Still avoiding the question

Nuala Moran

“We are satisfied the adverse incidents which occurred were not as a result of any errors made in the manufacturer of TGN1412, its formulation, dilution or administration to trial participants,” said Kent Woods, Chief Executive of the Medicines and Healthcare products Regulatory Agency (MHRA), as he released the final report into what caused the trial fiasco at Northwick Park Hospital, London on 13 March this year.

This conclusion followed further inspections by the MHRA and German regulators, backing up the findings of an interim report published on 5 April.

The MHRA did uncover some discrepancies with Good Clinical Practice in its investigation into the Phase I safety trial of the antibody treatment TGN1412, but stuck to the original conclusion that the life threatening immune reaction suffered by six healthy volunteers was due to, “an unexpected biological effect.”

Wider implications

At the time the interim report was released, the UK government announced it was setting up an expert group to investigate the wider implications and consider what changes to clinical trials procedures may be required. As the MHRA published its final report the Department of Health announced the membership of the 18-strong panel, whose prognostications will be observed by the European Medicines Agency, the UK Department of Health, the US FDA, German regulators and the Japanese Pharmaceutical and Medical Devices Agency.

The brief is to look at what safety requirements need to be applied in future in the transition from preclinical to Phase I safety studies of biological molecules with novel modes of action, new compounds with a highly species (ie human) specific action, and new drugs directed towards immune system targets. The group is due to publicise initial findings in three months.

Announcing the names, the health minister Andy Burnham said the group would “provide advice for the future authorisation of trials involving these type of products”.

Even in the immediate aftermath it was not hard to find experts in immunotherapeutics who were surprised the trial was approved, given what is known (and not known), about the role of the target, CD28, in the healthy immune system. Many have pointed out that there has been lengthy discussion in the literature of the suitability of CD28 as a drug target.

Indeed, one of the founding fathers of the monoclonal antibody field, Greg Winter, told BBC Radio the adverse side effects could have been predicted. Another expert, David Glover, said that even if there were no adverse effects in the preclinical trials, the effect was predictable from the basic science.

‘Totally inadequate’

The MHRA’s report was condemned as “totally inadequate” by the lawyer representing the two most seriously affected men, Ann Alexander of the law firm Irwin Mitchell. She called for an independent inquiry into how the trial was conducted, and described the self-regulating MHRA as, “an insular organisation with an archaic approach.”

But even this stinging criticism is missing the point. Surely the question should be, if so many experts agree on the risks of stimulating CD28, why was the trial allowed to proceed in the first place? The MHRA does not answer that question, and given its brief the Expert Group will not do so either. This leaves a gap, both in terms of honesty to the victims, and public trust in the clinical trials approval process.