What to Expect following Your Marketing Application Submission

Submitting a marketing application to the FDA is only the first in a cascade of events that lead to products being approved. However, this flurry of activity is not solely on the side of the regulators – there are also Sponsor-side responsibilities to be considered. Failing any one of these could unnecessarily jeopardize or delay approval. In this post, we will walk you through some of the key events and milestones between FDA submission and approval and offer some tips to help make the process as smooth as possible.

Filing and Review Process Overview

Once a submission is received, the NDA/BLA review process proceeds through the following phases:

Submission Processing
Filing Determination and Review Planning
Full Review
Official Action
Post-Action Feedback

The overall goal of the review process is to provide a thorough but efficient mechanism whereby the safety, effectiveness, and quality of a product can be adequately assessed and a regulatory decision can be made in a timely manner. The amount of time that applications spend between initial submission and a final regulatory decision varies. Current FDA performance goals under the Prescription Drug User Fee Act (PDUFA) stipulate that FDA intends to review and act on 90% of standard NDA and BLA submissions within 10 months of the filing date. The goal for priority review applications is 6 months. This review target is commonly referred to as the PDUFA goal date. However, FDA is currently experimenting with alternative review timelines (e.g., Real-Time Oncology Review pilot program) to provide patients with access to safe and effective therapies as soon as possible.

Submission Processing

Because all commercial marketing applications are now submitted electronically, the first hurdle is to pass an automated technical review. If a submission is missing key components or the study data fail to meet technical conformance criteria, then the application will receive a technical rejection. Assuming the application passes this automated review, it will be further processed and disseminated to the appropriate review division. The regulatory project manager (RPM) within the review division will ensure that the application meets preliminary regulatory and user fee requirements. If these requirements are met, then a review team is formed.

Filing Determination and Review Planning

From the time a marketing application is submitted, FDA has 60 days to perform an initial review. During this time FDA will determine if the submission is sufficiently complete to perform a more substantive review. Day 60 post-submission is designated as the filing decision date. Prior to the filing decision date, each review discipline will make a recommendation about the “file-ability” of the application. If the initial review uncovers deficiencies, FDA may alert the Sponsor at any time using information requests and/or may note the deficiencies as part of the filing letter. Refuse to file designations are made by Day 60 post-submission; otherwise, notification of filing review issues is provided to the Sponsor by Day 74 in a communication commonly referred to as the 74-Day Letter. Sponsors should note that their turnaround time to address deficiencies in the 74-Day Letter is limited and that they should plan resourcing accordingly. In addition to the filing determination, FDA also initiates review planning to work out timelines and review activities. This step helps ensure that the full review is timely and efficient. Following review planning, FDA will notify the Sponsor of any major review milestone timelines.

Full Review

The full review extends from the filing decision to around Month 8 post-submission and to Month 5 for priority applications. During this phase, FDA performs a detailed review of the application. This generally involves consults between primary, secondary, and supervisory reviewers, reviewers from other disciplines, and other consultants from the various offices within FDA, as needed. Sponsors will likely receive additional information requests from FDA during the full review phase. The Sponsor should be prepared to respond to all such requests as completely and expeditiously as possible. As part of the review process, there are a number of tasks beyond responding to information requests that require Sponsor participation. These include the Safety Update Report, Mid-Cycle Communication, Pre-approval Inspection (PAI), Late-Cycle Meeting, Advisory Committee (AC) Meeting (if required), and Labeling Discussions. Sponsors are required to provide FDA with what is commonly known as a 120-Day Safety Update, which is mandated by 21 CFR 314.50 (d)(5)(vi)(b). As the name suggests, this update must be provided to FDA within four months of the initial submission. This update ensures that FDA has the latest safety information prior to making their determination on approval and also ensures that product labeling and the medication guide accurately reflect this information. The Mid-Cycle Meeting occurs around month 5 and is an FDA internal meeting that provides management and review teams with an opportunity to discuss the review status, key findings, and any issues, update timelines, and make a determination about the need for formal risk evaluation and mitigation strategies (REMS) and any additional post marketing requirement (PMR) and post marketing commitment (PMC) studies. Generally, within 2 weeks of the mid-cycle meeting, the RPM and other appropriate members of the review team will call the Sponsor to provide an update on the review status. This is known as the Mid-Cycle Communication. One of the most significant events besides the full review of the quality sections (i.e., chemistry, manufacturing, and controls [CMC]) of the marketing application is the Pre-approval Inspection (PAI). If a PAI is conducted, FDA will send a team of experts to the manufacturing facility to assure that the facility is capable of manufacturing the drug and that data submitted with the marketing application are accurate and complete. A slide presentation on the PAI process and how to prepare for it is provided on FDA’s website. Toward the end of the Review Phase, a Late-Cycle Meeting is held between the FDA and Sponsor to discuss any major deficiencies, the need for a REMS or other risk management actions, major labeling issues, additional post marketing studies, and other updates/issues as appropriate. In addition, certain applications will require an advisory committee (AC) meeting. If FDA decides an AC meeting is warranted, then this will be communicated to the Sponsor as early as possible to allow both sides to share issues and prepare their presentations. An AC meeting may be sought for a number of reasons, including when:

