FDA Proposes Rule on Use of Innovative Technologies and Other Conditions of Use to Expand Options for Nonprescription Drug Products

On June 28, 2022, the US Food and Drug Administration (FDA) published a much-anticipated proposed regulation (Proposed Rule)¹ to establish parameters for nonprescription drug products with additional conditions for nonprescription use, or “ACNU”–such as apps, secure websites, automated telephone response systems, or requiring consumers to navigate  videos and associated tests. If finalized, the rule would establish requirements for nonprescription drug products with ACNUs that applicants would be required to implement to ensure appropriate self-selection and/or appropriate use by consumers without the supervision of a healthcare practitioner. In practice, providing applicants the option to implement ACNUs would facilitate the switching of new categories of prescription drug products to nonprescription status.

The Proposed Rule is intended to increase the options for safe and effective nonprescription drug products, broadening the types of such drugs available to consumers and thereby improving public health by mitigating the current undertreatment of many common diseases and conditions. Comments on the proposal are due to FDA by October 26, 2022 (Docket No. FDA-2021-N-0862). This Advisory provides a brief overview of the current regulatory framework, background regarding FDA’s efforts to expand the number of drug products accessible to consumers without a prescription, and a summary of key aspects of the proposed rule.

Current Framework

Most drug products must be dispensed pursuant to a physician’s prescription because they are not safe to use except under the supervision of a licensed healthcare practitioner because of toxicity or other potential to cause harmful effects, the method of use, or collateral measures necessary for use.² Nonprescription drug products are limited to drugs that can be labeled with sufficient information to enable consumers to appropriately self-select (i.e., decide whether or not to use the product) without the supervision of a healthcare practitioner and appropriately self-treat their condition.

There are currently two regulatory pathways to bring a nonprescription drug product to market in the United States: over-the-counter (OTC) drug monographs and the new drug application (NDA) process. Under the OTC monograph system, a nonprescription drug may be marketed without an approved NDA or abbreviated new drug application (ANDA) if the nonprescription drug product is deemed to be generally recognized as safe and effective (GRASE) under section 505G³ of the Federal Food Drug and Cosmetics Act (FD&C Act), meaning the drug product is in conformity with the requirements for nonprescription use of a final monograph or tentative final monograph. Under the NDA process, an applicant may submit an NDA or supplement for a nonprescription drug product using the pathways described in section 505(b)(1) or (2)⁴ of the FD&C Act to market a new drug product. Such products are generally first approved for prescription use and then switched to OTC status in whole or in part (e.g., different dosing) on the basis of data demonstrating that consumers can appropriately self-select and use the product safely and effectively without supervision by a healthcare practitioner.

Background

Many stakeholders have been frustrated by the slow pace of development of OTC products, citing the difficulties of meeting standards for switching to OTC status without use of new technologies and non-physician interventions–i.e., conditions of use–that would address specific self-selection and treatment issues, such as drug contraindications and other concerns. Recognizing this stagnation, FDA held a public hearing in 2012 to (1) seek input from stakeholders on a potential new paradigm where FDA would approve some drug products for nonprescription use with certain conditions where the product would otherwise require a prescription and (2) obtain information and comments on the feasibility of this paradigm and its potential benefits and costs.⁵ At the hearing, FDA received comments on a broad range of topics, including access to care, medication nonadherence, use of diagnostic aids and technologies as potential conditions for safe use, and potential effects on healthcare, healthcare costs, and medical conditions and diseases. This hearing was the first step in what FDA would later dub the Nonprescription Drug Safe Use Regulatory Expansion (NSURE) initiative.

