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Off-label use
Off-label use
Off-label use
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Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration.[1] Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although most studies of off-label use focus on prescription drugs.

Off-label use is very common and generally legal unless it violates ethical guidelines or safety regulations. The ability to prescribe drugs for uses beyond the officially approved indications is commonly used to good effect by healthcare providers. For example, methotrexate is commonly used off-label because its immunomodulatory effects relieve various disorders.[2] However, off-label use can entail health risks and differences in legal liability. Marketing of pharmaceuticals for off-label use is usually prohibited.

Indications and labeling laws

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An indication is when a drug is medically appropriate for a given condition; an approved indication is when a government drug regulatory agency formally agrees that the drug is medically appropriate for the named condition. Indications may depend not only upon the medical condition that is being treated, but also upon other factors, such as dose, the patient's age, size and sex, whether the patient is pregnant or breastfeeding, and other medical conditions. For example, aspirin is generally indicated for a headache, but it is not indicated for headaches in people with an allergic reaction to it.

When the drug's manufacturer has received a marketing authorisation from the government agency, then it is allowed to promote the drug for the specific, agreed-upon approved indications in that country. All legally approved indications are listed on the drug package insert or "label". Drug manufacturers are not legally permitted to encourage the use of regulated drugs for any indications that have not been formally approved by the country's government, even if significant scientific evidence exists for that unapproved indication, or if another country's drug agency has approved that indication.

However, healthcare providers are not required to limit prescriptions or recommendations to the indications approved by their country's drug regulatory body. In fact, the standard of care for many conditions involves off-label uses, either as first-line therapy or as a subsequent line. In other words, properly understanding why off-label use is common and usually appropriate, rather than rare and usually inappropriate, requires understanding that the distinction between regulatory-agency-approved use versus off-label use is not the same distinction as safe versus unsafe, tested versus untested, or good versus bad; it is a marker of increased certainty about a use being good (safe and effective), as opposed to less certainty—rather than a marker of good as opposed to bad. Regulatory approval for an indication requires a body of evidence that costs money to assemble, and as with evidence-based medicine generally, the desire for a vast, high-quality evidence base is an ideal that real-world practice can only aspire to and further approach, rather than completely match; there may not be enough resources to test every drug for every possible or logical indication to an exhaustive degree. Regulation of therapy freedom thus takes an approach in which anything not explicitly forbidden is allowed rather than an approach in which anything not explicitly allowed is forbidden, and it is accepted that drugs may be used in off-label ways as long as a competent professional prescribes them.

Frequency of off-label use

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Off-label use is very common. Generic drugs generally have no sponsor as their indications and use expands, and incentives are limited to initiate new clinical trials to generate additional data for approval agencies to expand indications of proprietary drugs.[1] Up to one-fifth of all drugs are prescribed off-label and amongst psychiatric drugs, off-label use rises to 31%.[3]

Among use of antipsychotic medications in the United States, a shift occurred from typical agents in 1995 (84% of all antipsychotic visits) to atypical agents by 2008 (93%). Atypical use has grown far beyond substitution for the now infrequently used typical agents.[4]

A 2009 study found that 62% of U.S. pediatric office visits from 2001 to 2004 included off-label prescribing, with younger children having a higher chance of receiving off-label prescriptions. Specialist physicians also prescribed off-label more frequently than general pediatricians.[5] In 2003, passage of the Pediatric Research Equity Act gave the FDA power to require pharmaceutical companies to perform clinical trials in all age groups in which clinical use is reasonably foreseeable. By some estimates, the number of clinical trials performed in children from 2002 to 2012 exceeded that in the prior 50 years.[6]

In 2014, the American Academy of Pediatrics released a statement regarding off-label use of pharmaceuticals in children. The article recommends to pediatricians that "Off-label use is neither incorrect nor investigational if based on sound scientific evidence, expert medical judgment, or published literature" and that "Evidence, not label indication, remains the gold standard from which practitioners should draw when making therapeutic decisions for their patients." The statement further advocates additional support and additional incentives for clinical testing of drugs in children, and publication of all results irrespective of positive outcome.[7]

A study published in 2006 found that off-label use was the most common in anticonvulsants. The study also found that 73% of off-label use had little or no scientific support.[3]

By default, use of non-approved drugs is common in obstetrics. By 2010, during almost five decades of activity, the Food and Drug Administration (FDA) had approved only two drugs for obstetrical indications, namely oxytocin and dinoprostone.[8] A small market and the high risk of medicolegal action, as exemplified by the Bendectin case, may explain the reluctance to develop drugs for approval.[8]

Some drugs are used more frequently off-label than for their original, approved indications. A 1991 study by the U.S. General Accounting Office found that one-third of all drug administrations to cancer patients were off-label, and more than half of cancer patients received at least one drug for an off-label indication. A 1997 survey of 200 cancer physicians by the American Enterprise Institute and the American Cancer Society found that 60% of them prescribed drugs off-label.[9][10] In some cases, patients may perceive the efficacy of treatments for off-label purposes to be higher than for their indicated purpose.[11] Frequently, the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs. An example is the use of tricyclic antidepressants to treat neuropathic pain. This old class of antidepressants is now rarely used for clinical depression due to side effects, but the tricyclics are often effective for treating pain (e.g. neuropathy),[12] as well as attention deficit/hyperactivity disorder (ADHD) particularly in adults.[13][14][15]

Society and culture

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Drug manufacturers market drugs for off-label use in a range of ways. Marketing practices around off-label use have caused various of lawsuits and settlements about inappropriately promoting drugs. Some of those lawsuits have ended granting the largest pharmaceutical settlements in the world.

In the United States in 2017, the government is considering allowing direct-to-consumer advertising to promote off-label drug use.[16] The appointment of Scott Gottlieb to become head of the United States Food and Drug Administration (FDA) furthered discussion, as this person advocates to allow that sort of promotion.[17][18]

Regulation in the United States

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In the United States, once a drug has been approved for sale for one purpose, physicians are free to prescribe it for any other purpose that in their professional judgment is both safe and effective, and are not limited to official, FDA-approved indications.[19][20] Pharmaceutical companies are not allowed to promote a drug for any other purpose without formal FDA approval. Marketing information for the drug will list one or more indications, that is, illnesses or medical conditions for which the drug has been shown to be both safe and effective.

