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AllTrials: have you reported all of your trials?

Published: 21 Sep 2018
Category:
By Síle Lane

Randomised clinical trials are by far the best tool we have to assess whether a medicine works or not. Governments and regulators demand to see the results of the highest quality trials to make decisions about treatments. Thousands of trials happen every year, all around the world, and hundreds of thousands of people volunteer to be part of them.

So it’s a problem that around half of these clinical trials have never reported results. The evidence base for medicines we use every day is incomplete and because trials that show a medicine works are twice as likely to have reported results than trials that show that a medicine doesn’t work, the evidence base is skewed. It means that the thousands of patients who gave up their time to join trials, trusting that what is found out about their condition or the medicine will be shared with doctors, have had their trust betrayed.

The AllTrials campaign is the global movement of 800 organisations and 90,000 people calling for all clinical trials to be registered and results from them to be reported. I help run AllTrials. I wrote here last year recommending that researchers start to publish unreported trials because AllTrials was going to start shining a light on researchers’ and organisations’ past reporting. Since then support has grown – some of the world’s largest funders and regulators have now committed to doing the same. Here’s where we are now.

Tracking tools

Over the last year we have launched a suite of public tracking tools that allow anyone to identify which clinical trials have reported results and which haven’t, and to see who is responsible for the trials. The TrialsTracker built by the EBMDataLab in University of Oxford is one of these tools. It pulls in information from the world’s largest clinical trial register, the US federal ClinicalTrials.gov, for all clinical trials registered there since 2006. Then it automatically searches the register and in the peer reviewed literature for results from the trials and flags each trial as either reported or not. The TrialsTracker currently shows that 45.2% of trials registered on ClinicalTrials.gov since 2006 are missing results.

What about trials that are running today? The new FDAAATracker tool4 flags trials on the US register in which reporting results are overdue under US law. The FDA Amendment Act is the law that says that trials must be registered when they begin and must report results to the register a year after they end. As I’m writing this piece the FDAAATracker is showing that only 65% of recently ended trials have reported results on time. It shows that the FDA is entitled to have collected fines of over $200 million from parties responsible for trials that have broken the reporting rules. You can see which trial sponsors are reporting the most, and the least, of their trials here fdaaa.trialstracker.net/rankings. Readers could have a look at how their own institution is performing. If it’s not good, let them know you’d like to see them improve.

The Unreported Trial of the Week

AllTrials has started to shine a light on specific unreported trials. We are running the AllTrials Unreported Clinical Trial of the Week – a weekly series of articles in the British Medical Journal on trials the FDAAATracker has flagged as unreported. So far we have written about nine unreported clinical trials including: a trial involving 200 cataract surgery patients, a trial run in New York investigating whether ketamine could treat cocaine dependence, and a trial involving 270 seniors across Europe and the US on strategies to reduce agitation in Alzheimer’s patients. Three of those previously unreported trials have gone on to submit results. We know this works!

Audits of funders and institutes

We have been taking a closer at how academic institutes and funders are responding to calls for transparency. A recent paper in the Journal of the American Medical Association found that most large charities and government bodies who fund clinical trials don’t have a policy to ask that the results from these trials are reported. This audit of the 18 philanthropic and public bodies that spend the most money on clinical research found that most (66%) do not require researchers to report results and that only half ask for clinical trials to be registered. Only two of these global bodies had a policy that reached the gold standard for transparency, the UK’s Medical Research Council and Germany’s research funding organisation Deutsche Forschungsgemeinscaft. Altogether the 18 funders spend around $40 billion on health research every year. If results from research isn’t shared, this money is wasted.

Another recent paper has shown that most academic institutes in the US do not have any publicly stated policy to ensure that clinical trials are registered and their results reported. Under half of them have a policy on registration of clinical trials (43%) and only around a third (35%) have a policy on results reporting.