Following this public hearing, FDA worked with the Brookings Institution to convene a series of expert workshops to seek stakeholder feedback on developing innovative and practical approaches for consumers to self-select nonprescription drug products appropriately and maintain safe and effective use of such products despite the lack of practitioner involvement. The Brookings Institution held three such workshops over the course of 2012 and 2013.⁶

In 2018, FDA published a draft guidance entitled “Innovative Approaches for Nonprescription Drug Products,” in which the Agency describes two innovative approaches for applicants to consider applying where the drug facts labeling (DFL) alone is not sufficient to ensure that a drug product can be used safely and effectively in a nonprescription setting.⁷ These two approaches are (1) the development and use of additional labeling, in addition to the DFL, to better inform consumers how to safely and effectively use the nonprescription product, and (2) the implementation of additional conditions for safe and effective use to allow consumers to appropriately self-select and use the nonprescription product. The June 2022 Proposed Rule would, if finalized, implement a formalized version of the “additional conditions for safe and effective use” approach first described by FDA in the 2018 draft guidance.

This is not the only important reform emerging in the nonprescription drug area. In March, 2020, the Over-the-Counter Monograph Safety, Innovation, and Reform Act (OTC Monograph Reform Act–see our Advisory here) was enacted as part of the Coronavirus Aid, Relief, and Economic Security Act (CARES Act). Most significantly, the OTC Monograph Reform Act introduced an administrative order process as a replacement for the cumbersome and time-intensive notice-and-comment rulemaking procedures as the mechanism by which the HHS Secretary can propose, finalize, or change OTC drug monographs.⁸ The Act also deemed existing final monographs and tentative final monographs final administrative orders able to be amended, revoked, or otherwise modified in accordance with the same procedures. Administrative orders may be issued by the HHS Secretary’s own initiative or at the request of a requestor, such as a drug manufacturer. While the OTC Monograph Reform Act significantly altered the federal government’s approach to regulating OTC drug products and made the process of developing OTC monographs less burdensome, it did not facilitate Rx-to-OTC switches.

Summary of Major Provisions of the Proposed Rule

The Proposed Rule, if finalized, would establish the requirements for a nonprescription drug product with ACNU, including additional application requirements for an NDA or ANDA, labeling requirements, and postmarketing reporting requirements. The evidentiary standards under the FD&C Act and current FDA regulations for demonstrating safety and effectiveness would continue to apply to nonprescription drug products approved with an ACNU. As defined in the Proposed Rule, a nonprescription drug product with an ACNU is “a drug product that could be marketed without a prescription if an applicant implements an additional condition to ensure appropriate self-selection or appropriate actual use, or both, by consumers without the supervision of a healthcare practitioner.”⁹ According to FDA, the Proposed Rule is “intended to increase options for applicants to develop and market safe and effective nonprescription drug products, which could improve public health by broadening the types of nonprescription drug products available to consumers.”¹⁰ The Proposed Rule does not apply to nonprescription drugs currently marketed under an approved application or nonprescription drugs marketed under section 505G of the FD&C Act, which includes OTC monograph products.

Since a drug product approved with an ACNU is a product for which labeling alone is insufficient to ensure appropriate self-selection or appropriate actual use, or both, it is not possible for these products to comply with the adequate directions for use provision under section 502(f)(1) of the FD&C Act. Therefore, the Proposed Rule adds an exemption for human nonprescription drug products approved with an ACNU from the requirement in section 502(f)(1) of the FD&C Act for drug products to have labeling that provides adequate directions for use, provided that the product contains the labeling required under proposed § 201.130(a) and the ACNU is implemented by the applicant as approved by FDA in the application.¹¹ Under the Proposed Rule, “[i]f a nonprescription drug product with an ACNU is made available to consumers without the labeling specified in proposed § 201.130(a) or the ACNU is not implemented by the applicant as approved by FDA in the application, the drug product would be misbranded under section 502(f)(1) of the FD&C Act.”¹² Additionally, if the nonprescription drug product with an ACNU is made available to consumers without the specific required labeling, the product would also be misbranded under section 502(a) of the FD&C Act.¹³ Making a nonprescription drug product approved with an ACNU available to consumers without the ACNU would make the product an unapproved new drug in violation of sections 301(d) and 505(a) of the FD&C Act.¹⁴

Below we discuss key provisions governing products with an ACNU in more detail, including the proposed definition for an ACNU, the proposed ACNU application process and requirements, and the proposed labeling and formatting requirements.