This off-label prescribing is most commonly done with older, generic medications that have found new uses but have not had the formal (and often costly) applications and studies required by the FDA to formally approve the drug for these new indications. However, there is often extensive medical literature to support the off-label use.

A leading example of how regulatory agencies approach off-label use is provided by the FDA's Center for Drug Evaluation and Research, which reviews a company's New Drug Application (NDA) for clinical trial data to see if the results support the drug for a specific use or indication.[21] If satisfied that the drug is safe and effective, the drug's manufacturer and the FDA agree on specific language describing dosage, route of administration, and other information to be included on the drug's label. More detail is included in the drug's package insert.

The FDA approves a drug for prescription use, and continues to regulate the pharmaceutical industry's promotional practices for that drug through the work of the Office of Prescription Drug Promotion (OPDP, formerly the Division for Drug Marketing, Advertisement and Communication (DDMAC).[22] The FDA does not have the legal authority to regulate the practice of the medicine, and the physician may prescribe a drug off-label.[19] Contrary to popular notion, it is legal in the United States and in many other countries to use drugs off-label, including controlled substances such as opiates. Actiq, for example, is commonly prescribed off-label even though it is a Schedule II controlled substance. While it would be legal for a physician to independently decide to prescribe a drug such as Actiq off-label, it is illegal for the company to promote off-label uses to prescribers. In fact, Cephalon, the maker of Actiq, was fined for illegal promotion of the drug in September 2008.[23] Under the Food, Drug, and Cosmetic Act (FDCA) at U.S.C. 21 §§301-97, manufacturers are prohibited from directly marketing a drug for a use other than the FDA-approved indication. However, in December 2012, the United States Second Circuit Court found that promotion of off-label uses by a company sales representative was considered to be protected speech per the First Amendment.[24] In addition, the Food and Drug Administration Modernization Act of 1997 created an exception to the prohibition of off-label marketing, allowing manufacturers to provide medical practitioners with publications on off-label uses of a drug, in response to an unsolicited request.[25] In 2004, the federal government and whistleblower David Franklin reached a $430 million settlement in Franklin v. Parke-Davis to resolve claims that Warner-Lambert engaged in off-label promotion of Neurontin in violation of the FDCA and the False Claims Act. At the time, the settlement was one of the largest recoveries against a pharmaceutical company in U.S. history, and the first off-label promotion settlement in U.S. history.[26]

Litigation around the marketing of ethyl eicosapentaenoic acid (E-EPA, branded as "Vascepa") by Amarin Corporation led to a 2015 court decision that has changed the FDA's approach to off-label marketing. E-EPA was the second fish oil drug to be approved, after omega−3-acid ethyl esters (GlaxoSmithKline's Lovaza which was approved in 2004[27]) and sales were not as robust at Amarin had hoped. The labels for the two drugs were similar, but doctors prescribed Lovaza for people who had triglycerides lower than 500 mg/dL based on some clinical evidence. Amarin wanted to actively market E-EPA for that population as well which would have greatly expanded its revenue, and applied to the FDA for permission to do so in 2013, which the FDA denied.[28] In response, in May 2015 Amarin sued the FDA for infringing its First Amendment rights,[29] and in August 2015 a judge ruled that the FDA could not "prohibit the truthful promotion of a drug for unapproved uses because doing so would violate the protection of free speech".[30] The ruling left open the question of what the FDA would allow Amarin to say about E-EPA, and in March 2016 the FDA and Amarin agreed that Amarin would submit specific marketing material to the FDA for the FDA to review, and if the parties disagreed on whether the material was truthful, they would seek a judge to mediate.[31]

Regulation in the United Kingdom

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Physicians in the United Kingdom can prescribe medications off-label. According to General Medical Council guidance, the physician must be satisfied that there is sufficient evidence or experience of using the medicine to demonstrate safety and efficacy. Prescribing may be necessary when no suitably licensed medicine is available to meet the patient's need (or when the prescribing is part of approved research).[32]

Regulation in Mainland China

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On 20 August 2021, the Standing Committee of the 13th National People's Congress of the People's Republic of China adopted the Medical Practitioners Law, which explicitly permitted off-label use under certain circumstances.[33] Prior to its adoption, there was no specific legislation regarding off-label use in China, and the practice existed in a legal grey area.[34]

Veterinary medicines

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The veterinarian has a much smaller pharmacopeia available than does the human practitioner. Therefore, drugs are more likely to be used "off-label" – typically, this involves the use of a human medication in an animal, where there is no corresponding medication licensed for that species. This problem is compounded in "exotic" species (such as reptiles and rodents) where there are very few, if any licensed medications. In addition, especially in Europe, equine veterinarians are forced to use many drugs off-label, as the horse is classified as a "food-producing animal" and many veterinary drugs are labeled specifically not for use in animals intended for human consumption.

In the United States, this practice is permitted by the Animal Medicinal Drug Use Clarification Act of 1994 (P.L. 103-396). The FDA specifically prohibits extralabel use of a number of antibiotics, anti-inflammatory drugs and hormones in food producing animals. FDA also tightly controls the use of certain veterinary-prescribed drugs when administered in the feed of food-producing animals.[35]

See also

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References

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Off-label use

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Off-label use denotes the prescription of pharmaceutical drugs for medical conditions, dosages, or patient demographics not explicitly authorized in the product's regulatory labeling, as determined by agencies such as the U.S. (FDA). This practice hinges on physicians' clinical discretion, drawing from emerging evidence, case studies, or extrapolations from approved uses, particularly when no labeled alternatives exist for serious or rare conditions. While the FDA approves drugs based on specific trials for safety and efficacy in defined contexts, off-label application shifts responsibility to the prescriber, who weighs potential benefits against unestablished risks absent comprehensive randomized data. In the United States, off-label prescribing remains legally permissible for licensed physicians, as federal regulations govern , approval, and promotional claims rather than the autonomous practice of . Prevalence varies by setting but constitutes 20% to 32% of overall prescriptions, rising to over 50% in and frequently exceeding 70% in due to limited pediatric-specific trials. Such uses have facilitated therapeutic advances, including repurposed agents for unmet needs like certain chemotherapies extended across cancer types or immunomodulators for diseases, often evolving into standard care through post-market evidence accumulation. Nonetheless, empirical analyses reveal that approximately 79% of off-label prescriptions lack strong supporting from rigorous trials, correlating with a 44% elevated incidence of adverse events compared to on-label uses. Key controversies center on evidentiary gaps, potential for in vulnerable populations, and disparities in regulatory : while patient access to innovative treatments underscores off-label use's pragmatic value, heightened risks and incomplete data necessitate vigilant monitoring, , and institutional review to mitigate liabilities. Pharmaceutical firms face strict prohibitions on off-label promotion, with violations incurring substantial penalties, yet prescriber accountability relies on adherence to evidence-based standards rather than blanket restrictions. This duality—enabling adaptive while exposing causal uncertainties—defines off-label use's role in bridging approval limitations and real-world exigencies.

