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Contributing authors: Carolina Ahrendt, MBA, PMP & Mike Fusakio.
Under Dr. Makary, the FDA has focused on the time it takes to complete certain FDA tasks. The FDA has released previous press releases on the proposed reduction in the use of animal models and the use of AI in FDA reviews. These changes are being made to speed up the drug development pathway and bring "more cures and meaningful treatments to the American public."
The Commissioner's National Priority Voucher (CNPV) is the latest change aimed to streamline and accelerate the time it takes to get new meaningful treatments to Americans. The goal with the CNPV is that it would drastically decrease the FDA review time for new drug applications from 10-12 months to one-to-two months or facilitate enhanced communication pathways for early-stage products. Enhanced communications during the early stage can provide key strategic insights into process development issues as they arise and potentially help make the overall development more efficient.
The application and selection process for the CNPV, presently, is not clearly defined, but we do know that programs will need to address at least one of the following criteria that are aligned with US national priorities:
As described, the CNPV program has a two-year lifetime, but it is not clear if it is renewable. It is
not transferable. Given the short timeline, will this open the door for post approval follow up
activities and commitments similar to what is granted for Emergency Use Authorizations?
Manufacturing Considerations
As sponsors consider applying for the CNPV, a key consideration is the impact of the accelerated timing on the development timelines for the CMC program. Thinking about this both strategically and tactically, the provision that allows the Module 3 CMC information to be provided up to 60 days in advance of filing the final marketing application can have a large impact on the timing for sponsors preparing the registration batches for the marketing application.
Regardless of whether a CNPV has been granted, the same requirement to provide at least 12 months of real time stability data with the marketing application applies. This means that at least 12 months of real time stability data for the drug product which has been manufactured by a process representative of the commercial process, stored in the final container closure system and held under the recommended long term storage conditions, must be submitted. The ramification of this outcome is the process must be hardened and next to final if not final (for a small molecule) or final and validated (for a biologic) approximately 16 months in advance of the anticipated marketing application date under this program. This has a ripple effect on the timing needs for formulation development, process development, analytical method development and validation, and Process Performance Qualification (PPQ) and Pre-Approval Inspection (PAI) readiness. While all of these are standard drug development activities, the opportunity to submit the CMC package 60 days ahead of the rest of the package will definitely impact the CMC timelines and should be taken into account. This can potentially lead to very shortened CMC development timelines.
Nonclinical Considerations
The same planning and strategic considerations noted for CMC must also be considered for a product’s nonclinical package. Sponsors must plan and discuss with the Agency ahead of time on the need and design of any additional nonclinical studies (i.e., DART or Carcinogenicity), as a rodent carcinogenicity study can take two plus years to perform. Sponsors must be prepared ahead of time either with a plan for their nonclinical studies or their approach for a waiver request.
The CNPV program may allow for certain nonclinical studies to be completed post-approval, but it is our recommendation that sponsors prepare as if the nonclinical package would need to be completed without agreement from the Agency. Taking the CNPV in consideration with other recent Agency focuses, sponsors should watch how the Agency may allow non-animal models to help meet these timelines. Sponsors within the CNPV program should plan to use the increased communication between sponsors and the Agency to evaluate additional means and get agreement on their proposed nonclinical package to meet these aggressive timelines required by the CNPV program.
While the concept of the CNPV is new, its core aspects seem similar, and it appears to be created with elements of other priority programs previously introduced at the FDA. In many ways, especially for early-stage programs that enter the CNPV program, participation may not be much different than the Agency’s Support for Clinical Trials Advancing Rare Disease (START) program, Fast Track Designation, or Real-Time Oncology Review (RTOR), with the benefit being enhanced communication with the Agency. The START program and CNPV both focused on a select grouping of products under development and required the CMC program to align with the overall submission timeline. Recent presentations from the START program participants like Larimar Therapeutics and Myrtelle have noted the positive impact of the increased communication on the program’s development. What is unclear at the moment is to what degree programs like START and CNPV will be able to afford sponsors increased communication with the Agency given the Agency’s decreased bandwidth. However, if the Agency can support it, Dr. Makary is correct that the benefits of a 15-minute call for sponsors could be significant in terms of shortening product development timelines. This increased communication will make the CNPV highly sought after.
The RTOR program incorporates many of the principles that the CNPV program looks to enact. The purpose of RTOR was to streamline the FDA review process by allowing sponsors to submit top-line data (i.e., safety and efficacy prior to study report completion) or proposed labeling language early on a rolling basis using a multi-part submission approach instead of separate completed modules or one complete submission with all components (clinical, nonclinical, quality, and regulatory; Modules 1-5) at the same time. This allowed the FDA to review some of the top-line data before the final submission was made. However, the determination of the final PDUFA date did not start until the final sequence was submitted. Thus, it brings into question: Will the CPNV program capitalize on this rolling approach to accelerate reviews as they have done for RTOR or prefer one completed submission?
Additionally, the RTOR program showed the potential for a faster review compared to the traditional standard review (12 months after submission; 2 months for validation and 10 months for FDA review) or priority review (8 months after submission; 2 months for validation and 6 months for FDA review). In two articles about RTOR (Feng et al, 2021 and Gao et al, 2022), they analyzed several marketing applications that were granted RTOR and for one of the applications (tucatinib), the FDA review time was as fast as four months after submission beating the planned PDUFA date. Thus, it brings into question: With a one-to-two-month review for the CPNV program, does this include the 60-day validation check and the actual accelerated review time of three-to-four months after the submission?Figure 1 shows the potential comparison of the FDA review timelines for standard, priority, RTOR, and the potential review times for the CPNV program.
Figure 1: Comparison table of the FDA review timelines for standard, priority, RTOR versus the potential review times for the CPNV program
In a recent RTOR submission that Halloran supported, we were able to make submissions in a rolling manner for a total of up to four submissions with varying content in each, utilizing the suggestions made in the guidance (top-line results first, followed by a mixture of content for nonclinical, CMC, and clinical). We had informed the sponsor of the potential FDA requests for information requests (RFIs), however, the majority did not arrive until after the final sequence was submitted. Additionally, there were a few ad hoc meetings for clarification with very little notice. Thus, it is essential for a sponsor to be ‘on call’ in the event of the issuance and response to FDA RFIs or to be prepared for ad hoc meetings for clarification.
While the full process and benefits of the CNPV program are still being defined, sponsors can begin to take steps to prepare. By using past experiences with other priority programs, sponsors can position themselves for success with the CNPV.
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