What the EU Clinical Trial Regulation requires of a sponsor
The EU Clinical Trial Regulation sets a European transparency regime for each individual trial. It runs through a portal and database of its own, separate from the European Medicines Agency's policy of publishing the clinical data in a marketing authorisation dossier. Under it each trial is registered, and its sponsor discloses the trial's summary results and makes its documents public, redacted to protect personal data and commercially confidential information, on timings that depend on the trial's category and the age of its participants. Transparency rules revised in June 2024 narrowed which documents become public and ended the deferral of their publication.
The Regulation and EMA Policy 0070 side by side
The Regulation is distinct from the agency's policy on the publication of clinical data, Policy 0070. The Regulation covers documents at the level of a single clinical trial performed in the EU or EEA. The policy covers clinical trial documents and data at the level of a marketing authorisation dossier: under it the agency proactively publishes the clinical study reports submitted with marketing authorisation applications for human medicines. So the policy reaches clinical reports of studies beyond the Regulation's scope, such as trials conducted outside the EU but submitted to the agency for marketing authorisation in Europe. The Regulation covers investigational medicinal products irrespective of their marketing authorisation status. The policy covers products whose marketing authorisation went through the centralised procedure, whether it was approved, rejected or withdrawn. The Regulation discloses through the EU portal and database, the policy through the agency's clinical data publication website.
The Regulation's portal and database
The Regulation transforms the level of information publicly available for each clinical trial carried out in the EU by requiring transparency on the authorisation, conduct and results of the trial. The Regulation's key instrument for dealing with clinical trials transparently is its clinical trial portal and database. It serves as the source of public information on the clinical trial applications assessed and the clinical trials conducted in the EU, from the decision on each trial up to the inclusion of its results.
The database is publicly available unless one or more of four exceptions apply: protection of personal data; protection of commercially confidential information, taking into account in particular the marketing authorisation status of the medicine, unless there is an overriding public interest; protection of confidential communication between member states in preparing their assessment; and protection of member states' supervision of clinical trials. How the Regulation's transparency rules would be applied in the database was put out to public consultation on 21 January 2015, with comments invited before 18 February 2015. The proposals under consultation aimed to balance the right of patients and the public to extensive and timely information on clinical trials against developers' and researchers' need to benefit from their investments, which the agency said would support the EU as a suitable location for innovative, cutting-edge research and development of medicines.
As planned in January 2015, the major characteristics of each trial, the start and end of recruitment, the end date and substantial modifications were to become public as they occurred, beginning with the decision on the trial. A summary of results was to be published 12 months after the end of the trial. For trials included in an EU marketing authorisation application, clinical study reports were to be published 30 days after the authorisation procedure had been completed or the application withdrawn.
As of 2020, the Regulation was expected to increase transparency requirements, with disclosure of clinical documents at a much earlier point in a trial's timeline than before. The database was to house all the relevant information on a trial: protocol, scientific summary, clinical study report and safety reports, including what may already have been disclosed through registration, results reporting and EMA Policies 0070 and 0043.
The three duties of trial-level disclosure
Disclosure at the level of one trial has three main parts: registration of a new trial, disclosure of the summary results of a completed trial, and upload of the data and documents relevant to the trial. Every interventional trial is registered. Registration is performed automatically for each new trial by the agency or the member state on receipt of the official request for authorisation, with selected information fields released to public view. The information submitted for registration is based on the protocol and includes the indication studied, the primary and secondary outcomes, the inclusion and exclusion criteria, the estimated number of participants and the estimated time of outcome completion. Updates are required as the study proceeds, and their dates and details form a version-control trail open to public view. The sponsor performs the other two parts actively: it discloses the summary results, and it uploads the data and documents, a duty that was to start when the new EU portal and database became active. Articles 94 and 95 of the Regulation require member states to develop penalties for failing to submit required information for public disclosure to the EU database.
The Regulation's operational requirements for disclosing information and documents often differ only slightly from a trial's usual reporting practices, but trial managers, medical writers, statisticians and data managers need to plan them so that information is entered efficiently into the public database.