Core Definitions and Principles

Off-label use refers to the prescription or administration of an FDA-approved drug or for an indication, dosage, schedule of administration, patient population, or method of administration not specified in the product's labeling. This includes scenarios such as treating a different than the approved one (e.g., using a agent approved for one cancer type in another), employing a dosage higher or lower than labeled, or applying it to age groups or conditions excluded from the original approval trials. Regulatory labeling, derived from manufacturer-submitted data demonstrating safety and efficacy in controlled trials, establishes a baseline for approved uses but does not encompass all potential applications emerging from subsequent clinical observations or . In the United States, off-label prescribing is legally permissible under the practice of , which reserves to licensed physicians the discretion to determine treatments based on individual needs, unbound by FDA pre-market approvals that focus solely on authorization rather than clinical utilization. The Federal Food, Drug, and Cosmetic Act empowers the FDA to regulate drug promotion and labeling but explicitly defers to professional medical judgment for post-approval use, recognizing that scientific knowledge advances independently of regulatory timelines. Manufacturers, however, face strict prohibitions against off-label promotion to avoid circumventing approval requirements, as evidenced by enforcement actions under the misbranding provisions of the Act. Foundational principles of off-label use prioritize from sources beyond labeling—such as peer-reviewed studies, pharmacodynamic principles, or expert consensus—while weighing causal risks and benefits through first-principles evaluation of drug mechanisms and . This approach accommodates therapeutic innovation where data lag behind real-world needs, as in or rare diseases where dedicated trials are infeasible, but demands rigorous documentation of rationale to mitigate uncertainties in long-term safety or efficacy absent label-specific validation. remains a ethical cornerstone, requiring disclosure of off-label status and evidentiary limitations to align treatment with autonomy and causal . Distinct from investigational use, which involves unproven agents under protocols, off-label application of approved products operates within routine care without mandatory research oversight, though it invites post-market surveillance to refine causal understandings.

Indications, Labeling, and Regulatory Distinctions

Drug indications specify the medical conditions, populations, dosages, routes of administration, or durations of treatment for which a pharmaceutical product has been evaluated in clinical trials and deemed safe and effective by regulatory agencies, such as the U.S. (FDA). These are established through substantial evidence from adequate and well-controlled studies submitted during the approval process, as required under the Federal Food, Drug, and Cosmetic Act. For example, a agent might be indicated for a specific cancer type in adults but not for pediatric use or alternative malignancies without separate approval. Labeling constitutes the official documentation accompanying the drug, including the package insert or prescribing information, which details approved indications in a dedicated "Indications and Usage" section, alongside contraindications, warnings, dosage instructions, and data. FDA regulations mandate that labeling reflect the conditions under which the drug's benefits outweigh risks, derived from data, and it serves as the primary reference for prescribers. Deviations from labeling—such as using a different or frequency—qualify as off-label, even if the core indication aligns partially. Regulatory frameworks distinguish on-label use, which aligns with approved labeling and benefits from full agency review of and data, from off-label use, where the application lacks equivalent pre-market scrutiny for that context. , off-label prescribing by licensed physicians is permissible under standards of practice, as affirmed by courts like in Buckman Co. v. Plaintiffs' Legal Committee (2001), but manufacturers face strict prohibitions on off-label promotion to avoid misleading claims without FDA verification. This distinction underscores that off-label applications rely on post-approval evidence accumulation, such as emerging clinical data, rather than mandatory randomized trials for each variant use. Internationally, distinctions vary; in the , off-label use is not uniformly defined at the supranational level, allowing member states flexibility, but promotional activities are broadly restricted under Directive 2001/83/EC, with national bodies like the EMA emphasizing evidence-based justification to mitigate unassessed risks. Unlike investigational uses requiring oversight or protocols, routine off-label prescribing operates within clinical discretion but without implied regulatory endorsement of efficacy or safety for the unlabeled purpose. These separations incentivize supplemental approvals for expanded indications while permitting adaptive practice amid evolving medical needs.

Historical Evolution

Early Medical Practices

In the 18th and 19th centuries, physicians prescribed natural extracts and early pharmaceuticals for diverse conditions guided by clinical observation, case studies, and inherited traditions, unconstrained by regulatory requirements for labeled indications or pre-market validation of . Without federal standards in the United States until the of 1906—which addressed only purity, strength, and basic labeling without mandating proof of therapeutic claims—drug application fell to individual judgment, often extending substances beyond initial documented uses to address urgent patient needs. This era's practices inherently mirrored modern off-label use, as standardized approvals did not exist, fostering innovation through trial but also risks from unverified dosing and effects. Digitalis, extracted from the foxglove plant (Digitalis purpurea), illustrates early empirical extension. In 1785, published findings from a decade-long study of over 200 cases, establishing its value for dropsy (congestive heart failure-related edema) after refining folk applications into a controlled , noting benefits in urinary output and alongside toxicity risks like and arrhythmias. By the early , practitioners adapted digitalis for irregular heart rhythms and other edematous states, adjusting regimens via patient response despite variable potency from plant sourcing. Quinine, derived from cinchona bark and isolated in impure form by 1820, provides another case. Initially targeted at malaria's paroxysms since Jesuit introductions in the , it was routinely prescribed in the for non-malarial fevers, neuralgias, and prophylactically—such as in the , where Union and Confederate forces distributed millions of doses to curb intermittent fevers and sustain operations, often at 3 grains daily regardless of confirmed . These adaptations, while effective against symptoms in some contexts, highlighted reliance on experiential data over causal mechanisms, predating rigorous testing and contributing to both therapeutic advances and occasional cinchonism from overuse.

