Science and Technology CommitteeWritten evidence submitted by PharmAware

Introduction

PharmAware is a student-led network, part of Medsin-UK, which aims to raise awareness of the importance of evidence-based medicine and ethical interactions between health professionals and the pharmaceutical industry. The national committee is composed of four medical students and one medical law student. Our vision is a world in which people’s health is improved, never jeopardised, by the pharmaceutical industry. We aim to achieve this through education, advocacy and action.

We welcome this inquiry as we feel it is both timely and important. We want to be able to make decisions about the people we treat in light of all the evidence and we want to be able to collaborate with the pharmaceutical industry. Yet that can only happen if we know we can trust the industry to report all clinical trial data.

1. 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?

1.1 From its introduction, the initial European Clinical Trials Directive has been heavily criticised. The new provisions introduced by the European Commission are an improvement on the existing directive and remove some of the barriers to conducting clinical trials. However, the revisions do not cover consent in emergency situations and will stifle research into emergency care.

1.2 We feel that the EU clinical trial regulation has a number of problems pertaining to reporting and patient safety.

1.3 The regulation doesn’t require trials to be justified following systemic review of previous trials in the same area. The CONSORT[1],[2] statement for reporting clinical trials states that the trial results should be interpreted in light of all the previous evidence; systematic reviews of all the available evidence will also allow decisions to be made on treatment and further research. If we know a drug works or doesn’t work, then we don’t need to randomise patients to trials anymore, avoiding potential harm.

1.4 The regulation states, “Within one year from the end of a clinical trial, the sponsor shall submit to the EU database a summary of the results of the clinical trial”. Instead of simply publishing summaries of clinical study reports, the full clinical study reports and raw data should be published. History has shown that publishing summaries is insufficient, Tamiflu being the most prominent example. The regulation also states “if it is not possible to submit a summary of the results within one year, the summary of results shall be submitted as soon as it is available”. There should be no exception to this one-year rule. Delays in the publication of data in medicine have real-life effects, and missing data in medicine costs lives.

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

No comment on this matter.

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

3.1 The pharmaceutical industry has been responsible for great advances in medical science, which have saved millions of lives. There is no medicine without medicines. But these past successes cannot excuse withholding essential information in the present day. Daily, doctors and patients must make decisions about prescribing with access to only a fraction of the available data. University teaching staff is teaching future doctors with incomplete knowledge about the drugs that they will need to understand and use in practice.

3.2 For decades, the pharmaceutical industry has been more likely to publish the results of clinical trials that show its products in a positive light.[3] Negative clinical trial data seems to disappear; it is never published and never seen by doctors and patients. This phenomenon is so widespread that it is known in epidemiology as “publication bias”. In addition to publication bias, positive results are more likely to be published rapidly, in English, more than once, and are more likely to be cited by others.

3.3 The current best estimate is that half of all the clinical trials that have been conducted and completed have never been published in academic journals; this information is hidden from doctors and patients. This figure comes from a systematic review conducted in 2010 by the NHS NIHR Health Technology Assessment programme.[4] This occurs in trials sponsored by the pharmaceutical industry and in publicly funded research.

3.4 In trials of statins, industry funded trials were twenty times more likely to give a positive result.[5] This was also shown to happen with antidepressants, proton pump inhibitors, antipsychotics, and vasodilator drugs.[6] It is estimated that only about half of research presented at academic conferences appears in the medical literature, the remainder disappears and isn’t published.[7] This is a systemic problem that is well documented for research in infectious diseases,[8] cancer[9] and psychiatry.[10]

3.5 This problem of negative trial data has been studied so much it has even been demonstrated in the form of a randomised controlled trial;[11] researchers sent well-conducted randomised controlled trials that differed only in their outcome to two peer-reviewed journals and they found that positive outcome bias was present during the peer-review process. A manuscript with a positive result was more likely to be recommended for publication than was an otherwise identical no-difference manuscript.

3.6 This phenomenon of missing trial data is nothing more than scientific misconduct and it undermines the integrity of evidence-based medicine. Failure to publish this data actively breaches several articles of the Declaration of Helsinki,[12] a set of ethical principles designed to oversee human experimentation. The Declaration expresses an expectation that every patient enrolled in a clinical trial should, at the end of the trial, be assured access to the best-proven therapy identified in the study.

3.7 The best-publicised example of the extent of missing trial data is the Tamiflu saga,[8] which is on going. Tamiflu (oseltamivir) is a drug manufactured by the Swiss pharmaceutical company Roche, which was stockpiled in response to the H1N1 pandemic of 2009. Governments around the world, including our own, stockpiled Tamiflu on the basis that it can reduce the risk of complications from H1N1. Tamiflu has so far not been shown to prevent such complications.

