New FDA Guidance on Determining Whether to Submit an ANDA or a 505(b)(2) Application

December 4, 2017

The U.S. Food and Drug Administration (FDA) recently published a draft guidance summarizing the differences between abbreviated new drug applications (ANDA) and 505(b)(2) applications. Both sections were added to the FD&C Act to provide new routes for obtaining approvals for drug applications.

The guidance focuses on ANDA submissions under Section 505(j) of the FD&C Act, petitioned ANDAs under Section 505(j)(2)(C), and NDAs pursuant to Section 505(b)(2) and discusses the regulatory and scientific considerations for determining whether to file an ANDA or 505(b)(2) application.

Under 505(j), ANDAs must demonstrate that the proposed generic drug and the reference listed drug are the same with respect to their active ingredients, dosage form, route of administration, strength, previously approved conditions of use and labeling (with certain exceptions). An ANDA must also demonstrate that the proposed product is bioequivalent to the reference listed drug and must include information that ensures the product’s identity, strength, quality and purity. If these criteria are all satisfied, FDA is obligated to approve the ANDA application (of course patent and regulatory exclusivities might still apply). Acceptable differences from the reference listed drug include a change approved in a suitability petition or certain differences in inactive ingredients, labeling or container closure systems, as long as investigations are not necessary to establish the safety or effectiveness of the drug product proposed in the ANDA.

Applications submitted under Section 505(b)(2) must contain full reports of investigations of safety and effectiveness. At least some of the information required for approval must come from studies not conducted by or for the applicant and for which the applicant has no rights (e.g., the Agency’s finding of safety or effectiveness for a reference listed drug or published literature). A 505(b)(2) applicant may rely on FDA’s finding of safety or effectiveness for a reference listed drug only to the extent that the proposed product in the application shares characteristics in common with the reference listed drug, for example., active ingredient, dosage form, route of administration, strength, indication, conditions of use. The application must contain sufficient data to support any difference between the proposed product in the application and the list drug.

Regulatory Considerations

  • Duplicates: FDA will refuse to file a 505(b)(2) application for a drug that is a duplicate of an already approved listed drug and that is eligible for approval under section 505(j).

  • Petitioned ANDAs: Under Section 505(j)(2)(C), an applicant may submit a suitability petition requesting permission to submit an ANDA for a generic drug product that differs from a reference listed drug in its route of administration, dosage form, or strength or that has one different active ingredient in a fixed combination drug product. These petitions are approved by FDA unless, among other reasons, FDA determines that the safety and effectiveness of the proposed change from the reference listed drug 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 listed drug named in the suitability petition.

  • Bundling: FDA has permitted applicants to submit a single 505(b)(2) application when seeking approval for multiple drug products where some qualify for approval under the 505(j) pathway (applications referencing an Orange Book listed product) and some qualify under the 505(b)(2) pathway.

Scientific Considerations

  • Confirmatory Studies: If the safety and effectiveness of a proposed drug product must be established by investigations, these investigations go beyond the scope of a limited confirmatory study and are generally not suitable for an ANDA. ANDAs may contain data that demonstrate that the characteristics that make a proposed drug product different from the listed drug do not alter its safety and effectiveness.

  • Active Ingredient Sameness Evaluation: If the active ingredient in the proposed drug product cannot be demonstrated to be the same as the active ingredient in the listed drug by using the information and data that may be submitted in connection with an ANDA, the drug product should not be submitted for approval in an ANDA.

  • Intentional Differences Between the Proposed Drug Product and Reference Listed Drug
    • Difference in formulation: Generally, differences in inactive ingredients are permissible if the safety and effectiveness of the proposed drug product is not adversely affected by the differences. For certain routes of administration other regulations may apply, e.g. parenteral, ophthalmic and otic drugs. An applicant should consider submitting a 505(b)(2) application if the proposed drug product contains changes to its formulation that are not permissible in an ANDA.

    • Differences in bioequivalence or bioavailability: An ANDA must contain information showing that the proposed drug product is bioequivalent to the reference listed drug. Bioequivalence means the rate and extent of absorption of the proposed drug are not significantly different from the rate and extent of absorption of the reference listed drug when administered at the same molar dose under similar experimental conditions. Where there is an intentional difference in rate (e.g., extended-release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action. If other differences in BE or BA exist, a 505(b)(2) submission is appropriate. However, a 505(b)(2) application is not appropriate for a drug product that failed to meet the 505(j) standards because the extent to which the API is made available to the site of action is less than that of the listed drug or the rate at which it is made available is unintentionally less than the listed drug.

    • Difference in conditions of use: Labeling information for properly submitted ANDAs must reflect previously approved conditions of use, except for labeling that excludes conditions of use approved for the reference listed drug that is omitted because of patents or exclusivity.

    • Other differences: Drug products that differ considerably from the reference listed drug are generally not candidates for a 505(j) submission. Differences are evaluated individually and as combined effects.
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