Unlocking Bespoke Product Approvals: FDA Puts Forth Plausible Mechanism Pathway

On November 12, 2025, the New England Journal of Medicine published an article authored by FDA Commissioner Marty Makary and Center for Biologics Evaluation and Research (CBER) Director Vinay Prasad introducing the concept of a "plausible mechanism" pathway to facilitate the development and approval of personalized therapies, in cases where traditional randomized controlled trials are not feasible. This pathway would apply to diseases with a well-defined biological cause and focus on conditions with significant unmet needs, particularly fatal, rare, and severe pediatric diseases, as well as common diseases with no alternative treatments.

The article notes that this initiative addresses feedback from stakeholders that existing regulations can impede innovation and are unnecessarily demanding. To support the development and introduction of important therapies to the market, the FDA seeks to collaborate on evidence standards that adapt to scientific progress while ensuring the appropriate implementation of safeguards.

The plausible mechanism pathway is illustrated by the case of “Baby K.J.”, a newborn with CPS1 deficiency, a rare urea cycle disorder causing high ammonia levels and inhibiting proper protein processing. For Baby K.J., the FDA approved a single-patient expanded access IND in just one week, allowing him to receive treatment through three doses of a lipid nanoparticle-delivered base editor to fix his specific genetic mutation. 

The article outlines five key elements that are relevant for the new plausible mechanism pathway: (i) identification of a specific molecular or cellular abnormality; (ii) products that target the underlying or proximate cause of biological alterations direct-targeting therapy; (iii) a good understanding of the untreated disease course; (iv) confirmation that the target was “successfully drugged, edited, or both” (via models or feasible biopsies); and (v) “improvement in clinical outcomes or course.”  Consistent improvements will be viewed favorably.  The FDA will also evaluate sustained improvement or longer remissions. 

According to the article, the FDA will move forward with generating marketing authorization for a product after a manufacturer has demonstrated success with several consecutive patients. Sponsors will be required to make post-marketing commitments to confirm the continued preservation of efficacy and to demonstrate that there are no off-target effects, in addition to studying the impact on childhood development to monitor and detect safety signals. 

The FDA’s innovative plausible mechanism pathway represents a pivotal shift toward regulatory agility, signaling an attempt to better align with the rapid pace of genomic breakthroughs. The plausible mechanism pathway has the potential to streamline access to life-altering therapies. This article, along with other recent programs announced by the FDA, such as the pre-check program, appears to support the FDA’s continuing commitment to evolve its processes to bring essential therapies and medicines to market.