House of Commons - Clinical Trials - Science and Technology Committee

Clinical Trials - Science and Technology Committee Contents

3 Barriers to conducting trials in the UK

Introduction

16. Between 2000 and 2006, the UK's global share of patients in pharmaceutical trials fell from 6% to 1.4%.[47] Between 2007 and 2011, the number of trials conducted in the UK also dropped by 22%, with the total number of trial applications to the Medicines and Healthcare products Regulatory Agency (MHRA) falling from 1208 in 2007 to 947 in 2011.[48] In its evidence to our inquiry, the Government acknowledged this drop, stating that recent years had seen "a decline in clinical trial activity" across the EU.[49] However, it also considered there to be "cause for optimism".[50] Lord Howe, Parliamentary Under-Secretary of State for Quality, Department of Health, stated that last year "over 99% of NHS trusts actively recruited patients" onto clinical studies and that there had been a 7% increase in the numbers of participants recruited onto clinical trials since the previous year, reaching 630,000 in 2012.[51] In addition, according to the Minister, "the number of new trials [...] in the NIHR clinical research network has more than doubled over the past five years".[52] Dr Bina Rawal, Director of Research, Medical and Innovation at the Association of the British Pharmaceutical Industry (ABPI), agreed that there had been an "upturn" in trial activity since around 2010, but considered that the UK had "suffered in recent years as a choice destination" for clinical trials compared with other parts of the world.[53] This Chapter examines some of the reasons for this decline.

European barriers to conducting a clinical trial

THE CLINICAL TRIALS DIRECTIVE

17. At least part of the decline in UK trial activity is the result of the Clinical Trials Directive (CTD), which, since its adoption in 2001, has imposed a significant burden on anyone wanting to conduct a clinical trial within the European Union. Both Cancer Research UK and the Association of Medical Research Charities told us that it was "widely" acknowledged that the CTD had "contributed to the general trend of decreasing numbers of clinical trials in Europe" while failing to deliver significant benefits to patients.[54] The NHS Europe Office, established to represent NHS organisations at EU level, argued that the CTD had "improved the safety and ethical soundness of clinical trials", but acknowledged that it had also:

The European Commission, which was responsible for drafting the CTD, stated in its announcement of the CTD's revision that this legislation had created "an unfavourable regulatory framework for clinical research" which had contributed to the recent decline in European clinical trial activity.[56]

18. Witnesses highlighted several issues with the CTD. Oxford University's Centre for Evidence-based Medicine described it as "too burdensome, too slow and beset with unnecessary administration without clear upsides", while a study conducted by CR-UK suggested that the CTD had "resulted in a doubling of the cost of running non-commercial cancer clinical trials in the UK" and had increased the time to set up a trial by 65%.[57] Of particular concern was the CTD's perceived lack of proportionality, whereby trials of vastly differing degrees of risk carried the same regulatory burden. Professor Sir Michael Rawlins, Academy of Medical Sciences (AMS),[58] described how, under the CTD, trials that involved giving a patient a dose of paracetamol would require the same level of authorisation as those involving "rather more toxic agents".[59] Sir Michael went on to give an example of how the CTD's "one size fits all" approach had prevented a group of palliative care doctors from conducting a low-risk trial investigating whether high-dose morphine affected cognitive thinking in end-stage cancer patients.[60] Sir Michael told us that, despite testing what was a "normal" treatment for such patients, this trial was judged to fall within the scope of the CTD, and researchers therefore had to obtain insurance, materially increasing the cost of the research. According to Sir Michael, the researchers "decided to give up and do something else", adding that "this is the sort of problem that we have [with the CTD]".[61]

19. Sir Alasdair Breckenridge, former Chairman of the MHRA, also highlighted the problem of "inconsistent interpretation of the Directive among [EU] member states".[62] He cited the example of a trial investigating feeding formula for newborn babies, which was judged by the UK's MHRA to fall within the scope of the CTD, but was considered by Dutch regulators to be out of scope and therefore not subject to the same regulatory requirements.[63] The Clinical Contract Research Association, a trade organisation, agreed that the UK had been particularly stringent in its implementation of the CTD, claiming that the legislation had been "gold-plated" in the UK compared with other countries and that, as a result, Europe had "not been a level playing field for clinical research".[64]