Trial categories and disclosure timing
For the purposes of the Regulation, trials fall into three categories.
- Category 1, pharmaceutical development trials: phase I trials in healthy volunteers or patients, phase 0 trials exploring pharmacokinetics or pharmacodynamics, bioequivalence and bioavailability trials, similarity trials for biosimilar products, and equivalence trials.
- Category 2, therapeutic exploratory and confirmatory trials: phase II and III trials, covering not only trials by the marketing authorisation holder but also trials by other researchers looking at safety and efficacy in new indications, pharmaceutical forms and routes of administration, or patient populations, and not covered by the definition of category 3.
- Category 3, therapeutic use trials: phase IV trials and low-intervention trials. A low-intervention trial is one in which the investigational products, excluding placebos, are authorised; under the protocol they are used within the terms of their marketing authorisation, or their use is evidence-based and supported by published scientific evidence on their safety and efficacy in any of the member states concerned; and the additional diagnostic or monitoring procedures pose no more than minimal additional risk or burden to the subjects' safety compared with normal clinical practice in any member state concerned.
The timelines for posting a trial's documents are not uniform but depend on the trial's category and the age of its participants. The regulators allowed later disclosure for category 1 trials than for category 3 trials, taking into account the products' stage of development. The rules and criteria for applying the Regulation's disclosure provisions are set out in an appendix on disclosure rules to the agency's functional specifications for the EU portal and database (EMA/42176/2014).
As set out in 2018, trial-level disclosure applied to trials in adults ongoing or started after May 2004 and to trials in children ongoing or started after May 2006. The Regulation provides for publicly disclosing details of phase 1 trials, contrary to the general understanding that they would not be in public view, and this disclosure was expected to start once the new database became fully operational. In 2018, however, data on phase 1 trials in adults that were not part of a paediatric investigation plan were not made public.
A trial counts as paediatric if it includes at least one participant younger than 18, and even the unintended inclusion of such a participant may bring the trial under the paediatric rules. A trial's completion date is the date on which the final subject was examined or received an intervention for the final collection of data, whether the trial was completed according to the protocol or stopped prematurely. When a trial's authorisation is denied, the date of the decision on the trial is taken as the date of its end for applying the disclosure rules and posting the relevant documents.
Summary results
Article 37(4) requires the sponsor to submit a summary of the trial's results to the Clinical Trials Information System, irrespective of the trial's outcome and in all the EU languages in which the trial was conducted, within one year of the end of a trial in adults and within six months of the end of a trial in children. Summary results are disclosed for any tested medicinal product, whether or not it has been approved. As of 2024, the paediatric requirements, the six-month deadline among them, also apply to adult trials included in a paediatric investigation plan and, in special circumstances, to paediatric trials run outside the EU and EEA.
As set out in 2018, the deadlines ran from the last patient's last visit. The twelve-month deadline could instead run from a later point that the protocol defines as the end of the trial. In 2020 one writer gave the paediatric deadline as six months from the global end of the trial. As of 2024, summary documents are due 12 months after the end of an adult trial in the EU and EEA, and six months after the end of a paediatric trial there. Where a trial has sites outside the EU and EEA and the deadline is to run from the global end of the trial, the protocol must capture those sites and define the global end.
The Regulation permits the summary to be submitted after its deadline if there are valid scientific reasons detailed in the protocol. The summary must then be submitted as soon as possible, and the protocol must specify when the results will be submitted, with a justification for the delay.
Annex IV of the Regulation sets out the content of the summary report and states that information shall be provided for as many endpoints as the protocol defines. On one reading, the summary is therefore expected to include the results of all primary and secondary endpoints defined in the protocol and the statistical analysis plan, not just the main or key endpoints as is sometimes assumed. Endpoints evaluated post hoc, as exploratory analyses or as "other" are not expected to be disclosed, although they may be, and the database has entry fields for them.
