As discussed in previous blog posts, a 505(b)(2) New Drug Application (NDA) is an abbreviated approval pathway. As described in the 1999 FDA draft guidance “Applications Covered by Section 505(b)(2)”, this pathway is to be used for NDA applications that fulfill the requirements for safety and effectiveness by including some or all data from studies not conducted by the applicant, where the applicant does not have the right of reference. A 505(b)(2) application may rely on published literature, the Agency’s finding of safety and effectiveness for an approved listed drug, or a combination of the two. To rely on information from the listed drug, the applicant must establish a bridge between the proposed product and the listed drug to show the reliance is scientifically valid.
A 505(b)(2) pathway may be appropriate for changes to previously approved drugs, such as changes to the route of administration, dosage strength, dosage form, formulation changes, or for combination products, among others. Once the listed drug has been identified, as described in a previous blog post, the bridging strategy (i.e., scientific evidence of bioequivalence) can be designed. Bridging studies generally fall into 3 types: clinical pharmacology studies, safety and efficacy clinical studies, or nonclinical studies. The type and number of bridging studies needed typically depend on the changes between the listed drug and product under development.
The most common bridge between a listed drug and new product being submitted under a 505(b)(2) application is a Phase 1, single dose bioavailability/bioequivalence (BA/BE) clinical study. For oral products, this study will also typically include a food effect evaluation. In a review of 505(b)2 NDAs approved by the FDA between 2012 and 2016, almost 70% of the applications used a single dose BA/BE study to compare the new product to the listed drug (Freije et al, 2020). For products to be considered bioequivalent, the 90% confidence interval for both the maximum plasma concentration (Cmax) and overall extent of absorption and exposure measured by area under the curve (AUC) should be between 0.80 and 1.25. In contrast to an ANDA [505(j)], products submitted under a 505(b)(2) pathway do not necessarily have to demonstrate bioequivalence to the listed drug; however, differences in bioavailability between the products may require additional studies to support the bridging strategy. For example, if a new product has lower exposure (Cmax and/or AUC) than the listed drug, additional Phase 2 and/or Phase 3 studies may be required to confirm efficacy, whereas a product with higher exposure than the listed drug may require an additional safety bridge be conducted, such as one or more additional nonclinical studies.
In addition to situations where the new product is not bioequivalent to the listed drug, there are several other scenarios that may require safety and efficacy studies as a bridge. For example, if the new product will be used in a different indication or in a different population than the listed drug, studies to support safety and/or efficacy in the new indication or target population may need to be conducted. A change in the route of administration may require some nonclinical and/or clinical local tolerability studies be conducted with the new formulation. Additionally, a new combination product submitted as a 505(b)(2) NDA will require clinical safety and/or efficacy studies as a scientific bridge to a listed drug(s) or combination product.
As discussed in a previous blog post and above, there may also be situations where nonclinical studies could be used as supportive bridging studies for a 505(b)(2) application, either instead of, or in addition to, clinical studies. An important consideration when evaluating whether additional nonclinical studies are needed is whether the nonclinical exposure data of the listed drug provide a margin of safety over the systemic exposure of the new product; if not, additional nonclinical studies will likely be needed to bridge to the listed drug. Changes in formulation, excipients, and the route of administration are common reasons why additional nonclinical studies may be needed as supportive bridging studies for a new product under a 505(b)(2) NDA.
While a 505(b)(2) NDA can potentially get a drug to market faster than a 505(b)(1) NDA, the choice of a bridging strategy to the listed drug is important and involves consideration of multiple factors. The examples mentioned above are just some of the varieties of approaches that may be taken for a bridging strategy for a 505(b)(2) development program. Applicants are encouraged to meet with the FDA for a pre-IND meeting to seek alignment for the overall development plan and the proposed bridging study strategy and design. Rho has an extensive history in supporting clients with their drug development programs and can help devise an appropriate strategy for building a scientific bridge for a 505(b)(2) submission. Additional information on requirements for clinical studies for 505(b)(2) programs, along with scenarios and a case study can also be found in a recent article available on the Rho website.
Guidance for Industry: Applications Covered by Section 505(b)(2) (Draft; 1999)
Freije I, Lamouche S, Tanguay M. Review of Drugs Approved via the 505(b)(2) Pathway: Uncovering Drug Development Trends and Regulatory Requirements. Ther Innov Regul Sci. 2020 Jan;54(1):128-138.
Amanda Mathis, Ph.D., Director of Clinical Pharmacology, has over 15 years’ experience working in the pharmaceutical industry. She received her PhD in Pharmaceutical Sciences from the School of Pharmacy at the University of North Carolina at Chapel Hill in 2007. At Rho, Dr. Mathis provides support regarding clinical pharmacology components of Integrated Product Development programs and Integrated Regulatory Submissions. This includes support for clinical pharmacology strategic planning, gap analyses, support for design, execution, analysis and reporting of clinical pharmacology studies, as well as authoring and reviewing study protocols, reports, and documents for regulatory submissions. She has supported multiple INDs and NDAs, and has authored clinical protocols, study reports, modules for regulatory submissions, briefing packages, and other regulatory documents.