From ‘No’ to ‘What’s Next?’

What you’ll learn:

A New Wave of CRLs, a New Set of Learnings

In our previous POV, “From No to Know: Translating Regulatory Setbacks into Competitive Advantages,” we examined the FDA’s first large-scale release of Complete Response Letters (CRLs) tied to drugs that had already been approved. Although those CRLs reflected initial setbacks, their retrospective disclosure offered the industry a rare look into how companies had overcome regulatory hurdles on their way to market. 

The FDA has taken an important next step. On September 4, 2025, the FDA released 89 CRLs, issued between January 2024 and August 2025, for products not yet approved. Unlike the first batch, these new disclosures provide insight into the barriers facing products currently in review. This action shifts CRLs from historical lessons into forward-looking signals with direct implications for strategy and competitive positioning.

Navigating the ‘No’

To analyze this latest set of 89 pre-approval CRLs, we applied the same standardized AI-driven, human-validated approach described in our LinkedIn post, “FDA CRL Analysis: AI Method Comparison.” This framework ensured consistency across the datasets and allowed us to identify recurring themes more precisely. We focused on the 77 unique CRLs, capturing the FDA’s initial review and identifying common patterns in early regulatory pushback. 

While this current set of letters contained more redactions than the previous one, it still provides reliable insight into areas where FDA scrutiny is most concentrated and what that means for products still under review.

Consistent drivers of CRLs: Manufacturing, Clinical, and Labeling Issues

The drivers of CRLs in this latest release were largely consistent with those in the first batch. Chemistry, manufacturing, and control (CMC) issues remained the most common, with facility inspection and product quality frequently cited. Clinical deficiencies, namely efficacy and safety issues requiring additional clinical trials, followed. However, unlike the first batch of letters, labeling concerns were less frequent, while other regulatory issues appeared more often. 

This shift may reflect the FDA prioritizing different aspects of an application and deferring labeling reviews until other deficiencies are addressed. While companies are naturally focused on addressing the issues that triggered the CRL, it is important to ensure that labeling documents align with the regulations so they don’t cause any additional delays when reviewed. While a pattern is emerging, continued releases will confirm whether this reflects a broader trend.

CRLs by Therapeutic Area

Continuing trends in CRLs

When comparing the two batches of CRLs, we see several continuing trends. Oncology remains the most represented therapeutic area (TA), accounting for 27% of CRLs in Batch 2, followed by cardiovascular and neurology. Across these areas, manufacturing issues continue to be the most cited reason for rejection, while neurology in particular shows a higher proportion of letters citing labeling gaps.

A notable shift is the growing proportion of Biologics License Applications (BLAs) in Batch 2 (32% vs. 22% in Batch 1). While this isn’t a big difference and may be due to the smaller number of letters overall, it may also reflect an increase in these types of submissions in general or an increase in BLA products with complex clinical trials and manufacturing processes. The pattern for the reasons for CRLs between NDAs and BLAs remained relatively consistent.

Our previous POV noted that a quarter of the products had received multiple CRLs. This trend continues, with 14% of products in  Batch 2 receiving at least a second CRL, even within the shortened time frame. These insights mirror the trend observed in Batch 1 and highlight the complexities and challenges companies face to get a product to approval in a single review cycle. 

From ‘No’ to ‘What’s Next?’

While regulatory learning is often retrospective, based on past CRLs, Untitled and Warning Letters, or published guidances, many companies are increasingly investing in forward-looking strategies. This analysis builds on that momentum, offering an opportunity to observe FDA feedback across multiple therapeutic areas in near real time.

Rather than waiting months or years for broader patterns to emerge, teams can now see where regulatory pressure is being applied today and begin adjusting their strategies before issues become roadblocks. Shifting perspectives from operational to strategic allows for earlier mitigation of known risk areas, sharper engagement with the agency, and stronger alignment across regulatory, clinical, and commercial functions.

What stands out in Batch 2 is how closely the findings align with those from the first release. CMC remains the most frequently cited deficiency, followed by clinical deficiencies. Oncology, cardiovascular, and neurology are the most commonly cited therapeutic areas. While the consistency of these patterns may signal persistent regulatory friction points, the sample size is limited. Ongoing monitoring will be key to validating whether these early signals are true trends or simply snapshots.

From a competitive standpoint, the value of early insight goes beyond avoiding setbacks. It creates a foundation for strategic advantage. In a landscape where approval timing, data quality, and regulatory alignment can influence market position, the ability to learn and adapt in real time is a differentiator.

Since the first batch of CRLs was released back in July, Klick’s Science + Regulatory team has been closely monitoring these developments to translate evolving FDA expectations into actions that sharpen the competitive edge for our clients. We can help identify what’s next for your own regulatory strategy.

Klick Health is the world’s largest independent commercialization partner for life sciences and a leading full-service pharma marketing partner, serving as agency of record for leading pharma, biotech, and healthcare brands. Klick’s specialized offerings are rooted in deep medical and scientific understanding, including market insights, award-winning creative, and proprietary AI and data models to craft impactful brand narratives and seamless customer journeys. Backed by nearly 250 medical experts and advanced healthcare analytics, Klick delivers integrated marketing strategy and communications, from new product launch strategy to MLR review with real-world evidence, helping brands thrive in today’s complex healthcare landscape. Learn more at Klick.com.