Additional Condition for Nonprescription Use Defined (Proposed 21 C.F.R. §§ 314.56(a) and 201.67(b))

The Proposed Rule defines the term “additional condition for nonprescription use” 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.”¹⁵ FDA emphasized that the definition for an ACNU is “intentionally broad to give applicants flexibility regarding the types of additional conditions applicants may propose and how those additional conditions can be implemented.”¹⁶

The Proposed Rule includes examples of ACNU, including requiring consumers to respond with specific answers to questions on self-selection tests made available through an app, secured website, or automated telephone response system or requiring consumers to view labeling through text or images in a video that describe how to appropriately use the nonprescription drug product with questions to confirm understanding.¹⁷ For example, consumers could complete a questionnaire on a secure website to determine whether a drug is appropriate for the consumer and after answering the questions, the website calculates the risk score for a serious side effect, allowing a consumer with an acceptable disease-specific risk score to purchase the drug on the applicant’s secure website or purchase the drug at a retail site after presenting a barcoded voucher.¹⁸ FDA stated in the preamble to the Proposed Rule that it “would generally expect any technology that is used to operationalize an ACNU to be easily usable to the majority of consumers.”¹⁹

Nonprescription Drug Product With an ACNU Application Process and Requirements

Separate Application Required for a Nonprescription Drug Product With an ACNU (Proposed 21 C.F.R. § 314.56(b))

While the Proposed Rule does not require a nonprescription drug with an ACNU to be first marketed as a prescription drug product, it requires applicants with a previously approved prescription drug product to submit a separate application for the approval of a nonprescription drug product with an ACNU, not a supplement to a previously approved prescription drug product application.²⁰ The prescription drug product under the original NDA can continue to be marketed simultaneously and used as a reference listed drug (RLD) for ANDAs for the prescription product. ²¹ However, an applicant with an approved nonprescription drug product with an ACNU may choose to discontinue the prescription product. Generic versions of discontinued NDA prescription drug products would still be eligible for approval relying on the discontinued NDA if FDA determines that the NDA for the prescription product was not discontinued for reasons of safety or effectiveness.²² Under the Proposed Rule, a different applicant may submit an NDA even if some of the information required for approval is derived from studies by or for the applicant or if the applicant does not have a right of reference or use.²³

The Proposed Rule also requires applicants with an existing ANDA approved as a prescription drug product to submit a separate application for the approval of an ANDA to market a nonprescription drug product with an ACNU.²⁴ However, the Proposed Rule would allow an applicant seeking approval of an ANDA to market a nonprescription drug product with an ACNU to submit an ANDA referencing a nonprescription drug product with an ACNU previously approved under an NDA and rely on FDA’s finding that the RLD is safe and effective.²⁵

Specific Requirements for an Application for a Nonprescription Drug Product With an ACNU (Proposed 21 C.F.R. § 314.56(c))

The Proposed Rule would require that applicants describe and submit information to support the ACNU. 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 healthcare practitioner);²⁶
2. a statement of the necessity of the ACNU;²⁷
3. a description of how the ACNU ensures appropriate self-selection or appropriate actual use, or both;²⁸
4. a description of the key elements of the ACNU;²⁹
5. adequate data or other information that demonstrate the necessity of the ACNU to ensure appropriate self-selection or appropriate actual use, or both;³⁰
6. adequate data or other information that demonstrate the effect of the ACNU on the appropriate self-selection or appropriate actual use, or both;³¹ and
7. a description of the specific way the ACNU is operationalized.³²

FDA would require that an ANDA for a nonprescription drug product with an ACNU is pharmaceutically equivalent and bioequivalent to its RLD and has the same clinical effect and safety profile as its RLD when administered to patients under the conditions specified in the labeling.³³ The Proposed Rule would require that an ANDA for a nonprescription drug product with an ACNU referencing a listed drug that has been approved with an ACNU include the following information about the ACNU:

