Decoding FDA's new ‘plausible mechanism framework’ guidance: what drug developers need to know

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

The FDA’s recently issued draft guidance on ‘plausible mechanism framework’¹ provides welcome details on the Agency’s new regulatory approach to the development and approval of individualized genetic therapies for ultra‑rare diseases.  Recognizing that traditional randomized trials are not feasible due to the specificity of the mechanism of action (MOA) of the individualized product and the rarity of the disease, the plausible mechanism framework allows for approval based on strong mechanistic rationale plus limited clinical data. 

Understanding the Plausible Mechanism framework 

Types of diseases and drugs covered 

This innovative regulatory approach is intended for treatments targeting rare genetic diseases. Although the guidance specifically discusses genome editing (GE) and RNA-based therapies, including those based on antisense oligonucleotides (ASOs),  it does not explicitly limit applicability of the Plausible Mechanism framework to only those product classes. The framework will be particularly useful for ultra-rare diseases where traditional clinical trials  present significant operational challenges. 

Qualifying criteria 

The pathway aims to balance flexibility with practicality, while still maintaining scientific rigor.  To qualify for development under this pathway, the following must be demonstrated:

Drug approval under the framework  

The plausible mechanism framework is not an approval pathway. Rather, the framework represents FDA’s recommendations and expectations for how to generate substantial evidence of effectiveness² to support the development of individualized therapies for ultra-rare diseases. 

Approval may occur via either the traditional approval pathway or the accelerated approval pathway depending on the endpoints used in the clinical study. Individualized therapies licensed under accelerated approval will be required to demonstrate efficacy in a post-approval confirmatory study. 

Additionally, post‑marketing studies and surveillance are required. Data from real‑world experience will be needed to confirm safety and efficacy, and to monitor for unexpected risks. 

Opportunities for Sponsors 

• First‑in‑human (FIH) trials can serve as pivotal trials to support approval – i.e., a single FIH study may double as a pivotal trial if the mechanistic evidence for the drug is strong. Accordingly, the FIH trials should be designed as adequate and well-controlled studies. 
• Strong role for biomarkers for efficacy support – Biomarkers can serve as surrogate endpoints or provide confirmatory evidence of effectiveness.  This highlights the opportunity for identification of new biomarkers and multi-disciplinary input to validate the biomarkers and provide reassurance that the results generated are of clinical relevance. 
• Flexibility in the nonclinical programs – such as the type of pre-clinical models needed and model selection for individualized therapies with a specific and well-characterized mechanism of action. The framework allows for leveraging existing data, such as proof of concept (POC) and safety data from similar clinical programs (e.g., multiple gRNAs and/or different versions of a genome editor).  Also, abbreviated nonclinical safety studies may be considered for an investigational ASO-based therapy, if the therapy belongs to a well-characterized class. 
• Exploration of new approach methodologies (NAMs) within the nonclinical program – The Plausible Mechanism framework is an exciting opportunity to identify and validate different NAMs and thereby contribute to the maturation of these methods.  NAMs have the potential to decrease the time and cost of nonclinical development.   
• Robust CMC strategy with leveraging of prior knowledge – The shortened development timeline and low number of batches necessitate early establishment of a clear CMC strategy that integrates key considerations of commercial manufacture even at early IND stage. Identification of reliable, reproducible and robust analytical methods early in development is also critical.  Development of platform technologies and the use of prior knowledge can inform the planning for the manufacturing process, control strategy, formulation and characterization of an investigational individualized therapy. Because Individualized therapies necessitate rapid CMC development, participation in FDA’s Manufacturing Pre-Check pilot program² can be one mechanism to avoid CMC roadblocks for approval. Frequent FDA feedback as part of this program can support CMC strategies including late-stage activities, such as facilitation of the manufacturing site inspection. 
• Shorter path to line expansion - Platform Technology designation for the product could enable expansion to additional mutations or related conditions, with post-marketing requirements to gather data on long-term safety, potential off-target effects, and developmental outcomes for pediatric patients.³ 

Overall, the Plausible Mechanism framework represents an important step toward increasing the availability of much-needed treatments for patients with rare diseases.  The framework shifts what comprises core evidence, with natural history and biomarker data now serving as critical elements of core evidence, with approval potentially based on the first trial in a single patient, or very few patients. To successfully implement the framework, sponsors must coordinate clinical, nonclinical, regulatory, and manufacturing programs that yield a tightly integrated narrative supporting efficacy and safety.  High‑quality regulatory science is foundational to the development program, and both early and frequent FDA engagement is essential.  For the framework to be of greatest benefit to patients, both sponsors and the FDA must consistently apply a science-driven, predictable regulatory approach. 

Next steps  

For sponsors considering alignment with the plausible mechanism framework, Parexel's regulatory experts provide deep insights into how to apply this regulatory framework to accelerate development and maximize approval success. Our team brings extensive experience in cell and gene therapy assessments within CBER/FDA, enabling us to translate complex regulatory expectations into actionable development strategies that strengthen regulatory submissions and build compelling, science-driven narratives.  

Please contact us; we are always available for a conversation. 

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References 

1. FDA Draft Guidance for Industry, Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause (2026). https://www.fda.gov/media/191247/download.  
2. FDA Draft Guidance for Industry, Demonstrating Substantial Evidence of Effectiveness with One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence (2023).  https://www.fda.gov/media/172166/download.  
3. FDA Manufacturing PreCheck Pilot Program.  Information available at: https://www.fda.gov/industry/fda-manufacturing-precheck-pilot-program 
4. FDA Draft Guidance for Industry (2024), Platform Technology Designation Program for Drug Development.   https://www.fda.gov/media/178938/download  

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