Final Rule for ACNU Arrives in Time for End of Year but Not Much New to Celebrate

As promised in the Fall Unified Regulatory Agenda, FDA issued the final rule to establish the pathway to obtain marketing approval of a nonprescription drug product with an additional condition for nonprescription use (ACNU) on December 26, 2024, before the end of the calendar year.  89 Fed. Reg. 105288 (Dec. 26, 2024).  We described the 2022 proposed rule and the ten-plus year history leading up to its issuance in our blog post here.

In response to the proposed rule, approximately 200 comments were submitted to the docket, and a meeting took place among FDA, the White House Office of Management and Budget (OMB) and the Consumer Healthcare Products Association (CHPA).  The changes made in the final rule were minimal and notably did not address two of the biggest subjects of substantive comments to the proposed rule.

Turning first to the four areas in which changes were made, the focus of two of those areas were the requirements for the required labeling statements for a product approved with an ACNU.  The third was the postmarketing requirement for reporting an “ACNU failure.” In discussing these revisions, FDA clarified that an ACNU failure must be reported even if the failure does not cause or lead to inappropriate medication use or consumer harm.  FDA also stated in response to comments that questioned FDA’s authority to require such reports in the absence of an adverse drug experience, that “ACNU failures generally would have a bearing on whether the Agency may consider withdrawal proceedings pursuant to section 505(e) of the FD&C Act.”

Finally, FDA revised language in the final regulation about the circumstances under which a drug product with an ACNU would be misbranded – though it is not clear that the language actually clarifies all that much.  The regulation now reads that a nonprescription drug product with an ACNU is misbranded if it is mislabeled or if the “ACNU is not implemented by the applicant in accordance with the following, as approved by FDA in the application: (i) The key elements [of the NDA or ANDA]; or (ii) The operationalization of the ACNU under [the NDA or ANDA].”  It is not obvious from this language what happens in the case of consumer error or consumer intentional misuse of the ACNU.  In either case, if the consumer wrongly enters their information, e.g., and as a result obtains a drug that had they entered the information correctly, they would not have received, does that make the drug misbranded and the drug manufacturer responsible for distributing a misbranded drug? Further elaboration of FDA’s view would be helpful.

We turn now to the two biggest issues that FDA declined to make changes to address: (1) whether allowing a prescription version and a nonprescription version of the same drug product with the only difference being the nonprescription drug’s having an ACNU violates FDA’s long-held policy against the simultaneous marketing of prescription and nonprescription drug products, and (2) the “fail first” approach to eligibility to submit an ACNU application.

FDA’s policy has prohibited the simultaneous prescription and OTC marketing of the same drug product under the same conditions of use unless there is a clinically meaningful difference between them.  Historically, this has meant a difference in dose, strength, indication, etc. The difference could be as subtle as how long the drug could be used for, e.g., up to 7 days versus chronic use.  FDA’s position expressed in the preamble is that if the only difference is the existence of the ACNU (i.e., all those other conditions are exactly the same), that is enough of a meaningful difference to allow simultaneous marketing.  This is one of the issues on which there were significant comments and was one of the topics of the meeting with OMB.

Interestingly, in the preamble, FDA also said that it would require a separate application rather than a supplement for an OTC switch involving an ACNU because if the ACNU switch of an RLD were approved, then all prescription generics referencing that RLD would be required to submit supplemental applications to switch their products from prescription to nonprescription with ACNU status, potentially removing all prescription products from the market and leavings only drugs that can be accessed via an ACNU on the market. In making this statement, FDA noted that this result would be counter to the purpose of the ACNU program of expanding access because there may be individuals who are not able to access the OTC drug because of their inability to navigate the requirements of the ACNU.  At the same time, if the RLD prescription drug and its generics have gone away, these individuals would not be able to obtain the medication by prescription from their healthcare provider.  This approach by FDA to trying to maintain a prescription option on the market seems to raise some significant issues that we may not have seen the last of.

Commenters, including CHPA, also raised concerns and provided comments on FDA’s “fail first” approach which requires that FDA determine that labeling alone is insufficient to ensure appropriate self-selection or appropriate actual use, and that the applicant provide adequate data or other information to demonstrate this, before it will accept an application for an OTC drug with ACNU. Numerous comments asked for clarifications or standards which FDA declined to provide, instead advising applicants to meet with FDA to discuss their development plans and recommending a step-wise approach to development which may include an iterative process.  While this is certainly the process undertaken by all nonprescription drug label developers to create a drug facts label that can meet the criteria for being able to provide directions for safe and effective use, proving a negative and testing against no standard poses significant challenges for which there are no precedents.  FDA did not acknowledge this concern speaking instead of the need of “optimizing” the label without more direction on how to determine when optimization is achieved.

Now that the ACNU rule is final, we eagerly await that first approval or first Advisory Committee meeting where we can all learn how FDA will apply some of the vaguer parts of this long-awaited program.

The final rule becomes effective on January 27, 2025.