Regulating researchBMJ 2011; 342 doi: https://doi.org/10.1136/bmj.c7461 (Published 11 January 2011) Cite this as: BMJ 2011;342:c7461
One word leaps out of the document A new pathway for the regulation and governance of health research, the keenly awaited report on research governance from the Academy of Medical Sciences. “It’s ‘proportionate’,” says Michael Rawlins, chairman of the National Institute for Health and Clinical Excellence and of the expert working group that wrote the report. “But I would say there is another word too: symmetry,” he adds. He is sitting in the refurbished offices of the academy in Portland Place, London, two days before Christmas while the report, in draft form, is being polished for release.
“These words are very important because the arrangements we have for regulation of trials are disproportionate and asymmetrical,” he adds. “They are disproportionate because the degree of risk is assumed to be constant, whereas in reality the degree of risk in trials varies hugely from ‘first in man’ studies to me giving you an aspirin and then asking you for a blood sample. They are asymmetrical because on the one hand it is quite appropriate for regulatory authorities or ethics committees to decline to approve inappropriate studies, but on the other hand to decline to approve an appropriate study carries the risk of losing the benefits that you could have got from doing the study. Some things are remarkably benign and some things are potentially very risky, but the whole system needs to be designed to take these things into account.”
The review was announced by the previous health secretary Andy Burnham in March 2010 and started in May. The academy was asked to review the regulation and governance of medical research in the United Kingdom, concentrating on clinical trials. The academy had already published a report in January 2010, Reaping the rewards: a vision for UK medical science, warning that, worldwide, the proportion of clinical trials that were conducted in the UK had fallen from 6% in 2000 to 2% in 2006. This was, the report said, because the regulatory requirements, particularly from the European Union’s Clinical Trials Directive, were stifling research in the UK.
The idea of a review seems to have been embraced by the present government, which, in its white paper Equity and excellence: liberating the NHS published earlier this year, committed to “consider the legislation affecting medical research, and the bureaucracy that flows from it, and bring forward plans for radical simplification.”
“They have been waiting for the academy’s review,” says Rawlins. “We got a move on. It helped that we had more responses to this than to any other inquiry the academy has ever done. We had more than 300 people write in. They told a very similar story. There was no great divergence of view. The working party itself comprised a disparate group of people—some from academia, some from industry—but you couldn’t put a piece of paper between their views.”
The EU Clinical Trials Directive
Respondents to the review cited two main bottlenecks to starting research projects. One was the Clinical Trials Directive, set up in 2001 to protect trial participants, improve ethical standards of trials across the EU, and harmonise the administration of the governance of clinical research. A public consultation on the effects of this legislation in January 2010 found that it had had some negative consequences, such as increased costs and more administrative hurdles in trials. The European Commission has since said it will revise the legislation.
“There is evidence that the directive is burdensome,” says Rawlins. “There is also evidence it has damaged academic and clinical trials. The proportion of patients in Europe who are in pharmaceutical trials, which make up 75% of all clinical trials, has fallen by a third. The European Commission said it would do a review a year ago, but now says it does not have enough staff to do anything until 2012.”
The directive is felt to be unfair by the research community in the UK because it is not implemented consistently across member states. “In the UK we implement it to the letter,” says Rawlins. “The directive is grossly over regulatory.”
The problem with consistency arises from the broad definitions in the directive of “clinical trial” and “investigational medicinal products.” For example, a trial of a licensed product for an established use in a group of patients who would receive it anyway can be classed as being an interventional clinical trial simply because an investigation such as a brain scan would be carried out to study disease progression.
Rawlins gives the example of a colleague who was studying in children the genes that regulate warfarin metabolism in white blood cells. The children were already on warfarin, but the extra blood sample drawn for the study meant that the trial was classified as being an interventional clinical trial and thus subject to the regulations of the directive. “Inspectors came round and gave him a hard time for not reporting serious unexpected adverse drug reactions, but those rules are for new drugs. For warfarin the adverse effects are known already,” says Rawlins. “There are some nonsense things in the directive. In our report we are asking the Medicines and Healthcare Products Regulatory Agency (MHRA) to take a more proportionate view of the European directive. There is latitude for them to be proportionate.”
Industry finds the directive easier to cope with than the academic community because it can afford to pay for departments to deal with the regulations. However, the MHRA has already recognised the need for risk stratification in clinical trials and, in partnership with the Medical Research Council and the Department of Health, is undertaking a project to look at the management of risk in trials within existing legislation.
The MHRA also performs what are called “good clinical practice inspections” to ensure that researchers doing interventional studies comply with regulatory requirements. The academy heard from some researchers who criticised the behaviour of inspectors, finding them unprofessional and intimidating. “If you’re an inspector you may feel you have to be adversarial,” he says. “We did hear evidence about the inspections being about ticking boxes.”
