Rules for drug trials should be tightened, say experts

London

Zosia Kmietowicz

Experts have made a raft of recommendations about how early clinical studies of new drugs should be designed, to improve their safety for the people taking part.

An interim report from an expert scientific group chaired by Gordon Duff, professor of molecular medicine at Sheffield University and chairman of the government’s Commission on Human Medicines, says that new high risk agents in phase I studies—the first time drugs are tested in humans—should be given to one person at a time, with an appropriate observation time between doses. The report follows events at Northwick Park Hospital, in London, where six volunteers were left seriously ill in a trial of the drug TGN1412 after all being given the drug at the same time (BMJ 2006;332:682).

In the trial of TGN1412 the men started to develop severe reactions within a few hours of being given the drug intravenously, and they all needed intensive care for multiple organ failure. The Medicines and Healthcare Products Regulatory Agency has since said that an "unpredicted biological action"—and not the manufacture or administration of TGN1412—was to blame for the adverse reactions seen (BMJ 2006;332:1290, 3 Jun).

Before these findings were made public, however, the secretary of state for health set up the expert scientific group to look specifically at trials of drugs that involve high risk products, such as monoclonal antibodies.

The report says that investigators should also consider whether it is appropriate to test a new drug in healthy volunteers or in volunteer patients when it is being tested for the first time in humans.

The report recommends that the doses of drug to be used in phase I trials should be calculated more thoroughly. At the moment, investigators often decide what dose of a drug they should use in humans according to the effects or adverse reactions seen in animal studies. But other factors should also be considered, such as the novelty of the agent; its mechanism of action and degree of species specificity; and dose-response data from animal and human studies.

One approach to calculating the dose, called MABEL (the minimal anticipated biological effect level), is "a good option," the report says. But when different methods give different estimates of a safe dose in humans, the lowest value should be taken as the starting point.

The report also calls for more dialogue between drug developers and regulators, especially when a high risk agent is being investigated. It recommends sharing information on the safety of novel drugs perhaps in the form of an open access database, with contributions from both researchers and regulators. Setting up specialist centres for early human trials of high risk agents to harness expertise in designing and conducting such trials should also be considered.

Professor Duff said, "Clinical trials in general have an excellent safety record, but in the light of the TGN1412 incident there is a need to look at the future safety of clinical trials involving novel and potentially higher risk drugs.

"Our interim report provides proposals for the future authorisation of trials involving these types of products and to further improve safety.

"Clearly the Northwick Park incident has informed the work of the group, but this is not a further investigation into the incident. It is about the wider issue of such clinical trials and about ways to ensure that this type of trial is safe and effective for the future."

The interim report is open to public consultation until 14 September, with a final report expected later this year. To see the draft report or take part in the consultation go to www.dh.gov.uk.