The application is for a new molecular entity
- Especially if the drug represents the first member of a new class
The clinical study design used novel clinical or surrogate endpoints
The application raises significant issues on drug safety and/or effectiveness
The application raises significant public health questions on the role of the drug in the diagnosis, cure, mitigation, treatment, or prevention of a disease.

Finally, if approval is anticipated, labeling discussions are held between FDA and the Sponsor in order to reach agreement on the contents and wording of the prescribing information (i.e., product label, package insert). This is a critical step because it determines the labeled use for the product and impacts how the product may be marketed. During this time any PMC, PMR, and risk management programs are negotiated. Because of tight time constraints, the Sponsor is encouraged to engage in clear and efficient correspondence with FDA and not to submit large amounts of new data to support labeling claims during this time.

Official Action

The Action phase involves finalization of the action package. This includes the Division and Office Director (i.e., signatory) reviews, the final action on the proposed PMC, PMR, REMS, and the official notification of the Sponsor. FDA’s determination is conveyed to the Sponsor via a formal communication known as an Action Letter. In the event that the signatory authority decides not to approve the application, the RPM drafts a Complete Response (CR) letter, which indicates deficiencies and recommendations for corrective action. The Sponsor may also receive discipline-specific deficiency letters. If the application is approved, the RPM drafts an Approval Letter. For approved applications, the discipline-specific reviews and the overall summary basis for approval are made public with appropriate redaction and may be found (for many, but not all drugs) on FDA’s Drugs@FDA website.

Post-Action Feedback

Following FDA’s decision on approval, the Post-Action phase begins. This phase presents opportunities for both the FDA and Sponsor. During this time, FDA may communicate internally regarding aspects of the review process that were successful and those that were less so. The purpose of these communications is to improve the process and to ensure consistency, efficiency, and alignment with PDUFA goals. If a Sponsor receives an Approval letter, a post-approval feedback meeting may be offered to discuss lessons learned on both sides of the application process (i.e., FDA and Sponsor). This meeting is not considered a PDUFA meeting but is intended to help improve processes for future applications. If a Sponsor receives a CR letter, then an End-of-Review Conference may be requested by the Sponsor, as described in 21 CFR 314.102(d). The purpose of this meeting is to ensure that the Sponsor understands the deficiencies in the application and the expected responses. To emphasize, this meeting is to promote mutual understanding and not necessarily agreement between FDA and Sponsor. If this meeting is requested within 3 months of the CR action, then it will be considered a Type A meeting; if requested later than 3 months, then it will be considered a Type B meeting (Type A meetings receive more rapid responses from FDA and earlier scheduling).

Conclusions

The marketing application review process can require considerable Sponsor involvement. In order to facilitate efficient review and a timely regulatory decision, Sponsors should:

Have a firm grasp on the review process
Understand Sponsor-side post-submission responsibilities
Ensure that the original submission is as complete as possible
Respond to all information requests in a thoughtful and expeditious manner
Ensure that adequate Sponsor-side resources are available throughout the review process
Plan ahead and anticipate potential issues before submitting the application

Finally, remember that while the filing and review process can be complex, you don’t have to go it alone. If you are planning a marketing application submission now or in the future, contact Allucent to learn how our team of industry veterans can help position your program for success.

Additional References