Authored by: Don Gieseker, Associate Vice President Regulatory Affairs
In the Drug Development 101 series here on Speaking of Sanofi, we have explored topics related to the FDA review process for new drugs, including the types of applications that can be submitted to the FDA and the meaning of a PDUFA date. Today, we shed some light on the next step – the way the FDA responds to an application, once its review is complete.
Before we get into the way the FDA responds to new drug applications (NDAs) or abbreviated new drug applications (ANDAs) today, it’s worth taking a step back and looking at the way the agency used to respond.
If a drug met all agency standards for safety and efficacy, the FDA would grant it an “approval” letter, indicating that the drug can be marketed for sale in the United States. This approval process remains the same today.
However, the FDA’s response to an application that is not ready for approval has changed.
In the past, if an application was not approved, the FDA would issue either an “approvable” letter or a “not approvable” letter. An “approvable” letter indicated that approval could come at a later date if certain changes were made. Meanwhile, a “not approvable” letter meant there were deficiencies that usually required the submission of substantial new data before it could be considered for approval.
The FDA announced a new approach in 2008 that streamlined the response to applications that cannot be approved without additional information or resolution of an outstanding issue(s). Instead of “approvable” and “not approvable” letters, the agency began utilizing “Complete Response Letters” – or “CRLs” for short.
Why did the FDA make this change? According to the FDA, CRLs provide a more consistent approach to alerting companies of changes that must be made before an application can be approved, with no implication regarding the ultimate approvability. The FDA was also already using CRLs to respond to biologic license applications (BLAs) that weren’t ready for approval, so standardizing the process by implementing their use for NDAs made sense.
Clarifying the Meaning of CRLs
Even though CRLs have been in use for NDAs since 2008, many people still don’t understand what they mean. Does a CRL mean the application was rejected and the drug will never come to market? Not necessarily.
A CRL simply indicates that the review cycle for an application is complete and the application will not be approved in its present form. It also describes any deficiencies in the application that prompted the CRL, along with recommended actions to get it ready for approval. These actions can vary in significance, based on the application at hand. For example, the FDA could require edits to the proposed labeling or they could require the execution of an entirely new clinical trial.
After receiving a CRL, applicants, working with FDA, must decide on the best course of action based on their specific situation. Some situations may call for the sponsor to withdraw the application because they think an approval is highly unlikely. However, many times the issues raised by FDA in the CRL are resolvable and the applicants decide to push forward, addressing the FDA’s feedback and resubmitting the application for another review (either two months, or 6 months depending on the complexity of the resubmission). A CRL is not an approval, but it is not necessarily the end of the road – every situation is unique.
We hope this overview helped give you a better sense of the process and what it takes to truly bring a drug to market. If you’d like to learn more, additional information is available here on the FDA website. Otherwise, remember to stay tuned for the next edition of our Drug Development 101 series.