Science and Technology CommitteeWritten evidence submitted by the Centre for Evidence-Based Medicine, University of Oxford

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?

1. Clinical trials affect health through the formation of new knowledge, and whilst a thriving research sector is fundamental to the delivery of clinical outcomes it also supports economic growth. Research budgets form a substantial portion of the budgets of developed countries: somewhere between 1.5% and 3% of GDP. Moreover, in the modern world health care is big business, on average 10% of GDP is spent on health goods and services in developed countries, and health care is currently the largest and fastest-growing industry in the world.

2. Given the importance of health care research and clinical trials, it is therefore not surprising that self-interests in research combined with increased global competition can undermine scientific integrity. As a consequence regulatory systems, which aim to underpin research, are under considerable strain. For instance, the US Food and Drug Administration and the European Medicine Agency require drug testing and demonstration of safety, yet it is largely up to the country hosting trials to ensure procedures are sound and ethical.

3. Clinical trials and drug studies are big business, valued at $30 billion across 105 countries, and in less developed countries the number of trials is growing rapidly. Yet, in direct contrast, the number of drug trials in the UK has fallen substantially, from 728 in 2008 to 470 in 2010.

4. This suggests a potentially worrying global trend whereby expediency in the conduct of trials, for example by minimising regulation in different countries around the world assumes a greater value than mechanisms to ensure that trials are conducted with integrity and quality.

5. The proposal for a regulation of the European Parliament and of the council on clinical trials on medicinal products for human use and, and repealing Directive 2011/20/EC highlights the problems that have occurred. The substantial increases in administrative burdens required in the EU at the outset of a clinical trial, lead to an increased delay for launching a clinical trial by 90%, which now takes on average 152 days.

6. This length of delay is untenable and directly contributing to relocation of many trials outside the EU and the UK, to no doubt less burdensome environments. In addition, the near 100% increase in administrative costs have not demonstrated parallel increases in safety and highlight all that is wrong with the current system. Too burdensome, too slow and beset with unnecessary administration without clear upsides.

7. The current proposals, laid out in the EU clinical trials directive do little to reduce this administrative burden. Indeed they will probably add an overly complex layer to suit just one type of trial, the multicentre pan-European studies that form only a fraction of the trials undertaken. Given there is no provision with the directive to cut the time to recruitment there is little to recommend within its current framework.

8. For industry, time is money and adding at least 150 days to the start of a trial means there is a loss of the equivalent time in direct sales. Therefore it is not surprising that there is a haemorrhaging of trials to less burdensome environments.

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

9. It is too early to tell if the HRA has been effective, but there are a number of points worth outlining within its current remit. The role of the HRA is to streamline the burden of research whilst protecting patients and public taking part in research.

10. The HRA needs to be held accountable for its research Support Services framework directive that includes a 70-day benchmark to recruit first patients for trials. Yet, it is unclear who has oversight for this function and exactly how the HRA is to deliver on this target. This is an ambitious target; but, if it fails on this remit, it should be deemed to be overall a failure. If it doesn’t stick to this clear mandate it risks adding an increase to the layers of bureaucracy, particularly given its alignment and role to deliver on the EU clinical trials directive and its application.

11. This target, of 70-days is currently unobtainable for drug trials. 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. Currently a funded trial requires the following permissions or approvals:

Peer review (no time limits).

Ethics (60 days approval time).

Research and development approval (30 days to get back) no time limits for local trusts.

MHRA (28 days for 1st report).

University sponsor (one week).

Service support costs (no time limits).

PCT approvals (no time limit).

Site participation (no time limits).

All of these specific requirements take considerable time and given there are many steps in the process, which require approvals without time limits; dealing with these should be the current priority of the HRA. Note that only one process, namely university sponsorship, currently has a realistic sense of urgency around its deliverables. There is no reason that many of the processes could be brought in line with a seven-day rule, with streamlining of the forms.

12. There is nothing within the HRA remit to highlight poor publication practices. If the HRA is to protect patients then it should ensure that all trials are published in a timely manner, thus preventing further unnecessary research for treatments that may be found to be ineffective and or harmful. Yet, there is a strong sense the HRA cannot deliver on this task and has stated that it does not have the appetite for the task at hand.[1] This is an error of judgement on the HRAs part, as ensuring timely open publication is one of its chief remits. If it is not, then it is hard to understand what is the exact purpose of the HRA.

