Rolling NDA and BLA Submissions: Accelerate Your Review Timeline

The standard electronic Common Technical Document (eCTD) submission for a New Drug Application (NDA) or Biologics License Application (BLA) includes submission of all five eCTD modules simultaneously (Figure 1).

With many sponsors looking to accelerate FDA review, a growing regulatory trend is to use a rolling NDA/BLA submission. This is where the sponsor spaces out the submission of the five eCTD modules into discrete units, usually by subject matter (i.e., non-clinical, clinical, CMC), with each unit submitted separately (Figure 2). The FDA may conduct rolling reviews of a marketing application for a product with a Fast Track Designation, Breakthrough Therapy Designation, or some other expedited review status.

 

What are the benefits of rolling NDA and BLA submissions versus a standard review?

In the “Standard” NDA timeline (Figure 1), the FDA receives all modules in August based on the availability of the final pieces of rate limiting data. However, in a rolling submission (Figure 2), data can be submitted as it becomes available. In this example, the nonclinical data is submitted in June, the CMC data is submitted in July, and the clinical data is submitted in August.

The rolling submission means the FDA will receive key portions of the application months in advance, compared with when they would in a typical timeline. This is the key advantage of a rolling submission: it gives FDA the opportunity to begin reviewing and resolving issues sooner, shortening the overall review time.

When will the FDA begin review of a rolling submission?

Sponsors may wonder if a rolling submission actually speeds up the review of their application. Does the FDA really begin reviewing those units as they are submitted? In the past, it was often the case that the FDA waited until they had received all parts of a rolling application before they began their review. However, Certara has recent experience with clients who began receiving Information Requests from the FDA related to the first part of their rolling submission, while the remaining parts of the application were still in progress and not yet submitted. It’s now clear that, in at least some circumstances, the FDA does begin reviewing a rolling submission as they receive the parts, rather than waiting for the submission to be completed. Close coordination with your Regulatory Project Manager at FDA will help confirm if this will be the case for your submission.

Note that the FDA does not consider a rolling submission officially (fully) received until they receive the final part of the application. After this, the FDA officially begins the process of filing and reviewing the application.

Challenges and risks with rolling NDA and BLA submissions

There are multiple challenges and risks associated with rolling submissions compared with standard submissions.

• You must get the FDA’s agreement before moving forward with a rolling submission. Once that agreement is obtained, you must adhere to the agreed timelines.
• Draft documents should not be submitted, and each rolling submission part should be complete and reviewable as submitted.
• A rolling submission multiplies the complexity of the application, with more deadlines, decisions, and document locations to be tracked.
• You must prepare and submit responses to Information Requests while still developing the other parts of the submission.

Overall, it is necessary to have an experienced submission manager to help align all the necessary pieces for each part of the submission and to keep the timelines in sync.

What does a sponsor need in order to proceed with a rolling submission, and how can they be successful?

First, the FDA must agree that the sponsor can proceed with a rolling submission. Ideally, this occurs at the pre-NDA/BLA meeting with a plan for the rolling submission. The plan needs to be clearly communicated. Once agreement is reached, the sponsor must abide by the timeline and submission parts. The “Expedited Programs for Serious Conditions—Drugs and Biologics” guidance provides more details on how to present a rolling submission plan to the FDA.

Second, the sponsor needs strong logistics management. To ensure a successful rolling submission, we recommend sponsors use robust management and tracking tools to ensure that nothing is forgotten or left off the timeline. This helps the submission manager focus on the details to ensure that the tracking of individual files aligns with the entire submission process, and to keep all moving pieces developing on time. It is important to keep lines of communication open between all groups on the status of each part of the submission, so that silos are avoided. Third, build timelines to ensure that final data and documents are submitted in each wave. It is standard practice that the FDA will only accept submission of a complete section of a BLA or NDA. There are only a few specific instances where draft data can be submitted (i.e., stability data), and this needs FDA agreement before doing so.

Finally, plan to accommodate FDA Information Requests before all parts of the submission are completed. It is necessary to respond to these requests in a timely manner, and to keep the subject matter experts informed and aligned on priorities. As turnaround times are very short, it can be helpful to designate a single person who is responsible for shepherding each Information Request response, including preparation and submission. You should also select a strategy for sequence numbering these requests relative to the Module submissions.

When it comes to managing your eCTD submissions, Certara Regulatory Operations and eCTD Publishing specialists and our GlobalSubmit eCTD software can help you simplify your regulatory processes and ensure submission success.