Now that the six volunteers hospitalised after exposure to an experimental antibody treatment in a Phase I trial appear to be on the road to recovery, all eyes are on the ongoing investigation into the study by the UK’s Medicines and Healthcare products Regulatory Agency.

An interim report from the MHRA released last week said the evidence points to a side effect that was not seen in animal studies, including those involving non-human primates, but which emerged only when the drug, called TGN1412, was tested in man. The trial protocol was adhered to, and no contamination seems to have occurred, it said.

Cue a sigh of relief from German biotech TeGenero which developed the drug, contract research organisation Parexel, which carried out the study at a dedicated unit it operates at Northwick Park Hospital in North London, and Boehringer Ingelheim, which manufactured the antibody doses.

But the regulatory agency is also looking at tightening up regulations on trials of the type of drug under testing in the study to see if such cases can be prevented in the future.

As soon as the news of the side effects from the Parexel trial emerged, the MHRA put a hold on tests on similar products and warned other regulators around the world to do likewise.

Expert group

The agency is setting up an international group of experts to look into the case, and this will "consider what necessary changes to clinical trials may be required," according to MHRA chief executive Prof Kent Woods.

The advisory group will be chaired by Prof Gordon Duff, professor of molecular medicine at Sheffield University. It will look specifically at how trials should be designed and overseen for biological molecules with novel mechanisms of action, especially those targeted at the immune system, and those with highly species-specific action.

An interim report is expected within three months, and the outcome "could potentially affect clinical trials regulation worldwide," according to the MHRA.

Dosing frequency

One aspect of the trial that has come under scrutiny is that patients were dosed with the antibody almost simultaneously, so all six men had received the drug before the first side effects emerged. Spacing out doses, even by a few hours, could have limited the number affected.

But a spokesman from the MHRA told “the Medicines for Human Use (Clinical Trials) Regulations 2004 do not contain requirements relating to the timing of dosing for ‘first in man’ studies.”

Another issue raised by the media in its handling of the case has been the offering of financial reward to the participants, but the MHRA spokesman stressed there are no legislative requirements on this issue.

Guidelines drawn up by the Association of the British Pharmaceutical Industry note that: “Volunteers may be rewarded in cash or in kind, but the amount should be reasonable and related to the nature and degree of inconvenience and discomfort involved.”

It is the responsibility of the trial’s ethical committee to review subject remuneration arrangements and the advertising material used to recruit trial subjects, and not the MHRA, he noted. There are no plans to investigate the ethics committee’s work.

Meanwhile, the ABPI and the Bio Industry Association (BIA) - have said they plan to set up an expert working group to provide industry input into the expert group's deliberations on the way clinical trials are conducted.

What went wrong?

The cause of the adverse reactions that affected the patients remains unclear. But one clue lies in the mechanism of action of TGN1412. This works as an anti-CD28 antibody, targeting a protein on immune cells that, it was thought, would stimulate regulatory T lymphocytes and dampen down the immune system, relieving autoimmune diseases and inflammatory conditions such as rheumatoid arthritis and multiple sclerosis.

But what actually occurred, it is thought, was a massive over-stimulation of the immune system known cytokine release syndrome, which caused it to attack tissues and led to the multiple organ damage that hospitalised the six volunteers.

The drug "is a new class of monoclonal antibody which has a stimulatory mode of action affecting certain types of cell in the immune system," said the MHRA in its interim report. And the fact that the risks were not found in animal studies "raises important scientific and medical questions about the potential risks associated with this type of drug and how to make the transition from pre-clinical testing to trials in humans," it went on.