Individualized Therapies on the Rise: Reflections from the Duke-Margolis/FDA Workshop

Sabine Ruehle, Director in the Regulatory Affairs team at Boyds, discusses the growing momentum behind individualized therapies and reflects on the insights from the recent Duke-Margolis / US FDA workshop on the topic.

Individualized therapies for a single patient (‘n-of-1’) or very small patient groups (‘n-of-few’), such as antisense oligonucleotides (ASOs) and emerging gene-editing approaches, are accelerating at a pace that challenges traditional drug development paradigms and associated regulations, which were developed to test single medicines that treat numerous patients. At the recent Duke-Margolis / US FDA workshop “Individualized Therapies on the RISE” (20 November 2025), stakeholders from academia, industry, regulatory agencies, and the patient community examined the current landscape and explored the scientific, regulatory, operational, and ethical considerations necessary for these therapies to become a realistic and accessible option for patients.

Several case studies illustrated how regulatory flexibility has already enabled individualized therapies to reach patients in months rather than years. These included Milasen, the first individualized ASO for CLN7 Batten disease (Kim et al., 2019), which opened the door for more than 40 subsequent INDs for individualized ASOs; followed by the recent gene-editing treatment for “Baby KJ”, delivered via a customized lipid nanoparticle for an ultrarare urea cycle disorder (Ahrens-Nicklas and Musunuru et al., 2025; Musunuru et al., 2025). These examples highlight both the promise of rapid, bespoke interventions and the complexity of ensuring consistent, safe, and interpretable development pathways.

Regulatory Expectations and Emerging Approaches

US FDA representatives from CDER and CBER emphasized that while regulatory standards remain unchanged, a fit-for-purpose approach may be applied for these therapies – with expectations tailored to specific circumstances, particularly in cases of rapid disease progression, high unmet need, and strong biological rationale. Key considerations include disease severity and trajectory, clarity of the causal mechanism, feasibility of generating traditional datasets, availability of predictive nonclinical models, availability of prior knowledge, and acceptable risk from a patient and caregiver perspective.

The call from developers and patient advocate groups to move away from the traditional models of drug development and evaluation, towards assessing platforms and processes, is recognized by regulators. First steps towards fit-for-purpose frameworks are being made, as reflected by the recent US FDA publication of the “plausible mechanism” pathway (Prasad, 2025), or – looking beyond the US – the UK MHRA’s policy paper on “Rare therapies and UK regulatory considerations” (MHRA, 2025). However, it is still early days, with the regulatory structures to operationalize this shift still evolving, highlighting the need for early regulatory engagement, transparency on uncertainties, and iterative learning across programs.

Nonclinical Development: Balancing urgency with data requirements

For individualized therapies, nonclinical development speed is often critical. Patients may deteriorate rapidly, sometimes before nonclinical studies conclude, illustrating the fine line between urgency and data requirements. For well-characterized ASO chemistries, FDA may accept abbreviated toxicology programs, with reduced study duration and a single justified species, provided that dosing rationale, exposure margins, and safety monitoring plans are clear. By contrast, gene-editing therapies typically require more extensive characterization, especially around biodistribution and off-target effects. Despite advances in in vitro and computational methods supplementing the nonclinical data package, these new approach methods (NAMs) may not fully replace in vivo data requirements. The importance of aligning nonclinical study design with the intended clinical use – ensuring coverage of anticipated dose ranges and exposure – and engaging early with regulators to establish a rational, risk-proportionate plan was underlined.

Clinical Development: Rethinking Evidence Generation

Clinical development for individualized therapies requires rethinking of traditional clinical trials for evidence generation. With limitations such as very small patient numbers, limited natural history information, and rapid disease progression, approaches such as patient-as-own-control designs, detailed baseline assessment, and carefully selected biomarkers can be utilized to overcome these limitations. Use of biomarkers, particularly pharmacodynamic measures, can support dose justification and provide early indications of clinical response when validated clinical endpoints are unavailable.

FDA representatives reiterated that flexibility does not equate to lowering standards. Instead,  benefit-risk assessments must be adapted to reflect medical urgency, biological plausibility, and feasibility constraints while still ensuring that decisions are grounded in systematic, interpretable data. Concepts such as master or umbrella protocols and adaptive designs were discussed as mechanisms to structure multiple n-of-1 efforts and build cumulative evidence to move on from single-patient approaches. However, practical implementation remains challenging. Early planning to determine the most meaningful outcomes and consistent data capture is critical to move beyond individual experimental treatments and enable regulatory decision-making in these small, complex programs.

Data Infrastructure: Enabling Learning Across Programs

To enable moving away from isolated n-of-1 therapies towards contributing to cumulative evidence generation, efforts to build registries, harmonize data elements, and create platforms that could support more robust comparisons across patients and diseases are needed. As more individualized therapies reach patients, shared data repositories combined with emerging analytical tools could enable more consistent evaluation of benefit and risk, support endpoint development, and reduce redundant work across programs.

Manufacturing and CMC: Platforms, Processes, and Practical Realities

The workshop participants agreed that a shift from approving fully characterized single medicinal products to evaluating the underlying processes and platforms that could support many individualized therapies is needed. Examples included shared chemistries for ASOs, modular lipid nanoparticle systems for gene editors, and platform-level validation strategies to streamline release testing and reduce redundancy. However, there remain many open questions, including what exactly constitutes a “platform” from a regulatory perspective, which elements of CMC packages can be reused across bespoke products and how to balance product-specific characterization with process-level assurances. While platform approaches hold potential promise, regulatory expectations are yet to be defined.

Beyond Regulatory: Reimbursement and Patient Access

Beyond evolving regulatory pathways, there are also reimbursement and access challenges that need to be addressed to allow wider patient access to these novel therapies. Currently, these therapies can reach a few individual patients, mostly due to philanthropic approaches. However, to allow more widespread access, incentives and clearer guidance for developers are needed. Evidence of clinically meaningful improvement will be necessary not just for regulatory approval but to justify payer coverage, particularly given the high per-patient cost of individualized therapies. Emerging models such as the UK’s Rare Therapies Launch Pad illustrate how regulatory and reimbursement pathways might begin to converge to support individualized therapies, but broader alignment between developers, regulators, payers, and patient groups is required.

Conclusion

Scientific and technological progress has made individualized therapies increasingly feasible, and when delivered in time, they can significantly impact patients’ lives. Workshop participants welcomed the FDA’s openness to adaptive, fit-for-purpose development pathways, balancing protection of public health with timely individual patient treatment. However, to transform these promising therapies beyond the treatment of single patients, system-level reforms in diagnostics, regulatory frameworks, manufacturing capacity, data infrastructure, and payment models will be essential.

References:

Ahrens-Nicklas RC, Musunuru K. How to create personalized gene editing platforms: Next steps toward interventional genetics. Am J Hum Genet. 2025;112(12):2826-2829.

Kim J, Hu C, Moufawad El Achkar C, et al. Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. N Engl J Med. 2019;381(17):1644-1652. 

MHRA Policy Paper, Rare Therapies and UK Regulatory Considerations, 2 November 2025; Accessed at: https://www.gov.uk/government/publications/rare-therapies-and-uk-regulatory-considerations/rare-therapies-and-uk-regulatory-considerations

Musunuru K, Grandinette SA, Wang X, et al. Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease. N Engl J Med. 2025;392(22):2235-2243.

Prasad V, Makary MA. FDA’s New Plausible Mechanism Pathway. N Engl J Med. Published online November 12, 2025. doi:10.1056/NEJMsb2512695