Paediatric Drug Development: The Role of Extrapolation, Modelling and Simulation
Published Feb 16, 2024
Published 02nd February 2024
On 5 October 2023, the European Medicines Agency (EMA) adopted revised transparency rules for the publication of information included in the Clinical Trials Information System (CTIS). The revision of the transparency rules followed an 8-week public consultation opened by the EMA in May 2023 which was triggered by stakeholder feedback regarding their experience of the system since its launch. The resulting simplification of the transparency rules aims to reduce administrative burden for clinical trial sponsors whilst maintaining a high level of transparency for patients and clinical researchers. Implementation of the revised transparency rules is expected to be finalised by the second quarter of 2024. Read our blog to understand the changes imposed by the revised rules, the benefits imparted and how to take advantage of the revisions in advance of their full implementation.
The Clinical Trials Regulation (EU) No 536/2014 (CTR), which entered into application on 31 January 2022, harmonises the submission, assessment and supervision of clinical trials conducted in the EU. Furthermore, it establishes the requirement for greater transparency of clinical trials information whilst balancing the need for protection of personal data and the legitimate commercial interests of clinical trial sponsors. Transparency is intended to protect public health, support public confidence in the regulatory process surrounding clinical trials and foster innovation.
CTIS has been established as the single-point entry system for the exchange of information for clinical trials conducted in the EU, used for the submission of all trial-related applications throughout the trial life-cycle, the exchange of information between clinical trial sponsors and Member State Concerned (MSC), and collaboration between MSC for submission evaluation and supervision of clinical trials.
The documentation and information contained within the CTIS database can be accessed by clinical trial sponsors and MSC authorities via the relevant secure workspaces. In compliance with the transparency requirements set out under the Clinical Trial Regulation, the database is also accessible to the public via a searchable website. This allows for the publication of certain clinical trial documentation, and information from CTIS structured data fields, for clinical trials for which a decision on the clinical trial application has been issued by at least one MSC. Clinical trial documentation is published in such a way that allows for the protection of personal data, commercially confidential information (CCI), and confidential communications between MSC in accordance with Article 81 (4) of the Clinical Trial Regulation.
The initial transparency rules outlined in the endorsed draft appendix identified which clinical trial documentation and information would be made public, and at which timepoint. Documentation to be published under these rules included, but was not limited to, the protocol, Investigator’s Brochure (IB), Investigational Medicinal Product Dossier for safety and efficacy (IMPD S and E), requests for information (RFI) issued by the Reporting Member State (RMS) or MSC and responses submitted by the clinical trial sponsor, and the final assessment reports from the RMS and MSC. Financial arrangements, the quality Investigational Medicinal Product Dossier (Q-IMPD), and any RFI and responses related to quality aspects were not made public.
To ensure the protection of personal data and CCI, redacted versions of clinical trial documentation for publication were submitted in CTIS alongside unredacted versions which were used for application assessment or trial supervision by the MSC. Clinical trial sponsors were expected to apply the minimum amount of redaction to ensure the published document was meaningful and supported public understanding of the clinical trial and the regulatory process.
Clinical trial sponsors additionally had the option to apply for a deferral at the time of the initial clinical trial application to delay the publication of key clinical trial documentation and information from CTIS structured data fields. Deferral was intended as an alternative mechanism to protect CCI, and the expectation was of a reduction in the extent of redaction required as information deemed CCI at the time of the initial clinical trial application would not still be considered CCI at the time of deferred publication. The information and documentation for which publication could be deferred, and the deferral period, depended on the category of the clinical trial which took into account the development phase of the Investigational Medicinal Product (IMP). Where a clinical trial sponsor did not apply for a deferral, or a deferral was not granted, the documentation was published at the earliest timepoint outlined in the initial transparency rules (e.g. for clinical trial documentation submitted as part of an initial application, publication would occur once the first decision from a MSC had been issued). As previously stated, deferral was intended as an alternative to redaction for CCI protection, however in practice the prediction of which information would/would not be considered CCI at the time of publication was difficult for sponsors and our experience has shown that the majority of sponsors applied a similar level redaction to documents regardless of deferral status, contrary to the objective of the deferral mechanism.
