Clinical Trials - Science and Technology Committee Contents

Conclusions and recommendations

What are clinical trials?

1.  Clarity in use of the term "clinical trial" is essential. The establishment of consistent terminology would be an important first step towards making the UK an easier place to conduct clinical research. We recommend that the Government agrees a set of simple definitions for the terms "clinical trial", "clinical study" and "clinical research" and ensures their consistent use across the Health Research Authority, Medicines and Healthcare Products Regulatory Agency, Medical Research Council, National Institute of Health Research and the NHS. (Paragraph 11)

The European Clinical Trials Directive

2.  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. (Paragraph 24)

UK regulatory and governance complexity

3.  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. (Paragraph 31)

4.  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. (Paragraph 32)

5.  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. (Paragraph 35)

6.  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. (Paragraph 37)

Patient recruitment

7.  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. (Paragraph 43)

8.  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. (Paragraph 44)

9.  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. (Paragraph 50)

10.  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. (Paragraph 51)

Clinical trial transparency

11.  Clinical trial transparency is important and greater transparency would be likely to provide a number of benefits, particularly if applied retrospectively. However, there are obstacles to achieving this and the drive for greater transparency must be balanced against other concerns, particularly the need to protect patient privacy. Greater disclosure does not necessarily equate to greater transparency if the information shared cannot easily be understood and we therefore recommend that efforts to increase the availability of clinical trial data focus on providing information that is accessible, assessable, intelligible and usable. (Paragraph 58)

Level 1: Trial registration

12.  We consider universal trial registration to be a crucial step in increasing clinical trial transparency and believe that all future trials should be included in a publicly-accessible register. This is clearly not the case at present, even for trials conducted in the UK. We recommend that the Government take steps to ensure that, in future, all clinical trials conducted in the UK, and all trials related to treatments used by the NHS, are registered in a WHO-listed primary registry. (Paragraph 63)

13.  Since the trials of treatments currently in use often occurred many years ago, retrospective disclosure is important if the benefits of clinical trial transparency are to be realised in the short to medium-term. Although retrospective trial registration will incur some cost, we consider that this will be outweighed by the public health benefit of having a complete picture of the trials conducted on treatments currently available to patients. The Government should support the retrospective registration of all trials conducted on treatments currently available through the NHS and should actively pursue policies to bring this about. (Paragraph 64)

Level 2: Summary-level trial results

14.  We consider that summary-level results should be made publicly available for all clinical trials and we welcome the many new media through which it is now possible to share this information. Nevertheless, peer review is vital to the reputation and reliability of scientific research and we deem it appropriate that journal articles remain the primary instrument for the publication of summary-level trial results. (Paragraph 68)

15.  Many historic trials remain unpublished, which is far from ideal. However, retrospective publication of all trials of all treatments currently in use, while desirable, would almost certainly be unachievable given the likely time and resources that this would require. We therefore emphasise again the importance of retrospective trial registration as a means of providing a vital "index" against which individual cases of non-publication can be identified and, where of particular importance, pursued on an ad hoc basis. (Paragraph 69)

16.  Given recent changes to academic publication models, we do not recognise as legitimate the argument that it is not possible to publish "negative" results in a peer-reviewed journal and we consider failure to publish on a timely basis to be poor scientific practice. However, we are sympathetic to the pressure that scientists are often working under and therefore we urge the Government and other trial funders to ensure that researchers are provided with the time and resources needed to meet their publication obligations. (Paragraph 70)

17.  We encourage academic publishers to remove "Ingelfinger" restrictions on the pre-publication of summary-level results through media such as trial registries, in order to facilitate greater openness and faster access to important scientific data. (Paragraph 72)

Level 3: Clinical study reports

18.  It would be unduly burdensome to mandate that clinical study reports (CSRs) be produced for non-commercial trials. We also consider that issues concerning the reliability of the information contained in academic journal articles should be dealt with at source, for example by strengthening the peer review process as recommended in our 2011 Report, rather than by effectively bypassing academic publication through greater reliance on CSRs. We therefore do not support any move to make it mandatory for non-commercial trials to produce a CSR, or any other document of an equivalent level of detail. However, we recognise that CSRs can provide a useful contribution to the scientific literature and, once a regulatory decision has been reached, we see no compelling reason why CSRs should not be placed in the public domain, with identifiable patient data redacted. (Paragraph 79)

Level 4: Individual patient-level data

19.  We are not in favour of placing anonymised individual patient-level data (IPD) in the public domain in an unrestricted manner, as we consider that the risk to patient confidentiality is too great and, for many past and current trials, this level of disclosure would go beyond the confines of previously obtained patient consent. Nevertheless, we recognise the scientific value of IPD and consider these data to be currently underutilised. We agree with the Caldicott 2 Review that providing specific individuals with controlled access to personal confidential data such as IPD through carefully managed and secure "safe havens", together with contractual agreements about how that data can be used, is the best way forward. We also consider that access should be facilitated by an independent "gatekeeper", responsible for evaluating research proposals and ensuring that data is handled responsibly and in a way that makes a useful contribution to scientific knowledge. (Paragraph 88)

20.  The UK could take the lead in shaping how a global system for sharing IPD for non-commercial trials might operate and a national system covering all non-commercial UK trials would be capable of delivering potentially significant benefits. We consider that the Health Research Authority (HRA) could act as developer, administrator and gatekeeper for a central repository of IPD for non-commercial UK trials. In order to achieve this, template consent forms provided by the HRA should allow for and emphasise to trial participants the benefits of data sharing. Research Ethics Committees should also take into account any transparency restrictions imposed by patient consent forms when evaluating research proposals for clinical trials. (Paragraph 89)