3.8 Cochrane Collaboration researchers set out to test Roche’s claim that Tamiflu prevented complications from influenza and reduced the number of people needing hospital treatment. The investigation has so far been hampered by Roche’s refusal to provide all of its trial data for analysis. The team obtained some clinical study reports from the European Medicines Agency (EMA), but found inconsistencies with published reports and possible under-reporting of side effects. They have parts of 16 clinical study reports but there is estimated to be at least 123 trials on Tamiflu, possibly more. Oseltamivir has been a great commercial success for Roche. Billions of pounds of public money have been spent on it, and yet the evidence on its effectiveness and safety remains hidden from appropriate and necessary independent scrutiny. For all we know, it may be no better than paracetamol.

3.9 There have been previous attempts to fix the problem of missing data. The International Committee of Medical Journal Editors wrote a policy paper claiming that they would only publish trials that had pre-registration of trial protocols. In 2009 it was shown that only half of all trials published after this requirement had been announced had been properly registered, and a quarter had not been registered at all.[13]

3.10 The Food and Drug Administration Amendment act 2007 required reporting of results one year after completion of a trial on clinicaltrials.gov.[14] An audit was conducted independently and published in the BMJ in 2012.[15] Only one in five trials had met this reporting requirement. Despite this fact, no fine has ever been levied against any company or researcher for failing to post results.

3.11 The BMJ has been at the forefront of the push for access to clinical trial data regarding Tamiflu (www.bmj.com/tamiflu), and of the alltrials.net campaign. The BMJ decided from January 2013, that trials of drugs and medical devices would be considered for publication only if the authors commit to making the relevant anonymised patient level data available on reasonable request.[16] We can all learn from their example.

3.12 Dr Hans Georg Eichler from European Medicines Agency stated in November 2012 that there is no way back from unpublished data, and the European Medicines Agency’s policy that will come into force in 2014 will define how data is going to be published. While this only applies to data submitted to the regulator for market approval, and is only proactive transparency, this is an amazing step forward. However, we do need proactive and retroactive transparency from EMA.

3.13 The focus of this question is pharmaceutical companies, however we should also say that the problem is multifaceted, and to lay blame solely with the pharmaceutical industry is shortsighted. Universities, academics, editors, regulators, ethics boards and doctors are all part of this flawed system of disseminating trial data.

3.14 We believe that there is another large barrier to access to missing clinical trial data. There is a document that contains a series of factually incorrect statements on important issues that have a significant impact on patient care, including medical education, and the availability of withheld data from clinical trials. The document is entitled “Guidance on Collaboration between healthcare professionals and the pharmaceutical industry,”[17] produced by the Ethical Standards in Health and Life Sciences Group (ESHLSG) and endorsed by the great and good of healthcare in the United Kingdom, including the Department of Health, Welsh and Scottish governments, British Medical Association, several Royal Colleges and many others. This document is currently being scrutinized by the Bad Guidelines campaign,[18] of which we are a part.

3.15 In this document, the ESHLSG pretend the problem of missing trial data doesn’t exist. It claims that “Information about industry-sponsored trials is publicly available”. This is untrue.

3.16 The document also claims that drugs company sales representatives “can be a useful resource for healthcare professionals”. While this is not the focus of this inquiry, this statement, again, is a misleading. The best available evidence from 58 studies summarised in a recent academic review[19] shows that overall, doctors who see drug company sales representatives are worse prescribers, prescribing more and with higher prescribing costs. No research has ever shown that “drug reps” improve prescribing.

3.17 These inaccurate statements are concerning and undermine on-going efforts to gain access to unpublished data from clinical trials. Members of the ESHLSG are notable for their absence among the group of organisations that have endorsed the All Trials campaign.[20] It is time that they joined GlaxoSmithKline, the Wellcome Trust, the Medical Research Council, the Cochrane Collaboration, more than eighty patient groups, professional organisations such as The Faculty of Intensive Care Medicine and tens of other organizations in showing real leadership and standing up for patients. These guidelines fly in the face of the best available evidence. We as part of the Bad Guidelines campaign have called on the organisations that have endorsed these guidelines to heed the evidence, reconsider their position and retract their support for this document.

3.18 So far, only the Lancet, one of the world’s most prominent medical journals, have taken a stand and withdrawn their support for the ESHLSG guidelines.[21] Other organisations have only stated that the guidelines should be revised, they’ve refused to retract their support and refused to explain why they agreed to claims that are completely untrue. We urge the committee to investigate this thoroughly.

3.19 In order to make the best decisions on a particular treatment doctors and patients need all the information from all trials, of all drugs that are currently in use, or have ever been used. They also need to know the context in which trials occurred, in order to make a fair and unbiased decision on the appropriateness of the drug for the presenting patient. This is undoubtedly one of the biggest ethical problems facing modern medicine; what we need is transparency in results, publicly accessible clinical trial registers and publication of the negative results to ensure the best care for future generation.

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

4.1 The problem of missing clinical trial data is multi-faceted and requires a solution that addresses each stage at which information is lost. Industry, universities, academics, ethics committees and regulators are all responsible for the reporting of clinical trial data. Transparency is enforceable at all levels. We feel that full disclosure is a moral responsibility incumbent on all these organisations and individuals, but when data is clearly not being released there should be enforceable penalties at different levels, from fines levied on companies to journals refusing to publish affected studies.

