Dec. 16, 2024
The term off-label drug use (OLDU) is used extensively in the medical literature, continuing medical education exercises, and the media. Yet, we propose that many health care professionals have an underappreciation of its definition, prevalence, and implications. This article introduces and answers 10 questions regarding OLDU in an effort to clarify the practice's meaning, breadth of application, acceptance, and liabilities. Off-label drug use involves prescribing medications for indications, or using a dosage or dosage form, that have not been approved by the US Food and Drug Administration. Since the Food and Drug Administration does not regulate the practice of medicine, OLDU has become common. It occurs in every specialty of medicine, but it may be more common in areas of medicine in which the patient population is less likely to be included in clinical trials (eg, pediatric, pregnant, or psychiatric patients). Pharmaceutical companies are not allowed to promote their medications for an off-label use, which has lead to several large settlements for illegal marketing. To limit liability, physicians should prescribe medications only for indications that they believe are in the best interest of the patient. In addition, health care professionals should educate themselves about OLDU to weigh the risks and benefits and provide the best possible care for their patients.
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Abbreviations and Acronyms: CME, Continuing Medical Education; FDA, Food and Drug Administration; OLDU, off-label drug use
The term off-label drug use (OLDU) is used extensively in the medical literature, continuing medical education (CME) exercises, and the media. It is a polarizing term because it can be associated with great benefit or harm to patients.1 In addition, OLDU, along with allegations of pharmaceutical company promotion of OLDU, has been the cause of major lawsuits and historically large out-of-court legal settlements.2-7 Therefore, all health care professionals have likely heard the term OLDU used, yet we propose that many have an underappreciation of its definition, prevalence, and implications. This article introduces and answers 10 questions regarding OLDU in an effort to clarify the practice's meaning, breadth of application, acceptance, and liabilities.
The most common form of OLDU involves prescribing currently available and marketed medications but for an indication (eg, a disease or a symptom) that has never received Food and Drug Administration (FDA) approval.8,9 Hence, the specific use is &#;off-label&#; (ie, not approved by the FDA and not listed in FDA-required drug-labeling information). The term OLDU can also apply to the use of a marketed medication in a patient population (eg, pediatric), dosage, or dosage form that does not have FDA approval.
The current role of the FDA is to control which medications are available commercially. Historically, the Food, Drug, and Cosmetic Act of required only that a new medication be safe.9 In , the Kefauver-Harris Amendment mandated that FDA-approved new drugs also must have evidence that they are effective.9 Therefore, the FDA approves new medications that have been shown to be safe and effective for specific indications (ie, &#;on-label&#; prescribing). The FDA does not limit or control how the medications are prescribed by physicians once the medications are available on the market. By definition, OLDU is prescribing for an indication, or employing a dosage or dosage form, that has not been approved through the FDA process.
Off-label drug use can be motivated by several factors. First, a medication may not have been studied and approved for a specific population (eg, pediatric, geriatric, or pregnant patients).10 Second, a life-threatening or terminal medical condition may motivate a health care professional to give any treatment that is logical and available, whether approved by the FDA or not. Third, if one medication from a class of drugs has FDA approval, physicians commonly use other medications in the same class without specific FDA approval for that use for the same indication.8,9 In addition, if the pathologic or physiologic features of 2 conditions are similar, a physician may use a medication approved for 1 of these conditions for both (eg, diabetes and metabolic syndrome; psychiatric diseases such as anxiety and posttraumatic stress disorder).8
Indeed, OLDU is common. Radley et al1 reported in that in a group of commonly used medications, 21% of prescriptions were for an off-label use. In certain subpopulations of patients, this rate may be even higher. For example, a study by Shah et al11 found that 78.9% of children discharged from pediatric hospitals were taking at least 1 off-label medication. In addition, in a pediatric emergency department, the rate of OLDU was estimated to be 26.2%.2 The off-label use of antidepressant, anticonvulsant, and antipsychotic medications is high and is more prevalent with increasing patient age.12 In an intensive care unit, Lat et al13 reported that 36.2% of medication orders were for an off-label use. In addition, β-adrenergic blocking agents are commonly prescribed for an off-label indication, and specialists may more commonly prescribe for off-label β-blocker use than primary care physicians.10 In a headache specialty practice, Loder and Biondi14 reported that off-label use accounted for 47% of prescriptions written.
