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Review of Drugs Approved via the 505(b)(2) Pathway: Uncovering Drug Development Trends and Regulatory Requirements

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Copyright © DrugPatentWatch. Originally published at Review of Drugs Approved via the 505(b)(2) Pathway: Uncovering Drug Development Trends and Regulatory Requirements

This paper was originally published by Ingrid Freije, Stéphane Lamouche, and Mario Tanguay in Therapeutic Innovation & Regulatory Science under a Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/)

A 505(b)(2) application is a type of US new drug application (NDA) that contains full reports of investigations of safety and effectiveness, but 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. Most 505(b)(2) applications consist of changes to a previously approved drug product (ie, a new dosage form, new routes of administration, etc). Sponsors often face challenges determining the studies to be conducted to support approval via 505(b)(2) pathway. This 5-year (2012-2016) retrospective analysis reviewed approved 505(b)(2) NDAs available on the FDA website, to determine the nature of studies (preclinical, clinical pharmacology, and efficacy/safety) conducted for various types of submissions and to better understand the trends in terms of regulatory requirements. The database consisted of 226 NDAs. One hundred twelve of those 226 had complete FDA review information, with the following FDA submission classes being more prevalent: type 3, new dosage form; type 4, new combination; and type 5, new formulation or new manufacturer. Therefore, only these 112 NDAs were further examined as they could show trends in terms of the studies conducted for various types of applications. Based on the investigation of NDA review documents, coupled with guidance documents, decision trees for studies to be conducted have been developed, which may serve as a guide of recommendations for a successful 505(b)(2) development program and NDA submission.

Background

In 1999, the FDA published the Draft Guidance for Industry Applications Covered by Section 505(b)(2) which introduced this section of the Federal Food, Drug, and Cosmetic Act and described certain regulatory aspects such as eligibility, submission, and patent/exclusivity protection. By definition, the 505(b)(2) application is “an application that contains full reports of investigations of safety and effectiveness but 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.”1 The 505(b)(2) is a pathway for new drug products that includes changes compared to an existing product, such as new formulations, routes of administration, and intended use. A drug submitted via 505(b)(2) can be approved based on data from studies not conducted by the sponsor, by relying on (1) Agency’s previous findings of safety and effectiveness (AFSE) of an approved drug; and/or (2) clinical and preclinical studies’ data from published literature without the right of reference. This requires not only a successful bridging to an RLD (reference listed drug), by the means of relative bioavailability (BA) or bioequivalence (BE) studies, but also some potential additional studies that may be needed to fully support efficacy and/or safety of the new product. If the sponsor has access to the originator data (ie, right of reference), then a supplemental NDA or the 505(b)(1) pathway would be applicable for the previous changes.

In light of the recent growing interest in the 505(b)(2) pathway, the industry finds itself looking for guidance on the specifics of the clinical development program of these NDAs. In addition to the specific FDA draft guidance on 505(b)(2), the FDA published a draft guidance on “Determining Whether to Submit an ANDA or a 505(b)(2) Application” that guides sponsors on the type of submissions (generic vs 505(b)(2)) that should be applicable to their specific drug, and an article that provides an overview of some clinical pharmacology aspects seen in approved 505(b)(2) NDAs.2,3 However, these guides do not provide details regarding drug development aspects. Since 505(b)(2) applications are considered NDAs, review of some US requirements described in the 21 CFR (Code of Federal Regulations) Title 21, Ch. I (ie, Part Sections 320.27; 320.24; 320.25; 320.22; 300.50; 314.50)4 and various FDA guidance documents provides valuable information regarding the design and conduct of studies submitted in NDAs in general.5–13 It is critical to understand FDA’s expectations in order to facilitate discussion with the Agency through pre-IND or other FDA meetings, and to avoid deficiencies in terms of data supporting approval for a new product submitted under the 505(b)(2) pathway.

This retrospective analysis aims to provide not only an overview of recently approved 505(b)(2) NDAs (2012-2016), but also to summarize the trends in the studies conducted to support NDA approval. It is important to recognize that, without a thorough understanding of the regulatory history, the clinical studies for each product may have been done to meet (1) FDA requirements, (2) other agency requirements, and (3) sponsor choice. However, upon the particular type of modifications made in the new drug product as compared to an RLD, as defined by the FDA submission classification type (Table 1),13 the recommendations concerning the preclinical, clinical, and especially the clinical pharmacology studies to support a 505(b)(2) NDA will be discussed. The ultimate objective of this review is to allow an easier navigation through the various types of 505(b)(2) submissions for drug development organizations.

Table 1 FDA Submission Classification Types
Table 1 FDA Submission Classification Types
Copyright © DrugPatentWatch. Originally published at Review of Drugs Approved via the 505(b)(2) Pathway: Uncovering Drug Development Trends and Regulatory Requirements
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