FDA Releases New Guidance Documents On When To Submit An ANDA Or 505(b)(2) Application And On Therapeutic Equivalence Evaluations

Last week, FDA issued two new guidance documents. The first was a revision to the draft guidance document describing when to submit an ANDA or 505(b)(2) application. It provides sponsors with greater clarity regarding when it is appropriate to use each of the abbreviated approval pathways available under the Federal Food, Drug, and Cosmetic Act. The document builds upon the agency's transparency initiative by filling procedural gaps that existed in the previous iteration of the guidance and by drawing clearer connections to existing guidance issued by FDA.

The second document is FDA's final guidance on the evaluation of therapeutic equivalence. It offers sponsors deeper insight into how the agency assigns therapeutic equivalence ratings, including the process for securing an A-rating for 505(b)(2) products.

Determining whether to submit an ANDA or 505(b)(2) application

Although both 505(b)(2) and 505(j) applications provide abbreviated approval pathways, they are used for different situations and have different approval standards. A 505(b)(2) application is a type of NDA and thus is approved based on full clinical reports showing that the drug is safe and effective. In contrast to a 505(b)(1) NDA, a 505(b)(2) application relies, at least in part, on reports in scientific literature regarding another drug, or on the agency's finding of safety or effectiveness of a previously approved listed drug for which the applicant does not have a right of reference. Products approved under section 505(b)(2) may be significantly different from the drug they reference, including in their labeling and conditions of use, and yet may still rely on FDA's prior approval of a listed drug or multiple listed drugs, and/or scientific literature, when scientifically appropriate. Generally, a 505(b)(2) application must bridge to the listed drug relied on for approval and support any differences with new data, which may include preclinical and/or clinical studies, that are necessary to demonstrate the safety and effectiveness of the new product.

In contrast, section 505(j) is the abbreviated pathway used for the typical generic drug. An abbreviated new drug application (ANDA) submitted under 505(j) is approved based on a showing of sameness to the reference listed drug (RLD). Specifically, an ANDA product must be pharmaceutically equivalent to the RLD (i.e., same strength, dosage form, route of administration, and active ingredient), have the same labeling as the RLD (with certain exceptions), and be bioequivalent to the RLD (i.e., same rate and extent of absorption at the site of action). In addition, there are formulation sameness standards for some types of products, such as parenterals. The sameness showing allows a generic applicant to rely entirely on FDA's previous finding of safety and effectiveness for the RLD rather than to independently demonstrate the safety and effectiveness of its proposed drug.

A principal benefit of an ANDA is to receive an A-rating as therapeutically equivalent in the Orange Book upon approval. With an A-rating, the generic drug product generally would be eligible to be substituted for the RLD at the pharmacy level. Although FDA is not precluded from assigning an A-rating to a 505(b)(2) product if it is pharmaceutically equivalent and bioequivalent to a listed drug, the A-rating is not automatic.

Despite there being material differences between ANDA and 505(b)(2) applications, it can be unclear which pathway is most appropriate. The updated draft guidance clarifies instances in which sponsors should consider pursuing an ANDA or 505(b)(2) application. Here we focus on what is new and notable. 

Duplicate drugs — when a 505(b)(2) may be appropriate

One of the most significant updates in the new draft guidance concerns when it is appropriate to submit a 505(b)(2) for a duplicate drug — defined as “a drug product that has the same active ingredient(s), dosage form, strength, route of administration, and conditions of use as a listed drug.”

As a general matter, FDA will refuse to file a 505(b)(2) application that is a duplicate of a listed drug and that is eligible for approval as an ANDA. In some instances, the studies typically expected to support an ANDA cannot be conducted because the RLD and reference standard have been withdrawn and there are no other drug products listed in the Active Section of the Orange Book that can be used as a reference standard for that RLD. The updated draft guidance explains that this is not automatic justification for submitting a 505(b)(2) application. Rather, it is recommended that sponsors, with the help of the Office of Generic Drugs (OGD), first consider alternative methods of establishing bioequivalence that are adequate to support an ANDA.

If FDA determines there are no acceptable alternatives to establish bioequivalence between a duplicate and the RLD, circumstances do exist in which submitting a 505(b)(2) application is appropriate. To determine when that is the case, the draft guidance now directs applicants to discuss their proposals with the appropriate review division of the Office of New Drugs (OND). That discussion should explain how the sponsor intends to bridge the proposed drug product to the listed drug, for example, by relying on published literature. 

ANDA waivers for formulation differences in certain drug products

The revised guidance also discusses circumstances in which FDA may waive the ANDA formulation requirements for parenteral, ophthalmic, and otic products. This clarifies FDA's pre-existing waiver authority and incorporates the policy set forth in the guidance, Considerations for Waiver Requests for pH Adjusters in Generic Drug Products Intended for Parenteral, Ophthalmic, or Otic Use.

Under section 505(j), a generic drug generally is allowed to have different inactive ingredients than the RLD. However, FDA regulations state that for some types of generic drugs (e.g., parenteral, ophthalmic, and otic drugs), sponsors are limited in their ability to make changes to the inactive ingredients of a formulation, and generally must have the same inactive ingredients as the RLD (though may still differ in certain excepted categories of excipients called “exception excipients”).

For example, a sponsor of a parenteral product that differs from the RLD in composition of the inactive ingredients would generally be required to submit a 505(b)(2) NDA rather that an ANDA. But in this new guidance, and the previous guidance on waiver requests for pH adjusters, FDA has indicated that it may use its longstanding waiver authority under the regulations (21 CFR 314.90, 314.99(b)) to allow formulation differences outside the traditional exception excipients provided there is suitable justification from the sponsor.

Evaluation of therapeutic equivalence for products approved under section 505(b)(2)

The final guidance provides an overview of therapeutic equivalence evaluations, including explaining when FDA evaluates therapeutic equivalence for 505(b)(2) NDA products and assigning therapeutic equivalence (TE) codes in the Orange Book. The guidance also includes a FAQ section. 

For ANDA products, FDA assigns TE ratings automatically upon approval. FDA will not routinely conduct TE evaluations for “standalone” 505(b)(1) NDAs or 505(b)(2) NDAs.

However, under the statute as amended in 2022, FDA is required at the sponsor's request to undertake TE evaluations for certain 505(b)(2) products. Namely, products for parenteral, otic, or ophthalmic administration when the sole difference from the listed drug is a difference in inactive ingredients not permitted under 505(j). Sponsors of 505(b)(2) NDAs may also use the citizen petition process to seek a TE evaluation where the drug product may otherwise meet the requirements for a TE rating while still being ineligible for approval under 505(j).

The guidance also describes differences between the 505(b)(2) and the listed drug that may preclude FDA from making a finding of TE. For example, the final guidance indicates that labeling differences beyond those permitted in an ANDA would generally preclude an A-rating. Similarly, differences in formulation, presentation, or other differences that give rise to a different clinical effect or safety profile when administered to patients under the conditions specified in the labeling, may also preclude an A-rating. For example, a difference in the device constituent part of a drug-device combination product may give rise to human factors, useability, and labeling issues that make an A-rating inappropriate.

Conclusion

The draft ANDA or 505(b)(2) application guidance document provides meaningful insight into FDA's current thinking on issues that routinely arise during abbreviated application strategy, including when a duplicate product may be appropriate for submission as a 505(b)(2) application and when applicants may seek waivers from certain ANDA formulation requirements.

The final TE guidance offers sponsors expanded insight into FDA's TE framework, particularly for 505(b)(2) products.