13. The HRA has the provision to operate in a closed manner. This ability to operate in a non-transparent manner is a mistake and should be changed.[1] The Authority must make such reports to the Secretary of State in such manner and at such time as the Secretary of State may direct, and must furnish to the Secretary of State such information as the Secretary of State may from time to time require.[2] A meeting of a committee or sub-committee of the Authority is not to be open to the public. The Authority may, by resolution, exclude the public from a meeting (whether during the whole or part of the proceedings) whenever publicity would be prejudicial to the public interest by reason of the confidential nature of the business to be transacted or for other special reasons stated in the resolution and arising from the nature of that business or of the proceedings.

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

14. Whilst modern medicine delivers great benefits to society, its harms due to the withholding of data often prove devastating—with numerous incidents, ranging from thalidomide and antiarrhythmic drugs to Cox II inhibitors. Work from several investigators have highlighted the problems associated with withheld data in which poor regulatory practices have led to (and continue to lead to) direct patient harm, excess costs and delays in the delivery of effective treatments.

15. Firstly, the extent of underreporting should not be underestimated. A study of 546 drug trials, published between 2000 and 2006 reported only 2/3rds had published their results. Rates of trial publication within 24 months of study completion ranged from 32% among industry-funded trials, to 56% among non-profit or non-federal organization–funded trials.[2]

16. A further analysis of trials listed on Clinical Trials.Gov, found that of 677 trials completed by 2007 only 46% were published in a peer reviewed biomedical journal, indexed by Medline, within 30 months of trial completion.[3]

17. Mandatory reporting of trials appears to have made little difference. For example, the overall rate of compliance with the mandatory reporting rate for 2009 trials listed on Clinical Trials.gov within one year following completion, is only 22%.[4] A further study of clinical trials.gov data between 2009 and 2010 reported that only 52% of 152 trials had associated publications within two years after posting.[5]

18. Secondly, Six recent case studies are outlined which highlight the problem and the harm caused: (more cases studies can be provided upon request).

Rofecoxib: failure to disclose evidence of harm

19. Research by Psaty et al published in JAMA is an example of the importance of withheld data. This case study, by reviewing information provided by the FDA, demonstrated two pivotal published articles of rofecoxib did not include analyses of mortality data, and because of this the studies wrongly concluded rofecoxib is “well tolerated”.

20. In direct contrast, and at the same time as publication, the company’s internal analyses of pooled data from the same trials identified a significant increase in total mortality. This equated to an overall three-fold increase in mortality of 34 deaths among 1,069 rofecoxib patients compared to 12 deaths among 1,078 placebo patients (HR, 2.99; 95% CI, 1.55–5.77).

21. What is striking about this case is these mortality analyses were neither provided to the US FDA nor made public.

22. Of more concern was the data submitted to the FDA in a Safety Update Report in July 2001. This data, submitted by the sponsor, reported 29 deaths (2.7%) among 1,067 rofecoxib patients and 17 deaths (1.6%) among 1075 placebo patients, thus masking the true mortality difference.

Rosiglitazone: research misconduct and failure to disclose harms

23. Rosiglitazone is a thiazolidinedione class of drug which was marketed as an addition and/or stand-alone drug to the oral hypoglycaemic agents available to treat patients with uncontrolled type 2 DM. Annual sales peaked at approximately $2.5 billion in 2006; the drug is now withdrawn due to safety issues.

24. Internal GSK company emails reveal a submitted journal publication, which showed rosiglitazone increased the risk of myocardial infarction, was leaked to GSK. GSKs internal analysis and their company statisticians confirmed the findings and internal company emails demonstrated the company had already come to similar conclusions yet failed to disclose this publically.[6,7,8]

Oseltamivir: Lack of access to full trial programmes

25. Further to these investigations we have taken a similar approach to Psaty[9] in the analysis of the effects of oseltamivir.[10] Only in response to substantial publicity generated by a joint BMJ-Channel 4 News investigation of oseltamivir, did Roche publicly pledge to make its unpublished full clinical study reports available.[11] The subsequent work has gone on to find a high risk of publication and reporting bias in the trial programme of oseltamivir, which significantly undermines the results published in journals.

