The FDA Announces Proposed Rule: Nonprescription Drug Product with an Additional Condition for Nonprescription Use – June 28, 2022

The FDA is announcing the availability of the proposed rule Nonprescription Drug Product with an Additional Condition for Nonprescription Use (Docket No. FDA-2021-N-0862). The proposed rule is available for public comment for 120 days. Comments should be submitted to docket FDA-2021-N-0862 on Regulations.gov.

The proposed rule, if finalized, would establish requirements for a nonprescription drug product that has an additional condition for nonprescription use (ACNU). The proposed rule is intended to increase options for the development and marketing of safe and effective nonprescription drug products, which could improve public health by broadening the types of nonprescription drug products available to consumers.

 Need for the Proposed Rule

The FDA recognizes the potential benefit of providing consumers with access to additional types of nonprescription drug products, such as some drug products that are currently available only by prescription.

Currently, nonprescription drug products are limited to drugs that can be labeled with sufficient information for consumers to appropriately self-select and use the drug product. For certain drug products, limitations of labeling present challenges for adequate communication of information needed for consumers to appropriately self-select or use the drug product without the supervision of a healthcare provider.

 Nonprescription Drug with an Additional Condition for Nonprescription Use (ACNU)

Under the proposed rule, when labeling alone is not sufficient to ensure that the consumer can appropriately self-select, appropriately use, or both, a drug product correctly in a nonprescription setting, an applicant may submit an application proposing an ACNU that a consumer must successfully fulfill to obtain the nonprescription drug product with an ACNU.

An ACNU is 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. For example, an applicant could propose an ACNU that requires a consumer to respond with specific answers to a set of questions on a self-selection test available by either a mobile application (“app”) or an automated telephone response system in order to purchase the nonprescription drug product.

 Major Provisions of the Proposed Rule

• Establish the requirements for a new drug application (NDA) or abbreviated new drug application (ANDA) for a nonprescription drug product with an ACNU, including the requirement to submit a separate application for approval
• Clarify that an ACNU would constitute a meaningful difference between a prescription drug product and a nonprescription drug product containing the same active ingredient; allowing both products to be simultaneously marketed even if they do not have other meaningful differences
• Specify that the FDA would refuse to approve an NDA or ANDA for a nonprescription drug product with an ACNU if the application fails to meet the applicable requirements or if the applicant is unable to demonstrate that labeling alone is insufficient to ensure that the consumer can appropriately self-select or appropriately actually use, or both, a drug product correctly in a nonprescription setting
• Establish postmarketing reporting requirements for a nonprescription drug product with an ACNU

 Description of the Proposed Rule

A detailed description of each proposed section is provided in sections A through K as follows.

A.  Applicability

• The proposed rule would apply to NDAs and ANDAs for nonprescription drug products with an ACNU.
• Nonprescription drug products currently marketed under an approved application do not need an ACNU to ensure appropriate self-selection and appropriate actual use because FDA previously determined that labeling alone is sufficient for these drugs to be used safely and effectively without a prescription.
• The proposed rule would not apply to nonprescription drugs marketed under section 505G of the FD&C Act.

B.  Definitions (Proposed §§ 314.56(a) and 201.67(b))

 C,  Separate Application Required for a Nonprescription Drug Product with an ACNU (Proposed § 314.56(b))

The proposed rule would not require a nonprescription drug product with an ACNU to be first marketed as a prescription drug product. However, in cases where there is an approved prescription drug product, the proposed rule would establish the requirement that a nonprescription drug product with an ACNU cannot be approved through a supplement to the approved prescription application. Rather, an applicant must submit a separate application for a nonprescription drug product with an ACNU. Although a separate application would be required, an applicant may cross reference information in its approved NDA for the prescription product and would not need to duplicate studies already conducted for and submitted in its NDA for the prescription product.

A different applicant may submit an NDA under section 505(b)(2) of the FD&C Act, where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use. This is provided the 505(b)(2) applicant establishes that the relied upon NDA or literature is relevant to its nonprescription drug product with an ACNU and its application includes support for any differences between the applicant's proposed drug product and the listed drug on which the applicant is relying to demonstrate the safety and effectiveness of the proposed nonprescription drug product with an ACNU.

The approved prescription drug product and the approved nonprescription drug product with an ACNU are two different products and could be simultaneously marketed.

Requiring a separate application for the nonprescription drug product with an ACNU would enable continued marketing of the prescription product under the original NDA and would allow it to serve as an RLD for ANDAs for the prescription product.

 D.  Specific Requirements for an Application for a Nonprescription Drug Product with an ACNU (Proposed § 314.56(c))

The proposed rule would establish the specific NDA and ANDA requirements for a nonprescription drug product with an ACNU (see proposed § 314.56(c)).

