Dr Sarah Markham, King’s Clinical Trials Unit, emphasises the importance of transparency by highlighting the AllTrials Campaign
The AllTrials campaign is an initiative of Bad Science, BMJ, Centre for Evidence-based Medicine, Cochrane Collaboration, James Lind Initiative, PLOS, and Sense About Science. It is being led in the US by Dartmouth’s Geisel School of Medicine and the Dartmouth Institute for Health Policy & Clinical Practice.
When the AllTrials campaign was launched in January 2013, it was a call to action for all clinical trials, past and present, to be registered and their full methods and summary results reported. The Declaration of Helsinki, which is the World Medical Association’s statement of principles for medical research involving people, states that every investigator running a clinical trial should register the study and report its results. Millions of volunteers have participated in clinical trials to help find out more about the effects of treatments on disease, yet that important ethical principle about reporting its results has been widely ignored. Information on what was done and what was found in these trials could be lost forever to doctors and researchers, leading to bad treatment decisions, missed opportunities for good medicine, and trials being repeated. The startling lack of transparency is what led to the creation of AllTrials, a campaign which is now supported by thousands of individual patients, clinicians and researchers across the world, as well as by hundreds of organisations representing millions of people.
There are four levels of information in clinical trial reporting: (1) knowledge that a trial has been conducted, from a clinical trials register; (2) a brief summary of the trial’s results; (3) full details about the trial’s methods and results; and (4) individual patient data from the trial. The AllTrials campaign is concerned with the first three. There are now initiatives in many countries that work out how individual patient data can be shared with other researchers.
The first robust evidence on missing trial results in medicine was published in 1980. The first strong prominent call for a trials register was in 1986. Since then there have been dozens of studies published on the prevalence of missing data, and endless broken promises, but the problem has not been fixed. Academic publications are a necessary first step to getting this global public health problem resolved, but on their own are insufficient to address the issue.
Checks on the registration status of published trials show approximately 40 percent of clinical trials concerning treatments in current use were not registered. This figure does not include unregistered trials that have never been published. Nevertheless, the situation is improving. Increasingly, funders and research organisations are insisting that trials are registered and that it be a legal requirement for trials on some medicinal products in the EU, USA and five other countries.
Meanwhile, the World Health Organization (WHO) has set out a 20 item Trial Registration Data Set of the minimum information that should be included when registering a trial. Registration should cover the rationale and background of the trial; information on study participants and informed consent; the intervention under investigation, primary and key secondary outcomes; and the method of data collection and statistical analysis plans.
Prospective registration is the gold standard for the reasons set out in the 2005 Ottawa Statement. AllTrials calls for all studies that were not prospectively registered to be done so retrospectively. They claim this is particularly important for trials conducted to evaluate the efficacy and safety of a treatment in current use, some of which were done before trial registration was possible.
There are no apparent barriers to registering trials. ClinicalTrials.gov is the world’s largest register. It accepts registration from anywhere in the world and allows retrospective registration of trials. There are numerous national and regional registries, and others held by funders, institutions and corporations. About 20 of these are collected in the WHO’s Registry Network.
The proliferation of registries with different requirements is, however, limiting the usefulness and transparency of reported information. A trial can be registered in multiple registries but the entries are not always connected together. It is not currently possible for researchers or patients to find all trials that have been done on a particular intervention, even if all the trials have been registered somewhere. The registration system could be streamlined and standardised internationally. Discussions are now underway on how to achieve this. A small number of global centres would make it possible to standardise the way data are structured so that entries can be linked and searched. Another option is to ensure registries require all clinical trials to give all other registries ID numbers for studies that appear on multiple registers.
The AllTrials campaign also calls for registration to be a necessary requirement before funding can be obtained for a trial, or to sell a product, or to obtain permission to do a clinical trial. The proposed EU Clinical Trials Regulation will require registration as part of approval for any new trial of a medicinal product. Additionally, the US TEST Act, tabled in 2013, would require trials used to support licensing applications to have been registered before they have started. The FDA Amendments Act 2007 already requires trials with at least one site in the US to be registered within 21 days of the first patient being enrolled.
The International Committee of Medical Journal Editors (ICMJE) committed in 2005 to publish only reports from trials that had been registered at inception. Requesting the trial number will help to monitor compliance with this more effectively. However, in order to overcome the historic gap in trial registration and reporting, AllTrials calls for journals to look at how they deal with any previously unreported trials that weren’t registered or pre-dated the registration requirement.
With regard to the reporting of summary trial results, AllTrials claims they should be posted publicly within a year of trial completion where the trial was registered. The US FDA Amendment Act 2007 requires that results must be posted on ClinicalTrials.gov within a year of the completion of the trial for all trials with at least one site in the US. The FDA has the power to fine trial sponsors who do not comply, but it appears they rarely do this. Whether or not a trial is required to post results – or has been granted an extension – is often the subject of legal discussion, and as a consequence there is no clarity about whether a trial is truly overdue by the terms of the Act. The proposed EU Clinical Trials Regulation will require summary results for every registered trial must be posted within one year of the completion of the trial, and the European Commission is discussing how to enforce this properly.
