Can a podiatrist rely on the evidence and his or her clinical experience when deciding to incorporate off-label use of a drug or device in a treatment plan? With this question in mind, this author delves into legal aspects, ethical considerations, risk management topics and relevant podiatric applications with off-label prescribing.
The Food, Drug and Cosmetics Act of 1938, including amendments in 1962, requires that all drugs and medical devices pass Food and Drug Administration (FDA) review for a specific use.1 Based on a long process of drug or device development, review and clinical trials, the FDA approves drugs and medical devices for specific indications. However, off-label prescribing is a fairly common practice that reportedly accounts for one in five prescriptions.2 That said, with increasing attention being paid to off-label prescribing of approved pharmaceuticals, there may be myths and misconceptions about this practice. As a result, off-label drug prescribing continues to be a complex and evolving issue in medicine.
Off-label prescribing refers to the prescription of a registered medicine for a use that is not included or disclaimed in the product information.3 The podiatric physician considering prescribing a certain medication for a purpose not on the given modality’s approved product information labeling must contemplate three aspects of this decision: legal/regulatory, clinical evidence and ethics. Accordingly, let us take a closer look at some key elements and concepts of off-label prescribing as it may pertain to podiatric medicine.
The first salient point is that off-label prescribing is legal in the United States. Clinicians can prescribe FDA-approved medications for purposes that are not included in the given medication’s product information if they feel that the medication is appropriate and beneficial for the patient. Secondly, the practice of prescribing drugs off-label is neither ethical nor unethical.4 Lastly, patients should be aware that a podiatric prescriber does not have a legal obligation to tell a patient when he or she prescribes a drug off-label.4 However, he or she may benefit from doing so for both risk management and patient education purposes.
Deciding to use a drug for an off-label purpose is a matter of medical judgment and not one of regulatory approval. The FDA has never had the authority to regulate the practice of medicine.5,6 A 1982 FDA Drug Bulletin policy statement specific to the use of approved drugs for unlabeled indications states, “The Federal Food, Drug, and Cosmetic (FD&C) Act does not, however, limit the manner in which a physician may use an approved drug.”7 Additionally, once a drug is approved for marketing, a physician may prescribe a drug product for uses, treatment regimens or patient populations not included in the approved labeling.
The enaction of section 214 of the Food and Drug Administration Modernization Act (FDAMA) by Congress prohibits the FDA from intruding into medical practice with respect to off-label use of medical devices.5,6 Chapter 15, section 50.4 of the Medicare Benefit Policy Manual endorses the practice of off-label prescribing.6,8
Approved drugs used for indications other than that identified on the official label may be eligible for coverage under Medicare if the insurance carrier deems the use medically acceptable and consistent with the drug compendia, authoritative medical literature and accepted standards of medical practice.6,8
Addressing The Marketing Of Pharmaceuticals And Off-Label Prescribing
It is currently illegal for pharmaceutical manufacturers to specifically promote their approved drugs for unapproved conditions.9 Before 1997, manufacturers could not even discuss off-label uses with clinicians nor could they distribute related written materials.
The passage of the Food and Drug Administration Modernization Act in 1997 (and subsequent clarifications in 2009 and 2018) permitted manufacturers to share written information with providers about safety and outcomes of an off-label use within certain guidelines.10-12 Pharmaceutical companies and other parties may also share this type of information. Manufacturers can additionally distribute off-label use information to key stakeholders such as pharmacy benefit managers, health insurance issuers, group health plans or federal and state government agencies. However, it is important to understand that drug companies still may not distribute or market off-label use information to either patients or the public at large.11,13
The American Podiatric Medical Association (APMA) offers its members a summary of its position on off-label prescribing.14 The APMA states that FDA regulations allow manufacturers to promote only approved indications for drugs and devices.14 However, the FDA does permit dissemination of purely educational, “non-promotional” materials about non-approved indications or uses to medical professionals.14 Also, if a manufacturer wants to share information about a new use, there must be a pending application to the FDA for approval of that new use. The manufacturer must also provide the practitioner with the FDA-approved labeling for the current indications and clearly disclose that the described off-label use is not yet FDA-approved.14
The APMA position statement offers that podiatrists themselves cannot promote or advertise off-label use of a drug or device. However, the APMA says a podiatrist may advise a patient about an off-label medication or device when he or she feels its use would be in the patient’s best interest.14
Addressing The Practical Realities Of Off-Label Prescribing
The practice of off-label prescribing of drugs and medical devices plays an important therapeutic role in the treatment of many disease states, including psychiatric disorders, human immunodeficiency virus (HIV) and diseases in children and other patient populations underserved by approved medicines.5,6 When using medications and devices off-label for medical treatment, the primary purpose is to benefit the individual patient and enhance well-being with an expectation of success.
