

    Has the FDA been contacted before use if appropriate and has the contact been documented?

  • •

    Should the hospital risk-management team be made aware of the proposed off-label use?
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Adapted from Yadin et al.5

FDA = Food and Drug Administration; IRB = institutional review board.

Regulating Off-Label Use

Regulating off-label use presents significant challenges because it would almost certainly require tracking, evaluating, and overseeing off-label prescribing at the practitioner level. Currently, the only sanctions physicians and other prescribers face if they misuse a drug or device for an inappropriate off-label purpose come from medical licensing boards and/or civil litigation when patients are harmed.62 Such deterrents are only effective against the occasional practitioner, and are unlikely to change inappropriate prescribing behavior on a broad scale. Proposed solutions, therefore, are almost always aimed at the source of the drug or device itself, and include steps to track off-label prescriptions at the pharmacy, make it illegal for a manufacturer to profit from an off-label use, and require manufacturers to pay for independent evaluation of off-label uses when off-label sales pass some critical threshold.10 However, these approaches face significant difficulties.

Identifying off-label prescriptions would require new regulations: in the case of drugs, for example, physician reimbursement and patient insurance reimbursement could be contingent on the recording of the purpose of the prescription, and the patient’s principle diagnostic and symptom codes, allowing evaluation of the prevalence of off-label use and potential outcomes. Unfortunately, the reliability of such data would be dependent on nonmanipulative data entry: a physician who knowingly falsifies prescribing information would have to be subject to severe penalties and would still be very difficult to identify. Tracking manufacturer profits from off-label sales is also a problematic proposal: manufacturers generally sell drugs in bulk to wholesalers or institutional intermediaries, and are not present at the point of use, which can occur long after the drug is sold. The problem of intermediary sales also makes it difficult for a manufacturer to determine when off-label sales has exceeded a certain threshold that might suggest off-label marketing and sales are occurring, and with multiple sales intermediaries, there is no other “central” entity from which to obtain such information.

Summary

Off-label use of drugs is common, constituting up to one-third of all prescriptions for common drugs in the United States overall, and up to 97% of drug use in some patient populations. Off-label use of medical devices has been less well reviewed, but raises similar concerns to off-label use of drugs. Off-label use of drugs and devices is legal, and provided it is based in sound medical evidence, it appears to have similar safety to on-label use. However, most off-label use, at least of drugs, is not based on strong medical evidence, poses serious risks to patients, and requires careful consideration. Expansion of off-label use is in the interest of manufacturers, which frequently strategize to increase off-label use. The second part of this review discusses off-label marketing strategies, and the risks off-label marketing presents to the integrity of the medical literature, as well as to researchers who may become involved in potentially illegal off-label marketing schemes through publications, speakerships, and other common academic activities.

Funding Support and Author Disclosures

Dr Van Norman has received funding from the American College of Cardiology, and has provided expert witness testimony regarding off-label drug and device use and marketing.

Footnotes

The author attests they are in compliance with human studies committees and animal welfare regulations of the author’s institution and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

References

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