Blog Post

Nonclinical Considerations for 505(b)(2) Development Programs

December 9, 2020

As discussed in our 19 November 2020 post, 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. Sponsors submitting a product through this pathway can generally plan for a nonclinical development program that is substantially curtailed compared to what is required for submission via the section 505(b)(1) stand-alone NDA pathway. Sponsors considering a 505(b)(2) submission may sometimes question whether the section 505(j) abbreviated NDA (ANDA) pathway is appropriate instead for their product. A drug that is a candidate for a section 505(j) ANDA submission [not including those under a petitioned ANDA per section 505(j)(2)(c)] is one that is identical with respect to the active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling (with some exceptions) and is bioequivalent to an FDA approved reference listed drug [1]. A 505(b)(2) application is one for which one or more of the investigations relied upon by the applicant for approval “were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted [2]. Thus, a candidate for a 505(b)(2) NDA application may include a new chemical entity (NCE) or a drug that is a change to a previously approved drug (i.e., a listed drug).

Although a 505(b)(2) NDA application must contain full reports of investigations of safety and effectiveness, the reduced need for nonclinical testing in a 505(b)(2) program is driven by the fact that applicants can rely upon studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use. Thus, public domain data (i.e., published literature) and previous FDA findings from safety and efficacy studies of the listed drug(s) that the 505(b)(2) NDA is based upon is included in the application. Although reliance upon safety and effectiveness data generated by others can allow a 505(b)(2) applicant to avoid conducting duplicate nonclinical safety studies, the applicant may need to conduct bridging studies to compare the safety or effectiveness of the new product to that of the listed drug. Some of the most common examples in which bridging studies (e.g., comparative bioavailability) and/or other nonclinical or clinical studies to support differences between the proposed drug and the listed drug may be required include reformulated products or products in which the indication, route of administration, or dosing regimen differs from that of the listed drug.

The FDA has issued a guidance that outlines some general recommendations for applicants submitting an NDA for a drug product that has been reformulated or is administered by an alternate route than the listed drug [3]. An important consideration for all new drug products is the systemic toxicity that can result from exposure. A comparison of the systemic exposure of the new drug to that of the listed drug will be important in determining whether the nonclinical data of the listed drug can be relied upon or whether additional studies will need to be conducted by the applicant. Drugs that will be administered by a different route of administration than the listed drug will usually be subject to additional route‑specific nonclinical safety testing.  Reformulated drugs that use different excipients relative to those in the listed drug may also require additional nonclinical testing depending upon whether the excipients have been previously approved for the given route of administration.

Since a variety of approaches may be taken for the nonclinical development program of a 505(b)(2) application, applicants are highly encouraged to meet with FDA for a pre-IND meeting to propose their nonclinical development plan and seek alignment from the Agency. The pre-IND meeting strategy for a 505(b)(2) application will also be different from that of a 505(b)(1) application. Unlike a development program for a 505(b)(1) application, where it is likely that some nonclinical data will not have been collected at the time of the pre-IND meeting, 505(b)(2) applicants should be ready to present to the Agency a very specific plan on what existing safety and effectiveness data they plan to leverage in their application and what data they plan to provide themselves as the sponsor of the nonclinical studies. Importantly, a 505(b)(2) applicant is still required to submit a full safety package to the FDA in support of their application, whether that be through relying upon previous findings of safety and effectiveness in the listed drug, reference to published literature, or in the conduct of their own studies. Thus, 505(b)(2) applicants are also encouraged to consult the ICH M3(R2) guidance and other relevant ICH guidance(s) to ensure that their nonclinical data are complete and appropriate to support their clinical development plan [4].


  1. Determining Whether to Submit an ANDA or 505(b)2) Application: Guidance for Industry (May 2019)
  2. Guidance for Industry: Applications Covered by Section 505(b)(2) (Draft; 1999)
  3. Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route: Guidance for Industry and Review Staff (October 2015)
  4. ICH M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (11 June 2009; implemented 01 January 2010 by US FDA)

Dr. Brenda Faiola, Ph.D., DABT, Director, Nonclinical Development, has over 15 years of experience in the pharmaceutical and medical device industries. She received her PhD in Immunology from Duke University in 2001 and has been a Diplomate of the American Board of Toxicology since 2004. At Rho, Dr. Faiola provides support regarding nonclinical aspects of Integrated Product Development and Integrated Regulatory Submissions for pharmaceutical, biologics, and medical device programs.




Kelsey Behrens, Ph.D., Integrated Product Development Associate, works to support regulatory submissions and product development. She has a decade of experience in writing, reviewing, and editing scientific documents and has prior experience in the design and management of both clinical and nonclinical studies. Dr. Behrens has participated in the authoring and preparation of US NDA and IND modules, clinical study reports, clinical study protocols, and briefing packages to support regulatory meetings.