19 October 202211 minute read

FDA’s proposed rule on Rx-to-OTC switch: Comment period extended by 30 days

FDA’s proposed rule “Nonprescription Drug Product with an Additional Condition for Nonprescription Use” was fast approaching the end of the comment period, set to close on October 26, when today FDA announced an unusual extension of 30 days in response to numerous requests for extension to the comment period.

To date, 107 comments have been submitted on the proposed rule. In addition to the overwhelming majority of comments which call for birth control to be made available without a prescription, commentors to date have raised key issues facing manufacturers, such as the lack of health literacy of the average U.S. consumer, as well as the challenges of operationalization of the required “additional conditions” and post-market reporting.

Nonprescription drug regulatory background

Over-the-counter (OTC) drugs, which do not require a prescription, may be legally placed on the market through a number of pathways. The drug sponsor must demonstrate that the product is both safe and effective for use without the supervision of a licensed healthcare practitioner through either conformity to an existing OTC drug monograph, or alternatively, through a New Drug Application (NDA) or Abbreviated New Drug Application.

Sponsors pursuing the NDA process to market a nonprescription product have multiple options available, the most common of which involves an Rx-to-OTC “switch.” Under this pathway, a company first obtains NDA approval for a drug and subsequently submits a supplemental NDA seeking to remove the prescription requirement as a condition of use. In the same vein, sponsors may employ a partial Rx-to-OTC switch strategy in which the indication for use is divided into those requiring a prescription, and those available OTC. However, due to the significant cost and regulatory burden of meeting the FDA’s product safety and efficacy requirements, few products have gone through the Rx-to-OTC switch process – less than 50 since 2001.

2022 proposed rule: “Nonprescription Drug Product With an Additional Condition for Nonprescription Use”

The proposed regulation is intended to expand options for consumers by establishing a vector for products that are only available under prescription to be considered separately for nonprescription use. Under the rule, if the labeling alone does not support nonprescription use, then a company can file a new application proposing additional condition(s) for nonprescription use (ACNU) that will ensure appropriate use or self-selection. The proposed rule, according to the FDA, is intended to broaden the range of marketed nonprescription drugs available to consumers, thus empowering them to self-treat certain common/chronic conditions and improving public health.

Additional conditions for nonprescription use are defined in this rule as “one or more FDA-approved conditions that an applicant of a nonprescription drug product must implement to ensure consumers’ appropriate self-selection or appropriate actual use, or both, of the nonprescription drug product without the supervision of a healthcare practitioner if the applicant demonstrates and FDA determines that labeling alone is insufficient to ensure appropriate self-selection or appropriate actual use, or both.”

The definition is intentionally broad to provide applicants flexibility in the types and implementation of additional conditions they may propose. While the Agency provides several examples of potential ACNUs– eg, interactive questionnaires through telephone or mobile application, consumer confirmation of understanding of the labeling – the list is not exhaustive, and leaves the door open for new and innovative approaches to be adopted.

Separate application for marketing allows greater access

The proposed rule requires a separate application for a nonprescription product with an ACNU. According to the FDA “[c]ontinued access to the prescription drug product, along with the availability of the nonprescription drug product approved with an ACNU, would ensure greater access to needed drugs by providing flexibility in how to obtain them.” While commenters generally agreed that the proposed rule would expand patient access to medications, some questioned whether insurance companies would cover the costs for ACNU products without a prescription and provider oversight, potentially engendering inequitable access to essential drugs. Further guidance has been requested to help to clarify the role and impact of insurance coverage on accessibility.

Misbranding concerns and “meaningful difference” carveout

Section 503(b) of the Federal Food, Drug and Cosmetic Act provides that “simultaneous marketing of two drug products with the same active ingredient as both a prescription and a nonprescription drug would result in one of the two products being misbranded.” However, the same drug product can be offered with or without a prescription if there is a “meaningful difference” between the prescription and nonprescription versions—indication, strength, or dosage form, for example.

In its proposal, the FDA maintains that the ACNU itself qualifies as the meaningful difference required by statute, since the ACNU would allow a nonprescription drug product to be safely used without the supervision of a healthcare professional. Therefore, under the FDA’s proposal, even without the traditional changes to indication or dosage form, versions of a prescription and nonprescription with an ACNU for the same product could be marketed simultaneously without running afoul of the misbranding prohibitions.

New requirements for nonprescription product labeling

FDA has had a proposed rule on improvements to nonprescription drug labeling in the works for several years now, dating back as early as 2012. In July 2018, the agency issued draft guidance which provided recommendations for labeling nonprescription drug products when the Drug Facts Label (DFL) alone did not sufficiently support nonprescription use, including “additional conditions” that would allow a drug to be considered nonprescription (Innovative Approaches to Nonprescription Drug Products).

The draft guidance proposed that the FDA may consider approving “additional labeling” beyond the DFL for certain OTC products to support safe use when the DFL alone is insufficient. This additional labeling could include, for example, informational leaflets, interactive digital displays or mobile application based informational portals. In 2021, the FDA held a meeting on potential improvements to OTC drug labeling, including how to make DFLs more understandable and how to leverage potential digital technology solutions for enhancing nonprescription labeling.

The proposed rule, if finalized, would add new labeling regulations for nonprescription drug products with an ACNU under 21 CFR 201. In addition to meeting all the current regulatory requirements for nonprescription drug products, labeling of OTC drugs with an ACNU would require a new statement under the “Directions” section on a product. In brief, the statement would direct consumers to resources and potentially a physical or virtual location to check whether the drug is safe for that person.

