Science and Technology CommitteeWritten evidence submitted by the Department of Health

Introduction

1. The Government ensures the safety of patients in clinical trials via the regulator—the Medicines and Healthcare products Regulatory Agency (MHRA)—and Health Research Authority (HRA) while providing national infrastructure through the NHS to encourage clinical trials to be conducted in the UK.

2. Clinical trials required to test new medicines are regulated by MHRA. Regulation is governed by the EU Clinical Trial Directive which has been transposed into UK law.

3. The following evidence addresses the matters set out in the inquiry’s terms of reference.

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?

4. In recent years we have seen a decline in clinical trial activity in the EU. The number of clinical trials conducted in the EU fell by 25% between 2007 and 2011. In the UK, the number of trials fell by 22% over the same period. This decline cannot solely be attributed to the Clinical Trials Directive:1 an independent review by the Academy of Medical Sciences of the regulation and governance of health research found that “the governance arrangements within NHS Trusts are the single greatest barrier to health research”,2 which the Government is addressing through initiatives of its National Institute for Health Research (NIHR).3 However, the current legislation has had an effect on the cost and feasibility of conducting clinical trials and the complexity of the regulatory framework has been cited as a barrier.

5. The European Commission’s proposal for a Clinical Trials Regulation was adopted on 17 July 2012. The Commission’s stated aim in publishing the proposal was to boost clinical research in Europe by simplifying the rules for conducting clinical trials.

6. The Government welcomes much of what is included in the European Commission’s proposal for a Clinical Trials Regulation. We consider that the proposal has the potential to create a more favourable environment for the conduct of clinical trials in the EU, by making it easier to conduct trials in multiple Member States and introducing a proportionate and risk-adapted approach to clinical trials.

7. There are several elements that the Government is particularly pleased to see included in the proposal, including:

the introduction of risk-adapted regulation of clinical trials, including the introduction of the concept of low-intervention studies, the streamlining and simplifying of the safety reporting requirements and the adoption of a proportionate monitoring approach;

the introduction of one application for multi-state clinical trials replacing individual applications in different Member States which we believe has the potential to decrease the burden on researchers and promote the conduct of clinical trials in the EU (although we will be looking to improve the efficiency of the process); and

the concept of one single submission and one single decision replacing the current separate regulatory approval and approval by Ethics Committees. This concept is introduced for both single and multi state trials.

8. There are, however, aspects of the proposal that the Government has concerns over. For example, we will be examining in more detail the proposal to oblige Member States to set up a national indemnification mechanism that, on a not-for-profit basis, provides insurance cover for all clinical trials conducted in the UK, giving sponsors the choice between private insurance and a Government scheme.

9. As regards disclosure of clinical trials data, the Government fully supports the Commission’s ambition to increase transparency and views positively the elements of the proposal designed to do this, including through ensuring that the EU database should be publicly accessible and that there should be a presumption that the summary of the results of clinical trials be made available to the public through this database. The Government is considering whether further measures could be included in the Regulation to increase transparency.

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

10. The Health Research Authority (HRA) was established on 1 December 2011 as a Special Health Authority. The overarching purpose of the HRA is to protect and promote the interests of patients and the public in health research. The HRA protects patients from unethical research while enabling patients to benefit from research by simplifying processes for ethical research.

11. Through the National Research Ethics Service (NRES), the HRA provides for the ethical review of health research proposals including clinical trials, to protect the rights, safety, dignity and wellbeing of research participants and potential participants. The HRA also acts as a member of the UK Ethics Committee Authority (UKECA) by agreement with the four nations. UKECA has responsibilities for establishing, recognising and monitoring ethics committees that give an opinion on the ethics of research under the Medicines for Human Use (Clinical Trials) Regulations 2004.

12. The HRA is simplifying processes for research through cooperation with other bodies such as the MHRA to create a unified approval process for research approvals and to promote consistent and proportionate standards for compliance and inspection.

13. From 1 April 2013, the HRA will be taking on further functions relating to approving the processing of confidential patient information. The Government intends to legislate to establish the HRA as a non-departmental public body when parliamentary time allows, and clauses in the draft Care and Support Bill for this purpose have been published for pre-legislative scrutiny.

14. The Government is committed to transparency and the publication of research findings is a high priority area for the HRA. Ethics committee review already asks whether research will be registered on a public database, and how researchers intend to report and disseminate the results of that research. The decision by an ethics committee to give a favourable opinion includes consideration of these plans.

15. A summary of the final report on the research should be submitted to the main research ethics committee within one year of the conclusion of the research. The HRA also publishes research summaries of approved studies on its website to promote transparency in research, to encourage registration and publication and to provide a simple website publication of research approved by NRES in the UK.

