When the U.S. Food and Drug Administration (FDA) issues Complete Response Letters (CRLs) when a New Drug Application (NDA), Biologics License Application (BLA), or Abbreviated New Drug Application (ANDA) is submitted, it is “go time”. This means the product cannot be approved in its current form. CRLs detail specific deficiencies and outline necessary steps for resubmission. Addressing the steps detailed in the CRL is critical for many reasons. Some of the reasons include wanting continuity with your filing with the same reviewers. Delays could shift reviewers who know the most about your product may not be available leading to extended review cycles of more questions. It also can mean that every delay will lead to lost market share, specifically in fast-moving therapeutic areas. Stakeholder confidence can wane, leading to negative market reactions. Delays can extend burn rates to operational costs. And the sooner approval is secured, the longer the period of market exclusivity – preserving Intellectual Property (IP) value.
CRLs span various product categories, but certain types are more commonly affected:
Biologics (BLAs): Biologic products, including biosimilars, frequently encounter CRLs (approximately 50% of the time as reported at the PDA Regulatory Conference 2024), often related to manufacturing concerns or inspection findings at third-party facilities.
Small Molecule Drugs (NDAs): These constitute a significant portion of CRLs. Issues often involve insufficient clinical efficacy data, manufacturing challenges, or inadequate pharmacokinetic information.
Complex Generics (ANDAs): These applications, especially those referencing complex reference products like inhalers, often receive CRLs due to challenges in demonstrating bioequivalence or meeting device-specific requirements.
The most common reasons for receiving a CRL include:
- Manufacturing and Quality Control Issues: Deficiencies in manufacturing processes or quality assurance can prompt CRLs.
- Clinical Efficacy Concerns: Applications may lack sufficient evidence to demonstrate effectiveness.
- Inspection Findings: CRLs can result from adverse findings during FDA inspections of manufacturing facilities, including those operated by third parties.
While CRLs can affect a range of pharmaceutical products, biologics, and complex generics are particularly susceptible, often due to clinical efficacy issues, manufacturing and quality control challenges, or inspection findings. Understanding these common pitfalls can aid pharmaceutical companies in preparing more robust applications and mitigating the risk of receiving a CRL.
Quality Executive Partners (QxP) play a critical role in helping pharmaceutical and biotech companies avoid, respond to, and recover from CRLs. Our history in the cell & gene category has led to resolutions in record times; increased shareholder confidence, large acquisitions of smaller companies, and critical access and availability of medicines to patients. Given the complexity and high stakes involved in resolving a CRL, QxP provides the expertise, objectivity, and strategic oversight necessary to guide companies through remediation and re-submission efforts efficiently.
One of the most valuable contributions QxP makes in these situations is in analyzing the CRL to translate FDA feedback into a prioritized, actionable plan. CRLs are often broad in scope, covering issues that span clinical design, CMC (Chemistry, Manufacturing, and Controls), GMP inspections, and labeling. We have helped companies interpret the deficiencies from both a technical and regulatory perspective, identifying which responses can be quickly addressed and which require deeper systemic changes or additional studies. Our outside perspective allows for an honest assessment of the gaps, free from internal bias, and grounded in experience across multiple sponsors and FDA interactions.
QxP also bring immense value on the regulatory front. For CRLs citing deficiencies in clinical design or statistical analyses, regulatory consultants collaborate with clinical and biostatistics teams to refine study protocols, perform gap analyses, and ensure that re-submitted data packages are aligned with FDA expectations. If a new clinical study is required, we guide its design, help justify endpoints and manage communication with the FDA through formal meetings like Type A or Type B interactions. For biologics or complex products like ADCs, mRNA-based therapies, or gene therapies, we have provided the specialized CMC and regulatory knowledge needed to meet rigorous review standards.
Moreover, QxP has helped strengthen an organization’s overall regulatory and quality maturity by its twinning model which leads to sustainable improvement for the company. By identifying root causes that led to the CRL—whether related to organizational silos, insufficient QMS infrastructure, or flawed development strategies—we have helped companies implement corrective measures that reduce the risk of future setbacks. For early-stage or resource-limited sponsors, this strategic guidance is invaluable for building long-term regulatory resilience.
Ultimately, a CRL is a significant but not insurmountable hurdle. QxP helps companies move from reactive damage control to proactive remediation, ensuring that their resubmission not only addresses the FDA’s concerns but sets a stronger foundation for commercial success. Whether through technical CMC expertise, regulatory strategy, inspection readiness, or quality remediation, Quality Executive Partners bring clarity, speed, and strategic focus to a process that is often marked by complexity and urgency.
QxP Vice President Christine Feaster is a 20+ year veteran in pharma quality assurance. Prior to joining QxP, Christine was a vice president of U.S. Pharmacopeia.
