The FDA's recent complete response letters (CRLs) for two promising immunotherapies have sent shockwaves through the biotechnology industry, highlighting the agency's increasingly stringent requirements for chemistry, manufacturing, and controls (CMC) in advanced therapy development. On July 22, 2025, Replimune received an unexpected CRL for its Biologics License Application for RP1 (vusolimogene oderparepvec) in combination with nivolumab for advanced melanoma treatment, followed by Capricor Therapeutics' CRL for CAP-1002 (deramiocel) on July 11, 2025, for Duchenne muscular dystrophy-associated cardiomyopathy.
Both rejections came as surprises to the companies, which had maintained regular FDA engagement throughout development and received positive signals during mid- and late-cycle reviews. "We are surprised by this FDA decision and disappointed for advanced melanoma patients who have limited treatment options," said Replimune CEO Sushil Patel, PhD, noting that "the issues highlighted in the CRL were not raised by the agency during the mid- and late-cycle reviews."
Rising Bar for Manufacturing Readiness
The unexpected nature of these CRLs reflects a broader shift in FDA expectations for biologics and advanced therapies. According to recent data, 74% of CRLs issued from 2020 to 2024 cited quality or manufacturing deficiencies, underscoring that CMC considerations have become a primary hurdle to approval.
"Late-stage FDA rejections, even after seemingly smooth submissions and inspections, underscore that 'guidance' is not approval," said Henrick Johanning, senior VP, Quality & Strategy, Epista Life Science. "Too often, analytical methods or tech transfer plans that passed early scrutiny collapse under the weight of commercial-scale expectations. The lesson is clear: CMC rigor and lifecycle planning must be treated as front-line regulatory strategy, not a post hoc technical detail."
The agency now requires rigorous demonstration of process and analytical method equivalency as products move to commercial scale, particularly for potency, purity, and viral titer measurements. Even minor deficiencies in potency assay validation and acceptance criteria justification commonly yield CRLs, including for cell and gene therapies.
Tech Transfer Emerges as Critical Risk Factor
Technology transfer has become a major point of regulatory inspection and scrutiny, particularly for advanced therapies where the transition from development to commercial manufacturing introduces significant risk. Common tech transfer pitfalls include poor documentation, equipment and process parameter differences, and lack of robust comparability protocols.
"I wonder if part of the problem is that many biotechs do not have sufficient experience in-house, and rely on contract organizations," observed Chris Moreton, PhD, VP, Pharmaceutical Sciences, FinnBrit Consulting. "However, the contract staff may not be sufficiently familiar with the details of the project they are working on. Thus things fall between the cracks, so to speak."
FDA inspections frequently reveal that process changes—even seemingly minor ones such as different purification filters—without proper justification lead to regulatory deficiencies. The agency expects detailed comparability protocols addressing process and assay changes, siting variability, and bridging studies before any modifications are implemented.
Analytical Consistency Under Scrutiny
The FDA's emphasis on analytical consistency across batches has intensified, with heterogeneity in patient responses highlighting the need for comparability data spanning clinical and commercial scales. Real-world studies confirm that even subtle assay inconsistencies may undermine approval prospects.
Specific analytical weaknesses flagged in recent CRLs include unclear linkage between assay outputs and clinical effectiveness, lack of justification for assay sensitivity limits, and use of different assay formats across development phases without bridging or revalidation studies. Without robust assay performance or clear comparability across lots, even well-conceived clinical trials can appear inconclusive to regulators.
Regulatory Landscape in Flux
These CRLs emerge amid significant changes at FDA, including the unprecedented posting of more than 200 CRLs issued between 2020 and 2024 for drug and biologic applications that were not approved during their initial review cycle. The agency has also seen leadership changes, with Peter Marks resigning as acting commissioner of Food and Drugs in March, citing concerns over scientific integrity.
Recent initiatives such as Project Optimus require tighter integration of CMC, analytical, and dose-response evidence early in development and before pivotal trials. Regulatory requirements now include commercial-ready tech transfer and operational manufacturing controls before study readout or data submission.
Strategic Implications for Industry
The RP1 and CAP-1002 CRLs illustrate that CMC and analytical disciplines now play roles as decisive as clinical data for product success. Companies must prioritize tech transfer and comparability by ensuring methods, equipment, documentation, and batch records align across all sites and phases.
Analytical validation must reflect all key populations enrolled in pivotal trials, with sponsors required to establish stratified quality control data by demographic, disease, and treatment subgroups. Without robust stratified QC systems, reviewers may attribute efficacy signals to uncontrolled process drift, prompting application denials even with persuasive clinical rationales.
As clinical trials become more representative of real-world populations, FDA expects similarly comprehensive CMC controls. This includes detailed comparability protocols and the ability to demonstrate consistent safety and efficacy across diverse patient subgroups through rigorous analytical bridging.
The evolving regulatory landscape demands that biomanufacturing and analytical teams approach CMC as a strategic priority rather than a technical afterthought, with proactive auditing and internal reviews becoming essential to reduce the risk of costly, late-stage FDA pushback.
