On September 29, 2023, the U.S. Food and Drug Administration (FDA) took action to help further accelerate the development of novel drug and biological products for rare diseases. The action, an announcement of an opportunity for a limited number of sponsors to participate in a pilot program (Support for Clinical Trials Advancing Rare Disease Therapeutics (START)), allows for more frequent communication with the agency to address clinical development issues as they arise.
As intended, insight gleaned from the START pilot program seeks to illuminate how best to propel more efficient development of potentially life-saving therapies with rare disease indications, as well as to guide sponsors towards generating robust high-quality and compelling data to support their future marketing applications.
In recognition of Rare Disease Day, here is an overview of the START pilot program, expectations to consider if you are applying into the program, and early preparation considerations.
START Program: Mission, Benefits, and Criteria
The Orphan Drug Designation represents an important milestone for sponsors developing products for rare diseases. The designation carries significant benefits to the sponsor including tax credits, user fee exemptions, and market exclusivity. While the benefit of an early engagement with the FDA, such as a pre-Investigational New Drug (IND) meeting or an end of Phase 1 meeting, can certainly aid in the progression from an IND to approval, challenges remain for rare disease drug sponsors.
All product activities (clinical, nonclinical, and chemistry, manufacturing, and controls (CMC)) in these development programs are challenged by multiple factors associated with expedited rare disease development programs. For example, clinical development must balance what is typically considered appropriately designed clinical trials against the ability to recruit patients (i.e. size and location of patient population), challenges in the use of placebo, and the small but robust clinical dataset intended to show substantial evidence of safety and efficacy. Encouragingly, these challenges have been recently highlighted by top FDA officials, including FDA commissioner Robert Califf, where he notes, “We’re about to see a tsunami of therapies for rare and ultra rare disease, and I don’t think any of us think the current pathways are optimal.”
In hopes of addressing these challenges, the FDA has launched the START program, which will be open to up to three sponsors in both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). The pilot program’s focus is to provide opportunities through the currently available meeting types for increased communication to aid in moving towards submission of a Biologics License Application (BLA) or a New Drug Application (NDA).
For the initial pilot, the FDA has established program criteria:
The third criterion differs for applicants of CBER and CDER:
START applications for this initial pilot program are due to the sponsor’s IND no later than March 1, 2024, and require inclusion of the program development plan and status for CMC, nonclinical, and clinical. The sponsor should highlight the specific issues they are seeking enhanced communication with the FDA to address, and the timeline for the studies intended to provide the primary evidence to either support approval or future pre-BLA/NDA meetings.
Selection will be based on the application criteria and factors such as potential clinical benefit, perceived benefit of enhanced communication to the proposed complications, breakthrough designation status, and the FDA has noted that for the initial pilot, significantly complicated combination products may be less likely to be selected.
As this is the first year of applications, there is a vagueness to the selection criteria for the program, which will undoubtedly be further defined as the program develops. For instance, the program does not specifically require sponsors to have clinical data (just potential for clinical benefit); however, applications with clinical data may be able to better demonstrate their pathway to marketing application. As the START program further develops, this will be an aspect for early-stage IND programs to watch.
As the START program is in its pilot stage, the exact implementation of ‘enhanced communication’ is still not clear. However, previous agency programs (i.e., the Emerging Technology Program) may give some insight into how this may occur. It is unclear at this stage if a specific group within the agency will be created and be responsible for these programs (i.e., the Emerging Technology Team), but the additional agency resources along with opportunities for additional and enhanced communication could address the potential pitfalls of program development.
Early Preparation Considerations
While much will be learned from the initial pilot program to aid potential applications for 2025, if the agency opens additional spots, sponsors should start to prepare now. The document will require significant cross-functional team input and sponsors should view the work at the level of a FDA meeting package. Addressing all aspects of development in meaningful detail will require the sponsor to plan, discuss, and agree upon reasonable development timelines prior to drafting. Sponsors should ensure their program management or regulatory teams have insight into all development plans across clinical, CMC, and nonclinical in preparation for preparing the application to ensure all challenges and discussion points are covered.
Halloran can assist clients through these significant program management barriers to develop a successful START application, and partner on their continued rare disease program development journey through our clinical, regulatory, and program management expertise.
Throughout the year, the START pilot program will be closely watched for aiding the selected sponsors in progressing the development programs for these rare diseases. The program will not fix all issues plaguing the development of products for rare diseases; however, the program offers the potential to alleviate many of the pitfalls sponsors encounter. The success of the pilot program will hopefully lead to increased opportunity in the 2025 application process in terms of the number of accepted applicants or expanding the eligibility criteria, and subsequently, the speed and ease at which these necessary products can be brought to market.
The effect of the START pilot program will be closely watched for its potential success in developing programs through approval and for the trends in accepted programs.
As you move through the early phases of clinical development, now is the time to consider and plan for the START program application as part of your regulatory strategy. Contact our team today to further the conversation.