FDA is seeking comments on the proposal through October 26.

Background

In order for FDA to permit a drug to be sold OTC, a drug’s label must contain enough information for consumers to appropriately self-select and use the product without a doctor’s supervision; however, in this proposed rule, FDA explains that there are situations where labeling alone cannot adequately communicate the information needed for consumers to do this safely and effectively without the supervision of a physician. FDA’s new proposed rule, which applies to drugs that go through the NDA or abbreviated new drug application (ANDA) process, aims to allow more drugs to be marketed OTC even when the labeling is insufficient for independent self-selection and/or actual use, by requiring applicants to implement an Additional Condition for Nonprescription Use (ACNU), which the proposed rule defines as an additional condition to ensure appropriate self-selection or appropriate actual use, or both, by consumers without the supervision of a health care practitioner.

The proposed rule comes more than ten years after the agency described this OTC+ idea as a way to make more drugs available OTC, then-dubbed “novel switches.” The new proposed rule would establish additional application requirements, labeling requirements, and postmarketing reporting requirements for a nonprescription drug product with an ACNU.

Observations

• In some ways, the ACNU can be seen as FDA allowing for questionnaires and modern technology instead of relying exclusively on physicians as the gatekeepers for the selection of certain pharmaceuticals. Under the statute, FDA cannot approve a drug for nonprescription use if the supervision of a healthcare practitioner is needed to ensure proper self-selection and actual use of the drug. However, the proposed rule would allow a questionnaire to be used to determine a consumer’s “disease-specific risk” where consumers could not do this on their own without a physician’s intervention, and such drugs could be made available without a physician’s prescription. In the past, FDA had taken the position that certain diseases or conditions are not amenable to lay diagnosis and therefore cannot have adequate directions for nonprescription use. The proposed rule, however, does not include the ability for self-diagnosis as one of the conditions for approving an OTC drug supported by an appropriate ACNU.

• Without much explanation, the proposal rule excludes the application of ACNUs to OTC monograph drug products, including those that FDA authorizes for marketing in response to an OTC drug Monograph Order Requests (OMOR) under the monograph reform legislation enacted as part of the CARES Act. The proposed rule specifically prohibits submitting such an OMOR for a drug with an ACNU. We think FDA should reconsider this restriction because an ACNU could be among the conditions of use for which an OTC drug could be demonstrated to be Generally Recognized as Safe and Effective (GRASE) and lawfully authorized for use without a new drug application.

• The proposed rule would allow a generic version of a Reference Listed Drug (RLD) with an ACNU to be approved even if the generic version “operationalized” the ACNU in a different way but still achieved the same purpose and if the differences are otherwise acceptable to FDA. This might allow for different technologies to screen patients, e.g., if the NDA applicant operationalized its ACNUs “using proprietary means.”

ACNU application requirements

Under the proposal rule, an NDA or ANDA applicant would be required to submit a separate application for the approval of a nonprescription drug product with an ACNU, rather than a supplement to an application approved as a prescription drug product. The proposed rule clarifies that an ACNU would constitute a “meaningful difference” between a prescription drug product and a nonprescription drug product that allows the nonprescription drug product to be used safely without the supervision of a health care practitioner licensed by law to administer the drug. For instance, a prescription and nonprescription version of a drug product could have the same active ingredient, dosage form, strength, route of administration, and indication, but one would be made available as a nonprescription drug product with an ACNU, and the other product made available, or remain available, only by prescription. This represents a significant shift from FDA’s current approach, which generally prevents simultaneous marketing of Rx and OTC version of drugs without clinically meaningful differences in the active ingredient, dosage form, strength, route of administration, or indication.

In addition to existing application requirements, NDA applicants would also be required to describe the ACNU and submit information to support the ACNU. Specifically, the proposed rule would require that an NDA for a nonprescription drug product with an ACNU include the following information about the ACNU:

1. A statement regarding the purpose of the ACNU (i.e., appropriate self-selection or appropriate actual use, or both, by consumers of the nonprescription drug product without the supervision of a health care practitioner);
2. A statement of the necessity of the ACNU;
3. A description of how the ACNU ensures appropriate self-selection or appropriate actual use, or both;
4. A description of the key elements of the ACNU;
5. Adequate data or other information that demonstrate the necessity of the ACNU to ensure appropriate self-selection or appropriate actual use, or both;
6. Adequate data or other information that demonstrate the effect of the ACNU on the appropriate self-selection or appropriate actual use, or both; and,
7. A description of the specific way the ACNU is operationalized.

The proposed rule provides a fictitious example of a nonprescription drug product with an ACNU that offers a simplified illustration of a product that may potentially be considered under this proposed regulatory framework.

