On October 13, 2017, the U.S. Food and Drug Administration (FDA) released for comment, by December 12, 2017, draft guidance for industry entitled, Determining Whether to Submit an ANDA or a 505(b)(2) Application. The purpose of the guidance is to assist applicants in determining which one of the abbreviated approval pathways under the Federal Food, Drug and Cosmetic Act (FD&C Act) is appropriate for the submission of a marketing application to the FDA.
With the passage of the Hatch-Waxman amendments, the FD&C Act describes different routes for obtaining approval of four categories of drug applications: (1) a “stand alone NDA (New Drug Application);” (2) a § 505(b)(2) application; (3) an Abbreviated New Drug Application (ANDA) for a duplicate of a previously approved drug product; and (4) a petitioned ANDA, a type of ANDA for a drug product that differs in certain respects from the Reference Listed Drug (RLD). The guidance briefly expands upon these four different pathways and discusses the regulatory and scientific considerations for determining whether to file an ANDA or § 505(b)(2) application.
Abbreviated Approval Pathways
This application contains “full reports of investigations of safety and effectiveness that were conducted by or for the applicant or for which the applicant has a right of reference or use.”
This application 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.” A § 505(b)(2) application may rely on the FDA’s safety and/or efficacy findings for a listed drug only to the extent that the proposed product of the § 505(b)(2) application shares characteristics with the listed drug, such as active ingredient, dosage form, route of administration, strength, indication, and/or conditions of use. To the extent that the listed drug and the proposed § 505(b)(2) drug differ, for example, in dosage form or increased bioavailability over the listed drug, the applicant must include sufficient data to support those differences. In particular, the applicant is expected to establish a bridge (e.g., by using comparative bioavailability data) between the proposed drug product and each listed drug upon which the applicant seeks to rely to demonstrate that such reliance is scientifically justified. A § 505(b)(2) application will not necessarily be rated as therapeutically equivalent to the RLD upon approval.
An ANDA applicant must demonstrate that the proposed generic drug product and the applicable RLD are the same with respect to their proposed active ingredient(s), dosage form, route of administration, strength, previously approved conditions of use, and labeling (with certain exceptions). An ANDA must also include sufficient information (1) to demonstrate that the proposed product is bioequivalent to the RLD, and (2) to ensure the product’s identity, strength, quality, and purity. An ANDA relies on the FDA’s finding of safety and effectiveness for an RLD and, as a result, safety and efficacy studies are not submitted in the ANDA.
A petitioned ANDA is a type of ANDA for a drug product that differs from the RLD in its dosage form, route of administration, strength, or active ingredient (in a product with more than 1 active ingredient), and for which the FDA has determined, in response to a suitability petition under § 505(j)(2)(c), that safety and efficacy studies are not necessary for the proposed drug product.
Regulatory Considerations for ANDAs and § 505(b)(2) Applications
The FDA generally will refuse a § 505(b)(2) application for a drug that is a duplicate of a listed drug and eligible for approval under § 505(j) of the FD&C Act. Unless a duplicate drug product is approved by the FDA after a § 505(b)(2) application is submitted, but before the § 505(b)(2) application is approved, the FDA will refuse the § 505(b)(2) application when it is a duplicate of a listed drug.
An applicant may submit a suitability petition to the FDA requesting permission to submit an ANDA for a generic product that differs from the RLD in its route of administration, dosage form, or strength, or that has one different active ingredient in a fixed combination drug product. The FDA generally will approve such a suitability petition unless, among other things, (1) “it determines that the safety and effectiveness of the proposed change from the RLD cannot be adequately evaluated without data from investigations that exceed what may be required for an ANDA,” or (2) the petition is for a drug product for which a pharmaceutical equivalent has been approved in an NDA, including for example, a § 505(b)(2) application that referenced the same RLD named in the suitability petition.
In circumstances where an applicant is seeking approval for multiple drug products containing the same ingredient, where only some of the products are listed in the Orange Book as RLDs, the FDA has permitted an applicant to submit a single “bundled” § 505(b)(2) application for all of the products, even though applications referencing the Orange Book-listed products would qualify for approval under the § 505(j) pathway.
Scientific Considerations for ANDAs and § 505(b)(2) Applications
If data are needed to establish safety or efficacy of a proposed ANDA product, then an ANDA application is not appropriate. Data from limited confirmatory testing may be submitted in an ANDA, however, to show that the characteristics that make the proposed drug product different from the listed drug do not alter its safety and effectiveness.
If the active ingredient in an applicant’s proposed drug product cannot be demonstrated to be the same as the active ingredient in the RLD by using the information and data that must be submitted in connection with an ANDA, the drug product should not be submitted for approval in an ANDA.
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