16. The HRA intends to follow up on applicant-declared intentions to register and publish trial results. It intends to monitor compliance, to identify researchers, funders and institutions that are not registering or publishing approved research. The HRA is currently exploring how best to implement these improvements and safeguards, and expects to establish a new system in 2013.

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

17. Clinical trials required to test new medicines are regulated in this country by the MHRA. The current legal requirements placed on companies carrying out clinical trials relate largely to ensuring that the rights, safety and well-being of clinical trial subjects are protected, and that the data generated is robust. Companies are required by law to report serious, unexpected adverse reactions experienced by trial subjects which are thought to be related to the medicine under test. They are also required to report the outcome of such trials, including negative outcomes, to the regulator.

18. All clinical trials relevant to evaluation of the product concerned are required to be included in submissions for marketing authorisations for new medicines, whether the results are favourable or unfavourable to the product. This includes details of abandoned or incomplete studies and trials concerning therapeutic indications not covered by the particular application. This is a requirement in legislation.

19. Following marketing of a drug, the legislation provides clear requirements that any request from the regulatory authorities to the marketing authorisation holders (MAHs) for the provision of additional information, including data from clinical trials, necessary for the evaluation of the benefits and the risks afforded by a medicinal product is answered fully and promptly. There is also a legal requirement that new information, including data from clinical trials, that may necessitate changes to a medicine’s product licence are provided to the MHRA.

20. Recent changes to legislation have provided further clarity that the requirements for provision of data relate to both positive and negative clinical trials and data relevant to use in all indications and populations and includes data from trials when the product has been used outside of the terms of the marketing authorisation (off-label use).

21. The system of regulation of medicine is predicated on the provision of all relevant information to regulators in order to conduct their assessment of the safety, quality and efficacy of the application. The marketing authorisation holder is responsible in legislation for submission of all information relevant to the evaluation of the medicinal product included in the dossier submitted in support of their application. Each application is accompanied by a signed declaration confirming inclusion of all relevant information. The MHRA does not have evidence that there is systematic or large scale withholding of data, but has investigated cases in the past where clinical trials and safety data were not properly reported.

22. For example, the MHRA carried out an investigation into GSK’s compliance with legal obligations to report key safety information and on promotion of unlicensed uses of Paroxetine (Seroxat). The investigation concluded that GSK could and should have communicated safety information sooner than they did but that the law was not sufficiently clear to support legal action. In response, the UK legislation on reporting requirements was strengthened in 2008. European law has now also been strengthened, the latest changes coming into force in August 2012.

23. More recently, the European Medicines Agency (EMA) issued infringement proceedings against Roche in October 2012, following an inspection carried out by the MHRA earlier in the year, which found amongst other things that a significant amount of safety data from clinical trials had not been reported. The EMA’s Pharmacovigilance Risk Assessment Committee is currently reviewing data provided by Roche and whether there will be a change to the balance of risks and benefits of any of the medicines involved. The review will reach its conclusion in March 2013.

24. Regulated clinical trials also require a favourable opinion from an ethics committee. Research ethics committees (RECs) within NRES ask their applicants about the intentions to register, publish and disseminate the findings of the research; to make data and tissue available; and to tell participants about the outcomes of the research. Now that NRES is part of the HRA, the HRA plans to look at compliance against those stated intentions.

25. HRA is exploring with RECs the issues they consider when they ask about these intentions and the extent to which they consider them as part of their opinion. From April 2013, it will start a simple check through the final report RECs receive to see whether or not people have published and made the data and the tissue available as they said they would to the REC.

26. HRA recognises that there are a range of issues: a deliberate act to not publish or not make data available when it has been agreed is misconduct, if wilful; studies that would be only of an educational value and unsuitable to be published and interpreted; barriers to publishing where people report that it is much more difficult to get some types of studies, and potentially negative results, published. HRA is in dialogue with key stakeholders to tease out the issues and is planning an event in April 2013 to debate them, following which it will publish a position statement.

27. In evidence on 31 January 20134 to the Joint Committee scrutinising the draft Care and Support Bill that would establish HRA as an executive non-Departmental public body, the HRA chief executive, Dr Janet Wisely, said HRA would, with a view to building confidence in research, support having a role for the HRA in promoting transparency in research mentioned on the face of the Bill. The Government awaits the Joint Committee’s report and recommendations with interest and will give them careful consideration.

28. At an HRA event on 7 February, Sir Iain Chalmers, co-ordinator of the James Lind Initiative, presented evidence suggesting that:

around half the trials registered by 1999 had been published by 2007, irrespective of country, size, trial phase, or funder (ie non-publication is not peculiar to the pharmaceutical industry), though UK Government-funded research compared favourably, with the NIHR Health Technology Assessment Programme publishing nearly 100%;

trials are being unnecessarily repeated because researchers are not cumulating all the evidence before designing and embarking on further trials (ie increasing the publication of trials can help make available more of the evidence researchers need to take into account in carrying out effective systematic literature reviews that inform future research).

