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The future of data disclosure in Europe

Published on 30/09/13 at 08:12am
EMA building

The debate of clinical trial transparency has at times appeared a peculiarly British issue, but plans are afoot in Europe to open up more data for third party consumption.

The European Medicines Agency has just completed a three-month consultation on new clinical trial transparency rules, and will now begin to deliberate on what stakeholders have been saying ahead of the policy changes next year.

As the EMA says itself: “Transparency is a key consideration for the Agency in delivering its service to patients and society.” But this all comes at a time when the EMA itself is under scrutiny for not being as transparent as it should be, and for having a paternalistic attitude.

This attitude was evident from a 2011 interview Pharmafile conducted with the interim EMA executive director Andreas Pott, who did not believe the Agency needed to show its working in public, and said patients should trust pharma and regulators implicitly without needing to see the data.

This also showed up during the debate on GlaxoSmithKline’s troubled diabetes drug Avandia, where the regulator’s US counterpart the FDA allowed open deliberations on the medicine’s safety, all of which were televised and attended by journalists.

This was in stark contrast to the EMA, which would not allow the public or the media to attend these types of regulatory meetings, meaning many were left in the dark as to how the regulator reached its decisions on the drug’s safety.  

Things were not made easier when the former EMA executive director Thomas Lönngren left under controversial circumstances in 2010, as he joined the NDA pharma consultancy group just two weeks after stepping down from the EMA’s top post.

In this position Lönngren was essentially helping pharma firms to get through the European regulatory process, even though he had intimate details of its practices that could have been an unfair advantage to pharma firms using the NDA group. 

In fact so unhappy was the European Commission with Lönngren’s new job - and a lack of gardening leave - that it delayed paying the Agency some of its back-dated funding until it cleaned up its act.

But things are now starting to change since the employment of a new full-time executive director in Guido Rasi, and the issue of transparency and open working has come to the fore.

It appears that a mixture of public and specialist group pressure has meant the EMA can no longer delay on issues of disclosure, and Rasi has seemingly come in with a remit to shake things up, with this new policy the practical outcome of a new direction.

Slow release of data

The Agency has been releasing clinical trial documents, including clinical trial reports, since November 2010, but only once the decision-making process for the medicine in question has been completed.

Figures show that between November 2010 and April 2013 the Agency released nearly two million pages of clinical-trial data in response to safety-related requests.

But this has not been enough, and it is now moving toward the ‘proactive publication’ of clinical trial data for medicines once the decision-making process on an application for an EU marketing authorisation is complete.

“The Agency has embarked on this process because it believes that the release of data is about establishing trust and confidence in the system,” it explains. “This will enable the independent re-analysis of the evidence used by the Agency’s committees to determine their benefits and risks and is expected to lead to public-health benefits.”

However, it does acknowledge that the publication of full sets of raw data runs the risk of breaching patient confidentiality and that analysis by independent groups does not guarantee it will be free of conflicts of interests, or of a high quality.  

This means that ‘raw’ or unfiltered data will most likely not be available to access, something that will displease the UK AllTrials initiative. This campaign group was established late last year by the British Medical Journal, Bad Pharma author Dr Ben Goldacre and Sense about Science, among others, and is asking for pharma to release as much data as possible, including older data for its medicines.

Draft policy

The EMA’s draft policy, which has just come back from consultation, makes it clear that the Agency wants to balance its commitment to give the widest possible access to data for independent scrutiny, with the need to protect personal data as well as legitimate commercially confidential information (the policy is available here).

This document essentially sets out the EMA’s stall on what the future will look like when it comes to releasing data in Europe. The most important piece in the policy is that the Agency now believes: “Clinical trial data cannot be considered commercially confidential information [CCI]; the interests of public health outweigh considerations of CCI.”

This is, from pharma’s point of view, a radical attitude for a regulator to take; it is in effect telling the industry that any new data will soon not be viewed as commercially sensitive, hence why it will be able to promulgate the information, even if pharma does not want it to.

Whilst radical in practice, the Agency has still been careful to sound cautious in tone, and adds that the policy: “Has no intentions to negatively impact on the incentives to invest in future bio-pharmaceutical research and development”. 

This is all set to come into effect from 1 January next year, but the Agency is committed to making ‘controlled access’ data available as early as is practical - where ‘controlled access’ means that access to these types of data will only be granted after the requester of the information has fulfilled certain requirements.

However, in light of the importance the Agency wants to place on patient confidentiality, steps will be put in place to ensure suitable standards, rules and procedures for removing the identity of patients.

All other clinical trial data currently held by the Agency - i.e., those on products already on the market - will however continue to be made available to requesters on a ‘reactive’ basis, and not in-line with the new policy.

The EMA said it will not immediately disclose any information about the person or group that has requested the information, but will rather: publish the identity, the list of the aims of accessing the data provided, and any uploaded documents, or the requester’s decision to decline to upload documents either when published, or one year after the data has been accessed.

It added that it will be working with sponsors and other concerned parties towards this goal, and expects to publish a guidance document no later than 31 October 2014, with a view to making available all controlled data submitted by sponsors on or after 1 January 2015.

Pharma not playing ball?

But pharma has not been happy with the EMA’s historical release of data, meaning the more liberal policy that is to come may cause the industry major headaches.

In fact two firms - AbbVie and InterMune - are currently suing the regulator to stop it from disclosing data on two medicines. AbbVie, the drugs unit of the now-split Abbott group, has taken exception to the EMA attempting to publish data on its big selling arthritis drug Humira, and filed two lawsuits against the regulator at the European Union General Court in Luxembourg earlier this year.

