Not so crystal clear: The EU’s clinical reporting problem

pharmafile | October 29, 2018 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing |  EBM Datalabs, clinical trial transparency, clinical trials, feature, pharma, transparency 

With shocking new findings revealing that around half of all clinical trial results in Europe go unreported, Matt Fellows explores the roots of this not-so-surprising revelation, what can be done, and why it all is so important.

Transparency is becoming a topic of increasing prevalence and importance in our everyday lives, and has come to prominence in impactful issues such as the responsible usage by organisations of consumer’s personal data, and the advent of GDPR, among other things. But transparency is critical in the clinical space for a number of reasons.

Where clinical trials form the basis of just about every decision made by researchers, scientists, industry healthcare professionals and governments, they influence a wide range of elements, determining which medicines make it through the development process and which ones are ultimately delivered to patients. It is crucial that decision makers in these processes have access to all the data to allow them to see the complete picture and make informed judgements on these crucial issues.

“When results from clinical trials aren’t shared we don’t know what was found out about the medicine and condition under investigation” Dr Sile Lane, Head of International Campaigns and Policy at Sense about Science, told Pharmafocus. “It means doctors can’t be sure they know everything they need to know when making decisions about medicines with their patients. It means researchers don’t know what was found out so might repeat clinical trials unnecessarily. It means regulators and payers can’t be sure they make the right decisions and aren’t unknowingly licensing or spending money on medicines that are ineffective.

“And lack of transparency is a kick in the teeth of the people who volunteer to take part in clinical trials,” she adds. “Clinical trials depend on people, patients mostly, to be willing to put themselves at some risk to be part of a trial. They volunteer trusting that what is uncovered in the trial will be shared with other researchers and doctors and will go to make live better for patients like them in the future. When results aren’t shared, it is a betrayal of this trust.”

An ethical failure

With this in mind, clinical research has been rocked by the recent findings emerging from Evidence-Based Medicine (EBM) DataLab at the University of Oxford, which reported a number of shocking revelations on the issue of clinical transparency.

EU guidelines have stipulate that all sponsors of clinical trials recorded on the EU Clinical Trials Register are required to upload all findings of said studies to the register within one year of the trial’s completion. Updated monthly, the resource was introduced to on the basis of an implicit understanding of the absolute necessity for clinical transparency, and monitors which trials have acquiesced to this requirement and which are overdue, with penalties threatened upon those who do not comply.

The EBM Datalab findings, published in the BMJ alongside the launch of its EUTrialsTracker resource, revealed that a staggering 48.9% of trials conducted in the EU, and required to publish their results under EU law, have failed to do so. Only 51.7% have complied. This represents a severe miscarriage of the crucial responsibility of clinical trial sponsors, and opens the door to a range of resonant consequences, from compromising the integrity of clinical decision-making, to threatening the foundations of the sometimes already shaky faith of the public in healthcare and the pharmaceutical industry in particular.

“This problem strikes to the heart of evidence-based medicine. We cannot make informed choices about which treatments work best, as doctors and patients, unless all results are reported,” remarked Dr Ben Goldacre, Director of the DataLab at the University of Oxford, and lead author on the paper, on its release. “We hope that our data will help trial sponsors to move fast and get their houses in order. We have identified the individual non-compliant sponsors, and trials, in order to help them do so.

“We would hope that public pressure and the ethical need for trial reporting should be enough. But the EU Clinical Trials Regulation is coming into force next year. It will bring substantial financial penalties for sponsors in breach of reporting requirements. All trial sponsors – especially universities – must get their house in order now.”

But perhaps the most damning aspect of the findings is that, to those close to the issue in the industry, these findings were not revelations at all.

“Lack of transparency of clinical trials is not a new phenomenon, but rather something that has received unfortunately limited attention. The findings from the EBM DataLab are important and quantify the scale of the problem,” noted Sarah Steingruber, Programme Manager at Transparency International Pharmaceuticals & Health. Dr Lane agreed, referring to the findings as “shocking but not that surprising.” She continued:” Over the last few decades, publication bias in clinical trials has been subject of academic discussion and research and studies have regularly shown that around half of all clinical trials haven’t reported results. So this result fits in with what we knew.

“It is, even so, still shocking because the rule on reporting trial results in the EU is so clear and straightforward – all trials on the EU clinical trials register must have summary results posted there within a year of the trial’s end – that there’s really no excuse for this not to happen.”