The removal of the deferral option for all categories of clinical trials is the most significant change in the revised transparency rules. This change is counterbalanced by the restriction of publication of clinical trial documentation to those deemed most valuable to patients and clinical researchers. Under the revised rules, the list of clinical trial documentation exempt from publication has been expanded to include documentation such as the IB, IMPD S and E, and the RFI issued by the RMS or MSC and responses submitted by clinical trial sponsors. A full overview of the changes is detailed in Annex I of the revised transparency rules. The clinical trial documentation for which publication is still required under the revised rules includes, but is not limited to, the protocol and synopsis, Informed Consent Form (ICF) and advertising materials.
The revised transparency rules retain the categorisation of clinical trials and the categories are used to define the publication timepoints of clinical trial documentation and CTIS structured data fields. In general, the removal of the deferral period results in an earlier publication timepoint than is foreseen under the initial transparency rules, however maintaining these categories allows for the IMP development phase to be taken into account and the publication timepoint to be adjusted accordingly.
For example, for a category 1 paediatric clinical trial with a deferral agreed at the time of initial submission, under the initial transparency rules the protocol would have been published either at the time of the Marketing Authorisation (MA) or up to 7 years after the end of the trial (whichever was earlier). The unavailability of the deferral mechanism under the revised transparency rules means that when submission of the initial application for the same trial is completed under the revised rules, the protocol will be published together with the summary of results once this is submitted in CTIS. This earlier publication timepoint balances the protection of CCI with the requirement for transparency. This balance is supported by the change in the publication timepoint for CTIS structured data fields containing IMP details for category 1 paediatric clinical trials. Under the initial transparency rules for this trial type, there was no option to defer publication of these fields and they were published at the time of the first MSC decision on the initial clinical trial application. The revised transparency rules recognise this information as CCI and publication at this timepoint is no longer envisaged.
The revision of the transparency rules brings a number of benefits. The simplification of the rules is expected to increase efficiency, reduce the workload arising from document redaction and improve the experience of those stakeholders providing information to CTIS.
It is also expected to improve the experience of patients and clinical researchers by reducing the complexity of information available via the public website whilst ensuring the most relevant clinical trial documentation is available at the earliest possible timepoint.
Whilst the implementation of the revised transparency rules is expected to be finalised by the second quarter 2024, clinical trial sponsors can already take advantage of the revised rules in the interim. For initial clinical trial applications, redacted versions of documents in scope of the revised transparency rules as detailed in Annex I may be uploaded to CTIS in the same way as completed under the initial transparency rules. The expectation remains that redactions are completed in such a way that the document remains meaningful for the public. For documents no longer subject to publication under the revised transparency rules, a document stating this can be uploaded to CTIS in place of the redacted version. It should be noted that as the revised transparency rules are not yet fully implemented, sponsors should continue to protect CCI and personal data in any RFI responses included in the relevant CTIS structured data fields as these will continue to be published until the required technical updates to CTIS are completed.
Similarly, for on-going clinical trials conducted under the Clinical Trials Directive (CTD), sponsors can already follow the revised transparency rules when transitioning the study to the Clinical Trial Regulation and redactions of only those documents which fall under the scope of the revised rules will be required to be uploaded into CTIS. Additional guidance for the transition of trials from the CTD to the Clinical Trial Regulation, including transparency requirements, can be found in the guidance for the transition of clinical trials from the European Commission.
With regards to applications submitted for on-going studies already conducted under the Clinical Trial Regulation (e.g. substantial modifications), sponsors are advised to consider the preferred approach to maintaining confidentiality of CCI and personal data with the aim of decreasing burden depending on the study status.
Further information on managing transparency requirements during this interim period, including recommended wording for the document replacing superfluous redacted documents, can be found in the Q&A on protection of Commercially Confidential Information and Personal Data while using CTIS, v1.3
Transparency is a central objective of the Clinical Trial Regulation, however this must be balanced with confidentially in relation to personal data and CCI. The EMA consultation and resulting revised transparency rules have taken into consideration the views and experience of stakeholders, enabling further optimisation of the rules to improve CTIS user experience and facilitate access to clinical trial information whilst maintaining the balance of confidentiality.
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