Are the risks faced by phase I clinical trial participants too great? The European Medicines Agency (EMA), the European Commission and the Member States of the European Union (EU) believe so. Together, they’re proposing changes to current guidance on first-in-human clinical trials that would, if successful, improve strategies for identifying and mitigating risks to study subjects.

“The purpose of the EMA’s review is to take stock of the evolution of practices in the conduct of first-in-human studies since the guideline that describes first-in-human clinical trials was first published in 2007,”  EMA spokesperson Sophie Labbé told CenterWatch.

The proposed changes—that mostly hinge on a slower acceleration of dosing—are, in part, a result of the phase I first-in-human Bial trial in Rennes, France, in which one person died and four became seriously ill in January.

Said Labbé, the EMA review “takes into account the lessons learned from the tragic incident.”

The ill-fated trial was investigating the safety of compound BIA 10-2474, designed to target pain relief by acting on cannabinoid receptors. The affected group of participants was due to receive the maximum 50mg dose of the drug for 10 days toward the end of the trial when five participants became critically ill. One died from brain damage. The drug had been considered low-risk as it had been tested in non-human primates with no ill effects at higher doses than those that were administered in the clinical trial. It later came to light, however, that mice administered BIA 10-2474 had suffered brain damage and died.

After the Bial trial tragedy, Janssen Pharmaceuticals, a unit of Johnson & Johnson, stopped research on similar compounds, and three Yale University trials using the same class of inhibitors were stopped. 

Labbé said that the EMA’s review of the guideline builds on certain recommendations from two in-depth investigations carried out by French authorities, one by the Temporary Specialist Scientific Committee (TSSC) set up by the French medicines agency ANSM, and the other by the Inspection générale des affaires sociales (IGAS), the inspectorate for social affairs in France, who said in an April report that, while the trial didn’t break any laws or regulations, Bial and CRO Biotrial made mistakes. According to the report, study participants were given too high of a drug dose, the companies delayed alerting authorities and Biotrial did not react quickly enough after the first participant became ill.

The EMA’s decision to change the guidance also follows a May review of the case in the British Journal of Clinical Pharmacology, which concluded that researchers and regulators should be much more careful about how they design first-in-man studies.

In the review, experts from the U.K. and the Netherlands said a more rigorous process of systematic risk assessment was needed for all trials involving new compounds. The authors called for the release of all trial data associated with the Bial drug so that lessons could be learned, and said that regulators should be given more information from preclinical studies before giving the go-ahead for first-in-human trials.

Proposed changes are outlined in a concept paper available on the EMA’s website. Comments are being accepted until September 30. A revised draft guideline is expected to be published before the end of 2016 for consultation.

Said Labbé, the days of all first-in-human trials involving just single ascending doses are no more. It’s time for the regulations to evolve and change, just as the research industry has.
“The current guideline reflects the practice at the time it was developed, which focused on single ascending dose designs for first-in-human trials,” said Labbé. “In recent years, the practice for conducting first-in-human clinical trials has evolved toward a more integrated approach, with sponsors conducting several steps of clinical development within a single clinical trial protocol [such as assessing] single and multiple ascending doses, food interactions or different age groups. The concept paper identifies those parts of the current guideline that need to be amended to take into account these evolution of practices.”

Regulatory bodies modernizing to keep up with the changing risk profiles within phase I studies makes sense, and yet some risk will always be there, said Arthur L. Caplan, the Drs. William F and Virginia Connolly Mitty Professor of Bioethics at New York University, Langone Medical Center.

“The reality remains: Phase I studies are risky,” he said. “You can limit risk by going slower, but there is ineliminable risk.” 

This article was reprinted from Volume 20, Issue 30, of CWWeekly, a leading clinical research industry newsletter providing expanded analysis on breaking news, study leads, trial results and more. Subscribe »