Science and Technology CommitteeWritten evidence submitted by the British Heart Foundation

Summary

The proposed replacement of the Clinical Trials Directive with a new Clinical Trials Regulation presents an opportunity to significantly improve how research is regulated in the UK.

The draft Regulation proposed by the European Commission requires further refinement to ensure that additional clarity is added to ensure a proportionate approach to regulating clinical trials.

Several barriers on regulation and governance in the UK still need to be addressed, in particular NHS Research and Development (R&D) permissions, which should be prioritised by the Health Research Authority.

Ensuring that research and clinical trial data are publicly open to scrutiny is important to ensure research findings are both robust and transparent.

Failure to publish research and clinical trial data can hinder medical and scientific progress and have a damaging effect on public health.

Peer-review is important in helping to ensure that the data in published research are robust.

Action to improve transparency needs to be proportionate in nature so as not to add to the regulatory burden medical researchers currently experience.

1. The British Heart Foundation (BHF) is the nation’s heart charity. From new discoveries about how the heart develops in the womb, to developing the treatments that could mend broken hearts in the future, we are the single biggest independent funder of cardiovascular research in the UK—funding around £100 million each year.

2. We welcome the opportunity to respond to the Committee’s inquiry on clinical trials and the disclosure of data. The UK is a world-leader in medical research and has historically been an attractive location for researchers to carry out clinical trials for new treatments for a range of diseases—including cardiovascular disease. However, unintended consequences resulting from legislation such as the Clinical Trials Directive have made it more difficult for researchers funded by the BHF to conduct clinical trials in the UK. The Clinical Trials Regulation proposed by the European Commission to replace this legislation has the potential to significantly improve how research is regulated within the UK—providing effective safety for patients and greater transparency in results.

Q1: 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?

3. A number of the issues surrounding the existing Directive are addressed in the proposed Regulation, which we welcome. We have signed a joint statement from non-commercial and commercial organisations on the Proposal for an EU Regulation on Clinical Trials, which identifies these positive changes and highlights further areas where clarity is needed.

A Risk-based Approach to Regulation

4. A key criticism of the existing Directive has been the “one size fits all” approach which fails to discriminate between trials of varying levels of risk. This approach currently applied by the Directive has proved to be unfit-for-purpose, and has exacerbated the problems associated with the Directive’s broad scope. The review of regulation and governance published by the Academy of Medical Sciences two years ago highlighted a number of examples where a lack of a proportionate approach has been shown to be problematic for UK medical research.1

5. Introducing the concept of a low-interventional trial is therefore an important step towards achieving a risk-based approach in clinical trials legislation. Many clinical trials can involve medicines where their safety has already been established—this is in contrast to, for example, a new drug being tested in people for the first time. It is appropriate that the Regulation reflects this range in risk. However, uncertainty remains over the extent to which the proposed Regulation will adapt the requirements for trials of marketed products used for a new purpose, which are not included in the low-interventional trial category. Further clarity is therefore needed on the two category risk based approach proposed in the draft Regulation.

6. It also needs to be established whether there is sufficient flexibility to apply greater risk differentiation within the Regulation. A recent paper by the MRC, DH and MHRA proposed that the potential risks of participation in a clinical trial should be balanced against the level of risk that a trial participant would be exposed to outside of the trial—suggesting a three-level categorisation of risk.2 The bi-partite system suggested in the proposed Regulation could mean that the majority of studies would be placed within the high risk group. A three-level categorisation would allow greater scope for the proportionate regulation of research. We believe the Commission should give this proposal greater consideration.

Clarity in the Scope’s Definitions

7. Inconsistent interpretation of the current Directive across the EU has to date contributed to inconsistencies in application. It is important that the definitions proposed in the Regulation do not result in similar problems. Additional clarity would therefore be helpful on the new concept of “clinical studies” to reduce the possibility of confusion in these proposals.

8. Similarly, some of the terms used in the proposed Regulation will add confusion without further clarification. For example, “low intervention trials” and “non-interventional trials” are not scientifically meaningful terms. There is a danger that confusion around terminology will lead to interpretations of the final regulation that could inhibit research.

