What the regulation requires of a lay summary, and where it stops
The EU Clinical Trials Regulation requires the sponsor of a clinical trial to submit a summary of the trial's results that laypersons can understand, together with the technical summary of results. It fixes which trials the requirement covers, when the summary is due, the database that holds it and what the consent form says about it. The requirement applied years after it was first planned to, and initial compliance with it was low. The United States does not require such a summary, some other countries have requirements of their own, and sources differ on whether a lay summary is also required for medical devices.
The EU requirement
Article 37 of the EU Clinical Trials Regulation, Regulation (EU) No 536/2014, requires the sponsor of a clinical trial to provide a summary of the trial's results that is understandable to laypersons. The summary is owed whatever the outcome of the trial. Its content is required to be unbiased and non-promotional. Annex V of the Regulation lists the ten elements the summary must address.
The requirement applies to clinical trials with at least one site in an EU member state. The Regulation covers all interventional clinical trials with medicinal products for human use conducted in the EU, and a lay summary is owed for all clinical trials, regardless of clinical phase and therapeutic area. Non-interventional studies and trials without medicinal products, such as surgery, fall outside the Regulation.
A generic medicine is not subject to the requirement, because its approval does not need clinical trials. Where the manufacturer of a generic runs a trial comparing it to its reference, though, the sponsor is required to develop a lay summary in addition to the technical trial report. A biosimilar needs a single clinical trial to establish clinical and safety equivalence, so a lay summary of that trial is required. From a regulatory perspective, lay summaries of clinical trials may therefore be more prevalent for biosimilars than for generics.
The Regulation requires member states to impose and implement penalties when its requirements are not met, and the penalties "shall be effective, proportionate and dissuasive".
Lay summaries are the one new aspect of the Regulation directly linked to patients and the general public. They are a novelty, because they are the first regulatory documents meant to inform the public. Other aspects of the Regulation, such as the central approval of clinical trials, were discussed intensively with stakeholders before they became part of it, but the lay summary requirement was included only at a later stage and without broad consultation. According to the European Patients' Forum, the requirements in Annex V were added at the last stage of negotiations, by the European Council and without consultation with patient groups.
Deadline, database and consent
Under Article 37(4) the lay summary accompanies the summary of results, and both are submitted to the EU database within one year of the end of the trial in all the member states concerned. For a paediatric trial, or a trial listed in a paediatric investigation plan, the deadline is six months. Where submission within a year is not possible, for instance because the trial is continuing at sites outside the EU, the results should be submitted as soon as possible, and the protocol should say so and give the reason. Once the Regulation is fully adopted, the sponsor must provide the summary as a separate document within twelve months of the end of the trial for each trial in category 2 and category 3, so the summary should be provided at the same time as the technical summary of trial results. A limited deferral is possible, depending on the trial's category and the disclosure option the sponsor chose.
The Regulation mandates that a lay summary of the results be made available to all trial participants no more than a year after the last patient's last visit. The summary of results and the lay summary were to be published twelve months after the end of the trial. For studies with sites in EU member states, the lay summary was to be published to the European database within 12 months of the last patient's last visit. In September 2020 the English lay summary and its translations into the local languages of the region where the trial is conducted were to be posted on the portal twelve months after the end of the trial. By March 2023 sponsors needed to submit the lay summary together with the summary of clinical trial results within twelve months of the end of most clinical trials.
The summary must be submitted to the Clinical Trials Information System. That system is an online portal designed to aid the dissemination of lay summaries. It replaces the EudraCT database and includes a searchable database for healthcare professionals, patients and the general public, which is to contain detailed information on all clinical trials authorised through the system, including their outcomes. Within the EU database, the technical summary, the lay summary, the protocol and the clinical study report of one trial are to be made available together, and linked to data from other trials using the same investigational product. Once the Regulation replaced the directive, a lay summary of results was to be posted on the portal, following health literacy and numeracy principles and detailing in lay language how the trial was conducted and its results.