THE PROPOSED CLINICAL TRIALS REGULATION

20. In December 2008, the European Commission announced and consulted on plans to review the functioning of the CTD and, in July 2012, the Commission adopted its proposal for a new Clinical Trials Regulation, intended to replace the CTD from 2016.[65] The MHRA launched a consultation on the draft Regulation in late 2012, the results of which were fed back to the Commission, and the draft has since been considered and voted on by the European Parliament's Environment, Public Health and Food Safety (ENVI) Committee. The Regulation is scheduled for first reading at the European Parliament's plenary session in March 2014.[66]

21. Overall, the Regulation was viewed positively by witnesses, with Professor Sir John Bell, Regius Professor of Medicine at the University of Oxford and a non-executive Director of several life science companies, echoing the views of many when he told us that it represented "a significant advance" over the CTD.[67] Roche told us that "as one of Europe's largest sponsors of clinical trials" it saw "the changes being introduced through the new clinical trials Regulation as positive" and the BioIndustry Association, a trade body representing healthcare-focused bioscience companies, stated that it offered "an improved, simplified and more efficient regulatory framework for clinical trials".[68] Key differences between the new Regulation and the existing CTD include the following:

Legal form: as a Regulation rather than a Directive, the new legislation will automatically become law across all Member States, reducing the potential for inconsistent interpretation. Thus, according to CR-UK, "as a Regulation this legislation will achieve one of its principal goals in harmonising the regulatory system for clinical trials across Europe".[69]
Proportionality: the Regulation contains a greater level of differentiation between high and low-risk trials than the CTD and the Government stated that it was "particularly pleased" to see "the concept of low-intervention studies" introduced.[70] However, the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust argued that "the revisions make only a crude attempt at distinguishing between the different levels of risk that trials present, and so fail to properly reshape the Directive's flawed, one-size-fits-all approach".[71] The Trial Steering Committee for two ongoing low-risk trials agreed that "the substantive barriers to low-risk, cost-effective trials" had "not been addressed by the 2012 proposed revision of the Directive".[72]
Single submission and accelerated approval for clinical trials: Roche welcomed the proposed consolidation and acceleration of the clinical trial application process, stating that "a single portal for submission, with harmonised decision-making, is a major simplification and the proposal to introduce a timeline for the ethical committee approvals is most welcome".[73] The AMS agreed that "single submission via an EU portal" and "ambitious timelines to speed up the approval process" were strengths of the proposed Regulation.[74]
Transparency requirements: plans to increase disclosure requirements for trials falling within the scope of the Regulation were generally welcomed, with the Government stating that it "view[ed] positively the elements of the proposal designed to do this".[75] However, not everyone felt that the Regulation went far enough. Dr Ben Goldacre, a practising clinician, author and campaigner for greater trial transparency, stated that "the current form of the draft EU Clinical Trials Regulation is weak, and does not adequately address the problem of missing results for medicines currently in use".[76] The topic of trial transparency is considered further in Chapter 4.

22. Although broadly welcomed, some agreed with the AMS that, while the Regulation represented a marked improvement on the CTD, "outstanding concerns remain".[77] In particular, it was suggested that a lack of clarity in the text of the Regulation might lead to it being interpreted as "more restrictive" than intended, potentially undermining the advantage of its more prescriptive legal form.[78] The Wellcome Trust referred to some of the terminology used in the Regulation as "confusing" and urged the Government to "seek further clarity on the amount of flexibility inherent in the Regulation".[79]

23. The Government stated that it welcomed the European Commission's proposal for a new Clinical Trials Regulation, and considered this to have "the potential to create a more favourable environment for the conduct of clinical trials in the EU".[80] It also stressed the active role it considered itself to have played in the Regulation's development, stating that it had been "fully engaged in the negotiations" taking place at European level.[81] The Minister told us that:

Sir John Bell agreed that the MHRA had made a "substantial effort to ensure that the views of the UK were heard during the process of re-drafting the directive".[83] Overall, according to the Minister, the Government was "pleased by the tenor and direction of travel of the [European] Commission in putting together its proposals" for the new Regulation.[84]

24. We recognise the significant barrier to research posed by the European Clinical Trials Directive and welcome proposals for a new European Clinical Trials Regulation. However, we are concerned that a lack of clarity in the detail of the Regulation could lead to inconsistencies in its implementation across Member States, and we are not persuaded that proposals go far enough in ensuring that low-risk trials are regulated in a proportionate way. We urge the Government and MHRA to continue engaging at a European level to resolve these issues and to work together to ensure that, when the resulting legislation is introduced, the administration of clinical trials in the UK will be pragmatic and proportionate.

