Excerpt from original article, "Consider drug efficacy before first-in-human trials," posted on Nature, February 2017.
On 17 January 2016, a healthy man was declared brain-dead after receiving an experimental drug in a first-in-human trial in France. Four of five other subjects receiving the same dose have serious, ongoing neurological complications. Investigations into the trial described many troubling safety practices, such as steep increases in dose levels delivered to sequential subjects without sufficient delays to check for safety.
The year since has brought intense scrutiny about how the debacle could have been anticipated and prevented. However, another issue is still largely overlooked: the duty to evaluate whether an experimental treatment is promising enough to warrant testing on people.
In the wake of the tragedies, the French medicines safety agency (ANSM) ordered an examination of the information that the drug developer, Bial, based in Trofa, Portugal, had supplied to ethics committees and potential researchers before the trial (see go.nature.com/2j88gqy). The report notes that the 63-page Investigator Brochure describing the trial included fewer than two pages of evidence that the drug had the desired pharmacological activity. It identified only two studies presented as evidence for efficacy, both problematic. In one, Bial had data for a different marketed drug showing it was more effective than Bial’s drug at relieving pain in animals, but did not include that information in a summary figure. Both preclinical studies showed only “moderate” positive effects. Moreover, Bial’s drug had been tested at a range of doses in micethat made it impossible to estimate the most likely effective dose in humans.
Press coverage following the tragedy quoted independent experts concluding that there was little evidence to support a trial, and that at least five other drugs designed to act in a similar way had been tested in people without success.(Bial maintains that toxicities were not predictable and that it has followed all human-testing norms. We approached the company for more information about the event for the purposes of this Comment but received no response.)
As bioethicists, we have studied the ethics of first-in-human (FIH) and early-phase research for more than a decade. We discuss ethics review with regulators, ethics oversight committee members, investigators and others. We also have personal experiences serving as reviewers on dozens of early phase trials.
We contend that a lack of emphasis on evidence for the efficacy of drug candidates is all too common in decisions about whether an experimental medicine can be tested in humans. We call for infrastructure, resources and better methods to rigorously evaluate the clinical promise of new interventions before testing them on humans for the first time.