Written evidence submitted by AllTrials campaign (RIN0067)

The AllTrials campaign for clinical trial transparency was launched in 2013 by Sense about Science, Ben Goldacre, BMJ, Centre for Evidence-based Medicine, Cochrane Collaboration, James Lind Initiative and PLOS. It is run by Sense about Science, by Sense about Science USA in the USA and by groups of voluntary campaigners in Ibero-America, Norway and Italy. AllTrials calls for all clinical trials, past and present, to be registered and their methods and results reported.

Clinical trials have been the subject of some of the most thorough research into integrity and transparency. Publication bias in clinical trials has been the subject of discussion and research since at least the 1980s. From that research, this is what we know:

There is a bias in publishing positive versus negative results. Results from clinical trials with positive results are twice as likely to be published as others[1].

Industry-funded trials are more likely to report positive outcomes than trials funded by other sources. One piece of research found that industry funded trials reported positive results 85% of the time while government funded trials reported positive results 50% of the time[2].

Around half of the clinical trials have never reported results. A great deal of research has looked at publication rates of clinical trials. Each individual piece of research has looked at a subset of clinical trials that have been carried out, for examples trials carried out in a specific region, on a particular disease area or treatment type; trials run by a certain sponsor; on medicines approved in a certain year; or trials on one particular register. We do not advocate rolling the results of all these disparate pieces of research into one spuriously precise number, but around half is what we can reasonably say. A full setting out of the state of research on this is on the AllTrials website here: http://www.alltrials.net/wp-content/uploads/2016/03/AllTrials-briefing-doc-how-many-clinical-trials-unreported.pdf (I am happy to submit this document separately to the committee if that would be useful.)

Automatic trial tracker tools show that around half of trials have not reported results. The new TrialsTracker tool[3], built by the Evidence-Based Medicine Data Lab, at the University of Oxford automatically pulls in information from the world’s largest register (clinicaltrials.gov) and from PubMed about trials carried out by the largest trial sponsors[4] that were posted on the register between January 2006 and two years ago (it is updated regularly). As of 10th March 2017 it shows that 45.2% of trials have not reported results. 

The situation around past trials is urgent. We have not seen any evidence that significant numbers of previously unreported past trials are now being reported. Unreported results are at risk of turning into lost results as researchers and software retire. The majority of medicines prescribed in the UK have been on the market for more than a decade[5] and so were tested in trials in the preceding decades. Researchers describe a ‘golden age’ of drug development in the 1990s, when medicines were discovered that may never be bettered. The trials testing those medicines are essential for current medical practice. But not only do results from past trials contain information on the efficacy and safety of today’s medicines, they also set the standards against which tomorrow’s medicines will be assessed.

The impacts of lack of clinical trial transparency

The results of clinical trials are used by regulators to decide whether to allow a medicine to be sold, by governments to decide whether to pay for the medicine, by doctors to decide whether to prescribe the medicine to their patients, and by researchers deciding whether to follow a promising pathway of research on that medicine. When the results from trials are kept hidden it means those decision makers don’t have the full information they need to make good decisions.

Doctors can’t know for sure that they are prescribing the best medicines to their patients and are not unknowingly doing harm. A heart drug called Lorcainide was tested in a trial in 1980. The results showed that the people who were taking Lorcainide were far more likely to die than those not taking it. But those results weren’t published until 1993, thirteen years later. In those thirteen years, doctors continued to give patients medicines in the same drug class as Lorcainide and it is estimated that 100,000 people in the US died as a result.

When trial results are kept hidden governments and regulators are at risk of making the wrong decisions. The MHRA recommended that the Government buys a stock of a drug for flu called Tamiflu on the basis of the results of clinical trials that it had seen. The UK government spent £424 million on Tamiflu[6]. Researchers found out that the results from some trials had never been reported and the regulator had only seen a proportion. When all the results were revealed they showed that Tamiflu was less effective than previously assessed.

When results aren’t published, medics and researchers can’t build on research that has already been done. Potential new innovations never get to be explored and knowledge generated in trials is lost.

There is a human cost to lack of clinical trial transparency. People, patients and non-patients, volunteer to be part of trials. They volunteer knowing that it may or may not help them personally but trusting that if something is uncovered about the condition or the medicine that researchers could use to make life better for patients in the future. When the findings they helped to generate are never shared with doctors and researchers, and never used to benefit other people, that is an enormous betrayal of their trust. Given that thousands of trials have never reported results, hundreds of thousands, maybe millions, of volunteers have been betrayed.