UK barriers to conducting a clinical trial

25. Several witnesses pointed out that, while there were improvements to be made to the regulatory framework at European level, there remained several barriers to conducting a clinical trial "specifically within the UK".[85] The result, according to Roche, was that UK trials were becoming "increasingly costly and bureaucratic" compared to those conducted elsewhere in the EU.[86] This section of the Report examines these UK-specific issues.

REGULATORY AND GOVERNANCE COMPLEXITY

26. Dr Catherine Elliott, Director of Clinical Research Interests, Medical Research Council (MRC), stated that, while there was "no doubt" that the CTD had contributed to difficulties in conducting trials across Europe, in the UK this legislation was "overlaid on to an already complex regulatory framework".[87] This framework is illustrated through the Clinical Trials Routemap (Figure 1)—an interactive resource developed by the Government in 2004 to "help clinical trialists and R&D managers understand the regulations and requirements" for conducting a trial in the UK.[88]

Figure 1: The Clinical Trials Routemap[89]

27. The complexity of this environment was widely acknowledged, including by the Government: Bill Davidson, Acting Deputy Director and Head of Research Standards and Support at the Department of Health, agreed that "the regulatory framework for research has become increasingly complex, which is one of the main reasons why we established the [HRA]".[90] When we asked Dr Janet Wisely, Chief Executive of the HRA, how easily researchers were able to find their way through this framework in order to initiate a clinical trial, she told us that "many do have a good understanding", but acknowledged that "others find it difficult to navigate what is a complex system".[91] She considered that, "however much we improve the efficiencies around approvals, it is still going to be quite a complex task" to initiate a clinical trial, and that researchers needed to make themselves familiar with the system.[92] Sir Kent Woods, Chief Executive of the MHRA at the time of our inquiry, told us that this was particularly difficult for those "relatively new to the clinical trials field and without the resources of a regulatory affairs department behind them"—a view borne out by a May 2013 report published by the Association of Medical Research Charities, which found that 40% of polled hospital doctors "cited difficulties navigating regulatory processes as a barrier to them taking part in medical research in the last two years".[93] The BioIndustry Association (BIA) pointed out that delays in the commencement of trials acted as a "significant drain on [...] companies' finite resources", and was particularly detrimental to small to medium enterprises which were often "pre-revenue and equity-backed" and were less likely to possess regulatory expertise.[94]

The performance of the Health Research Authority

28. A 2011 Academy of Medical Sciences report commissioned by the Department of Health, A new pathway for the regulation and governance of health research, recommended the establishment of a new independent agency, intended to bring together existing approval processes and simplify the UK regulatory and governance landscape for clinical trials.[95] In response, the Government established the Health Research Authority (HRA) in December 2011.[96] The HRA's remit is to "promote and protect the interests of patients and the public in health research" and, ^{according
to Dr Wisely,} the HRA also has "a much wider role, which is largely about making it easier to do good quality research within the NHS".[97] Key HRA functions currently include:

operating the National Research Ethics Service;
acting as the appointing authority for Research Ethics Committees (RECs) in England;
operating the integrated research application system, which is "a UK-wide e-submission system through which applications for [selected] regulatory and governance approvals for health research" can be made;[98]
providing access to confidential patient information under Section 251 of the NHS Act 2006;[99]
encouraging patient and public involvement in health research, and
encouraging transparency, both in the HRA's own operations and by promoting good research conduct.[100]