IT Systems Associated with the Regulation

9. The timelines that have been set by the proposed Regulation both for Member States to gain ethical and regulatory approval and also for sponsors to respond to regulatory queries are ambitious. We welcome the efforts to speed up the assessment process—efficient operation of the IT systems associated with the single portal proposed will be essential to ensure this. We believe the EU institutions should therefore outline to the community how it will go about creating and implementing the IT systems associated with the Regulation. The introduction of a single application portal with a single application dossier is particularly attractive to streamlining and harmonising the application process for clinical trials, so it is important that this is sufficiently supported by the necessary infrastructure.

Co-sponsorship

10. The requirement under the current Directive for trials to have a single sponsor for the application continues to provide practical difficulties for academic sponsors, as it is difficult for an academic sponsor to hold the responsibility for clinical trials performed in another Member State—particularly when there have been differences in the way the Directive has been implemented. We therefore welcome the introduction of the concept of co-sponsorship for clinical trials in the proposed Regulation.

Emergency Trials

11. In addition, the current Directive does not sufficiently address the issue of consent for clinical trials in emergency situations—in situations such as myocardial infarction where it may not be feasible to obtain informed consent from the patient. Since the Directive was transposed, the UK legislated to allow clinical trials in emergency situations, with many other Member States similarly amending their own legislation. We are pleased that this gap is being addressed in the proposed Regulation, though the specific requirements in the proposals that this type of trial should not impose more than minimal additional risks or burdens on patients are potentially too broad. We believe the requirements for entry into clinical trials in emergency situations should be reviewed to ensure they do not inadvertently limit the intended provision.

Indemnity Scheme

12. The introduction of a Government-run indemnity scheme for clinical trials is of potential interest—a more detailed outline of this proposal from the Commission needs to be provided before it is given full consideration.

Improvements to Regulation and Governance in the UK

13. While there are a number of improvements that can be made at European level to the regulation of clinical trials, there remain several barriers specifically within the UK that contribute to delays in clinical trials.

14. The BHF strongly supports the Academy of Medical Sciences’ report on research and governance, which has identified the main obstacles to medical research in the UK. The complexity of the regulatory pathway, delays and duplication for permissions from NHS Trusts, and the problems within the culture of the NHS to facilitate research were all areas that we highlighted in our response to the Academy’s call for evidence. The creation of the Health Research Authority (HRA) is the first step towards helping to simplify the regulatory pathway, facilitate research and ensure that governance does not impede progress. We believe the Government should ensure the full implementation of the Academy’s recommendations is completed as soon as possible.

15. A key barrier to date has often been that research is not seen as a core function by many within NHS Trusts. A much more research-oriented mentality is needed, particularly among health service managers, to ensure that R&D departments promote and facilitate research. The Health and Social Care Act 2012 placed duties on all the main commissioners and providers to promote research—it is vital that this supportive attitude towards research is now embedded into practice on the ground.

16. The UK Government has taken a number of encouraging steps to implement many of the recommendations of the Academy of Medical Sciences review, but there are several that have not been implemented that would further streamline regulation and governance. But we remain concerned that some of the roles recommended for a single health research regulator, specifically around incorporating NHS R&D permissions, have not been included within the remit of the new HRA. Researchers continue to raise this as a major barrier to cardiovascular research being conducted. One recent example is the BHF-funded PATHWAY study (Prevention And Treatment of resistant Hypertension With Algorithm based therapy). This study took more than a year to get started because of delays caused by governance and NHS funding issues. The study comprises of three clinical trials in eight centres—five based in England, three in Scotland. The longest delays occurred in agreeing the contracts between the lead site at the University of Cambridge and seven other centres. For combined university and health trust sign-up, some sites wanted separate agreements for each trial, which would have amounted to 21 agreements for the University of Cambridge to prepare for just one grant.