Off-label drug uses can become widely entrenched in clinical practice and become predominant treatments for a given clinical condition. For example, tricyclic antidepressants do not have FDA approval as a treatment for neuropathic pain, yet this class of drugs is considered a first-line treatment option.15 The use of aspirin provides another interesting example of OLDU. Aspirin was widely used before the introduction of the Food, Drug, and Cosmetic Act of . Therefore, aspirin was grandfathered and approved as an existing drug without the rigorous testing that modern medications undergo. Currently, aspirin is FDA approved for use in patients with pain, fever, rheumatic diseases, cardiovascular diseases (eg, acute myocardial infarction, previous myocardial infarction, angina pectoris, and previous cerebrovascular disease), and a history of a revascularization procedure (eg, coronary artery bypass grafting and carotid endarterectomy).16 However, aspirin does not have an indication for coronary disease prophylaxis in diabetic patients, yet guidelines recommend its use in these patients.8 Therefore, aspirin prophylaxis for coronary disease in high-risk patients is an off-label use.
Elsewhere, medications are often prescribed for OLDU with poor or absent clinical evidence. Radley et al1 reported that 73% of medications prescribed for an off-label use had poor or no scientific support. In critical care patients, OLDU was without adequate evidence 48.3% of the time.13 Because OLDU is typically less critically evaluated than is on-label drug use, OLDU may be associated with an increase in medication errors.17 Rinke et al17 studied pediatric antidepressant drug use in a national error-reporting database and found that 77% involved off-label prescribing.
There are examples of widely practiced OLDUs in every specialty of medicine (Table). Since the patient population in pediatrics is often excluded from clinical drug studies, examples of OLDU are especially abundant. For example, morphine has never received an FDA indication for pain treatment in children, but it is extensively used for this indication in hospitalized pediatric patients.11 In another example, researchers discovered in the s that the nonsteroidal anti-inflammatory agent indomethacin was efficacious as a medical therapy for closing a persistent, symptomatic patent ductus arteriosus in newborns.18 Thus, a trial of indomethacin became the treatment of choice for many affected newborns in an attempt to avoid curative surgery. Indomethacin has never been approved for this indication and, as such, this use remains an OLDU. In addition, many inhaled bronchodilators, antimicrobials, anticonvulsants, and proton pump inhibitors are often used in the pediatric population without formal FDA approval.30
Examples of Common Off-label Uses of Drugs
Category and drug Off-label use(s)a Allergy Diphenhydramine Chemotherapy-related emesis, insomnia16 Anesthesiology Propofol Intracranial hypertension Dexamethasone, propofol Postoperative nausea Meperidine Postanesthetic shivering Cardiology Amiodarone Supraventricular tachycardia16 Aspirin Antithrombosis in atrial fibrillation, Kawaskai disease16 Atorvastatin, simvastatin Extended-interval dosing for hyperlipidemia16 Indomethacin Pharmacologic closure of patent ductus arteriosus18 Dermatology Azathioprine Atopic dermatitis, pemphigus; psoriasis19 Biologic agents (eg, etanercept, infliximab, intravenous immunoglobulin, rituximab) Alopecia areata, atopic dermatitis, Behçet disease, dermatomyositis, hidradenitis suppurativa, pemphigoid, pityriasis, vasculitis20 Gastroenterology Erythromycin Gastroparesis21 Omeprazole Reflux-related laryngitis16 Hematology/oncology Alendronate Hypercalcemia of malignancy16 Dabigatran Venous thromboembolism prophylaxis after orthopedic surgery22 Doxorubicin Refractory multiple myeloma16 Furosemide (nebulized) Dyspnea16 Rituximab Idiopathic thrombocytopenic purpura, Waldenström macroglobulinemia16 Infectious disease Linezolid Infective endocarditis16 Sulfamethoxazole-trimethoprim Sinusitis16 Nephrology Acetylcysteine Prevention of contrast nephrotoxicity16 Albuterol Hyperkalemia16 Erythropoietin Anemia of chronic disease16 Neurology Atenolol, metoprolol, propranolol Migraine prophylaxis10 Isoflurane Seizure, status epilepticus Donepezil Frontotemporal dementia23 Gabapentin Bipolar disorder, diabetes, fibromyalgia, neuropathic pain symptoms, headache, hiccups, hot flashes, restless leg syndrome24 Lidocaine Postherpetic neuralgia24 Tricyclic antidepressants Bulemia, insomnia, irritable bowel syndrome, neuropathic pain symptoms15,16,24 Obstetrics Magnesium sulfate Premature labor16 Volatile anesthetics (eg, enflurane, isoflurane, halothane) Intraoperative uterine contraction Pediatrics Amoxicillin (high dose) Otitis media in children16 Atenolol Hypertension in children16 Intranasal desmopressin Nocturnal