Frequently Asked Questions
Research vs practice
The FDA makes it clear that it does not regulate the practice of medicine and that the federal Food, Drug, and Cosmetic Act of 1938 will not play a role in creating physician liability for OLDU. 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.” 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. 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.” 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.” 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.
Medical malpractice: Informed consent
No court decision to date has mandated that a physician must disclose, through an informed consent process, the off-label use of a drug. 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.
Perhaps the most cited modern legal case involving the medical informed consent process is Canterbury v Spence. The Canterbury court held that “the test for determining whether a particular peril must be divulged is its materiality to the patient’s decision.” 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.”
Many courts have not considered OLDU to be an independent material issue requiring disclosure during the consent process. A 1996 Ohio court held that off-label use of medical devices was a “matter of medical judgment.” According to the court, physicians may be subject to professional liability for medical negligence involving OLDU but will not be held liable for nondisclosure.
The results of a 2006 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. 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. 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.
Medical malpractice: Informed consent
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. 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. 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. 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.
To help determine whether the standards of practice are being met when prescribing medications for OLDU, physicians should first ask themselves several questions: (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.” 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.”
Research vs practice
The FDA makes it clear that it does not regulate the practice of medicine and that the federal Food, Drug, and Cosmetic Act of 1938 will not play a role in creating physician liability for OLDU. 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.” 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. 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.” 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.” 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.
Medical malpractice: Informed consent
No court decision to date has mandated that a physician must disclose, through an informed consent process, the off-label use of a drug. 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.
Perhaps the most cited modern legal case involving the medical informed consent process is Canterbury v Spence. The Canterbury court held that “the test for determining whether a particular peril must be divulged is its materiality to the patient’s decision.” 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.”
Many courts have not considered OLDU to be an independent material issue requiring disclosure during the consent process. A 1996 Ohio court held that off-label use of medical devices was a “matter of medical judgment.” According to the court, physicians may be subject to professional liability for medical negligence involving OLDU but will not be held liable for nondisclosure.
The results of a 2006 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. 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. 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.
Medical malpractice: Negligencea
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. 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. 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. 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.
To help determine whether the standards of practice are being met when prescribing medications for OLDU, physicians should first ask themselves several questions: (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.” 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.”
Reports to evaluate new drug therapies seeking FDA approval
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. In addition, phase 4 trials are completed after FDA approval to further delineate the drug’s effects and adverse reactions.
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.
Reports to evaluate off-label uses, or describe adverse effects, of drugs approved for other indications
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. 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) 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).
All information was taken from a medical journal titled “Ten Common Questions (and Their Answers) About Off-Label Drug Use” by Dr. Christopher M. Wittich, which you can read by clicking
here.
