Rewriting Approval: The FDA's Emerging Framework for Faster Access to Therapies

This year, the nation celebrates the 250^th anniversary of the American Revolution. At the same time, the U.S. Food and Drug Administration (FDA) is undertaking what may be viewed as a conceptual revolution of its own, reflecting a growing independence from one‑size‑fits‑all regulatory assumptions developed for traditional, population‑level drug development. Through a series of policy initiatives, the FDA is enabling certain medical products to reach the public more quickly through existing statutory authority and regulatory discretion.  

First, in January, the FDA published two updated guidance documents addressing: (1) low-risk digital health devices for general wellness use; and (2) clinical decision support (CDS) software. These documents clarify the circumstances in which the FDA may exercise enforcement discretion, allowing some companies to commercialize qualifying products without premarket authorization. See our prior discussion of the updated guidance and the FDA's continued refinement of its approach to software-driven innovation, including lifecycle expectations for artificial intelligence (AI) and machine learning (ML) for software as a medical device (SaMD).  

The FDA’s push to bring new drugs to market outside of the traditional approval process continued in early April, when the FDA announced plans to consider reclassifying certain currently unapproved, injectable peptides to permit their sale by pharmaceutical compounders, notwithstanding ongoing questions regarding the sufficiency of available safety and effectiveness data. See our recent discussion of the FDA’s announced plans.  

A third foray in the FDA’s alternative pathway revolution is now underway: this time for rare disease treatment modalities. On April 26, 2026, the comment period closed on a new draft FDA guidance describing a proposed framework for developing certain individualized therapies that have not yet been tested in humans, where sponsors can demonstrate a scientifically plausible mechanism of action and meet FDA’s evidentiary standards.  

As with any change in regulatory approach, a central question behind the FDA’s proposed “plausible mechanism framework” is whether the need for immediate treatment options justifies greater regulatory flexibility in evidentiary expectations, as compared to traditional clinical trial paradigms. Given the stakes for patients with rare, life-threatening disorders lacking treatment options, the FDA has articulated a policy rationale for advancing this initiative, particularly in circumstances where no adequate or available therapeutic alternatives exist. 

Accelerated Approval Program 

The FDA already has a rule in place, the Accelerated Approval Program, allowing for earlier approval of drugs that treat serious conditions based upon the use of a “surrogate endpoint,” consistent with FDA’s authority under the Federal Food, Drug, and Cosmetic Act (FDCA). A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure thought to predict a clinical benefit in the absence of comprehensive clinical trials. Companies are still required to conduct post-treatment studies to confirm the clinical benefit. If no benefit is confirmed, the FDA could remove the drug from the market. Examples of treatments approved through this program include malignant hematology and oncology indications.   

Plausible Mechanism Framework 

The proposed “plausible mechanism framework” arose after physicians successfully employed experimental gene therapies to address ultra-rare disorders, where engaging in the full clinical trial process was just not feasible. One frequently cited example is the story of Baby K.J., where an infant with urea cycle disorder was treated with the world’s first personalized CRISPR gene editing drug product.  

The proposed plausible mechanism framework is not a new approval pathway; rather, it reflects the FDA’s interpretation of how sponsors may satisfy the statutory requirement for substantial evidence of effectiveness, as required by law, to support the development of individualized therapies for ultra-rare diseases (particularly genome editing and RNA-based products) in the absence of full-blown clinical trials. The proposed framework would only apply to certain qualifying therapies, such as gene therapies that correct single-letter DNA errors, where large-scale, randomized clinical trials are often not feasible or ethically justifiable. A prime example is gene therapy for cystic fibrosis. Although the disorder affects approximately 40,000 people in the U.S., hundreds of gene mutations can cause it. Accordingly, clinicians generally cannot rely on a single gene therapy formulation to treat every patient. But if a gene-editing tool and delivery technique have been safe in past human trials, then such tools and techniques can be customized for specific mutations in each cystic fibrosis patient. Due to the individual nature of each patient’s treatment, traditional large-scale randomized trials may not be feasible; but clinicians can extrapolate from similar treatments that the proposed individualized treatment plan would “plausibly” succeed.  

As discussed in the draft guideline, the plausible mechanism framework requires sponsors to demonstrate the following:  

1. Identification of a specific genetic, cellular, or molecular abnormality clearly linked to the disease;  
2. Demonstration that the therapy directly targets the underlying biological mechanism; 
3. Support from well‑characterized natural history data from untreated patients; 
4. Evidence of successful target engagement, drugging, or editing; 
5. Demonstration of clinically meaningful improvement or beneficial effects on validated biomarkers; and 
6. Robust chemistry, manufacturing, and controls (CMC) data and compliance with Current Good Manufacturing Practice (cGMP) to support the quality of the product. 

Postmarketing surveillance will be critical to the framework's long-term viability. In proposing the framework, the FDA recognized that safety datasets at approval will be limited; thus, continued demonstration of both safety and clinical benefits are essential.  

The Path Forward 

Prior to the close of the comment period on the draft guidance, the FDA received over 150 comments, most of which were overwhelmingly supportive of the initiative. The main questions raised regarding the new guidance center around three areas.  

First, while the new framework is largely designed to address bespoke treatments for ultra-rare diseases affecting one or very few patients, the scope of the framework suggests that it could be expanded in the future to cover small molecules, antibodies, and other therapies for non-rare diseases. Will the framework spur development of novel products, as intended, or will sponsors seek to test the boundaries of the framework as a less resource-intensive evidentiary approach for products already in development?  

Second, how will the flexibilities outlined in the guideline be applied in practice? There have been certain cell and gene therapy (CGT) decisions within the past year where the FDA declined to approve novel and other rare disease therapies and instead requested more traditional randomized, controlled trials. Does the new guidance truly represent a change in the FDA’s approach?  

Third, and above all, the success of the program will depend upon how rigorous sponsors are in their post-market study of a rare disease drug’s effectiveness and safety. The absence of lengthy randomized clinical trials pre-approval points to the need for robust and continuous post-trial monitoring for both safety and efficacy. As one medical ethicist reviewing the framework noted, “post-approval monitoring of drugs has never been done with earnestness, despite promises made by sponsors… If we're going to take more risk to go faster at the front end, you have to beef up what's required and what's going to be monitored at the back end, post approval." 

The plausible mechanism framework outlined in the new draft guidance represents a significant evolution — if not a conceptual revolution — in the FDA's regulatory approach. Much like the policy initiatives discussed at the outset of this article, the framework reflects a broader willingness to reconsider long‑standing regulatory paradigms in light of new scientific realities. In particular, the program seeks to reconcile the fundamental tension between precise new therapeutic tools and approval standards developed for an earlier era of drug development without requiring changes to the underlying statutory framework governing drug approval. Sponsors considering individualized or bespoke therapies should therefore assess, early in development, whether their programs can meet the framework’s scientific, manufacturing, and post-approval monitoring expectations. 

Authored by Maria-Cristina Smith, Berkley Life Sciences, VP, Products & Professional Liability Specialist