Key Regulatory Milestones and Shifts

The Federal Food, Drug, and Cosmetic Act of 1938 established the foundational requirement for drugs to be proven safe before marketing and prohibited misbranding, including promotions inconsistent with approved labeling, thereby implicitly distinguishing labeled from unlabeled uses. The Durham-Humphrey Amendment of 1951 further delineated prescription-only drugs, granting physicians professional judgment in their use while reserving FDA oversight to manufacturing, labeling, and promotion rather than individual prescribing decisions. The Kefauver-Harris Amendments of 1962 mandated proof of both safety and efficacy for drug approvals, solidifying the scope of official labeling and rendering uses beyond those indications as off-label, though FDA policy has consistently permitted physicians to prescribe approved drugs for unapproved uses when deemed medically appropriate. This permissive stance on prescribing contrasted with strict enforcement against manufacturer promotion of off-label uses, viewed as potential misbranding under the 1938 Act. A significant shift occurred with the FDA Modernization Act of 1997, which introduced a temporary safe harbor allowing manufacturers to disseminate peer-reviewed journal articles and reference texts reprinting off-label information, provided they submitted supplemental applications for new indications within specified timelines; these provisions expired in 2006 but influenced subsequent policies. Concurrently, the 1998 Washington Legal Foundation v. Friedman ruling declared certain FDA restrictions on off-label commercial speech unconstitutional under the First Amendment, prompting FDA to refine its approach and recognize protections for truthful, non-misleading disseminations. The of 2016 marked another liberalization by amending the FDCA to permit manufacturers to provide economic on off-label uses to payors and formulary managers under defined conditions, aiming to facilitate discussions without constituting promotion. In January 2025, FDA issued final guidance outlining for firms communicating scientific on unapproved uses of approved drugs, emphasizing case-by-case evaluations based on and to balance innovation with safeguards. These developments reflect an evolving tension between restricting unproven promotion and accommodating First Amendment protections and practical needs in medical practice.

Prevalence and Usage Patterns

Frequency in Human Medicine

Off-label prescribing accounts for a substantial share of utilization in human , with estimates indicating that 21% to 32% of prescriptions overall involve off-label uses. , analysis of outpatient prescriptions for 160 commonly prescribed drugs from data revealed that approximately 21% were off-label, though this rate exceeded 50% for specific classes including anticonvulsants, antipsychotics, and inhibitors. These figures underscore the routine integration of off-label practices, particularly in fields lacking extensive labeled options, such as and , where evidence from smaller trials or clinical experience often drives decisions despite regulatory distinctions. Prevalence varies by region and setting. In French general practice, a 2018-2019 study of over 4,900 prescriptions identified 18.5% as off-label, primarily due to unapproved indications (17.6%) rather than dosage or factors. European inpatient data similarly show elevated rates in specialized populations; for instance, off-label use in neonates and infants ranged from 31.7% to 93.5% across retrospective analyses in from 2011-2016. Recent syntheses confirm broader patterns, with off-label prescriptions comprising 20% to 40% globally, surpassing 50% in select categories like certain antidepressants or analgesics. Pediatric medicine exhibits particularly high frequencies, reflecting limited pediatric-specific labeling. A of global pediatric and neonatal departments reported an average off-label and unlicensed prescription rate of 56%, with hospital-based studies often documenting 70% or more in vulnerable subgroups. In contrast, adult outpatient settings tend toward lower but persistent levels, as evidenced by data from 2005-2009 showing 11% off-label use, highlighting how resource constraints and evolving evidence sustain these practices despite potential risks. Such disparities emphasize off-label use's role as a pragmatic response to evidentiary gaps, though tracking remains inconsistent due to reliance on claims data and voluntary reporting.

Application in Veterinary Medicine

In veterinary medicine, extra-label drug use (ELDU), also known as off-label use, is a common practice necessitated by the limited number of drugs specifically approved for animal species, conditions, or routes of administration compared to human pharmaceuticals. Under the U.S. Animal Medicinal Drug Use Clarification Act (AMDUCA) of 1994, licensed veterinarians may prescribe approved human or animal drugs outside their labeled indications within a valid veterinarian-client-patient relationship (VCPR), provided no approved alternative exists, the health of the animal is threatened, and use does not endanger public health, such as through drug residues in food-producing animals. ELDU is particularly prevalent in companion animal practices, where surveys indicate that up to 86% of human-registered medications are used off-label, often for antimicrobials, analgesics, or behavioral therapies due to gaps in veterinary-specific formulations. Patterns of ELDU vary by animal type and production system. In small companion animals like dogs and cats, antimicrobial administrations constitute about 18% of total drug uses in some clinics, with off-label human antibiotics (e.g., amoxicillin-clavulanic acid, , ) frequently employed for infections where veterinary equivalents are unavailable or suboptimal. Psychoactive drugs, such as selective serotonin reuptake inhibitors or antidepressants originally approved for humans, are commonly prescribed off-label for anxiety or , reflecting a reliance on extrapolated data. In contrast, food-producing animals face stricter constraints; ELDU is prohibited for certain drugs (e.g., , ) to mitigate risks of (AMR) or violative residues in meat, milk, or eggs, with over-the-counter antimicrobials like penicillin or oxytetracycline often used extra-label under withdrawal periods calculated by resources like . Prevalence data underscore ELDU's integral role, with U.S. veterinary teaching hospitals reporting routine incorporation of compounded or human medications to address unmet needs, though exact national figures remain elusive due to decentralized record-keeping. In equine and exotic species practices, off-label applications extend to anesthetics and anti-inflammatories licensed for other animals or humans, enabling therapeutic flexibility but requiring judicious oversight to balance benefits against potential adverse effects like toxicity or inefficacy from untested pharmacokinetics. Regulatory bodies emphasize that ELDU should be exceptional, with veterinarians documenting rationale and monitoring outcomes to safeguard animal welfare and human food safety.

