New approaches needed to make sure Phase I trials are safe say experts

This is the conclusion of the government appointed expert group set up to make recommendations on the future conduct of Phase I clinical trials following the catastrophic immune responses suffered by six healthy volunteers at a trial in Northwick Park Hospital, London in March 2006.

The experts concluded there was no evidence that the reaction to the drug, TGN1412, was caused by anything other that an ‘on target’ effect of the monoclonal antibody triggering a cytokine storm.

Tests are still being carried out to try and find out why preclinical studies did not predict the human response to the starting dose, but the report says there is an “inherent hazard” because drugs with a species specific mode of action will have reduced effects in other animals.

“Species specificity does not imply there is always an increased risk but it makes preclinical evaluation of the risk much more difficult,” says the report.

Although most of the focus of the expert group is on biologics, it points out that the same problems could occur with small molecule drugs that are highly specific for novel targets.

The trial of TGN1412, produced by the now-bankrupt German biotech TeGenero AG, was approved by two European regulatory agencies and a local research ethics committee. An earlier investigation by one of these, the UK MHRA (Medicines and Healthcare Products Regulatory Agency) concluded there was nothing wrong with the conduct of the trial or with the manufacture of the drug.

The expert group recommends that in future the strategy for the preclinical development of a new medicine should be made and justified on a case-by-case basis, by investigators with appropriate training. Independent scientific expertise should be sought also.

There should also be earlier dialogue between the drug developer and regulator to allow for submission and review of safety-based data prior to formal submission of a clinical trial application.

Traditional approaches, based on toxicological effect in animal studies, may not be appropriate for calculating doses to administer these drugs in first in man studies. Instead of relying on the ‘no effect level’ in animal studies, a different basis of ‘lack of biological effect’ should be used, the report says.

In some circumstances, and particularly if the drug is expected to affect the immune system, it might be more appropriate that first in man studies are in patients, but this should be a case by case decision.

The first dose in man should be given to one person only, leaving sufficient time for any adverse reaction to develop.

The report also recommends the setting up specialist centres carry out Phase I studies on “higher risk agents.”

Although there is a newly created EU database of suspected, unexpected, serious adverse reactions to drugs in trials, there is currently no access to information about trials that were halted for safety reasons in the past.

Industry and regulators should consider ways to collect and share such data to both protect public health and prevent unnecessary duplication of drug development and trials.

The public is invited to submit comments on the interim report, and the final version is due to be published at the end of November.