Section 505(b)(2) is a new drug application (NDA) that represents a hybrid of 505(b)(1) and 505(j) applications. It is used for approved drugs for which an “improvement” has been made and generally must show comparable bioavailability, although not necessarily identical pharmacokinetics, to the reference listed drug (RLD).
The FDA covers 505(b)(2) drugs in the guidance, “Applications Covered by Section 505(b)(2).” 505(b)(1) covers NDAs, such as those used for new chemical entities (NEC), and 505(j) is used for abbreviated NDAs, using the generic equivalent (dose, design and administration route) as the RLD. The label is identical, and evaluation is based entirely on a pass/fail bioequivalence assessment.
The 505(b)(2) contains full information on the safety and effectiveness in humans of a new drug product (NDP), but it allows a limited amount of the information required for registration to come from the literature or studies conducted with the RLD. However, the information that’s allowed needs to be negotiated with the FDA as early as possible during the development phase.
- Pre-clinical toxicity and pharmacokinetic (PK) information
- Proof of Concept (POC) and/or dose ranging information
- Certain PK information (e.g., ADME, DDI)
- Information in the label common to both the NDP and RLD
- Phase I studies that have characterized the PK of the drug itself, without reference to drug delivery approach being tested as part of a 505(b)(2) application
Submitting a 505(b)(2) can lower development costs by reducing the potential pre-clinical and clinical studies, speeding drug development, using well-established therapeutic dose (or dose range), reducing development risk by leveraging existing information related to safety, efficacy, DDI potential, contraindications, etc. and lessening the intensity of a review due to FDA familiarity with the drug.
Timely meetings with the FDA are critical, particularly face-to-face meetings. Unlike ANDAs, a 505(b)(2) application requires an investigational new drug (IND) meeting. A pre-IND meeting can help move the application along. Provide a briefing document with all necessary questions to gain approval, and be sure to focus on added value of a new product (e.g., distinguishing features). Any agreements made with FDA officials should be clearly stated in a Final Meeting Minutes document.
Other types of meetings include: an End-of-Phase 2 meeting prior to Phase 3; a pre-NDA meeting to agree on submission requirements; and type C meetings to address development issues as they arise.
Additional considerations for 505(b)(2) applications
505(b)(2) applications are generally allowed in these situations. The drug label likely will be composite of old and new information.
- Active pharmaceutical ingredient (API) change (salt, ester, enantiomer, pro-drug etc.) delivering same active moiety
- New dosing regimen, formulation or strength
- New indication
- A NCE or naturally derived ingredient where part of the information/data is from studies not conducted by the applicant
- Rx to OTC switch
- Substitution of an AI in a combination product
- Bioequivelance in “some cases” where BA/BE is “different” from the RLD
- New route of administration
An application other than a 505(b)(2) is required in these instances:
- An application that is a duplicate of a listed drug and eligible for approval under a 505(j) application (i.e., ANDA)
- An application in which the only difference from the RLD is the extent to which the active ingredient (AI) is absorbed or made available to the site of action is less than the listed drug
- An application in which the only difference from the RLD is that the rate of absorption of AI or (or rate made available to the site of action) is unintentionally less than that of the RLD
The differences among applications can become confusing if a new formulation was designed simply to overcome intellectual property issues.