Using Patient Data to Help Clinical Trials

17. Patient records provide useful data that medical researchers can use in a variety of different ways, from evaluating current healthcare interventions to looking at links between disease and someone’s lifestyle. These data are also used to help identify patients that would potentially benefit from participation in clinical trials. The NHS holds the medical records for the largest single patient pool in the world and therefore potentially provides researchers in the UK with an invaluable resource for research. There are a number of barriers currently preventing researchers from readily using these data to their full potential in medical research, which we have highlighted in our report Clear and Present Data.3 These concerns have also been reflected in our response to the Department of Health’s Information Governance Review.

Q2: What is the role of the Health Research Authority (HRA) in relation to clinical trials and how effective has it been to date?

18. As part of the Academy of Medical Sciences review of regulation and governance, we responded to the second call for evidence highlighting our support in principle for the creation of a single research regulator, which could provide a number of opportunities to improve the system of approval. We hope that the HRA will develop a streamlined system whereby there is a single point of entry and exit for researchers’ applications.

19. It is still too early to judge the effectiveness of the HRA in improving how research is regulated in the UK. However, we are encouraged that one of its first initiatives has been to commence a study to examine the feasibility of establishing an HRA assessment that would combine and replace aspects of the current review by NHS R&D and Research Ethics Committees (RECs). While this has the potential to speed up the approval process, ultimately we believe bringing NHS R&D permissions within control of the HRA, in line with the recommendations of the Academy of Medical Sciences review, would have the greatest benefit in improving this barrier.

Q3: What evidence is there that pharmaceutical companies withhold clinical trial data and what impact does this have on public health?

20. The pharmaceutical industry makes a vital contribution to medical research in the UK, and has been key to the development of many of the treatments used in the treatment of cardiovascular disease today. As a funder of medical research, the BHF predominantly supports the basic science and pre-clinical work that results in new medicines reaching the stage where it is tested in clinical trials. It therefore often takes the resources provided by a pharmaceutical company to conduct the large-scale clinical trials required to ensure safety and efficacy before a new medicine is ultimately prescribed to patients.

21. Clinical trial data are essential in establishing whether a new treatment is both safe for patients and effective. Ensuring that these data are publicly open to scrutiny is important to ensure research findings are robust and transparent. Publishing data in a form where this can be achieved is therefore essential.

22. However, there are some examples in the past where clinical trial data have been withheld by pharmaceutical companies. One instance within cardiovascular research concerns anti-arrhythmic drugs. Several Class 1 anti-arrhythmic drugs were the subject of two Cardiac Arrhythmia Suppression trials (CAST and CAST-II) that ran from 1986. The trials found that these Class 1 anti-arrhythmia drugs, rather than reduce mortality, actually increased mortality in the results published in 1991.4 The finding led to a dramatic reduction in the usage of these agents, particularly in Europe and Australasia.5 Earlier unpublished research from 1980 on another Class 1 anti-arrhythmia drug could have highlighted the dangers posed. This research looked at the use of the drug lorcainide in 95 patients with suspected acute myocardial infarction in a double-blind study, and while finding it to be an effective anti-arrhythmic agent found that there were nine deaths among the 49 patients treated with lorcainide compared with only one in the patients given placebo. An analysis part-funded by the BHF found that the results of this unpublished study were consistent with those from the later CAST and CAST-II trials.6 This highlights the importance of publishing results from clinical trials, as this mortality link could have potentially been established earlier. The issue of pharmacovigilence—whereby the safety and efficacy of drugs or devices used in healthcare is monitored—is also one where better access to patient records would be beneficial.

23. Failure to publish research and clinical trial data can therefore hinder medical and scientific progress and have a damaging effect on public health. Clinical trial data showing that a particular treatment is not effective are just as useful to research as data showing a benefit. Much of the clinical research in the UK is undertaken by academic and NHS clinicians with no financial interest in the outcome of that research, but the importance of publishing trial results applies to both commercial and non-commercial research. We recognise that transparency is an important issue for clinical trials—not only for those that make use of the results, but also for those that fund, conduct and participate in trials. For research that we fund, our conditions of award state that the findings from the research funded by the grant should be made freely available to the broader scientific community as soon as possible. In addition, the conditions state that grant holders must comply with the BHF’s Policy on Open Access and deposit within Europe PubMed Central an electronic copy of each paper funded wholly or in part by the BHF, which is accepted for publication in a peer reviewed journal, within six months of publication.