29. Witnesses generally considered it too early to judge whether the HRA had been successful in meeting its objectives, although its positive attitude was widely praised: the BIA commended the HRA's "open and transparent spirit of engagement" which it stated had been "warmly welcomed by the sector" and the Clinical Contract Research Association considered that the HRA had already "streamlined clinical trials ethics regulation", making the UK "a more attractive location to conduct clinical trials".[101] However, the UK Clinical Research Collaborations Registered Clinical Trials Units Network, a group responding on behalf of 15 UK clinical trial units, while welcoming "the spirit of the HRA" argued that it was yet to have "demonstrable impact [...] on the operations of clinical trials units".[102] King's Health Partners (KHP), one of England's first academic health sciences centres,[103] stated that "most clinical researchers and R&D staff in KHP have very little awareness of the HRA aside from the fact it exists"—a statement echoed by the Royal Pharmaceutical Society and the National Pharmacy Clinical Trials Advisory Group.[104]

30. According to its most recent Business Plan, the HRA is expected to spend £9.68 million in 2013-14, over half of which relates to the operation of its ninety-one Research Ethics Committees.[105] Roche questioned whether this budget was congruent with the HRA's objectives, claiming that there were concerns that it had "not been given the resources to achieve its role effectively and therefore may be at risk of either scaling back its remit or slowing down its work and the research and trials that rely upon it".[106] Although other witnesses did not comment on the HRA's budget, the Association of Medical Research Charities emphasised the need for it to "assess and demonstrate its effectiveness", and the AMS agreed that the development of "reliable metrics" would be "extremely important both in terms of providing feedback on the success of initiatives [and] communicating success internationally to companies and researchers seeking locations for clinical trials".[107] This need for formal performance measurement appears to have been recognised by the HRA, which stated in its 2013-14 Business Plan that it needed to "do further work over the coming months with stakeholders to identify what success will look like, feel like and measures that can be used to demonstrate it".[108] Nevertheless, it was the Minister's view that "by common consent the HRA has got off to a very good start indeed".[109]

31. We commend the establishment of the Health Research Authority (HRA) and note that feedback on the HRA's performance to date has been largely positive. However, we are unable to judge whether the HRA has so far been effective in achieving its objectives, as the necessary performance indicators are not currently in place. We recommend that the HRA establishes and publishes a suite of relevant key performance metrics and targets in its 2014/15 Business Plan, and monitors performance against these targets annually. We further recommend that a triennial review of the HRA takes place no later than December 2014, three years after its creation as a Strategic Health Authority.

32. Over a year after its creation, some stakeholders (including an academic health science centre, intended to be a centre of excellence for UK health research) remained unaware of the function, or even the existence, of the HRA. Although these stakeholders also bear some responsibility for their own awareness of such developments, we consider that the HRA should now place greater emphasis on engaging with the clinical research community and raising the profile of its work. The HRA should detail in its response to this Report how it intends to do this.

NHS RESEARCH AND DEVELOPMENT APPROVAL

33. According to many, "by far the greatest impediment" to conducting a clinical trial in the UK is the requirement for researchers to obtain separate approvals from each NHS organisation involved—a requirement referred to as NHS R&D approval.[110] Professor Sir Michael Rawlins, Academy of Medical Sciences (AMS), explained that most trials take place across multiple NHS locations, each of which have their "own governance arrangements, with all of them looking [separately] at things like criminal records reviews and patient consent forms".[111] He gave the example of a principal investigator for a study involving 62 hospitals, who underwent 62 Criminal Records Bureau checks before being able to begin the trial.[112] A further example was provided by the British Heart Foundation (BHF), which told us about a study that "took more than a year to get started because of delays caused by governance and NHS funding issues".[113] According to the BHF, "the longest delays occurred in agreeing the contracts between the lead site at the University of Cambridge and seven other centres", which, as a result of each NHS site requesting separate agreements for each of the three trials making up the study, led to the university having to prepare 21 different contracts for a single study.[114] The BIA emphasised the "added cost, both in terms of staff and time and financial outlays" incurred as a result of such delays, which meant that many businesses found that conducting trials could be "demonstrably cheaper and more efficient in other jurisdictions".[115]