4.2 Clinical trial data should be stored indefinitely, in searchable, accessible electronic formats such as a pdf. Scanned copies are not acceptable because they are not searchable, and are too lengthy to be analysed in a practical timeframe. The clinical trial data should be accessible to everyone; if we have many eyes looking at the data, we will be able to spot things that one individual cannot. For individuals accessing the data, it would be good practice to post a publicly accessible analysis protocol before accessing the data.

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

5.1 The best example that we are aware of is an initiative set up at Yale University. The Yale University Open Data Access (YODA) project was set up to develop, test and implement methods to disseminate research data as widely, comprehensively, responsibly and productively as possible.[22] The model is designed to provide analysis that will be scientifically rigorous, objective and fair. The YODA model is a good model to promote transparency.

References

[1] Schulz K F, Altman D G, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c332.

[2] Moher D, Hopewell S, Schulz K F, Montori V, Gøtzsche P C, Devereaux P J, Elbourne D, Egger M, Altman D G, for the CONSORT Group. CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trial. BMJ 2010;340:c869.

[3] Lexchin J, Bero L A, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003;326;1167–7

[4] Song F, Parekh S, Hooper L, Loke Y K, Ryder J, Sutton A J, et al. Dissemination and publication of research findings: an updated review of related biases. Health Technol Assess 2010;14(8).

[5] Bero L, Oostvogel F, Bacchetti P, Lee K. Factors Associated with Findings of Published Trials of Drug-Drug Comparisons: Why Some Statins Appear More Efficacious than Others. PLoS Med 2007; 4(6):e184.

[6] Bourgeois F T, Murthy S, Mandl K D. Outcome Reporting Among Drug Trials Registered in ClinicalTrials.gov. Annals of Internal Medicine 2010; 153(3): 158–66

[7] Scherer R W, Langenberg P, Von Elm E. Full publication of results initially presented in abstracts. Cochrane Database Syst Rev 2007; 2: MR000005

[8] BMJ. Tamiflu Campaign. Available at: www.bmj.com/tamiflu

[9] Ramsey S, Scoggins J. Commentary: Practising on the Tip of an Information Iceberg? Evidence of Underpublication of Registered Clinical Trials in Oncology. The Oncologist 2008;13:925–929

[10] Turner E H, Matthews A M, Linardatos B S, Tell R A, Rosenthal R. Selective Publication of Antidepressant Trials and it’s influence on apparent efficacy. N Engl J Med 2008; 358:252–260

[11] Emerson G B, Warme W J, Wolf F M, Heckman J D, Brand R A, Leopold S S. Testing for the Presence of Positive Outome Bias in Peer Review: A Randomized Controlled Trial. Arch Intern Med 2010; 170(21): 1934–9

[12] WMA Declaration of Helsinki—Ethical Principles for Medical Research Involving Human Subjects. Available online at: http://www.wma.net/en/30publications/10policies/b3/]

[13] Mathieu S, Boutron I, Moher D, Altman D G, Ravaud P. Comparison of Registered and Published Primary Outcomes in Randomized Controlled Trials. JAMA 2009: 2;302(9):977–84.

[14] Food and Drug Administration. Food and Drug Administration Amendments Act (FDAAA) of 2007. Available at: http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/default.htm Accessed 21/2/13

[15] Prayle AP, Hurley MN, Smyth AR. Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study. BMJ 2012;344:d7373

[16] Godlee F, Groves T. The new BMJ policy on sharing data from drug and device trials. BMJ 2012;345:e7888

[17] Ethical Standards in Health and Life Sciences Group. Guidance on collaboration between healthcare professionals and the pharmaceutical industry. Available at: http://www.abpi.org.uk/our-work/library/guidelines/Documents/Guidance%20on%20collaboration.pdf

[18] Bad Guidelines. Available at www.badguidelines.org Accessed on 8/2/13

[19] Spurling G K, Mansfield P R, Montgomery B D, Lexchin J, Doust J, et al (2010). Information from Pharmaceutical Companies and the Quality, Quantity, and Cost of Physicians’ Prescribing: A Systematic Review. PLoS Med 7(10): e1000352. doi:10.1371/journal.pmed.1000352

[20] Alltrials.net Available at: www.alltrials.net

[21] Horton R. Falling out with Pharma. Lancet 2013;381, Issue 9864, Page 358

[22] Yale University Open Data Access Project. Available at: http://medicine.yale.edu/core/projects/yodap/index.aspx

Declaration of Interests

Dr Ben Goldacre spoke among others at the conference “We Have a Drug Problem” in London on 24–25 November which was part organized by PharmAware.

PharmAware are currently part of the Bad Guidelines campaign with Healthy Skepticism-UK, Conflict Free Conferences, MedAct and Dr Ben Goldacre.

Two members of the national committee are members of the non-governmental organisation Health Action International, An independent network working to improve access to, and the rational use of, essential medicines with evidence-based advocacy.

February 2013

Prepared 16th September 2013