Yesterday, the UK parliament’s SciTech Committee invited a panel of three experts to London to discuss how to get all clinical trials registered and their results reported.
Dr Ben Goldacre, author of the bestselling book Bad Pharma, told MPs that:
“I think it would be a very very straightforward thing to fix. This [SciTech] Committee could write to the Health Research Authority and say, ‘We want you to audit every clinical trial you approve… line by line. We want you to identify the individual trails and trialists that haven’t published their results.’”
Easily said, but what about the practical barriers to solving the problem?
Below, I debunk five common myths.
MYTH ONE: WE DON’T HAVE THE DATA
FACT: Luckily, Britain already has the perfect regulatory setup for monitoring trials.
Each and every trial conducted in the country requires ethics approval from a Research Ethics Committee (REC) to go ahead, and the Health Research Authority already collects all documentation from the country’s 68 RECs and centrally archives it. In other words, all information required is already at the regulator’s fingertips. As Dr Simon Kolstoe explained,
“Ethics committees are at a point in time where they see all documentation. They have access to everything across the board."
Dr Sile Lane from the AllTrials campaign concurred:
“The HRA [Health Research Authority] are in a good position to monitor and audit compliance with those rules because of the information that they hold.”
Note that the Health Research Authority alone has the information required to monitor all trials – including those conducted by industry. Funder audits by themselves would miss industry trials.
MYTH TWO: THIS IS ALL AWFULLY COMPLICATED
FACT: A basic national audit system would only involve checking whether a trial was (1) registered and (2) has posted its summary results.
This is not rocket science.
Checking whether a trial is registered is easy: either it is registered on one of a handful of WHO-approved trial registries – or it is not.
The difficulty of monitoring results reporting depends on how ‘reported’ is defined. The easiest approach is to check whether or not a trial has posted its summary results onto the trial registry where it was registered. Ben Goldacre emphasized that reporting results in this manner should be regarded as sufficient. Indeed, research shows that summary results posted on registries typically provide a more complete and accurate picture of trial outcomes than journal articles do. Checking for summary results is neither complicated nor time intensive. (In contrast, Simon Kolstoe’s pilot audit of a sample of REC-approved trials was more ambitious in scope, checking a variety of factors, and hence was far more labour intensive.)
Note that posting summary results is already an EU regulatory requirement for many drug trials; the World Health Organization has explicitly stated that all trials should post summary results within 12 months maximum. Posting the summary result of a trial typically only involves a few days of work – negligible input compared to the overall cost of running a trial. Brexit provides an opportunity to improve on EU transparency rules by adopting WHO best practices.
MYTH THREE: THIS WILL BE TRICKY TO IMPLEMENT
FACT: If the Health Research Authority sticks to the basics, and only looks at registration and summary results, monitoring could be extremely easy.
A microfinance company I sometimes work with sets up software solutions enabling small banks in unlikely places like Kenya and Kazakhstan to monitor tens of thousands of tiny loans in real time. Microfinance is all about maximizing efficiency and minimizing transaction costs, so these systems don't require additional paperwork or red tape.
Banks do it by capturing relevant data electronically upstream – something that could easily be done for trials during the ethics approval process. Any retail bank manager can at the click of the mouse see who is in arrears, and get summary data on overdue loans by bank branch, borrower type, loan type, loan sum, etc.
The Life Sciences Sector Deal just published as part of the Industrial Strategy annoounces that the Health Research Authority will integrate, optimise and automate approval processes in order to speed up ethics approvals (see page 22). This presents a unique opportunity to redesign the ethics approval system to enable the HRA to perform nation-wide clinical trial audits routinely and at minimal cost in terms of staff time.
If a small bank serving poor (and sometimes illiterate) farmers in rural Africa can effectively and efficiently track tens of thousands of loans, surely the UK government can manage to track the fate of a few thousand clinical trials conducted wthin its jurisdiction.
MYTH FOUR: WE CANNOT ENFORCE COMPLIANCE
FACT: This is less of a problem than it seems.
In theory, the Health Research Authority is responsible for enforcing compliance with UK trial registration and EU summary results posting regulations. In practice, it has been unable to do so due to understaffing and a lack of legal powers.
However, experience shows that whenever trial sponsors’ performance on reporting results becomes publicly visible (as with the 2015 STAT investigation and the 2016 TrialsTracker), institutions start to take compliance seriously, even without the threat of legal sanctions. Thus, monitoring alone can significantly improve compliance.
Simple reminders can also improve compliance. For example, microfinance banks use software that automatically notifies borrowers whose repayments are overdue (via email, SMS and phone calls). In the vast majority of cases, a simple reminder is enough to ‘nudge’ a client to repay. Unsurprisingly, a pilot study has already shown that such nudging also works with trialists.
MYTH FIVE: WE SHOULD NOT ENFORCE COMPLIANCE
FACT: In the United States, trial sponsors already have to post the summary results for some types of trials within 12 months - or pay a hefty fine.
Under U.S. law (FDAAA 2007), for every day a trial is overdue, the sponsor has to pay a fine of $10,000. Every day! As is so often the case in this sector, the law has not been enforced to date – but it certainly is an interesting model the UK and other countries can learn from.
In London, all three experts seemed to agree that for now, the HRA should only monitor performance and make the results public. By itself, this could hugely improve current registration and reporting rates. Also, granting a limited grace period makes good sense. Many universities’ performance is so dismal at present that they will need at least a year to get their acts together and put strong systems into place.
This does not mean that, of all people, those conducting medical research in human beings should indefinitely be permitted to ignore sensible rules that were adopted to protect patients. When people get caught driving while drunk, they are fined and forced to pay that fine. If they do it again, we take away their driving licenses and maybe even put them behind bars.
Like drunk driving, the failure to registering and reporting trials is not a victimless crime.
It is deeply unethical and harms patients.
In a democracy, nobody – and certainly not medical researchers – should be above the rule of law.