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High stakes, high risks
Leading Edge
High stakes, high risks March, 2007, marks the 1-year anniversary of the disastrous trial of the anti-CD28 monoclonal antibody, TGN1412, at Northwick Park Hospital, Harrow, UK, in which six healthy volunteers developed a cytokine storm leading to multiorgan failure within hours of being given the drug. The volunteers continue to have sequelae, such as headaches and memory loss, and one participant needs ongoing treatment for dry gangrene of his fingers and toes. In the year since this event, what lessons have been learnt, and what measures have been put into place to ensure that such a disaster never happens again? In the aftermath of the trial, the UK Secretary of State for Health convened a taskforce, the Expert Scientific Group (ESG), to recommend ways to improve the safety of first-in-man trials of high-risk drugs such as: biological molecules with novel mechanisms of action; new agents with a highly specific action; and new drugs targeting the immune system. The ESG’s final report was published in December, 2006. The brief was not simple: how to optimise safety of such drugs without creating undue barriers to drug development. The 22 recommendations span preclinical development, preparation of applications for appraisal, administration of initial doses, and where and by whom such studies should be done. From the recommendations, it is clear that had several been in place a year ago, the incident at Northwick Park might have been averted. For example, the report recommends that for high-risk drugs the starting dose should be calculated by use of the Minimal Anticipated Biological Effect Level rather than by use of the No Observable Effect Level or No Observable Adverse Effect Level. This would have yielded a starting dose of 0·005 mg/kg rather than the starting dose of 0·1 mg/kg actually used. Furthermore, TGN1412 was infused over 3 to 6 minutes, with a 10-minute interval between volunteers—the report proposes such drugs be infused slowly over several hours, and that dosing between study participants be separated by an observation interval appropriate for the setting. The Greek philosopher Heraclitus said 2500 years ago: “All is flux, nothing stays still”. Medicine is continually in flux—preclinical and clinical research is in the midst of an unprecedented expansion of drug classes and targets. http://oncology.thelancet.com Vol 8 February 2007
Therefore, it is important that regulatory authorities are as fast moving and as up-to-date as the field they are regulating. Attitudes towards the findings of unsuccessful trials must also change. It is not acceptable for data from such trials to be discarded, or for researchers and drug companies to hide negative findings behind a veneer of commercial or academic sensitivity. Researchers planning and doing new trials, as well as those approving trials, must have all the relevant information to hand— information that might improve the efficiency of future trials; prevent duplication of effort; help predict trials that could fail; or anticipate toxic effects. The European clinical trial database for first-in-man trials (EudraCT) is a laudable start, as is the UK requirement, since 2004, for all suspected unexpected serious adverse reactions in phase I trials to be reported to the regulator, and for all phase I trials involving healthy volunteers to be authorised by regulators. Acknowledging the need for proper dissemination of findings from phase I trials, The Lancet and The Lancet Oncology have recently agreed to consider such studies providing they: test a new substance, or a new indication of an existing drug, in patients with a specific disease; highlight a strong or unexpected beneficial or adverse response; or shed light on a new mechanism of action that might trigger new research. In this month’s journal we publish our first phase I study. Although many issues still remain—for example, the ESG report does not make recommendations for highrisk drugs whose toxic effects might be delayed, or for the use of drugs in particular populations that might be at a higher risk of toxic effects—the proposals are a good start. Implementation will not be an easy task. The recommendations must be discussed and coordinated internationally to prevent any temptation to run trials in countries with less stringent criteria. Proposals in the ESG report, such as creating specialist research centres for running high-risk phase I trials, the development of a national professional accreditation system for principal investigators, and creation of a standing expert advisory group of the UK Commission of Human Medicines, must be seriously considered to prevent the events of March, 2006, from being repeated. ■ The Lancet Oncology
See Lancet Oncol 2006; 7: 355 For results of the TGN1412induced cytokine storm see N Engl J Med 2006; 355: 1018-28
For the final ESG report see http://www.dh.gov.uk/assetRoot /04/14/10/43/04141043.pdf
