Goodbye NSURE, Hello ACNU! FDA Issues Long-Awaited Proposed Rule to Bring OTC Drugs with a Little Something Extra to Market

Ten years in the making, a proposed rule was issued by FDA last week that has the potential to bring some prescription drugs that have not been able to gain an OTC approval to retail shelves at long last.  Sponsors have been unable to overcome the challenges of switching some widely used prescription drugs to OTC for a very long time and a path to market may be clearing for at least some of these and others.  In March 2012, FDA convened a public meeting to discuss a new paradigm under consideration, “Using Innovative Technologies and Other Conditions of Safe Use to Expand Which Products Can Be Considered Nonprescription”.  The purpose of the meeting was to explore the feasibility of imposing conditions or requirements beyond what can be contained in the Drug Facts Label (DFL) to allow certain prescription drugs to be available OTC when labeling alone will not suffice to ensure safe and effective use without a prescription and the oversight of a healthcare professional.  A wide variety of novel ideas were floated and showcased – such as kiosks and websites to question consumers and expanding the role of pharmacists to be a sort of gatekeeper to these OTC drugs for customers.  FDA was and remains clear, however, than any such drug would still be a nonprescription drug, and the statutory provisions identifying only two classes of drugs – prescription and nonprescription (colloquially, OTC) – would be respected.

A flurry of activity followed the 2012 meeting including several workshops organized by the Brookings Institute and the launch of a new (and apparently now abandoned) acronym by FDA: NSURE – Nonprescription Drug Safe Use Regulatory Expansion.  Then, essentially nothing until July 2018 when FDA issued a draft guidance entitled, “Innovative Approaches for Nonprescription Drug Products”, outlining two potential approaches for demonstrating safety and effectiveness for an OTC drug when the DFL alone is not sufficient to ensure the drug can be used safely and effectively in a nonprescription setting.  The first was to develop labeling beyond the DFL and the second was to propose “additional conditions that a consumer must fulfill” with the examples self-selection tests utilizing a mobile app or a requirement for the consumer to affirm they have watched a video or read text about use of the drug.  To date, no OTC drug has been approved under this guidance.

The recently proposed rule stays true to much of what has been discussed by FDA over time but also introduces a new acronym – ACNU for Additional Conditions of Nonprescription Use – as well as several new concepts and requirements.

An NDA or ANDA (more on ANDAs later) for an OTC drug with ACNU would need to be submitted as a separate NDA or ANDA from the existing prescription approval and could not be done through a supplement.  Among other things, the applicant would need to include a statement of the necessity of the ACNU.  FDA makes it clear that it will not approve an application for a drug with ACNU if those ACNU are not necessary to the safe and effective use of the drug OTC.  Drugs currently on the market OTC would not be approved with ACNU.  The application also would need to describe the ACNU and provide information to support its use including its purpose and how it ensures appropriate self-selection or actual use or both, a description of the key elements of the ACNU, supportive data, and a description of “the specific way the ACNU is operationalized”.

This concept of operationalizing (operationalization?) is new to this proposed rule and appears intended, at least in part, to solve thorny issues related to identifying and approving a generic version of a product approved with ACNU. FDA states that the specific way the ACNU is operationalized is not a key element of the ACNU and provides an illustrative example of the difference.  In the example, the applicant has demonstrated that consumers cannot appropriately self-select based on the DFL alone and provides the information supporting the use of a proposed ACNU requiring all consumers to complete a questionnaire on a secure website that uses the responses to calculate a risk score and determine whether the score is acceptable to allow the consumer to use the OTC drug.  In this case, the key elements of the ACNU include the questions in the questionnaire, but not how the questionnaire is administered (e.g., through a kiosk at the retail store, through a mobile app, via telephone).  How the questionnaire is administered is how it is operationalized.

This brings us back to the ANDAs.  Under the proposed rule, an ANDA seeking approval for a drug with ACNU (i.e., the reference listed drug or RLD) must include the same key elements of the ACNU as the RLD, but may propose a different way to operationalize the ACNU.  This would seem to allow a generic to be approved even if the ANDA applicant cannot utilize the same mechanism such as a kiosk or mobile app (perhaps due to patents on the kiosk or software) provided the way the ANDA proposes to operationalize the ACNU achieves the same purpose as the ACNU for the RLD and the ANDA contains appropriate support.

FDA is seeking comment on, among other questions, whether patents claiming aspects for the ACNU should be listed in the Orange Book and on any other issues related to the proposed rule that FDA should consider in implementing the proposal to help avoid unnecessarily delaying the entry of generics with an ACNU to the market.  FDA is also seeking comment on the proposal to allow differences in the ways to operationalize in an ANDA.

The proposed rule also includes obligations for new postmarketing reports related to incidents of failure of the ACNU and specific additional labeling requirements for drugs with ACNU.

Comments on the proposed rule are due by October 26, 2022. (Note that as of this writing the link to submit comments on FDA’s website is not working, but the docket can be reached through the www.regulations.gov website by searching for the docket number FDA-2018-D-2281 .)