N=1 Collaborative: FDA’s New Plausible Mechanism Pathway

November 19, 2025

By Julia Pian, MD

Last Wednesday, the U.S. Food and Drug Administration announced the Plausible Mechanism Pathway, outlining in broad strokes a new regulatory strategy for supporting the responsible advancement of precision genetic therapies [1]. As an independent, cross-sector non-profit, the N=1 Collaborative welcomes this move, signaling the FDA's willingness to be a creative partner in developing models to unlock the potential of precisely targeted, programmable therapies, a critical sector of technology that currently lacks sustainable models for patient access.

The following key aspects of cases that would qualify for this pathway represent a deliberate approach to balance the risk-benefit of bespoke therapies: 

1. Identification of a specific molecular or cellular abnormality

2. Targeting the underlying or proximate biological alterations 

3. Availability of well-characterized natural history of the disease in the untreated population 

4. Confirmation of successful target engagement (when possible)

5. Improvement of clinical outcomes and course 

The FDA states that “once a manufacturer has demonstrated success with several consecutive patients with different bespoke therapies, the FDA will move toward granting marketing authorization for the product”[1]. We see this as an important initial step towards hope for life-changing individualized medicines for patients suffering from genetic diseases. 

As the N1C had published in a Comment last year [2], regulatory change is one of three key pillars that we see will drive access to potentially life-changing medicines for patients. Additional critical pillars include 1. early engagement with payors around innovative reimbursement models, and 2. data sharing to ensure transparency and community trust in this new process.

For those that want to learn more about these topics, we encourage you to browse our resource navigator, including:

• Publication Pian et al 2024 How to pay for individualized genetic medicines Nature Medicine

  • N1C Fireside Chat on the Publication

• Publication: The Rare Therapies Launchpad: a pilot program for individualized medicines in the UK

• N1C Seminar: Snakeholders and Stakeholders: How Zookeepers and Border Smugglers Set the Stage for Antivenom Commercialization in the USA, October 2024

• N1C Seminar: New Business Models and Funding Strategies for Developing and Paying for Rare Diseases with Andrew Lo, July 2023

• N1C Seminar: Transforming Patient Access to High-Cost, On-Time Treatments through Financial Engineering Innovation August 2024

• N1C Seminar: Regulatory: The Future Pathway to Access November 2023

For those interested in being a part of our community and work, please reach out to info@n1collaborative.org.

Sources: 

1. Prasad and Makary 2025 FDA’s New Plausible Mechanism Pathway NEJM

2. Pian et al 2024 How to pay for individualized genetic medicines