What disclosure means and how the requirement grew
Disclosing clinical trial data means making it available to third parties, and the term carries different senses for publication and regulatory professionals. The requirement grew in stages, from registering a trial to posting its results, publishing whole clinical documents and sharing participant data sets, driven by regulators in the United States, Europe and elsewhere.
What disclosure means
Clinical trial disclosure is the act of making clinical trial data available to one or more third parties. It is not the conflict-of-interest disclosure that doctors make under US legislation. Transparency means openness and accountability.
Public disclosure means different things to different groups of medical writing professionals. To publication professionals it means publishing research findings whether the outcomes are negative or positive, and disclosing, among other things, funding, the involvement of medical writers in developing a publication and conflicts of interest. To regulatory professionals it means the registration, status reporting and results posting of clinical studies in publicly accessible internet registries. It also covers the on-request or proactive sharing of clinical regulatory documents, such as synopses, clinical study reports, clinical overviews and clinical summaries, or of individual patient data, and the publication of clinical trial results in journals.
Public disclosure can be thought of as a continuum that includes clinical trial data published in peer-reviewed journal articles. Many peer-reviewed journals require authors to share their raw, unprocessed data with other scientists or to state the availability of raw data in the published article, and minimum standards for anonymising data published in journal articles have been proposed.
The stages of the requirement
Before 2000 clinical trial data were kept very secret: even protocols were not often published, and trial data were released perhaps only in journal articles, which might carry only part of the data. Over the years disclosure moved from voluntary to mandatory, and from the study design and certain sections of the protocol to a required summary of results, then to whole documents, and towards full data-set disclosure.
When registration of clinical trials in a publicly accessible database was first required, some twenty years before 2018, the goal was to inform patients, relatives and treating physicians that a clinical trial exists, and so make enrolment into it easier. Registration then progressed to the disclosure of summary results for completed clinical trials for all drugs investigated in clinical trials, irrespective of their marketing approval status. The further development being implemented in 2018 was the sharing of de-identified or anonymised trial participant data sets, which would enable re-analysis by a wider community of researchers. Such additional analyses could potentially expand the insights into the safety or efficacy of the investigated product, and data from several trials could be pooled into a meta-analysis, enriching the information available to inform medical and prescribing decisions that would otherwise be based on individual studies.
Regulators' drive to make more information on clinical research publicly available has resulted in requirements for sponsors to publish summary results of clinical trials, on registries such as ClinicalTrials.gov, EudraCT and other regional registries, and clinical trial documents such as protocols, statistical analysis plans, clinical study reports, clinical overviews and summaries. Publication driven by regulators includes robust validation and controls, in which a regulatory reviewer reviews the information or automated system controls validate it. To improve transparency, the regulatory health authorities of various countries have mandated the publication of clinical documents, which give detailed information about the design, conduct and analysis of clinical trials and more comprehensive information on trial results than more traditional public sources such as journal manuscripts. The publication of clinical data enables a comprehensive and independent analysis of trial results.
The agencies behind it
The US Food and Drug Administration was founded as a scientific institution in 1848, and the US Congress passed the Pure Food and Drugs Act in 1906; thereafter legislation gradually required greater accountability for marketing food and drugs, which in turn increased the need for testing drugs in clinical trials. The European Medicines Agency was founded in 1995 as a partner of the European Commission and of the regulatory authorities within individual countries. Both agencies, often in partnership with patient advocacy organisations, have been influential in advancing the concept of clinical trial disclosure.
The countries of the EU and of the European Economic Area (Iceland, Liechtenstein and Norway) and the United States are particularly active in advocating and enforcing clinical trial disclosure, and some 40 further countries worldwide have national disclosure obligations, some of them with more than one relevant registry or database that needs attention.
The Declaration of Helsinki
The 2000 version of the Declaration of Helsinki was the first to highlight the need to share research results publicly: authors have a duty to make publicly available the results of their research on human subjects and are accountable for the completeness and accuracy of their reports, and negative and inconclusive as well as positive results should be published or otherwise made publicly available. The updated Declaration of 2008 included a statement that making study results available to the public was an ethical duty. Under the Declaration, the design and results of all clinical studies should be publicly available and are subject to ethical standards.
In the United States
The United States was at the forefront, with the creation of the ClinicalTrials.gov registry, of which the FDA Modernization Act of 1997 was the main driver. ClinicalTrials.gov began requiring protocol registration in 2000, and at its launch it included only a subset of the clinical studies conducted in the United States. Since 2005 the International Committee of Medical Journal Editors has required a trial to be registered before patient enrolment begins if its results are to be considered for publication, and other editors and some countries and regions also require clinical trial information to be registered on publicly available websites before enrolment.
The Food and Drug Administration Amendments Act of 2007 (FDAAA), signed on 27 September 2007, had among its goals to improve the transparency of clinical trials. The Food and Drug Administration Revitalization Act, signed into law on 27 September 2007, set a precedent by requiring sponsors of clinically directive therapeutic trials of phase II and higher to register them upon inception in a public database sponsored by the National Library of Medicine, in a specified table format, so bolstering the position of the International Committee of Medical Journal Editors. Title VIII of the FDAAA expanded registration to all clinical trials of drugs, biologic agents and devices except phase I trials, where previously the FDA had required registration only of trials for serious or life-threatening diseases, although many medical journals required trials to be registered for their results to be published. Title VIII also required the summary results of clinical trials to be posted in a newly established databank, an obligation that began in 2008 for studies of approved products: within 30 days after the drug's approval for trials completed before it, and no later than one year after the completion date for trials completed afterwards. Failing to publish the data within the required time carried significant monetary penalties, of $10,000 per day. A new section of the Prescription Drug User Fee Act, renewed in September 2007, required clinical trial sponsors to show evidence of having submitted a report for publication within one year of last patient, last visit, and the results to be published or posted on a public website within two years.