enuresis25 Pediatrics (continued) Morphine Pain in children11 Sildenafil Pulmonary hypertension in children16 Pulmonary Volatile anesthetics (eg, enflurane, isoflurane, halothane) Status asthmaticus26 Psychiatry Atypical antipsychotics (eg, risperidone, olanzapine, quetiapine) Anxiety, dementia, eating disorders, obsessive-compulsive disorder, personality disorders, posttraumatic stress disorder, substance abuse27 β-Blockers Social phobia, public speaking28 Citalopram Alcoholism, fibromyalgia, irritable bowel syndrome, obsessive-compulsive disorder, pathologic gambling, stuttering16 Fluoxetine Borderline personality disorder, diabetic neuropathy, fibromyalgia, hot flashes, premature ejaculation24 Trazodone Insomnia in elderly patients16 Urology Sildenafil Sexual dysfunction symptoms in women29 Open in a new tabThe FDA has attempted to lessen the gap between FDA approval and contemporary drug-prescribing practices in pediatrics through the FDA Modernization Act of . This Act created incentives, including exclusive marketing and patent extension, for pharmaceutical companies to test medications on children.31
Medications for psychiatric disorders are also frequently used for unapproved indications.12,32 Patients with psychiatric disorders are often excluded from clinical trials, and these disorders are inherently difficult to study. Moreover, there is often crossover in symptoms from disease state to disease state, which has lead physicians to use psychiatric medications approved for one psychiatric condition for additional unapproved indications. For example, selective serotonin reuptake inhibitors have been used off-label for rare or difficult-to-study disorders, such as borderline personality disorder, stuttering, pathologic gambling, and alcoholism.16 Moreover, selective serotonin reuptake inhibitors (eg, paroxetine, sertraline, and fluoxetine) are considered first-line treatments for premature ejaculation, another off-label use.33 In recent years, antipsychotic drug use for unapproved FDA indications has increased. Alexander et al32 estimated that the cost of off-label antipsychotic drug use in was $6.0 billion.
During the s and s, there was a proliferation of cardiac surgery to repair or replace diseased heart valves. Disease in many of these patients was the result of rheumatic abnormalities in patient populations with inadequate or no antibiotic drug treatment of infections earlier in their lives. In these patient populations, hemodynamic stability was of utmost concern during anesthesia, surgery, and the immediate postoperative course. Lowenstein34 reported that high-dose morphine, combined with amnestic agents, could provide the type of stable anesthetic required for these patients and that the beneficial effects of the anesthetic would continue into the postoperative intensive care period. With the later introduction of the short-acting opioid fentanyl, it was infused in doses much greater than approved by the FDA, thus converting a short-acting drug into a long-acting drug. High-dose morphine- and fentanyl-based anesthetics, highly favored therapy for valve replacement surgery, were retained as core anesthetics with the introduction of coronary artery bypass graft surgery. Today, patients are typically brought to surgery much earlier in the disease course (hence, they tend to be more stable hemodynamically), and there is a focus on shortening stays in the intensive care unit after cardiac surgery. In addition, improvements in surgical technique have shortened operation times. For these reasons, high-dose opioid anesthesia is less common than in the past, although it is still used. These high doses of morphine and fentanyl have never been approved by the FDA, and, therefore, their use has always been off-label.
Postoperative nausea and vomiting in surgical patients can add to patient morbidity and the cost of health care. Postoperative nausea is common, occurring in nearly 70% to 80% of high-risk patients.35 Because of this, practitioners have empirically explored a variety of antiemetic therapies. In patients at high risk for postoperative nausea and vomiting, bolus or infused propofol and bolus dexamethasone have gained favor as antiemetic regimens. However, these treatments have never been approved by the FDA for this indication. As such, they represent OLDUs.
Obtaining a new FDA approval for a medication can be costly and time-consuming. To add additional indications for an already approved medication requires the proprietor to file a supplemental drug application, and, even if eventually approved, revenues for the new indication may not offset the expense and effort of obtaining approval.8 Finally, generic medications may not have the requisite funding foundations needed to pursue FDA-approval studies.8 For these financial reasons, drug proprietors may never seek FDA approval for a new drug indication.