Managing multiple trusts
The second bottleneck, and the most irksome for many researchers, is obtaining permission from NHS trusts to carry out the research. The report says that current processes are bureaucratic, with duplication and reinterpretation of checks by NHS trusts, inconsistency in those checks (for example, with different rules for accessing patient data), and no clear mechanism for signing off multicentre studies.
Submissions to the academy highlighted the inconsistencies and delays in the permissions process and the difficulties in negotiating contracts and costs to do research. The National Institute for Health Research coordinating system for gaining NHS permissions was cited as having helped to streamline the approval process. The academy’s report includes evidence from Kidney Research UK showing that for one trial getting permissions from individual trusts took anything from five to 29 weeks.
“It is a rate limiting step to get approval from all trusts in a study. It requires lots of duplicated effort,” says Rawlins. “Also, trusts are risk adverse.”
A national governing body
Out of the report’s 32 recommendations, the one that Rawlins believes will solve the major problems stifling research is the creation of a new agency that will act as a single regulator.
“This health research agency was more than hinted at in the government’s white paper,” says Rawlins. “The government was minded to set it up but wanted to wait for our report to say what should be in it. We are proposing that the health secretary creates a special health authority as an interim measure for this new health research agency so that we can start the reforms in the report.”
The new agency would provide a single point of entry for research applications in the UK (although Rawlins acknowledges that it may not be possible to do this because of differences in legislation in the devolved nations). It would oversee approvals for medical research involving humans, provide a single ethics opinion (subsuming the functions of the National Research Ethics Service), provide specialist approvals and licenses, and include a new National Research Governance Service that would streamline and centralise checks on research projects in the NHS. This governance service would replace the current process of multiple checks by individual NHS trusts with study wide checks on the governance of trials. It would also recommend whether research projects are suitable, and introduce timelines for providing NHS permission as well as a costing structure for research studies. Individual trusts would be left to undertake only local checks for feasibility and to report within 20 working days on their willingness to participate in a study. Rawlins cites the success of the National Research Ethics Service in streamlining ethics approval for multicentre trials and talks of the benefits of accessing the rest of the system through one point of contact. “We would like some of the glitter from the NRES [National Research Ethics Service],” he says.
The academy’s report stresses the importance of a cultural shift within the NHS: for it to embrace the importance of research in all of its trusts. “We want trust boards to take a much greater interest in the research they’re doing,” says Rawlins. “We want research directors to be tabled to talk to the board about how their trust is performing in terms of number of patients recruited into trials, number of trials, and, eventually, the number of papers published. We want them not only to take an interest in but to have some pride in their contribution to the growth of knowledge. Trust boards have some responsibility to the patients of the future. Otherwise we’ll be standing still all the time.”
Rawlins is keen to emphasise that he isn’t advocating that research is for everyone. It is equally important to encourage doctors to learn the skills of critical appraisal. “Juniors need to have some idea of what research should influence their practice. They should know the difference between good and bad research,” he explains. “Otherwise they will be locked in permafrost for their future practice.”
Given that cultural change is notoriously difficult to achieve in the NHS, the academy suggests the importance of research should be visible at the level of the new NHS Commissioning Board. “The director general of research should be on the new commissioning board,” says Rawlins. “The board should hear reports of research activities in trusts.”
Does Rawlins think his report will upset any of the stakeholders who gave evidence to the review? “Some NHS trusts may feel that research isn’t their thing,” Rawlins answers readily. “I hope they will get over that defensive reaction and come round to thinking, as I do, that clinical research is good for patients.”
The place of research governance
This report is, says Rawlins, who has been chairman of NICE since it was set up in 1999, one of the most important he has been involved in. “When I look back to when I started doing research, there was no regulatory system. We did what we wanted, mostly to each other.”
As a junior doctor Rawlins and a colleague brewed up blood cells, mixed in dead bacteria, and infused the solution in to each other to induce fevers. He set up his first ethics committee after the dean of Newcastle University Medical School refused to allow him to study the addictive effects of cannabis by trying it himself.
“We objected and said we should have a proper ethics committee,” says Rawlins. “So the dean said I could set one up and run it. I have always been a passionate believer in clinical research: it’s the best way of finding how disease occurs and new ways to treat it.”
A new pathway for the regulation and governance of health research: main recommendations
The European Commission should act quickly to revise or amend the EU Clinical Trials Directive
The Department of Health should establish a new National Research and Governance Service to oversee a streamlined, common process for acquiring research and development permission for all studies in the NHS
A national Health Research Agency should be established as an arm’s length body to oversee the regulation and governance of health research
This agency should set and deliver standard national timelines for approval of trials
Cite this as: BMJ 2011;342:c7461
Competing interests: LD is a non-executive director for NHS Direct and writes a column in the Guardian.
Provenance and peer review: Commissioned; not externally peer reviewed.