Further, the drug’s principal display panel (PDP) would include a specifically-formatted statement indicating that an extra step is needed to use the drug, and an alert that the ACNU “must be fulfilled to ensure safe and effective use” would also be required.

Operationalization issues of ACNUs

FDA is specifically seeking comments on potential issues which may arise for retailers or consumers based on the way the applicant operationalizes the ACNU. This may include equity in accessibility for consumers with hearing or vision impairments, or for those who do not have smart phones.

Comments to the administrative record thus far point to technical issues at a store kiosk or on a website, lack of Internet access for online surveys, and the potential fraud facilitated by an ACNU being fulfilled in a public location (ie, nearby consumers for whom the product may not be suitable might replicate “correct” answers obtained by observing another individual fulfilling the ACNU in order to gain access to the product). (Comment)

Another stakeholder, an ER nurse, discussed the “unusual ability for seemingly benign medications to become an abused drug.” The commenter said that in certain instances, a questionnaire may be appropriate in assisting consumers, but indicated that a virtual questionnaire needs to be simplistic and clear, perhaps taking into account language barriers which can exacerbate the process.

While the rule proposes labeling regulations intended to protect patients from improper use of OTC products, various commenters expressed concern over the “significant health illiteracy in our country.” (Comment) This lack of health knowledge may increase the risk of harm to consumers, thus highlighting the need for professional intervention which no kiosk, video, or questionnaire could replace, since it is not uncommon for individuals to assume a product is safe simply because it is available OTC. (Comment) The critical role of the healthcare professional involves patient education at multiple stages, from initial treatment to follow-up, whether for short-term illness or chronic conditions.

Others posited that most people do not read and/or follow instructions, increasing the risk that consumers use a nonprescription drug without verifiably checking the additional conditions set forth in the product label. While the usual OTC product liability claims may still apply for ACNU drug suppliers, new causes of action may emerge based on the ACNU itself (or lack thereof).

In order to address these operationalization issues, it seems clear that protocols must be established to ensure patients have properly fulfilled all ACNU requirements. More than one comment submitted mentioned the invaluable role pharmacists may play in the implementation of this rule, explaining that pharmacists are the most accessible healthcare providers, especially in rural and underserved areas. Pharmacists, as a reliable resource with respect to dosing and interactions, could help ensure these nonprescription drugs are used appropriately.

Post-market reporting issues for implementation failures

In addition to soliciting comments on operationalization, the FDA is seeking input on the proposed post-market surveillance requirements for drugs approved as nonprescription with an ACNU.

Under this new rule, the FDA would require sponsors to report any “failure in the implementation” of an ACNU using the FDA Adverse Event Reporting System, regardless of whether the failure resulted in an adverse event, eg, consumer accessed the product without fulfilling the ACNU, could not access the drug after fulfilling the ACNU, or experienced a technical issue affecting consumer access to the ACNU.

Since this reporting would likely require quality assurance systems that appropriately capture these failures in implementation, the FDA is requesting comments on the burden and benefits of submitting an individual report to the Agency for each individual failure in implementation of an ACNU encountered by a consumer (as opposed to a single, consolidated report for all such failures). Under the single-report structure, a sponsor could be subject to multiple reports of several individuals impacted by the same failure – for example, each consumer being individually unable to access a mobile application while offline.

The Consumer Health Products Association believes that summary periodic reporting of what the proposed rule terms “additional conditions of nonprescription use failure” is the most effective method to track and report relevant concerns to the Agency without being overly burdensome. (Comment) However, the FDA should more clearly define “failure” as outlined in the proposed rule, as it directly impacts collection of relevant consumer data.

One telemedicine company suggested that the nature of the failure should determine the proper reporting response, similar to the process for controlled substances and certain medical devices: “lower risk” failures might be reported on a consolidated basis, while failures determined to introduce high risk might be reported for each individual affected. Alternatively, the FDA could establish classes of failure with specific criteria and reporting requirements.

Next steps

While some commenters agreed that the proposed rule would allow increased availability and equitable access to medication without the involvement of a healthcare provider, bridging a sometimes large healthcare gap in certain communities, a number of operationalization questions still need to be addressed.

Some have requested the FDA provide further clarification in its final rule on the data requirement for the ACNU, specifically on the definitions of "adequate data" and "other information" as required in new applications. Additionally, Agency guidance on expectations for design, justification, and operation of an ACNU over the life of a product, including direction on how to sufficiently measure the effectiveness of an ACNU, will also be critical. Without these explanations, the potential for litigation increases, exposing manufacturers to potential product liability claims, including by individuals who are inappropriately accessing OTC drugs, whether by innocent or fraudulent means. Drug manufacturers will also need to consider how to minimize risk associated with self-misdiagnosis and undiagnosed disease progression that could typically be identified by a healthcare provider, thus enabling companies to safely provide the broader treatment access that the FDA seeks to confer through the proposed rule.

The Agency is seeking an effective date of 60 days after final rule publication, during which time the FDA would likely aim to issue additional guidance to fully implement the new regulations; this may include a new version of its 2018 draft guidance on Innovative Approaches for Nonprescription Drug Products.

We will continue to monitor any updates from the FDA and provide timely updates on this topic. For information about Rx-to-OTC switching and the evolving FDA regulation, please contact your DLA Piper relationship partner, the authors of this alert or any member of our FDA practice group.