How Start-Up Biotechs Can Actually Use the FDA’s Published Complete Response Letters (CRLs)

💡 Smart ways to learn from other sponsors’ stumbles

In a move being hailed as a step toward “radical transparency,” the FDA has started publishing select Complete Response Letters (CRLs)—official notifications issued when an application (typically an NDA or BLA) cannot be approved in its current form. (You can download them here.)

For emerging biotechs and small pharma teams, this is a goldmine of real-world regulatory insight—if you know how to use it.

Below, we break down what this change means and how your team can leverage CRLs to improve your submission strategy, avoid common pitfalls, and better anticipate FDA concerns.

📬 First: What Are Complete Response Letters (CRLs) and Why Do They Matter?

CRLs are the FDA’s formal explanation for why an application can’t be approved. They outline specific deficiencies—clinical, CMC, regulatory, or otherwise—and suggest what a sponsor must do to resolve them.

Until now, the content of CRLs was kept private unless a company chose to disclose it. But as part of a pilot transparency program, the FDA has begun proactively publishing a limited set of anonymized CRLs for NDAs and BLAs, particularly when the sponsor also shares the letter publicly.

This opens the door for peer-to-peer learning at a scale we’ve never seen.

🔍 5 Concrete Ways to Use Published CRLs

1. Identify Patterns in Regulatory Pushback

Reading CRLs helps you see what’s tripping up other sponsors—especially those working with similar mechanisms, patient populations, or development strategies. Is the FDA consistently asking for another pivotal study? Raising concerns about surrogate endpoints? Flagging CMC comparability data? That’s intel worth tracking.

Pro tip: Look for repeat issues in your therapeutic area or molecule class. If others are struggling there, get proactive.

2. Pressure-Test Your Submission Strategy

CRLs reveal what didn’t satisfy the agency. Use them as a mirror: would your clinical justification or CMC story hold up under that kind of scrutiny?

Use CRLs to run a "pre-mortem" on your NDA/BLA package. Ask:

• Would we have answered this question?

• Are our bridging data or trial designs vulnerable to similar criticism?

3. Improve Briefing Documents and Meeting Readouts

Regulatory strategy is often shaped by early-stage communications (Type B meetings, pre-NDA meetings, etc.). If a CRL shows the agency was still unsatisfied despite prior feedback, that’s a sign the messaging or documentation fell short.

Review how others presented their justifications. Could your own briefing content be clearer or better aligned with agency expectations?

4. Inform Internal SOPs and Readiness Planning

For small teams especially, CRLs can spotlight areas where SOPs, documentation practices, or internal QA reviews need tightening.

For example, if a CRL flags inadequate validation or incomplete study data, ask whether your internal controls would’ve caught similar gaps before submission.

5. Build Better Risk Communication with Investors & Execs

It’s tough explaining to non-regulatory stakeholders why your team is pushing for an extra study or delaying submission prep. CRLs offer real-world proof of the consequences when you don’t.

Point to specific CRLs when making the case for more time, resources, or contingency planning.

🧠 Final Thoughts

For emerging biotechs, getting regulatory feedback without going through the full NDA/BLA process yourself is incredibly rare—and valuable. The FDA’s move to publish CRLs won’t solve every challenge, but it does give you a clearer view of the path ahead.

This is the kind of smart regulatory awareness that saves time, builds credibility, and strengthens your position with both the FDA and investors.

🚀 Need help prepping for your IND, NDA or BLA?

The Sugar Water Operations Team helps early-stage companies turn regulatory strategy into regulatory success. Whether you're preparing for your first IND, managing a complex NDA, or just need help interpreting where your program stands—we're here to help.