29. On 8 February, the HRA board agreed to sign the AllTrials.net petition,5 which calls for all trials past and present to be registered, and the full methods and the results reported.

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

30. The Government is fully supportive of transparency in the publication of clinical trial results including the proposal being considered by the HRA set out in paragraph 27. Academic trials for which funders or sponsors are responsible should ensure transparency in the publication of results for the trials they fund, as at present a significant proportion are not published. The Government also believes that an increase in voluntary action on the industry’s part will build public trust. The Government is therefore encouraged by voluntary schemes which individual companies are developing themselves. The Government is in discussions with all stakeholders, including industry, to see how publication of clinical trial data can be further encouraged, whilst being mindful of the need for a proper balance between data transparency and the legitimate concerns of industry.

31. Since July 2012, the MHRA has begun publication of all UK approved SPCs (Summaries of Product Characteristics) and PILs (Patient Information Leaflets) on its website.6 The MHRA is publishing this information in stages. This first wave is for products that have been checked and are up to date with the licensing history. Information on further products will be added over the coming months.

Since October 2005, MHRA has published public assessment reports following approval of new medicines, providing details of the information on which its decision to approve a marketing authorisation was based.7 The EMA publishes similar public assessment reports for all new medicines approved by the European Commission.8 Public assessment reports have been published in the EU since the adoption of the European Community Code for medicinal products9).

32. At European level, the EMA established the EudraCT clinical trial database in May 2004. Details of trials of investigational medicinal products are placed on EudraCT as part of the clinical trial authorisation process. Data extracted directly from EudraCT were made available to the public in March 2011 as the fully searchable EU Clinical Trials Register.

33. This Register gives public access to information10 on interventional clinical trials of medicines authorised in the 27 EU Member States and Iceland, Liechtenstein and Norway since May 2004. The database also allows the public to search for information on all clinical trials of investigational medicinal products authorised to be carried out outside the EU if these trials are part of a paediatric investigation plan. The Register does not, however, currently include the results from these clinical trials.

34. Through the NIHR, the Department of Health part funds the UK Clinical Trials Gateway, which enables patients and clinicians to search a number of different international trial registries including the US ClinicalTrials.gov registry.

35. As stated earlier, the Government is fully engaged in the negotiations on the new EU Clinical Trials Regulation and agrees with the Commission’s proposals to increase transparency. The Government is considering whether further measures could be included in the Regulation to increase transparency.

36. AT EU level, the EMA has been taking forward work to increase the amount of the information made publicly available. As a result, from late 2013 it is planned that EU Clinical Trials Register will also provide public access to summary trial results for all trials of investigational medicinal products on the Register (once these have been included in EudraCT).

37. In addition, the EMA has committed to the proactive publication of the data from future clinical trials supporting the authorisation of medicines. To address the practical and policy issues that will arise, including exactly which data fields will be published, the EMA is developing a policy on proactive publication of clinical-trial data. This is expected to come into force on 1 January 2014. The Government fully supports the work that is being done by the EMA.

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

38. Looking further afield than the UK and the EU, the Government is following developments in other countries. While registries of clinical trials have been set up in some countries (US, Australia and New Zealand), the issue of disclosure of results does not appear to have been fully resolved anywhere.

39. The US trials registry ClinicalTrials.gov created a results database in September 2008 to implement Section 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA 801), which requires the submission of “basic results” for certain clinical trials, generally not later than one year after the Completion Date. A BMJ paper (BMJ 2012;344:d7373) however found that only 22% adhered to the mandatory reporting rules.

40. We continue to monitor these developments as input into our own considerations on the issues.

February 2013

1 Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use

2 Academy of Medical Sciences. A new pathway for the regulation and governance of health research. Jan 2011. http://www.acmedsci.ac.uk/p47prid88.html

3 National Institute for Health Research. Faster, easier clinical research. http://www.nihr.ac.uk/systems/Pages/faster_easier_clinical_research.aspx

4 http://www.parliament.uk/business/committees/committees-a-z/joint-select/draft-care-and-support-bill/publications/

5 http://www.alltrials.net/

6 http://www.mhra.gov.uk/Safetyinformation/Medicinesinformation/SPCandPILs/index.htm

7 http://www.mhra.gov.uk/Publications/PublicAssessmentReports/index.htm

8 http://www.ema.europa.eu/ema/index.jsp?curl=/pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124

9 Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use

10 The details in the clinical trial descriptions available in the EU Clinical Trials Register include: the design of the trial; the sponsor; the investigational medicine (trade name or active substance identification); the therapeutic areas; the status (authorised, ongoing, complete).

Prepared 16th September 2013