Fears for UK clinical trials as antibody inquiry proceeds
pharmafile | April 10, 2006 | News story | Research and Development |
The MHRA is to put together an expert group to examine the need for new safety measures in the wake of the clinical trial incident at Northwick Park hospital.
The news has been welcomed by researchers in the UK, including the pharma and biotech industries – but it has also raised fears that new safety checks could stop research being conducted in the country.
The investigation is in response to six men who became critically ill in March after having been given TGN-1412, a new monoclonal antibody treatment as part of a phase I trial.
The UK is home to around half of all Europe's phase I studies, and some fear disproportionate safety measures could be put in place, potentially undermining the country's research base.
Northwick Park could also have global implications, with researchers and regulators around the world having to balance new safety fears against the demand for fast and cost-effective early-stage research.
In recognition of this, the expert group will draw on the expertise of leading international researchers in the field to further investigate the problem.
UK pharma and biotech industry associations the ABPI and BIA have also announced they will set up a joint committee of experts, some of whom they hope can be included in or at least advise the MHRA panel.
"The group will need to review the evidence from the TGN-1412 case and consider what necessary changes to clinical trials may be required," confirmed MHRA chief executive Professor Kent Woods.
Parexel, the company running the trial on behalf of TeGenero, has been cleared of any serious misconduct by the MHRA's interim report, its investigators confirming the volunteers displayed severe reactions never seen before in such trials.
The MHRA report, released on 5 April ruled out human error in the production or administration of the drug, and concluded the severe reactions were caused by the drug itself – side-effects which animal trials had failed to detect in advance.
"Our main conclusion is that there was a powerful pharmacological action of this drug in man, which was not detectable in the pre-clinical studies done in the non-human primate species, even in far-higher doses," Prof. Woods told a press conference.
The long-term ramifications of this conclusion could be far-reaching, with doubts growing about the usefulness of animal tests in predicting how newer drugs will work in humans.
The MHRA says a 'precautionary approach' will be taken with immediate effect in regard to any new monoclonal antibody (regardless of target) or other novel molecule. The drugs will face extra safety questions on top of existing regulatory checks before permission for a phase I trial is granted.
The regulator says such trials will only be authorised after extra opinion is sought on whether the TGN-1412 incident could be repeated in the candidate drug.
The MHRA's senior scientist Professor Gordon Duff is to chair the expert group, which will include distinguished experts in relevant fields such as immunology, toxicology and clinical trials. The group will look specifically at monoclonal antibodies, which are at the cutting edge of research but less well understood than conventional drugs.
The working group will be up and running as soon as the MHRA's final report is ready, ensuring no time is wasted in deciding what steps to take in response to the incident.
The ABPI has welcomed the swift action, but said that while lessons need to be learnt about what went wrong with the drug, it is also important to stress that: "The basic clinical trial system is robust and has proved itself over decades."
It added that monoclonal antibodies have made a great contribution to treating diseases such as cancer and arthritis.
Dr. Richard Barker ABPI director general said: "There will always be some uncertainty in the process of developing new medicines, but we need to balance this with the benefits to the millions of patients in need of appropriate treatments."
Parexel's internal documents record that the patients experienced a life-threatening incident of "Cytokine Release Syndrome" – a process triggered when the substance release by activated T cells produces a type of systemic inflammatory response.
In the weeks following the incident, speculation had been rife about its root cause, and several leading scientists had reached the same conclusion as the MHRA.
Roberto Solari, the chief executive of Medical Research Council Technology told the Guardian newspaper he believed the novel mechanism of TGN-1412 was behind the alarming reactions.
"It is designed to turn on white blood cells, particularly a sub-set called regulatory cells," he said.
Inflammatory reactions in rheumatoid arthritis are caused by an over-stimulation of cells in the immune system, and the drug is designed to activate other cells with the power to switch off troublemakers.
Dr. Solari said it was possible that "instead of switching on the regulators, we have switched on the activators and super-induced the immune system."
Aisling Burnand, chief executive of UK biotech industry organization, the BIA, says it is important to recognise that the TeGenero trial was exceptional and seems to be related to a specific pathway and mechanism of TGN-1412.
She added her voice to cautions about what steps should be taken.
"More than 250 million patients worldwide have benefited from approved biotech medicines to treat or prevent heart attacks, multiple sclerosis, breast cancer, cystic fibrosis and leukaemia," she added.
Whilst we fully support appropriate measures to prevent a reoccurrence of this situation, UK patients would lose out if the development of all new biological drugs were unnecessarily delayed.
There are approximately 20 therapeutic monoclonal antibody products already on the market, including notable drugs such as Roche's Herceptin and Abbott's Humira, and the large molecules form an ever-increasing proportion of the medicines being taken by patients around the world.
Around 500 monoclonal antibody products are estimated to be under development by more than 200 companies for a broad range of diseases, with approximately 80 of these already in clinical trials.
