Since the publication of Dr Ben Goldacre’s Bad Pharma book in 2012, the issue of clinical trial transparency has gone from being a piece of esoterica discussed in the halls of academia to a major public campaign.
Shortly after Bad Pharma was published – a book in which Dr Goldacre lambasted pharma and regulators over their lack of transparency – AllTrials was established by The BMJ, Sense About Science, Dr Goldacre and others, which began lobbying for all clinical trials to be registered and published.
This period marked a real turn in the transparency debate. It began in earnest in the 1980s with Sir Iain Chalmers and the Cochrane Collaboration demanding more trial information from pharma and regulators, in order for doctors and researchers to better understand whether these medicines were safe and effective.
They were however for many decades denied this information. But in 2012 the European Medicines Agency (EMA), headed – until very recently – by the new and reforming Professor Guido Rasi, made the first real commitment from any regulator to open up clinical trial data.
It’s a process that has experienced many delays and much watering down criticism and debate from both the industry and the research community.
But in October this year the EMA announced that from January 1, 2015 the Agency will begin to publish the clinical study reports (CSRs) contained in all applications for centralised marketing authorisations for new medicines.
Restrictions and redactions can however still be made (although the EMA stresses only in a small number of cases) and data from drug applications made before January 1, 2015 (which make up the vast majority of all medicines) will not yet be made available.
This has been seen as a positive step forward by many stakeholders, but there is a still a long way to go for full transparency across the world.
The US regulator the FDA, for example, still remains closed to the idea of open data and does not even consider the trial information it holds to be its own and subject to Freedom of Information (FOI) requests.
The FDA in fact possesses more clinical trial data than any single company and any other regulator – yet it has no plans to share this information.
And the EMA is not the only regulator in Europe, given that there are still local regulators for each EU country, and therefore does not have data for many medicines.
The regulatory balancing act
But this does not mean that the EMA’s decision to start publishing CSRs from next year is insignificant, and marks a real change in philosophy, as well as policy, on behalf of the regulator.
Speaking to PME shortly before his appointment as EMA executive director was annulled, Prof Rasi said: “The Agency has embarked on this transparency drive because it believes that the proactive release of clinical trial data will help to build trust and confidence in the regulatory system.”
This is a much different attitude to its former executive director Thomas Lonngren, who through his long tenure at the EMA blocked the active disclosure of data, saying it would affect the commercial business plans of pharma.
In December 2010 Lonngren left the Agency to work for the NDA Group, a major pharma consultancy firm. That same month the EMA made its first commitment to seeking greater transparency.
Rasi admited that given this past it has not been an easy few years, and says that the new policy – which has taken four years and several consultations – has been shaped by the “many, often conflicting, comments we have received” over its transparency policy.
This includes those from groups such as AllTrials, which wants total transparency on all data, and the pharma industry, which does not want the ‘indiscriminate publication’ of trial data, and would prefer to self-regulate.
But Rasi believes that the final policy, published in October, has created a ‘workable solution’ for all its stakeholders – including pharmaceutical companies – as the policy allows the Agency to increase access to clinical trial data while discouraging unfair commercial use of the data.
“In fact we have seen that the discussion initiated by EMA has led to changes in the attitude of certain stakeholders, including the pharmaceutical industry, towards greater transparency,” he said.
“For example: the EMA’s view that clinical data transparency also has advantages for drug developers has been recently supported by the decision of several major pharmaceutical companies to join the Responsible Clinical Trial Data Sharing [which is also backed by the European and US pharma lobby groups EFPIA and PhRMA], a common online scheme aimed at promoting innovation and progress in drug research and development.”
He added that the Agency “can certainly be proud” to have delivered on its 2012 ambition to create a transparency policy, and “to have contributed to the general drive towards more transparency in Europe”.
But Rasi admited that this is not the end-game, saying: “Of course this is a step in a process”.
‘Proof in the pudding’
Dr Goldacre told PME that he believes this is a good first step, and fought hard during the three delays over the past 15 months to the introduction of the EMA’s new policy, which was meant to start from 1 January 2014.
For Dr Goldacre, “The proof of the CSR plans will be in the pudding”, but he is not feeling confident.
He pointed to recent lawsuits from AbbVie and InterMune against the EMA over its policy to publish data about its drugs Humira, for auto-inflammatory diseases (and the biggest-selling medicine in the world) and the lung-scarring treatment Esbriet, respectively.
The lawsuits were dropped earlier this year after the Agency agreed terms with how the data was to be published.
