Extensive media coverage was given to the shocking story of the Northwick Park first-in-man clinical trial in March 2006. Six study subjects suffered very serious adverse reactions to the monoclonal antibody TGN1412 within a matter of minutes, leaving them in intensive care with multiple organ failure and an uncertain future.

As a result, the Secretary of State for Health set up the Expert Scientific Group (ESG) to review the trial and to make recommendations to increase the safety of future trials for certain types of medicines. The ESG published its final report into phase one (first-in-man) clinical trials in December 2006 and made 22 recommendations.

TGN1412 was designed to treat multiple sclerosis, leukaemia and rheumatoid arthritis. TeGenero, the German makers of the drug, thought that it would subtly ‘retune’ the immune system.

Instead, the immune system of the six trial subjects went into overdrive and, within hours, all six were admitted to the intensive care unit at Northwick Park Hospital with a very severe systemic inflammatory reaction that progressed to multi-organ failure. The phenomenon, known as a ‘cytokine storm’, caused the subjects’ heads and bodies to swell, with one subject being described as looking like ‘the Elephant Man’. Another subject lost his toes and the tips of his fingers through a reaction similar to frostbite.

The ESG concluded that the preclinical studies performed with TGN1412 did not predict a safe dose for use in humans, even though current regulatory requirements were met. It was acknowledged, however, that the cynomolgus monkey used to calculate the dose for human exposure did not experience the same ‘cytokine storm’ reaction, despite being given 500 times the dose administered to the subjects.

Those responsible for the conduct of the trial have been criticised for administering the drug to all six subjects within the space of an hour, as this exposed five of the subjects to unnecessary harm, which would have been avoided if the drug was administered sequentially and observations were made to identify any adverse reactions. The Medical and Healthcare products Regulatory Agency (MHRA) have also been criticised for approving the trial without commenting on the proposed sequence of administration.

Recommendations of the ESG

The ESG were given two terms of reference to guide their review of the TGN1412 trial:

? to consider mandatory requirements for trials in the transition from pre-clinical to first-in-man phase one studies

? to provide advice in the form of a report to the Secretary of State for Health for the future authorisation of such trials.

Having sought the views of major stakeholders, the ESG made 22 recommendations, which are expected to have far-reaching implications for those involved in the conduct and safety of first-inman clinical trials.

Key recommendations included:

? the need for the regulator to have access to scientific advice from independent experts before approving trials of high risk substances

? wider availability of information about unpublished clinical trials and adverse reactions occurring in trials

? closer scrutiny of the conduct and environment of clinical trials, and those conducting them

? a more rigorous clinical trial application process

? adequate medical back up for trial units, in case of problems arising.

The ESG recommended that monoclonal antibody drugs should be administered sequentially to subjects with an appropriate period of observation between dosing of individual subjects. Also, careful consideration should be given to the route and rate of administration of the first doses, with careful monitoring for adverse or exaggerated responses.

The ESG also emphasised the need to collect safety information from unpublished clinical studies. In the aftermath of the TGN1412 trial, it emerged that similar results had been seen in at least one previous trial. In that case, the drug was being administered at a slow rate, to one individual subject, and was withdrawn immediately upon the first signs of an adverse reaction. It appears that those conducting this trial were unaware of those earlier results.

The call for increased transparency in publication of clinical trial results has been welcomed by pharmaceutical companies. Many claim that they already endeavour to publish all results, including negative results and those from trials which have been aborted. There are however legitimate concerns about sensitive confidential (and commercial) information being revealed to competitors.

Other areas of concern

Some issues were raised by the major stakeholders, which the ESG noted needed to be taken up as a high priority. These included:

? the process of informed consent and clarity of information

? communication between clinical investigators and clinical trial subjects before and during a trial

? insurance cover

? the role of Research Ethics Committees (RECs) and

? clinical follow-up of trial subjects who had experienced an adverse reaction.

Following the TGN1412 clinical trial, it became apparent that the insurance cover TeGenero had in place was potentially inadequate. Solicitors for some of the trial subjects revealed that the insurance cover is limited to £2m. When divided between the six individual subjects, whose injuries and prognosis vary, the amount each subject could hope to get is limited. Furthermore, the insurance provides no indemnity to TeGenero in the event that litigation is commenced. This has left the trial subjects with a dilemma as to possible targets for litigation.

The hole in the insurance cover also reflects a shortcoming in the REC. The REC reviewing the TGN1412 trial documentation prior to approval of the trial failed to recognise that the insurance cover was potentially inadequate.

Going forward

The outcome of the TGN1412 trial was catastrophic. However, it remains that first-in-man clinical trials have had a very good safety record. Such instances of serious unexpected side-effects are very rare and, with implementation of the ESG recommendations, a repeat of the ‘Elephant Man‘ trial should be avoidable.

The MHRA has already indicated that for certain first-in-man trials, advice will be sought from an Expert Advisory Group or Commission on Human Medicines before approval of a trial will be given. The MHRA has requested that sponsors contact them before making a clinical trial authorisation application and provide a data package enabling the MHRA to obtain that advice.

From insurers’ point of view, more detailed information and evidence may be demanded of clinical trial sponsors, to satisfy insurers that every effort has been made to comply with the recommendations of the ESG, before they will underwrite this type of risk.

The future for the six trial subjects involved in the TGN1412 clinical trial remains uncertain. They have been told that they now face a risk of cancer or immunological disease, such as multiple sclerosis.

As the drug’s sponsor is now insolvent, and the insurance cover in place is said to be inadequate, solicitors for some of the trial subjects have been considering alternative targets for a claim. One option is to pursue Parexel, the company who carried out the trial, or even the MHRA, the regulator that approved the trial. Such a move would be unprecedented. The prospects of a claim succeeding against the regulator are difficult to assess. Any such claim would presumably focus on the existing regulatory requirements, which failed to ensure that a safe dose for use in humans was predicted before the trial was approved.

Action against the REC that reviewed the trial has also been mooted, but is unlikely.

A successful claim against the trial organiser would seem to be the most fruitful. Indeed, solicitors recently issued an ultimatum to Parexel: if settlement proposals were not received before the anniversary of the trial, proceedings would be issued.