All of this is happening in spite of laws, regulations and guidelines that mandate and recommend that clinical trials are registered and results are reported, including:

• European law, including Directive 2001/20/EC the Clinical Trials Directive, the Good Clinical Practice Directive 205/28/EC  and the Paediatric Regulation: (EC) 1901/2006
• United States Food and Drug Administration (FDA) Amendment Act of 2007
• World Medical Association Declaration of Helsinki[7]
• World Health Organisation statement on clinical trial registration[8] and statement on public disclosure of clinical trial results[9]
• Research regulator policies including the Health Research Authority’s policy that clinical trials must be registered as a condition for ethical approval to run the trial[10]
• Clinical trial funders’ policies including US National Institutes of Health[11] and UK NIHR[12]
• Pharmaceutical industry body guidelines, including Europe’s EFPIA’s position on clinical trial registration and reporting[13] and the US industry body PhRMA’s Principles on Conduct of Clinical Trials Communication of Clinical Trial Results[14]

Solutions

The AllTrials campaign has been joined by more than 90,000 people and 700 organisations who are involved in funding, running, overseeing and publishing clinical trials. The organisations include the world’s largest medical associations, research organisations, research funders, and medical and scientific publishers; global medical assessment groups; the pharmaceutical company GlaxoSmithKline; universities; and hundreds of patient organisations who between them represent the voices of over half a billion patients. Many of these groups have taken the lead in developing solutions to lack of trial transparency for their own sectors. We have gathered many of the initiatives already being implemented and suggestions for more in our roadmap to transparency available here http://www.alltrials.net/wp-content/uploads/2017/02/AllTrials-Roadmap.pdf

Suggestions to the committee

1. That the committee recommends that the government supports widespread auditing of clinical trial registration and reporting.

Auditing is a recognised tool to drive up performance in medicine. It can uncover good practices that can be shared across sectors. Audits of clinical trial registration and reporting are possible to do, even for past trials. Here are two recent examples:

In 2015 the Health Research Authority funded an audit[15] of the publication rates of clinical trials approved by one UK research ethics committee. The researchers who carried out the audit said: “This study showed that the problem of publication and outcome reporting bias is still significant in the UK. The method described here demonstrates that UK NHS research ethics committees are in a good position to detect such bias due to their unique access to original research protocols. Data gathered in this way could be used by the Health Research Authority to encourage higher levels of transparency in UK research.”

In 2016 two Oxford research centres, the Oxford Biomedical Research Centre (BRC), and the Oxford Musculoskeletal Biomedical Research Unit (BRU) who together received over £160m of public funds from the NIHR since 2007 published an audit of the registration and reporting rates of their clinical trials[16]. Based on the audit findings, the audit team and BRC/BRU directors produced a set of recommendations, published in the BMJ Open,[17] to improve the transparency and encourage timely publication, and have committed to making these improvements. The government should adopt these recommendations for all publicly funded research.

2. That the committee recommends that UK clinical trials law continues to reflect the EU Clinical Trials Regulation after the UK exits the EU

The EU Clinical Trials Regulation is expected to come into effect in 2018. It says that information from clinical study reports of trials should not generally be considered commercially confidential and will:

• Establish a new publicly accessible EU clinical trials register, to be run by the European Medicines Agency.
• Require that all drug trials in Europe are registered before they begin on the new register and that a summary of the results is posted on the register within a year of the trial’s end.
• Require that a lay summary of all clinical trial results is published on the register.
• Require clinical study reports to be made publicly available, where they are produced.
• Require that all trials used in support of an application to run a new clinical trial are registered and have published results.
• Impose financial penalties on anyone running a clinical trial who breaches these new laws.

MEPs voted by a large majority to adopt the Clinical Trials Regulation, 547 in favour and 17 against. They were urged to do so by thousands of people and organisations from the UK.

In June 2015, then Prime Minster David Cameron pledged at the G7 meeting in Germany that “The UK will be the first country in the world to require clinical trials and disease control operations to be fully transparent.[18]” In September 2016 the United Nations High-Level Panel on Innovation and Access to Health Technologies called on every government to enact laws to make registration of clinical trials and reporting of results mandatory[19]. The government should commit to retaining the clauses on clinical trial transparency in UK law after the UK exits the European Union.

March 2017