The Final Rule (42 CFR Part 11) of the US National Institutes of Health, of January 2017, covers the protocol registration of applicable clinical trials, the disclosure of trial results, the disclosure of the full protocol and statistical analysis plan after appropriate redactions, and the consequences of non-compliance. The FDA initiated a pilot project to release summaries from the pivotal clinical trials included in approved new drug applications. The FDA's Clinical Data Summary Pilot Programme, of January 2018, covered pivotal phase III clinical study reports; it was run on a single clinical study report, which was completed and whose learnings were shared, and further information was awaited. The FDA also released a redacted drug approval package.
In the European Union
Registration and results
The EU started perhaps a little late and had some catching up to do, and it then moved very fast. In Europe the driving legislation was already in place in 2001: Regulation (EC) No 1049/2001 stipulates the fundamental right of EU citizens to information access and governs public access to the documents of the European Parliament, the Council and all other institutions, including the EMA. This access-to-information law was the foundation of EMA Policy 0043 (2010), the EU Clinical Trials Register (2011), the EU Clinical Trials Regulation (2014) and EMA Policy 0070 (2016). Directive 2001/20/EC, released in 2001 to harmonise requirements and ensure data quality for clinical trials across all EU member states, stipulated the creation of an EU-wide database, later called EudraCT, in which clinical trials conducted in the EU had to be registered, but in 2008 the EU had no legally binding obligation to publish trial results. Protocol registration in the EU began with the beginnings of the EU clinical trials register. The EU Clinical Trials Register began publishing protocol and results information on interventional clinical trials from EudraCT in September 2011. A 2012 European Commission guideline obliged sponsors to post in EudraCT the summary results of all clinical trials conducted in at least one EU member state, but the functionality for posting did not become available before June 2014. From July 2014 the EMA required summary results to be posted in EudraCT 12 months after study completion, or 6 months for paediatric trials.
The Clinical Trials Regulation
Regulation (EU) No 536/2014 on clinical trials dates from April 2014 and came into force on 16 June 2014. Several articles of the Regulation mention transparency, and transparency is also an important element of the draft medical device regulation. Transparency was expected to affect the device area as well, although how remained an open question. The Regulation was implemented on 31 January 2022, and document publication through the Clinical Trials Information System began at the beginning of 2022. Following a public consultation on the rules for the operation of the Regulation and its Clinical Trials Information System, the EMA Management Board adopted revised transparency rules for the system in October 2023.
EMA Policy 0070
EMA Policy 0070 was published in October 2014 and became effective on 1 January 2015, setting the scene for the EMA's proactive publication of entire clinical trial reports and clinical submission documents. The EMA was the first regulatory authority to publish the clinical data included in marketing authorisation applications. Document publication under Policy 0070 began in 2016, when posting became a reality in October. In the autumn of 2016 the EMA clinical data website went live, and clinical study reports saw the light of day for the first time. Publication under Policy 0070 was suspended from September 2018, except for COVID-19 studies, and restarted in 2024.
Voluntary disclosure by industry
In July 2013 the member companies of the European Federation of Pharmaceutical Industries and Associations and the Pharmaceutical Research and Manufacturers of America committed to publishing summary results of clinical trials for products approved in the United States or the EU and its member states, and several pharmaceutical companies have since started sharing trial results with trial participants voluntarily. The commitment to some extent pre-empted some of the requirements introduced by the EU Clinical Trials Regulation.
Clinical data are also disclosed voluntarily, on many company websites and through clinicalstudydatarequest.com, a consortium of some of the biggest pharmaceutical companies through which a researcher can register and request access to clinical trial data.
Other regulators
Japan's Pharmaceuticals and Medical Devices Agency began its disclosure of information in November 1999, covering all Module 2 documents of the common technical document, clinical study report synopses and mini-narratives for serious adverse events, with full clinical study reports out of scope. Health Canada followed the EMA in March 2019 with its Public Release of Clinical Information, which makes anonymised clinical information in drug submissions and medical device applications publicly available for non-commercial purposes.
Where disclosure stood and where it was heading
In 2017 the expected next steps were data-set disclosure, the further implementation of the Clinical Trials Regulation, the release of the medical device regulations, expected in 2017 with implementation a few years later, and a single EU portal, planned for 2018, that would bring the data sets, the documents and the registry together with a certain level of public access. Disclosure has become a requirement at different levels: at the clinical trial level through registration in the EU register, at the marketing authorisation application level through the disclosure of documents under Policy 0070, and at the data-set level as the next step.
A paradigm shift in clinical trial data reporting was occurring as data became increasingly publicly accessible, and the US FDA, Health Canada and other health authorities were expected to follow the EMA in publishing clinical data. How similar the processes would be across individual regulatory authorities remained unclear, and as the different health authorities put new processes and systems in place, fulfilling all requirements for public disclosure of clinical data would become increasingly challenging.
The COVID-19 pandemic brought a worldwide surge in freedom-of-information requests for COVID-19 vaccine clinical trial data. By 2024 many of the regulations and policies governing public disclosure of clinical trial data and documents remained unchanged, but the way they were implemented had changed significantly. By 2024 over half a million studies were registered on ClinicalTrials.gov and over 4,000 on the recently launched EU Clinical Trials Information System, approximately 430 marketing authorisation procedures were on the EMA clinical data website, and over 650 records were on Health Canada's Public Release of Clinical Information. Transparency and disclosure were still nascent in other fields of research: clinical research on medical devices and in vitro diagnostics was still awaiting a fully functional European Database for Medical Devices (EUDAMED) to be on a par with medicinal products, with a clinical investigation module of EUDAMED expected in 2027–2029.