34. The problem of NHS R&D approval was strongly underscored by the AMS's 2011 report, which recommended the creation of a National Research Governance Service (NRGS) to streamline this process.[116] The AMS envisaged that the NRGS would form a "core component" of the HRA and would "oversee a streamlined, common process for NHS R&D permission for all single and multi-site studies in the NHS in England".[117] The Government has not, to date, taken up this recommendation, although the Minister told us that the HRA was "looking at ways to speed up the whole research journey".[118] He added that the HRA was currently "running a feasibility study, including a number of pilots, to test the effect of rationalising and combining NHS study-wide review with elements of the Research Ethics Committee review into a single HRA assessment".[119] This study, announced in October 2012 and commenced in June 2013, was widely welcomed and Cancer Research UK stated that, if successful, this would be the "biggest step" towards achieving a more streamlined governance process for clinical trials.[120] The Minister cautioned that "we cannot expect overnight results" and was unable to provide us with any milestones for next steps.[121] The report of this study was considered by the HRA's Board in June 2013, following which recommendations were made to the Department of Health.[122] The HRA stated in August that the results of the feasibility study had demonstrated that "both study-wide and local R&D assessments [could] be integrated into an HRA assessment" and that a business case for implementation was currently being prepared.[123]

35. We welcome moves by the HRA to streamline NHS governance arrangements and stress the importance of this initiative, which, in our view, should be given the highest priority. Following completion of the feasibility study, we recommend that a timeline detailing the next steps be published as part of the HRA's response to this Report. The Government should assist the HRA in its efforts to meet this priority, including making additional resources available if necessary.

MONITORING NHS TRUST PERFORMANCE

36. The Government has repeatedly pledged to monitor "how many Trusts are getting clinical trials started quickly" and stated, in 2011, that Trust performance against a 70 day target would be published from 2012.[124] Oxford University's Centre for Evidence-based Medicine, however, considered this target to be "unobtainable for drug trials" since, "as a lead investigator on a NIHR funded trial, the best we can currently obtain is around the 150-day mark, which is the European average".[125] When asked in June 2013 how NHS Trusts were performing compared with this benchmark, the Minister replied that he did "not yet have robust data" and would not be in a position to answer our question until later in the year.[126] The Minister explained that the benchmark had been included in all new contracts with NHS Trusts since April 2012 and that a process to track performance was currently being tested. When we asked if this target was likely to be achievable, the Minister replied "yes" but considered that "it may take a little time before we see majority compliance".[127]

37. We are disappointed that the Government has failed to meet its own 2012 deadline for measuring NHS Trust performance against a 70-day benchmark for clinical trial initiation and we query whether this target is realistic in the short-term. We recommend that the Government updates us on current performance and on how many NHS Trust contracts now include this benchmark in its response to this Report.

PATIENT RECRUITMENT

Public attitudes to and awareness of clinical trials

38. Simon Denegri, NIHR National Director for Public Participation and Engagement in Research and Chair of INVOLVE, the national advisory group for public involvement in research, highlighted that clinical trials "would not happen if patients and people did not come forward voluntarily and freely contribute their time".[128] Fortunately, public attitudes to clinical trials in the UK are generally positive—according to a 2011 survey commissioned by the Association of Medical Research Charities (AMRC), 72% of people would like to be offered the opportunity to be involved in a clinical trial.[129] Mr Denegri suggested that many patients felt "as though they might get better care" as a result of participating in a clinical trial, in addition to believing that they might benefit from a new treatment or therapy.[130] Others confirmed that, for some conditions, clinical trials represented an important treatment option. Professor Karol Sikora, Medical Director of Cancer Partners UK and Dean of the University of Buckingham Medical School, said that for cancer patients there was often "a sense of desperation" among those who have failed to get better with conventional treatments, meaning that they "actively seek out centres where there are clinical trials".[131] Professor Peter Johnson, Chief Clinician at Cancer Research UK (CR-UK), added that different groups of people had "different levels of enthusiasm to take part in research", and considered that "in general, people diagnosed with cancer have a very high level of motivation".[132] As a result, patient participation in cancer research is high, with around one in five people diagnosed with the condition taking part in one of CR-UK's trials.[133] However, positive attitudes appeared to be weaker when trials were known to be funded by industry. A 2013 public dialogue exercise commissioned by the HRA found that "the general public were deeply suspicious of the pharmaceutical sector and many held a view that making a profit was incompatible with developing products of benefit to patients".[134]In addition, pharmaceutical trials were thought to develop in isolation to the NHS and the links between different organisations were not recognised.[135]