Empirical Benefits and Innovations

Therapeutic Successes and Case Examples

Off-label use of in patients demonstrated early therapeutic efficacy prior to its formal approval for this indication in 2006. In a study of 84 patients, achieved an overall response rate of 32%, including two complete responses, highlighting its potential in advanced disease settings where standard therapies failed. Subsequent clinical trials incorporating into induction and maintenance regimens post-autologous transplantation reported median of 34 months compared to 23 months in control groups, with hazard ratios indicating significant delays in disease progression. These outcomes contributed to extended median overall survival exceeding seven years when combined with agents like , underscoring off-label innovation's role in transforming myeloma management. Ketamine, approved solely for , has shown substantial benefits when administered off-label via low-dose intravenous infusions for . A prospective study reported significant reductions in depressive symptoms, anxiety, and illness severity persisting for one month post-treatment, with response rates exceeding 50% in many cohorts. In a randomized, double-blind trial comparing repeated ketamine infusions to , ketamine yielded superior effects after five doses, with rapid symptom relief often within hours to days. Real-world data from treatment-resistant patients indicated 52% achieving remission after three infusions over 11 days, providing a critical option for those unresponsive to conventional s. Such applications leverage ketamine's mechanism to bypass monoamine pathways, offering faster onset than standard therapies despite lacking label endorsement for psychiatric use. In pediatric , off-label rituximab for —an orphan condition—has provided symptomatic relief where approved alternatives were absent, supported by case series demonstrating reduced and mucocutaneous lesions. Similarly, aspirin, originally indicated for analgesia and fever, proved effective off-label in , mitigating coronary artery aneurysms through anti-inflammatory and antiplatelet effects, as evidenced by reduced complication rates in empirical protocols before guideline adoption. These instances illustrate how off-label prescribing, grounded in emerging clinical evidence, can address unmet needs in rare or refractory conditions, often preceding formal label expansions.

Evidence from Clinical Data and Studies

Clinical studies evaluating off-label drug use have demonstrated that, in scenarios with direct comparative trial data, off-label applications do not consistently underperform approved uses in terms of or ; approval status alone does not predict superiority. For instance, a review of randomized controlled trials comparing off-label versus labeled treatments found no reliable pattern favoring one over the other, indicating that physician-selected off-label options can yield comparable therapeutic results when supported by available . In , particularly pediatric cases, off-label prescribing of inhibitors has shown feasibility and safety, with retrospective analyses at specialized centers reporting tolerable adverse event profiles and potential response rates aligning with adult-approved indications. One study of 22 pediatric patients treated off-label with these agents for solid tumors or lymphomas documented partial responses in 18% and in 32%, underscoring signals in unapproved settings where standard options are limited. Observational data further link off-label prescriptions to tangible health improvements, including reduced rates (48.8% versus 56.2% for labeled uses) and associations with better patient-reported health status alongside lower medical costs. This suggests that, in practice, off-label decisions informed by clinical judgment can optimize outcomes, particularly in subpopulations underrepresented in trials. Pediatric meta-analyses highlight high off-label —up to 40-50% in hospitalized children—but also effective real-world application, as systematic reviews of utilization patterns reveal no disproportionate rates when uses align with extrapolated adult data or smaller pediatric studies. In fields like and rare diseases, such practices have facilitated access to therapies preceding label expansions, with post-marketing evidence often validating initial off-label successes through subsequent approvals.

Risks, Harms, and Criticisms

Safety and Efficacy Concerns

Off-label drug use inherently lacks the rigorous pre-market evaluation of safety and efficacy required for approved indications, as regulatory bodies like the FDA mandate substantial evidence from controlled clinical trials demonstrating benefits outweighing risks for specific uses. Without such data, prescribers rely on extrapolations from limited studies, case reports, or mechanistic assumptions, which may not accurately predict outcomes in diverse patient populations, leading to uncertainties in dosing, interactions, and long-term effects. This evidentiary gap contributes to a higher incidence of adverse drug events (ADEs), with cohort analyses indicating off-label prescriptions are associated with elevated risks compared to on-label use. Empirical studies consistently link off-label prescribing to increased ADE prevalence and severity. A large-scale review of adult electronic health records found off-label use correlated with a 44% additional of adverse events , often due to unestablished pharmacokinetic profiles or contraindications overlooked in unapproved contexts. In pediatric populations, where off-label prescribing exceeds 50% of prescriptions in some settings, unlicensed or off-label drugs are implicated in ADRs at a of 1.67 (95% CI 1.38-2.02) versus authorized medicines, with factors like and immature organ systems amplifying vulnerabilities. Meta-analyses further substantiate these patterns, showing off-label utilization in children tied to greater and failure rates absent confirmatory trials. Efficacy concerns parallel safety issues, as many off-label applications rest on weak or absent bases. Systematic reviews reveal that supporting data for off-label pediatric uses often comprise low-quality studies, such as small cohorts or expert opinion, rather than randomized controlled trials, resulting in unproven therapeutic value and potential for ineffective treatments delaying proven alternatives. Adult off-label prescribing similarly shows inconsistent signals, with analyses indicating only a backed by strong (e.g., meta-analyses favoring the indication), while others expose patients to risks without commensurate benefits, exacerbating healthcare costs and morbidity. These patterns underscore a causal link: regulatory safeguards ensure on-label uses meet probabilistic thresholds of net benefit, whereas off-label deviations introduce unquantified variances that can manifest as harms when scaled across populations. Contraindicated off-label use compounds these risks, correlating with poorer health outcomes in outpatient settings, including prolonged hospitalizations and diminished quality-of-life metrics. While some off-label practices evolve into approved indications through post-market research, initial deployments without prospective validation prioritize expediency over empirical caution, as evidenced by historical failures where unanticipated toxicities emerged only after widespread adoption. Addressing these concerns demands vigilance, emphasizing evidentiary limitations, and incentives for generating real-world data to bridge knowledge gaps.

