Getting Ready For The Upcoming Revised EMA CTIS Transparency Rules

The revised transparency rules governing the transparency of information submitted to the Clinical Trial Information System (CTIS), as adopted by the European Medicines Agency (EMA) on 5 October 2023, will come into effect on 18 June 2024, thesame day thenew CTIS portal will launch. The CTIS, established under the Clinical Trials Regulation (EU) No 536/2014 (CTR), aims at facilitating the information exchange on trials in the European Union (EU). It operates on the principle of public disclosure, with the exception of information relating to personal data and Commercially Confidential Information (CCI).

Preparation is crucial for sponsors conducting clinical trials in the EU as they may need to adapt ongoing trial documentation and future submissions. Our blog post sets out the key changes and provides tips for preparation.

Background

Under the currently applicable but soon to be "old" rules, nearly all trial information in CTIS is published, but publication can be deferred for years post-trial. According to EMA's experience with the current CTIS publication rules, extensively redacted documents, combined with deferral mechanisms, have proven complex to manage from an information management and data security perspective. This, according to the EMA, caused delays in publishing crucial documents for patients or researchers (e.g. protocols). These issues prompted the EMA to introduce the revised transparency rules. This was preceded by a public consultation that was open for feedback between May and June 2023.

Revised transparency: What's new?

The revised CTIS transparency rules aim to achieve earlier publication of information and limit it to what is deemed relevant for patients and researchers, avoiding unnecessary redactions, and simplifying the CTIS functioning. The revised rules introduce three changes:

• Only key documents of interest are published;
• Deferral requests for publication are no longer an option;
• Redaction is the method to safeguard CCI and personal data.

Note that certain documents which were subject to publication under the old rules will no longer be published under the revised rules, including:

• The safety and efficacy sections of the Investigational Medicinal Product Dossier (i.e. IMPD-E and IMPD-S);
• Investigational brochure (IB);
• GCP inspection reports;
• Union Control Reports;
• Documents provided with corrective measures including sponsors' opinion; and
• Assessment Reports.

Additionally, some structured data that were subject to publication under the old rules, will no longer be published under the revised rules, including details on the sponsor's legal representative; third country inspection details; and responses to requests for information.

i. Application of the revised rules

The start of application of the new rules depends, in practice, on the submission date of trial applications. Notethat, in this context, clinical trial applications (CTAs) include both initial clinical trial applications, but also post-authorisation applications for substantial modification and notification of non-substantial modifications, as well as additional Member State Concerned (MSC) applications.

• Trial applications submitted before 18 June 2024:
  • Considered 'historical' for the purposes of the new CTIS transparency rules;
  • Scope: Only structured data will be published; not the documents contained in CTIS.
• Trial applications submitted on or after 18 June 2024:
  • Must follow the revised CTIS transparency rules in regards to redacting CCI and personal data;
  • Scope: Both structured data and documents subject to the revised rules will be published.

The revised CTIS transparency rules apply differently depending on the categorisation of the clinical trial. The existing trial categorization, as currently applicable, is retained:

• Category (Cat.) 1: Covers Phases 0 and I trials, as well as bioequivalence, similarity, and equivalence trials. Different rules apply within Cat. 1 based on the age of the trial population (adults/paediatrics);
• Cat. 2: CoversPhases I and II integrated trials, and Phases II and III trials;
• Cat. 3: Covers Phases III and IV integrated trials, Phase IV trials, and low interventional trials.

The publication of the information (i.e. structured data and documents) will take place according to the timing provided in the revised CTIS transparency rules. The moment of publication differs depending on the trial category (see above) and the information types, as will be seen on the tables below.

ii. Structured data

Structured data in CTIS refers to user-entered information in predefined values or free texts. This includes information on:

• Other CTA fields populated by the sponsor:
  • Inclusion and exclusion criteria to take part to the trial;
  • Primary and secondary endpoints; and
  • Details on the trial's investigational medicinal product;
• CTA fields populated by the sponsor:
  • Public title;
  • Study design;
  • Trial identifiers in registers, protocol code;
  • Phase, medical cond., rare disease, therapeutic area;
  • Population age, gender;
  • Sponsor details; and
  • Details of investigator sites.
• Relevant dates (e.g. end of trial, conclusion of Part I/II of the application);
• Outcome of the authorities' evaluation (e.g. decision on application, conclusion on Part I/II);
• Corrective measures (i.e. suspend, revoke, or request to modify an application);
• Trial notifications on trial status and recruitment (e.g. temporary halt);
• Safety notifications (e.g. serious breach, unexpected event); and
• Product/AS details:
  • Product strength;
  • Active substance;
  • Daily and maximum dose allowed;
  • Maximum treatment duration; and
  • Daily and total dose unit measure.

Structured data cannot be redacted, so no CCI or personal data should be included. Structured data from all trials (including historical) will be published at the timelines specified in the table* below.

iii. Documents

Only documents submitted to the CTIS for trial applications submitted on or after 18 June, falling within the scope of the revised rules, will be subject to publication. These include:

• Protocol, synopsis, patient facing documents;
• Final results summary;
• Lay person summary of results;
• Summary of medicinal product characteristics (SMPC): Only in Cat. 2 and 3 trials;
• Informed consent form (ICF) and patient information sheet: Only in Cat. 2 and 3 trials;
• Recruitment arrangements (including procedures for inclusion and copy of advertisement materials): Only in Cat. 2 and 3 trials; and
• Clinical study report (CSR).

The documents will be published at the timelines specified in the table* below.

For documents subject to publication, sponsors can submit a version 'for publication' after redacting CCI and personal data, following the applicable guidance document, the Q&A on the protection of Commercially Confidential Information and Personal Data while using CTIS (Q&A on CCI and personal data); and a version 'not for publication'. Non-publishable documents allow submitting a 'not for publication' version only.

Note on historical trials: Applications submitted after 18 June will trigger the publication of documents subject to the revised rules. However, for non-substantial modification or additional Member State applications, only Part II assessment documents will be published. This is because Part I documents cannot be modified through these applications, thus redaction is not possible in these cases.

How sponsors can prepare

i. Interim period – Until 18 June

Until 18 June, the old rules continue to apply. However, sponsors can already adhere to the principles of the revised rules without waiting until then. The EMA advises sponsors to the following:

• In initial applications:
  • For documents falling under the revised rules, submitting a 'for publication' version with CCI redacted; and for documents no longer subject to publication under the revised rules, submitting a document stating their exemption.
  • No longer possible to submit deferral requests, as CCI is redacted in 'for publication' versions.
• In modifications/additional Member State applications: Choosing to adhere the old rules or revised rules depending on which causes less burden (i.e. if deferrals are in place, it may be less burdensome to continue following the old rules).
• In applications to transition from the Clinical Trials Directive to the CTR: Submitting a redacted 'for publication' version of the protocol, subject information sheet and ICF, as these are the minimum documents required in the transitional application.

ii. After 18 June

We recommend sponsors to anticipate for which of the currently ongoing trials are intending to submit any applications for modifications in order to ensure that those comply with the revised rules We also suggest start preparing redacted versions of these documents as required, while retaining non-redacted versions.

In addition, training the relevant personnel involved in document preparation on the revised rules and on the Q&A on CCI and personal data will be important to ensure future compliance with the rules.

*The tables are based on tables contained in the EMA's Quick guide for users on the revised transparency rules.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.