Learning from the Letters: FDA Complete Response Letter Trends (2020–2024) and What They Mean for Sponsors
Introduction: A New Era of Transparency
In July 2025, the FDA released an unprecedented set of 202 redacted Complete Response Letters (CRLs) issued between 2020 and 2024, all of which pertained to applications that were eventually approved. These letters, once confidential, now provide a valuable dataset that pharmaceutical sponsors, regulatory consultants, and quality professionals can analyze to better understand the patterns behind non-approvals. Historically, sponsors were able to selectively disclose the content of CRLs, often omitting or generalizing the FDA’s concerns. This made it difficult for stakeholders to learn from past mistakes.
With this new release, we can now examine concrete examples of the deficiencies most commonly cited by the FDA and identify the characteristics of applications and sponsors most frequently affected. This blog explores these trends in depth—focusing particularly on Chemistry, Manufacturing, and Controls (CMC) deficiencies, clinical shortcomings, and distinctions between large pharmaceutical companies and emerging biotech firms. It also offers insights into how these patterns inform regulatory strategy for all sponsor types.
The Scope and Composition of the CRL Dataset
The 202 CRLs span a diverse range of therapeutic areas: roughly 16% (32 letters) were for oncology products, with the remaining letters distributed across neurology, infectious disease, cardiology, endocrinology, and other therapeutic classes. Applications ranged from NDAs and BLAs to 505(b)(2) submissions and even ANDAs. Although the dataset excludes applications that were withdrawn or never resubmitted, it remains the most comprehensive window into FDA regulatory feedback ever made public.
Importantly, a single CRL often includes multiple deficiency types, and many include both clinical and manufacturing concerns. As such, the categorical breakdown of deficiencies reflects frequency of citation, not mutually exclusive categories.
Top Deficiency Categories: What CRLs Tell Us
CMC and Manufacturing Deficiencies (~74%)
By far the most cited category, manufacturing-related issues appeared in nearly three-quarters of all CRLs. These issues spanned process validation gaps, GMP non-compliance, inadequate stability data, incomplete control strategies, and unvalidated analytical methods. Pre-approval inspection failures and insufficient oversight of third-party manufacturers (CMOs) were also recurring themes.
Examples include:
Fennec Pharmaceuticals’ Pedmark (sodium thiosulfate): delayed by GMP issues at the manufacturing site.
Toripalimab: a BLA delayed due to the FDA's inability to inspect the facility in China during COVID-19.
Mirikizumab (Lilly): CRL issued for manufacturing site deficiencies despite strong clinical data.
Clinical Data Deficiencies (~50%)
Roughly half of the CRLs cited concerns with clinical evidence. Issues included insufficient efficacy data, unresolved safety signals, flawed trial designs, and lack of statistical robustness. In many cases, the FDA requested additional clinical trials.
For example:
Small sponsors were more likely to be asked to conduct entirely new efficacy trials.
Some CRLs highlighted the use of unvalidated surrogate endpoints or poorly justified population choices.
Labeling and REMS (Frequently Mentioned, Rarely Primary)
Labeling issues were cited in the majority of CRLs, but rarely as a standalone cause for non-approval. These concerns usually involved inaccurate or unsupported claims, inadequate instructions, or incomplete risk management language. Only a handful of CRLs (<5%) listed labeling as the primary issue.
Preclinical Deficiencies (<10%)
Toxicology and other nonclinical data gaps were relatively rare, reflecting that most applications are submitted after preclinical packages have been finalized. When cited, these typically involved new safety signals or additional animal studies (e.g., DDI, reproductive tox).
Regulatory and Trial Design Flaws (Notable Contributor)
CRLs often flagged issues not directly tied to clinical or CMC content, but to how the study was designed or executed. Examples include:
Inadequate control arms.
Trials conducted exclusively in non-U.S. populations (e.g., sintilimab).
Lack of alignment with FDA guidance documents.
Multiple Deficiencies Per CRL: The Norm, Not the Exception
A critical insight from the dataset is the high incidence of multi-faceted letters. Over half of CRLs involved more than one major category of deficiency. For example, an oncology drug might receive a CRL citing both manufacturing validation gaps and the need for an additional Phase III trial.
