This week, FDA published a proposed rule that would amend its medical product "intended use" regulations, 21 CFR §§ 201.128 and 801.4 and replace the 2017 Final Rule about the same issue that never became effective. In FDA nomenclature, "intended use" refers to the objective intent of the persons legally responsible for the product's labeling and can determine whether a product is FDA-regulated at all or whether an FDA-regulated product requires a new premarket submission because its intended use has changed.

The proposed rule seeks to address confusion caused by the last sentence in the intended use regulations that could be read as requiring firms to provide adequate labeling for an unapproved use of their product if they have mere knowledge that their product is being prescribed or used for such off-label use. Under FDA law this, in turn, could render the distribution of many products unlawful if not accompanied by a new approval or clearance. Specifically, the last sentence of the current regulations read:

"But if a manufacturer knows, or has knowledge of facts that would give him notice that a drug [or device] introduced into interstate commerce by him is to be used for conditions, purposes, or uses other than the ones for which he offers it, he is required to provide adequate labeling for such a drug [or device] which accords with such other uses to which the article is to be put."

Recall that the 2017 Final Rule also sought to provide clarity on this point by amending the last sentence in the intended use regulations to establish a "totality of evidence" standard for determining a firm's objective intent for the use of its product. But instead of adding clarity, this addition created confusion and consternation among stakeholders regarding the meaning and boundaries of "totality of evidence" and the fact that "knowledge" could still be used by FDA to evaluate intended use, and the 2017 Final Rule never became effective. 

This week's proposed rule seeks to address the challenges made against the 2017 Final Rule by abandoning the "totality of circumstances" language, and explicitly states that mere knowledge of an unapproved use is insufficient, by itself, for FDA to find a new intended use by adding:

"…a firm would not be regarded as intending an unapproved new use for an approved drug [or an approved or cleared device] based solely on that firm’s knowledge that such drug [or device] was being prescribed or used by health care providers for such use."

However, the preamble makes clear that "knowledge" will still remain a factor in FDA's overall evaluation of objective intent as FDA intends to look at "all relevant evidence" in making its determination of intended use, of which a firm's knowledge that health care providers are prescribing or using their product for unapproved or uncleared uses is but one factor. Thus, while rightfully the "totality of evidence" standard will not be codified, the concept still remains.

Perhaps the most valuable aspect of the proposed rule is the examples set forth in the preamble of the types of "relevant evidence" FDA will consider in its evaluation of a firm's objective intent, which gives stakeholders some idea of the expansiveness of FDA's thinking on the issue, and examples of factors that standing alone would not be determinative of a new intended use. For example, in addition to express claims and representations in labeling, promotional material and advertising, FDA stated that it also will look at such things as:

• Implied claims (e.g., product names or directions for use that suggest a different use, or representations that a product contains a specific ingredient, e.g., aspirin on the ingredient list, implying a physiological effect
• Product characteristics and design, such as inclusion of specific ingredients with known physiological effects (e.g., an API or THC) in products that are not approved for medicinal use, the known use of a product that is unapproved for medical use (e.g., herbs for pain management), or the product's technical features (e.g., products purported for one use but specifically sized for another)
• Circumstances of the sale or distribution, such as who the sales force is detailing (e.g., providers with patient populations outside of the intended use) or the context surrounding the sale (e.g. nitrous oxide-filled balloons sold outside a rock concert)

With respect to the examples of evidence that, standing alone, would not be dispositive of a new intended use, FDA indicates that in limited circumstances, a firm might be permitted to provide safety and warning information to health care professionals regarding an unapproved use to minimize patient risk. The specific example, however, is quite narrow: a drug with an unapproved use broadly accepted in the medical community; the firm has submitted an efficacy supplement to add such new intended use; and the boxed warning and REMS materials already warn of the risks of such unapproved use in general terms. In such instance, according to the example, if the firm disseminates additional specific safety and warning information to health care professionals in order to minimize patient risk in connection with the unapproved use, and the information does not promote efficacy of the new use explicitly or implicitly, then that dissemination, standing alone, would not be dispositive of a new intended use. It is unclear, however, whether FDA would find such dissemination permissible if, for instance, the supplement had not been filed or the risks had not already been included in general terms, or how broad the acceptance of such use needs to be before a firm can distribute the specific risk information.

Overall, the proposed rule does not seem to move the needle much with respect to intended use, and , it remains important that firms establish clear policies regarding sales and promotional activities and include regulatory or legal review at each step of product commercialization. In addition, while the examples provided in the preamble are helpful, they are very fact specific, and depending upon each unique situation, may be evaluated differently. Comments to the proposed rule are due October 23, 2020.