the Issue in Focus

​In order to be legally marketed in the United States, medical products must undergo the FDA approval process. This process only applies to the specific uses proposed and documented by the manufacturer in the application process; any other uses are considered "off-label" (Lofholm and Katzung). Medical products are classified as drugs, devices, or biologics and are evaluated by the corresponding FDA division. Drugs (e.g., antibiotics, antidepressants) are "approved" by the Center for Drug Evaluation and Research, devices (e.g., pacemakers, prosthetic joints) are "approved" or "cleared" by the Center for Devices and Radiological Health, and biologics (e.g., blood products, vaccines) are "licensed" by the Center for Biologics Evaluation and Research. (U.S. FDA "Is the Product"; U.S. FDA "List of Medical Devices"; Thomadsen et al.)

When FDA grants approval for a product, the agency approves a specific label as well. FDA approval indicates that the product is "safe and effective when used as directed" and that it may be marketed in the United States. The product label of FDA-approved drugs provides information about the drug, including the approved dose(s) and how it is to be given to treat the medical condition for which its use is approved. When a drug is used differently than as described in the FDA labeling, this is called an "off-label" use. This can mean that any of the following (U.S. FDA "Understanding"): ​

• The drug is used for a different disease or condition than indicated on the label.
• The drug is given in a different way (e.g., a different route) than indicated on the label.
• The drug is given in a different dose than indicated on the label.

Medical devices and biologics can be used off-label as well. For example, devices may be used for a different procedure or a biologic may be administered for a different condition. ​

For a variety of reasons, the labeled indications arising from the FDA approval process may not include all of the conditions for which the product might be useful, even if there is supporting medical evidence for other uses. Manufacturers do not typically undertake the formal, lengthy, and costly studies required by FDA to approve new uses for medical products (U.S. FDA "Understanding"). Therefore, clinicians may wish to prescribe products for additional uses and can often rely on adequate or even compelling scientific evidence. (Lofholm and Katzung)

Off-label use is neither inherently improper nor illegal; rather, this term indicates that the product has not been evaluated in a specific context (e.g., population, condition, route, dose). Although there has been no evaluation by FDA of the usage in question, off-label use is common, accepted, and legally authorized under a prescribing physician's scope of practice. Federal laws governing FDA regulations and drug use place no restrictions on physicians' use of the product, and the agency has no authority to either allow or disallow off-label use. (Lofholm and Katzung; Thomadsen et al.)

Off-label use is also referred to as "non-approved, "out-of-label," "unapproved," and "unlabeled" use; the terms "physician-directed application" and "usage outside labeling" are also used interchangeably (AAOS; ASHP; U.S. FDA "Understanding").

Clinical Context

There is an important distinction between off-label use and research, also called "experimental" or "investigational" use. Use of medical products for research purposes, while an important risk management topic, is outside the scope of this guidance article. For additional information on clinical trials, see the guidance article Clinical Trials: Risk, Safety, and Liability. Off-label use is also distinct from prescribing contrary to a known contraindication (Buppert).

The realm of off-label prescribing includes long-standing uses that, while unapproved, have become the standard of care with established support (e.g., the off-label use of tricyclic antidepressants as a first-line treatment for neuropathic pain). It also includes novel or innovative off-label uses, defined as "prescribing with reasonable rationale for use, but insufficient evidence to allay safety, efficacy, and cost-effectiveness concerns, yet is not clinical research." (Ansani et al. "Designing"; Wittich et al.)

Prevalence

Off-label prescribing has been called an "integral part of contemporary medicine" (Dresser and Frader). A 2012 literature review identified frequencies that varied according to specialty and population. For example, one study found that nearly 80% of children discharged from pediatric hospitals were prescribed at least one off-label medication, 36% of medication orders in an intensive care unit were for off-label use, and 47% of prescriptions written in a headache specialty practice were for off-label uses. The same review identified that the most common form of off-label prescribing is the use of currently available and marketed medications for an indication (e.g., disease, symptom) that has not received FDA approval. (Wittich et al.)

In some situations, off-label use has actually been found to be more common than use for labeled indications. For example, one study of a biologic agent approved for the treatment of uncontrolled bleeding in hemophilia found that it was only used for its approved indication 3% of the time in hospital settings; some of the remaining 97% of unapproved uses identified included the treatment of severe bleeding in trauma and intracranial hemorrhage. (Yank et al.)

In addition to highlighting prevalence, this study also demonstrated the potential for harm to patients as a result of off-label prescribing. First, researchers found no evidence of efficacy (e.g., decreased mortality) in the treatment of off-label indications. Furthermore, in some off-label uses, an increase in adverse events (e.g., thromboembolism) was observed. (Yank et al.)

Potential Benefits

Off-label use of medical products is typically associated with clear therapeutic goals and numerous potential benefits; when evidence is supportive, off-label prescribing serves patients' interests. An off-label use may be the best available intervention in a given situation and can even be the standard of care; in certain practice areas, patient care could not proceed without off-label prescribing (Dresser and Frader).

Rare diseases, conditions that are inherently difficult to study, and particularly vulnerable patient populations that are not typically studied in clinical trials (e.g., psychiatric, pediatric, geriatric, obstetric) all contribute to the prevalence of off-label use (Gianutsos; Wittich et al.). Off-label drug use is also common in oncology, estimated to make up at least 50% of chemotherapy regimens, for a variety of reasons. For example, oncologists and their patients are often faced with problems for which there are few approved treatment options and may be more willing to try off-label drugs than other medical specialties (ACS).