FDA says its proposed definition for an ACNU is “intentionally broad,” in order to give applicants flexibility around the types of conditions they propose and how they implement those conditions. The proposed rule offers these examples:

• An applicant could propose an ACNU that requires consumers to answer a set of questions on a self-selection test, available by either a mobile application or an automated telephone response system, before they can purchase the nonprescription drug.

• A drug sponsor could propose to FDA that consumers be required to review the drug’s labeling through text, images, or video that describes how to use the drug, with the consumers responding to a set of questions to confirm they understand the instructions.

ACNU labeling requirements

The “Drug Facts Labeling” (DFL) on nonprescription drug packaging is the primary source for information about a product’s intended use, directions for use, and important safety information, all designed in understandable language that is tested for consumer comprehension. The proposed rule would clarify that a nonprescription drug product with an ACNU must comply with all applicable regulatory requirements for nonprescription drug products, including the existing content and format requirements for the DFL.

In addition to those existing requirements, the proposed rule would require the labeling for all nonprescription drug products approved with an ACNU to include a statement directing consumers where to go for more information on the drug’s safety or proper use (e.g., a website or specific retail location). The statement must also alert persons other than the original purchaser that the product is not suitable for all individuals, and that consumers should carefully examine any labeling accompanying the nonprescription product with an ACNU before using the product. The proposed rule outlines with specificity the format requirements for this required ACNU statement, which must be in bolded black type with a yellow background. We believe this is the first color requirement for the Drug Facts Label.

All labels and other written, printed, or graphic matter that are necessary to effectively implement the ACNU (e.g., questions associated with a self-selection aid) would be considered to accompany the nonprescription drug product and, therefore, would be regulated as “labeling” under the Federal Food, Drug, and Cosmetic Act. Accordingly, the proposed rule says ACNU applicants should describe in their applications the process for ensuring consumers have access to the approved labeling prior to fulfilling the ACNU.

The failure of a nonprescription drug product approved with an ACNU to bear the required labeling statements described in the proposal would constitute a failure to reveal material facts about the product, and would be deemed to misbrand the product.

ACNU postmarket requirements

Under the proposed rule, NDA and ANDA applicants would be required to submit a report with information concerning any incident of failure in the implementation of an ACNU using the FDA Adverse Event Reporting System (FAERS). A failure in implementation of an ACNU is broadly applied to cover a deviation in implementation that “may cause or lead to inappropriate medication use or consumer harm,” including the following circumstances:

1. The consumer accessed or used the drug product without successfully fulfilling the ACNU.

2. The consumer successfully fulfilled the ACNU but could not access or appropriately use the drug product in the nonprescription setting.

3. The consumer was unable to make an attempt to fulfill the ACNU due to systematic, technological, or mechanical errors in the implementation of the ACNU.

In addition, if an applicant receives information of an adverse event associated with a previously submitted report in FAERS of a failure in implementation of an ACNU, a follow-up report must be submitted to FAERS as an individual case safety report (ICSR) of an adverse event.

A report to FAERS for a failure in implementation of an ACNU would be submitted when the applicant has at least the minimum dataset for a failure in implementation, no later than 15 calendar days from the date when the applicant has acquired the minimum dataset for a report of a failure in implementation of an ACNU. Further, if an applicant obtains or otherwise receives any new information about previously submitted reports about the failure in implementation of an ACNU, the applicant would be required to investigate the new information, assess the relationship or impact of the new information on the initial report, and submit follow-up reports as soon as possible, and also within 15 days.

FDA notes that to meet these reporting requirements, applicants will likely need quality assurance systems in place to capture instances where failures in implementation of an ACNU occur. The agency is proposing to require an applicant to maintain for 10 years the records of all reports of failures in implementations of an ACNU and associated adverse events known to the applicant.

Next steps

FDA is seeking comments on the proposal through October 26, 2022, and specifically invites comments on the content of statements advising consumers to complete the ACNUs present on drug labeling, and the benefits/burdens of filing reports related to failures in implementing ACNUs in settings due to a single point of failure for multiple consumers.

Pharmaceutical and biotechnology companies will want to consider whether their products may be eligible for OTC approval under the ACNU pathway, which we see as being particularly relevant for treatments for chronic conditions such as hyperlipidemia, diabetes, and hypertension.

If you have any questions on the proposed rule, switching prescription drugs to over-the-counter status, or may wish to submit a comment, please contact any of the authors of this alert or the Hogan Lovells attorney with whom you generally work.

Authored by Heidi Gertner and David Horowitz