FDA Complete Response Letters: Strategies to Regain Approval

Navigating Complete Response Letters: how Clarivate solutions can help pharmas chart their path to approval

When a drug’s path to market is complicated by an unanticipated regulatory action, pharmaceutical companies face a critical juncture: respond effectively and quickly, or watch development timelines—and competitive advantage—slip away. Two of the therapies highlighted in the Clarivate “Drugs to Watch 2026” report, Sanofi’s tolebrutinib and Corcept Therapeutics’ relacorilant, faced such setbacks in the last days of 2025. The FDA sent Complete Response Letters (CRLs) for tolebrutinib to treat non-relapsing secondary progressive multiple sclerosis (nrSP-MS) on December 23, 2025, and relacorilant to treat Cushing syndrome on December 30, 2025.

The decisions surprised many observers. Tolebrutinib held both Priority Review and Breakthrough Therapy designations, while relacorilant’s pivotal GRACE trial had met its primary endpoint with supportive confirmatory data from the GRADIENT trial.

What is a complete response letter (CRL)?

Created in 2008 to replace the FDA’s “approvable” and “not approvable” letters, CRLs were designed as a neutral mechanism to communicate that an application cannot be approved as submitted. Despite their official neutrality, CRLs carry significant weight, detail specific deficiencies identified by the FDA, and typically recommend steps to address them. Common reasons include safety or efficacy concerns requiring additional data, manufacturing or quality control deficiencies, inadequate risk management strategies and insufficient evidence for benefit-risk assessment.

CRLs are setbacks, not rejections

Although setbacks, CRLs are not rejections: roughly 41% of submissions receive a CRL, and more than half of those ultimately gain approval. Understanding what drove these decisions and what comes next offers important lessons for developers navigating regulatory expectations.

For Sanofi and Corcept Therapeutics, the path forward requires sophisticated intelligence, precedent analysis and strategic evidence generation. Clarivate’s integrated, artificial intelligence (AI)-enabled solutions are designed to support regulatory decision-making, strengthen resubmission strategies and help advance therapies to patients.

Distinct regulatory challenges require tailored strategies

Before examining specific solutions, it’s important to recognize that Sanofi and Corcept face fundamentally different CRL challenges requiring tailored approaches.

Sanofi’s tolebrutinib confronts a safety-focused CRL centered on severe drug-induced liver injury (DILI) risk that the FDA characterized as “substantial and unusually high.” The agency concluded it “was unable to identify a population for which the benefit could be clearly established and for which that benefit would be anticipated to outweigh the serious risk of severe DILI.” This requires Sanofi to either demonstrate enhanced risk mitigation strategies, identify lower-risk patient subpopulations or generate additional safety evidence.

Corcept’s relacorilant received an evidence adequacy CRL in which the FDA acknowledged the GRACE trial met its primary endpoint but stated it “could not arrive at a favorable benefit-risk assessment for relacorilant without Corcept providing additional evidence of effectiveness.” This suggests the agency needs more comprehensive demonstration of clinical meaningfulness and benefit-risk across the heterogeneous Cushing’s syndrome population.

How the Clarivate integrated intelligence platform supports CRL responses

Clarivate integrated data platforms and AI-powered solutions provide life sciences companies with intelligence, analytical capabilities and strategic insights. Our AI-powered approach can dramatically reduce the time from question to insight throughout the drug development and commercialization lifecycle, transforming processes that previously required weeks of manual analysis into insights delivered in hours.

This integrated approach proved particularly valuable when choosing our Drugs to Watch and, for life sciences companies, its value applies to responding to CRLs, where multiple data sources and analytical perspectives must converge rapidly. Real-time updates of critical information from trusted sources support agile responses, whether re-evaluating the impact of regulatory decisions on the potential market, understanding the impact of a drug on patients or determining the path forward after a CRL.

Clarivate solutions that enable stronger CRL resubmissions

Clarivate offers 10 integrated, AI-enhanced datasets spanning the R&D and commercialization lifecycle, with several proving especially critical for CRL response:

Cortellis Regulatory Intelligence (with AI-powered Regulatory Assistant): e.g., precedent analysis, regulatory strategy development, understanding FDA’s evidence bar
Cortellis Clinical Trials Intelligence: e.g., design enhanced safety monitoring protocols and potential subpopulation trials with the highest success probability
DRG Fusion (real-world data analytics platform): e.g., generate additional effectiveness and safety evidence from real-world sources, identify lower-risk subpopulations
Epidemiology Intelligence: e.g., quantify addressable patient populations in lower-risk subgroups, define subpopulations with clearest demonstrated benefit
Cortellis Competitive Intelligence: e.g., maintain strategic awareness during extended development and use predictive analytics in pharma to understand the impact of decisions on the launch timeline and sales forecasts
Disease Landscape & Forecast: e.g., maintain competitive awareness and portfolio strategy during extended development
Access and reimbursement intelligence: e.g., build and refine market access strategy during extended development to accelerate post-approval uptake

The next post in this series examines how these AI-powered Clarivate tools can help companies navigate risk-benefit evaluations in regulatory submissions.

Learn more about our 2026 Drugs to Watch , and you can read about how Clarivate is using AI tools to empower its clients to make better decisions faster.