In a statement the US firm said it was: “Seeking to protect AbbVie’s confidential and commercially sensitive information,” adding that it opposes the publication of information: “That does not meaningfully contribute to the scientific review or evaluation of our products.”  

In a separate case the biotech firm InterMune is also taking the EMA to court after the regulator allowed a competitor to see information concerning its Esbriet lung drug.

Speaking in March this year Jim Goff, a spokesman for InterMune, said the Brisbane, California-based company is challenging the EMA’s decision as it considers this information to be commercially confidential.

On the basis of current rules, it may very well have a point - but under the new policy guidelines, this will longer be a defence against publication for new drugs from next year. The suing of the EMA has put the case for transparency under the spotlight and pharma remains unwilling to sign up for exactly what the EMA and AllTrials want.

The European pharma lobby group EFPIA has promulgated it response to the consultation, and is looking to offer an alternative to what the European regulator is aiming for.

In a nutshell EFPIA is looking to self-regulate when it comes to the release of data, and argues that the plans forwarded by the EMA may still risk patient privacy and stifle R&D innovation, as it could also infringe on patent rights if competitors can see other companies’ data.  

But it was exposed in July of trying to secretly get patient groups on its side of the transparency debate in a leaked memo seen by The Guardian newspaper, damaging its reputation and taking focus away from its agenda.

The EMA has a lot to contemplate when considering the responses to its consultation - and whilst it aims to create a balance between public safety and the commercial interests of pharma, it will need to prepare itself for a tough response regardless of what its final policy will look like.

Editor’s comment

The EMA has come under pressure for its clandestine practices in recent years, and its new policy must be viewed in this context as it has spent just as much time delaying any transparency drive, and yet it becomes suddenly imperative when the regulator itself comes under scrutiny.

This does not mean, however, that transparency is wrong or that it shouldn’t be striving toward it. Rather than fighting against it, pharma should have a long hard look at its practices and ask itself some tough questions.

Speaking to me earlier this year Dr Keith Bragman, head of the Faculty of Pharmaceutical Medicine, said that all patent issues are ‘wrapped-up tight’ by the time a drug reaches human testing in Phase I trials, meaning that the argument about intellectual property is essentially redundant.

The bigger issue here is a concern that data is being published selectively for a reason: to hide negative data and unevenly promote positive data. There have been a few notable examples in recent years of this behaviour, but the biggest is the furore over the billions of dollars spent by many governments around the world stockpiling Tamiflu during the swine flu outbreak in 2009 and 2010.

After evaluation of trial data, the Cochrane group says that Tamiflu appears to affect antibody production - a claim that Roche refutes. This is important, say Cochrane, because influenza vaccination relies on an antibody response to be effective. But when asked by the BMJ, Roche refused to explain how the drug works.

The Cochrane group said: “Until more is known about the mode of action of neuraminidase inhibitors [such as Tamiflu], health professionals, patients and other decision-makers need to reflect on the findings of this review before making any decision about the use of the drug.”

But interpretation of data is not an easy task. In 2010 researchers from Germany’s cost effectiveness body IQWiG unearthed a mountain of unpublished data from trials of Pfizer’s antidepressant reboxetine, that show that the antidepressant may be harmful.

They found published studies overestimated reboxetine’s benefit by 115% when compared to placebo, and 23% when compared with other antidepressants - and that they also underestimated harm. The researchers also found that 74% of the data from patients in trials for the antidepressant had gone unpublished.

Their findings, which were published in the British Medical Journal, concluded that: “Reboxetine is, overall, an ineffective and potentially harmful antidepressant.”  

But in response to these findings the UK drugs regulator, the MHRA, conducted a UK and European-wide review of available efficacy and safety data, which later confirmed that reboxetine “has benefit over placebo in its authorised indication”.

It found that efficacy was ‘clearly shown’ in patients with severe or very severe depression and established that there were no new safety issues. But it added that like many antidepressants, there are “limited efficacy data for the use of reboxetine in patients with mild to moderate-severity depression”.

These claims and counter-claims do little to instil confidence in the public: Pfizer’s drug was initially shown to be safe and efficacious by regulators; then allegedly hidden data was unearthed and interpreted to in fact show the opposite; another review is conducted but finds that the drug remains safe and effective.

So what is the truth and who can be trusted to interpret these data correctly and without bias? These are still the questions that need to be answered by the EMA, AllTrials and pharma - but the public too needs to be more involved given it has the most at stake in this debate.

One of the things AllTrials doesn’t deal with is that independent analysis per se, is no guarantee of high quality, or a correct interpretation. The regulatory community has been confronted with meta-analyses that were later contradicted by additional evidence, or found to be flawed.

The Cochrane Collaboration, which has spent many years undertaking meta-analyses of datasets, is the preferred third party group for many to have access to these data, but even this highly respected body can make mistakes.

But this does not mean that the data should only be seen by pharma - it too can make errors, and the more qualified people who view the trial information, the clearer the picture of how that drugs works and whether it is safe will become.

Regardless of the outcome the fact remains that in a science-led field, all data must be published in order to have the clearest picture of how a drug works. It is an affront to those patients who took part in a clinical trial, and all those that ran it, if their outcomes are hidden for business reasons.

Self-regulation is not the answer: if some in the industry have by omission or by design not published data for purely commercial reasons, something separate from pharma needs to be in place to ensure this does not happen again.

If it were data that could have saved the lives of those who died whilst taking Merck’s Vioxx, or data that could have helped cash-strapped governments not spend billions of dollars on a product that might not work, then there should be no argument about data transparency.

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