A clear division

Interestingly, EBM Datalab’s report found that trials sponsored by companies were much more likely to report their results than those with sponsorsed by academic institutions, with 68% of commercially sponsored trials reported compared to just 11% of those from non-commercial sponsors. 32% of pharmaceutical companies failed to report their findings on the EU’s register, which is problematic enough, but almost eclipsed only by the mind-boggling fact that 90% of universities, hospitals, governments and charities also failed to do so. Even 32 major institutions reported precisely zero of their research findings. While hugely worrying on both sides of the aisle, what is the reason for such a discrepancy?

“Companies seem to be complying with the rules about reporting results much more closely than non-commercial sponsored trials, ie those run by universities, charities, hospitals and governments. I think this is because companies work in a far more regulated environment than academics,” suggested Dr Lane. “They generally have legal departments tasked with staying up to date with rules and regulations in any region they want to sell their product in. Because they won’t be able to sell their products if they don’t. Academics don’t have this motivation to adhere to rules. And since there hasn’t ever been anyone sanctioned for breaching the EU’s reporting rules academics haven’t been feeling much pressure to follow them.”

This last point is a key one – despite the promise that institutions would face consequences for non-compliance, lack of any meaningful follow-through on this could be a significant factor in lagging reporting rates.

Steingruber adds: “The existing push and pull factors experienced by researchers along the academic career path do not incentivise transparency in clinical trials. I would not claim that there are intentional or vindictive motives to not publishing research, though I would not rule them out either; there are many elements at play. We know that academic researchers may be in time-bound research positions, their funding may dictate that they stop one area of research to take up another, at the beginning of careers there is extreme pressure to publish interesting findings and the criteria to publish set out by journals are incredibly strict, people retire, funding dries up, time is limited. Large companies on the other hand have large, vertically integrated and well-funded teams.

“One thing that did surprise us is that while many major pharmaceutical companies now do well in terms of trial reporting, there is still a huge problem with registry entries with inconsistent or incomplete data by those same companies. This does not inspire confidence in their overall data management systems. Companies need to address this issue.”

However, some did manage to stand out from the pack in the report. “The EU CTR tracker does show that some universities have achieved 100% compliance with the reporting rules,” Dr Lane notes. “Clearly, it is possible for academic institutes to comply.” For reference, there were eleven such companies – Boehringer Ingelheim, Chiese, Almirall, Gilead, Otsuka, CSL Behring, Ferring Pharmaceuticals, Alcon, Vertex, Genentech, and Daiichi Sankyo.

“When we have spoken with the universities and charitable funders achieving good compliance about what it took to get there,” she continued, “they generally say something about making the issue someone’s responsibility, It seems like if there is a person or a team responsible for monitoring publication and for notifying researchers about when they should be reporting, that’s what makes the difference.”

So there are definitely methodologies which set the compliant institutions apart from the rest. But what can non-commercial sponsors learn from commercial sponsors in order to replicate their relative success with regards to reporting rates?

“When it comes to companies they talk to us about how they plan and run research projects differently from academic research – they work to tightly drafted standard operating procedures which there is no scope for company researchers to deviate from or to leave out some steps,” Dr Lane explains. “This means that once reporting results becomes part of the standard operating procedure, it happens. To get reporting into the SOP though is prior another step. People from companies that were early adopters of transparency again talk to us about the need for someone in the company – someone at CEO or CMO level – who is personally committed to transparency to push through new policies.”

Steingruber pitches in on the issue: “In order to fix this problem, universities must first and foremost assume central oversight over their clinical trial portfolios, past and present. In many universities, individual researchers still register trials and manage registry entries. A few UK universities are making large progress in this regard and are actively clearing their backlog of unregistered trials, but many others across Europe are still at the beginning of this journey.

“Funders can encourage this by making future funding contingent on the reporting of past trial results, and reputation could be gained by transparency markers.”

The elephant in the room

Impossible to escape but impossible to ignore, Brexit is a crucial consideration with regards to clinical transparency for trials UK conducted within the context of the EU, as well as cross-regional studies, as it is in almost all other industries and sectors. And as is the case in these areas, any attempts to truly quantify the situation are rendered almost fruitless given the lack of clarity given so far. However, despite this, things may not be as gloomy in this regard as one might think.

