Complete Response Letters: What Drug Manufacturers Hope to Avoid

When the FDA approves a new drug, it is an important event for patients, prescribers, payors, investors, and manufacturers. But what happens when the agency decides that an application for a new drug does not meet all the requirements for approval? In these cases, the FDA issues a complete response letter (CRL).

To earn approval, a drug application must provide convincing evidence to the FDA that a potential new drug meets the following requirements:

• It is safe and effective in its proposed use.
• The benefits outweigh the risks.
• The proposed labeling for the drug is appropriate, and manufacturing methods maintain drug identity, purity, quality, and strength.¹

If any of these areas are deficient, the FDA will respond to the manufacturer with a CRL. By issuing a CRL, the FDA is communicating that it does not approve the drug application as it was submitted. In simple terms, a CRL may be thought of as a rejection. However, it does not mean that the drug can never be approved. In the CRL the FDA provides a specific description of the requirements that were not met and, when possible, recommendations for what the manufacturer can do to satisfy the unmet requirements.²

After receiving a CRL the manufacturer has a few options for how to proceed:

• Address the issues raised in the CRL and resubmit the application to the FDA for further review.
• Withdraw the application. The drug will remain unapproved, but the manufacturer may resubmit the application, or it may decide not to make any further effort to acquire approval.
• Request a hearing. The grounds for why the CRL was given may be discussed further if the FDA agrees.²

If the manufacturer resubmits the application, the FDA will have a certain amount of time to make another decision. This decision may result in approval or another CRL. This process may be repeated until the drug is eventually approved or the manufacturer decides that it is not willing or able meet the requirements.²

There are many potential stumbling blocks for a drug application, and it is common for a CRL to cite multiple issues. The most commonly cited issue recently is related to manufacturing deficiencies, specifically, the failure to follow good manufacturing practices (GMPs). GMPs are a detailed set of procedures that manufacturers are required to follow for a wide variety of activities. Given the attention placed on the safety and efficacy results of drugs in development, a drug application receiving a CRL for manufacturing issues may be surprising to those who follow drug development and a disappointment for the manufacturer. The good news is that most manufacturing issues are correctable and can often be resolved more easily than a CRL because of problems related to drug efficacy and safety. Issues related to efficacy and safety may require more supporting evidence, such as an additional clinical trial, which is costly and time consuming.³

How common are CRLs? In 2016, the FDA’s Center for Drug Evaluation and Research approved 22 novel new drugs and issued 14 CRLs to novel new drug applications. However, that year saw a lower-than-average number of new drug approvals and a higher-than-average number of CRLs. The FDA may have placed an increased emphasis on manufacturing inspection recently, or perhaps some drug makers may let have their standards slip in this area. Of the 47 CRLs issued between 2010 and 2015, just 4 listed GMP compliance issues as a primary area of deficiency.⁴

The FDA issues a CRL to the manufacturer that submitted the drug application but does not make the information public knowledge. It is up to the manufacturer to reveal the news of the CRL. The requirements for a manufacturer to disclose a CRL for a product do not come from the FDA but are related to Securities and Exchange Commission rules. In general, when a company receives a CRL, it makes it known to the public, but it may not always divulge a great deal of detail.³

Understanding CRLs can be useful for those who have an interest in drug development. Their purpose is to make sure that drugs meet all the necessary standards before they reach patients. Drugs that don’t meet all requirements are not able to enter the market immediately, but are still allowed the opportunity for manufacturers to correct issues to perhaps gain approval at a later date.

References

1. FDA. New drug application (NDA). fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/NewDrugApplicationNDA/default.htm. Updated March 29, 2016. Accessed November 28, 2017.

2. FDA. CFR — Code of Federal Regulations Title 21. accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm. Updated August 14, 2017. Accessed November 28, 2017.

3. Romza-Kutz DJ, Roth FE V, Complete response letters. Husch Blackwell LLP. google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&cad=rja&uact=8&ved=0ahUKEwjw8dS2jeTXAhUGxoMKHaQGBv4QFgguMAE&url=https%3A%2F%2Fwww.healthcarelawinsights.com%2Fwp-content%2Fuploads%2Fsites%2F278%2F2015%2F01%2FCRL_Whitepaper.pdf&usg=AOvVaw28h6qwj99o7D9eYpqsbGwT. Accessed November 28, 2017.

4. Jenkins J. A review of CDER’s novel drug approvals for 2016. blogs.fda.gov/fdavoice/?s=jenkins&submit=Search. Published January 4, 2017. Accessed November 29, 2017.