Under its new leadership, FDA has started publishing its Complete Response Letters (CRLs) for public consumption (though they will be redacted to protect intellectual property and trade secrets), reversing a trend where they withheld publishing CRLs for pending applications.1 Most CRLs now published cite issues with safety, efficacy, bioequivalence, and manufacturing / quality deficiencies, and often require companies to repeat clinical studies to address the issues. Historically, the extent of these observations and any FDA-provided recommendations for remediation have been sent directly to sponsors and have only been partially disclosed. Now, they will be available to the public. This means that everyone, including investors, will be able to see the FDA’s full rationale for rejecting an application.
While this transparency is designed to eliminate uncertainty, encourage the sharing of lessons learned, and speed remediation of deficiencies to deliver treatments to patients faster, it can also provide valuable insights for a sponsor’s clinical risk mitigation strategy and quality approach.
To mitigate the thematic issues we observed throughout these CRLs and preserve funding pathways, sponsors must accelerate their integration of safety, quality, and data controls into the clinical development process.
While patient safety and pharmacovigilance has always been a paramount concern, the design and execution of these programs in early stages, especially in smaller start-ups, are often deficient due to lack of experience. In addition, the design and implementation of fit-for-purpose quality systems has often lagged similar efforts in scientific advancement. Given the implications of CRLs being part of the accessible public records, leveraging the right expertise to set up robust pharmacovigilance and quality capabilities as early as possible is critical.
It is evident that clinical risk mitigation strategies should have an earlier focus on digitized and validated data capture, transformation, and analysis. Also, having a compliant set of Quality SOPs and actively controlling change across the clinic, vendors (e.g., CROs and CDMOs) from late discovery through human trials will help mitigate issues seen in many of the CRLs published.
Specific steps to take to avoid similar rejections and/or reduce the severity of a CRL include:
- Ensuring the processes and technologies around clinical and safety data capture, integrity, and validity is both fully compliant and provides rapid, visible, and actionable results. Consider a digital-first approach to your clinical trial management, data collection, and laboratory processes. And, to ensure compliance and integrity, start your Computer Systems Assurance program as soon as possible.
- Design and implement fit-for-purpose, phase-appropriate quality systems that can be built modularly to scale towards GMP compliance. Creating a pragmatic, fully-defensible risk-based approach to quality oversight of a sponsor’s network of clinical, manufacturing, and laboratory services providers is a fundamental first step. This starts with quality agreements that ensure near real-time data and process visibility, and close collaboration between the partner and the sponsor’s Quality units. It will mean including an experienced quality leader or contracted professional by the sponsor earlier than has historically been the case.
- Prepare for all Agency interactions (Type A, B, and C meetings) well in advance, with input from Regulatory experts who are versed in industry trends and changing Regulatory expectations. An independent review of all submissions to identify potential gaps can increase the likelihood of approval.
For sponsors moving forward with their first candidates, the steps outlined above can sometimes be outside the organization’s core capabilities, or are simply beyond the bandwidth of internal resources who are focused on the science aspects of clinical trials. In these cases, there is value in leveraging external experts to help drive these activities.
By gleaning lessons learned from previous CRLs and following the suggestions above, sponsors can help ensure manufacturing, quality, safety, and data integrity issues don’t get in the way of successful science. These steps will decrease the likelihood of repeating studies and the impact of negative findings in a Complete Response Letter, thus helping to ensure financial viability and bring needed therapies to patients.
Mike Shafer, Managing Director, Quality & Compliance
Mike is a seasoned executive in life sciences, focused on risk-based Quality Management. He is passionate about helping clients scale quality as a competitive advantage. Mike brings deep Quality & Compliance expertise to TriRadial, including:
- Quality Assessments
- QMS Design and Remediation
- Phase-appropriate Quality Management and risk-based compliance
- Quality Process Transformation and SOP Optimization
- Computer Systems Assurance
- Inspection Readiness
References:
1US Food and Drug Administration. (2025 Jul 10). FDA Embraces Radical Transparency by Publishing Complete Response Letters. FDA. https://www.fda.gov/news-events/press-announcements/fda-embraces-radical-transparency-publishing-complete-response-letters