An unexpected side effect of the disastrous clinical trial at Northwick Park Hospital was the claim that volunteer enquiries for Phase I studies surged in the wake of the incident reports Peter Mansell.
Given that six of the TeGenero volunteers ended up on the critical list, a sudden burst of altruism seems unlikely. More feasibly, people have realised there is money to be made and are willing to take the risks.
The internet is awash with requests for healthy volunteers offering payments of £80-£150 per day and something akin to a holiday camp atmosphere.
Here is a representative sample from the website of Parexel, the clinical research organisation responsible for the TeGenero trial:
“You may be helping friends and family by being involved in the development of a new medicine or helping to improve an existing one. You’ll receive a thorough medical check up – FREE! You’ll be paid for your time and inconvenience. Free food for the duration of your stay – and NO shopping or washing up! You'll have plenty of free time to read or study, or just relax - with digital TV, pool table, videogames, DVD player, and now FREE internet access! You can even just catch up on some sleep!”
Parexel declined to comment on whether it now intends to tone down its advertising. Yet the company and other CROs are already going some way beyond the Guidelines for medical experiments in non-patient human volunteers published by the Association of the British Pharmaceutical Industry.
A student population
Public notices soliciting volunteers should mention neither “payment nor the level thereof,” the guidelines say. Moreover, “widespread or public advertising, especially if it is aimed at the poor, needy or socially disadvantaged, is unacceptable.” The tone of Parexel’s copy accurately reflects its target audience. Universities are a traditional breeding ground for Phase I volunteers. But, if the primary motivation is financial, is that in itself a bad thing?
An estimated quarter of all trials end because of a lack of volunteers. So the industry needs volunteers and the volunteers seem to need a material incentive. To turn the argument on its head, volunteers could justifiably insist on payment for taking the kind of risks – albeit rarely manifest – that the TeGenero trial brought to light.
The problem is, healthy volunteers are not paid for risk-taking. The ABPI is emphatic on this point: “Payment should never be offered for undergoing risk. Payment of excessive amounts is discouraged, especially as this may lead to inappropriate volunteering solely for financial gain.”
Moreover, guidelines and regulations stress the risk to trial subjects should be as low as possible. The “rights, safety, and wellbeing of the trial subjects are the most important considerations and shall prevail over interests of science and society,” state the UK’s Medicines for Human Use (Clinical Trials) Regulations 2004.
Where volunteer studies are concerned, the ABPI takes this logic further. They are “not mandatory” and “should not be performed if they involve medicines whose identifiable toxicity or lack of safety is only compensated for by their potential unique efficacy,” the guidelines note.
But the question remains whether these risks - however remote - are properly understood by volunteers: particularly if they sign up expecting easy money and trial centres are promoted as little more than chill-out zones.
The General Medical Council’s guidance on good practice in research says any remuneration on offer should not be “at a level which could induce research participants to take risks that they would otherwise not take, or to volunteer more frequently than is advisable or against their better interests or judgement.”
Comments the Institute of Clinical Research: “Levels of remuneration reflect, for example, the inconvenience of a protracted domicile within a research unit, and are carefully reviewed by independent ethics committees to ensure that they do not represent undue levels of inducement to participate.”
At your leisure
There are also firm safeguards to ensure volunteers know what they are taking on, the ICR insists. “All volunteers must have a full verbal and written explanation of the potential risks before they may participate in any study. Investigators will not accept consent from any volunteer if they have concerns that a volunteer does not understand the information presented, has had an adequate opportunity to ask questions and is in a position to give fully informed written consent.”
Moreover, providing leisure facilities is a responsibility rather than a hook, the ICR argues: “For safety reasons, volunteers must often stay domiciled within a unit for one to two weeks and therefore units have a responsibility to provide leisure facilities to afford volunteers an acceptable quality of life during their stay.”
Ultimately, it is up to research ethics committees (RECs) to assess the interplay between these factors in reviewing applications for volunteer studies. RECs were given statutory weight in the clinical trials regulations, which tightened conditions for Phase I studies by making them conditional on approval both by an independent REC and the MHRA.
The Central Office for Research Ethics Committees says volunteers should be able to measure the risk of a trial from the participant information sheet, which the committees review to ensure it is accessible to a lay person.
So has the Northwick Park incident cast these procedures and practices in a different light? Not according to the MHRA, whose final report on the study identified a number of discrepancies, such as non-adherence to unblinding procedures, but did not mention recruitment strategies or the degree of risk conveyed to participants.
Lawyers for the volunteers claim, however, the risks of the trial were underplayed and some of the participants felt under pressure to sign the informed consent form without having time to understand it fully. They are calling for an independent inquiry into all aspects of the study, including the recruitment and informed consent procedures.
As things stand, this looks unlikely to materialise. The Department of Health confirmed that the 'independent expert scientific group’ appointed to examine the implications of the Northwick Park incident would “only look at the science.”
COREC recently ended a consultation on implementing the recommendations of the government’s Ad Hoc Advisory Group on the Operation of NHS Research Ethics Committees. But this did not include policy issues such as volunteer recruitment, which were the province of the DoH, the Office noted.
From the industry side, the ABPI has convened a joint task force with the BioIndustry Association to advise the government’s expert group on the fall-out from TGN1412. The task force may examine the broader issues around Phase I trials, the association noted, although the ABPI has no current plans to update its guidelines on volunteer recruitment.
The ICR said guidelines on recruitment strategies were “already robust,” adding: “We await the assessment of the MHRA and the National Patient Safety Agency, on behalf of the ethics committees, on this matter.”
For the moment, it said, “the UK remains one of the most experienced and safest environments in the world for the conduct of early drug development and we are not aware of any indications of a recruitment crisis.”
Nor does the Institute believe CROs are under commercial pressure from their clients to cut corners. “Whilst a fast development programme is desirable from a commercial perspective, business interests can never be served by poor quality research which is ultimately of no value to medical science, the public or commercially,” it said.