Science and Technology CommitteeWritten evidence submitted by the Medical Research Council

Introduction

1. The Medical Research Council (MRC) is a UK-based non-governmental organisation funded by a grant-in-aid by the UK tax payer. The mission of the MRC is to improve human health and support economic growth through supporting the delivery of world class medical research. The MRC has a long-standing interest in the development and implementation of clinical trials; and is a major funder of academic clinical trials in the UK and internationally. The MRC is grateful for the opportunity to provide evidence to the Committee and is strongly committed to transparency in registration and publication of clinical trials.

The MRC and Clinical Trials Funding

2. The MRC funds a wide spectrum of medical research from basic and preclinical work through experimental medicine studies to early proof of efficacy trials. It also provides support for a range of population based epidemiological and public health studies. In considering the area of this inquiry it is important to have clearly agreed terminology. The term “Clinical trial” includes trials of investigational medicinal products (IMPs) as defined in the current UK and EU legislation. However, the Committee will be aware that there are also clinical trials that assess the safety or efficacy of medicines not defined as IMPs or of devices or other interventions, such as surgical techniques or behavioural therapies. There are also clinical studies—a term that MRC uses to describe other research involving people, often with the aim of understanding the pathways to disease or health but not assessing the safety or effectiveness of interventions. The need for clarity in these definitions is very important in determining the optimal means of ensuring transparency of clinical trial findings and assessing whether these are appropriately adopted.

3. The MRC has a long history of funding early and late phase clinical trials conducted in the UK and internationally. In 2006 there was an alignment of the remits of the MRC and the National Institute for Health Research (NIHR) in clinical trials funding in England. The MRC has responsibility for funding first-in-man and early phase trials and NIHR has responsibility for funding later phase trials through the Health Technology Assessment (HTA) panel with intermediate (efficacy and mechanism) trials being funded under the joint MRC-NIHR EME programme. The MRC also funds Global Health trials, in coordination with DFID, at both early and later stages.

Clinical Trial Findings and Data

4. In relation to questions about publication and transparency it is again important that consistent terminology is used to allow clarity as to what is required from all involved in any aspect of clinical trials. The MRC considers it is important to differentiate between:

(a)Clinical trial findings or outcomes—the final outcomes of the trial after appropriate statistical analysis. These should be published in accordance with the CONSORT guidelines,1 where these apply, and this is a requirement for MRC funded clinical trials.

(b)Research Datasets—these range from aggregated to anonymised to complete identifiable datasets for each participant. The MRC requires researchers to allow access to their research data in accordance with the Data Sharing Policy.2

MRC Funded Clinical Trials: Registration and Publication

5. The MRC is committed to promoting the highest standards of good practice in the conduct of the research that it funds. Prior to the adoption of the EU Clinical Trials Directive the MRC led the way in providing guidance on Good Clinical Practice for Clinical Trials (published in 1998) which included requirements for Independent Data Monitoring Committees and Trial Steering Committees for clinical trials. These two committees provide a very important role in independent review of clinical trial data, analysis and outcomes. The MRC was a founder member and has Board representation on ISRCTN—one of the first global clinical trial registers which accepts registration of all clinical trials assessing efficacy of any intervention (not restricted to IMPs) in people. The MRC also funds the CONSORT group which provides authoritative guidelines on transparent clinical trials reporting.

6. The MRC requires access to funded research data and sharing through policy requirements and supports this through the MRC Data Sharing Initiative.3 The MRC has been a lead partner in development of Open Access to research publications. The MRC initially developed the MRC-DH Clinical Trials toolkit4 (now hosted by NIHR) and continues to provide authoritative advice and guidance on best practice in all areas of clinical research through the MRC Regulatory Support Centre.5

7. These initiatives support our commitment to best practices in transparent reporting and access to research data, however, there may be further needs to address gaps in this area and the MRC is committed to providing resource to address these, acting with relevant partners and stakeholders.

8. The MRC policy on publication of clinical trial (and other clinical study) results states that:

Results of MRC-funded clinical studies (whether positive or negative) must be published within a reasonable period (generally within a year of completion) following the conclusion of the study. Results should be reported in accordance with the recommendations in the CONSORT statement [Schulz et al. BMJ 2010;340:c332]. Data should be made available in line with the MRC Policy on Data Sharing.

