In July 2025, the FDA began publishing past Complete Response Letters (CRLs). Triangulating those releases with company disclosures and primary reporting shows two dominant themes: CMC (quality/manufacturing/testing) & Pre-License Inspections (PLI), and the strength of efficacy evidence / trial adequacy. This article synthesizes six prominent 2024–2025 cases and turns them into a practical, submission-ready checklist.
Co-design CDMO alignment, tech-transfer, and a defensible comparability package early.
4. Pre-Submission “Red Pen” Checklist
PLI: CAPA closure evidence, data integrity, consistent deviation/change control
Comparability: bridge across process/scale/site (CQA/potency continuity)
Potency: MOA-aligned validity & reproducibility
Trial design: adequate & well-controlled where feasible; rigorous selection/adjustment for external controls
Meetings: document agreements in Type A/B minutes; lock submission staging
Note: Some figures (e.g., “~40% of INDs halted for CMC”) reflect expert opinion in media reports. Treat numbers without official backing as opinion, not statistics.
5. Wrap-Up
CMC/PLI is the final gate, but substantial evidence and adequate trial design are equally decisive. Reverse-engineer approval by embedding comparability, potency, and change control, and by locking agreements in minutes—the fastest way to avoid a CRL and to resubmit effectively.
After completing graduate school, I studied at a Top tier research hospital in the U.S., where I was involved in the creation of treatments and therapeutics in earnest. I have worked for several major pharmaceutical companies, focusing on research, business, venture creation, and investment in the U.S. During this time, I also serve as a faculty member of graduate program at the university.
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