Impact case study database

The reviews of neuraminidase inhibitors [2,3]; the development of new methods [1] and the TrialsTracker [4]; and the resulting insights into compliance [5,6] have underpinned campaigns for greater transparency in clinical trial reporting, influenced global changes in healthcare policy, and helped to hold public bodies to account.

Data from the UK National Audit Office confirmed that between 2006/7 and 2012/13, the Department of Health and Social Care spent GBP424,000,000 on oseltamivir (“Tamiflu”) for use in a pandemic, but had to write off GBP74,000,000 of the stockpile [A]. Expenditure in the USA was reportedly in excess of USD1,300,000,000.

Following the first publication of the Cochrane review [2] in January 2012, the UK Parliamentary Public Accounts Committee called in 2013 for an inquiry into the UK government’s policy of stockpiling antiviral drugs. Part of the remit was to explore “ the Cochrane Collaboration’s updated review of Tamiflu and the ramifications that access to clinical trial data has for the whole of medicine.” The University of Oxford lead for the review, Heneghan, gave written evidence based on this research including reflections on the difficulties encountered in obtaining full information on trials for [2]. The Committee concluded that the failure of trial sponsors to share the full results of clinical trials undermined the ability of doctors, researchers and clinicians to make informed decisions about treatments, and thus undermined the use of medicines by the NHS [A].

In 2016, the University of Oxford researchers published an audit of the registration and publication of a set of clinical trials funded by the NIHR and undertaken at two large research units in Oxford, at the request of the associated Patient Involvement Working Group [B]. In March 2017, Goldacre gave written and oral evidence to the Parliamentary Science and Technology Commons Select Committee, drawing on this proof-of-concept audit and other work from the Oxford group. In 2018, the Select Committee’s report “ Research integrity: clinical trials transparency” recommended that the NHS “ should be provided with funding to establish a national audit programme of clinical trials transparency, including the publication of a single official list of which UK trials have published results and those which are due to but have not.” [C].

Based on these recommendations, the NHS Health Research Authority (HRA) launched the “ Make it Public” campaign in June 2019, citing the 2017/18 ‘ Research integrity’ report [C]. The University of Oxford provided data from EU TrialsTracker to inform the consultation, which was acknowledged in a summary in the consultation document highlighting that ‘ around 25% of UK sponsors do not report results on time’. The consultation stated that the HRA planned to change their processes to address this challenge and included proposals on how to improve reporting. [D(i)]. The resulting policy, ‘Make it Public: transparency and openness in health and social care research’, was published in September 2020 and outlined a vision for research transparency and an expectation that results be reported within 12 months of the study end date and annual publication of compliance rates [D(ii)].

In 2015, on the basis of the work undertaken to establish trial reporting transparency for neuraminidase inhibitors [2, 3], the WHO commissioned the Centre for Evidence-Based Medicine (CEBM) at the University of Oxford to provide the background briefing document [E(i)] for the WHO consultation on data and results sharing during public health emergencies. The resulting WHO statement and consensus in September 2015 [E(ii)] resulted in the implementation of a new protocol for data sharing during the Zika outbreak of 2016 [E(iii)], that was subsequently important in the response to COVID-19. The Head of Research and Development at WHO said “ That work and the consultation it supported was very influential as the norms for sharing information prior to manuscript publication have shifted dramatically…. During the 2020 pandemic Medrxiv, Biorxiv and other preprint servers have become critical information sharing modalities; something that was called for during the 2015 meeting” [E(iv)].

In May 2017 the WHO led the development of a joint statement on the public disclosure of results from clinical trials, in which various non-commercial funders, including the MRC, the Wellcome Trust and CEPI, committed to implement key trials transparency policies [F]. The Head of Research and Development at WHO confirmed that the Oxford researchers “played key roles in helping to develop international standards around transparency in clinical research” and that “ The joint statement has led to real changes in the policies of major funders” [E(iii)].

In March 2017 an expert committee of the WHO, citing [2], recommended deleting the antiviral drug oseltamivir from the Core Essential Medicines List (the most efficacious, safe and cost-effective medicines for priority conditions) [G(i)] and transferring it to the Complementary List (medicines which are not necessarily affordable, or for which specialised health care facilities or services may be needed), where it has since remained [G(ii)]. The peer review report [G(iii)] making this recommendation noted that [2] “ includes data from the complete set of clinical study reports of clinical trials of oseltamivir”.

