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FDA guidance steers COVID-19 drug developers to controlled, sub-grouped trials

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A pair of new FDA guidance documents covering COVID-19 drug development provides much needed clarity for the hundreds of drugmakers that have embarked on clinical and preclinical development programs for the novel coronavirus over the past four months.

At least 240 clinical and 180 preclinical compounds are in development for the indication, according to BioCentury’s COVID-19 Resource Center.

The new documents provide separate guidelines for pre-IND meetings with FDA and for conducting Phase II and III trials for therapeutics, consolidating the FDA filing process and guiding sponsors to trial designs with the best chances of producing conclusive data.

The guidances will be in effect for the duration of the public health emergency declared by HHS, but they’ll also help steer COVID-19 drug development after its termination.

The pre-IND guidance consolidates the FDA review process by funneling all new communications on COVID-19 therapies through pre-IND meeting requests rather than pre-EUA requests.

“At the time a sponsor initiates drug development discussions with FDA, there will generally be insufficient information to assess whether or at what point an EUA might be appropriate,” it states. “Providing information in a pre-IND meeting request will generally facilitate a more efficient development process.”

It also outlines the recommended information for pre-IND requests, including preclinical safety data and detailed clinical trial plans.

The clinical guidance provides clarity on patient characteristics and endpoints, and states that trials should be randomized, placebo controlled and double-blind superiority trials by design.

The current COVID-19 therapeutic landscape includes a large number of small clinical trials with poorly defined endpoints, controls and clinical objectives that have wasted resources and resulted in conflicting and often inconclusive data (see “Stakeholders Call for Trial Standardization”).

The guidance recommends designing trials to adapt to a changing standard of care, directing therapies with strong preclinical evidence straight to pivotal trials and characterizing patients by disease severity, then subgrouping them for analysis.

As treatments prove effective for COVID-19 -- remdesivir from Gilead Sciences Inc. (NASDAQ:GILD) being the first example -- they will be incorporated into standard of care. That means if SOC could evolve over the course of a trial, the active drug should be compared with placebo as an add-on to the standard of care.

Therapies with compelling preclinical or preliminary clinical evidence may move directly into pivotal trials, and therapies with less clear evidence of benefit may be tested in small proof-of-concept studies, the guidance recommends. The trials should also have criteria to stop early for futility built in.

Certain therapeutic classes may prove more effective at different stages of disease. For example, antivirals may be most valuable in the early, mild stages of infection while immune modulators may help in the later stages, so characterizing patients by disease severity is an important step in all trials (see “Closing in on Matching Therapeutic Mechanism to Disease Stage”).

The guidance also provides a list of potential endpoints, adjusted for disease severity.

Randomized controlled trials are a step in the right direction to preserve resources; they can be stretched further by master protocol trials that evaluate multiple treatments using a single study protocol, control arm and set of endpoints (see Master Protocols Emerge as a Critical Clinical Tool).

While the guidance states that “it may be appropriate to conduct decentralized and/or platform clinical trials” under some circumstances, it doesn’t provide guidelines. Instead, FDA “may provide additional recommendations as we gain more experience regarding their use in this context.”

The two new guidances join a growing list of 43 other FDA guidance documents that have been issued for COVID-19, which includes guidance on the use of convalescent plasma, product-specific guidance for the use of hydroxychloroquine and adjusted guidelines for running clinical trials in other indications during the emergency (see “FDA Clarifies Remote Trial Monitoring Guidance”).

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