Earlier this summer, FDA posted docket FDA-2026-N-4699 to the Federal Register, describing a pilot program to accelerate Investigational New Drug (IND) applications and shorten time to first-in-human clnical trials, and requesting comments from the public. Sonia and I posted comment FDA-2026-N-4699-0187 describing our experience filing an IND for our divalent siRNA for prion disease, and describing what we believe needs to happen to accelerate early learnings from human clinical trials of new drugs. Below is the text of this public comment.

August 24, 2026

U.S. Food and Drug Administration
5630 Fishers Lane Room 1061
Rockville, MD 20852

Re: Docket No. FDA-2026-N-4699 for “Expedited Investigational New Drug Pilot Program; Request for Information.”

We, Sonia Vallabh and Eric Minikel, are a patient-scientist team running a biomedical research laboratory at the Broad Institute in Cambridge, MA. Sonia’s mother died of genetic prion disease in 2010 and genetic testing revealed that Sonia inherited the causal mutation, making her very likely to develop the same disease in middle age. We, then a recently married couple, changed our careers to retrain as scientists, earned PhDs, and dedicated our lives to developing a preventive therapeutic for prion disease. We currently run a first-in-human clinical trial of an intrathecal siRNA for prion disease (NCT07444580) under Research IND 167326. We have spoken publicly about the challenges facing academic sponsors in rare disease drug development — for instance, Sonia spoke at the Duke Margolis RISE Forum (Nov 20, 2025) and the CDER & CBER All Hands: Implementing the FDA’s Plausible Mechanism Framework (May 4, 2026). We have made our regulatory documents public as a service to the rare disease community. We have also interacted with the Agency about regulatory pathways to preventive prion disease drug development under IND 141250, and about a one-time gene therapy for prion disease, AAV PRNP-CHARM, under Pre-IND PS009720/3. We appreciate this opportunity to provide feedback on FDA’s Expedited Investigational New Drug Pilot Program.

We applaud the Agency for focusing this program on a critical problem: the time to reach first-in-human clinical trials and therefore first human proof-of-concept for a new therapeutic. Many other FDA programs already designed to accelerate rare disease drug development are focused on the milestone of marketing approval, while the barriers to reach a first human trial remain enormous. We strongly agree that accelerating time to first-in-human will have enormous benefits for patients by allowing more potential therapies and therapeutic hypotheses to be tested sooner.

In our siRNA program, we identified the drug candidate in November 2022, held a Pre-IND meeting with FDA in June 2023, filed our IND in February 2025, and dosed the first patient in June 2026. This timeline of ~3.5 years from drug candidate to first human dose was praised by some of our colleagues in private biotech companies as being impressively fast. At the same time, prion disease is rapidly progressive and uniformly fatal, and an estimated ~2,000 Americans died of prion disease in that time interval. We prioritized speed to clinic in several aspects of program design, including: use of one GMP batch for both toxicology and human studies; a single-dose GLP toxicology study; and a non-pharmacodynamically relevant toxicology species.

In our experience, the biggest drivers of timeline were the wall time required to complete GMP manufacturing and GLP toxicology, both of which would still need to be completed before IND clearance under the proposed pilot program. We received very helpful input on both aspects from FDA at our Pre-IND meeting and did not have outstanding major questions thereafter, nor did we receive hold comments for our symptomatic patient population once our IND was reviewed. The nature of our drug (intrathecal) and of our rare disease compelled us to work with major academic medical centers established in our disease, rather than selecting sites known for quick contracting, IRB review, or site initiation. Our reliance on NIH funding meant that we needed to achieve IND clearance prior to IRB submission. Like private sector drug developers, we employed experienced CMC and toxicology consultants who, though expensive on a per hour basis, were nonetheless a very small part of our budget compared to manufacturing and toxicology studies, and provided the expertise that QRIs are proposed to provide. For all of the above reasons, in our case, we do not believe that rolling review, input from QRIs, or parallel IRB review could have accelerated our timeline. Our comments below are focused on other approaches that we believe could accelerate time to first human dose.

C.1. What additional/alternative approaches could achieve similar goals of accelerating Phase 1 FIH IND study initiation in the U.S.? The approaches proposed in the pilot program appear intended to a) parallelize, and b) pre-vet prior to submission, all the standard components of an IND, while not reducing the overall burden of studies required for an IND. For severely debilitating or life-threatening diseases (SDLTs) with no standard of care, a reduction in IND requirements would be commensurate with the justifiable risk. For our disease, we believe that rodent-only toxicology would be adequate to justify first-in-human trials. For redosable drugs (not AAV), a lower starting dose and more gradual dose escalation could mitigate the risks of extrapolating doses from smaller animals to humans. The duration of toxicology studies could be shortened, as is permitted in oncology. For patient populations with a short survival time, data from a single dose study in humans could be used to justify expanding to repeat dose trial designs, without requiring chronic toxicology. Drug-drug interaction and genotoxicity studies could be forgone. CMC requirements could be reduced.

C.2. What are the advantages and disadvantages of the proposed pilot compared to these alternatives? It is worth acknowledging that our proposed alternatives would carry risk. Accordingly our approach could be especially applicable to severe, rare diseases. It might be undertaken in consultation with patient advocacy groups who can speak to their population’s risk appetite. It should be accompanied by robust informed consent about the risks involved in trials. In contrast to the proposed pilot, our approach might reduce not only timeline but also cost, thus enabling more new therapeutic hypotheses and drug technologies to be de-risked and acquire human proof-of-concept, accelerating innovation.

We are grateful for the Agency’s partnership with us on advancing our programs and appreciate the opportunity to participate in this dialog about how to further accelerate progress for patients.

Respectfully,

Eric Minikel, PhD
Sonia Vallabh, PhD
Directors of Prion Therapeutic Science
Broad Institute
415 Main St
Cambridge, MA 02142