Past initiatives to increase clinical trial transparency

21.  We support the development of the EU Clinical Trials Register (EU CTR) and hope it will also include summary-level results, as promised, by the end of 2013. However, we do not consider the register to represent a complete solution to the problem of non-registration of clinical trials, as it does not include all the trials that have been conducted on all medicines currently available in Europe. The Government should encourage the EMA to further increase the scope of the EU CTR, for example by including phase I trials and trials conducted outside of the EU. We also recommend that the Government monitor the EMA's fulfilment of its pledge to include trial results on the register and obtain an explanation if the EMA fails to do so by the end of 2013. (Paragraph 94)

22.  As a major direct and indirect funder of clinical trials, the Government can influence behaviour across both the public and charitable sectors. This influence has not been wielded effectively to increase transparency, meaning that many publicly-funded trials remain unregistered and unpublished. We recommend that registration in a WHO-listed registry and publication of summary-level results in a peer-reviewed journal be made contractual requirements for all publicly-funded trials, including research supported by the Charity Research Support Fund. The wording of these requirements should be standardised across all contracts to ensure consistency. We also recommend that public funders of research rapidly put in place mechanisms to monitor compliance with transparency policies and ask the Government to detail in its response to this Report how and when this will be done. (Paragraph 99)

23.  Since the Government has encouraged industry to disclose retrospectively the results of past trials, we think that it should be prepared to do the same for the major trials that it has funded. We therefore recommend a retrospective audit of all public phase III trial grants awarded since 2000, followed by action to ensure that any failures to register or publish the summary-level results of these trials are rectified within 12 months. Any failures to correct these mistakes should be taken into account when considering future grant applications from principal investigators of previously unregistered or unpublished trials. In future, for grants awarded to fund phase III clinical trials we suggest that the MRC and the NIHR allocate a small proportion of funding to cover the time and resource requirements of preparing a manuscript for publication, and withhold this funding until the results of the trial are ready to be published. (Paragraph 100)

24.  We suggest that the academic publishing industry put in place robust measures to ensure that unregistered trials are not just rejected, but that the trial sponsor(s) and funder(s) are notified that the trial has not been properly registered. (Paragraph 101)

Current initiatives to increase clinical trial transparency

25.  In mandating trial registration, publication of summary-level results and publication of CSRs for commercial trials, we consider that the European Parliament's ENVI Committee appears to have reached a reasonable decision regarding the transparency requirements of the proposed EU Clinical Trials Regulation. (Paragraph 104)

26.  The Government should clarify why Department of Health or MHRA officials were not present at recent discussions relating to the EMA's revised transparency policy. We hope that the Government will be more fully engaged in the next stages of the development of this policy. (Paragraph 106)

27.  We agree with the Joint Committee that the Care and Support Bill should make the promotion of research transparency a statutory objective of the HRA and we recommend that the Government includes the necessary provision. (Paragraph 109)

28.  Research Ethics Committees should have a role in considering and monitoring compliance with transparency policies. As such, we welcome the HRA's new transparency policy and support, in principle, the proposals made in its May 2013 paper. We recommend that the HRA initially retains full responsibility for policing its own policies and ensures that all trials have been registered and published according to an agreed timeline, rather than performing checks on a sample basis. In addition, there must be penalties for non-compliance. We recommend that the HRA provides us with a progress update on implementation of its new transparency policy by the end of 2013. (Paragraph 110)

29.  We recognise the efforts of some members of the pharmaceutical industry, particularly GSK, to increase clinical trial transparency and hope that other companies will act in the same spirit in implementing industry-wide principles for responsible clinical trial data sharing. We suggest that all companies endorsing such principles agree and report on a common set of clinical trial transparency metrics each year in their annual reports. (Paragraph 113)

30.  We are supportive of the broad aims of the AllTrials campaign and agree that all clinical trials should be registered and their results reported. We suggest that the AllTrials campaign clearly set out what it considers a full trial report to contain, particularly when prepared for non-commercial purposes, so that its supporters can work together to achieve a specific set of common goals. (Paragraph 116)

Value-based pricing and the renegotiation of the PPRS

31.  Value-based pricing (VBP) is predicated on the idea that the Government is able to influence industry's behaviour through its spending power. We therefore consider VBP—and to a lesser extent the PPRS—to be tools that could also be used to encourage and reward industry for making its clinical trial data more transparent. The Government should consider ways in which clinical trial transparency could be incentivised in the future through VBP and the current renegotiation of the Pharmaceutical Price Regulation Scheme (PPRS). (Paragraph 118)

Incorporating emerging evidence into clinical practice

32.  Increased transparency is unlikely to lead to improved medical outcomes unless mechanisms are in place to ensure that emerging evidence is quickly and effectively incorporated into clinical practice. Given the high degree of reliance placed on NICE's guidance by health professionals, we consider it essential that this advice remains fully up to date and that processes are in place to ensure that emerging evidence is rapidly incorporated. The Government should ensure that, as improved transparency leads to ever greater volumes of trial data becoming available, NICE continues to receive the resources it needs to assimilate emerging evidence into its guidance in a timely manner. (Paragraph 122)


33.  We consider that more can and should be done to make the UK a more attractive location to conduct clinical trials. (Paragraph 123)

34.  We are confident that the Government is aware of these problems and the need to resolve them, but its promises have yet to be matched by effective action. We strongly urge the Government to act on our recommendations and put an end to these long-standing issues, so that the UK can continue to make progress towards being the location of choice for the global life sciences industry. (Paragraph 124)

35.  We call on the Government to take decisive steps, as outlined in this Report, to ensure greater transparency in all future trials conducted in the UK, in order to demonstrate to the rest of the world how effective solutions might one day be applied at a global level. (Paragraph 125)

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Prepared 17 September 2013