Physicians have been involved in legal claims due to an adverse reaction related to a medication prescribed for an off-label use.8,36 The legal theories used in these lawsuits include unregulated use of a research drug, failure to provide adequate informed consent for an OLDU, and medical negligence.37 In developing legal precedents for off-label therapies, the courts have typically treated drugs and devices as coequals. As such, many of the courts' views on OLDU have evolved from decisions regarding off-label uses of medical devices.
The FDA makes it clear that it does not regulate the practice of medicine and that the federal Food, Drug, and Cosmetic Act of will not play a role in creating physician liability for OLDU.38 However, the FDA requires stringent review before drugs and medical devices are involved in research to ensure that steps are taken to properly protect human study participants. When not classified as tools involved in research, medications can be prescribed and medical devices can be used in an off-label manner without FDA regulatory oversight. Regarding this point, during its evaluation of possible harm arising from placement of an orthopedic spine medical device, an Ohio appellate court stated that &#;the off-label use of a medical device is merely a matter of medical judgment and, as such, subjects a physician to professional liability for exercising professional medical judgment, but off-label use of a medical device is not barred by the U.S. Food and Drug Administration.&#;38,39 By way of legal precedent and similar FDA regulatory processes, the same standard would apply to OLDU.
Drawing a clear line of demarcation between a drug's use in research vs practice can often be difficult. Prescribing a drug in a new and yet untested manner does not alone brand it as an interest of research.38 The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research has attempted to define whether a drug's use might be classified as a practice or research tool, and their definitions follow. The goal of medical practice is to &#;provide diagnosis, preventative treatment or therapy.&#;38 Research, on the other hand, is &#;designed to test a hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge.&#;38 When not deemed research, legal claims brought solely on the basis of failure to gain adequate FDA approval before prescribing an off-label drug will likely be struck down. However, physicians may not be sheltered from other forms of liability theories.
No court decision to date has mandated that a physician must disclose, through an informed consent process, the off-label use of a drug.40 Two arguments are often voiced by those who oppose any routine requirement for disclosure: (1) disclosure may unduly frighten patients and (2) the extensive burden placed on physicians to constantly review and communicate medication risk and benefit information may divert attention away from other more important patient care issues.40
Perhaps the most cited modern legal case involving the medical informed consent process is Canterbury v Spence.41 The Canterbury court held that &#;the test for determining whether a particular peril must be divulged is its materiality to the patient's decision.&#;41 A material risk is one in which &#;a reasonable person, in what the physician knows or should know to be the patient's position, would be likely to attach significance to the risk or cluster of risks in deciding whether or not to forego the proposed therapy.&#;41
Many courts have not considered OLDU to be an independent material issue requiring disclosure during the consent process.38 A Ohio court held that off-label use of medical devices was a &#;matter of medical judgment.&#;38,42 According to the court, physicians may be subject to professional liability for medical negligence involving OLDU but will not be held liable for nondisclosure.38,42
The results of a nationwide poll on the public's view of OLDU may precipitate concerns for future court challenges not fully appreciated by previous legal opinion. Half of the poll's respondents falsely believed that a drug could be prescribed only for its primary FDA-approved use.43 An almost similar percentage felt that physicians should be prohibited from prescribing drugs for off-label use. Nearly two-thirds of those responding felt that except for use in clinical trials, OLDU should be completely banned.43 This is a remarkable aggregate response given that a considerable fraction of those responding negatively to OLDU had likely benefited from the practice at some point in their lives (although they were probably unaware).
Although many courts do not require physicians to disclose OLDU, patients may have a different belief and concern regarding their use. Whether these matters will develop into a greater expectation for adequate disclosure remains unknown. Some physicians have suggested that providing patients with information about OLDU may afford greater protection from future liability suits.38
Medical malpractice is a broad term that includes the action of negligence. In fact, 4 elements of tort law dealing with negligence must be proved before liability can be found to exist: (1) the prescribing physician must have a duty to the patient, (2) that duty must be breached, (3) there must be some injury requiring compensation, and (4) there must be a causal link between the breech and that injury.
