Why Biopharma Developers Should Care About FDA’s New Personalized Therapy Approval Process

FDA’s novel regulatory framework, dubbed the “plausible mechanism” pathway, is intended to allow approval of highly individualized therapies based on a small number of patients, rather than the large randomized trials typically required, according to a statement drafted by FDA Commissioner Marty Makary, MD, and Chief Medical and Scientific Officer Vinay Prasad, MD, and published in the New England Journal of Medicine on November 12, 2025 (1).

In the statement, Dr. Prasad and Dr. Makary note that the traditional regulatory model is burdensome for conditions for which patient populations are extremely small. “Critics may contend that there is no need for an alternative pathway and that existing FDA operations are able to address bespoke, transformative therapies,” they wrote (1). “Unfortunately, the FDA has heard from patients, parents, researchers, clinicians, and developers that current regulations are onerous and unnecessarily demanding, provide unclear patient protection, and stifle innovation. We share this view.”

The move comes at a time when biopharmaceutical companies developing gene-editing or cell therapies for ultra-rare diseases argue that the development cost and regulatory burden are insurmountable given tiny populations (2). The new pathway is designed to address this gap while still requiring evidence of target engagement, biological plausibility, and observed clinical improvement.

How will this pathway affect drug manufacturing and development?

Under the new paradigm, a therapy must address a known biological cause of disease (e.g., a specific gene mutation), demonstrate that the therapeutic interacts with that target (i.e., by showing an edit or modification in the target cells), and show clinical improvements in the treated patient or patients (1). This new pathway creates both opportunities and challenges for manufacturers and drug developers. On one hand, developers of bespoke treatments—such as custom gene-editing therapies tailored to a single patient—may see accelerated access to regulatory approval. The case of an infant successfully treated with a bespoke CRISPR therapy for a urea-cycle disorder is cited by FDA as emblematic of the new approach (1).

On the other hand, such therapies pose distinct manufacturing challenges, such as one-off or small-batch production, personalized supply chains, and real-world evidence (RWE) commitments post-approval. As the agency signals that approvals under this pathway will require ongoing monitoring of safety and efficacy in the real-world setting, developers must factor in post-market obligations earlier in the manufacturing design process (3).

From a development cost perspective, time-to-market could be shortened and development risk mitigated if sponsors are allowed to demonstrate efficacy with small patient numbers rather than extensive randomized trials. By extension, this pathway may also reduce manufacturing scale-up risk and may also encourage investment in platform technologies that can service multiple personalized indications (3).

“The key challenge today is that drug manufacturing rules impose a one-size-fits-all burden that slows innovation for rare and ultra-rare diseases," Sadik Kassim, PhD, chief technology officer, Life Sciences Omics Solutions Group, Danaher, told BioPharm International. "Without a viable CMC [chemistry, manufacturing, and controls] framework, developers are forced to shelve promising therapies even when a single manufacturing run could treat every patient. Fixing this mismatch is critical for accelerating progress."

What are the broader industry implications and risks?

This regulatory shift is important for the biopharma industry because it signals a substantial change in how novel therapies, especially gene and cell therapies, may be regulated and brought to market. By lowering the barrier for approval of individualized treatments, FDA is effectively expanding the viable market for ultra-rare disease therapies and platform technologies that can serve them (3).

However, risks remain in that the pathway still demands rigor in demonstrating biological mechanism and safety. The lack of large randomized trials means uncertainties about long-term safety and durability may remain greater than in traditional routes.

As a result, manufacturers will need to monitor post-marketing data and build manufacturing processes that can support RWE collection, scaling of bespoke therapies, and adaptation from single-patient to multiple-patient (or platform) models (3). The pressure to maintain quality, reproducibility, and cost-effectiveness in highly individualized manufacturing may become a differentiator in the industry.

References

1. Prasad, V.; Makary, M. A. FDA’s New Plausible Mechanism Pathway. N. Engl. J. Med. Nov. 12, 2025. DOI: 10.1056/NEJMsb2512695
2. Wong, C. H.; Li, D.; Wang, N.; et al. The Estimated Annual Financial Impact of Gene Therapy in the United States. Gene Ther. 2023, 30, 761–773. DOI: 10.1038/s41434-023-00419-9
3. Sutter, S. US FDA’s ‘Plausible Mechanism’ Pathway: A Platform-Based Approach Not Just for Rare Diseases. insights.citeline.com/pink-sheet, Nov. 12, 2025.