On another reading, the Regulation describes less definitively which endpoints are required. On that reading, at least one primary endpoint is required, and as of 2018 the European Medicines Agency recommended that data for key endpoints be disclosed rather than mandating the reporting of all primary and secondary endpoints. The agency had earlier advised that there was no link between the results that must be disclosed and the primary and secondary endpoints specified in the protocol.
Where the protocol provides for an intermediate data analysis before the end of the trial and its results are available, a summary of those intermediate results should be submitted to the EU database within one year of the intermediate analysis date. So it is important to finalise the interim analysis report in time for that obligation to be met.
The provisions on endpoints, on intermediate analyses and on disclosing phase 1 trials bear on study planning, on how endpoints are defined in the protocol, on how often data are evaluated during the study, and on the preparation of the clinical study report. In 2020 one writer judged it likely that, during the first phase of implementation, the format required for the results summary of intermediate and end-of-trial analyses would be similar to a clinical study synopsis or disclosure synopsis. In that case the requirement for full data sets in EudraCT might phase out and the effort of preparing results summaries there would be reduced, although this might change as new functionalities were added to the portal.
Trial documents and their deferral before June 2024
As set out in 2018, the Regulation discloses clinical trial information generated during a trial's life cycle, including each version and modification of the clinical study protocol, the assessment and decision on trial conduct, the summary of trial results with its lay summary, the redacted main part of the clinical study report, inspection reports, the investigator's brochure, the safety and efficacy sections of the investigational medicinal product dossier, and the subject information sheet. The dossier's sections are best structured as modules that can be separated easily and sent for public posting on different timelines, and its quality section is not disclosed.
The Regulation created provisions for deferring the publication of clinical documents according to the trial's category. As set out in 2018, deferral of posting was possible for trials in adults but not for trials with paediatric participants or trials included in a paediatric investigation plan. As of 2020, the provisions were as follows.
| Category | Phases | Deferral term | Documents that may be deferred |
|---|---|---|---|
| 1 | Phase I, phase 0, bioequivalence, bioavailability | Until marketing authorisation of the investigational product used in the trial or seven years from the end of the trial, whichever is earlier | Protocol, subject information sheet, changes to previously public information or documents, investigator's brochure, safety and efficacy sections of the product dossier |
| 2 | Phases II and III | Until marketing authorisation of the investigational product or five years from the end of the trial, whichever is earlier | Protocol, subject information sheet, changes to previously public information or documents, safety and efficacy sections of the product dossier |
| 3 | Phase IV, low-intervention | None | The protocol may be deferred until the summary results are reported if the sponsor justifies the novelty of the trial's design and hypothesis |
In 2020 one writer judged the deferral rules to be of no significant benefit to sponsors, because other platforms and policies, such as the EU Clinical Trials Register and EMA Policies 0043 and 0070, would continue to request protocol information, clinical study reports and clinical and safety modules to be made public irrespective of the trial's phase.
Redaction and anonymisation
The sponsor, or whoever submits a report or data set to the public database, is responsible for redacting or anonymising it before loading it into the database, so that personal data, especially those of trial participants, and commercially confidential information are not disclosed. Before submitting to the Clinical Trials Information System, sponsors need to anonymise personal data and commercially confidential information in the clinical documents, the applications and their substantial modifications, the study results and ad hoc reports. In 2018 the agency planned separate guidance on redacting and anonymising documents disclosed under the Regulation, expected to be consistent in scope with that already available for EMA Policy 0070.
What the June 2024 revision changed
The revision of the Clinical Trials Information System's transparency rules was triggered by stakeholders' feedback after the system's initial launch. The revised rules were adopted by the agency's Management Board on 5 October 2023, following a public consultation held between May and June 2023. They were implemented on 18 June 2024, when a new version of the system's public portal was launched. The rules reduce the amount of information submitted to the agency for public disclosure, simplify the sponsor's processes, strike a balance in protecting personal data and commercially confidential information, and focus on simpler and earlier disclosure to patients and researchers. The agency puts that balance as one between transparency of information and the protection of commercially confidential information. Striking it was the aim of the system's relaunch. The agency holds that the rules benefit patients, because the key trial information that patients flagged as most relevant to them is published early, sponsors, because they introduce process simplifications, and healthcare professionals, because the system is more user-friendly, easing access to information on trials and enrolment in them and raising awareness of possible treatment options. When the new version launched, about 4,000 trials with issued decisions became publicly accessible through the system's search, the portal was to add about 500 newly authorised trials a month, and further features to improve its usability were to follow over the next months.
