The EMA has restricted access to key documents that provide unparalleled insight into the benefits and harms of drugs on the European market, prompting transparency advocates to warn of "a major threat to open and transparent access to important clinical data".
In 2016, the agency won effusive praise for becoming the first regulator worldwide to proactively release Clinical Study Reports (CSRs), documents typically thousands of pages in length that contain extremely detailed information on the conduct and outcome of clinical trials. Between October 2016 and April 2018, the EMA released over 1.3 million pages of CSRs. Over 4,000 researchers have already used this data, accessing a total of 160,000 documents.
The EMA has now suspended the proactive release of new Clinical Study Reports until March 2019, citing the extra workload incurred by its relocation from London to Amsterdam. More worryingly, the EMA has also permanently restricted access to older CSRs.
In future, only European Union citizens will be able to request access to old CSRs. As other regulators, including the U.S. Food and Drug Administration, still keep CSRs under lock and key, this means that scientists from the United States and other non-EU countries (possibly including the UK, depending on the final Brexit deal) will no longer be able to review these key documents.
The EMA has stated that it does not intend to reinstate global access to older CSRs – which cover most of the drugs taken by patients today – after its move to Amsterdam.
“Deaths and other serious harms are much under-reported in published trials, and we therefore need unhindered and immediate access to Clinical Study Reports and other relevant documentation that the EMA holds,” Peter Gøtzsche, director of the Nordic Cochrane Centre, told the BMJ.
Kamal Mahtani, deputy director of the University of Oxford’s Centre for Evidence Based Medicine, called the move “a major threat to open and transparent access to important clinical data. Without this data, it may not be fully possible to independently appraise, synthesise, and implement important information related to the use of medicines”.
Pharmaceutical companies have to provide regulators with CSRs when they apply for a marketing license for a new drug, but traditionally regulators have refused to share these documents with independent researchers and even other government agencies. Previously, scientists could only access CSRs held by the EMA by filing Freedom of Information requests, a process that could take several years’ time.
When third parties have gained access to CSRs, they have often uncovered vital information on drug safety not available from any other source:
-> When independent researchers analyzed the CSRs of clinical trials for a widely used diabetes drug, they concluded that the drug was linked to an increase risk of strokes, heart attacks, and heart related deaths. Regulators in both the US and in Europe promptly reacted by revising their previous assessments of the drug’s safety; at least one regulator recommended that it should be taken off the market altogether.
-> In 2016, an independent team of researchers examined seven previously undisclosed CSRs from the European Medicines Agency (EMA) and unearthed data on adverse effects that had neither been thoroughly gathered nor fully reported. The researchers concluded that harms had been “systematically understated” not only in academic papers, but also in the summarised results submitted to the EMA during the drug’s approval process. The lead author concluded that “[i]t is very unlikely that the EMA discovered the difference in duration of adverse events… The EMA relies on the analysis conducted by the sponsor and typically does not do their own statistical analysis.”
-> In 2013, a team from the German health technology assessment agency IQWiG reviewed 101 clinical trials whose full CSRs had been voluntarily supplied by pharmaceutical companies. They found that CSRs provided over twice as much information on patient relevant outcomes than all publicly available sources combined. The IQWiG scientists concluded that CSRs were “essential sources to inform meaningful indirect comparisons [between different drugs]”, and recommended that “CSRs should be made publicly available”.
Numerous other studies have similarly concluded that access to CSRs by the wider scientific community can significantly improve our understanding of the benefits and dangers of medicines.
Cochrane reviewers Dr Tom Jefferson and Dr Lars Jorgenson recently noted that "for every page of journal article, there may be up to 8000 pages of regulatory data on the same clinical trial." Citing multiple studies, they added that Clinical Study Reports "provide sufficient data for carrying out stratified analyses, and more often report patient-relevant outcomes".
Dr Beate Wieseler, the long-standing head of IQWiG's Drug Assessment Department, has long argued that access to Clinical Study Reports could improve the quality and reliability of health technology assessments, systematic reviews and clinical guidelines.
Meanwhile, accessing CSRs held by the U.S. Food and Drug Administration remains virtually impossible; a recent FDA transparency pilot is extremely limited in scope.
Transparency International, Cochrane, TranspariMED and the AllTrials campaign have all called for regulators worldwide to make all CSRs – old and new – available to the global scientific community in order to safeguard patient safety and enable the accurate assessment of the benefits and harms of drugs.
In theory, it should be easy for regulators to make CSRs available, as these are distinct documents that they already hold on file. However, the EMA redacts CSRs to remove potential commercially confidential information before their release, and that process is time-consuming, even though less than 0.01% of CSR pages eventually get redacted.
TranspariMED understands that the capacity strains the EMA is currently under due to the agency’s move to Amsterdam may have necessitated a slowdown in the release of CSRs, and applauds the agency’s commitment to resume proactively releasing new CSRs after the move (Policy 0070). However, TranspariMED strongly deplores the EMA’s decision to restrict access-on-demand to older CSRs to EU citizens only (Policy 0043).
Science is a global enterprise that thrives on transparency. It is in European patients’ interest that as many scientists as possible – irrespective of national boundaries and citizenship – can access the full information on drugs on the market to detect previously unrecognized benefits and harms.
For an overview of what CSRs are and why they matter, please see this study. This excellent BMJ article discusses the recent EMA move in more detail. The EMA press release is here.
Note: This blog was written based on research conducted by TranspariMED as part of a grant awarded by HealthWatch UK, an independent British charity. HealthWatch UK did not review this blog prior to publication. The content of this blog is the sole responsibility of TranspariMED, and should not be taken to reflect the position of HealthWatch UK.