Clinical Study Reports or their equivalent in non-commercial settings contains a large amount of detailed information about the methods, analysis, results and conclusions of a clinical trial. Therefore, AllTrials calls for trial sponsors or others who produce a full report for marketing authorisation or any other purpose to make this publicly available. The narrative reports of adverse events and individual patient data in a full report can be redacted and available on request to researchers, in the same way that reports of adverse incidents currently are, with a commitment that no reasonable request will be refused.
In July 2015, AllTrials announced that investors in pharmaceutical companies representing over €3.5 trillion in investment assets were supporting the AllTrials campaign. This group of 85 pension funds and asset managers were writing to the companies they invest in to ask them to set out plans to ensure their clinical trials, past, present and future, are registered and results reported. AllTrials worked with BNP Paribas Investment Partners to run workshops with the investors to develop the steps they have called on companies to take. Helena Vines Fiestas from BNP Paribas Investment Partners explained why investors want transparency: “Alongside doctors and their patients, investors also risk being misled,” she said. “It is essential that companies publish complete and accurate information on trial results so that investment decisions can be fully informed.”
That is why investors, including Aviva Investors, Boston Commons Asset Management, RobecoSAM, 65 UK local authority pension funds, and the investment arm of the Wellcome Trust, have written to pharma companies asking them to be more transparent.
This was covered extensively in the financial press by outlets, such as the FT (Financial Times), the Economist, and the Wall Street Journal among others each giving Pharma a clear message that public calls for transparency had significant investor support and were becoming harder to ignore.
On July 28, 2015, the judgement in a judicial review brought in May 2015 by a leading clinical trials company Richmond Pharmacology against the HRA's proposed plans to require all future drug trials to be registered, was published. The judge found that the HRA has a clear legal right to monitor researchers’ compliance with legal and ethical obligations to register clinical trials. The Judge said that the HRA has a remit to impose sanctions on researchers who breach those obligations. But he also found that the HRA’s website is currently too ambiguous and confusing about what those obligations are to be lawfully able to do this. The Judge asked the HRA “as a responsible public body to cast a self-critical eye over the whole of its website material in this domain.”
The Judge also said he was grateful to AllTrials for their clear, strong submission which, together with the HRA's evidence, helped narrow the case down from Richmond’s initial broad arguments to a discussion on the day of the hearing about the meaning of some words on a page on the HRA’s website. It took five months of legal argument and cost hundreds of thousands of pounds to reach the judgment.
The HRA now has a clear mandate to continue its work promoting trial registration and reporting. The judgment is a very clear and comprehensive setting out of the issues and of the legal and ethical obligations on researchers.
On July 29, 2015, AllTrials announced that 50 patient groups, consumer organisations and medical societies had come together to launch AllTrials USA today. The groups said, "We are calling on everyone in our sector to join us in supporting the AllTrials campaign. Hundreds of thousands of patients have taken part in clinical trials which have never reported results. For every day that passes, more information is at risk of being lost forever. We have to make every clinical trial count. Join us today."
Patient activist AnnaMarie Ciccarella said: “We provided our bodies, our tissue samples, our data. I’ve heard the same sentiment expressed many times from patients in clinical trials, ‘This may not help me, but it may help another person.’ It’s time to honour that sentiment.”
On August 8, 2015, the Royal College of Surgeons of England (RCS), a professional membership organisation and registered charity representing over 20,000 surgeons internationally has joined AllTrials. Writing in RCS BLOG, Professor Derek Alderson, Vice President, Royal College of Surgeons of England said: “Lack of regulation makes it easier for non-drug trials to slip under the radar. A third of completed surgical trials are not published and selective reporting of positive outcomes has been found to be prevalent in published surgical trials. If things are left to continue along these lines, our evidence base for surgical trials will be biased. This will likely lead to flawed treatment decisions, detrimentally affecting patient care and outcomes.”
Furthermore, AllTrials and the Ethical Medicines Industry Group (EMIG) sent a joint letter to the HRA, setting out why it should not be dissuaded from its path of monitoring compliance with regulations and good practice in trials transparency. It was published Pharmafile.
Regulatory bodies in other countries have been considering whether to adopt the HRA approach, which currently has the backing of AllTrials supporters, the UK biopharmaceutical industry, and the English courts. Organisations such as the Office for Human Research Protections in the US, the Federal Institute for Drugs and Medicines in Germany, and the Brazilian National Health Surveillance Agency will hopefully read the letter and act on it. The AllTrials campaign has called on those associated with people at organisations such as these to make them aware of the letter and the AllTrials website www.alltrials.net.
*AllTrials is supported by donations. You can donate at www.justgiving.com/alltrials or email email@example.com to donate in other ways
Dr Sarah Markham
King's Clinical Trials Unit
Institute of Psychiatry, Psychology and Neuroscience
King's College London