VOLUME 2, ISSUE 4: Rethinking Private Equity

BECOME A LEADER

Medicolegal Implications of Off-Label Drug Use

Following the standard of care is a must.

Alan J. Ruby, MD

At A Glance
  • It is estimated that up to one-fifth of prescriptions are given for indications not approved by the US FDA.
  • Medicolegal risk from off-label use depends on a number of factors, including the existence of evidence for the safety and efficacy of the drug for the intended indication.
  • Use of a certified compounding pharmacy is vital for off-label medication use.

The use of a drug for a purpose or indication that has not been approved by the US FDA is referred to as an off-label use of that drug. It is estimated that more than 20% of prescribed medications are given for indications not approved by the FDA based on large prospective randomized clinical trials.1 The Food, Drug, and Cosmetic Act of 1938 required only that new drugs be safe. It was not until the Kefauver-Harris Amendment to the act was passed in 1962 that the FDA also required evidence that drugs be effective.

As a result of these policies, off-label drug use requires not only that the safety of the drug has been demonstrated, but also that efficacy for the off-label indication has been shown in multiple, peer-reviewed studies, and that the treatment conforms to the standard of care for the indication for which it is being used. (Use of off-label drugs for research purposes have a special exemption, which will be discussed below.)

The current widespread use of drugs for off-label indications potentially exposes prescribing physicians to legal risks that are not carried by on-label uses. This article addresses some of the legal implications of off-label drug use in ophthalmology and safeguards that prescribing physicians can take to reduce their risk of litigation.

CLINICAL TRIAL DATA NEEDED

Does off-label use of a drug inherently subject the prescriber to an increased risk of litigation solely on the basis of its off-label status? This depends on a number of factors.

As is the case in prescribing any drug, the physician has the legal responsibility to discuss with the patient the risks, benefits of, and alternatives to the medication, and to adhere to the standard of care. When a drug is used for a labeled indication, the physician has the benefit of relying on large prospective studies that have demonstrated efficacy and safety and that were used to gain FDA approval for the prescribed indication for the drug. In prescribing an off-label drug, the physician still must be able to cite peer-reviewed clinical data to demonstrate the safety and efficacy of the off-label use of the medication.

To date, no court decision has mandated that a physician must disclose to a patient that a drug is being used off-label. However, through the informed consent process, the physician must demonstrate that he or she is meeting the standard of care in prescribing the off-label medication. As part of this process, the physician must demonstrate evidence of the acceptance of the off-label use in the medical community as a treatment for the off-label indication for which it is being used.

When a lawsuit is brought, in order for the complainant to prove negligence, it must be demonstrated that the physician deviated from the standard of care, independent of whether the medication was off-label.

INVESTIGATIONAL USE

One area in which physicians run the risk of legal liability is in the use of an off-label drug for investigational purposes. Investigational use differs from clinical off-label use and is subject to an entirely different set of regulations.

Investigational use implies the use of a medication in the context of a clinical study. In a study setting, the physician may be required to submit a study protocol for approval by an institutional review board. This is different from off-label use of a medication for the clinical treatment of a particular patient based on previously demonstrated off-label indications of the drug. FDA regulations allow the off-label use of medications in the treatment of patients, but not the off-label use of a medication for investigational purposes (unless as part of a research protocol).

COMPOUNDING RISKS

One of the greatest legal risks that physicians face in using off-label drugs is potential liability from using a compounding pharmacy to prepare a drug for off-label use. The most common example of this in ophthalmology is the widespread use of bevacizumab (Avastin, Genentech) for the treatment of a wide variety of retinal disorders. Compounded drugs are not FDA approved; that is, the FDA does not verify their safety or efficacy.

Unfortunately, there have been many episodes of contamination of compounded drugs. The most serious in recent memory was the fungal contamination of steroid compounds used in the treatment of spinal and joint disease, resulting in an outbreak of fungal meningitis.2

Although this outbreak received a high degree of attention from the public, it was by no means an isolated event. There have been numerous instances of contamination, mislabeling, and poor-quality preparation of compounded drugs that have resulted in the closings of compounding pharmacies or recalls of dispensed medications.

Contaminated batches of bevacizumab have been recalled from many compounding pharmacies, and some such cases of contamination have resulted in patients being blinded. Liability in these instances has largely fallen on the compounding pharmacies. Courts have generally ruled that, as long as the physician met the standard of care and obtained adequate informed consent, no negligence occurred on the physician’s part. In instances in which the ophthalmologist was found at fault, there have usually been other circumstances around the use of the off-label drug that resulted in the guilty verdict, such as inadequate preparation of the injection site, puncturing a single-dose vial multiple times, or use of the drug in conjunction with other drugs in a single syringe.3

Physicians must be sure that the compounding pharmacies they use are certified as approved providers of compounded medications as defined under an FDA guidance document.4 Physicians should contract only with facilities that have certification to provide the off-label drug. Additionally, physicians should maintain close working relationships with these pharmacies to ensure prompt notification of any issues at the compounding facility that may affect the quality of the manufactured drug. Failure to adhere to these safeguards may result in the physician being found negligent in the event that a drug is contaminated.

BILATERAL INJECTION

Another issue that deserves attention is the use of bilateral injections of an off-label drug in the treatment of retinal disorders. Many physicians perform same-day bilateral injections to reduce the treatment burden on patients with bilateral retinal diseases. Multiple studies have shown no significant difference in the incidence of local complications resulting from bilateral versus unilateral injections of anti-VEGF drugs in the treatment of retinal diseases.

But what is the increased liability if a patient were to develop endophthalmitis in both eyes as a result of injection of a contaminated compounded drug? There have been no reports of contamination of the FDA-approved anti-VEGF intravitreal injections (ie, ranibizumab [Lucentis, Genentech] and aflibercept [Eylea, Regeneron]) for the treatment of neovascular age-related macular degeneration. However, there have been numerous reports of bacterial or fungal contamination of compounded bevacizumab. Physicians may want to consider whether they are willing to risk performing bilateral injections of compounded off-label drugs, given the small but not insignificant risk of drug contamination.

CONCLUSION

The off-label use of a medication may present the physician with increased legal risks. Most of these can be mitigated by adhering to guidelines that the physician should follow regardless of whether the drug or therapy is labeled for the intended indication or not.

The best protection for the physician is to adhere to the standard of care and obtain informed consent from the patient before administering the drug for an off-label indication. In addition, the use of a certified compounding pharmacy is crucial to reduce the risk of drug contamination that may result in harm to the patient.

By adhering to these general guidelines, physicians can continue to use drugs for off-label indications in the treatment of their patients while protecting themselves from increased legal risks that may result from their use.

1. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med. 2006;166(9):1021-1026.

2. Centers for Disease Control and Prevention. Multistate Outbreak of Fungal Meningitis and Other Infections. October 30, 2015. https://www.cdc.gov/hai/outbreaks/meningitis.html. Accessed October 14, 2019.

3. Bucsi RM. Closed Claim Study: Endophthalmitis outbreak following intravitreal injections. The OMIC Digest. 2018;28(2):6.

4. Guidance Document. Facility Definition Under Section 503B of the Federal Food, Drug, and Cosmetic Act. May 2018. US Food and Drug Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/facility-definition-under-section-503b-federal-food-drug-and-cosmetic-act. Accessed October 14, 2019.