FDA's single-trial guidance calls for the good, bad and ugly data to support effectiveness

Biopharmas looking to submit a drug for approval to the FDA based on just one clinical trial better be thorough in the data they include—good and bad—and they should get in touch with the agency as early as possible.

That’s the headline from new draft guidance (PDF) issued by the FDA Monday, seeking to clarify how companies can demonstrate substantial evidence of effectiveness with one adequate and well-controlled trial and confirmatory evidence. The issue has come into focus in recent years as the FDA cracks down on companies submitting drugs for approval based on only one clinical trial. While the agency standard is two studies to demonstrate efficacy and safety, Congress has allowed some regulatory flexibility for instances where completing more than one trial would be difficult or impossible prior to approval.

The draft guidance builds off of a similar paper issued in 2019 called Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products. This earlier guidance addresses what the FDA considers adequate and well-controlled clinical investigations with a focus on trial design, endpoints and statistical considerations.

When a drug submission is based on one adequate and well-controlled clinical trial and confirmatory evidence, the FDA says that “the quality and quantity” of that data are important considerations. Confirmatory evidence, specifically, should be generated from quality data from an appropriate source.

“It may be possible for a highly persuasive adequate and well-controlled clinical investigation to be supported by a lesser quantity of confirmatory evidence, whereas a less-persuasive adequate and well-controlled clinical investigation may require a greater quantity of compelling confirmatory evidence to allow for a conclusion of substantial evidence of effectiveness,” the FDA explains in the draft guidance.

But drug sponsors must include a description and analysis of all data or information relevant to the safety and efficacy of the therapy, whether that information is foreign or domestic, positive or negative. Companies should not cherry-pick evidence that only supports a conclusion of effectiveness.

“The results of a clinical investigation or confirmatory evidence can be called into question by conflicting evidence unless there is a sufficient scientific justification that may explain the disparate findings,” the FDA explained.

Drug sponsors should also take account of the clinical context for the drug they are seeking approval for, such as disease-specific considerations. Is there an unmet need in this population? Is there a small population for this specific disease? All of these things may mean a single-trial approach is appropriate.

If companies intend to seek approval based on one clinical trial, the FDA recommends early communication with regulators, such as during a pre-investigational new drug meeting. This communication should happen no later than the end of phase 2 meeting. Companies should arrive at these meetings ready to justify why a single-trial design is necessary and equipped with a description of the proposed program. Then the FDA and company can work out early if a single trial will be enough to establish substantial evidence of effectiveness.

Of course, it’s the results of the single trial that matter when meeting the regulatory bar for efficacy, the FDA noted.

To show confirmatory evidence, drug sponsors have plenty of options and they may not have to reinvent the wheel to find it. The FDA provided some examples, noting that some of the recommended data points are typically generated within a normal clinical development program anyway.

Options include efficacy evidence from a previously submitted or approved indication for a drug; preclinical data from an established animal mode; evidence from therapies in the same pharmacological class; natural history data; real-world data or evidence; and data from an expanded access program.

Evidence on the drug’s mechanism of action can also be used when the pathophysiology of the disease is well understood, the FDA noted. This may be appropriate for confirmatory data when a disease is caused by a single gene or enzyme defect.

The FDA’s Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research are seeking comments on the proposed guidance until December 18.