FDA Expedited IND to Lean on Rolling Submissions/Reviews

A central feature of FDA’s new expedited IND pilot program will be a rolling pre-IND submission process. Under the current system, sponsors generally prepare for one formal pre-IND meeting and must decide when they have sufficient information to engage FDA on their development program.

Under the pilot, sponsors and their designated qualified research institutions (QRIs) would be allowed to submit individual components of an IND as they become ready, enabling FDA to provide feedback during the development process rather than waiting for most of the application to be assembled, according to officials who detailed the program in a Webcast last week.

The agency said the purpose of involving QRIs is to improve the quality of submissions and provide expert scientific and regulatory advice before material reaches FDA reviewers. Better-prepared submissions should allow FDA scientists to concentrate on substantive scientific and safety questions rather than resolving deficiencies or uncertainties in the application.

Earlier this month, acting CBER director Karim Mikhail  outlined the agency’s intention to overhaul the early-stage clinical development process through the IND pilot, arguing that the changes are needed to prevent drug development from shifting overseas and to accelerate first-in-human clinical trials in the U.S. He said the agency is seeking to modernize a regulatory process described as outdated and increasingly unable to support today's complex drug development landscape, particularly for advanced therapies such as cell and gene therapies.

The pilot’s rolling process is intended to be iterative, FDA officials said during the Webinar. For example, a sponsor and QRI could submit a nonclinical development plan early, obtain FDA feedback, and then use that information to develop subsequent components. The principal components expected to receive FDA engagement during the rolling pre-IND process are chemistry, manufacturing and controls (CMC), nonclinical and clinical.

The agency said sponsors will still be subject to the existing 30-day IND review period once the complete application is submitted. However, FDA expects much of the substantive work to have occurred during the rolling process, potentially reducing the amount of work required during the 30-day period.

FDA officials said the agency is not seeking to lower safety standards. Instead, the goal is to identify unnecessary sequential steps, clarify Phase 1 IND requirements and ensure that sponsors generate information appropriate to the stage of development. For a Phase 1 IND, the central question is whether the proposed study can proceed without exposing participants to unreasonable and significant risk.

Under the proposed pilot, drug sponsors’ partnership with QRIs will be a key component of its success. QRIs would provide sponsors with scientific and regulatory advice during the pre-IND phase, with expertise expected across nonclinical development, CMC, clinical development, clinical pharmacology and regulatory affairs. The agency said the QRI's expertise should match the therapeutic area and specific first-in-human study being developed.

The pilot initially will be limited to commercial INDs. FDA said it wants to test different sponsor-QRI operating models rather than have the agency match sponsors with institutions. Existing relationships between sponsors and academic medical centers, CROs or other organizations could be used to form pilot partnerships.

Officials also noted that the pilot will attempt to reduce delays after IND submission by encouraging IRB review to proceed in parallel with FDA's IND process. They said some IRBs currently wait for a "safe to proceed" determination before beginning their review, even though the original intent was for IRB and FDA review activities to proceed in parallel. Under the pilot, once a draft clinical protocol is available, the sponsor could submit it to an IRB while the IND remains under FDA review.

The goal is for IRB approval, site contracting and FDA authorization to be completed at approximately the same time, allowing a trial to begin sooner, the officials explained. QRIs are expected to help coordinate these activities among sponsors, IRBs, clinical sites and FDA.

FDA emphasized that the pilot will not transfer regulatory authority to QRIs. The agency will retain responsibility for IND decisions, clinical holds and other regulatory functions, as well as its authority over investigators and clinical trial inspections.

FDA officials repeatedly stressed that the initiative is intended to make requirements "phase appropriate," rather than less stringent. The agency is also pursuing related efforts involving CMC flexibilities, nonclinical approaches, new approach methodologies, quantitative systems pharmacology, minimum anticipated biologic effect level dose selection and other tools intended to reduce unnecessary preclinical work while maintaining participant protections.

The agency plans to evaluate the pilot using several measures, including time from the pre-IND phase to FDA authorization, time from IND submission to first patient enrolled, and the rate of full clinical holds following IND submission.

FDA also expects to assess the quality of the work performed by QRIs, including whether their recommendations and submitted components are sufficiently complete and scientifically sound to minimize additional FDA review and follow-up.

Officials said the greatest opportunity for time savings may occur before and after the formal IND review rather than during the 30-day statutory review period. Scheduling a traditional pre-IND meeting can take roughly 60 to 70 days, according to the Webinar presentation.

FDA said it expects to open applications for sponsor-QRI pairs next month, with participant selection and pilot launch planned for the fourth quarter.

Additionally, the agency has launched a Phase One IND Navigator intended to give sponsors — particularly smaller companies and academic investigators — a centralized source for relevant FDA guidance, CMC flexibilities, frequently asked questions, procedures, policies and regulatory requirements. FDA has also established a dedicated contact point for Phase 1 IND questions.