Article 29(6) requires the informed consent used to enrol patients to explain that the technical and lay summaries will be available in the database and, as far as possible, when.
The application date
Regulation (EU) No 536/2014 was adopted on 16 April 2014, repealing Directive 2001/20/EC, and came into force in 2014. Accounts differ on when it was published: two have it published in May 2014, one of them on 27 May, and another has it released in June 2014. Its full implementation was to come on 28 May 2016 at the earliest.
Article 99 makes the Regulation apply six months after the European Commission publishes a notice confirming that the EU portal and database are fully functional, a date predicted in 2015 to be 28 May 2016 at the earliest. The Regulation was to apply to clinical trials registered once it was in operation, not before 28 May 2016. It was also to become effective "not earlier than 28 May 2016", or once the new EU database had become available.
In June 2018 three accounts gave different dates. One expected the Regulation to come into force in 2019 and to be fully applied only then, once the EU database that includes lay summaries became fully functional. A second expected it to become applicable six months after the European Commission confirmed that the portal and database were fully functional, which was expected to happen in early to mid-2020. A third had its provisions taking effect no earlier than mid-2020, delayed by the challenges of the single EU portal and database, with the Clinical Trials Directive 2001/20/EC and the Paediatric Regulation (EC) No 1901/2006 remaining in force in the meantime.
In June 2019 the requirement was to go live with the launch of the EU Clinical Trial Portal and Database, which was expected during 2019.
The requirement had originally been planned to take effect in 2018, but the creation of the database and upload portal was delayed, so it was then likely not to be implemented before 2020. Another account had the Regulation likely to be implemented in 2023.
Before the portal for uploading summaries opened, companies were expected to prepare the summaries, following the list of ten required items, and make them available. In the meantime many pharmaceutical companies, UCB and Boehringer Ingelheim among them, made their summaries available to the general public on their own websites.
The requirement came into effect in January 2022, after the launch of the Clinical Trials Information System, and became compulsory for all interventional clinical trials in the EU with the opening of that system's portal. The Regulation came into application at the end of January 2022 with a three-year transition period: the system became mandatory for all new clinical trial applications as of January 2023, and by 31 January 2025 all ongoing trials approved under the Clinical Trials Directive were to be governed by the Regulation and transitioned to the system.
How far the requirement is met
Fewer than 2% of all clinical trials completed or terminated within a three-year period had returned results to study volunteers in plain language. Research has indicated that the accessibility of lay summaries to patients is lacking and that initial compliance with the Regulation has been low, though compliance may improve with the legislation in effect. Despite the movement towards clinical trial transparency, easily accessible plain language summaries of clinical trials are scarce, and it is hoped this will change as demand from, and awareness among, patients and the general public increases.
The requirement in the move towards plain language
The requirement belongs to a wider move towards plain language. Support for presenting clinical trial information in plain language is growing, the field is rapidly evolving and regulations are being introduced to encourage it, with the European Medicines Agency taking the lead in requiring plain language summaries. The requirement is part of efforts to increase the disclosure and transparency of clinical trial results. It is also part of a continuing drive to inform and involve patients better, and acknowledges the important contribution patients make to the advancement of medical research.
The public's demand for more and better scientific information is not new, and regulators have already responded with more transparency and patient engagement. The largest changes to documents have been the patient-friendly part of the risk management plan, mandated by the European Medicines Agency in 2013, followed closely by Regulation (EU) 536/2014, which mandates a lay summary of clinical trial results.
Medical devices
The Clinical Trials Regulation does not apply to studies of medical devices, unless the devices are part of a clinical trial involving a medicinal product. Practitioners differ on whether a lay summary is also required under the EU Medical Device Regulation. One understood, as far as they knew, that it is required only under the Clinical Trials Regulation, while another held that it is required under the Medical Device Regulation too, as part of an MDCG document.
