For developers seeking to obtain approval for previously approved drug products in the United States, the U.S. Food and Drug Administration (FDA) offers two abbreviated approval pathways — an abbreviated new drug application (ANDA) and a 505(b)(2) application. Both of these applications rely on the agency’s finding of safety and effectiveness for a listed drug, but the data needed to support an ANDA and 505(b)(2) may differ. In May 2019, the FDA finalized guidance to help determine whether an ANDA or a 505(b)(2) application is more appropriate for a drug. This guidance, Determining Whether to Submit an ANDA or 505(b)(2) Application, includes a revised section on scientific considerations for ANDAs and 505(b)(2) applications.¹

In this blog, we explore the differences between ANDAs and 505(b)(2)s, providing insight on which pathway may be more suitable for your particular drug.

Submitting an ANDA

Both the ANDA and the 505(b)(2) application offer flexibility in the types of studies, data, and other information required for submission. One notable difference is that ANDAs do not require independent clinical investigations that establish safety and effectiveness. Instead, to obtain ANDA approval for a generic drug, you must identify the previously approved drug you seek to duplicate — the reference listed drug (RLD) — and demonstrate that the generic drug is bioequivalent to the RLD. Specifically, the drug must have the same:¹

Active ingredient(s)
Conditions of use
Route of administration
Dosage form
Strength
Labeling (with certain permissible differences)

If in vivo bioequivalence testing is required, these studies must be conducted using a reference standard chosen by the FDA. While the reference standard is generally the RLD, there may be circumstances — for example, when the RLD is no longer marketed — where the agency selects a different drug product.

Some differences between the drug product and the RLD, such as certain labeling differences, may be allowed in an ANDA. The FDA guidance also offers recommendations on what to do when there are intentional differences — such as in formulation, bioavailability, and conditions of use — between the proposed drug and the RLD. If the drug product differs substantially from the RLD or requires submission of clinical investigations to establish safety or effectiveness, it would likely not be a candidate for the ANDA pathway.

Submitting a 505(b)(2)

A 505(b)(2) application is a new drug application 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.”² For these applications, you can rely on data for an RLD only to the extent that the proposed product shares key characteristics with that listed drug. More specifically, you must demonstrate scientific justification for the reliance on each RLD. Where the proposed drug product differs from the listed drug(s) referenced, the application must include data to support these differences. Examples of differences that require a 505(b)(2) include a formulation change not permitted under an ANDA, use of a novel excipient that requires clinical investigations, change in route of administration or dosing regimen, or pursuit of a new indication that requires clinical investigations to support clinical safety and efficacy.

Of note, if multiple drug products contain the same active ingredient(s) and some qualify for the ANDA pathway and others for the 505(b)(2) pathway, you may bundle all of these drug products into one 505(b)(2) application.²

Selecting an RLD

As a general rule, if the drug product is a duplicate of the RLD, the preferred pathway is an ANDA. If the drug product differs from the RLD, however, you have the option to submit a suitability petition to the FDA requesting permission to submit an ANDA.²

The FDA released a guidance on Referencing Approved Drug Products in ANDA Submissions in October 2020.³ This document provides information on how to identify the RLD, reference standard, and basis for ANDA submission. In addition, the FDA publishes an annual resource titled Approved Drug Products with Therapeutic Equivalence Evaluations, commonly referred to as the Orange Book, which identifies all drug products currently approved by the agency. In May 2020, the agency released a draft guidance, Orange Book Questions and Answers, to assist developers in using the Orange Book.⁴

Seeking regulatory guidance

Determining which abbreviated approval pathway is the most appropriate for a drug requires an understanding of the options available and the data needed to support each type of application. For questions, ANDA applicants are directed to communicate with the Office of Generic Drugs, and 505(b)(2) applicants are advised to contact the appropriate review division at the Office of New Drugs. The FDA also has published product-specific guidances (PSGs) to help developers generate the evidence needed to support ANDA approval.⁵ Currently, there are 1,896 published PSGs in the agency database.⁶

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[1] U.S. Food and Drug Administration. Product-Specific Guidances for Generic Drug Development. Available at https://www.fda.gov/drugs/guidances-drugs/product-specific-guidances-generic-drug-development.

[2] U.S. Food and Drug Administration. Product-Specific Guidances for Generic Drug Development. Available at https://www.accessdata.fda.gov/scripts/cder/psg/index.cfm. Accessed June 5, 2021.

[3] U.S. Food and Drug Administration. Referencing Approved Drug Products in ANDA Submissions. October 2020. Available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/referencing-approved-drug-products-anda-submissions-guidance-industry.

[4] U.S. Food and Drug Administration. Orange Book Questions and Answers. May 2020.

[5] U.S. Food and Drug Administration. Product-Specific Guidances for Generic Drug Development. Available at https://www.fda.gov/drugs/guidances-drugs/product-specific-guidances-generic-drug-development.

[6] U.S. Food and Drug Administration. Product-Specific Guidances for Generic Drug Development. Available at https://www.accessdata.fda.gov/scripts/cder/psg/index.cfm. Accessed June 5, 2021.