9. In the MRC data sharing policy it is stated that:

The MRC expects valuable data arising from MRC-funded research to be made available to the scientific community with as few restrictions as possible so as to maximize the value of the data for research and for eventual patient and public benefit. Such data must be shared in a timely and responsible manner.

10. Advances in information systems, grant coding and tracking are making confirmation of registration of clinical trials more accurate and less resource-intensive. In order to establish a current baseline for registration and reporting of MRC funded work we are undertaking an initial review of registration and publication of outcomes for MRC funded clinical trials. The baseline position from this review will also provide the opportunity to identify whether and how MRC policies and compliance review might need to be more explicit or stringent in relation to registration and publication. It is likely that there is scope for improvement in ensuring a joined-up approach from initial clinical trial registration to recording final outcomes and publications. The MRC is committed to supporting improvements that may be required, in partnership with other funders and sponsors across the spectrum of clinical trial funding.

Responses to the Questions of the Science and Technology Committee

Do the European Commission’s proposed revisions to the Clinical Trials Directive address the main barriers to conducting clinical trials in the UK and EU?

11. The proposed revisions will address only interventional clinical trials of IMPs and so are not relevant to non-IMP clinical trials. The main regulatory barriers to clinical research in the UK have been reviewed by the MRC in partnership with other funders and academic societies. The MRC, on behalf of RCUK, submitted two responses to the Academy of Medical Sciences Working Group6 which published the report “A New Pathway for Regulation and Governance of Health Research.7 The MRC supported the recommendations in this Report which identified that there are barriers to conducting clinical trials in the UK that arise from the current Clinical Trials Directive. However, further significant barriers do not stem from the Clinical Trials Directive, but from other aspects of the complex regulatory framework for clinical trials and other clinical research in the UK. This is particularly marked for clinical trials that occur across several sites and for those that require access to patient data for follow-up of outcomes. The underpinning issues include a lack of clarity on roles which are often duplicative; requirements for multiple NHS R+D approvals; and the particularly complex framework relating to access to and use of NHS patient data for clinical research.

12. The proposed revisions to the EU Regulations have been welcomed by the MRC and partner organisations.8 , 9 As drafted, they will address many of the barriers that have arisen from the current Clinical Trials Regulations. In particular, the revisions allow for a more risk-proportionate framework and improved harmonisation of review of multinational trials.

13. However, there are remaining issues in relation to the scope of the revised legislation, for example, in its definition of interventional clinical trials; in the delineation of risk categories and the requirements for reporting adverse events. Many of the proposed amendments to the draft legislation from the Rapporteur are welcome in addressing these issues although there is a risk that some of the amendments will further increase the regulatory burden without improving protections for patient safety, rights and well-being. In particular we are concerned at an emphasis on publication of Clinical Study Reports (CSRs) as an assurance of transparency. Such reports are provided for marketing submissions but not for the vast majority of clinical trials in the academic sector where their provision can take at least three months. Therefore, requiring this for each academic clinical trial would be a significant burden on academic funders.10 The CSR is unlikely to provide any more relevant information than ensuring publication of outcomes and access to appropriate final data, including the statistical analysis plan. The MRC will be submitting comments on the proposed amendments to the draft Regulations and can provide these to the Committee once available.

14. The proposed revisions will not address other regulatory barriers to research in the UK as outlined above, for example, access to records or Registers for follow-up of participants of a clinical trial. This currently requires approval from an NHS research ethics committee, from NHS R+D at each NHS Trust or body involved as well as the local Caldicott guardian and/or s251 approval. These approvals are not coordinated so duplicative or contradictory views can be provided and the timescale for completion of approvals is often long. We are extremely concerned that proposed amendments from the LIBE Rapporteur on the draft European Regulations on Data Protection may make such research much more difficult, if not impossible.

What is the role of the Health Research Authority (HRA) in relation to clinical trials and how effective has it been to date?

15. The role of the HRA includes the role previously delivered by the National Research Ethics Service (NRES) in coordination of governance and guidance for the NHS research ethics committees (RECs) which provide review of clinical trials. In addition, the HRA will oversee the s251 approvals process through which researchers request access to NHS health records when explicit consent is not in place. The HRA is a relatively new body and so there has been a very short period over which to judge its effectiveness.

