FDA IND Pilot Plan Shows How First-in-Human Drug Trials Get the Green Light

The acting head of the US Food and Drug Administration's Center for Biologics Evaluation and Research says the country is losing ground on early clinical trials. In an FDA Voices post on Aug. 5, Karim Mikhail wrote that “Phase 1 trials that may take up to two years to complete here in the United States are completed in nine months in China.”

His proposed remedy is an Expedited IND Pilot. Qualified Research Institutions, such as academic medical centers and contract research organizations, would act as scientific partners to drug sponsors while they prepare an investigational new drug application, and FDA would review parts of the application as they are completed rather than waiting for the full package. FDA has released a request for information on the design and held a stakeholder webinar on Aug. 6, Applied Clinical Trials reported.

The pilot is built around the existing IND process, which decides when a new drug or biologic can first be given to people.

The 30-day clock

Under 21 CFR 312.40, an investigational new drug may be used in a clinical investigation only once the sponsor has submitted an IND and it is in effect. An IND goes into effect 30 days after FDA receives it, unless FDA notifies the sponsor that the studies are subject to a clinical hold, or earlier if FDA says the studies may begin. Until then, the regulation says, an investigator may not give the drug to human subjects.

Mikhail's post describes the steps around that clock. Before filing, the current process offers a single pre-IND meeting, which he said is expected to settle nonclinical, clinical, and chemistry, manufacturing and controls questions all at once. Under the pilot, sponsors and their partner institution would submit components on a rolling basis, and, he wrote, “The formal 30-day review clock would only begin when the final component of the IND is submitted.”

What a clinical hold is

The 30 days give FDA time to decide whether to stop a study before it starts. Under 21 CFR 312.42, a clinical hold is “an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation.” Under a hold on a proposed study, participants may not be given the drug; under a hold on an ongoing study, no new participants may be recruited.

For a Phase 1 study, FDA may impose a hold if it finds that participants would be exposed to an unreasonable and significant risk of illness or injury; that the named investigators are not qualified; that the investigator brochure is misleading, erroneous or materially incomplete; or that the IND lacks sufficient information to assess the risks. The hold may be imposed by phone or in writing, a written explanation must follow within 30 days, and the study may resume only after FDA notifies the sponsor it can proceed.

Mikhail tied the hold rules to delays. He wrote that existing guidance was not written specifically for Phase 1 trials, so sponsors “routinely over-submit data” for fear of clinical holds. He also pointed to delays after an IND is in effect, including institutional review board review, site contracting and enrollment, which he said are the target of HHS's Operation TrialBlazer.