The US Food and Drug Administration (FDA)’s recently issued final rule establishing application, labeling, and postmarketing reporting requirements for a nonprescription drug product with an “additional condition for nonprescription use” (ACNU) goes into effect on January 27, 2025.

This long-awaited rule, which we reported on in October 2022, is expected to help expand access to drugs over-the-counter (OTC) that typically would require a prescription, particularly for chronic conditions. The final rule is intended to increase options for applicants to develop and market safe and effective nonprescription drug products, with the intent to improve public health.

What are nonprescription drugs with an ACNU?

A “nonprescription drug product with an ACNU” is a medication that may be sold in OTC settings when an FDA-approved additional condition is met to ensure a consumer’s appropriate self-selection or appropriate actual use, or both, without the supervision of a licensed practitioner. Examples of ACNUs identified in the final rule include interactive phone questionnaires, mobile application questionnaires, or consumer engagement with pharmacy kiosks to confirm consumers’ understanding of the labeling, and which provide additional information that is otherwise not permitted on a product’s drug facts label (DFL).

Before the final rule, nonprescription drugs could be placed on the market through compliance with an established OTC monograph, after being approved for nonprescription use by FDA through one of the new drug application pathways (new drug application (NDA) or abbreviated new drug application (ANDA)), or after FDA approved a full or partial Rx-to-OTC switch. Such medications were available to consumers without requiring a prescription because they were shown to be safe and effective without the supervision of a healthcare provider. These include, for example, medications that treat fever, pain, and allergies which are widely available at retail to the general public.

In contrast to a traditional Rx-to-OTC switch, where an approved drug (for full switches) or one or more of the approved conditions of use (for partial switches) is completely switched from prescription to nonprescription use, this new marketing pathway would allow the same drug with the same active ingredient to be sold simultaneously as a prescription drug and as a nonprescription drug with ACNU.

Stakeholder feedback on FDA's proposed rule

For years, FDA has considered various options to benefit public health by increasing the availability of drugs in OTC settings, from modernizing the process by which FDA regulates OTC monograph drugs through the CARES Act and facilitating the update and creation of monographs, to improving OTC drug labeling by making drug facts labels more understandable for consumers. In continuing these efforts, FDA published its proposed rule, “Nonprescription Drug Product with an Additional Condition for Nonprescription Use,” in June 2022, intending to broaden the types of nonprescription drugs available to consumers, particularly for chronic conditions.

The proposed rule garnered almost 200 comments, including stakeholder concerns on a range of issues. These included the applicability of the rule, the operationalization challenges of implementing “additional conditions,” simultaneous marketing of prescription and nonprescription products, and post-market reporting obligations.

Broad definition of “additional condition for nonprescription use”

Despite several comments calling for further specificity, FDA has maintained its intentionally broad definition of ACNU to provide applicants flexibility in the types and implementation of additional conditions that applicants may propose. In the newly added 21 CFR 201.67(b)(1), ACNU is defined 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 practitioner licensed by law to administer such drug if the applicant demonstrates and FDA determines that labeling alone is insufficient to ensure appropriate self-selection or appropriate actual use, or both.”

This flexibility affords applicants the ability to tailor the ACNU to a specific drug product.

Separate application for a nonprescription drug with an ACNU

The final rule requires approval of a separate NDA/ANDA application for a nonprescription drug product with an ACNU. This requirement applies even if there is already an approved application for prescription use of the drug product. FDA declined to remove this separate application requirement, as it is “essential to achieving the key policy goal of increasing consumer access to appropriate drug products,” (89 FR 105288, para. 126). The Agency’s rationale is that creating a new pathway to simultaneously market a prescription drug product along with a nonprescription drug option – with an ACNU – allows consumers to obtain the drug, even if they are not able to access or fulfill the ACNU.

On this topic, commenters expressed concerns that submitting a separate application is more burdensome and costly than submitting a supplement, suggesting that this requirement would therefore disincentivize innovation, limiting utilization of the ACNU pathway. However, FDA maintains that the ACNU pathway is estimated to increase manufacturer revenues by allowing the drug to be sold in nonprescription settings, and potentially attracting new-to-therapy consumers that are more likely to purchase nonprescription products. The Agency further pointed out that applicants submitting separate applications may cross-reference information from their approved prescription drug product application, if applicable, and would not need to duplicate certain studies already submitted in the latter application.

Regulatory framework of FDA's new rule

After extending the comment period and pushing the final rule target date back, the final rule was issued by FDA on December 23, 2024. This new rule adds regulations under 21 CFR Parts 201 and 314 with respect to applications for approval of nonprescription drug product with an ACNU, labeling, and postmarketing reports.

Applications

First, NDAs must include the following elements:

• A statement regarding the purpose of the ACNU
• Statement of necessity of the ACNU
• Description of how the ACNU ensures appropriate self-selection or appropriate actual use, or both
• Description of key elements of the ACNU
• Adequate data or other information that demonstrate the effect and necessity of the ACNU, and
• A description of the specific way(s) the ACNU is operationalized.

