Phase I trials need improvement: UK group

An expert group convened by the UK government to review the safety of Phase I trials made 22 recommendations today (July 25) to improve first-in-human studies, responding to an incident last March when six healthy volunteers developed life-threatening side effects during a phase 1 trial of a monoclonal antibody.

An investigation of the trial, using the monoclonal antibody TGN1412, attributed blame to an unexpected biological effect of the molecule.

Since then, the experts, led by Gordon Duff of Sheffield University, have met six times. Their recommendations focus on calculating and administering first doses, sharing information regarding safety, and giving regulators access to specialist opinion in appraising trial applications for high risk drugs.

"Clinical trials in general have an excellent safety record, but in the light of the TGN 1412 incident there is a need to look at the future safety of clinical trials involving novel and potentially higher risk drugs," Duff said in a statement.

Specifically, Duff and his colleagues recommend that in drug trials for new and possibly risky drugs, researchers should give the first dose to one person only, leaving sufficient time for any adverse reaction to develop before further doses or administration to more people.

On the subject of dose calculation, they say that a broader approach needs to be taken that goes beyond relying on "no effect level" or "no adverse effect level" in animal studies.

They recommend that, in some circumstances -- and particularly if the drug is to affect the immune system -- it may be more appropriate to include patients being treated for the disease in phase I studies, rather than healthy volunteers.

Duff and his colleagues also call for earlier dialogue between the drug developer and regulator when testing higher risk agents to allow thorough review of safety data, better international sharing of information about serious adverse reactions to drugs in trials, and the development of specialist centers to undertake early trials.

"They're saying all the right things," Neil Williams, from the University of Bristol, told The Scientist. "But I think for me it's going to be difficult to see what the impact will be until the recommendations are put into practice."

Much could hinge on how the recommendations are interpreted, Williams noted. "There's a lot in there that would be a major change to current practice, but reading it another way it could mean very little," he said. For example, staggering the dosing could entail waiting weeks between each participant if investigators waited for some types of adverse events, or could be done much faster if they were looking only for acute impacts, he said.

Jeffrey Aronson, president-elect of the British Pharmacological Society and a clinical pharmacologist at Radcliffe Infirmary, University of Oxford, said his initial reaction was that the recommendations were all sensible and achievable.

"The most important recommendation in my view is that the relation between a complete range of doses and concentrations of a new compound and its biological effects should be carefully studied, for example in human cells, before first-in-man administration," he said in a statement.

A public consultation on the interim report will run until September, giving interested parties a chance to comment on the recommendations and give evidence.

Stephen Pincock
spincock@the-scientist.com

Links within this article

Expert Scientific Group on phase one clinical trials
http://www.dh.gov.uk/assetRoot/04/13/74/06/04137406.pdf

S. Pincock, "Drug effect blamed in UK trial," The Scientist, May 25, 2006.
www.the-scientist.com/news/display/23496/#23507

A McCook, "UK drug trial effects were 'unpredicted,'" The Scientist, April 6, 2006.
www.the-scientist.com/news/display/23275/

Expert Scientific Group on phase one clinical trials: a consultation
www.dh.gov.uk/Consultations/LiveConsultations/LiveConsultationsArticle/fs/en?CONTENT_ID=4137501&chk=x%2BoJ/%2B