39. When asked what might prevent someone from becoming involved in a clinical trial, Mr Denegri highlighted the issue of public awareness and told us that knowledge about clinical trials was "pretty low in the general population".[136] He continued, "it probably increases as one becomes a patient, particularly if one has a condition such as cancer or if one is going to be treated for a long period of time" but described the process through which people could find out about clinical trials as "quite hit and miss".[137] Sharmila Nebhrajani, Chief Executive of the AMRC, agreed that there was "definitely a knowledge and access barrier" for people wanting to participate in a clinical trial, telling us that "patients want to do it, but they have no idea how".[138] According to Professor Johnson, "a much higher level of awareness among the general population would be enormously helpful".[139]

40. Despite generally positive public attitudes to clinical research, Roche told us that recruiting the requisite number of patients to UK trials was "often a more time-consuming process than in other EU countries".[140] William Burns, a Member of Roche's Board of Directors, considered that there was no "hesitancy from patients themselves" and that difficulties in patient recruitment were down to "an issue of process".[141] Roche considered that this was because "the NHS does not see clinical trials as part of its day to day operation" and others also highlighted what the British Heart Foundation called the absence of a "research-oriented mentality" in the NHS.[142] A recent NIHR "mystery shopper" survey, involving 82 hospital sites across 40 NHS Trusts, found that 91% of hospitals did not have any public information about studies they were supporting in "basic point of contact areas" and only 34% had information about clinical research on their websites that was useful to patients.[143]

41. Health professionals also appeared to be relatively uninformed about research opportunities, making it difficult for them to talk to patients about potential participation. Mr Denegri told us that a patient's relationship with their doctor was "pivotal" in influencing their decision about whether to take part in a trial but, according to the AMRC, a third of surveyed GPs and nurses said that they were not very confident talking about research with their patients, and 21% of health professionals were either unaware of, or failed to use, any of the tailored information resources available to support such conversations.[144] A reluctance to discuss research also appeared to exist on the part of patients: a recent poll found that "only 21% of patients and the public said that they would feel confident asking their doctor about research opportunities".[145]Mr Denegri considered that health professionals, who in the past had "not been very helpful" to patients wanting to find out about research opportunities, were gradually being excluded from the decision-making process, as patients increasingly attempted to "self-refer to take part in research".[146]

42. The Government has responded to this reluctance to talk about research by launching the OK to Ask campaign, which promotes "the fact that it's OK to ask about clinical research".[147]The Minister explained that this campaign was intended to:

148

The launch of the OK to Ask campaign followed the March 2013 update of the NHS Constitution, which strengthened the NHS's commitment to health research by pledging to "inform" patients of "research studies in which [they] may be able to participate".[149] Professor Johnson welcomed this change as "extremely positive" and Nicola Perrin, Head of Policy at the Wellcome Trust, agreed that the new pledge would "hopefully" be "very helpful", while adding that it needed to be "accompanied by much better information" for patients.[150] The AMRC agreed that patients needed to understand "what this commitment means to them" and pointed out that staff also needed guidance on "how they should meet this pledge and why", concluding that the change to the NHS Constitution was "welcome, but not sufficient".[151]The Minister told us that as a result of this "pledge to promote the existence of clinical trials" there was now "an onus on the system itself to do this".[152]

43. We welcome changes designed to make the NHS Constitution more research-focused and the launch of the Government's OK to Ask campaign. However, we are cautious of any suggestion that the system, as a result of this new onus, will automatically act to promote the existence of and encourage involvement in clinical trials. We recommend that the Government provides details of how changes to the NHS Constitution and the OK to Ask campaign have been communicated and promoted, both within the NHS and to the general public. In twelve months' time it should publish evidence on how the measures have affected both public and professional attitudes to, and participation in, clinical trials.

44. We note the apparent lack of public confidence in the pharmaceutical industry and are concerned that this may increasingly pose a barrier to conducting trials in the NHS. Industry should act to regain trust lost through past examples of poor behaviour by engaging more effectively and transparently with the public in the future. In addition, Trusts need to do far more to educate patients about the benefits, both to them and to the wider community, of participating in research and allowing properly controlled sharing of patient data.