Potential Risks

Despite acknowledged prevalence and potential benefits of off-label use, there are inherent risks. By its very nature, FDA review does not address off-label indications; a product deemed safe and effective for one indication could present an entirely different risk-benefit profile in other indications or populations. Drugs can have different effects at different dosages or with different methods of administration, and products that worked safely in adult trial participants might perform differently in children or older adults.

By virtue of not undergoing the safety and efficacy evaluation for specified populations, indications, and dosages upon which FDA approval is predicated, off-label use may be associated with potential harm to patients (e.g., medication errors, side effects, adverse reactions), creating patient safety and risk management concerns and an associated increase in liability.

Misperceptions about Approval

Providers. Evidence that physicians may lack awareness of the approval status of the drugs that they prescribe is an additional concern regarding off-label use. For example, a 2009 study of primary care physicians and psychiatrists demonstrated that the average respondent accurately identified the FDA-approval status of just 55% of the survey's drug-indication pairs. Accuracy only increased to 60% when limited to drugs the respondent reported prescribing during the previous 12 months. Of particular concern, 41% of physicians believed that a specific use was FDA-approved, when, to the contrary, it was not merely unapproved but also the subject of a black box warning. (Chen et al.)

"Black box" warnings, as they are commonly called, indicate the potential for serious and even life-threatening consequences of product use; they are required by FDA in three situations. First, they are issued in the case of adverse reactions so significant as to require serious consideration in the assessment of risks versus benefits for prescribing the drug. Next, they are used for drugs with potential for serious adverse reactions, the risk of which could be modified by appropriate prescribing. Finally, box warnings are also used for drugs that have mandatory restrictions to ensure their safe use (e.g., administration only in supervised settings). (O'Connor)

Patients. Research demonstrating public confusion and misunderstanding about off-label prescribing indicates that public perception of off-label use is another factor that may increase potential liability for prescribers. Approximately half of U.S. adults polled in 2006 believed that physicians are only permitted to prescribe drugs for labeled indications, and approximately half of respondents also believed that physicians should be prohibited from prescribing off-label. (Harris Interactive)

Caregivers. A 2014 study found an even lower level of parental awareness regarding off-label drug use in children, with only 30% of parents surveyed aware that the practice occurs in pediatric treatment when, in fact, the practice is highly prevalent because children are not typically participants in clinical trials. Furthermore, over 90% of the same respondents felt that off-label status would increase side effects and indicated that they would want to be informed if an off-label prescription was provided (Bang et al.).

This study, while conducted outside of the United States, underscores the concept that many potential recipients of off-label medical products are from vulnerable patient populations and are not necessarily their own medical decision makers. It also reinforces the importance of patient and caregiver education prior to initiation of off-label use.​

Patient Safety

Off-label use of medical products is an ongoing patient safety concern due to the fundamental issue that while safety and efficacy for the off-label use may have been established (e.g., in peer-reviewed medical literature), they have not necessarily been proven to the degree upon which FDA approval is predicated. Degree of risk for harms such as side effects, interactions, and adverse events naturally varies according to each specific off-label use in individual situations. See the discussion Promote Strategies to Decrease Risk for detailed recommendations that prescribers can follow to decrease the risk of poor outcomes and associated liability.

Lawsuits

In the event of an adverse event or poor outcome, off-label use of a medical product can increase the likelihood of a malpractice lawsuit. Courts have typically treated drugs and devices similarly in the development of legal precedents in various types of litigation, such as medical negligence cases involving off-label uses, lawsuits alleging lack of informed consent for the off-label use, and cases in which the plaintiff characterizes the off-label use as the conduct of unapproved clinical research. (Wittich et al.)

Whether providers must discuss the regulatory status of a medical product with the patient (i.e., FDA approval) is determined by application of controlling state law in individual circumstances, and courts have held both for and against discussion of regulatory status for informed consent. The majority of jurisdictions, however, recognize the distinction between a product's regulatory status and medical information that would be material to a patient's decision making and have held that discussion of a product's FDA regulatory status is not required in obtaining a patient's informed consent.

In jurisdictions in which providers are not required to disclose off-label use, documentation of medical decision making, rationale, and a comprehensive informed consent process can aid in the defense of malpractice allegations. Though free to initiate off-label use of medical products, physicians expose themselves to increased risk of litigation in the event of a poor outcome. Negligent failure to obtain informed consent may tip the scales in the plaintiffs' favor.

If a case goes to trial, the court may consider the package insert labeling as a complete listing on the indications for which the drug is considered safe. The defendant clinician might counter the plaintiff's charges through the opinion testimony of an expert witness that the use in question is considered safe and that the off-label use did not breach the standard of care. (Lofholm and Katzung)

Certain types of off-label uses have been shown to be attacked most frequently in litigation following an adverse event ("Liability and Off-Label"):

• Prescription of significantly higher doses than approved in labeling
• Prescription for an unapproved indication
• Prescription for patients not part of a population included in the clinical trials that were evaluated as part of the labeling process ​

Off-Label Use Case Examples

In 2014, the Delaware Supreme Court affirmed a trial court's judgment in favor of a patient who sued both his surgeon and hospital for failure to obtain informed consent in a case involving the off-label and allegedly "experimental" use of a catheter for administration of medication to treat rib fracture pain. The allegedly experimental nature was one factor in the court's ruling against the surgeon when the catheter, which the defendant surgeon was being paid to evaluate, became displaced and caused organ damage, resulting in the need for additional surgeries, prolonged hospitalization, and rehabilitation (Houghton v. Shapira; Shapira v. Christiana).

