As discussed in previous blog posts, applicants planning to submit a product for approval through the section 505(b)(2) new drug application (NDA) can benefit from a less costly development program with the potential for a faster route to market than a traditional 505(b)(1) program. As a reminder, according to section 505(b)(2) of the Food, Drug, and Cosmetic Act, the 505(b)(2) NDA is an application that fulfills all requirements of safety and effectiveness but where some of the information required for approval comes from studies not conducted by or for the applicant. The 505(b)(2) NDA is appropriate when you are relying upon published literature and/or the Agency’s previous findings of safety and effectiveness for an approved drug for which you do not have right of reference. Using this information provides certain advantages as a result, if your product qualifies, by serving as a foundation for your development program and NDA, likely reducing the number of nonclinical or clinical studies needed for approval.

In accordance with 21 CFR 314.54, to obtain approval for a new product via the 505(b)(2) pathway relying upon the Agency’s findings of safety and efficacy for a previously-approved drug, the applicant must explicitly identify at least one “listed drug” for which FDA has made a finding of safety and effectiveness, containing the same active ingredient as the applicant’s new product. According to 21 CFR 314.3, a listed drug is defined as “a new drug product that has been approved under section 505(c) of the FD&C Act for safety and effectiveness or under section 505(j) of the FD&C Act, which has not been withdrawn or suspended under section 505(e)(1) through (5) or section (j)(6) of the FD&C Act, and which has not been withdrawn from sale for what FDA has determined are reasons of safety or effectiveness.” The FDA’s Orange Book, also known as the Approved Drug Products with Therapeutic Equivalence Evaluations, categorizes these products as “active” or “discontinued” depending on whether the product is approved for sale (prescription or over‑the‑counter) or has been withdrawn from market, respectively. The Orange Book is a primary resource for identifying the most appropriate listed drug candidates for your 505(b)(2) application.

You should note that among the listed drugs for a given active ingredient, the Orange Book also identifies at least one “reference listed drug” (RLD). An RLD is a listed drug designated by FDA as the approved drug product upon which an applicant for a generic drug relies in seeking approval of an abbreviated NDA (ANDA). Although intended for generic drug ANDAs, the RLD for a given active ingredient is an obvious candidate to serve as the listed drug for a 505(b)(2) development program.

Also, the requirement for identifying a “listed drug for which FDA has made a finding of safety and effectiveness” generally means that you should not select a generic drug product approved under an ANDA as one of your listed drugs for a 505(b)(2) NDA development program because generic drugs are approved based upon findings of bioequivalence to an approved drug rather than safety and effectiveness.

When reviewing the Orange Book for your particular active ingredient, you may find yourself constrained to just one available listed drug in situations where only one drug product with that active ingredient has been approved previously by FDA. On the other hand, if the Orange Book lists more than one approved drug product (including perhaps multiple products designated as RLDs), then you have other factors to consider when deciding the appropriate listed drug(s) to use, such as how similar or different the listed drugs are from your product and what information is available in the label for each listed drug to support your Target Product Profile. Keep in mind that you can reference more than one listed drug in your NDA if the circumstances warrant and you provide sufficient rationale. For example, there may be two listed drugs for one drug substance, one administered orally and one intravenously or via another route. The labels may have different safety or efficacy data, in which case you could rely on both products. Regardless of whether you have one or more listed drugs to reference for your 505(b)(2) application, you will need to establish sufficient rationale for your reference(s), as well as provide a bridge (i.e., scientific evidence of bioequivalence) to each listed drug. (We will discuss approaches to bridge appropriately to your listed drug(s) in a future blog post.)

It is important to propose a 505(b)(2) early in your product development, as identifying potential listed drugs and understanding what scientific gaps remain to be filled will help move your program forward through clinical studies to NDA submission. If you are interested in learning more about whether your product is eligible for a 505(b)(2) submission, as well as navigating this regulatory pathway, choosing the appropriate listed drug for your product, or developing bridging studies for your program, please contact us. Rho has extensive experience in clinical trials regulatory consulting and supporting marketing applications through various regulatory pathways, including successfully supporting more than 20 applications through the 505(b)(2) approval pathway.

Kevin Barber, PhD, RAC, PMP, Vice President of Regulatory Strategy & Submissions, has more than 20 years of experience in regulatory affairs and product development, working for both sponsor companies and CROs, across all stages of development from pre-clinical through product launch and post-approval life cycle management. He has led the preparation and execution of integrated regulatory strategy and clinical development plans for drug, biologic, and medical device products in therapeutic areas including dermatology, nephrology, urology, women’s health, CNS/neurology, cardiovascular diseases, virology, oncology, immunology, infectious diseases, blood products, and gene therapy. Dr. Barber has significant experience preparing and filing regulatory submissions, including more than 45 US INDs and more than 40 marketing applications in the US, Canada, Europe, Latin America, Australia, and New Zealand. He also has experience with medical device and in vitro diagnostic development programs and regulatory submissions including pre-IDE meetings, IDEs, 510(k)s, and PMAs.

Christine Psaltis, PhD, Integrated Product Development Associate, works to support regulatory submissions and product development at Rho. With nearly a decade of experience in scientific writing, she has authored and prepared various regulatory documents, including clinical protocols, NDA and IND modules, clinical study reports, and investigational brochures. Dr. Psaltis has experience leading and designing both clinical and nonclinical studies in a variety of therapeutic areas.