ANDAs for a nonprescription drug product with an ACNU, on the other hand, must meet the application content and format requirements under § 314.94, and must include:

• A statement regarding whether the purpose of the ACNU is to ensure appropriate self-selection or appropriate actual use, or both (and must be the same as the purpose of the ACNU for its reference listed drug (RLD))
• Information demonstrating that the key elements of the ACNU are the same as that of its RLD, and
• A description of the specific way(s) the ACNU is operationalized.

New product labeling

In addition to meeting all the current regulatory requirements for nonprescription drug products, labeling of nonprescription drugs with an ACNU must adhere to new content and formatting requirements set forth in the newly added 21 CFR 201.130 and 201.67. At a high level, the labeling must include:

1. Specific ACNU instructions in the drug facts panel and placed under specific sections depending on the purpose of the ACNU, and
2. The mandatory ACNU Statement on the principal display panel in a yellow background banner.

The regulations contain specific text to be used for both the ACNU instructions and ACNU statement, but also allows the applicant to use alternative text that has been approved by FDA. Failure to comply with these product labeling requirements would render the product misbranded.

Post-market reporting

In terms of post-market obligations, FDA requires sponsors to report any ACNU failure, ie, a failure in either the implementation or operationalization of an ACNU using the FDA Adverse Event Reporting System (FAERS). Examples may include a consumer accessing the product without fulfilling the ACNU, not being able to access the drug after fulfilling the ACNU, or experiencing a technical issue affecting consumer access to the ACNU. In addition, applicants must develop written procedures for the surveillance, receipt, evaluation, and reporting of such ACNU failures to FDA.

Impact and unanswered questions

Despite numerous comments on the docket, FDA kept a lot of the rule provisions intentionally broad with the goal of extending access to safe and effective treatments to the public, which leaves a number of concerns unanswered among various aspects, including around written procedures, the meaning of adequate data, and operationalizing additional conditions.

Written procedures

To minimize the burden and address expressed confusion of manufacturers, FDA modified the final rule to better align with existing postmarketing reporting requirements for adverse events (see § 314.80) by adding § 314.81(b)(3)(v)(B), requiring that applicants develop written procedures for the surveillance, receipt, evaluation, and reporting of ACNU failures to FDA. With this broad language, FDA stated that it intends to give applicants flexibility to develop procedures specific to each drug product, and potentially align with any existing procedures established with respect to § 314.80. The Agency anticipates that applicants could easily adapt any such written procedures to also include instances of an ACNU failure.

Adequate data for NDAs

In that same vein, stakeholders requested the FDA clarify the “adequate data” and “other information” requirements in new NDA applications to establish the effect and necessity of the proposed ACNU, as well as expectations for design, justification, and operation of an ACNU over the life of a product, such as how to sufficiently measure the effectiveness of an ACNU. In the final rule, FDA provides that data must show that consumers appropriately self-select or use the drug product safely and effectively, or both, with the ACNU. Since nonprescription products with an ACNU would be used by consumers from the general population without the supervision of a health practitioner, applicants are expected to include a wide range of subjects – including a representative proportion of so-called low-literacy subjects – in consumer studies, and to keep exclusion criteria to a minimum. (89 FR 105288, para. 161) As with the study design of any drug product, whether prescription or not, the study population should be representative of the population that is expected to use the nonprescription drug product.

Potential role of pharmacists in operationalizing ACNUs

Additionally, applicants must address in their applications how they will operationalize the ACNU such that patients can properly fulfill all ACNU requirements. Some commenters suggested that pharmacists could serve a key role in operationalizing ACNUs because they are the most accessible healthcare providers, especially in rural and underserved areas. Pharmacists could potentially serve as a reliable resource with respect to dosing and interactions, helping to ensure these nonprescription drugs are used appropriately. However, FDA rejected the idea of nonprescription drugs with an ACNU only being available after consultation with a pharmacist or where a licensed pharmacist is available to assist, explaining that this restriction would run counter to the rule objective of increasing options to develop and market drugs in OTC settings. (89 FR 105288, para. 100) Therefore, while FDA declined to require pharmacist involvement in dispensing nonprescription drugs with an ACNU, the rule does not preclude manufacturers from integrating such a consultation into their ACNUs to help mitigate risk of improper use, though this may be viewed as being inconsistent with the intent to sell products in OTC settings without the need for intervention by a licensed practitioner.

Looking ahead

As this final rule goes into effect in the coming weeks, DLA Piper is monitoring the developments in this space, given the flexibility FDA has baked into the regulations to advance efforts in expanding access to safe and effective treatment without requiring a prescription.

For information about nonprescription drugs with an ACNU and the implementation of this new rule, please contact the authors of this alert, or your DLA Piper contact.