Experts testified that the standard of care for treating rib facture pain was oral pain medication, and, if necessary, epidural injection; expert testimony also stated that the procedure performed was experimental for treatment of rib pain. The court found that the surgeon neither advised the patient of available alternatives to the off-label device nor advised the patient of his financial relationship with the catheter manufacturer (i.e., that he received compensation for promoting the off-label use and gathering data about its efficacy).

The court found that in neglecting to explain that the procedure was "experimental" and provide the patient with the option of receiving an epidural injection rather than undergo catheter insertion, the surgeon failed to meet his obligation for informed consent under a Delaware statute (i.e., to disclose alternatives to treatment that a reasonable patient would consider material in their decision-making process) (Del. Code tit. 18, § 6801[6]). The court also found the physician's failure to disclose the conflict of interest created by business relationship with the manufacturer constituted an additional failure of informed consent.

In addition, the court found the hospital liable both directly and for the physician's actions as its agent. Evidence showed that although the hospital's institutional review board (IRB) had approved the surgeon's plan to study the effectiveness of the catheter, the hospital failed to investigate the surgeon's relationship with the manufacturer and failed to instruct the surgeon to obtain informed consent for off-label use of the catheter.

The trial court awarded damages, attorneys costs, and interest totaling $5.5 million; the verdict was upheld on appeal.

A separate case settled before trial after a Florida woman underwent a routine procedure to remove scar tissue from her gastrointestinal tract; her surgeon performed an off-label procedure without her knowledge or consent. The patient's colon ruptured after the surgeon attempted to repair it with a stent that was only approved for use in the esophagus. She sustained serious complications, among them the need for a colostomy and development of a blood clot that led to amputation of her leg. (Lawson)

The patient's claims against the surgeon were settled for an undisclosed amount; her claims against the hospital where the surgery took place are pending. The hospital has thus far disavowed liability for the surgeon, an independent contractor; however, among other factors, the patient has cited the hospital's billing for the device as indicative of its involvement. (Lawson)

Courts have also found a patient's knowledge of regulatory status not relevant to informed consent. For example, the Maryland Court of Appeals, in the case of a patient who died after receiving an off-label drug in the course of his prostate cancer treatment, held that while lack of FDA approval may be relevant to a claim of medical negligence, it is not relevant to a claim for lack of informed consent. (Shannon v. Fusco)

While being treated for prostate cancer, the patient received a drug that was approved by the FDA only for use in head, neck, and kidney cancer. His estate alleged that the drug contributed to his death and that he would not have consented to it if he had known that it was not FDA-approved.

While Maryland's legal standard for informed consent requires physicians to disclose material information that they know or ought to know would be significant to a reasonable person in the patient's condition in deciding whether to submit to a proposed medical treatment or procedure, the court of appeals found that information about the FDA status of a drug provides no information about the treatment itself. Concurring with the Pennsylvania Supreme Court opinion regarding a medical device, the court stated that the FDA label does not constitute a material fact, risk, complication, or alternative to a proposed procedure and found that physicians are not legally obligated to disclose the drug's regulatory status as part of the informed consent process.

Reimbursement

Many off-label uses, if supported by evidence, are covered by Medicare, Medicaid, and various third-party payers. However, reimbursement for off-label use can be confusing; problems with payment can create additional financial risk for facilities. In response to quality concerns, Congress has required federal healthcare programs to cover medically appropriate off-label uses of drugs to treat cancer (ASCO). One example of a third-party coverage policy deems off-label use of a drug medically necessary when the patient has tried and failed FDA-approved or clinical-guideline-recommended therapy and the requested use is supported by scientific evidence that demonstrates safety and efficacy for the requested use or by at least one specified compendium (Wellmark).

The Centers for Medicare and Medicaid Services (CMS) has identified four compendia that it recognizes as authoritative for use in the determination of a "medically accepted indication of drugs used off-label in oncology" (i.e., the American Hospital Formulary Service Drug Information, the National Comprehensive Cancer Network Drugs and Biologics Compendium, Thomson Micromedex DrugDex, and Clinical Pharmacology) (CMS "Compendia"). CMS stated that medically accepted indications may also be drawn from peer-reviewed medical literature that appears in certain publications. See Resource List for a link to the CMS transmittal listing the compendia and peer-reviewed journals.

When in doubt, organizations should consult proactively with local Medicare carriers and third-party payers. Knowing whether the off-label use will be covered at the outset mitigates financial risk. It also decreases the likelihood that a patient could be angry about uncovered products or services, which could factor into a decision to pursue malpractice action in the event of a poor outcome. (Dresser and Frader; Thomadsen et al.)

REGULATIONS AND STANDARDS

Food, Drug, and Cosmetic Act

In addition to establishing the basic authority for FDA, the Food, Drug, and Cosmetic Act (FDCA) governs interstate distribution of drugs, medical devices, and biologics (21 USC § 301). Neither FDA nor the FDCA regulates the practice of medicine (e.g., off-label uses of medical products); however, regulations apply to marketing and place significant restrictions on the promotion of off-label uses of medical products.

