Question: An internist added a DPP-4 inhibitor to treat an uncontrolled diabetic patient on increasing doses of insulin. The Physicians’ Desk Reference does not indicate this to be an approved use of the drug. However, some endocrinologists in the community are using it in this manner, and a speaker at a recent drug promotion dinner stated that such use is effective. The internist did warn the patient of the increased risk of hypoglycemia, but did not specifically disclose that the drug’s use in combination with insulin is not approved by the Food and Drug Administration. The patient subsequently developed hypoglycemia. Which of the following statement best describes the legal consequences?
A. The doctor is liable for off-label use.
B. The doctor is liable for failure to obtain informed consent.
C. The drug company is liable for off-label marketing.
D. All are correct.
E. All are incorrect.
Best answer: C. The FDA reminds physicians that if they use a product for an indication that is not in the approved labeling, they have the responsibility to be "well informed about the product, to base its use on a firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects." There is no liability for off-label prescriptions. However, disclosure of known risks is necessary, although it is uncertain if lack of FDA approval needs to be a part of the discussion. On the other hand, manufacturers are absolutely forbidden from marketing their drugs (or medical devices) for a nonapproved use, and some firms have incurred heavy fines for off-label promotions by sales representatives during office visits, or by paid speakers at dinner programs.
The FDA reviews all prescription products for specific uses or “indications.” By law, FDA approval must be based on “substantial evidence” of efficacy and safety from adequate and well-controlled investigations, typically in the form of prospective, randomized, double-blind, and placebo-controlled clinical trials.
On the other hand, physicians may use their professional judgment in deciding whether to use such drugs to benefit their patient, even in ways not approved by the FDA. Such off-label practice is widespread, accounting for 21% of overall prescriptions in the outpatient setting, the most commonly implicated being cardiac and anticonvulsant medications (Arch. Intern. Med. 2006;166:1021-6). In that study, the authors identified two drugs – gabapentin (83%) and amitriptyline (81%) – as having the greatest proportion of off-label use among 160 medications. They also concluded that some 73% of off-label drug use had little or no scientific merit.
Off-label use commonly takes the form of a prescription for a condition that is not specified in the package insert, in doses other than those approved, or during pregnancy or in populations such as children. For example, three-fourths of the prescription drugs in the United States lack full pediatric approval and are labeled with such disclaimers. Lack of FDA approval simply means that the agency has not reviewed the product for that use. Unapproved use must be distinguished from disapproved or contraindicated uses. Professional organizations (for example, the American Academy of Pediatrics) and the FDA itself have endorsed off-label use under appropriate conditions. The AAP emphasizes the best interest of the patient, allowing off-label use based on "sound scientific evidence, expert medical judgment, or published literature" (Pediatrics 2002;110:181-3).
Off-label use is not dabbling in human experimentation, and liability is a factor only if the action itself is negligent, which is determined by the same legal parameters irrespective of whether the product’s use is approved or unapproved. In Femrite v. Abbott Northwestern Hospital (568 N.W. 2d 535) in 1997, the Minnesota Court of Appeals held that the off-label use of a screw device for spinal surgery was not negligent. The plaintiffs had argued that the product could be used only within the context of clinical investigation. But the defendant contended that implantation of the screw device in spinal-fixation surgeries is an off-label use because the FDA had already approved the device for use in long and flat bones. As such, it involved medical discretion, which was beyond FDA regulation. The court concluded "as a matter of law that the physicians’ implantation of the screw devices in appellants’ surgeries was a permissible ‘off-label’ use not in violation of FDA regulations."
In Weaver v. Reagen (886 F. 2d 194) in 1989, the state of Missouri failed in its effort to exclude certain Medicaid patients who did not meet FDA criteria from access to the anti-AIDS drug, azidothymidine. The 8th U.S. Circuit Court of Appeals noted that FDA-approved indications were not intended to limit or interfere with the practice of medicine or to preclude physicians from using their best judgment in the interest of the patient. The fact that the FDA had not approved labeling of a drug for a particular use did not necessarily bear on those uses of the drug that were established within the medical and scientific community as medically appropriate.