USFDA Draft Guidance: Determining Whether to Submit an ANDA or a 505(b)(2) Application

Sharan Murugan
1 hour ago
7 min read

Choosing the appropriate abbreviated approval pathway is an important consideration when developing a drug product for submission to the U.S. Food and Drug Administration (FDA). The pathway selected determines the type of information and data that can be used to support the application.

The FDA has published the Guidance for Industry: Determining Whether to Submit an ANDA or a 505(b)(2) Application, which provides recommendations to help applicants determine whether a proposed drug product is more appropriately submitted as an Abbreviated New Drug Application (ANDA) under section 505(j) or as a 505(b)(2) application under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The August 2026 document is a draft guidance that revises the May 2019 guidance and, when finalized, will replace the 2019 version.

Understanding the Two Abbreviated Approval Pathways

The guidance explains that an ANDA is used for a drug product that is a duplicate of a previously approved drug product, known as the Reference Listed Drug (RLD). An ANDA relies on FDA's finding that the RLD is safe and effective.

A proposed generic drug product generally needs to have the same active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling as the RLD, with certain permitted differences. The application must also contain information demonstrating bioequivalence and adequate information to ensure the identity, strength, quality, and purity of the drug product.

A 505(b)(2) application is an NDA that contains full reports of investigations of safety and effectiveness, 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 pathway provides greater flexibility for differences between the proposed drug product and the listed drug.

When an ANDA May Be Appropriate

An ANDA may be appropriate when the proposed drug product meets the applicable requirements for a generic drug and can rely on the FDA's finding of safety and effectiveness for the RLD.

The proposed product generally needs to demonstrate the required sameness to the RLD and establish bioequivalence. Certain differences may be permitted, including some differences in inactive ingredients, labeling, or container closure systems, provided the applicable requirements are met and clinical investigations are not necessary to establish the safety or effectiveness of the proposed drug product.

If clinical investigation is necessary to establish the safety or effectiveness of the proposed product, the information generally goes beyond the scope of what may be relied upon for an ANDA.

When a 505(b)(2) Application May Be Appropriate

A 505(b)(2) application may be appropriate when the proposed drug product does not meet the requirements for an ANDA and relies, at least in part, on information from sources other than investigations conducted by or for the applicant.

The applicant may rely on FDA's finding of safety and/or effectiveness for a listed drug to the extent that the proposed product shares relevant characteristics with the listed drug. The applicant is expected to establish a scientific bridge, such as through comparative bioavailability data, to support the scientific basis for relying on the listed drug.

When the proposed product differs from the listed drug, the 505(b)(2) application must contain sufficient data to support those differences.

Duplicates and the Choice of Pathway

The guidance places particular emphasis on duplicate drug products.

FDA generally will refuse to file a 505(b)(2) application for a drug product that is a duplicate of a listed drug and is eligible for approval under section 505(j). Therefore, a product that meets the requirements for an ANDA should generally not be submitted through the 505(b)(2) pathway simply because it has certain differences from the listed drug.

The guidance also describes circumstances involving discontinued listed drugs and reference standards where comparative studies needed to demonstrate bioequivalence cannot be conducted. In such situations, applicants may consider whether alternative methods can establish bioequivalence and are encouraged to discuss the proposed approach with the Office of Generic Drugs (OGD) before submission.

Petitioned ANDAs

Certain differences between a proposed generic drug product and its RLD may be permitted through an approved suitability petition.

A suitability petition can request permission to submit an ANDA for a product that differs from the RLD in route of administration, dosage form, or strength, or has one different active ingredient in a fixed-combination drug product.

An ANDA based on a suitability petition that is pending or has been denied will not be received for review because the application does not have a legal basis for submission. The guidance also explains circumstances in which an approved suitability petition can no longer be used as the basis for an ANDA after an NDA is approved for the change described in the petition.

Bundling Multiple Drug Products

In some situations, an applicant may seek approval for multiple drug products containing the same active ingredient or ingredients, where some products could qualify for the 505(j) pathway and others for the 505(b)(2) pathway.

The FDA has permitted applicants, in certain circumstances, to submit a single 505(b)(2) application for multiple drug products that can be bundled into one NDA.

For example, when multiple strengths of the same dosage form are proposed and only some strengths are duplicates of previously approved products listed in the Orange Book, an applicant may submit one 505(b)(2) application covering the proposed strengths rather than submitting separate applications through different pathways.

