Complete Response Letters: Implications for Product Access

  • This page as PDF

Summary

Receiving a complete response letter is not a rejection, but it introduces important business questions for product launch planning.

Note: This insight was originally posted on November 12, 2018. It was updated on November 30, 2023, to include new information.

What Does it Mean When a Manufacturer Receives a CRL?

A complete response letter (CRL) is a notice issued by the Food and Drug Administration (FDA) indicating that an application will not be approved in its present form. This can be issued in response to a New Drug Application (NDA), Abbreviated New Drug Application (ANDA), or Biologics License Application (BLA). The CRL explains why the submission was deemed inadequate and often includes the FDA’s recommendations on how the sponsor can address those deficiencies.

Importantly, receipt of a CRL is not a rejection of an application. Instead, it is the method that the FDA uses to provide sponsors with an opportunity to course-correct an application so that it may be approved in a subsequent review. It is also not an unusual occurrence: In the 2018–2022 cycle of Prescription Drug User Fees, 37% of BLAs and NDAs received a CRL.

Importantly, sponsor re-submissions in response to CRLs do not guarantee approval.  The FDA will evaluate the resubmitted application based on its regulatory authority and will determine whether it meets the benefit-risk assessment required for approval.

CRL Response Timeline Impacts Product Access Planning

The timeline for reconciling a CRL begins when the FDA sends the letter, which can occur at any point during an accepted review of a product application. The reconciliation timeline will depend on the severity of the deficiencies and the sponsor’s capacity to address them quickly.

Resubmissions fall into two categories:

  • Class I resubmissions: If the FDA determines that additional information or data from the sponsor can easily address minor deficiencies in their application, it is classified as a class 1 resubmission. Upon resubmission, the FDA has two months to review these applications.
  • Class II resubmissions: If the FDA determines that significant changes or new data are needed to address sponsor deficiencies in their application, it is classified as a class 2 resubmission. Upon resubmission, the FDA has six months to review these applications.

Based on the resubmission type, the sponsor will need to consider the types of data that must be generated and collated for a new submission. While the extent of the deficiencies will influence the resubmission timeline, the manufacturer is not required to adhere to any specific resubmission timeframe. Figure 1 illustrates the resubmission and review process for a hypothetical product that receives a Class II resubmission CRL, followed by a Class I resubmission CRL. Due to timing shifts associated with reconciling application deficiencies, the launch planning timeline shifts relative to the number of review cycles that the product undergoes to get approved.

Figure 1. Illustrative FDA Review Cycles and Shifts in Market Access Timeline

*10-month review is the review period for standard applications; priority review can be sought with the FDA, which reduces the first cycle review period to six months.

Post-CRL Access Strategy Planning

After receiving a CRL, the sponsor is tasked with evaluating the cost-benefit dynamics of two potential paths. One path involves swiftly addressing the deficiencies in their application to expedite resubmission. The other path involves a more measured approach to reconciliation, which, while resulting in a delayed launch, may allow the sponsor to capitalize on evolving commercial opportunities. The choice between these paths hinges on the relative costs and potential upside of each. Several factors may shape sponsors’ decision, including the:

  • Reason for rejection: If the product or data has fundamental flaws that cannot be feasibly addressed, it may render further development unviable.
  • Costs associated with resubmission: Sponsors should rigorously weigh these costs against their commercial access goals when determining the appropriateness of resubmission.
  • Likelihood of success: The class of resubmission and the CRL’s content offer guidance on the potential for subsequent approval or lingering uncertainties.
  • Competitive landscape: Sponsors should also consider on-market and pipeline competitors and shifts to market share as a more saturated competitive market may alter the value proposition for the product at launch.

Dive Deeper

Avalere’s team of experts in competitive marketplace dynamics, regulatory strategy, and commercial viability assessments assist clients with understanding pathways for mapping clinical and regulatory processes to broader access strategies. To learn more about how Avalere can support you, connect with us.

 

 

Webinar | A Closer Look at Patient Support On June 6 at 2 PM ET, Avalere experts will explore how potential implications of the Inflation Reduction Act (IRA)’s out-of-pocket cap, in addition to other key regulatory and policy activities shaping benefit design and patient cost-share (e.g., EHB), could impact patient commercial and foundation assistance. Learn More
Register
From beginning to end, our team synergy
produces measurable results. Let's work together.

Sign up to receive more insights about Regulatory Strategy and FDA Policy
Please enter your email address to be notified when new Regulatory Strategy and FDA Policy insights are published.

Back To Top