DUBLIN – The EMA launched a formal consultation process Tuesday on the development of a new guideline for first-in-human and early stage clinical trials of investigational drugs.
The agency published a draft guideline, to which it is inviting responses from interested parties by Feb. 28, 2017. It aims to publish a final version during the first half of 2017. That would then form the basis of a new approach to the conduct of phase I and early stage trials – failure to follow them could compromise a drug developer’s application for approval.
“Scientific guidelines reflect a harmonized approach of the EU member states and the agency on how to interpret and apply the requirements for the demonstration of quality, safety and efficacy set out in the community directives,” an EMA spokeswoman told BioWorld Today. “The agency strongly encourages applicants and marketing authorization holders to follow these guidelines. Applicants need to justify deviations from guidelines fully in their applications at the time of submission.”
The move is part of the London-based EMA’s formal response to the fiasco that occurred at a Biotrial Research SAS clinical research facility in Rennes, France, last January, when one volunteer, 49-year-old father of four Guillaume Molinet died and five others suffered neurological injuries during a phase I trial of BIA10-2474. Porto, Portugal-based Bial Portela & CA had been developing the compound, which it described as an oral fatty acid amide hydrolase (FAAH) inhibitor, for treating neuropathic pain. (See BioWorld Today, Jan. 20, 2016.)
Although not directly involved in sanctioning the trial – its oversight was the responsibility of the French regulator L’Agence nationale de sécurité du médicament et des produits de santé (ANSM) – the EMA started a formal review of its guidelines in first-in-man trials in May. A concept paper, which it published in July, noted that the existing guideline, which dates back to 2007, focuses mainly on the nonclinical aspects of drug development, such as animal toxicology testing, and on single ascending-dose trial designs.
The review is intended to reflect both the lessons learned from the Bial fiasco and the evolution in trial design that has occurred during the past decade. (The last revision occurred in the wake of the disastrous Tegenero trial of TGN1412 in London). First-in-man trials are now increasingly complex and include both single and multiple ascending-dose phases, food interaction studies and assessment of the investigational compounds effects in subjects of different age, for example.
The draft guidance proposes extending the nonclinical aspects of the guideline to better integrate nonclinical pharmacology and toxicology data into an overall risk assessment for first-in-human and early stage trials. It seeks to include the extrapolation and verification of the assumptions made in translating nonclinical data to the human setting and to expand on the so-called Mabel approach to analyzing the minimum anticipated biological effect level of a drug.
“Guidance is also provided on clinical aspects, including criteria to stop a study, the rolling review of emerging data with special reference to safety information for trial participants, and the handling of adverse events in relation to stopping rules and rules guiding progress to the next dosing level,” the spokeswoman stated.
The dust has by no means settled on the Bial case, meanwhile. Last month, lawyers acting on behalf of Rennes-based Biotrial issued a statement condemning “a campaign of denigration” orchestrated by the French newspaper Le Figaro, which is critical of the continued operation of Biotrial’s Rennes facility. Although reports into the trial from two French agencies, ANSM and the social affairs directorate IGAS (Inspection générale des affaires sociales), concluded that the trial protocols were administered and followed appropriately, the English version of the IGAS report makes for grim reading.
BIA10-2474’s structure did not set any alarm bells ringing, but its affinity and specificity for its supposed target were so weak that calling it an FAAH inhibitor is scientifically questionable. It had just micromolar levels of affinity for human FAAH. Inhibitors that other firms tested, including Pfizer Inc., had nanomolar affinity for human FAAH and far less affinity for other human hydrolases.
Pfizer, moreover, tested its compound, PF-04457845, against 68 receptors and a panel of 20 hydrolases, whereas Bial tested BIA10-2474 and one of its metabolites against just three serine hydrolases and five other enzymes. Johnson & Johnson, similar to Pfizer, was rigorous in its testing of its compound, JNJ-42165279. The FDA, drawing on data supplied by the EMA and the ANSM, concluded in August that BIA10-2474 “exhibits a unique toxicity that does not extend to other drugs in the class.”
What had potential as a poorly performing me-too drug ended up taking the life of a healthy volunteer. Ten years on from the Tegenero fiasco, it is clear that not all of the lessons learned in that case were fully absorbed. It is impossible to state with any confidence that this time will be different.