Under the FDCA, manufacturers are required to specify all intended uses of their products in their application for FDA approval. FDA approves all product labeling (including the package insert, print and broadcast advertisements, brochures, and patient education materials) prior to distribution. FDA expressly prohibits "misbranding" of medical products, which includes labeling a product with misleading information, such as off-label uses. (Wittich et al.)

Although these restrictions impact manufacturers first and foremost, they are also relevant to the provider community. For example, providers may only obtain information about off-label uses from manufacturers through one of two approved methods: either by submitting an unsolicited inquiry to the manufacturer's medical affairs office (as opposed to through the pharmaceutical sales representative) or by reading peer-reviewed publications regarding off-label use. (Wittich et al.) However, providers are free to seek out such information from all other sources (e.g., professional society position statements, pharmaceutical reference texts), which is best practice to ensure an unbiased conclusion. See Action Plan for additional information on identifying resources for decision making.

FDA Guidance and Regulations

FDA periodically publishes and updates guidance for industry reflecting current thinking on a topic, and in 2014, relevant to off-label promotion, distributed Distributing Scientific and Medical Publications on Unapproved New Uses—Recommended Practices as an update to Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices, which was published in 2009.

Good Reprint Practices, as it has been called, states that clinical and scientific information regarding off-label uses should address adequate and well-controlled clinical investigations and not be false or misleading or pose a significant threat to health. Information disseminated should be from journals that require full disclosure of conflicts of interest or biases on the part of the authors or reviewers. Articles must have undergone peer review and not be in a supplement funded by a manufacturer. Reprinted information should be offered in an unabridged, unsummarized format and should not be marked, highlighted, or characterized by the manufacturer in any way. The information should be accompanied by the currently approved labeling of the drug or device, with a prominent statement that the use described has not been approved by FDA. A relevant bibliography and a publication that reaches a different conclusion about the unapproved use must also be distributed, if one exists. The recommendations also address the types of information that can be disclosed, sources for such information, and disclosures that should be made to article recipients. (U.S. FDA "Good Reprint")

The 2014 updated guidance includes reference to two additional categories of typically distributed materials, medical reference texts and clinical practice guidelines, and reiterates the value for patients in both FDA approval and the availability of unbiased information to support clinical decision making (U.S. FDA "Distributing Scientific").

While aimed at manufacturers, the guidance also provides a frame of reference for providers to evaluate medical and scientific information, both that provided by a manufacturer as well as information that the provider should seek independently in pursuit of evidence to support a potential off-label use.

FDA regulation of medical product manufacturers does not necessarily mean that providers can rely on manufacturers' compliance, such as in the case of a patient undergoing knee replacement whose surgeon used a cutting guide that had not been approved by FDA. The patient had a poor outcome and needed to undergo a complex revision procedure and lengthy rehabilitation.

The device manufacturer agreed to settle criminal and civil charges of off-label marketing for $80 million. However, this was not before 18,000 of the devices had been sold without FDA approval. There were warning signs in the medical community, such as case studies in a peer-reviewed journal that found an association between the device and high risk of early implant failure. However, many physicians used the device for several years, which may have been a factor in the dismissal of the patient's negligence lawsuit. (Allen and Pierce)

An organizational commitment to systematically evaluate innovative off-label use might have identified the potential risks in the situation described above; at the very least it would have prompted thorough documentation of clinical decision making and comprehensive informed consent.

False Claims Act

The federal False Claims Act (FCA) prohibits the submission of "false claims" to the government; misbranded medical products are included in this broad category (31 USC § 3729). The FCA is relevant to providers in the context of off-label prescribing because it has been implicated in such significant civil and criminal litigation against so many drug and device manufacturers in recent years so as to prompt widespread changes within the industry. The following federal enforcement actions against manufacturers are examples of the types of off-label promotional strategies to which organizations should be alert:

• In May 2012, Abbott Laboratories, Inc. pleaded guilty and agreed to pay $1.5 billion to resolve criminal and civil liability stemming from unlawful promotion of Depakote (divalproex sodium) for off-label uses. Although FDA approved Depakote for only epileptic seizures, bipolar mania, and prevention of migraines, Abbott admitted that the company trained a specialized sales force for the express purpose of marketing the medication for the control of behavioral disturbances in dementia patients, despite the absence of evidence for safety and efficacy. (U.S. DOJ "Abbott")
• In July 2012, GlaxoSmithKline (GSK) agreed to plead guilty and pay $3 billion to resolve criminal and civil liability related to unlawful promotion of off-label drugs. Among other allegations, GSK pled guilty to participation in the preparation, publication, and distribution of a misleading medical journal article on the use of the antidepressant Paxil (paroxetine), which did not have FDA approval for pediatric use, in patients under age 18. Allegedly, the study upon which the article was based did not demonstrate efficacy, and GSK allegedly also failed to make available two other studies in which Paxil also failed to demonstrate efficacy in treating depression in children under 18. The allegations were particularly serious given the fact that shortly after the alleged period of off-label promotion, a black box warning stating that antidepressants may increase the risk of suicidal thinking and behavior in patients under 18 was included in Paxil's labeling. (U.S. DOJ "GlaxoSmithKline")
• In November 2013, Johnson & Johnson and its subsidiary Janssen agreed to pay over $2.2 billion to resolve criminal and civil liability related to, among other allegations, misbranding the antipsychotic drug Risperdal (risperidone) and introducing it into interstate commerce for an unapproved use. Allegedly, although Risperdal was FDA-approved only for treatment of schizophrenia, Janssen systematically promoted the drug to physicians and other prescribers who treated children and elderly patients with symptoms such as anxiety, agitation, depression, hostility, and confusion. (U.S. DOJ "Johnson & Johnson")
• In related litigation, in 2015 a Philadelphia jury awarded a $2.5 million verdict to an autistic man who took Risperdal (risperidone) for seven years during childhood and later developed gynecomastia, the abnormal development of breasts in males. The man's family successfully alleged that Johnson & Johnson negligently failed to warn of this risk, hiding data regarding the development of gynecomastia in children from FDA, prescribing physicians, and parents. (Silverman) 