16. Prior to establishment of the HRA, NRES fulfilled a commendable role in developing consistency across RECs; providing governance and streamlining approvals such that a single REC approval applied to all clinical trial sites in the UK. In addition, development of the Integrated Research Approvals System (IRAS) is widely recognised as a very positive step to a single portal for applications for approvals of research studies.

17. To date the HRA has shown a commitment to continue the positive approach of NRES and also to commence a review of the processes and requirements for research approvals in the UK. The proposed pilot on facilitating NHS research approvals is very welcome. The effectiveness of the HRA in improving the clinical trials environment will be predicated upon its ability to conduct such a review; to ensure that its findings can be implemented and effective collaboration with other regulators, in particular MHRA. An optimal approach that will streamline research approvals in the UK while protecting participant safety and rights may require amendments to legislation or Codes of Practice as well as significant changes in how other Regulators and NHS Trusts deal with local and central research approvals.

What evidence is there that pharmaceutical companies withhold clinical trial data and what impact does this have on public health?

18. There have been widely publicised examples of large fines imposed on pharmaceutical companies for not making relevant data available to Regulatory authorities. Where this has occurred there are potential risks to public health and to the progress of medical research in identifying new effective and safe therapies. Regulators need the most complete information available to take a balanced view as to the risk/benefit ratio of the use of a drug. In addition, other researchers benefit from knowing results from previous trials in order to avoid duplicative approaches. There may also be unidentified benefits of treatments in clinical trials that could be found from access to appropriate datasets. These last two benefits need to be balanced with the commercial interests of companies in proprietary data whereas the requirement of disclosure to regulators is absolute.

19. There have also been recent announcements of steps that companies are taking to increase transparency and access to trial data. One example is the recent announcement by GSK of its intention to allow access to clinical trial data.11

20. The MRC collaborates in research funding with industry partners and considers this a valuable and important approach to medical research. Such collaborations are funded under an MRC Industry Collaboration Agreement (MICA) which includes agreement on publication of results and data in accordance with standard MRC policies with the potential to recognise a period of exclusivity for commercially privileged information.12

21. It should be noted that there are also failures of non-commercial trials to publish outcomes or make data available in an appropriate and timely way. The factors and consequences of non-publication may differ from those relating to commercial trials. However, there is good evidence that trials which give negative results have been under-reported, leading to bias in the available body of evidence towards positive outcomes of new interventions. One consequence of this is seen when meta-analyses clarify from large, authoritative trials that the benefits of an intervention are lower than originally supposed, or absent altogether—revealing a waste of time and resources invested in conducting unnecessary further trials.

How could the occurrence and results of clinical trials be made more open to scrutiny? Who should be responsible?

22. In order to ensure transparency for the public, regulators and other researchers, the MRC strongly agrees with the need for all clinical trials to be registered on publically accessible registers. This applies to all clinical trials of investigational medicinal products as an absolute minimum. However, there should also be registration of non-IMP interventional trials, as provided by, for example, ISRCTN. Other approaches to enhance registers and make them more accessible are also valuable—for example the NIHR sponsored Clinical Trials Gateway. The MRC, with other Research Councils also makes publically available the full portfolio of funded research alongside information on outputs.13

23. It should also be mandated that the outcomes of all clinical trials are published in peer-reviewed journals or otherwise made publically accessible—this is a requirement of MRC clinical trial funding. Further, there needs to be clear linkage of publications of the results to the registration in order to facilitate discovery of the relevant data and also to provide a straightforward check on compliance. There also needs to be a means for clinical trial findings that are not accepted for peer-reviewed publication or that are not completed be made publically available.

24. The MRC is committed to ensuring that clinical trials are registered and that outcomes are accessible and will provide additional support for this. It is important that approaches to registration and publication of findings are easily accessible to all ensuring that a full overview of open clinical trials is available to patients as are the outcomes of all clinical trials relevant to their condition. There are improvements that could be made to the current approaches to these and the MRC will support the development of improvements needed in this regard in relation to its remit in clinical trials support.

