Off-label use differs from investigational use

If the intent is research, IRB review will be required

By J. Mark Waxman, JD
General Counsel
CareGroup Healthcare System

Spotlight on Compliance

Drugs and devices that are prescribed must be approved by the U.S. Food and Drug Administration (FDA) for use. In this context, it is recognized that although a drug or device may be approved for a specific use, it also may be used to treat other conditions, not specified when originally approved. This use is often referred to as an off-label use. To the FDA, the off-label use of a drug or device is part of the acceptable practice of medicine. Use of a drug in this way does not require an IND — Investigation of New Drug Application (or the comparable IDE — Investigational Device Exemption for devices), or even IRB review.

They’re not the same thing

Off-label use, however, must be carefully distinguished from investigational use, which is use that is part of an attempt to create generalized knowledge or information beyond the care and treatment of a specific, individual patient. If the intent of the prescription extends to research purposes, the research oversight processes of the institution must be employed, and IRB review will be required.

The investigational use of drugs and devices approved for marketing would also potentially require submission of an IND or IDE. If an IDE is required, then the requirements elaborated in 21 CFR Part 312 must be met. For example, §312.3(b) makes it clear that a "clinical" investigation means "any experiment" in which a drug is used except for the use of a marketed drug in the course of medical practice, and that the provisions apply to all clinical investigations unless specific exception exists.

Clinical trial exemptions

One of the principal exemptions relates to clinical investigations conducted through an appropriately supervised clinical trials process. This exemption requires an investigation meeting the following conditions [21 CFR §312.1(b)]:

• It is not intended to support a new indication for use or any other significant labeling change.

• It is not intended to support a significant change in advertising.

• It does not involve a route of administration or dosage level, use in a patient population, or other factor that significantly increases risks (or decreases the acceptability of the risks) associated with the use of the drug product.

• IRB oversight and the related informed consent processes are present.

• The rules applicable to promotion and charging for investigational drugs are followed (see §312.7). For example, this means that charging for the drug under the clinical trial would not be permitted without prior FDA approval.

One question that arises from the distinction between an off-label drug use and an experimental or research use is whether disclosure of the fact that the prescribed use is off-label should be part of the informed consent process. While a discussion of the risks and benefits of various treatment alternatives are clearly part of the informed consent process, it is generally accepted that a discussion of whether a use is off-label, need not be part of the informed consent process. See e.g., Gaston v. Hunter, 588 p. 2d 326, 350-51 (Ariz. Ct. App. 1978); Smith v. Yohe, 194 A.2d 167 (Pa 1963).