Physician Payments Sunshine Act

The Physician Payments Sunshine Act, a provision of the Patient Protection and Affordable Care Act, required the establishment of a transparency program, known as Open Payments, with the intent of increasing public awareness of financial relationships between drug and device manufacturers and certain healthcare providers.

The Sunshine Act requires applicable manufacturers of covered medical products to report payments or other transfers of value they make to physicians and teaching hospitals to CMS. This data is then made available to the public on the Open Payments website. Items for which reporting of payment to physicians and teaching hospitals is required include but are not limited to the following (CMS "Open"):

• Charitable contributions
• Consulting fees
• Education
• Entertainment
• Food and beverages
• Gifts
• Grants
• Honoraria
• Research
• Travel and lodging

Although they are not required to report (this responsibility falls to manufacturers), CMS encourages physicians and teaching hospitals to keep records of all transfers of value received from industry, examine information submitted by manufacturers on their behalf, and work with manufacturers to resolve any discrepancies. (CMS "Open")

A recent survey of physicians across multiple specialties indicated both the need for physicians to familiarize themselves with the Sunshine Act, and, for many, the need to work to resolve a discrepancy on their behalf. The survey revealed that 16% were "not at all familiar" with the Sunshine Act, while 47% responded that they were "somewhat familiar" and only 37% were "very familiar." The same survey found that of the physicians who visited the Open Payments website, almost half found inaccuracies in reported data, such as manufacturers reporting payments that physicians were unaware of and omitting payments that the physicians were certain they had received. (Policy and Medicine)

State Law

In the context of off-label prescribing, state law is meaningful in two major ways. First, state law and accompanying regulations as administered by state licensing boards provide the authority and establish the legal standards for the practice of medicine (as well as standards for nonphysician providers with prescriptive authority [e.g., nurse practitioners, physician assistants]). It is these standards against which providers are judged in a negligence action.

Second, state law establishes the applicable legal standard for informed consent. This varies from state to state, with each state determining whether information is "material" to informed consent by statute or through precedential case law (Riley and Basilius). There is simply no substitute for risk managers and clinicians maintaining a solid working knowledge of informed consent requirements in their state. See Action Plan for a comprehensive discussion and resources for informed consent.

ACTION PLAN

Develop Policies and Procedures

Action Recommendation: Establish a committee and develop a framework to guide off-label uses.

To support patient safety, reduce the risk of harm, promote ethical conduct, and avoid conflicts of interest, healthcare facilities may wish to develop policies and procedures regarding the off-label use of medical products. Documentation of scientific support, adherence to accepted medical practice standards, and description of medical necessity may be among the topics addressed by the organization's interdisciplinary clinical committee, which includes representatives from pharmacy, ethics, biomedical engineering, and other departments.

A healthcare organization may wish to develop its own policy addressing whether it requires IRB review for innovative off-label use in a clinical setting. Off-label use of medical products in a clinical setting for individual patient care typically does not meet the U.S. Department of Health and Human Services Office for Human Research Protections' definition of research—"a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge" (45 CFR § 46.102). Consequently, off-label use to treat patients does not require submission for review to an IRB. FDA states the following:

Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment . . . [and] to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product's use and effects. . . . However, the institution at which the product will be used may, under its own authority, require IRB review or other institutional oversight. (U.S. FDA "'Off-Label'")

Research has shown that although less than half of institutions have policies addressing off-label use, these policies can be beneficial. A survey conducted of 104 U.S. academic medical centers revealed that only 33 facilities had a policy addressing off-label medication use in their institutions. The same study found that 44% of institutions that have such policies require IRB review for off-label use that would occur outside an IRB protocol. Most organizations with such policies reported that the policies were helpful in providing quality patient care and preventing unsafe use of medications at their institutions. (Ansani et al. "United States")

Risk managers may wish to consider using an approach similar to one adopted by a Pittsburgh, Pennsylvania, academic medical center for developing a policy and procedure for innovative off-label use of medication. The organization convened a multidisciplinary ad hoc task force, including representatives from the medical staff, pharmacists from the organization's pharmacy and therapeutics committee, risk management and ethics personnel, attorneys, and the IRB, to address the issue. The task force identified the following specific issues to be addressed in the policy and procedure (Ansani et al. "Designing"):

• Standardized methods of formulary review and systematic processes
• Peer review to reduce the risk of physician and institutional liability
• Evaluation of outcomes to minimize the risk to patient safety
• Promotion of evidence-based safe medication practice
• Methods for meeting ethics obligations