A physician's duty of care is defined as the same degree of care provided by other physicians practicing under similar circumstances. Use of off-label medication alone does not result in liability under negligence standards.44 When a patient believes that he or she was harmed by an off-label use of a medication, it must be established that the prescribing physician deviated from the standard of practice.38 Because the FDA prohibits manufacturers from sponsoring physician education for off-label use of their medications, physicians may find it difficult to establish how others in their field are using medications outside their FDA-approved uses.37 As peer-reviewed published evidence focusing on a drug's off-label use grows over time, new standards of practice involving the off-label use of a drug begin to develop.38
To help determine whether the standards of practice are being met when prescribing medications for OLDU, physicians should first ask themselves several questions38,45,46: (1) Does the native drug have FDA approval? (2) Has the off-label use been subjected to substantial peer review? (3) Is the off-label use medically necessary for treatment? (4) Is the use of the medication nonexperimental? To mitigate the risk of liability, physicians should always prescribe off-label drugs in &#;good faith, in the best interest of the patient, and without fraudulent intent.&#;45 This 3-pronged approach to prescribing medications will also ensure that the tenets of the FDA&#;s requirement are met; specifically, physicians prescribing medications for off-label use should &#;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.&#;47
Reports on OLDU, particularly original observations, are not only tolerated by indexed medical journals but also may actually be encouraged. The most welcomed reports may follow several patterns, the 2 most common of which are described in the following subsections.
Before a drug use can be approved by the FDA, drug utilization for this specific application must undergo extensive studies of efficacy and safety in humans. The data from multiple phases of study are needed for the drug's proprietor to file a New Drug Application to the FDA. Studies of new drugs or studies involving expanded use of an existing drug are, by definition, &#;off-label&#; indications until FDA approval is obtained. These studies may take the form of phase 0 (pharmacokinetic and pharmacodynamic studies of subtherapeutic drug doses in small numbers of patients), phase 1 (small studies of drug pharmacodynamic properties in healthy volunteers), phase 2 (larger studies of drug pharmacology, safety, and efficacy in volunteers and patients), and phase 3 (large, randomized, multicenter trials of drug safety and efficacy; drug compared with a placebo or an existing treatment standard) trials.48 In addition, phase 4 trials are completed after FDA approval to further delineate the drug's effects and adverse reactions.48
Although preliminary research on drug pharmacology and safety intended to support a petition for FDA approval may be important to the proprietor and the FDA, articles based on these data may be difficult to publish in competitive biomedical journals because the data may not be of interest to the journal's target audience. As such, initial research may not pass peer review because of journal priorities. However, as subsequent trials evaluate drug efficacy and safety using methods that mimic the drug's use in clinical practice, journals' interest in the research will be piqued. The more novel the therapy (eg, a new class of drug for a common application, in contrast to a &#;me too drug&#;), the more likely the research data will be competitive for publication in better-quality medical journals. In fact, journals may introduce the reports with editorials and engage in media promotion of the discoveries, both testaments to the value the journals place on the research.
As previously described, a large fraction of drug use is off-label, and these indications may even become the standard of care (see Question 3). In these instances, the FDA will have previously approved the drug for clinical practice but for an indication other than the one under question. Medical journals and their readers may have a keen interest in original observations related to this form of drug use. Articles may not only become accepted for publication but may also get journal promotion (editorials and media promotion) reserved for the highest-priority articles. Clearly, a journal's enthusiasm for these types of articles is coupled with the quality and statistical power of the data, the novelty of the observation, the generalizability of the results, and the relevance of the observations to the intended audience's interests. As such, a journal may publish OLDU articles on drugs' effects and adverse effects related to indications for which FDA approval may never be sought.
Prospective trials of drug use in humans must conform to federal regulations, be approved by the institutional review boards of all participating institutions, and be registered in one of many appropriate registries (eg, ClinicalTrials.gov) to be considered for publication in biomedical journals.49,50 Retrospective OLDU observations in patients, whether of a drug's effects or adverse effects, also must have accompanying institutional review board approval before reporting the observations to a biomedical journal. However, the standards of approval for retrospective observations are much less stringent than for prospective research.
Indexed biomedical journals are less likely to publish review articles on drugs that are seeking FDA approval for a first use. Reviews with the best probability of getting published are those that describe novel drug mechanisms or success in treating conditions in which other drugs have limited efficacy. Articles primarily intended to support a marketing angle for the proprietor (ie, seeding reports)51 have difficulty getting published in the most competitive medical journals. In contrast, journals may welcome review articles that address a widely applied OLDU. As information on a given OLDU grows, journals may even welcome updated reviews or new reviews that address novel aspects of the OLDU experience (eg, new information on a drug's effects or adverse effects, updates on the operant mechanisms of action, and articles on drug-use adherence and economics).