Documented Adverse Events and Failures

Off-label drug use has been associated with a higher incidence of adverse drug events compared to on-label prescribing. A of over 1.6 million adults found that off-label use correlated with a 44% increased likelihood of adverse effects, including hospitalizations and visits, attributed to insufficient pre-approval safety data for untested indications. Similarly, in pediatric populations, off-label prescribing—common in up to 60% of childhood prescriptions—links to elevated risks of severe adverse events, such as allergic reactions and organ toxicity, due to physiological differences not evaluated in original trials. These patterns underscore how the absence of regulatory scrutiny for novel uses can amplify harms when extrapolated from approved contexts. A prominent example involves atypical antipsychotics prescribed off-label for behavioral disturbances in elderly dementia patients, despite lacking FDA approval for this indication. Multiple studies document increased all-cause mortality, with hazard ratios up to 1.6-2.0 times higher among users versus non-users, alongside risks of stroke, myocardial infarction, and venous thromboembolism. In response, the FDA issued a black-box warning on April 11, 2005, citing analyses of 17 placebo-controlled trials showing a 1.6-1.7-fold elevated death risk, primarily from cardiovascular or infectious causes, affecting an estimated 20-30% of nursing home residents at the time. Post-warning reductions in usage correlated with modest declines in mortality rates, though off-label prescribing persists due to limited alternatives. Antidepressant use in children and adolescents represents another documented failure, where off-label prescribing for depression—prior to limited approvals like in 2003—prompted regulatory action after emerging suicidality signals. FDA-mandated analyses of 24 trials involving over 4,400 pediatric patients revealed a twofold increase in and behavior (from 2% to 4%) during early treatment phases, leading to a class-wide black-box warning on October 15, 2004, extended to young adults in 2007. This warning highlighted risks absent in adult data, with post-marketing surveillance confirming rare but severe outcomes, including completed suicides, in off-label contexts lacking pediatric-specific . Cardiovascular interventions provide further cases, such as off-label deployment of drug-eluting , which comprised 60% of placements in 2007 and correlated with higher rates of and target vessel compared to on-label uses. In , compounded for —used off-label intravenously or nasally—has yielded reports of psychiatric dissociation, spikes, and abuse potential, with FDA alerts in 2023 noting respiratory depression and misuse in unregulated settings. These events, drawn from spontaneous reporting and cohort data, illustrate how off-label can precipitate failures when benefits remain unproven against amplified harms.

Regulatory and Policy Landscape

Framework in the United States

In the United States, the regulatory framework for off-label use of prescription drugs is primarily established under the Federal Food, Drug, and Cosmetic Act (FD&C Act), administered by the (FDA). The FDA approves drugs for specific indications, dosages, routes of administration, and patient populations only after manufacturers demonstrate safety and efficacy through clinical trials, as required by sections 505 and 505A of the Act (21 U.S.C. §§ 355, 355a). Off-label use occurs when an approved drug is prescribed for an unapproved indication, such as a different , age group, or dosage, and is explicitly permitted for licensed physicians exercising clinical judgment, since the FDA defers regulation of the practice of medicine to state medical boards and professional standards. Manufacturers face strict prohibitions on promoting or distributing drugs for off-label purposes, as such activities render the product misbranded under section 502 of the FD&C Act (21 U.S.C. § 352), which mandates that labeling be truthful and not omit material facts regarding intended uses. Violations, including off-label via sales representatives, publications, or websites, can lead to injunctions, seizures, fines up to $250,000 per violation for individuals or $500,000 for corporations, and up to one year for misdemeanors or three years for felonies, enforced through civil actions by the FDA and criminal prosecutions by the Department of Justice. Limited exceptions exist, such as responding to unsolicited requests from healthcare professionals with truthful, non-promotional information, or disseminating peer-reviewed journal articles and texts under policies derived from the FDA Modernization Act of (though its formal regulations expired in 2006). No federal mandate requires specific for off-label prescribing, distinct from investigational uses under FDA's or regulations, though physicians must adhere to general ethical duties of disclosure under state laws and standards from bodies like the . Off-label prescriptions lack pre-market FDA review of safety and efficacy data for the unapproved context, potentially elevating risks without the agency's validation, and insurance coverage varies, often denying reimbursement absent compelling evidence. Oversight relies on post-market surveillance via the FDA's Reporting System (FAERS), voluntary reporting, and liability under law, where manufacturers generally shield from suits for unpromoted off-label uses per interpretations of doctrines like Buckman Co. v. Plaintiffs' Legal Committee (2001).

Regulations in the United Kingdom

In the , off-label use of s—defined as the prescription, administration, sale, or supply of a licensed medicine outside the terms of its marketing authorisation, such as for an unapproved indication, dosage, or patient population—is permitted under the Human Medicines Regulations 2012 (HMR 2012), subject to clinical justification and heightened professional responsibilities. The Medicines and Healthcare products Regulatory Agency (MHRA) oversees the regulatory framework, emphasizing that licensed medicines should be prioritized over off-label or unlicensed alternatives whenever possible to ensure established safety, quality, and efficacy data. Schedule 17 of the HMR 2012 provides exemptions allowing off-label medicines to be sold, supplied, or administered by healthcare professionals when no suitable licensed option exists and the use aligns with best clinical practice supported by evidence, such as national guidelines or peer-reviewed data. Prescribers, including doctors, dentists, and certain nurse or prescribers, bear primary legal and ethical responsibility for off-label decisions, which must demonstrably serve the patient's and involve evaluation of available evidence on risks and benefits. The General Medical Council (GMC) mandates that off-label prescribing occur only after confirming no licensed alternative meets the clinical need, with prescribers required to inform patients (or their guardians) of the unlicensed/off-label status, potential uncertainties in safety or efficacy, and any increased risks of adverse reactions compared to authorized uses. Documentation of the rationale, evidence reviewed, and patient discussions is essential, alongside ongoing monitoring for adverse effects, which should be reported via the MHRA's Yellow Card scheme. Non-medical prescribers must operate within their competence and may require additional oversight. Pharmaceutical manufacturers and marketing authorisation holders are strictly prohibited from promoting off-label uses, with all promotional materials confined to the approved indications specified in the Summary of Product Characteristics (SmPC). Violations can result in enforcement actions by the MHRA or the (PMCPA), reflecting the framework's aim to prevent unsubstantiated dissemination of unapproved claims while allowing clinical discretion for prescribers. In contexts like Patient Group Directions (PGDs), off-label inclusion requires explicit justification, , and alignment with legal exemptions, ensuring non-prescribing professionals do not administer without prescriber direction. This structure balances access to innovative treatments—common in areas like paediatrics and —with safeguards against unverified applications, as affirmed in MHRA guidance unchanged in core principles since 2012 despite post-Brexit adaptations to the authorisation process.