The task force also developed a statement that clarified the concept that the oversight of off-label use was in the context of patient care, in contrast to clinical research. It developed therapeutic guidelines for the innovative off-label use of FDA-approved drugs to enhance the quality of patient care management, with the intent of standardizing innovative off-label medication use and permitting early critical analysis of patient outcomes to gather data support for future therapeutic recommendations. Potential decisions were divided into four categories (Ansani et al. "United States"):

1. Approving use of the drug based on clinical judgment that adequate evidence exists for off-label formulary addition
2. Approving innovative off-label use based on therapeutic rationale but restricting the use of the drug to within the institution's therapeutic guidelines for the innovative off-label use of FDA-approved drugs
3. Restricting off-label use to IRB-approved clinical research
4. Denying approval for off-label use

In addition to clinically driven policies, a policy that addresses visits by pharmacy and medical device sales representatives to staff and clinicians at the facility can support ethical and regulatory compliance. For a list of issues that facilities may consider in developing a policy regarding visits from sales representatives, see Strategies for Developing a Policy for Pharmaceutical Sales Representatives.

Similarly, facilities should consider development of policy and procedure to support record keeping related to the Physician Payments Sunshine Act, applicable to both physicians and teaching hospitals. See the discussion Regulations and Standards and Resource List for more information on the Sunshine Act.

Be Aware of Regulations and Enforcement Actions

Action Recommendation: Stay abreast of regulatory developments and enforcement actions impacting the pharmaceutical and device industries; educate providers accordingly.

In recent years, there have been numerous federal enforcement actions, settlements, and updates to FDA guidance on off-label promotion of medical products in response to alleged industry distortion of information provided to the medical community in the pursuit of profit. Pharmaceutical and medical device manufacturers remain under intense scrutiny and increased legal requirements, among them public reporting of payments made to physicians and teaching hospitals.

Medical product manufacturers' promotional activities must be limited to the intended uses that FDA approved. Allegations in the enforcement actions, to which many manufacturers have pleaded guilty, suggest just the opposite—that off-label uses were promoted with targeted sales tactics and misleading information, despite evidence that such uses were neither safe nor effective. Promotion by the manufacturer for off-label uses renders the product misbranded and in violation of the FDCA. Several major pharmaceutical manufacturers agreed to pay billions of dollars each to resolve a variety of false claim allegations related to fraudulent marketing practices in the past three years, including claims related to the off-label promotion of medical products (U.S. DOJ "Abbot"; U.S. DOJ "GlaxoSmithKline"; U.S. DOJ "Johnson & Johnson").

These developments are relevant to the provider community because healthcare professionals need access to high-quality, unbiased information upon which to base off-label prescribing decisions. It is important for prescribers to be aware of the ways in which they could be presented with information that falls short of this standard so that they can recognize and judge it accordingly.

Risk managers should contribute to this effort by utilizing a variety of resources to stay abreast of FDA regulations and industry enforcement actions and disseminating the information to clinicians as indicated. This can be accomplished through both public and industry resources, many of which are low-cost and freely available. For example, in addition to monitoring the popular press for related items, risk managers can subscribe to e-mail updates from the U.S. Department of Health and Human Services' Office of Inspector General; these e-mails contain daily news on the compliance and enforcement actions described herein. See Resource List for a link.

Risk managers should also take advantage of existing resources within their organizations—for example, by working in collaboration with the corporate compliance officer. This will assist the risk manager in accessing up-to-date enforcement information and interpreting how it may be relevant to various clinical and operational areas. Such collaboration will also facilitate compliance officer involvement in interrelated initiatives with risk managers as they pertain to off-label use (e.g., ensuring a robust process for identifying potential conflicts of interest).

Promote Strategies to Decrease Risk

Action Recommendation: Become familiar with strategies to decrease risk related to off-label prescribing, and encourage clinicians to do the same.

A practitioner may be accountable for the negligent use of any medical product in a civil action, regardless of FDA approval. Furthermore, off-label prescription or use of medical products can be a source of increased liability for physicians when results fall short of patients' expectations. Risk management strategies are particularly important when there is potential for serious side effects due to off-label use. The two most likely causes of action in a malpractice claim related to an allegedly improper off-label use are failure to obtain informed consent and general negligence. (Riley and Basilius)

Several strategies have been identified as useful in decreasing risk of liability in off-label prescribing. Some are reflected in the provider responsibilities for off-label prescribing specified by FDA (U.S. FDA "'Off-Label'"):

• Be well-informed about the product.
• Base its use on firm scientific rationale and sound medical evidence.
• Maintain records of the product's use and effects.

Patient Management

Prioritize patient interests. First and foremost, prescribers considering an off-label use should be principally motivated to diagnose and treat in good faith toward the best interests of the patient. In the context of clinical treatment, neither investigation nor any other incentive should be prioritized over patient interests. Although this might seem axiomatic, conflict of interest can occur even in well-intentioned practitioners. (AAP; Riley and Basilius; Wittich et al.)

History and physical. Next, it is essential that the provider obtain a detailed history and complete a thorough exam to identify any underlying medical conditions or treatments that would represent a contraindication or increase the risk of side effects or adverse events associated with the proposed off-label use (CMPA).

