Europe Tackles New Rules for Non-Clinical to Clinical Handoff

Unsurprisingly, the European Medicines Agency (EMA) has decided it is time to look again at first-in-man clinical trials. As with the current European guidelines, adopted in 2007 after the disastrous U.K. trial of TGN1412, the trigger this time round is the damage done to volunteer subjects in the Phase I trial in France earlier this year.

After the death in January of one volunteer and the hospitalization of five others during a trial conducted by French research organization Biotrial for the Portuguese drugmaker Bial, French health minister Marisol Touraine called for a review of the way first-in-man clinical trials are authorized across Europe.

The reaction is similar to the furor caused by the multi-organ failure among six volunteers in the 2006 Phase I study of a CD28 superagonist antibody, TGN1412, which had been designated as an orphan medical product by the EMA the year before. That time, the product was developed by TeGenero Immuno Therapeutics, tested by Parexel and manufactured by Boehringer-Ingelheim.

Part of the reaction then was the EMA publication in 2007 of its “Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products.” That is still the main advice on the data needed for appropriate design and initiation, and it is, according to the EMA, no longer up to the job. The ICH requirements-ICH M3 (R2) and the related Q&A document-are not enough either.

With this further French demonstration of the risks in progressing from the conduct of non-clinical studies to clinical trials for investigational drugs in humans, it has become clear that the rules merit reconsideration. In late July, the EMA published a concept paper on “changes intended to support best practices,” and it is seeking comments before the end of September. 

So what’s new in the approach? Certainly not the underlying objective, which predictably remains “to further improve strategies to identify and mitigate risks to trial participants.” And not the attitude toward clinical studies, either. “Clinical trials are essential for the development of medicines and without them patients cannot gain access to new potentially life-saving medicines,” the EMA prefaces its remarks.

The agency adds that the release of the concept paper is only “part of” a review of the 2007 guideline-and a slightly subsidiary one, at that. Already it has reached a view on what needs changing, based on the views of a group of EU experts, and endorsed by the Committee for Medicinal Products for Human Use (CHMP).

What the changes focus on are the parts of the current guideline that “need to be amended to take into account the evolution of practices in the conduct of these studies.” Principally, it says, this is the shift over recent years to a more integrated approach, with sponsors conducting several steps of clinical development within a single trial protocol. This more structured approach, with incremental decisions on next steps based on the data collected at each previous step, makes it possible to take more account of the specificities of each drug, its mechanism of action and intended therapeutic use.

So it is time to move on from the limitations of the current guideline, which reflects practice of more than a decade ago in focusing on non-clinical aspects and the use of animal data, and which relies mainly on a single ascending dose design. Since the early years of this century, there has been a big evolution in the integration of the non-clinical data available and the pharmacokinetic, pharmacodynamic and human safety data emerging during a trial. Consequently, many studies are now performed with integrated protocols potentially combining a number of different parts, such as single and multiple ascending doses, food interaction, different age groups and early-proof-of-concept or early proof-of-principle parts. First-in-man and early phase clinical trials with multiple study parts are increasingly being submitted for regulatory review as part of a single application, the agency points out. 

To cope with the increased complexity of the protocols, EMA is suggesting that there should be exploration of a dozen areas, and is seeking views accordingly. Top of the list is extending the guidance to early phase trials that include single study or integrated protocol designs.

The non-clinical aspects of the guideline also need to be expanded, the agency suggests. Provision should be made for better integration of non-clinical pharmacology and data from the toxicology testing into an overall risk assessment. New attention should be devoted to translating non-clinical data into human use by extrapolation, and the assumptions made should be verified. The minimum anticipated biological effect level approach should be more generously interpreted, taking all biological effects into account.

The role of non-clinical data should be amplified in estimating the therapeutic dose, maximum human dose level, dose escalation steps and dosing frequency and intervals. It should also play a bigger part in definition-of-stopping criteria for the trial, and identification of safety aspects to monitor.

The clinical part of the guideline should be strengthened with new guidance on integrated trial designs and study endpoints, including decision-making aspects, and should explicitly cover more than just single ascending dose trials, incorporating other early phase trials and designs. Clarification is needed on the choice of trial subjects, on the overall dose/exposure range and scheme, including stopping rules, and there should be a rolling review of emerging human data during the study.

Once this consultation is completed and the views have been digested from stakeholders (“patients, physicians, academia, ethics committees, pharmaceutical industry, sponsors, investigators, contract research organizations and regulatory authorities”), the next stage will be further discussions among a multidisciplinary group that includes experts from CHMP and the Heads of Medicines Agencies’ Clinical Trial Facilitation Group. All this will feed into a draft revised guideline before the end of this year, the EMA predicts.

No amount of regulation can hope to eliminate all risk, but with two attempts to improve the rules in less than a decade, the pressure is now on the authorities to make sure that its guidelines are at least in tune with contemporary practice. And the pressure is all the greater on the clinical trial community to make sure it gets it right with first-in-man trials.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium