On October 13, 2017, the U.S. Food and Drug Administration (FDA) released for comment, by December 12, 2017, draft guidance for industry entitled, Determining Whether to Submit an ANDA or a 505(b)(2) Application.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

  • Stand-Alone NDA (submitted under § 505(b)(1) and approved under § 505(c) of the FD&C Act)

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.”

  • 505(b)(2) Application (submitted under § 505(b)(1), approved under § 505(c))

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.

  • ANDAs (submitted and approved under § 505(j))

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.

  • Petitioned ANDAs (submitted and approved under § 505(j))

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

  • Duplicates

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.

  • Petitioned ANDAs

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.

  • Bundling

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

  • Limited Confirmatory Studies

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.

  • Active Ingredient Sameness Evaluation

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.

  • Intentional Differences Between the Proposed Drug Product and an RLD
  • Formulation Differences

Certain differences in inactive ingredients (formulation differences) are permissible with a justification demonstrating that the safety and effectiveness of the proposed drug product is not adversely affected by the differences. Regulations limit the permissible changes to inactive ingredients for parenteral, ophthalmic, and otic drug products. An applicant should consider submitting a § 505(b)(2) application if the proposed drug product contains either changes to its formulation that are not permissible in an ANDA or a novel excipient that has not been used in an FDA-approved drug product and the safety of which cannot be established without clinical testing.

  • Bioequivalence and/or Bioavailability Differences

An ANDA must contain information to show that the proposed drug product is bioequivalent to the RLD: the rate and extent of absorption of the proposed drug and RLD do not show a significant difference when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses. The FDA noted, however, that “[(w]here there is an intentional difference in rate (e.g., in certain 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.” An application for a proposed drug product where the rate and/or extent of absorption exceed, or are otherwise different from, the § 505(j) standards for bioequivalence may be submitted under the § 505(b)(2) pathway and may require studies to show the safety and efficacy of the proposed product at the different rate and/or extent of delivery. However, the FDA generally will not accept a § 505(b)(2) application if the only difference from the RLD is that the extent to or rate at which the proposed product’s active ingredient is absorbed or otherwise made available at the site of action is less than that of the RLD.

  • Conditions of Use Differences

A § 505(j) application must include a statement that the conditions of use prescribed, recommended, or suggested in the labeling for the proposed drug product have been previously approved for the RLD. If the proposed drug product has added a new indication, the application cannot be approved as an ANDA. However, the FDA will not refuse to approve an ANDA whose proposed labeling excludes conditions of use approved for the RLD because of patents or exclusivity.

  • Labeling Differences

An ANDA must contain “information to show that the labeling proposed for the new drug is the same as the labelling for the [RLD] . . . except for changes required because of differences approved under a [suitability petition] . . . or because the new drug and the [RLD] are produced or distributed by different manufacturers.” An ANDA is not appropriate if the proposed drug product would have a new indication or a new dosing regimen as compared to the RLD. Further, if the differences between the products are such that they would require safety or efficacy investigations for the proposed product or necessitate such significant labeling differences that the labeling no longer satisfies the “same” labeling requirement, the proposed product should be submitted under § 505(b).

  • Other Differences

Drug products that differ considerably from the RLD are generally not candidates for the § 505(j) pathway. In its assessment, the FDA examines both individual differences between the products and the combined effects of those differences.