In a major shift that could change how drug developers approach approvals, the FDA has begun releasing Complete Response Letters (CRLs) in real time. These letters, previously confidential, explain exactly why the agency is not approving a drug or biologic application (NDA or BLA). With the September 2025 release of 89 previously unpublished CRLs, the agency has not only opened the curtain on its decision-making process but also challenged long-standing norms around regulatory confidentiality. Here’s why it matters.
What Are CRLs and Why Should You Care?
CRLs are the FDA’s formal explanation for why an application can’t be approved in its current form. They typically cite issues like:
- Safety or efficacy concerns
- Manufacturing or facility deficiencies
- Trial design or data problems
- Labeling or bioequivalence issues
These aren’t rejections per se—more like “not yet” letters. But they are critical to understanding the agency’s standards and where a sponsor’s submission fell short.
The Big Reveal: 89 CRLs Released
On September 4, 2025, the FDA released a batch of 89 CRLs for applications that were pending, withdrawn, or never approved. This follows a July 2025 release of 200 CRLs for drugs that ultimately made it to market. What’s different now? These new releases show the full spectrum—not just the success stories but the roadblocks, too.
Trends and Common Pitfalls
Several clear themes emerged:
- Manufacturing Woes Are Widespread: Nearly every CRL mentioned Chemistry, Manufacturing, and Controls (CMC) deficiencies or facility compliance issues.
- Safety and Efficacy Remain the Cornerstones: Many applications lacked convincing clinical evidence or raised safety flags. Some failed to meet endpoints, others showed marginal benefit.
- Trial Design Still Trips Up Sponsors: Poorly defined endpoints, small sample sizes, or flawed comparators were common culprits.
- Missing or Inadequate Data: Whether it’s pharmacokinetics, stability, or long-term follow-up, incomplete datasets regularly delay approvals.
Why This Matters to Industry Professionals
For regulatory professionals, this is a goldmine. You can now study exactly why others have failed—and avoid those traps. Expect smarter trial designs, more proactive CMC planning, and better communication with FDA reviewers.
This transparency also increases accountability. Sponsors can no longer release vague press statements and hope no one notices the gaps. The full FDA narrative is available for anyone to read—investors, providers, and even competitors.
The Legal and Competitive Edge
Of course, not everyone is thrilled. Critics argue this may skirt FDA confidentiality rules. Some worry about IP leakage or reputational damage. Others point to the market impact—a CRL highlighting facility issues could spook investors or competitors.
That said, companies can adapt. Label proprietary content clearly. Align regulatory and investor communications. And most importantly, plan for quality from the outset.
What Comes Next
The FDA is just getting started. All future CRLs will be released shortly after issuance. Older, unreleased CRLs may also come to light. The agency says it will redact confidential commercial info, but make no mistake: the days of quiet failures are over.
Final Thought
This is more than just a transparency push. It’s a culture shift. One that favors preparedness, honesty, and learning. In a field where missteps are costly and time is precious, knowing what not to do might just be the most valuable data yet.
Stay sharp, stay compliant, and most of all, stay informed.