It is clear that rapid developments in medical science often outpace the speed with which regulatory authorities like the FDA can move to approve new therapies or new indications for previously approved therapies.5,6
Accordingly, clinicians may prescribe any drug off-label provided they practice a standard of care based on sound evidence including consistency of treatment for a given condition and/or a clinician’s anecdotal experience with the product.15,16 One author proposes that off-label drug prescribing may actually constitute the current standard of care in some cases, and one may in turn consider failure to provide or discuss off-label therapy malpractice.8
There is no uniformly accepted specific guidance to assist clinicians in making decisions about the appropriateness of off-label prescriptions. Instead, other clinicians may learn from published case reports about off-label uses of drugs and use these treatments on a greater number of patients.6,9 A prescriber may surmise that these case studies do not have the same degree of scientific scrutiny required for labeled indications from drug manufacturers.6,16 To establish sound practices, Gazarian and colleagues have outlined consensus recommendations for evaluating appropriateness of off-label use of medicines.3,6
It is important to note that the FDA does not evaluate the safety and efficacy of off-label indications as they emerge in the field. The possibility of adverse reactions or ineffective treatment along with a lack of evidence supporting such indications and prescribing practices are all concerns regarding off-label drug use. Despite these apprehensions, the FDA also recognizes that off-label drug use may be a relevant treatment option and, in some cases, could even represent a standard of care.10,17 For some of the reasons why a clinician may prescribe a drug for off-label use, see “Reasons A Clinician May Prescribe A Drug For Off-Label Use” above.
Risk Management Aspects Of Off-Label Prescribing: What You Should Know
What is the risk of liability if a patient suffers harm from taking an off-label drug prescribed by a podiatric physician? A common allegation is that the physician deviated from the standard of care when prescribing a drug off-label. The fact of the matter is that off-label prescribing does not by itself indicate malpractice.18
Various authors have recognized and explored the misconception that off-label use of an approved medication is itself an illegal or risky endeavor.3,5,6,8,9,15,16 According to Bellione, the claimant must prove through evidence that the physician deviated from the standard of practice by prescribing the drug.18 A second allegation that one may assert is a lack of informed consent. One could contend that if the physician tells the patient about the off-label status of the prescription, the patient may not consent to taking that prescription.18 Bellione asserts that such an informed consent discussion is wise, including the nature of the off-label use and what it means.18 It is also important to document the discussion in the patient’s chart.18
Other authors suggest obtaining the patient’s written consent for off-label drug use.11 Further, key points in patient education and obtaining consent include:
1. a statement that the off-label use is “experimental” so all possible side effects and complications are not known;
2. a list of the common and/or known risks and complications with use of the medication;
3. a statement outlining that the patient received a full explanation of the details of the treatment in easily understood terms; and
4. a statement that the prescriber gave no guarantees of any particular outcome; and
5. a statement that the patient is not required to take the off-label medication.11
The podiatric physician would benefit from contacting his or her malpractice carrier or attorney for guidance on how to document off-label drug use. A patient should always feel comfortable inquiring and asking questions of the podiatric physician when receiving a new medication prescription. Accordingly, providers should anticipate certain common questions and have readily available answers.
A Quick Review Of Off-Label Prescriptions Relevant To Podiatric Practice
It is the duty and responsibility of both providers and dispensing pharmacists to make certain that any off-label use of a drug or device has support from credible, evidence-based medicine.6 Below are some examples of medications that may have off-label applications in podiatric medicine.
• Misoprostol has potential pharmacological benefits in cutaneous wound healing that are possibly explained by the drug’s effect on prostaglandins in the wound healing process.6
• Nifedipine is a calcium ion influx inhibitor (calcium ion antagonist) that inhibits the transmembrane influx of calcium ions into both cardiac muscle and vascular smooth muscle. It does so without altering serum calcium concentrations. Cellular calcium metabolism appears to regulate extracellular matrix production as well as other critical steps in wound healing.6,19,20
• Phenytoin can modify collagen remodeling in wound healing by decreasing collagenase activity. Currently approved as an anticonvulsant, phenytoin as a topical wound therapy is an off-label usage.21
• Cimetidine is a histamine-2 antagonist typically used for gastric acid suppression. Small studies in pediatric populations have suggested the immunomodulatory effect of cimetidine at high doses (30 to 40 mg/ kg/day) as a treatment for warts.22-24 These reports show good tolerance of the medication without any major side effects.22-24
• Codeine was a common drug that was prescribed for years for pain relief in children having surgery. The FDA later reported a risk of serious or fatal adverse effects due to respiratory depression in children with certain liver enzymes that are ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism. Now codeine-containing products have a boxed warning and carry a contraindication after surgery in children younger than 18 years of age.25
• Gabapentin has a history of off-label use for fibromyalgia, hiccups, hot flashes and restless leg syndrome.26-28
• Tricyclic antidepressants are one class of drug that physicians have used off-label for neuropathic pain.29,30
Off-label drug prescribing is a complex and evolving issue in medicine. Ultimately, regardless of the legality of unlabeled drug use, if a podiatric physician plans to use an approved drug for unlabeled purposes, he or she should carefully weigh the risks and benefits before, during and after treatment. Clinicians should also have a strong grasp of key elements and concepts of off-label prescriptions that may pertain to the practice of podiatric medicine and appropriate risk management.
Dr. Smith is currently in private practice in Ormond Beach, Fla. Dr. Smith was deployed to Iraq as a member of a medical team to create, establish and operate an inpatient and outpatient pharmacy for military and civilians from 2013 to 2016. Dr. Smith continues to consult for multiple government agencies.
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