International Variations and Harmonization Efforts

In the , off-label prescribing is permitted under national laws but lacks harmonization across member states, with regulations varying significantly; for example, a 2017 study found that 10 out of 21 participating countries had specific policy tools such as compassionate use programs or reimbursement criteria, while others like and rely primarily on physician discretion without dedicated . In , off-label use often requires approval through named patient programs, whereas in it is allowed for unmet needs with and pharmacovigilance reporting. In Canada, off-label prescribing is legal and not prohibited by Health Canada, occurring commonly across medical specialties, though physicians bear responsibility for informed consent, adverse event reporting, and ensuring evidence-based justification, with promotion by manufacturers strictly forbidden under the Food and Drugs Act. Australia's Therapeutic Goods Administration (TGA) similarly does not regulate prescribing practices, allowing off-label use when approved drugs are unavailable, ineffective, or unsuitable, provided clinicians document clinical rationale and monitor outcomes, though manufacturer promotion of unapproved indications is banned. Japan maintains a more restrictive framework, where off-label indications often require review by the Ministry of Health, Labour and Welfare for reimbursement or public approval via re-examination processes, with the 2021 Physician Law introducing further oversight to limit unverified uses despite from abroad. These differences stem from varying emphases on coverage, liability, and thresholds, leading to disparities in access; for instance, drugs approved off-label in Western countries may remain uncompensated in pending domestic trials. Global harmonization efforts for off-label prescribing remain limited, with bodies like the International Council for Harmonisation (ICH) prioritizing alignment in drug approval standards and post-marketing safety surveillance—including off-label data in reports—rather than standardizing national prescribing rules. Initiatives such as ICH pediatric guidelines aim to reduce off-label reliance through expanded approvals, particularly for children, but do not address prescribing variations directly. The has not issued binding frameworks for off-label use, focusing instead on to monitor risks across borders, while regional collaborations like EU-wide highlight ongoing challenges in reconciling divergences without supranational mandates.

Controversies and Ethical Debates

Pharmaceutical Promotion and Incentives

In the United States, the (FDA) regulates pharmaceutical promotion under the Federal Food, Drug, and Cosmetic Act, which indirectly prohibits manufacturers from actively marketing approved drugs for off-label uses by deeming such promotion as misbranding if it lacks substantial evidence of safety and efficacy for those indications. This framework aims to ensure promotional materials align with FDA-approved labeling, though exceptions exist for distributing certain peer-reviewed scientific or clinical practice guidelines under strict conditions, such as when the material is truthful, non-misleading, and not used to promote the product directly. Violations have led to substantial enforcement actions, including criminal and civil penalties, reflecting the high financial stakes involved. Pharmaceutical companies face strong economic incentives to encourage off-label adoption, as it can extend product revenue streams without the substantial costs—often exceeding hundreds of millions of dollars—and timelines (typically years) required for FDA supplemental approvals through additional clinical trials. For instance, off-label prescribing accounts for up to 20-30% of overall drug use in some therapeutic areas, potentially generating billions in unapproved sales that bolster profitability, particularly for older, generic-competing drugs nearing patent expiration. These incentives persist despite legal risks, as evidenced by major settlements: agreed to pay $2.3 billion in 2009 for off-label promotion of drugs including Bextra and Geodon; GlaxoSmithKline paid $3 billion in 2012, the largest healthcare settlement at the time, partly for promoting Paxil and Avandia off-label; settled for $520 million in 2010 over Seroquel; and paid $2.2 billion in 2013 for Risperdal and other drugs. To navigate prohibitions, companies have employed indirect strategies, such as funding (CME) programs, research grants, or speakers' bureaus that feature key opinion leaders discussing off-label applications, which can subtly influence prescriber behavior without overt marketing. Implicit promotion—hinting at unapproved uses through selective data presentation or device demonstrations—has also drawn scrutiny, as it evades direct claims while potentially driving off-label prescriptions. These tactics underscore a tension: while off-label use can address unmet needs, unchecked incentives risk prioritizing sales over rigorous evidence, leading to overprescribing and associated costs, as seen in cases where fines, though record-breaking, represent a fraction of generated revenues. Recent FDA guidance, finalized in January 2025, clarifies allowable off-label communications like responses to unsolicited provider inquiries but reinforces bans on proactive promotion, aiming to balance information access with regulatory safeguards.

Patient Autonomy vs. Oversight Conflicts

In the context of off-label drug use, conflicts arise between to exercise through and regulatory oversight aimed at ensuring treatments are supported by rigorous evidence to minimize harm. Under U.S. law, physicians retain the authority to prescribe approved s for unapproved indications based on their professional judgment, reflecting a prioritization of medical discretion over strict labeling adherence. This autonomy enables personalized care, particularly when standard treatments fail or when patient-specific factors, such as rare conditions or comorbidities, necessitate deviations from approved uses. However, regulators like the (FDA) emphasize that off-label prescribing often lacks the data required for approval, potentially exposing patients to unverified risks without the safeguards of formal evaluation. Ethical debates center on the adequacy of as a mechanism to reconcile these tensions, with proponents arguing that full disclosure of off-label status—including limited , potential alternatives, and risks—empowers patients to make decisions while mitigating regulatory concerns over uninformed use. For instance, in pediatric care, where up to 80% of prescriptions may be off-label due to ethical barriers in pediatric trials, advocates highlight the need for physician flexibility to address unmet needs, yet critics contend this practice heightens vulnerability without enhanced oversight, such as mandatory reporting of outcomes. Regulatory bodies counter that unrestricted could undermine by encouraging uses akin to experimentation, as seen in calls for heightened professional scrutiny and government monitoring to track adverse events from off-label applications. These conflicts intensify during public health emergencies, where patient demand for unproven off-label options clashes with oversight caution; for example, during the , off-label uses of drugs like were justified by some on grounds of potential benefit in severe cases absent alternatives, but regulatory warnings highlighted insufficient evidence and documented cardiac risks, illustrating the trade-off between rapid access and evidence-based restraint. Legal frameworks, such as the FDA's prohibition on manufacturer promotion of off-label uses while permitting physician discretion, further underscore this divide, as patients may face barriers like denials for unapproved indications despite informed choice. Proposals to resolve such tensions include expanding mandates to explicitly cover off-label risks and establishing post-market surveillance for common off-label practices, aiming to preserve without eroding .

