FDA complete response letters provide transparency on drug approval hurdles.
Key takeaways
Facility and product quality issues drive most approval delays.
Strong vendor oversight and quality governance can reduce regulatory risks.
The U.S. Food and Drug Administration released complete response letters (CRLs) to biopharma and other life sciences companies for drug approval applications submitted between 2020 and 2025. These letters inform companies of deficiencies and the next steps toward approval.
FDA’s CRL release: A transparency shift
The first batch of roughly 200 letters was released in the summer of 2025, and a second set of 89 followed weeks later with the FDA stating a commitment to publish CRLs “promptly after they are issued to sponsors,” according to an agency press release.
While many of these letters were previously available on the FDA’s Drugs@FDA database, this was the first time they were compiled and released together. This was a significant move in the life sciences ecosystem because, according to the agency, approximately 40% of the time, sponsors do not reveal that they were required to complete additional clinical trials for safety or efficacy.
RSM analyzed the first set of over 200 CRLs for drugs that were eventually approved to determine the reasons for earlier nonapproval. Over half of the deficiencies identified fell into two categories: facilities and product quality. Other deficiencies included clinical efficacy, safety profile, labeling and patent concerns.
One significant finding was that, on average, more than 2.5 years had passed between the initial CRL publication date and the final approval date. For a company launching their first drug, this extended approval timeline could result in a substantial increase in time to commercialization and, in many instances, increase launch costs.
Outsourcing risks and oversight challenges
With potential timeline delays in mind, facility- and manufacturing-related product quality concerns should be addressed early in the pre-commercialization process to reduce the likelihood of deficiencies and regulatory delays. For many biopharma sponsors, outsourcing to a contract research organization (CRO) or contract development and manufacturing organization (CDMO) is essential to accelerate development timelines, control costs and access specialized expertise. However, selecting and managing the right partner is more than an operational choice. This relationship must be managed with the same rigor as internal operations and treated as a strategic, quality-driven decision that can significantly influence regulatory outcomes, including new drug application (NDA) approval.
Further analysis of the CRLs reinforces this point: More than half of facility-related deficiencies occurred because the FDA could not complete the required preapproval inspections (PAIs). This exposure highlights a crucial oversight challenge: as operations move outside the sponsor’s four walls, risk becomes harder to see and even harder to respond to in real time.
This requires an organization’s strong quality culture and governance to extend across their outsourced network. By integrating quality, risk mitigation and long-term business strategy into outsourced operations from the start, sponsors strengthen their ability to meet FDA expectations and reduce the likelihood of costly delays that disrupt launch timelines and patient access.
Further, the earlier quality requirements, governance structures and oversight mechanisms are embedded into outsourced operations, the fewer bottlenecks later in the commercialization journey, and the stronger a sponsor’s position becomes when the FDA arrives for a PAI.
Building quality into vendor relationships
As life sciences organizations expand their reliance on CROs and CDMOs, the challenge isn’t just outsourcing—it’s doing so with confidence, compliance and continuity. Success requires a structured approach that goes beyond cost and capability, embedding quality and risk management into every stage of the collaboration. The following practices help build resilient, quality-driven outsourcing strategies that minimize regulatory risk and prevent costly setbacks.
Vendor evaluation and alignment
- Look beyond technical capability and cost to assess:
- CRO/CDMO core competencies and operational maturity
- Alignment with sponsor’s corporate strategy and long-term goals
- Formalize expectations in a robust quality agreement that defines roles, shared accountability and performance metrics
Risk assessment as a foundation
- Identify and document critical risks related to:
- FDA inspection readiness
- CGMP (current good manufacturing practice) compliance and data integrity
- Scalability and continuity
- Define and agree upon mitigation or risk acceptance strategies
- Feed outcomes into quality agreements and operational plans
Performance metrics and governance
- Define metrics that are:
- Measurable, meaningful and proactive (not just lagging indicators)
- Balanced across efficiency, effectiveness and customer satisfaction
- Use codeveloped scorecards to track trends and drive continuous improvement
- Maintain transparency through regular governance and mandatory reviews
Exit strategy and continuity planning
- Define exit considerations at the outset of the agreement to minimize disruption, including:
- Knowledge transfer and documentation requirements
- Transition planning to a new partner or reintegration
- Protect patient access, regulatory timelines and investor confidence
Digital quality systems enablement
- Shift oversight from reactive to proactive through:
- Electronic Quality Management System (eQMS) platforms that provide real-time visibility and traceability
- Integrations that connect quality, supply chain, manufacturing, IT and audit
- Automate workflows for:
- Change control, deviations, supplier qualification and audits
- Preserve compliance continuity during transitions with digitized records
Strategic outcomes
- Integrated, quality-driven vendor relationships reduce CRL risk. Benefits include:
- Stronger inspection readiness
- Protected regulatory timelines
- Faster patient access to therapies
The takeaway
The FDA’s release of CRLs marks a major transparency shift, revealing common approval hurdles such as facility and product quality deficiencies that can delay commercialization for years. For biopharma sponsors, proactive quality governance, especially in outsourced operations, is critical to mitigate regulatory risk, protect timelines and accelerate patient access.
RSM contributors
-
-
-
Liz BouchardSupervisor
Subscribe to Life Sciences Insights
Knowledge is power. Stay up to date with key life sciences trends and timely insights, delivered straight to your inbox.