In 2013, the University of Oxford (as the CEBM), Goldacre and the BMJ co-founded AllTrials.net, a global campaign for trials transparency. By 2020, AllTrials had 95,000 individual supporters, 727 organisations (including patient groups, academic bodies, drug companies), and advocates for all past and present clinical trials to be registered, with their methods and results reported in full. Following their 2018 report on ‘Research Integrity’ [C] and the launch of the EU TrialsTracker in 2018 [6], in early 2019 the Parliamentary Science and Technology Commons Select Committee asked Goldacre to provide data on the reporting performance of all UK universities and NHS Hospital Trusts. The Committee reminded all universities and NHS Hospital Trusts of their responsibilities (regardless of current performance) and demanded overall compliance to improve. For a follow-on hearing, Goldacre and AllTrials provided written evidence with updates on performance across all UK universities and Trusts to the Committee [H]. This evidence showed that in the 12 months following the publication of the report (Oct 2018 to Oct 2019), reporting rates for both UK university-sponsored and NHS Trust-sponsored clinical trials increased significantly (59.7% to 72.1% and 35.4% to 56.3% respectively, by October 2019 covering 1,349 trials due to report). It also resulted in warnings from the government to institutions with poor reporting levels.

In 2015, the European Medicines Agency (EMA) published its policy on clinical data for medicinal products for human use (EMA Policy 0070), which required that previously unpublished clinical reports (including clinical study reports) from central regulatory applications be published in an anonymised format [I]. Following publication of the EU TrialsTracker [6] in September 2018, the reporting rate of EU clinical trials rose rapidly over the subsequent 12 months [6] in September 2018, from 51.2% to 61.5%, and increased further to 68.1% as of December 2020 [J(i)]. Clinical trial reporting by industry has also significantly improved as a direct result of TrialsTracker. The Director of the Clinical Disclosure Office at Novartis stated that “ *The TrialsTracker…helped allow Novartis to improve its excellent transparency compliance and achieve 100% compliance in the EU in 2020. In the US, we are proud to use these trackers to highlight our excellent compliance record.*” [K(i)]. Eli Lilly stated that TrialsTracker is used to provide monthly compliance reports and enabled them to meet EMA expectations [K(ii)].

The transparency advocacy organisation TranspariMED, citing TrialsTracker, reported that UK universities outperform European universities in clinical trial reporting [J(ii)], concluding that this was a result of combined pressure from parliament [C], research funders [F] and the media.

The findings from the Cochrane A159 review [2] were covered widely, criticising the money wasted on stockpiling unevidenced drugs. In June 2015, the UK Chief Medical Officer, concerned that widespread coverage could affect public trust negatively, asked the Academy of Medical Sciences to investigate how to restore public trust in scientific evidence for decision making. In their report (June 2017), ‘Enhancing the use of scientific evidence to judge the potential benefits and harms of medicines’, the Academy, cited the Cochrane review [2] as a case study in the introduction, stating that this emphasised “ the need for openness in decision-making processes to allow wider society to judge whether decisions are made based on sufficiently robust and relevant evidence” [L]. Recommendation 5 of the report addressed the publication of research findings.

Following the publication of the Select Committee report on Research integrity [C], the Telegraph used the EU TrialsTracker to identify three unreported vaccine trials from Public Health England [M(i)]. As a result of this coverage, and pressure from Sir Norman Lamb MP, PHE apologised, citing the EU TrialsTracker [6], and reported the results of all three trials [M(ii),(iii)]. In December 2020, PHE was at 100% compliance on the EU TrialsTracker.

TranspariMED has consistently used TrialsTracker data to pressure academic institutions in the US and Europe, resulting in increased compliance. The founder of TranspariMED states that “ TranspariMED has…used data from the Trials Trackers as the backbone of most of its advocacy work” and that they “have never encountered a data tool that has had such a dramatic and sustained positive impact on institutions’ and regulatory bodies’ behaviour” [N(i)]. TranspariMED reports of clinical trial reporting by German universities, using TrialsTracker data, resulted in increased compliance [N(ii)]. TranspariMED also affirm that after they used TrialsTracker data for a report on compliance in the US, “ the majority of the universities flagged as having compliance gaps have substantially improved their performance” [N(i)], illustrating the value of the FDAAA capabilities [5] developed by the DataLab team. Similar outcomes are described by TranspariMED in Austria, Denmark, the Netherlands and Spain [N(i)].