THE CLINICAL TRIALS GATEWAY

45. In its 2011 Strategy for UK Life Sciences, the Department for Business, Innovation and Skills (BIS) included a commitment to "re-launch an enhanced web-based UK Clinical Trials Gateway", which would "provide patients and the public with authoritative and accessible information" about clinical trials taking place in the UK.[153] The Gateway, operated by the NIHR, was re-launched in April 2012 and currently contains details of around 14,500 trials taking place in the UK, approximately 3,100 of which are listed as recruiting.[154]

46. Mr Denegri considered the Gateway to be a "good initiative" that had been "very much welcomed" by patients, and the AMRC agreed that it was a "valuable resource".[155] BioMed Central, an open-access scientific publisher, cited the Gateway as evidence that "increased participation in trials" remained "very much supported by the UK Government".[156] However, the Gateway does have several limitations. Mr Denegri stated that there were "two broad issues":

157

BioMed Central summarised the Gateway's challenges slightly differently, as ones of "coverage" and "accessibility", explaining that additional trial databases would need to be searched to ensure full coverage and pointing out that "clinical trial descriptions are often not in plain English", reducing the resource's accessibility.[158] A 2012 patient survey found that 67% of respondents considered the information contained on the Gateway to be either very clear or fairly clear but there were also "many requests for information to be kept up to date, clear, simple and relevant to its purpose".[159] Some respondents also felt that "there was too much medical and technical information" and that lay summaries were used inconsistently across the Gateway.[160]

47. The same survey also found that 80% of respondents—primarily patients and carers, who are the most likely users of the resource—had not heard of the Clinical Trials Gateway.[161] When questioned about this, the Minister acknowledged that "knowledge of the Gateway is less than we would like" but added: "I understand that the NIHR is taking various steps to promote the existence of the Gateway, as indeed the NHS itself must do".[162] When asked to expand upon how this was being achieved, the Minister responded that the NIHR had ensured that all parts of the NHS were "made aware" of the Gateway's existence, so that "at relevant opportunities, clinicians and others are encouraged to draw attention to it when they have a patient sitting in front of them".[163] However, he acknowledged that efforts to "promulgate the existence of the Gateway" had had "limited success so far".[164] The Minister also stressed that the Gateway had "recently been updated and renewed and is in the process of being improved still further", for example by giving it a better geographical focus, as highlighted by Mr Denegri, "so that, if you are living in a certain part of the country, you can find out what trials are going on nearby".[165]

48. The CancerHelp UK clinical trials database, funded and operated by CR-UK, is an online resource dedicated to UK cancer trials. According to CR-UK, unlike other trial registries, which are typically clinician or researcher-focused, the trial summaries included on CancerHelp UK "are written specifically with patients in mind".[166] Professor Johnson, CR-UK's Chief Clinician, stated that "about six whole-time equivalent staff" were "continuously trawling the different databases" to identify new trials, following which they wrote bespoke trial information sheets, "usually in concert with the researchers".[167] He continued:

168

In comparison, support and development of the Government's Clinical Trials Gateway is performed by contract staff, equating in total to "two whole time equivalents" and most of the information it contains is pulled from existing sources, such as regulatory trial registers, not specifically designed for a lay audience.[169] Box 2 contains a comparison of entries for a current phase I/II cancer trial on the Clinical Trials Gateway and the CancerHelp UK trials database.

49. Dr Elliott, MRC, stated that CR-UK had done a "great job with CancerHelp" and Ms Perrin, Wellcome Trust, agreed that it was an "excellent" resource.[170] This is reflected in the level of traffic received by the site: according to CR-UK, each month, on average, 35,000 full trial summaries are viewed on the CancerHelp UK database—more than the number of people diagnosed with cancer each month.[171] In comparison, the Government stated that in May 2013 (a month that included International Clinical Trials Day[172] and the launch of the Government's OK to Ask campaign) 41,115 pages on the Clinical Trials Gateway—covering not just cancer, but all conditions—were viewed, although it did not specify whether all of these views were of trial summaries.[173] The Government told us that, since 2008, it had invested £611,000 in the Gateway, part of which related to "limited advertising and promotional materials" including leaflets, postcards and placards.[174]

Box 2: Comparison of information on the UK Clinical Trials Gateway and CancerHelp UK

The ARISTOTLE study is a phase III trial looking at the use of irinotecan, a chemotherapy drug, in treating rectal cancer. It is currently attempting to recruit patients in the UK and is detailed on both the CancerHelp UK trials database and the UK Clinical Trials Gateway.

