Agency Finalizes Rule on Off-Label Uses Liability and Rights of Laboratories to Create LDTs

On Aug. 2, 2021, the U.S. Food and Drug Administration (FDA) published the long-awaited final rule updating its “intended use” regulations for medical devices and drugs. Here is a quick briefing of the new rules, which took effect on Sept. 1.

The “Intended Use” Regulations

In 2015, FDA proposed to eliminate a regulatory requirement that a manufacturer “provide adequate labeling” to account for unapproved, i.e., off-label uses, about which it “knows, or has knowledge of facts that would give him notice.” A 2017 final rule did remove the provision but also required manufacturer to incorporate an unapproved use into the labeling if the “totality of the evidence” establishes that the manufacturer objectively intended to introduce the product for that use. But the agency delayed the effective date of the final rule in response to industry concerns over the “totality of the evidence” clause.

So, the agency went back to the drawing board, issuing a new proposed rule in September 2020, clarifying that:

• Knowledge of off-label use of a product by a physician cannot by itself establish a manufacturer’s intended use for the product; and
• Any relevant source of evidence may be considered as establishing “intended use,” not just the manufacturer’s promotional claims about the product.

The 2021 Final Rule

The newly published final rule reaffirms that the agency may consider “any relevant source of evidence,” including “a variety of direct and circumstantial evidence” in determining “intended use.” Nothing in the Federal Food, Drug, and Cosmetic Act (FDCA) limits FDA to relying only on promotional statements. Besides, the final rule adds, the ability to rely on a broader base of evidence about a product’s intended use enables the agency to curb “distribution of dangerous and fraudulent products” more effectively.

However, the final rule reassures that a manufacturer will not be automatically deemed to have intended an off-label use based solely on knowledge that its approved product is being used or prescribed off-label. The basis of this approach is FDA’s longstanding “practice of medicine exemption” of not regulating off-label use of a lawfully marketed drug/device by a licensed health care practitioner in the context of caring for an individual patient.

The LDTs Provisions

Of more direct concern to laboratory test makers, the final rule language also preserves the ability of laboratories to develop laboratory-developed tests (LDTs) using either in vitro diagnostic (IVD) or research use only (RUO) components, provided that the LDTs comply with Clinical Laboratory Improvement Amendments (CLIA) regulations in their development and are offered on the order of a health care provider.

Note that the final rule applies to both devices granted marketing authorization (thus covering those brought to market via the de novo pathway) and those brought to market through 510(k) clearance or PMA approval, as well as to those exempt from premarket notification.

FDA also left in place a complimentary provision under which a third party may be held liable for furthering an off-label use. Specifically, a distributor, seller or other person who receives an article and furthers its commercialization for a different, unapproved purpose is required to supply adequate labeling for that use, or risk liability for marketing a misbranded article.

Here are some of the key new FDA EUAs and clearances announced in September 2021:

New FDA Emergency Use Authorizations (EUAs) & Approvals