Transparency of clinical trials and its influence on the documentation under the Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use

February 18, 2022
Transparency of clinical trials and its influence on the documentation under the Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use

One of the objectives of the Regulation No 536/2014 is to increase the transparency of clinical trials among the general public. The public access to the data of clinical trials will be guaranteed by the EU portal and database – Clinical Trials Information System (CTIS). The CTIS workspaces and system functionalities will vary among different groups: Authorities of EU Member States, European Commission, Sponsors, Market authorisation (MA) applicants and Market authorisation holders (MAH) and Members of the public. However, it should be emphasized that as a result of the provisions of the Regulation, public access to data related to a clinical trial will be greater than in the case of the Directive 2001/20/EC. The data provided to the public will cover the period from the authorization of the clinical trial to its final results. Thus, the future publication of clinical trial data and appropriate preparation of documentation for a clinical trial should already be taken into account when planning the initial submission of an application for clinical trial authorization under the Regulation or transition of the clinical trial from the regulatory framework of the Directive to the regulatory framework of the Regulation.

According to “Appendix, on disclosure rules, to the “Functional specifications for the EU portal and EU database to be audited – EMA/42176/2014  “” supplementing the Regulation, during establishing the rules on transparency of clinical trial data, it was extremely important to maintain a balance between the rights of patients, the public’s entitlement to information on clinical trials, and the interests of developers and researchers to benefit from investments. Overall, publicly available data on clinical trials in the CTIS will include:

  • the main characteristic of the clinical trial (e.g. design, therapeutic intent, information on investigational medicinal product);
  • completion of the assessment and decision on authorization of the clinical trial;
  • start and end dates of recruitment;
  • information on substantial modifications and notifications to trials;
  • information about the end of clinical trial (also premature termination) and within 1 year the summary of the results which should be accompanied by a summary written in a manner that is understandable to laypersons;*
  • for clinical trials included in a MA application in the EU clinical study reports should be submitted within 30 days after the day the MA has been granted, the procedure completed, or the applicant has withdrawn the application.

* The Regulation meets most of the requirements previously imposed by the Paediatric Regulation (EC) No 1901/2006 regarding clinical trials conducted in the EU. However, the deadline for the submission of results is much shorter for paediatric clinical trials.

According to the Regulation, data will not be made available to the public in the CTIS if their confidentiality is related to:

  • personal data protection,
  • the protection of the commercially confidential information, in particular through taking into account the status of the marketing authorisation for the medicinal product, unless there is an overriding public interest in disclosure,
  • the confidential communication between Member States in relation to the preparation of the assessment report,
  • ensuring effective supervision of the conduct of a clinical trial by Member States.

The “Appendix, on disclosure rules, to the “Functional specifications for the EU portal and the EU database to be audited – EMA/42176/2014”” accurately describes the principle of data transparency including personal data protections rules. No personal data of trial subjects should be uploaded or be publicly accessible in the EU portal and database. It means that individual subjects’ personal data, the so-called raw data, sometimes included in the attachments to clinical study reports, cannot be included in the EU database, nor made public and personal data must be anonymised in clinical study reports prior to submission. Moreover, in order to avoid including trial subject identifiers in the clinical trial result summaries, a special structure of a such document has been proposed, which is described in the Regulation.

The personal data (other than trial subject data) should only be included in the database to the extent required to apply the Article 81(2) of the Regulation, which article specifies the goals of the EU database. The only required contact details, given as functional roles or as contact details of natural persons to be made public, are the sponsor’s contact point for information on the trial and the sponsor’s contact point for information on the scientific aspects of the trial. Also, optionally, investigator sites can create available to the public a contact point for trial subjects or their healthcare providers or carers to facilitate the search for more information about participating in a study (also provided as functional roles or contact details of natural persons).

In general, personal data on the sponsor’s staff will not be recorded in the EU database, with some exceptions where necessary, which are normally not made public. The only exceptions that will be made public are legal persons, including the sponsor’s legally designated representative of the sponsor, or where the sponsor is a natural person.