Under the EU Medical Device Regulation, the lay summary is a new document of a device clinical investigation, addressed and accessible to the lay public, that may need to be published in the local language. Disclosure on the European database on medical devices was expected to resemble that for medicines in its protocol and results postings.
The United States
The FDA does not require a lay summary of clinical trial results, but recommends patient-friendly summaries of them. Lay summaries are not specified in the FDA Amendments Act, which legislates the disclosure of clinical trial results in the United States, though the FDA encourages plain language summaries of aggregate results and has provided draft guidance for developing them voluntarily.
The technical summary of results that Article 37 obliges the sponsor to submit was expected to be very similar to the results postings on ClinicalTrials.gov and EudraCT, but unlike in the United States the posting "shall be accompanied by a summary written in a manner that is understandable to laypersons", whose requirements Annex V sets out briefly. Returning summary results of clinical trials to patients and the public had been discussed for some years in the United States and the EU, but the annex was the first list a regulatory agency had given of the items such a document should include.
Much of the discussion on lay summaries has focused on the EU, but in 2007 United States legislation already allowed for a lay summary of results, without making it mandatory. The FDA Amendments Act of that year expanded ClinicalTrials.gov to include basic results posting and, in Title VIII, §801, introduced a provisional requirement allowing for the dissemination of a summary of the clinical trial and its results written in non-technical, understandable language for patients, without being misleading or promotional. Because that summary was not mandatory under US law and a final ruling was pending, it was widely ignored. The FDA nonetheless encouraged returning results to trial participants and, like the European Medicines Agency, supported the work of the Harvard Workgroup and the Center for Information and Study on Clinical Research Participation.
By 2018 the United States encouraged sponsors to provide plain language summaries to trial participants, but its Final Rule on registering trials and submitting results did not include them. By June 2018 the regulators working on the Final Rule under FDAAA 801 had declined to require lay summaries of clinical trial results for the time being, until further research determined whether such summaries can be produced reliably and consistently without being promotional or misleading.
By September 2024 two pieces of legislation had pushed for lay summaries to be made available to the public, through ClinicalTrials.gov in the United States and through the European lay summary that became mandatory with the Clinical Trials Information System.
Other countries
Accounts differ on whether a lay summary is required outside the EU. One holds that explicit legislation has not been introduced beyond the EU, and that in the United Kingdom the Health Research Authority, a division of the National Health Service, "asks" research sponsors to submit plain language summaries as part of the final research reports published on its website. Another has the United Kingdom requiring them, through the "Make it Public" strategy of the Medicines and Healthcare products Regulatory Agency, under which research sponsors must publish a plain language summary of their findings no later than 12 months from the end of the study, and through the Health Research Authority, which requires sponsors to make lay summaries of trial results available to the public.
The United Kingdom's National Institute for Health and Care Research requires plain English summaries, in the style of the plain language summary that accompanies a publication, alongside research proposals. In September 2024 the Netherlands' Medical Research Involving Human Subjects Act required trials conducted in the Netherlands to disclose study results within 12 months of study completion, as a scientific summary or a plain language summary, on the registry of the Central Committee on Research Involving Human Subjects. Ukraine and Türkiye may be introducing requirements for plain language summaries of results.
Towards a global standard
Lay summaries of clinical trials were expected to become standard in clinical research. Because the EU Regulation was to make them mandatory in the EU and expectations on returning clinical trial data to patients were also increasing in the United States, it was judged highly likely that they would become a standard in clinical research conducted at a global level.
In June 2019 lay summaries were required only for trials with a site in the European Union, and other regulatory bodies were expected to introduce similar requirements in the future. In December 2020 a tightening of the clinical trial results regulation and its enforcement was expected in the EU and North America, and it could result in global adoption, with the potential to increase patient engagement and trust in clinical development. A sponsor acting globally needs data disclosure policies that comply with the requirements of the FDA and with the EU regulations as well.