Lessons from recent FDA actions in precision medicine 

Over the past few years, several cell and gene therapies (CGTs) in precision medicine have received FDA Complete Response Letters (CRLs). As the agency increases transparency by making some of these CRLs public, the industry now has greater insight into the recurring issues that stall promising advanced therapy programs.

This article synthesizes key lessons for precision medicine developers, from preventable protocol missteps to chemistry, manufacturing, and controls (CMC) gaps. Understanding why certain submissions were not approved can help future sponsors avoid similar mistakes and accelerate time to market.

Manufacturing and CMC challenges in cell and gene therapies

One striking pattern is the frequency of chemistry, manufacturing, and controls (CMC) issues cited in CRLs for advanced therapies. Of the cell and gene therapies (CGTs) approved to date, at least ten received CRLs at one point due to manufacturing or product quality concerns. These therapies involve complex biological products, so regulators hold a high bar for consistency and quality. 

Common manufacturing pitfalls

1. Potency assays not aligned with clinical effect: The FDA has flagged cases where the chosen biomarker or assay didn’t clearly correlate with the therapy’s mechanism of action or patient outcome. Developers should ensure their potency tests truly reflect the product’s intended effect, with appropriate modern methods and bridging data if assays evolve during development.
2. Inadequate comparability of product lots: Several CRLs noted that sponsors failed to demonstrate that later-stage or scaled-up production batches were comparable to the material used in pivotal trials. Any changes in process, scale, or site must be bridged with data; otherwise, the FDA questions whether the commercial product will be equivalent to the clinical trial product.
3. Facility and personnel readiness: The FDA has issued CRLs after facility inspections revealed shortcomings. In some cases, standard operating procedures were insufficient or staff training was lacking to reliably manufacture a safe product. Sponsors have to prove their manufacturing sites meet strict aseptic processing standards and are free of contamination risks before approval. Conducting mock pre-approval inspections and fixing gaps proactively is key.
4. Product stability data gaps: CGTs are often one-time or short-course treatments, but they still require stable shelf-life. FDA reviewers have cited sparse real-time stability data and unclear specifications for product storage. Generating stability data early (including shipping validations and interim shelf-life plans) can prevent questions about whether the product remains potent and safe through distribution.

Real-world examples

• Ultragenyx’s UX111 for Sanfilippo syndrome received a CRL in 2025 due to CMC and facility findings even though the clinical data raised no concerns.
• Rocket Pharmaceuticals’ gene therapy for LAD-I immunodeficiency received a CRL in 2024 requesting more CMC information despite excellent one-year survival outcomes.

In both cases, the lesson for sponsors is clear: invest early in robust manufacturing processes, comparability studies, and facility readiness. The FDA will not hesitate to delay a promising therapy if there are unresolved questions about product quality or consistency.

Insufficient efficacy evidence and trial design flaws

Another major shortcoming is insufficient evidence of efficacy. Although rare disease trials often involve small populations, the FDA still requires convincing, well-controlled evidence that benefits are meaningful and reproducible.

1. Submissions lacking adequate pivotal data

When programs rely on a single study or surrogate endpoints, the FDA may request confirmatory evidence. For example, PTC Therapeutics’ vatiquinone for Friedreich’s ataxia received a CRL in 2025 stating that substantial evidence of efficacy was not demonstrated, with the FDA requesting an additional well-controlled study.

2. Endpoints not demonstrating clinically meaningful benefit

Even if a therapy meets a surrogate or intermediate endpoint, the FDA evaluates whether the observed effect clearly translates into patient benefit. Capricor Therapeutics is now resubmitting an application to the FDA for its Duchenne cell therapy CAP-1002 after initially receiving a CRL. The agency had concluded that the available data did not yet provide sufficient evidence of clinical benefit.

3. Trial designs lacking adequate controls

While placebo-controlled trials are not always suitable for rare disease programs, recent CRLs demonstrate that the FDA will not accept trial designs that do not provide sufficiently robust comparative evidence. For example, Mesoblast’s Ryoncil, a cell therapy, was approved at the end of 2024 after two CRLs, one in 2020 and another in 2023, each requesting additional controlled data and adult patient evidence.

More recently, in 2025, the FDA issued CRLs to Replimune and Capricor after determining that the studies supporting their BLAs were not sufficiently controlled to demonstrate substantial evidence of efficacy, even though the sponsors believed their designs were aligned with earlier FDA feedback. These cases underscore that sponsors cannot assume single-arm data or early trial-design agreements will satisfy regulatory expectations and should plan for more rigorous control strategies wherever feasible.

Post-approval follow-up plans

Efficacy alone is not enough. For CGTs in particular, the FDA now treats strong post-approval follow-up planning as an essential part of the risk-benefit assessment. Sponsors must show that they can reliably track delayed adverse events, durability of effect, and real-world outcomes across the entire lifecycle of the therapy.

Recent FDA guidance and review practices highlight several expectations that are especially relevant in precision medicine:

• Long-term patient follow-up: Many gene therapy programs are expected to include 10 to 15 years of structured long-term follow-up through observational studies, patient registries, or similar approaches that allow sustained monitoring over time.
• Clear durability assessment plans: Regulators want to see how sponsors will evaluate long-term clinical durability and identify any decline in treatment effect, particularly for one-time interventions.
• Reliable patient tracking systems: The FDA evaluates whether sponsors have feasible plans for maintaining patient participation and engagement over many years, including strategies for continued data collection if patients move, transition care, or age into new clinical settings.
• Use of real-world evidence: Because many precision medicine therapies have small or heterogeneous patient populations, the FDA often expects sponsors to incorporate real-world data to supplement long-term safety and effectiveness surveillance.

Together, these expectations reinforce that sponsors who build strong monitoring strategies early in the program can reduce approval risks, support a more complete understanding of safety and durability, and increase confidence among regulators.

Conclusion: Proactive planning to avoid CRLs

The recent wave of FDA CRLs in precision medicine highlights a consistent theme. Many deficiencies are preventable when teams anticipate regulatory expectations and build programs with rigor from the start.

Companies that ultimately succeeded did so by strengthening manufacturing controls, generating longer-term efficacy data, or conducting additional trials. Early cross-functional planning across clinical development, CMC, safety, regulatory, and post-market teams significantly reduces the likelihood of surprises along the way.

As the FDA continues to make past CRLs public, sponsors have more opportunities to learn from precedent. Teams that study these examples, address potential issues early, and engage the agency throughout development can significantly increase their chances of first-cycle success and deliver innovative therapies to patients faster.

To explore more practical strategies, read our blog, Top five regulatory signals sponsors can act on now. For a deeper look at the regulatory trends shaping advanced therapy development, download our whitepaper, The FDA and precision medicine in 2025.