Speakers at accredited CME courses are allowed to discuss OLDU during their presentations. The Accreditation Council for Continuing Medical Education historically required that all discussions of OLDU be disclosed during the CME presentation. However, current Accreditation Council for Continuing Medical Education requirements state that all clinical presentations should be based on &#;evidence that is accepted within the profession of medicine.&#;52 If the discussion of OLDU conforms to this mandate, no specific disclosure is required.
The Food, Drug, and Cosmetic Act gave the FDA the power to regulate promotional materials on medications.53 Two provisions from the FDA prohibit most promotion of off-label uses of medications by pharmaceutical manufacturers and marketers. First, the FDA requires approval before distribution into interstate commerce of all medication labeling (including the package insert, print and broadcast advertisements, brochures, and patient education materials).53 Second, the FDA prohibits &#;misbranding&#; of medications. Misbranding includes labeling a medication with misleading information, including off-label uses.53
Although pharmaceutical manufacturers are not allowed to promote off-label uses of medications, they are allowed to respond to unsolicited questions from health care professionals about off-label use and to distribute peer-reviewed publications regarding off-label use.53 Responses to questions regarding off-label use must be completed by the manufacturer's medical affairs office and not their sales representatives, and interactions with the questioner must be documented.53
Historically, the FDA Modernization Act allowed manufacturers to distribute to health care providers peer-reviewed journal articles about unapproved uses of medications.54,55 If a given drug company chose to engage in distribution of this type of information, it was required to submit an application for approval of that indication within a rigid and prespecified period. These requirements were subsequently revised in with the approval of new FDA guidelines.53 The new guidelines clarified existing rules and allowed distribution of information on off-label uses by pharmaceutical manufactures if specific regulations were followed.53 After , pharmaceutical manufacturers could distribute information, including journal articles and textbook chapters, describing unapproved uses for their medications. The FDA demanded that the information in these OLDU publications be accurate, the relationship between the distribution of information and the sponsoring drug manufacturer be disclosed, and the published material not be edited or presented in an abridged form.53 In addition, the manufacturer is no longer required to submit an application for approval for that indication.53
With the increase in direct-to-consumer marketing by pharmaceutical manufacturers, in the FDA introduced the Truthful Prescription Drug Advertising and Promotion (Bad Ad) Program. This program provides a mechanism by which health care professionals and patients can report illicit OLDU promotion to the FDA.
Despite regulations that ban pharmaceutical manufacturers and marketers from promoting OLDUs, some have ignored this mandate. In fact, one study found that off-label marketing by drug companies was one of the most common causes of Medicaid fraudulent claim investigations.2,56 In addition, marketing of off-label uses has been the source of costly lawsuits and out-of-court penalties for pharmaceutical manufacturers. In , GlaxoSmithKline paid a record $3 billion to settle a dispute, including alleged illegal off-label marketing involving paroxetine in children (approved only for use in adults), the antidepressant bupropion as a weight loss aid, and failure to report safety information about the antidiabetes medication rosiglitazone.5 In , Abbott paid $1.6 billion in penalties for alleged off-label marketing of valproic acid.7 In , Eli Lilly paid $1.4 billion in a settlement for alleged off-label marketing of olanzapine for dementia.3 That same year, Pfizer paid $2.3 billion for alleged off-label marketing of 4 of its medications.4
Orphan drugs are medications that are developed and used for rare, or orphan, diseases. Owing to a drug's limited clinical use for an orphan indication, it will typically generate insufficient profitability for the drug's sponsor to seek FDA approval for the narrow indication. As such, practitioners are typically forced to use medications in an off-label manner to treat orphan diseases. Therefore, orphan drugs are often a subtype of OLDU. However, in , the FDA implemented the Orphan Drug Act, which offered incentives to pharmaceutical manufacturers that developed and marketed new drugs for rare diseases.57 Incentives include tax breaks, exclusive marketing rights, and reduced drug application fees. In addition, the FDA has offered grants for the development of drugs for rare diseases. These measures have been successful in increasing the development of new, FDA-approved (ie, &#;on-label&#;) drugs for orphan diseases.57 Examples of off-label uses of medications for orphan disease include aspirin for Kawasaki disease and rituximab for Behçet disease.16,20
Off-label drug use involves prescribing medications for an indication, or using a dosage or dosage form, that has not been approved by the FDA. Since the FDA does not regulate the practice of medicine, OLDU has become common. It occurs in every specialty of medicine, but it may be more common in areas of medicine in which the patient population is less likely to be included in clinical trials (eg, pediatric, pregnant, or psychiatric patients). Pharmaceutical companies are not allowed to promote their medications for an off-label use, which has lead to several large settlements for illegal marketing. To limit liability, physicians should prescribe medications only for indications that they believe are in the best interest of the patient on the basis of the most credible available evidence. In an era of global exchange of medical information, this approach to physician prescribing practices may have greater utility than restricting practices solely to indications approved by a US-based pharmaceutical labeling system. Health care professionals should continually educate themselves about OLDU to weigh the risks and benefits and provide the best possible care for their patients.