Dr Goldacre said that these new terms were not, however, within the spirit of transparency. “It is not reassuring that the agreement with AbbVie, for sharing their CSRs, has allowed them to withhold information on protocol changes on the grounds that they contain ‘commercially confidential information’ [the element that will be removed by the new EU regulation].”
Beyond the debate on CSRs is also the separate need for the publication of individual patient data – something promised by the EMA in 2012.
“But this has been heavily delayed and yet to be delivered in even draft form … so we shall see how the EMA will perform from 2015.”
A legislative approach
Rasi says that the EMA’s new policy will also serve as a useful ‘complementary tool’ ahead of the implementation of the new EU Clinical Trials Regulation that will come into force before May 2016.
This new Regulation, passed into law by MEPs in April this year, will allow for greater transparency as it removes the legal framework for pharma to not publish its data.
The Labour MEP and rapporteur for the Regulation, Glenis Willmott, took a personal interest in this legislation, but says it was not easy to get this law on to the European statute book.
She explained to PME: “Whilst pharmaceutical companies would tell me they had no problem with increased transparency, they did then raise problems with specific proposals. It was also clear that there was a lot of lobbying going on behind the scenes.”
And it was not just the pharma industry which made passing this Regulation difficult.
“At first it seemed the opposing views in the European Parliament would make it very difficult to make any progress. But after agreeing on a way forward I was determined that we would get the agreement of Member States and the European Commission for these measures. There were last minute attempts in the negotiations to water down the measures, but I made it clear it was an absolute red line for the European Parliament.”
When asked what has helped prompts these changes in philosophy over transparency, she explains: “I think the AllTrials campaign has been a great success in raising the issue with the general public and policy makers.
“Although it may seem like a difficult issue to understand at first, once the implications of unpublished trial data are explained, everybody agrees that this is something we have to change.”
GSK: Transparency ‘necessary’
The president of pharmaceuticals R&D at GlaxoSmithKline, Patrick Vallance, has become deeply involved in the transparency debate, and echoes Willmott’s sentiment.
GSK is currently the only pharma firm to have signed up to the AllTrials register, and has enacted a series of internal reforms to ensure it is compliant with greater data disclosure.
Vallance told PME: “I have been a strong advocate for [transparency] from my time as a doctor and academic, and of course retained that commitment when I joined GSK.
“Fundamentally, I believe that good science demands that we must make data available for others to scrutinise – it can prevent unnecessary duplication of research and, ultimately, it has the potential to benefit patient care.
“I also believe that transparency is necessary to build trust in decisions that affect public health – when we are ill we need to be able to place trust … it has never been more important for the pharmaceutical industry to show that patients’ interests are put first and we are doing that by making fundamental changes to how we do business. Historically, industry hasn’t done a good enough job to be transparent.”
Vallance said that despite being the only firm to sign up to AllTrials (which is something the UK pharma lobby group the ABPI is not advising others to do), it “made absolute sense to us” as increasing transparency is “a critical area we’ve been pursuing at GSK for a decade and we are publicly disclosing more of our research than ever before”.
But Vallance said that having just GSK on board is not enough. “Importantly, if the drive towards greater transparency is to be truly successful, we need engagement from not just industry but from academic and public institutions – all those carrying out research,” he explains.
He said that a number of pharma firms have signed up to other transparency initiatives, but argued again that “this isn’t enough”. He went on: “I want to see a broader system that brings data together not just from industry but also academia and the broader scientific community. Clinical data can’t be hidden away or ‘owned’ in a way that diminishes the chance to identify truths”.
On the EMA’s new plans, Vallance agreed with Dr Goldacre that this is a good step forward, and believes its open access to CSRs is aligned with the commitment GSK made when it signed up to AllTrials and forms part of a wider commitment to data disclosure.
A change in attitudes?
Attitudes to the new transparency plans coming from both the EMA and the European Parliament have been a mixed bag. The new EU Regulation has been a big hit with lobby groups such as AllTrials and the Cochrane Collaboration, but the long road to the EMA’s new policy has left a bad taste in some people’s mouths.
Fundamentally, most of the data from nearly all the drugs regularly prescribed in Europe will still not be made available for external scrutiny after January 1, 2015 or even May 2016, as the updated rules apply only to new medicines authorised after those dates. And this still irks many who want to see all of the data.
But what has been achieved is nothing short of a major shift, in just a few years, from a paternalistic attitude from both pharma and the EMA that believed the data need only be seen by these two groups, to a proactive stance by the regulator and even by some (though not all) in pharma to share this information more widely.
It is a quiet and steady revolution, but one that will likely mark a major shift in pharma’s business model and corporate culture in the years to come.