Paroxetine: withholding trial data and risk of suicide

26. GSK was caught withholding clinical trial data showing Paroxetine increased the risk of suicide in young people. The Chief Executive of the MHRA said, “I remain concerned that GSK could and should have reported this information earlier than they did”.[12]

Reboxetine: effects of publication bias

27. Reboxetine was eventually found to be an ineffective and potentially harmful antidepressant after researchers found that 74% of the data from clinical trials had been suppressed during the lead up to the approval of the drug for the treatment of severe depression.[13]

Rimonabant

28. In 2007, the FDA’s concluded the French manufacturer Sanofi-Aventis failed to demonstrate safety of rimonabant and did not recommend the anti-obesity treatment. The drug had been on sale in Europe for one year previously. The company spent nearly four years withholding data on the risks and benefits of two weight-loss drugs. Eventually, Acomplia had to be taken off the market: its harms outweighed its benefits.[14]

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

29. Globally the development of new treatments is grinding to a halt. The lack of transparency means ineffective treatments continue to waste scarce healthcare resources. Putting it simply, we currently have a system that favours conflicts and deters transparency. Therefore, making the results of trials more open will not be, and should not be seen as a simple process. Voluntary arrangements will have little impact on the current status quo and will be little more than window dressing. In addition, given the complexity of the current problem it is highly likely that a number of solutions will be required.

30. The following highlights five possible means of action and there are likely to be more:

31.(a) Legislation is required to make clinical study reports, of all completed trials, available within one year of trial completion.

32.(b) NICE should have a remit to ensure that all the data is provided and made transparently available for any drugs that they provide guidance upon.

33.(c) EMA aims to ensure that by 2014 that all data and clinical study reports they receive shall be made available. However, this does not cover pre 2014 trials. Therefore they should ensure that a full list of clinical study reports in their possession, going back 20 years are posted on the internet, and allow access for these clinical study reports upon request.

34.(d) The MHRA should have a responsibility to ensure all post marketing studies, required by regulators are up to date and published in full.

35.(e) Ethics committees should have a responsibility to follow up all trials that have been approved under their committees. Investigators, sponsors, manufacturers not complying should be barred form further ethical review until the position is rectified.

36.(f) There is a need to set up an independent body to oversee the standards and practices related to publication transparency.

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

37. The simple answer is no. This is a global phenomenon, riddled with conflicts, and in need of robust legislation to tackle the problem. As highlighted, the size of the market, the profits to be made simply means the current system is not fit for purpose. No one has yet come up with a robust solution to the problem and there is a direct to be more transparent in terms of clinical trial results.

Conflicts of Interest

Carl Heneghan and Matthew Thompson have received research funding from the National Institute of Health Research for work related to Tamiflu and access to trial data.

February 2013

References

1. [http://policyblog.amrc.org.uk/2013/02/01/talking-about-the-health-research-authority/]

2. Bourgeois F T, Murthy S, Mandl K D. Outcome reporting among drug trials registered in ClinicalTrials.gov. Ann Intern Med. 2010 Aug 3;153(3):158–66.

3. Ross J S, Tse T, Zarin D A, Xu H, Zhou L, Krumholz H M. Publication of NIH funded trials registered in ClinicalTrials.gov: cross sectional analysis. BMJ. 2012 Jan 3;344:d7292.

4. Prayle A, Hurley M & Smyth A R. Compliance with mandatory reporting of clinical trials results on ClinicalTrials.gov: cross sectional analysis. BMJ 2012; 344:d7373

5. Deborah A Zarin, Tony Tse, Rebecca J Williams, Robert M Califf, and Nicholas C Ide. The ClinicalTrials.gov Results Database—Update and Key Issues. N Engl J Med 2011; 364:852–860March 3,

6. United States Senate, M.B., Chairman, Chuck Grassley, Ranking Member., Staff Report on GlaxoSmithKline and the Diabetes Drug Avandia. Prepared by the staff of the Committee on Finance. http://finance.senate.gov/press/Gpress/2010/prg022010a.pdf.

7. Nissen, S E and K Wolski, Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med, 2007. 356(24): p. 2457–71.

8. Nissen, S E, Setting the RECORD Straight. JAMA, 2010. 303(12): p. 1194–5.

9. Psaty, B M and R A Kronmal, Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment: a case study based on documents from rofecoxib litigation. JAMA, 2008. 299(15): p. 1813–7.

10. Jefferson, T, et al, Ensuring safe and effective drugs: who can do what it takes? BMJ, 2011. 342: p. c7258.

11. Cohen, D, Complications: tracking down the data on oseltamivir. BMJ, 2009. 339: p.b5387.

12. http://www.nelm.nhs.uk/en/NeLM-Area/Evidence/Patient-Safety/500721/

13. http://www.bmj.com/content/341/bmj.c4737

14. http://www.acompliareport.com/News/news-061807.htm—http://www.dailymail.co.uk/news/article-2241431/Scandal-poison-pen-pushers-How-doctors-patients-kept-dark-potentially-dangerous-everyday-drugs.html

Prepared 16th September 2013