25. Once optimal systems are in place to allow discovery of which clinical trials have been undertaken and what their outcomes are, there also need to be mechanisms to ensure compliance with requirements for all clinical trials be recorded in this way. The MRC has identified that in order to implement effective monitoring of compliance there needs to be appropriate and consistent definitions of projects to be tracked; effective systems to track projects from funding to trial registration to outcomes and sufficient resources to complete the analysis. Many of the challenges can be addressed through improvements to evaluation and IT systems.

26. The MRC strongly supports the requirement for researchers to facilitate access to appropriate clinical trial data to inform and support further research and to review clinical trial findings. The mechanisms by which such access should occur are currently under discussion and expert reports from the Caldicott review, the Royal Society and European Medicines Agency (EMA) are due to be published in the first half of 2013 and will inform conclusions on the preferred model. It is clear that such access needs to provide a straightforward and timely route to disclosure of usable datasets that do not breach participant confidentiality; vitiate their consent or undermine data integrity. One approach, that MRC has endorsed, is to use “safe havens” to store, collate and provide access to single or combined datasets. There are also examples of Centres of Excellence that facilitate access to requested data without transferring to a safe haven—as is the case for the MRC Clinical Trials Units. Whichever mechanisms are adopted, it is important to ensure that the data made available are high quality, reliable and provided in a usable format within a reasonable timeframe. The MRC has supported development of “safe havens” and appropriate standards of research data for sharing through the MRC Data Sharing Initiative.

27. The question of whether these datasets should be made openly and publically available without any access “gatekeeper” or redaction is more complex. The key factors to be considered include the information and consent provided to and given by clinical trial participants; the risks of inadvertent identification of participants (particularly pertinent to smaller sample groups; rare diseases or stratified approaches). There is also the risk that data may be used for methodologically flawed research which may be linked to the original research group or funder to give an impression of quality or authority; or which might be used to promote agendas which the trial participants would not have consented to. In addition, there is a serious risk of deliberate misuse, such as deductive identification of trial participants to link to their health details or outcomes. The MRC’s view is that the use of neutral “safe havens” or Centres of Excellence to curate and provide data through an independent access procedure provides the best way of balancing the need to respect the concerns of participants; to ensure governance and ownership of research is clear; and to realise the benefits from broadening access to clinical trial data. The MRC has welcomed the increased emphasis on the potential benefits of research participation for patients in the NHS Constitution and recognises the desire of many people to be more aware of research outcomes and current clinical trials relevant to their condition. The MRC would welcome enhanced measures to make information about relevant clinical trials more easily available to patients, clinical teams and carers at the point of care.

Can lessons about transparency and disclosure of clinical data be learned from other countries?

28. The position in the EU is being reviewed by EMA building on its workshop in November 2012. The MRC does not have further specific examples to provide at this point.

February 2013

1 http://www.consort-statement.org

2 http://www.mrc.ac.uk/Ourresearch/Ethicsresearchguidance/datasharing/index.htm

3 http://www.mrc.ac.uk/Ourresearch/Ethicsresearchguidance/datasharing/index.htm

4 http://www.ct-toolkit.ac.uk/

5 http://www.mrc.ac.uk/Ourresearch/Ethicsresearchguidance/RegulatorySupportCentre/index.htm

6 Academy of Medical Sciences review of regulation and governance of medical research: Call for evidence: June 2010—http://www.mrc.ac.uk/Utilities/Documentrecord/index.htm?d=MRC007048 and August 2010: http://www.rcuk.ac.uk/documents/submissions/RegulationMedicalResearch_Aug2010.pdf

7 http://www.acmedsci.ac.uk/index.php?pid=99&puid=209

8 Joint statement on the Clinical Trials Regulation: http://www.acmedsci.ac.uk/p47prid118.html

9 MHRA consultation on the draft EU Regulation for Clinical Trials for Medicinal Products: December 2012: http://www.mrc.ac.uk/Utilities/Documentrecord/index.htm?d=MRC009007

10 The MRC Clinical Trials Unit completes an average of eight trials a year. Provision of a CSR for each would require up to £100,000 per annum.

11 http://www.bmj.com/content/345/bmj.e6909

12 http://www.mrc.ac.uk/Fundingopportunities/Grants/MICA/Specification/MRC005438#P26_1314

13 RCUK Gateway to Research: http://gtr.rcuk.ac.uk/

Prepared 16th September 2013