Follow up and monitoring. Finally, it has been proposed that "an extra layer of vigilance" is warranted in off-label prescribing, since clinical evidence of safety and efficacy for the particular indication are not necessarily established in the same way that they are for an FDA-approved indication (Gianutsos). Once a provider proceeds, careful monitoring is required both during and following off-label treatment to identify side effects or adverse or unknown reactions. This is particularly advisable given that off-label use is most common in vulnerable patients who might not be able to recognize or communicate such problems (e.g., pediatric, psychiatric, or elderly individuals).

In addition to utilizing the organizational event reporting system as per applicable policy and procedure, in the event of an adverse event resulting from an off-label use, organizations should consider contributing to the knowledge base of the product through voluntary reporting to FDA's MedWatch system. See Resource List for links to MedWatch and its e-mail update system.

Provider Knowledge Base

Prescribing clinicians have an obligation to maintain a working knowledge of the medical products that they prescribe, as well as a duty to develop knowledge of new products prior to use. Only when providers actively seek information and are fully knowledgeable about products can they accurately weigh the risks and benefits, and help patients do the same. (Dresser and Frader; Wittich et al.)

At the outset, providers must ensure that the off-label use is not experimental; it must have FDA approval for some use and not be "investigational." Providers must then become knowledgeable about the product, its originally approved use, and the new off-label use, including the potential risks and complications, side effects, and contraindications associated with its use.

Off-label prescribing should be supported by reputable peer-reviewed medical literature based upon sound scientific evidence as well as supported in the medical community (e.g., local colleagues, relevant professional societies) to indicate that it is in keeping with present standards of practice (CMPA; Riley and Basilius). See the discussion Provide Resources for Decision Making for further information.

Ensure Appropriate Documentation

Action Recommendation: Promote best practices in documentation of clinical rationale for off-label uses.

Although research has shown that most physicians weigh the reasons for choosing one medication over another carefully, it has also indicated that they frequently neglect to record their rationale (Edersheim and Stern). Since off-label use of medical products can increase a practitioner's liability risk in the event of an adverse event or poor outcome, providers must understand the importance of documenting their decision-making process in the medical record (AAP).

Clear documentation of the prescribing practitioner's rationale for clinical recommendations is a critical part of the strategy to limit liability in the event of an adverse outcome associated with off-label prescribing. Documenting a thoughtful decision-making process demonstrates high-quality care and professional judgment in development of treatment recommendations. Such documentation is especially important for off-label uses because these prescriptions involve at least one variable not supported in the clinical trials leading to FDA labeling.

Thorough documentation of good clinical decision making is thought to be invaluable in proving that the provider performed up to the standard of care. As such, a well-reasoned and documented choice is thought to discourage many plaintiffs' attorneys from accepting a case. Conversely, poor documentation of excellent clinical care can make an attractive target. (Edersheim and Stern; "Liability and Off-Label")

In addition to educating providers about the value of this documentation, risk managers can encourage them to maintain files that provide clinical rationale for off-label uses. Such files could include reprints of peer-reviewed articles, continuing medical education materials, and other sources that collectively demonstrate that the chosen intervention was within the acceptable standards of medical care. (Edersheim and Stern)

Involve Patients in Informed Consent

Action Recommendation: Involve patients, and as appropriate, family in a comprehensive informed consent process.

Although off-label use, as commonly practiced by clinicians for treating individual patients, may not fall under the requirements for informed consent under federal regulations, risk managers need to be aware of any applicable laws in their organizations' jurisdictions, including state law, regulations, and case law, which may require informed consent for off-label use.

The legal doctrine of informed consent requires physicians to disclose to patients information regarding material risks that a reasonable patient would consider significant, and a minority of jurisdictions require disclosure of risks that a reasonable physician would disclose. However, in most states, there is no legal requirement for physicians to obtain a patient's informed consent specifically for off-label use of a drug or medical device, outside use in a clinical trial. Many jurisdictions take the view that the FDA status of a medical device or drug is not medical information that concerns a material risk to patients (Blazoski v. Cook).

Incorporating Patient Education

Informed consent is much more than a prerequisite to treatment; it is an opportunity for the provider to educate the patient and family about the proposed treatment, the alternatives, and the risks and benefits of each. It also provides a forum to address any questions about larger issues, such as treatment plan and prognosis. Because the prescribing physician has an obligation to disclose medical risks inherent in the use of the drug or device, regardless of FDA regulatory status, obtaining and documenting a patient's informed consent to off-label use may be an appropriate patient safety and risk management strategy that can be addressed in institutional policies, regardless of applicable jurisprudence. The process of obtaining a patient's informed consent to an off-label use may better enable patients to become more actively involved in their own healthcare. Advocates for requiring informed consent for off-label prescribing point to studies that have shown that most off-label uses lack medical evidence of the drug's safety or efficacy and that physicians sometimes rely solely on manufacturers' data and information concerning off-label use. (Johns)

The context of off-label prescribing as it frequently occurs in vulnerable populations, in which patients may not be their own decision makers (e.g., pediatrics, geriatrics), is an important consideration in the informed consent process. Providers must discuss all off-label use openly and thoroughly with patients and, as appropriate, their medical decision makers in advance of treatment and document accordingly.