Q4: How could the occurrence and results of clinical trials be made more open to scrutiny? Who should be responsible?

24. Public registration of clinical trials is important in ensuring transparency and researchers in the EU have a legal responsibility to register clinical trials of investigational medicinal products on the EudraCT clinical trials database. This registration is also a pre-requisite for applying for authorisation from the MHRA and for research ethics committee approval. Information on many UK trials that are currently recruiting is also included on the online UK Clinical Research Network portfolio database, which is beneficial in helping patients find out about suitable clinical trials to take part in. The EU Clinical Trials Register website was also launched to provide the public with information held in the EudraCT database of clinical trials.

25. Sponsors of trials also have a legal responsibility under the Medicines for Human Use (Clinical Trials) Regulations 2004 to provide an end-of-trial report 12 months from the end of the trial. The EudraCT database does not, however, collect the results of clinical trials and there is no single place where clinical trial results are published. Current plans from the European Commission would lead to EudraCT collecting results and making them publicly available.7 This could go some way towards improving transparency.

26. It is important that published clinical trial data accessible to the public is in a form that is of use to researchers and has been collected using sound clinical trial methodology. Publishing data that is not sufficiently robust can be potentially damaging because such data may lead to misinterpretation and incorrect conclusions as a result. Peer-review in this regard is therefore important in helping to ensure that the data are robust, which normally takes places via journals.

27. Ideally, clinical trials would publish results within a year of completion, but publishing data can be delayed for valid reasons—for example, more data may be required or there may be questions from reviewers during the peer-review process that require a resolution.

The act of finalising results can therefore take time, particularly if this involves presentation in a series of papers. This also often occurs alongside other pressures on researchers. For example, the reports of the Heart Protection Study took substantial time to write, at a time when those that conducted the trial were conducting other trials during this period.

28. As highlighted above, medical researchers currently experience a complex environment for regulation and governance in the UK. Legislation has, as shown by the Clinical Trials Directive, been disproportionate in its application on medical research. Any actions taken to improve transparency of clinical trial data therefore need to be proportionate in nature—a one-size-fits-all approach on publication within a certain timeframe is unlikely to be appropriate if it fails to take into account the consideration of large-scale trials. The issue of improving transparency for clinical trials should also not be taken by the UK in isolation—the new Clinical Trials Regulation provides a means for this to be applied across all Member States.

February 2013

1 Academy of Medical Sciences (2011) A new pathway for the regulation and governance of health research

2 Medical Research Council, Department of Health, Medicines and Healthcare Products Regulatory Agency. Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products; 2011. Available at: http://www.mhra.gov.uk/home/groups/l-ctu/documents/websiteresources/con111784.pdf

3 British Heart Foundation. Clear and present data; 2012. Available at: http://www.bhf.org.uk/patientdata

4 Echt D S, Liebson P R, Mitchell L B, Peters R W, Obias-Manno D, Barker A H, Arensberg D, Baker A, Friedman L, Greene H L. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 Mar 21;324(12):781-8. Available at: http://europepmc.org/abstract/MED/1900101

5 Campbell T J, Williams K M. Therapeutic drug monitoring: antiarrhythmic drugs. Br J Clin Pharmacol. 1998 October; 46(4): 307–319. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1874159/

6 Cowley A J, Skene A, Stainer K, Hampton J R. The effect of lorcainide on arrhythmias and survival in patients with acute myocardial infarction: an example of publication bias. Int J Cardiol 1993, 40(2):161-166. Available at: http://europepmc.org/abstract/MED/8349379

7 http://ec.europa.eu/health/files/eudralex/vol-10/2012_302-03/2012_302-03_en.pdf

Prepared 16th September 2013