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Back to Basics: 505(b)(2) FAQs Part 2: Clinical and Nonclinical Studies

As the 505(b)(2) expert, Premier Consulting is frequently asked questions about how to get a product approved via the 505(b)(2) regulatory pathway and if this pathway is appropriate. Given the growing popularity of the 505(b)(2) pathway for approval of repurposed, reformulated, or unapproved-marketed products, we thought it would be worth providing a refresher. Here is Part 2 in our series of frequently asked questions (FAQs). Stay tuned to this blog for more FAQs and Premier Consulting’s responses in the coming weeks.

Q1: Can you skip Phase 1 and Phase 2 [studies] for a 505(b)(2)?

In theory, yes. A 505(b)(2) application may be approved on the basis of any combination of studies or even no studies. However, more typically, a Phase 1 study will be required. This is because a 505(b)(2) application relies on existing information from approved products or products in the literature. This is in contrast to a 505(b)(1) or new chemical entity application in which the sponsor conducts all studies required for approval. To rely on existing information, a sponsor must demonstrate how similar or different their product is from the product used in the existing information. This is known as establishing a scientific or clinical bridge, and is frequently fulfilled through a Phase 1 bridging study.

Having said this, an in-depth knowledge of, and experience with the 505(b)(2) pathway can allow a sponsor to eliminate costly and time-consuming studies, including Phase 1 studies. Premier Consulting has accomplished this is the past via innovative animal or in vitro studies, or for some products by leveraging specific information in the literature. As every 505(b)(2) is different, different strategies can be employed to reduce a sponsor’s clinical (and nonclinical) program.

Q2: For a fast route for NDA filing via 505(b)(2), is it feasible to do so via BA/BE studies instead of following the routine steps of Phase 1,  Phase 2 and Phase 3?

Absolutely! As discussed in the previous question, a ‘typical’ 505(b)(2) application (if there is such a thing) is more likely to contain a Phase 1 bioavailability/bioequivalence (BA/BE) bridging study and fewer, if any, Phase 2 or Phase 3 studies than an application for a new molecular entity. A faster development program with fewer studies is one of the major benefits of the 505(b)(2) pathway.

Q3: Are clinical trials required for a 505(b)(2)? If so, how is that different from 505(b)(1)?

The requirement for clinical studies will depend on various factors, including how different the proposed product is from the existing product, including indication, dosage, route of administration, and on the type and quality of the information available in the literature or in approved-product labeling. If the Phase 2 and/or Phase 3 studies have already been conducted, this data can be referenced in the 505(b)(2) application in place of sponsor studies.

This is in contrast to a 505(b)(1) application in which the sponsor must submit full reports of safety and efficacy for its proposed product. This means all studies required for approval must be conducted by the sponsor.

Q4: Are nonclinical studies required for a 505(b)(2) application?

Many 505(b)(2) applications do not require the sponsor to conduct nonclinical studies. In these cases, the successful application will contain adequate evidence of safety for the proposed product. This may include clinical data, nonclinical studies reported in the literature or approved product labeling, or other justification of why the product is safe for its proposed use.

Q5: Can we refer to the original NDA for Toxicology and Bioavailability data when we file 505(b)(2)? If yes, then how does that process work?

Information in the product labeling can be referred to if it is appropriate for the proposed product. However, while toxicity or bioavailability data that only appears in the Drug Approval Package (Summary Basis of Approval or SBA) can be referenced as supportive information, it cannot be relied on to avoid conducting a study. This is because the product labeling represents a finding of safety and efficacy by the FDA, but the Approval Package represents only the comments of individual reviewers rather than the FDA.

What happens if you need the information in the Approval Package for the 505(b)(2) submission? Once again, experience with 505(b)(2) may offer innovative options for referencing data from other sources such as the literature or toxicology databases that may fulfill the requirement for nonclinical studies.


From the answers above, you can see that every 505(b)(2) submission differs. While one 505(b)(2) development plan may contain one required clinical study, another may require two, for different reasons. And the possibility of a literature-only submission also exists.

The one common factor in 505(b)(2) applications is that each one relies on existing material. The discovery and application of the existing information requires creativity, depth and breadth of knowledge, long-standing experience with the FDA to understand the current reasoning and history, as well as multi-disciplinary expertise within 505(b)(2) to pull the entire program together. Without this, a program aiming to become approved via the 505(b)(2) pathway may be misaligned (risking clinical hold), or over-programmed such that the benefits of 505(b)(2) are not fully realized.

For an assessment of whether your product is appropriate for approval via the 505(b)(2) pathway or to learn more about ways Premier Consulting’s multi-disciplinary team can help you create an optimized development plan to get your product approved, read more here or contact us.

Other installments in “Back to Basics: 505(b)(2) FAQs”:


Angela Drew, Ph.D.
Product Ideation Consultant