See editorial comment,page 932
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Author Interview Video
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Video 1
Author Interview Video
When patients and their families are considering enrolling in a clinical trial, they often have lots of questions &#; from &#;how does a clinical trial work?&#; to &#;what are clinical trial eligibility criteria?&#; &#; that need to be answered.
At myTomorrows, we have helped more than 10,000 patients around the world search for clinical trials. As part of a free service that we offer to help patients and their physicians find clinical trials, each patient who reaches out to myTomorrows is assigned a Patient Navigator.
Patient Navigators not only help patients find clinical trials, but they also have medical backgrounds and are trained to explain clinical trials and medical information in a way that is easier for patients to understand.
We thought about some of the common questions to ask before joining a clinical trial, and we made this list of 10 questions to ask before participating in a clinical trial.
Clinical trials are research studies that evaluate treatments or drugs that are being developed. When a new drug or treatment is in development, it must be tested extensively to evaluate its safety and effectiveness for patients.
Clinical trials may give patients the opportunity to get access to a new drug before it is available to the public. However, there also may be risks involved with participating in a trial, such as the risk of stopping your current medication or the possibility of experiencing side effects.
Watch our video to learn more about clinical trials.
The purpose of a clinical trial is to evaluate the safety and efficacy of a drug, treatment or medical device.
Clinical trials are an essential part of developing new drugs and ultimately making new drugs available to treat patients with unmet medical need. Participating in a clinical trial helps advance medicine for future patients by helping researchers understand how a medication works (or doesn&#;t work) for patients.
Clinical trials gather data about the effectiveness and potential side effects of the drug or treatment being tested, and then researchers compare this data to standard treatments or placebo. This helps researchers figure out if the new treatment is safe and effective for specific patients &#; and if it is more effective than the standard treatment options currently available to patients.
Randomized controlled trials are considered the gold standard in measuring the effectiveness of a new drug or treatment compared to a standard treatment or placebo.
&#;Randomized controlled&#; refers to the way patients are randomly assigned to either receive the new treatment (the &#;experimental arm&#; of the trial) or the placebo/standard treatment (known as the &#;control arm&#; of a clinical trial). This is often done by a computerized or automated randomization system.
Randomized controlled trials may also be &#;double-blind,&#; which means that neither the patients nor the researchers conducting the trial know which patients are receiving the treatment being tested and which are receiving standard treatment (or the placebo). Blinding is done in order to help reduce any potential bias when researchers are comparing the new drug to the standard treatment or placebo.
Clinical trials for cancer or other serious conditions usually do not use a placebo. Instead, they often give patients the standard, approved treatment that is already available. In most cases, cancer clinical trials do not use a placebo, as it is often considered medically unethical to give a cancer patient a placebo if there is a standard treatment available. This may be one of the questions to ask about cancer clinical trials when patients are discussing their possible options with their oncologist.
However, placebos are used in clinical trials when there is no standard treatment available for a condition, such as a very rare disease. A placebo is designed to look the same as the drug being tested so that physicians and patients cannot tell the difference (but it does not contain any medicine).
Clinical trials have eligibility criteria that explain who can take part in the clinical trial. For example, a trial may be seeking patients with certain types of mutations and a specific age range, while they may exclude patients with other unrelated health conditions (such as diabetes or mental health conditions) from taking part. This is known as inclusion and exclusion criteria.