MA applicant should remove from the clinical study report the personal information identifying MAH or applicant personnel prior uploading the report to the EU database. However, the names of the signatories of the clinical trial report (the sponsor and the coordinating investigator) should be publicly available, but without a visible signature, and also the name of the investigator who led the trial.

In the case of documents requiring signature, copies of documents with the name of the signatory and the date of signature, but without the actual signature, will be provided for public information, and at the same time, documents that will not be made public will be uploaded with a copy of the actual signature page along with a scan of the signature.

It is important to realize that both the names of clinical investigators and information about the study sites are a part of the clinical trial authorization dossier, which means that they will be publicly available and will be stored in the EU database. The following documents uploaded to the EU database will be made public: the list of principal investigators’ names and the names and addresses of the trial sites; Curriculum Vitaes of the principal investigators; description of any conditions such as economic interests and institutional affiliations that might influence the impartiality of the investigators; and also the written statement issued by the head of the clinic/institution or some responsible person testifying to the suitability of the facilities and human resources available for the trial is part of the application dossier (it will contain the name of the person issuing the document).

What information should be commercially confidential, what data should not be disclosed immediately and only after some time, all these aspects should be taken into account when planning the study. The sponsor before submitting the application for authorization of the clinical trial should develop the internal strategy for the deferral requests for publication of specific data (documents). In general, only after a decision on a clinical trial has been made, the application dossier will be available to the public. However, if there is an overriding public interest, it may be disclosed even earlier. Information on authorized and rejected clinical trials will be made public. Information on applications considering only assessment of Part I of the dossier, and also on applications not validated or withdrawn by the applicant prior to the announcement of the decision will not be made public, but in the case of overriding reasons relating to the public interest, they may be disclosed to the public.

The Category of the clinical trial [1 (pharmaceutical development clinical trials), 2 (therapeutic exploratory and confirmatory clinical trials), 3 (therapeutic use clinical trials)] will have an impact on the timing of the release of the data / documents to the public. The maximum delay in public access to data / documents for Category 1 clinical trials (e.g., Phase 0, Phase I, Bioequivalence and bioavailability trials, Biosimilarity trials) is 7 years, for Category 2 clinical trials (Phase II, Phase III) is 5 years, for Category 3 (Phase IV, Low-intervention clinical trials) is 1 year. A several-year delay in public access to documents such as an investigator’s brochure or an investigational medicinal product dossier (IMPD) is to provide sponsors with sufficient time to protect their economic interest. Documentation from clinical trials, the IMP from which will never have marketing authorization, is also made public. The IMPD-Quality section will not be made public, however if a Summary of product characteristics (SmPC) is submitted instead of the IMPD-Quality section, it will be made public. In conclusion, it should be realized that data / documents such as e.g. decisions on a trial, the main characteristic of clinical trial, a subject information sheet, a protocol, IMPD-Safety and Efficacy sections, an investigator brochure, information on notifications or substantial modifications, requests to sponsor / assessment reports / responses from sponsor in relation on any aspects of the trial, conclusions on Part I, conclusions on Part II, a clinical trial summary, a clinical study report will be made public, but in some cases they do not have to be made public right away, but may be deferred. It is worth remembering that inspection reports, Union Control reports, serious breach reports and their follow-up and corrective measures will also be available to the public.

Proper preparation of documentation for a clinical trial is one of the most important elements of a clinical trial at the planning, course and completion stage. Only reliably prepared and maintained documentation allows to obtain the results of a clinical trial of the highest standard while maintaining patient safety. One more aspect of a clinical trial now needs to be considered, i.e., its transparency for the public, which is achieved by entering clinical trial documentation into the EU portal and database. The dedicated Clinmark team has many years of experience in advising, preparing, properly maintaining clinical trial documentation as well as in conducting audits. Thanks to our know-how and knowledge the team can support the development of documentation both in terms of substantive issues and requirements related to the Regulation (EU) No 536/2014.

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