1. a statement regarding the purpose of the ACNU (the same purpose as the ACNU for the RLD);³⁴
2. information demonstrating that the key elements of the proposed ACNU are the same as the key elements of the ACNU for its RLD;³⁵ and
3. information on the way the ANDA applicant intends to operationalize the proposed ACNU.³⁶

Refusal to Approve an Application With an ACNU (Proposed 21 C.F.R. §§ 314.125(b)(20) and 314.127(a)(15))

Under the Proposed Rule, FDA would refuse to approve an NDA or ANDA for a nonprescription drug product with an ACNU if the NDA or ANDA fails to meet the requirements in § 314.56 applicable to NDAs³⁷ or ANDAs.³⁸ FDA would also refuse to approve an application for a nonprescription drug product with an ACNU if “FDA has determined that the applicant failed to demonstrate that labeling is insufficient to ensure consumers' appropriate self-selection or appropriate actual use, or both, of the nonprescription drug product without the supervision of a healthcare practitioner or if the applicant failed to demonstrate that its proposed ACNU is adequate to ensure appropriate self-selection or appropriate actual use, or both, by consumers without the supervision of a healthcare practitioner.”³⁹ FDA may also refuse to approve an NDA with an ACNU if the proposed labeling does not comply with part 201 or refuse to approve an ANDA with an ACNU if its labeling is not the same as the labeling of its RLD, with certain permitted exceptions.⁴⁰

Required Postmarketing Reporting (Proposed 21 C.F.R. § 314.81(b)(3)(v))

The Proposed Rule would also establish postmarketing reporting requirements for a nonprescription drug product with an ACNU, including mandatory reports to the FDA Adverse Event Reporting System (FAERS) with information about failures in implementation of an ACNU, including, for example, a consumer gaining assess to a drug product without fulfilling all necessary conditions or a consumer who fulfilled the conditions being unable to access the product.⁴¹

General Labeling Requirements (Proposed 21 C.F.R. § 201.67(c)) and Format Requirements for Required ACNU Statement (Proposed 21 C.F.R. § 201.67(d))

The Proposed Rule would still require a nonprescription drug product with an ACNU to comply with all applicable regulatory requirements for nonprescription drug products, including the current format and content requirements for nonprescription drug product labeling under § 201.66, which requires a Drug Facts Label, and the new required statements specified in § 201.130(a).⁴² The Proposed Rule would require the labeling for all nonprescription drug products approved with an ACNU to include: “To check if this drug is safe for you, go to [insert where or how consumers can find information about the ACNU; for example, applicant's website, applicant's phone number, or specific retail location] and [insert action to be taken by consumer]. Do not take this drug without completing this step.” as the first statement under the heading “Directions.”⁴³

The Proposed Rule would also requires the statement “You must complete an extra step to see if this drug is safe for you before you use it. Do not take this drug without completing this step. See the Drug Facts labeling for more information.” to appear on the immediate container label and, if one exists, the outside container or wrapper of the retail package.⁴⁴ Under the Proposed Rule, the statement must be visible to consumers at the time of purchase and use, appear on the principal display panel,⁴⁵ and appear on the immediate container surface that the consumer is most likely to view when seeking information about the drug product.⁴⁶ Further, the Proposed Rule would require that the statement be prominently presented in boldface and black type in a high contrast yellow background banner with no other information and a font size at least 25 percent as large as the font size of the largest printed words on the container surface.⁴⁷

FDA proposed that “[a]ll 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 meet the definition of labeling.”⁴⁸

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The Proposed Rule would expand access to nonprescription drug products, potentially benefitting consumers, applicants, the government, and private insurers. If FDA finalizes the rule, we can anticipate seeing proliferation of new models for nonprescription drugs, including use of innovative approaches to meeting self-selections, and entirely new therapeutic categories of self-treatment. Stakeholders interested in emerging strategies for consumer drug product innovation should consider commenting on the proposed regulatory framework.

*Samuel Williams contributed to this Advisory. Mr. Williams is a graduate of the University of Michigan Law School and is employed at Arnold & Porter's Washington, DC office. He is not admitted to the practice of law.

© Arnold & Porter Kaye Scholer LLP 2022 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.