See Articles page 111
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High stakes, high risks March, 2007, marks the 1-year anniversary of the disastrous trial of the anti-CD28 monoclonal antibody, TGN1412, at Northwick Park Hospital, Harrow, UK, in which six healthy volunteers developed a cytokine storm leading to multiorgan failure within hours of being given the drug. The volunteers continue to have sequelae, such as headaches and memory loss, and one participant needs ongoing treatment for dry gangrene of his fingers and toes. In the year since this event, what lessons have been learnt, and what measures have been put into place to ensure that such a disaster never happens again? In the aftermath of the trial, the UK Secretary of State for Health convened a taskforce, the Expert Scientific Group (ESG), to recommend ways to improve the safety of first-in-man trials of high-risk drugs such as: biological molecules with novel mechanisms of action; new agents with a highly specific action; and new drugs targeting the immune system. The ESG’s final report was published in December, 2006. The brief was not simple: how to optimise safety of such drugs without creating undue barriers to drug development. The 22 recommendations span preclinical development, preparation of applications for appraisal, administration of initial doses, and where and by whom such studies should be done. From the recommendations, it is clear that had several been in place a year ago, the incident at Northwick Park might have been averted. For example, the report recommends that for high-risk drugs the starting dose should be calculated by use of the Minimal Anticipated Biological Effect Level rather than by use of the No Observable Effect Level or No Observable Adverse Effect Level. This would have yielded a starting dose of 0·005 mg/kg rather than the starting dose of 0·1 mg/kg actually used. Furthermore, TGN1412 was infused over 3 to 6 minutes, with a 10-minute interval between volunteers—the report proposes such drugs be infused slowly over several hours, and that dosing between study participants be separated by an observation interval appropriate for the setting. The Greek philosopher Heraclitus said 2500 years ago: “All is flux, nothing stays still”. Medicine is continually in flux—preclinical and clinical research is in the midst of an unprecedented expansion of drug classes and targets. http://oncology.thelancet.com Vol 8 February 2007
Therefore, it is important that regulatory authorities are as fast moving and as up-to-date as the field they are regulating. Attitudes towards the findings of unsuccessful trials must also change. It is not acceptable for data from such trials to be discarded, or for researchers and drug companies to hide negative findings behind a veneer of commercial or academic sensitivity. Researchers planning and doing new trials, as well as those approving trials, must have all the relevant information to hand— information that might improve the efficiency of future trials; prevent duplication of effort; help predict trials that could fail; or anticipate toxic effects. The European clinical trial database for first-in-man trials (EudraCT) is a laudable start, as is the UK requirement, since 2004, for all suspected unexpected serious adverse reactions in phase I trials to be reported to the regulator, and for all phase I trials involving healthy volunteers to be authorised by regulators. Acknowledging the need for proper dissemination of findings from phase I trials, The Lancet and The Lancet Oncology have recently agreed to consider such studies providing they: test a new substance, or a new indication of an existing drug, in patients with a specific disease; highlight a strong or unexpected beneficial or adverse response; or shed light on a new mechanism of action that might trigger new research. In this month’s journal we publish our first phase I study. Although many issues still remain—for example, the ESG report does not make recommendations for highrisk drugs whose toxic effects might be delayed, or for the use of drugs in particular populations that might be at a higher risk of toxic effects—the proposals are a good start. Implementation will not be an easy task. The recommendations must be discussed and coordinated internationally to prevent any temptation to run trials in countries with less stringent criteria. Proposals in the ESG report, such as creating specialist research centres for running high-risk phase I trials, the development of a national professional accreditation system for principal investigators, and creation of a standing expert advisory group of the UK Commission of Human Medicines, must be seriously considered to prevent the events of March, 2006, from being repeated. ■ The Lancet Oncology
See Lancet Oncol 2006; 7: 355 For results of the TGN1412induced cytokine storm see N Engl J Med 2006; 355: 1018-28
For the final ESG report see http://www.dh.gov.uk/assetRoot /04/14/10/43/04141043.pdf
See Articles page 111
85