Scientific Considerations for ANDA and 505(b)(2)

The guidance explains that the types of studies, data, and information needed can differ between ANDAs and 505(b)(2) applications.

Applicants submitting 505(b)(2) applications have significant flexibility in the types of studies, data, and information that may be submitted to support NDA approval. This can include clinical investigations to establish the safety and/or effectiveness of the proposed drug product.

ANDA applicants may also have flexibility in the information submitted, provided that clinical investigations are not necessary to establish the safety or effectiveness of the proposed product. The precise scope and type of information required may vary and may be discussed between the applicant and FDA during drug development.

Active Ingredient Sameness

For an ANDA, the proposed generic drug product generally needs to demonstrate that its active ingredient or ingredients are the same as those in the RLD.

If the active ingredient cannot be demonstrated to be the same using the information and data permitted in an ANDA, the proposed product should not be submitted through the ANDA pathway.

The FDA has flexibility in determining whether the information submitted is sufficient to conclude that the proposed active ingredient is the same as the active ingredient in the RLD. The guidance also recognizes that scientific understanding and technology can evolve and may allow ANDAs to be considered in circumstances where the scientific basis was previously unavailable.

Differences in Formulation

Certain differences in inactive ingredients may be permitted in an ANDA. The applicant must provide information on the identity and quantity of the active and inactive ingredients and characterize permitted differences from the RLD, together with justification showing that the differences do not adversely affect safety and effectiveness.

For parenteral, ophthalmic, and otic drug products, specific requirements apply to inactive ingredients. Certain exception excipients may be permitted to differ from the RLD when the applicable requirements are met.

If a proposed formulation contains changes that are not permissible in an ANDA, including changes that would require clinical investigations to establish safety, the applicant should consider whether the 505(b)(2) pathway is appropriate.

Bioequivalence, Bioavailability and Conditions of Use

An ANDA must contain information demonstrating that the proposed drug product is bioequivalent to the RLD.

A proposed product with intentional differences in the rate or extent of absorption that go beyond the standards applicable to an ANDA may be submitted through the 505(b)(2) pathway and may require additional studies to support the safety and effectiveness of the proposed product.

However, a 505(b)(2) application is not appropriate simply because a duplicate product is unintentionally less bioavailable and fails to demonstrate bioequivalence to the listed drug.

The conditions of use are also important. An ANDA must include conditions of use that have previously been approved for the RLD, subject to permitted labeling carve-outs. A proposed new indication or other change to the conditions of use would mean that the product could not be approved as an ANDA.

Other Differences and Labeling

Drug products that differ considerably from the RLD are generally not candidates for approval under the ANDA pathway when the differences require data beyond the scope of studies that can be reviewed in an ANDA.

The guidance also addresses drug-device combination products and labeling. An ANDA generally requires labeling to be the same as the RLD, subject to permitted differences. Certain differences may be acceptable because of differences between manufacturers, patents, exclusivity, or other circumstances recognized by the applicable requirements.

However, an ANDA would not be appropriate where the proposed product has a new indication or a new dosing regimen compared with the RLD. If labeling differences require clinical investigations to establish safety or effectiveness, or are significant enough that the labeling no longer satisfies the applicable same-labeling requirement, the applicant should consider a 505(b)(2) application.

Requesting Assistance From FDA

Applicants who are uncertain about the appropriate abbreviated approval pathway can seek assistance from FDA before submitting an application.

For a product intended to have the same active ingredient or ingredients, conditions of use, route of administration, dosage form, strength, and applicable labeling as an RLD, applicants can submit controlled correspondence to OGD or request a pre-ANDA meeting with OGD.

Controlled correspondence is appropriate for a specific and targeted inquiry about generic drug development. A pre-ANDA meeting can be used when a prospective applicant seeks advice on a particular matter that falls outside the scope of controlled correspondence.

For products with differences that may support a 505(b)(2) application, applicants should contact the appropriate Office of New Drugs (OND) review division for assistance.

The August 2026 draft guidance provides a structured approach for determining whether a proposed drug product should be submitted through the ANDA or 505(b)(2) pathway. By considering factors such as duplication, active ingredient sameness, formulation, bioequivalence, conditions of use, labeling, and the type of supporting data required, applicants can better assess the appropriate abbreviated approval pathway and seek FDA assistance when questions remain.