This has practical implications:
Sponsors must develop cross-functional regulatory responses.
CRL remediation often requires clinical, CMC, labeling, and regulatory affairs teams working in tandem.
Sponsor Trends: Size and Resources Matter
A notable trend in the CRL data is the disproportionate burden on small and emerging biotech firms:
Approximately 70% of CRLs in the dataset were issued to small or mid-sized sponsors.
Among 505(b)(2) applications, nearly all CRLs affected small companies.
First-time filers were significantly overrepresented.
Why the disparity?
Regulatory experience: Small firms often lack internal expertise in FDA engagement.
CMC investment: Smaller firms may cut corners or outsource to CMOs with varying quality systems.
Trial design pitfalls: Inexperienced sponsors may misalign study endpoints, control groups, or statistical analysis plans with FDA expectations.
Optimism bias: Some sponsors file marginal applications hoping for leniency, only to be met with a CRL requiring additional trials.
Conversely, large pharmaceutical companies were more likely to receive CRLs for:
Comparability issues between clinical and commercial batches.
Complex manufacturing challenges for biologics or gene therapies.
Inspection findings at third-party partners.
Examples:
Eli Lilly’s mirikizumab: CMC-driven CRL despite positive trial data.
Regeneron and Novartis: CRLs for site readiness and comparability gaps.
CMC Trends by Product Type
CMC deficiencies differ in nature depending on the product class:
Small Molecules: Most common issues include process validation, impurity profiles, inadequate dissolution methods, and stability data gaps.
Biologics and Biosimilars: Frequent problems include comparability, immunogenicity, facility inspection findings, and analytical method limitations.
Combination Products: Unique concerns include device usability, container/closure integrity, and fill-finish issues.
Cell and Gene Therapies: These applications often faced CRLs due to sterile processing, vector consistency, and lack of validated assays.
Geographic Trends and Inspection Constraints
Sponsors relying on international manufacturing sites faced heightened CRL risk during the pandemic:
COVID-19 travel restrictions prevented pre-approval inspections in China, India, and parts of Europe.
CRLs explicitly cited FDA's inability to inspect as a barrier to approval.
International companies (and U.S. companies with overseas CMOs) should now:
Build inspection readiness earlier in the development lifecycle.
Use mock audits or third-party pre-inspections.
Engage FDA proactively regarding remote inspection options or inspection timelines.
Strategic Implications for Sponsors
The newly available CRL data offers several lessons:
Treat CMC as Critical Path
Invest early in robust CMC programs and facility readiness.
Prioritize GMP compliance and validated analytical methods.
Engage FDA Early and Often
Use pre-IND, pre-NDA/BLA, and Type C meetings to clarify expectations.
Review precedents in CRLs to prepare targeted questions.
Mitigate CMO Risk
Maintain oversight of third-party operations.
Qualify backup suppliers or production lines.
Resource Planning for Small Firms
Bring in experienced regulatory consultants.
Consider partnerships or co-development agreements.
Respond Holistically to CRLs
Address not only the specific deficiencies cited, but potential adjacent gaps.
Consider whether your clinical and CMC narratives align.
The Role of Radical Transparency Moving Forward
By publishing these CRLs, the FDA aims to:
Improve regulatory predictability.
Promote best practices across the industry.
Encourage early alignment between sponsors and the agency.
For industry stakeholders, the implications are profound. Sponsors can now benchmark against real-world FDA feedback and learn from both failures and successful resubmissions. Investors and patient advocates also gain visibility into the rigor of the approval process.
Conclusion: A Roadmap for Better Submissions
The 2020–2024 CRLs show that many deficiencies—especially in manufacturing—are avoidable. Sponsors that integrate CMC excellence with clinical development, maintain oversight of third-party operations, and align study design with FDA guidance will be better positioned for first-cycle approvals.
Large pharma and small biotech firms alike must take stock of these findings. The publication of CRLs is more than an act of transparency; it is a call to raise the bar on regulatory readiness. The opportunity is now in plain sight. It’s up to sponsors to act on the lessons encoded in the FDA’s own words.