The "lay summary" contained on the Clinical Trials Gateway was taken directly from the UK Clinical Research Network (UKCRN) portfolio database—a system designed for use by clinical researchers.[175] It stated that:
ARISTOTLE is a randomised multi-centre phase III trial with a target accrual of 920 patients with MRI defined locally advanced non metastatic rectal cancer. [...]
The trial aims to determine whether the addition of a second drug (irinotecan) to the standard treatment of oral chemotherapy using capecitabine and radiotherapy improves outcome.[176]
In contrast, the summary provided by CancerHelp UK was written specifically for a lay audience and described the trial as follows:
This trial is looking at adding irinotecan to the standard treatment for cancer of the rectum that has spread into the surrounding tissues (locally advanced cancer). [...]
Doctors usually treat locally advanced rectal cancer with chemotherapy and radiotherapy followed by surgery. Having both treatments together is called chemoradiotherapy. As well as killing cancer cells, some chemotherapy drugs can make cancer cells more sensitive to radiotherapy. Having chemotherapy with radiotherapy is often better at shrinking cancer than radiotherapy alone. The chemotherapy drug capecitabine with radiotherapy is standard treatment to shrink rectal cancer before having surgery to remove it.
In this trial, researchers are looking at adding another chemotherapy drug called irinotecan. They want to find out

If adding irinotecan to standard treatment stops or helps to delay the cancer coming back following surgery
More about the side effects

This is a randomised trial. It will recruit about 920 people in the UK. The people taking part are put into 2 groups by a computer. Neither you nor your doctor will be able to decide which group you are in.[177]

50. We were impressed by the quality and accessibility of Cancer Research UK's trials database, which is reflected in the high volume of traffic that it receives. In contrast, while we are satisfied that the Government is working to improve and promote its own Clinical Trials Gateway, we were concerned to find that only 20% of its target users were aware of its existence as of mid-2012, and that the Minister was unable to give us a more detailed account of what was being done to improve this. The Government must improve the Clinical Trials Gateway and raise its profile with patients, clinicians and the general public. We recommend that the Government provides details about how it will achieve this, together with indicative timelines and targets, in its response to our Report.

51. We consider it important that the information contained on the Clinical Trials Gateway is accessible to the lay person, which does not appear to be consistently the case at present. The Government should ensure that all trials listed on the Gateway include a plain language summary written specifically for a lay audience. Where such summaries are not already in existence, the Government must be prepared to commit the time and effort needed to create them. Taking into account the Gateway's current resource levels, we recommend that, where possible, preparation of a lay summary should be included as a requirement for publicly-funded trials, but that the Government remain open to the option of increasing the level of resource dedicated to the Gateway if necessary.

47 Ev 79, para 2; "All together now: improving cross sector collaboration in the UK biomedical industry", NESTA, 2011 Back

48 Ev 53; "2007 applications received by phase" and "2011 applications received by phase", available at "Clinical trials for medicines: UK clinical trial authorisation assessment performance", MHRA, mhra.gov.uk, accessed September 2013 Back

49 Ev 53, para 4 Back

50 Q 185 [Lord Howe] Back

51 Q 185 Back

52 Q 185 Back

53 Q 63 Back

54 Ev w 108, para 5; Ev90, para 6 Back

55 Ev 61, para 3 Back

56 "Fostering EU's attractiveness in clinical research: commission proposes to revamp rules on trials with medicines", European Commission press release, 17 July 2012 Back

57 Ev w45, para 6; Ev 90 para 6 Back

58 Sir Michael Rawlins is a Fellow of the Academy of Medical Sciences and was Chair of the Academy's 2010 Working Group on regulation and governance in health research. When he gave evidence, Sir Michael was also Chair of the National Institute of Health and Care Excellence (NICE). Back