As the world comes to grips with the devastating spread of COVID-19, research institutes and drug companies are mobilising to find and test treatments for the disease – in a big way. But how can we be certain that the results of trials will be made public, and what are the costs of non-transparency?
AllTrials, an international campaign driven by UK charity Sense about Science, grew out of these considerations. Working with governments, regulatory bodies and research funders, AllTrials calls for all clinical trials, past and present, to be registered and their full methods and results made public within a year of completion.
AllTrials is very relevant right now because there are so many trials going on that we need published quickly,” says Tracey Brown, campaign co-founder and director of Sense about Science.
More than 5,000 COVID-19-related clinical trials are currently recorded on the World Health Organization’s International Clinical Trials Registry Platform. Human trials of potentially life-saving drugs such as hydroxychloroquine, remdesivir and dexamethasone regularly make headlines.
While this burst of activity may increase the odds of finding an effective coronavirus treatment, with the world asking the same questions with the same urgency, there is a huge risk of studies being repeated unnecessarily, wasting time and resources and putting participants’ lives at risk. This is why it is now a legal requirement in many jurisdictions to register clinical trials on one of the international registries and report results promptly.
That wasn’t always the legal requirement, and it still isn’t in some parts of the world. Although AllTrials is still a work in progress, the campaign has made significant inroads in a relatively short period. When it launched in 2013, only around half of clinical trials in the UK reported results. Now, almost all do, Brown told The Brilliant: “We want to get the UK to as close to 100% as possible – and we’re not far off. And we are working with partners around the world to achieve that everywhere.”
Clinical trials and tribulations
Brown has always held a deep interest in research, but at the start of her career, she was focused more on social science, not medical. In the early 90s, she worked in Russia to help develop a European social science and research collaboration.
That time, she recalls, opened her eyes to the idea of scientific thinking as public empowerment. “It was a profound thing to experience a society that had been unable to reflect openly on itself now beginning to use social statistics and test explanations – and to see the energy of a new generation of researchers wanting to help people to do this.
“I suspect Sense about Science’s focus on accountability and transparency owes something to those days too.”
Meanwhile, a prime example of the potentially widespread and fatal effects of clinical trial non-reporting was coming to a head. A trial of the heart arrhythmia drug lorcainide in 1980 found the drug increased a patient’s chances of dying: of the 49 patients who received lorcainide, nine died, compared with one in the placebo cohort of 46.
These results weren’t published – at least, not until 1993, by which time other drug companies had already developed and trialled the same class of anti-arrhythmic drugs. It’s estimated roughly 100,000 people died needlessly in the US alone after being prescribed similar medications.
In the decades since, the number of clinical trials has ballooned. When the US-based ClinicalTrials.gov registry launched at the start of 2000, only 1,255 clinical studies were disclosed on the platform. Twenty years later, that figure has risen to 325,839.
Despite this massive increase in the number of registered trials, plus the potentially lethal risks of keeping negative results under wraps, reporting rates remained low.
In 2012, Ben Goldacre, British physician and author of the book, “Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients”, approached Brown. He was frustrated that the problem of unreported trials, which medical institutions had been aware of for over two decades, was continuing to put lives at risk. The pair agreed to start AllTrials together.
“Our aim was to set out a divide between those in the medical establishment who wanted to fix the problem and those who just paid it lip service. We signed up tens of thousands of patients and doctors to press for clinical trial transparency and gave organisations the opportunity to get on the right side of history. It worked,” says Brown.
European achievements
The AllTrials campaign focuses on timely full reporting of results, and enforcement of this by registries, funders and trial licensing bodies. Some organisations and companies, such as GlaxoSmithKline, have taken it upon themselves to ensure that all their trial results are reported and to find and publish missing results from past trials.
What’s changed most is where companies have seen the writing on the wall with the new regulations we have achieved in the US and the EU and have gone ahead and done it themselves,” Brown says.
Research funders, too, are starting to evaluate whether their grantees are publishing their trials, and making that a funding condition. For instance, before a research group receives money, they must sign a document that says they’ve reported results from all previous trials.
This, Brown adds, “is quite a big barrier for people. It’s one thing to ignore the fact you should have published a trial, but it’s quite another to sign the declaration to say you’ve published when you haven’t.”
Since the WHO backed AllTrials’ call for full reporting, 15 of the world’s most prominent research funders have undertaken to do this, and to audit whether the trials they fund are reported. “And in some cases, they’ve done that really well. The Medical Research Council in the UK, which is one of the world’s biggest funders, has actually implemented measures and is tracking their impact.” The UK’s Health Research Authority, has also just this July made past reporting a condition of ethical approval for new trials – something that other licensing bodies are expected to follow.
EU regulation, too, has recognised the importance of clinical trial registration and reporting. Amendments to the EU Clinical Trials Directive – successfully proposed by the AllTrials campaign – passed in 2014 and contained law that states clinical trials in Europe must be registered and reported in a publicly available database. If trial results aren’t made public within a year, researchers can be fined.
But despite being adopted six years ago, the regulation is not yet fully executed, Brown says. “Hopefully we’ll have something from the EU soon about when the trials directive is going to be implemented.”
Sights set across the Atlantic
The next challenge for AllTrials is the home of the largest share of clinical trials in the world – the United States – and things are finally moving.
The US Food and Drug Administration (FDA) Amendments Act, passed in 2007 and revised in January 2018, requires trials with at least one location in the US be recorded on ClinicalTrials.gov within three weeks of the first patient enrolling.
Most clinical trials – including those involving an intervention, such as a drug or medical device – must also report their results within a year of completion. But only around two-thirds so far have, according to the FDAAA Trials Tracker, and the FDA’s enforcement of reporting was non-existent until now, Brown says.
“We can see that millions and millions of dollars’ worth of fines could have been levied and they just haven’t implemented it. It is vital that they impose those penalties, in order to make a difference. Fines make shareholders and funders ask questions.”
There has been a breakthrough. Just a few weeks ago the US FDA finally announced that it will start enforcing its fines for late reporting. Perhaps the COVID-19 pandemic, which has sparked thousands of new clinical trials, might have played a part in recognising the value of prompt reporting of results in terms of saving lives and avoiding harmful treatments.
Some of the major funding organisations in the US, such as the Gates Foundation, have signed up to the WHO funder declaration and are already putting pressure on grantees to publish results.
“And in a sense, that should make it easier for the regulators because they can more easily isolate those areas where reporting is not happening,” Brown says.
Still, in just seven years, AllTrials has made a lasting impact on clinical trial registration and reporting. It has changed the way Europe, the US and international organisations such as the World Health Organization mandate trial registration and reporting, and continues to push for more open research.
“We started out with next to no funding – we crowdsourced it – and here we are,” Brown says.
We signed up fund managers with three trillion euros worth of funds under investment to push companies to report on their clinical trials. We’re getting close to 100% reporting rates in some sectors of the UK now, and across Europe patients, doctors, researchers and funders are contacting us for help to achieve the same in their countries. The US is improving a little bit more slowly, and internationally, the picture’s changing. The Cochrane Collaboration, TranspariMED and other groups are taking up the pursuit of trials country by country. We’re really excited by that.”
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