“Everything depends on the final Brexit deal, so it is too early to tell. However, the UK has traditionally been a global leader on transparency in clinical trials, and that is not likely to change,” Steingruber says. “The many submissions on this topic to parliament’s recent enquiry on research integrity show that numerous UK stakeholders are keeping a close eye on sponsors’ performance, and some have proposed the establishment of national clinical trial audit system to cover all clinical trials conducted in the country, irrespective of wider European frameworks.”

Dr Lane shares Steingruber’s cautious optimism, but calls for vigilance: “The UK government led the drive to include laws on transparency in the EU Clinical Trials Regulation when it was being drafted and amended in 2013/14. It would such a shame if researchers and patients in the UK don’t get the chance to benefit from all that hard work after Brexit. However, the UK government has said that it intends to align the UK’s clinical trials laws as closely as possible to the EU Regulation. Probably, the same rules will apply to UK sponsors and they will be continued to be scrutinised to the same degree. We are certainly recommending that UK academic institutes don’t start imagining they won’t have to meet the EU standard for transparency soon. They will.”

Broken trust

Public confidence in pharma, and sometimes in medicine more generally, has been historically shaky to say the least, and this makes the release of EBM Datalab’s somewhat grim findings all the most impactful – perhaps understandably, they could serve to heavily damage the already fragile trust the public has in the clinical space – a trait that the patient/clinician relationship dynamic absolutely relies upon. But on this notion, Steingruber has an illuminating point to make:

“I see this as more of an opportunity; it is highlighting a problem that we already knew was there,” she explains. “My hope would be that this wakes up policy makers and enforcers to actually apply the mechanisms they have at hand and for the public to start demanding greater transparency as well.  

“The good news is that trials trackers, such as the EUTrialsTracker allow one to distinguish between those companies that are doing well, and those that fail to meet minimum transparency standards. This may enable strong performers to build a favourable reputation despite weak public confidence in the sector as a whole.”

This presents the idea that this broken trust can be somewhat rectified by redressing a key issue: the weak position the patient occupies in this power structure, and making the problem of poor reporting a public one can serve to better educate and empower them.

Gene Matthews and Stuart Warmington, Partners at Leigh Day, agree, arguing that this approach should be twinned with the adoption of a tough attitude by the EU to make good on their threats of consequences to incentivise sponsors to comply with its transparency regulations.

“Our view is that the new findings show how far those who conduct clinical trials are still able to rely on the fact that individuals are generally passive on these issues and simply rely on industry, regulators and clinicians to provide them with treatments that are proven to be safe and effective,” they explain. “Few patients have the inclination, or the expertise, to properly interrogate the evidence underpinning the treatment they are being prescribed. Industry and academia must focus on honouring their obligations, and regulators must ensure full transparency – where an organisation is found wanting, they should be penalised. Generally, effective enforcement means that a ‘big stick’ (by way of the threat of significant financial penalties) must be used to encourage the bodies, at risk of paying them, to take notice.  The ‘carrot’ is ethical, higher quality, research which has the potential to bring real benefits to patients.

“The pharmaceutical industry is well known to have a polished public relations operation and to be one of the most effective lobbyists there is. However, if patients are empowered with an understanding of the need for full transparency, pressure can be brought to bear on regulators and Government to ensure the safe development of new drugs.  This is something we can all agree society desperately needs.”

Steingruber concludes with the message: “The report is very clear – there is urgent need to increase transparency across the research and development process, not only for those trials going forward, but also retrospectively for trials that have already completed. The medicines and devices of tomorrow were tested in the trials of yesterday and in order to truly understand their safety and efficacy profiles and guarantee that healthcare professionals are able to make decisions that are in patients’ best interests we need that data to be available. For this reason, Transparency International and other transparency advocates expect trial sponsors to achieve compliance with WHO global best practices, not just narrow legal compliance. To date, there has been far too little political will to enforce existing regulations. We are working to generate the political momentum required to decisively tackle opacity in medical research.

“Transparency in this sector is a one-way street, and pressure on trial sponsors to perform better is growing as an increasing number of stakeholders are becoming actively engaged with this topic. Industry and academia should get ahead of the curve by aiming for full compliance with WHO best practices, rather than trying to play catch-up with rapidly evolving legal and regulatory requirements. The public takes it for granted that institutions conducting medical research comply with the law. Building public trust requires exceeding minimum expectations.”