Clinical trial eligibility criteria are designed to ensure that the patients participating in a trial are similar enough that researchers can be sure that the results they measure are due to the investigational drug being studied (and not affected by other factors such as age or other health conditions). Clinical trial eligibility criteria are also designed to keep patients safe.
Side effects are unintended effects that may be related to a drug that a patient has taken. Side effects can range from minor issues, such as a headache or an upset stomach, to life-threatening or even fatal incidents. Side effects are sometimes also called adverse reactions.
It&#;s important to discuss possible side effects and whether the potential benefits outweigh the potential risks of participating in a specific clinical trial with your physician.
Each trial will require a different level of involvement and time commitment. It&#;s important to ask about the type of monitoring involved and the number of visits, blood tests, diagnostic procedures, etc.
It&#;s also essential to consider whether there is travel involved. Furthermore, patients and families should consider the impact of time away from school and work.
There are four phases of clinical trials, from Phase 1 to Phase 4. Prior to these phases, something called &#;preclinical studies&#; are conducted. Preclinical studies are research studies that use animals to evaluate a drug &#; before any testing in humans ever takes place.
Here is a brief description of each phase, from Phase 1 to Phase 4, and an explanation of what each phase aims to study.
Phase 1 Clinical Trial: These early trials test a drug on a small group of people (usually about 10 to 30 people) in order to study its safety and side effects. Phase 1 clinical trials are also used to evaluate dosages and determine the correct dosage. These trials typically last several months to a year.
Phase 2 Clinical Trial: A Phase 2 clinical trial is focused on studying a drug&#;s effectiveness. These trials, which usually last about two years, gather preliminary data on whether a drug works in patients with a specific disease. Phase 2 clinical trials also continue to study safety and any possible side effects.
Phase 3 Clinical Trial: These are larger trials, typically ranging from several hundred patients to 3,000 patients. Phase 3 clinical trials, which usually last from a year to four years, are focused on studying how a drug works in diverse populations at various dosages.
Phase 4 Clinical Trial: Phase 4 clinical trials are conducted after a drug or has received regulatory approval (e.g., approved by the European Medicines Agency or the U.S. Food and Drug Administration). These trials monitor a drug&#;s safety and effectiveness and in larger and more diverse populations than earlier trials did.
On average, the process of evaluating a drug or treatment through these phases of clinical trials takes six to seven years. Overall, it takes at least ten years from the time a new drug is discovered until the time when that drug goes on the market and becomes available to patients.
Patients usually do not have to pay for costs involved in a clinical trial. Drug manufacturers typically supply the drug used in a clinical trial free of charge, as well as pay for any required blood tests, diagnostics and extra doctor visits. Patients and their families should discuss any possible costs with the clinical trial staff and their insurance provider when considering enrolling in a clinical trial.
For example, in the United States, federal law requires most health insurers to cover the routine costs of care of patients who enroll in clinical trials as long as they meet certain conditions. These conditions state that the patient must be eligible for the clinical trial and the trial must be an approved clinical trial, and that the trial must not involve out-of-network physicians or hospitals if your insurance plan does not cover out-of-network care.
Further, it&#;s important to also consider any other non-medical costs that may be involved in participating in a clinical trial. Most clinical trials will help reimburse patients for expenses such as hotels, parking, tolls, gas, food, etc. However, there may be other costs such as childcare or the cost of lost wages from taking time off work that may not be reimbursed.
When a clinical trial ends, sometimes the drug or treatment will be approved by regulatory authorities, such as the European Medicines Agency or the U.S. Food and Drug Administration, and it will go on the market and become available to patients. However, sometimes a clinical trial ends because the BioPharma company stops it due to poor results, inadequate enrollment, funding challenges or regulatory issues.
Sometimes there is also a window of time between when the trial ends and when the drug becomes widely available. In some instances, BioPharma companies may offer something called &#;post-trial access,&#; which allows clinical trial participants to continue to access a drug after a clinical trial ends. If you or a family member decides to enroll in a clinical trial, you may want to ask the principal investigator about whether there are any protocols for post-trial access.
To learn more about possible clinical trials and get help finding clinical trials, schedule a call with a Patient Navigator.
The information in this blog is not intended as a substitute for a medical consultation. Always consult a doctor before receiving a diagnosis or treatment.
The myTomorrows team
Anthony Fokkerweg 61-2
CP Amsterdam
The Netherlands
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