Steve:  Welcome to the CDER Small Business and Industry Assistance (SBIA) Podcast Series

Today’s topic: Abbreviated Approval Pathways for Drug Product: 505(b)(2) or ANDA?

Determining the right abbreviated approval pathway for submitting a drug product application to FDA requires an understanding of the options available and what types of data are permitted to support a selection. The Drug Price Competition and Patent Term Restoration Act of 1984 added section 505(b)(2) and 505(j) to the Federal Food, Drug, and Cosmetic Act, establishing abbreviated pathways for obtaining approval for new drug applications (or NDAs) and abbreviated new drug applications (or ANDAs).

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.

 

An ANDA is an application submitted and approved under section 505(j) for a drug product that is a duplicate of a previously approved drug product. It relies on FDA’s finding that the previously approved drug product (the reference listed drug or RLD),  is safe and effective, and may not be submitted if clinical investigations are necessary to establish the safety and effectiveness of the proposed drug product. An ANDA generally must contain information to show that the proposed generic product is the same as the RLD with respect to the active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling (with certain permissible differences) and is bioequivalent to the RLD.

Today we are joined by Elizabeth Friedman from the Office of Generic Drug Policy to discuss key considerations in determining whether to submit an ANDA vs. 505(b)(2) application.

Elizabeth: Thank you Steve.

FDA issued the final guidance for industry “Determining Whether to Submit an A-N-D-A or 505(b)(2) Application” to assist prospective applicants and provide direction in determining which one of these abbreviated pathways is more appropriate. The guidance highlights considerations for submission of A-N-D-As versus 505(b)(2) applications.

If the drug product is a duplicate of an already listed drug and eligible for approval as an A-N-D-A, FDA generally will refuse to file a 505(b)(2) application for such a product.

If the applicant plans to submit an A-N-D-A for a generic drug product that differs from an R-L-D in its route of administration, dosage form, or strength or that has one different active ingredient in a fixed-combination drug product, they may request permission to do so from FDA by submitting a suitability petition.

A situation may arise where an applicant may seek approval for multiple drug products containing the same active ingredient, where some of these products would qualify for approval as an A-N-D-A and others under the 505(b)(2) pathway. In this case, the applicant may bundle these drug products by submitting a single 505(b)(2) application. For example, an applicant seeking approval for multiple strengths of a product, only some of which are included in the Orange Book as listed drugs, may submit one 505(b)(2) application for all of the proposed strengths.

The types of studies, data, and information that may be necessary to support the approval of drug products proposed in A-N-D-A s compared to 505(b)(2) applications may differ. 

Generally, A-N-D-A applicants have significant flexibility in the types of studies, data, and information they may submit in the A-N-D-A to support the requirements for A-N-D-A approval, so long as clinical investigations are not submitted to establish the safety or effectiveness of a product.

However, 505(b)(2) applications may include clinical investigations to establish the safety and/or effectiveness of a drug product. The precise scope and type of information necessary for approval will vary and may be the subject of discussion between the applicant and FDA during the drug development process.

Active ingredient sameness is evaluated to demonstrate that the proposed generic drug product is the same as the RLD with respect to the active ingredient. As scientific understanding and technology evolve, FDA may be able to receive, review, and approve A-N-D-As where it previously lacked the scientific basis to do so.

Sometimes there are intentional differences between the proposed drug product and the RLD, such as differences in formulation, bioequivalence and/or bioavailability, and conditions of use.

• An A-N-D-A generally may differ from the RLD in inactive ingredients, but must include information regarding the identity and quantity of all active and inactive ingredients of the proposed drug product.
• It must also include a characterization of any permitted differences between the formulations of the proposed drug product and the RLD, along with a justification demonstrating that the safety and effectiveness of the proposed drug product is not adversely affected by these differences.
• A 505(b)(2) application should be considered if the proposed drug product contains changes to its formulation that are not permissible in an A-N-D-A. For example, a proposed drug product that contains an excipient that requires clinical investigations to establish safety of the excipient would not be permitted in an A-N-D-A but may be submitted in a 505(b)(2) application.
• An A-N-D-A must contain information to show that the rate and extent of absorption of the proposed drug product does not show a significant difference from that of the RLD.
• A 505(b)(2) application may be submitted if the rate and/or extent of absorption exceed, or are different from the 505(j) standards, and may require studies to show safety and efficacy of the proposed drug product.
• However, a 505(b)(2) application is generally not appropriate for a drug product that should have been submitted under the A-N-D-A pathway, but would have failed to meet the 505(j) standards. For example, a 505(b)(2) application may not be appropriate if the proposed drug product is a duplicate of a listed drug but is unintentionally less bioavailable and fails to demonstrate bioequivalence to the listed drug.
• An A-N-D-A must also include a statement that the conditions of use in the labeling for the proposed drug product have been previously approved for the RLD. If the proposed labeling reflects different conditions of use than the RLD labeling, such as a new indication, the application could not be approved as an A-N-D-A. However, the A-N-D-A labeling may exclude (or “carve out”) conditions of use approved for the RLD that may be omitted from the proposed A-N-D-A labeling because of patents or exclusivity.

Certain differences in labeling between generic products and RLDs may be allowed, such as --differences in expiration date, formulation, bioavailability or pharmacokinetics, labeling revisions made to comply with current FDA labeling guidelines or other guidance, or omission of an indication or other aspect of labeling protected by patent or accorded exclusivity.

However, products that differ considerably from the RLD or require submission of data that could be considered beyond the scope of studies that can be reviewed in an A-N-D-A are generally not candidates for approval under the 505(j) pathway.

FDA encourages prospective applicants with questions about whether their proposed drug product is appropriate for submission in an A-N-D-A to contact the Office of Generic Drugs through a Controlled correspondence or by requesting a pre-ANDA meeting, as appropriate. Questions about submission of an application through the 505(b)(2) pathway should be directed to the appropriate Office of New Drugs review division.

The guidance was published as part of the agency’s Drug Competition Action Plan, and to assist in clarifying the A-N-D-A submission process, provide assistance to potential applicants, and ultimately expand access for patients to lower cost high quality medicine.

Steve: A link to the full SBIA Chronicles article and more information about CDER’s SBIA Program can be found at: www.fda.gov/cdersbia. Thanks for tuning in!