3 Common Misconceptions about Nonclinical 505(b)(2) Development Programs

The US Food and Drug Administration 505(b)(2) New Drug Application (NDA) pathway allows sponsors to use existing public data in lieu of conducting nonclinical and clinical studies, potentially offering significant drug development and marketing advantages. Nonclinical testing programs for 505(b)(2) submissions are often reduced relative to novel 505(b)(1) NDA approvals and, in some cases, not required. Given the wide range of requirements for 505(b)(2) nonclinical development and depending on a sponsor’s experience with this pathway, they may assume an approach that worked for one program is applicable for another program. Here we tackle three common 505(b)(2) development myths by assessing the latest data on nonclinical programs supporting 505(b)(2) approvals.  

Myth 1: Nonclinical studies are not needed for a change in formulation 

While some changes to a formulation can be considered safe without the need for nonclinical studies, others, particularly those that alter the pharmacokinetic profile or introduce excipients at levels higher than previously approved, need nonclinical testing to ensure safety of the new drug product.  

Interestingly, from 2019-2023, 13% of approvals needed to conduct standalone toxicology studies solely to qualify novel excipients and impurities. Ensuring appropriate excipient concentrations when designing new formulations and controlling impurities during the manufacturing process are ways to minimize the need for animal studies in the development process. 

Myth 2: Dermal carcinogenicity studies are needed when topical administration is a new route of administration 

A dermal carcinogenicity study is a long-term animal study designed to assess the potential of a topically applied substance to cause cancer through skin exposure. Typically conducted in rodents over a two-year period, these studies evaluate whether chronic application of a test substance leads to the development of skin tumors or systemic cancers. Dermal carcinogenicity studies are part of broader nonclinical safety assessments for pharmaceuticals, particularly when a new route of administration—such as topical—is introduced and there are concerns about potential long-term carcinogenic effects unique to that route. 

In the past five years, 10 topical products were approved and only one program conducted a dermal carcinogenicity study. The other approvals relied on the approved labeling from the listed drug (i.e., the branded drug that is referenced and relied upon in the 505(b)(2) NDA for the existing nonclinical studies) or used a Weight-of-Evidence (WOE) approach, presumably using a similar approach as outlined in ICH S1B(R1) Addendum to S1B Testing for Carcinogenicity of Pharmaceuticals. 

A WOE approach is a scientific method used to assess potential human carcinogenic risk by integrating data from multiple sources rather than relying on a single definitive study. In the context of dermal carcinogenicity, a WOE assessment may combine findings from genotoxicity studies, repeat-dose toxicity studies, human exposure data, structure-activity relationships, and information from related compounds or drug classes. This comprehensive evaluation is used to determine whether a dedicated carcinogenicity study is necessary, allowing for more efficient drug development while maintaining scientific rigor and patient safety. 

A successful WOE justification is not a simple undertaking and requires a comprehensive and scientifically rigorous assessment that incorporates animal, human, and class-specific information to provide a strong rationale for whether or not animal carcinogenicity studies would add value to the overall human carcinogenicity risk assessment. 

Carcinogenicity Assessment Strategy for Dermal Products	Number of Approvals
Reliance on Listed Drug	6
Weight-of-Evidence approach using data from Sponsor-conducted chronic dermal toxicity study showing no preneoplastic lesions	3
Conducted a dermal carcinogenicity study	1

Myth 3: 505b2 products cannot be New Molecular Entities 

From 2019-2023, 21 of the 505(b)(2) approvals were classified as New Molecular Entities (NME), specifically, Type 1 NDA. For 20% of them (four out of 21), no nonclinical studies were needed for approval. All of these were radiopharmaceuticals for medical imaging and relied on published literature, such as data on the non-radiolabeled molecule for approval. Of the NME approvals, only three had small nonclinical programs, such as a general toxicity study plus genotoxicity studies. These three approvals were diagnostic imaging agents and relied on published literature for pharmacology, pharmacokinetic and absorption, metabolism, distribution, and excretion information. The other NME approvals had larger programs, ranging from three-four kinds of studies.

For example:  

• General toxicity + carcinogenicity study + genotoxicity 

• General toxicity + developmental and reproductive tox + irritation studies + excipient qualification studies 

• Full nonclinical package  

Thus, NMEs can be 505(b)(2) programs, though the size of the nonclinical package needed for approval varies.  

Navigating 505(b)(2) nonclinical programs with clarity  

Understanding the nuances of nonclinical requirements in 505(b)(2) development programs is essential for efficient regulatory strategy and successful approval. While the pathway offers opportunities to streamline development by leveraging existing data, assumptions based on previous programs or common misconceptions can lead to missteps. A data-driven, case-by-case approach—grounded in scientific rigor and regulatory insight—is key to navigating these complexities. By staying informed of current trends and applying tailored strategies, sponsors can maximize the advantages of the 505(b)(2) pathway while ensuring patient safety and regulatory compliance. 

Toxicologists at Premier Research have extensive experience evaluating nonclinical 505(b)(2) strategies, conducting comprehensive WOE assessments, and designing and monitoring active testing programs. Contact us today to learn more.   

About the data 

Premier Research maintains a database collecting 505(b)(2) approval data published by the US FDA annually. The database contains key information from these approvals, e.g. type of approval, indication, division, review type, etc.  

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