Recent High-Profile Cases

One prominent case involved the off-label use of , an antiparasitic drug approved for conditions like intestinal , for preventing or treating . During the pandemic from 2020 onward, some physicians and public figures advocated its use based on early observational data and small trials suggesting potential benefits, leading to widespread prescriptions and self-administration despite lacking FDA authorization for this indication. However, large-scale randomized trials, including a 2024 Oxford-led study, found no clinically meaningful reduction in hospitalization or mortality risks, prompting regulatory bodies like the FDA to issue warnings against its use for due to insufficient evidence and risks of toxicity from veterinary formulations. The controversy escalated with claims, resulting in a 2024 federal settlement where the FDA removed posts discouraging its use after physicians argued they overstepped . A 2023 survey indicated 6% of U.S. patients used , often linked to lower trust in institutions and higher endorsement of unverified treatments. Another high-profile example is the off-label prescribing of (marketed as Ozempic for ) for , surging from 2021 amid celebrity endorsements and hype. While a higher-dose formulation (Wegovy) gained FDA approval for chronic in 2021, Ozempic's off-label use for without led to national shortages by 2023, prioritizing cosmetic applications over approved diabetic patients and raising ethical concerns about . This practice has been associated with adverse events, including and non-arteritic (NAION), prompting over 2,190 lawsuits by October 2025 alleging inadequate warnings from manufacturer . Compounded versions of , not FDA-approved, have been linked to at least 10 U.S. deaths and 100 hospitalizations as of November 2024, highlighting risks from unregulated off-label formulations amid demand exceeding supply. Studies show 42% of off-label users achieve over 15% body weight loss, but two-thirds regain it within a year post-discontinuation, questioning long-term efficacy. The off-label administration of (GnRH) agonists, known as puberty blockers, to minors with has also drawn significant scrutiny since the mid-2010s, intensifying post-2020. These drugs, approved for or adult conditions like , lack pediatric FDA approval for and are used off-label to suppress , with limited long-term safety data for this cohort. The 2024 Cass Review in the UK, analyzing over 100 studies, found weak evidence for benefits and recommended halting routine NHS prescriptions due to risks like loss and impacts, influencing restrictions in . In the U.S., by 2025, over 20 states enacted bans or limits on such use for minors, citing insufficient rigorous trials and potential irreversibility, amid lawsuits challenging medical protocols as experimental. Critics, including some endocrinologists, argue the practice bypasses standard approval processes, with U.S. prescriptions rising sharply from 2017 to 2021 despite unresolved debates over desistance rates in youth .

Broader Impacts and Future Directions

Societal and Economic Dimensions

Off-label prescribing constitutes approximately 20-40% of all prescriptions in developed economies, with rates exceeding 50% in specialties such as and . This prevalence reflects its societal role in addressing unmet medical needs, particularly for rare diseases, pediatric populations, and conditions lacking approved therapies, where clinicians rely on emerging from peer-reviewed studies to extend applications. Such use promotes therapeutic flexibility and access to potentially beneficial interventions ahead of formal regulatory approvals, fostering incremental innovation through rather than solely new molecular entity development. However, it also introduces societal risks, including a 44% higher likelihood of adverse reactions compared to on-label use, which can erode public trust in healthcare providers and exacerbate disparities in treatment outcomes across demographics. Economically, off-label utilization supports cost efficiencies by leveraging existing drugs for new indications, avoiding the full expense of de novo development, which averages $2-3 billion per new drug. Repurposed generics, often prescribed off-label, incur development costs 50-60% lower, around $300 million, enabling faster market availability and reduced overall healthcare spending in scenarios like substituting lower-cost alternatives for high-cost on-label options. For instance, off-label use of (Avastin) for wet age-related macular degeneration has demonstrated substantially lower per-treatment costs than the on-label alternative (Lucentis), despite similar efficacy profiles supported by clinical data. This approach aligns with causal mechanisms of , prioritizing evidence-based extensions over redundant R&D investments estimated at $314 million to $4.46 billion per approval. Conversely, empirical analyses indicate that off-label prescribing frequently elevates economic burdens through heightened rates, medical expenditures, and work-loss costs stemming from adverse events and suboptimal . A nationwide study found off-label use associated with increased healthcare utilization and , contrasting with on-label applications that correlate with improved health status and lower expenditures. coverage compounds these effects, as many payers restrict for off-label uses absent compelling peer-reviewed or compendia support, leading to out-of-pocket costs that deter access and inflate total societal spending—exemplified by $247 million in U.S. expenditures on off-label prescriptions in recent years. requirements further amplify administrative overhead, potentially offsetting any upfront savings. These dimensions underscore a tension between off-label use's role in accelerating therapeutic adaptation and its potential to impose uncompensated externalities, such as for prescribers and systemic inefficiencies from unproven applications. While it mitigates gaps in approved therapies—critical in fields like where off-label rates surpass 50%—unregulated expansion risks overprescribing and resource misallocation, as evidenced by contraindicated uses comprising up to 54% of certain prescription cohorts. Future economic modeling should weigh these trade-offs against innovation incentives, recognizing that empirical data from large-scale datasets reveal net cost increases in aggregate health outcomes without rigorous post-market surveillance. In January 2025, the U.S. (FDA) finalized guidance on firm-initiated communications to providers regarding scientific information on unapproved uses of approved drugs, establishing an enforcement discretion that permits such sharing when it adheres to specified criteria, including reliance on peer-reviewed publications and avoidance of promotional intent. This update relaxes prior restrictions, aiming to facilitate evidence-based discussions while mitigating risks of misleading information, as evidenced by the guidance's emphasis on truthful, non-misleading data from systematic reviews or well-controlled studies conducted in humans. The builds on the FDA Amendments Act of 2007, which enhanced post-market surveillance, and responds to ongoing debates over balancing physician autonomy with public safety. Legislative efforts have included proposals for targeted exemptions from off-label promotion prohibitions, particularly for vulnerable populations such as those with rare diseases or terminal conditions, requiring FDA oversight of data and safeguards to encourage innovation without undermining regulatory standards. The Right-to-Try Act of 2018 expanded access to investigational drugs for terminally ill s, indirectly supporting off-label applications in compassionate use scenarios, though it does not alter core FDA approval processes. Internationally, China's Physician Law of 2021 introduced explicit requirements for off-label prescribing, mandating , evidence of necessity, and documentation to curb unregulated use while permitting it in evidence-supported cases. Emerging trends indicate rising off-label prescribing for agonists (GLP-1 RAs), such as (Ozempic), for in non-diabetic patients, with patterns showing increased utilization despite pending label expansions, driven by clinical demand and accumulation. In parallel, there is growing emphasis on and to evaluate off-label efficacy, as seen in guidelines from organizations like the (ASHP), which advocate systematic pharmacist-led assessments in inpatient settings to prioritize uses backed by high-quality data over anecdotal practice. These developments reflect a broader shift toward data-driven reforms, including potential harmonization efforts under frameworks like those of the (EMA) for compassionate access, amid pressures from and drug repurposing initiatives.

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