Providers should be candid in disclosing possible side effects of off-label uses and what course of action the patient should take if these side effects occur. A mutual discussion of realistic expectations and potential problems can strengthen the patient's understanding and commitment to treatment while minimizing surprise and misunderstanding. This approach also confers risk management benefit, since appropriate informed consent shifts some of the responsibility to the patient, who has been forewarned of the risks of treatment. (Edersheim and Stern)

An informed consent discussion for some patients may include discussion of reimbursement for off-label use, particularly in circumstances in which off-label use of a drug may represent a last clinical resort. Although many states have passed legislation prohibiting health insurance companies from excluding coverage for off-label uses of drugs for the treatment of certain disease—HIV infection or cancer, for example—some patients with rare diseases who require off-label use of drugs or devices may face significant reimbursement restrictions. Private payers may consider off-label use in this circumstance an "experimental" use, even when some clinical evidence of effectiveness has been shown. Patients may have to navigate a complex system of appeals to obtain reimbursement or pay for the drugs or devices out of pocket, often at considerable personal expense.

Documentation

Documentation of informed consent is another critical risk management focus as it relates to off-label use. It has been proposed that many more physicians engage in high-quality informed consent discussions than documentation reflects. Of course, undocumented discussions offer no legal protection. (Edersheim and Stern)

Documentation of informed consent should reflect discussions with the patient (and, as appropriate, their medical decision maker) regarding the nature of the treatment, the risks and benefits of both the proposed treatment and any other available treatments, the risks and benefits of doing nothing, and the parties' understanding of the discussion ("Liability and Off-Label").

A record of informed consent that contains a narrative portion, in addition to a checklist, provides evidence of an individualized discussion. Additionally, informed consent documentation that includes a specific area for patient questions, in which patients can document any concerns or the absence thereof, has been helpful in defending against claims of lack of informed consent. The patient and the provider should both sign the form, and the original should become part of the patient's medical record. (Edersheim and Stern)

See Consent to Off-Label Treatment for a sample consent form for innovative off-label use of medications.

Ethical Considerations

In addition to patient safety, risk, and reimbursement considerations, support for obtaining informed consent for off-label uses draws upon established principles of medical ethics (Ansani et al. "Designing"). Medical ethicists have proposed that informed consent would be especially important to "reasonable patients" in the following situations (Dresser and Frader):

• When an off-label use lacks strong support in the scientific or medical literature
• When experience suggests that the use involves substantial risk
• When there is a possibility that insurers will refuse to cover a costly off-label application​

There are also arguments against obtaining informed consent for off-label prescribing, including the prevalence of off-label prescribing in the daily practice of medicine, the potential to confound patient decision making by diverting attention to legal and administrative (rather than medical) information, and the fact that FDA approval does not guarantee safety (Mithani).

However, when clinicians provide more information about alternative therapies or treatments and their risks and benefits, it becomes less likely that patients will successfully assert that the clinician failed to provide adequate information. Although disclosing that a proposed use is off-label is not consistently required under the legal standard of practice, doing so may add an extra level of protection against a potential finding that a clinician did not obtain a patient's informed consent. (Riley and Basilius)

See the guidance article Informed Consent in Acute Care for additional information on the process.

Provide Resources for Decision Making

Action Recommendation: Become familiar with available resources, ensure that practitioners are aware of them, and advocate for additional resources as needed.

Off-label use in absence of a solid evidentiary basis is associated with the most significant potential for harm to patients (Dresser and Frader). Materials distributed by manufacturers should be evaluated with an abundance caution due to history of industry involvement in so-called research; they should not be a primary source upon which to base off-label decisions. Therefore, clinical staff must be able to access high-quality, peer-reviewed medical literature regarding the proposed use. However, because FDA prohibits manufacturers from sponsoring physician education for off-label use of their products, clinicians may have difficulty establishing how others in their field are using medications outside their FDA-approved uses (Wittich et al.).

Resources for addressing the quality of evidence and peer support for off-label uses include medical library services, databases for scientific literature searches, peer-reviewed specialty journals, evidence-based treatment guidelines, compendia, and a variety of materials from professional societies, including practice guidelines and policy statements, consensus statements, handbooks, and meeting minutes. The Agency for Healthcare Research and Quality also provides evidence summaries for some off-label uses (AAP; Dresser and Frader). See Resource List for links to a variety of professional society position statements addressing off-label use.

Use an Enterprise Risk Management Approach

Action Recommendation: Employ organizational resources for proactive risk management.

Risk managers can help their organizations identify and manage the risks associated with off-label use of medical products more comprehensively through use of an enterprise risk management framework. By expanding the traditional scope of clinical risks and individual events to a broader view, risk managers can utilize existing resources and contribute to organizational goals.

For example, in the context of off-label prescribing, risk managers should consider not only overall clinical risk to individual patients but also technical risk of new and/or unapproved devices, financial risk of difficulty with reimbursement, legal risk of negligence actions, and compliance risk related to conflicts of interest.

Risk managers can leverage the benefits of existing systems and resources to minimize the potential for poor outcomes associated with off-label use, at both the individual and organizational level. For example, risk managers should do the following:

• Utilize IRB expertise for policy and procedure development as well as support for ad hoc issues
• Involve the ethics committee for situations that fall outside of established procedures
• Ensure that the organization's event reporting system captures problems related to off-label use
• Ensure that corporate compliance procedures support appropriate practices (e.g., annual conflict-of-interest disclosures for all providers and staff)