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

Abstract

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.

Biocompatible Chemotherapy for Leukemia by Acid-Cleavable, PEGylated FTY720

“…These results imply that the acid-transforming prodrug formulation is a viable option to utilize the therapeutic benefits of FTY720 against leukemia and other cancers with avoided adverse side effects. Since FTY720 is an FDA-approved drug for multiple sclerosis and is selectively toxic to cancerous cells, a viable prodrug formulation with a preserved anticancer activity with lowered toxicity is highly beneficial for fast clinical translation, not only for therapeutic efficacy but also improved quality of patient life post-treatment. ,, …”

“…Since FTY720 is an FDA-approved drug for multiple sclerosis and is selectively toxic to cancerous cells, a viable prodrug formulation with a preserved anticancer activity with lowered toxicity is highly beneficial for fast clinical translation, not only for therapeutic efficacy but also improved quality of patient life post-treatment. 2,33,34 Minimized Epigenetic Age by FTY-k-PEG. DNA methylation-derived biomarkers are currently gaining significant interest as changes in the epigenetic age are known to be associated with several pathological conditions including cancer 69 as well as treatment with certain chemotherapeutic drugs.…”

“…Most importantly, this approach is not generalizable to other chemotherapeutic agents. Prodrug formulation presents a less costly alternative through the 505­(b)(2) development process, which could take as few as 30 months for FDA-approval. , Therefore, a generalized approach to the development of prodrug to specifically eliminate side effects of an already approved drug is highly meritorious from a scientific and translational standpoint.…”

US FDA Regulatory Framework for Generic Peptides Referring to rDNA Origin Reference Products

“…A bridging is required with the RLD to establish similarity in terms of bioavailability and bioequivalence. Some additional studies to support safety and efficacy may also be required [14].…”