The results of these two recent papers are shocking. The requirement to register and report trials is moral, ethical, professional and legal (see the box), and institutions should have a policy and a public commitment to compliance. The academic research sector is lagging behind on this. An audit of the world’s largest pharmaceutical companies’ policies on transparency that we published in the BMJ last year, found that over 90% of companies have policies to both register their trials and to report summary results. Dr Ben Goldacre of the EBMDataLab at the University of Oxford -a co-founder of the AllTrials campaign, said, “Public funders have fallen well behind and are now doing worse on transparency than the pharmaceutical industry. We need these funders to show leadership, to tell their grant recipients very clearly that all trials must be registered and reported.”

In May 2017 the World Health Organisation (WHO) backed this effort when it asked charities and governments worldwide to sign up to its strong standard on transparency. The WHO has long held that registering clinical trials and publicly sharing results from them is an ethical imperative for all researchers. Their statement asked funders of clinical trials to write and implement a new strong policy that will guarantee that all funded researchers register and report their trials. Twenty-one funders, including the Bill & Melinda Gates Foundation, Médecins sans Frontières and the Wellcome Trust have joined the WHO’s statement. We will be auditing these funders soon to ensure that they have done what they promised.

I would advise every researcher to get all past trials reported, soon. The FDA said it will focus its sanctioning efforts on trial supporters who have not complied with reporting guidelines in the past. The US federal funder, the National Institutes of Health, has just said that it will no longer fund research if it cannot verify that the researcher registers and reports their trials. Other funders are considering adopting this policy too. The Health Research Authority is going to start asking researchers applying to run a new clinical trial about whether their past trials have been registered and reported. More research regulators around the world are going to adopt this too. Soon, if a researcher wants to get approval to run a trial, to get a trial funded, published and accepted by a regulator, they’ll soon be asked not just whether that trial will be registered and reported but whether all other trials they’ve run in the past have been too. Don’t risk getting caught out - make reporting your trials your priority now.

The obligations on researchers to report clinical trials are...

..ethical

The Declaration of Helsinki, adopted by the World Medical Association in 1964, last amended in 2000, is the internationally agreed ethical standard for clinical researchers. It says that researchers have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports.

It also says that ethical imperative to report includes results of unreported trials conducted in the past. And that: “Negative and inconclusive as well as positive results must be published”.

The World Health Organization states: “The registration of all interventional trials is a scientific, ethical and moral responsibility” and: “The key outcomes are to be made publicly available within 12 months of study completion by posting to the results section of the primary clinical trial registry.”

...legal

All trials registered on the EU clinical trial register since 2004 must have results reported. The new EU regulation 536/2014 from 2019 will make this a legal requirement that can be enforced through fines and other sanctions

The FDA Amendment Act 2007 requires that trials with a site in the US or forming part of treatment licensing are registered on ClinicalTrials.gov and report results within 12 months of completion.

Fines of up to $10,000 a day can be imposed by the FDA. In 2015 the United Nations began urging every government to ensure it has legal enforcement measures to require researchers to disclose clinical trial results.

...contractual

Many of the world’s largest medical funders – including the US National Institutes of Health, the European commission, the Australian National Health and Medical Research Council, foundations and patient non-governmental organisations – mandate that results from trials they fund must be reported.

Funders around the world are signing up to a WHO-led statement committing to audit their grants for compliance. This is one reason institutional reviews boards and other approval bodies are now asking about researchers’ reporting histories in new applications.

...professional

International good clinical practice for running clinical trials includes reporting results.

Many professional registration bodies include this explicitly in their definition of professional standards, or implicitly through reference to the standards above, which means failure to report is professional malpractice.

..decent

Full reporting of results improves medicine and improves research – so it improves lives. People who volunteer for clinical trials trust that the results will contribute to understanding. Researchers who do not report results are choosing to flout the legal, ethical and professional requirements related to their own trials and choosing to damage that trust for all others.

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About the author

Síle is the head of international campaigns and policy at Sense about Science, the UK charity that campaigns around the use and misuse of evidence in public life. Sense about Science runs the AllTrials campaign for clinical trial transparency which the British Pharmacological Society supports.