 1. New Drug Application

In addition to applicable 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 must, when fulfilling the content and format requirements under § 314.50, include the following information about the ACNU in the application:

(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) (see proposed § 314.56(c)(1)(i));

(2) a statement of the necessity of the ACNU (see proposed § 314.56(c)(1)(ii));

(3) a description of how the ACNU ensures appropriate self-selection or appropriate actual use, or both (see proposed § 314.56(c)(1)(iii));

(4) a description of the key elements of the ACNU (see proposed § 314.56(c)(1)(iv));

(5) adequate data or other information that demonstrate the necessity of the ACNU to ensure appropriate self-selection or appropriate actual use, or both (see proposed § 314.56(c)(1)(v));

(6) adequate data or other information that demonstrate the effect of the ACNU on the appropriate self-selection or appropriate actual use, or both (see proposed § 314.56(c)(1)(vi)); and

(7) a description of the specific way the ACNU is operationalized (see proposed § 314.56(c)(1)(vii)).

The first four requirements for the ACNU in the application (see proposed § 314.56(c)(1)(i) through (iv)) and the last requirement for the ACNU in the application (see proposed § 314.56(c)(1)(vii) provide statements, including explanations, descriptions, and justifications, about the ACNU; the remaining requirements for the ACNU in the application (see proposed § 314.56(c)(1)(v) through (vi)) provide data or other information to support these statements.

 2. Abbreviated New Drug Application

Applicants may submit an ANDA referencing a listed drug that has been approved with an ACNU under section 505(c) of the FD&C Act and rely on FDA's previous finding that the RLD is safe and effective. The proposed rule would require that an ANDA for a nonprescription drug product with an ACNU must, when fulfilling the content and format requirements under § 314.94:

(1) state the purpose of the ACNU (the same purpose as the ACNU for the RLD),

(2) include information demonstrating that the key elements of the proposed ACNU are the same as the key elements of the ACNU for its RLD, and

(3) include information on the way the ANDA applicant intends to operationalize the proposed ACNU. If an applicant believes the ACNU is operationalized in the same way as the RLD (e.g., both use a mobile application), the ANDA must include information demonstrating the operationalization of the ACNU is the same as the RLD. If the ANDA proposes a different way to operationalize the proposed ACNU, the ANDA must include information to show that this different operationalization of the proposed ACNU achieves the same purpose as the ACNU for its RLD and the differences from the RLD are otherwise acceptable in an ANDA (see proposed § 314.56(c)(2)).

 E.  Nonprescription and Prescription Approval and Simultaneous Marketing (Proposed § 314.56(d))

Under this proposed rule, the additional condition(s) that allow a nonprescription drug product to be safely used without the supervision of a healthcare practitioner would be a meaningful difference between the prescription drug product and the nonprescription drug product with an ACNU. Therefore, under the proposed rule, a prescription drug product and a nonprescription drug product with an ACNU that contain the same active ingredient can be simultaneously marketed even if they do not have other meaningful differences, such as different indications or strengths (see proposed § 314.56(d)).

The proposed rule would require applicants seeking approval for the first time of an NDA for a nonprescription drug product with an ACNU to submit a separate NDA, rather than a supplement to an approved NDA (see proposed § 314.56(b)). The approval of a separate NDA would permit simultaneous marketing and access to the drug as both a prescription drug product and a nonprescription drug product with an ACNU.

 F.  Refusal to Approve an Application with an ACNU (Proposed §§ 314.125(b)(20) and 314.127(a)(15))

 G.  Other Postmarketing Reports (Proposed § 314.81(b)(3)(v))

The proposed rule would require NDA and ANDA applicants to report to FDA information concerning any incident of failure in the implementation of an ACNU using the FDA Adverse Event Reporting System (FAERS) (see proposed § 314.81(b)(3)(v)).

 H.  General Labeling Requirements (Proposed § 201.67(c))

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 those under part 201. Specifically, the applicant must comply with the existing content and format requirements for nonprescription drug products in § 201.66, known as the DFL (see proposed § 201.67(c)(1)).

 I.  Format Requirements for Required ACNU Statement (Proposed § 201.67(d))

 J.  Exemption from Adequate Directions for Use (Proposed § 201.130)

Consistent with the proposed definition of ACNU, a drug product can only be approved with an ACNU if the applicant demonstrates and FDA determines that labeling alone is insufficient to ensure appropriate self-selection or appropriate actual use, or both.

 The proposed rule would require that the following statement appear as the first direction under the heading “Directions” in the labeling, as required in § 201.66(c)(6): “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, phone number, or specific retail location] and [insert action to be taken by consumer]. Do not take this drug without completing this step.” (See proposed § 201.130(a)(1).) The applicant would include information to inform consumers where the additional condition would be found and explain the additional condition that the consumer must fulfill.

 The proposed rule would also require that the following statement appear on the immediate container label and, if one exists, the outside container or wrapper of the retail package: “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.” (See proposed § 201.130(a)(2).) This statement must meet the specific format requirements as specified in proposed § 201.67(d). The statement would remind the original purchaser and alert persons other than the original purchaser that these nonprescription drug products are not suitable for all individuals and should only be used after fulfilling the ACNU.

K.   Misbranding (Proposed § 201.67(e))

Author: Amit Chougule, RAC, ICON Plc.

Related Information

Federal Register Notices

• Nonprescription Drug Product with an Additional Condition for Nonprescription Use (Docket No. FDA-2021-N-0862)
• Draft Guidance: Innovative Approaches for Nonprescription Drug Products, July 2018