The requirements up to and after 18 June 2024 differ in these respects. Before that date all documents except quality-related ones were public; afterwards only documents of key relevance to researchers and patients are. All versions of a document were public, and now only the most recently approved version is. Publication could be deferred to protect commercially confidential information, and deferral is no longer available for any documentation. The deferral mechanism had allowed a sponsor to delay publishing key documents for up to seven years after the end of the trial in the EU and EEA. Redaction of documents is now recommended to protect personal data and commercially confidential information. With deferral revoked, redaction is the method sponsors must rely on to protect them in published documents. Almost all of an application's data fields were public, and fewer of its structured data fields are now. Historical trials, whose applications were submitted before 18 June 2024, now show only their structured data, and none of the documents submitted for publication before that date will become public, although certain updates to such an application trigger publication of the documents in scope of the revised rules.
For applications submitted on or after 18 June 2024, the publication of data and documents can no longer be deferred, they are published on the timelines set for the trial's category, the participants' age and the trial phase, and publication focuses on key documents of interest. Data on applications submitted earlier are published in line with the principles and timelines of the revised rules.
The investigator's brochure is no longer published, as Annex I, Table VI of version 2 of the agency's guidance on protecting personal data and commercially confidential information in the system now states. This rationalisation of the published documents is meant to reduce the complexity and the workload of those doing redactions.
Which documents become public, and when, since the revision
Documents must be submitted to the system disclosure-ready. Where redaction is needed to protect personal data and commercially confidential information, the sponsor must submit two versions, one for publication and an unredacted one not for publication that is used for the regulatory assessment, and has to upload them in the correct order for each to be channelled correctly. Annex I's Table VI lists the fields and documents not intended for public access.
The deadlines for submitting results documents are defined in the Clinical Trials Regulation and the Paediatric Regulation, separately from the publication timelines, and the two sets should be told apart. The publication timelines, from Annex I's Table II, depend on the trial category. The protocol, its synopsis and the patient-facing documents related to trial endpoints become public for every trial: for category 1 trials in children or in a paediatric investigation plan when the results summary is submitted, for category 1 trials in adults 30 months after the end of the trial in the EU and EEA, and for category 2 and 3 trials at the first member state's decision on the application. The subject information, informed consent form, recruitment arrangements and summary of product characteristics become public only for category 2 and 3 trials, on the member state's decision. The lay summary, the summary of results and any clinical study report become public as soon as they are submitted, except for category 1 trials in adults, where they become public 30 months after the end of the trial in the EU and EEA. Intermediate or interim results summaries specified in the protocol must be submitted when available but are not made public.
The system has more structured data fields than EudraCT had, and what is entered in them cannot be redacted. When each field becomes public depends on the trial's category, the type of information and whether the Paediatric Regulation applies, and that timing needs attention.
The revised rules were implemented together with the release of the agency's guidance on protecting personal data and commercially confidential information, its Annex I and other related documents. Version 2 of that guidance, issued on 18 June 2024, aligns with the revised rules: it drops its chapter 5 as no longer applicable and adds sections on the publication principles for historical trials and on transition trials. Its principles of protection are unchanged from earlier versions, it should be read with its Annex I, and a questions-and-answers document is also available. Two further agency documents, on application fields and on notifications and results, let a sponsor check which structured fields and documents apply to each trial category. The resources created to help sponsors understand the revised rules include a user guide and an overview of which data and documents with key information are published in the system. The agency also publishes supporting documents on the clinical trial disclosure processes and activities.