How the new CTIS transparency rules may impact a Sponsor’s document redaction approach

Since the EU Clinical Trial Regulation (EU CTR) 536/2014, the EU regulatory network has been committed to continually improving the experience of clinical trial sponsors and participants, healthcare providers, and patients in the EU region. Clinical data transparency has been a key consideration in these efforts, with the objective of building trust, dissipating beneficial knowledge, accelerating innovation and improving patient recruitment. The Clinical Trials Information System (CTIS), which was launched in Feb 2023, is one of the initiatives that has been instrumental to serve these objectives.

In the summer of 2023, after a few months of CTIS use and input by stakeholders, the EMA identified that amongst other challenges, the complexity of the transparency rules and system may be perceived by sponsors as an obstacle to clinical trial registration in the EU region.[1] Sponsors were concerned about these complexities, particularly the redaction of documents and the short CTR-mandated timelines, increasing the probability of human and technical error in the clinical trial registration process. From another point of view, non-sponsor stakeholders like patients and academicians raised concerns about the delay in the publication of some of the key documents and information related to clinical trials, namely the protocol, which may be published up to seven years from the end of the trial due to deferral allowances. The EMA also acknowledged the decline in clinical trial registrations in the EU region.

In response to these observations, the EMA has proactively sought feedback, specifically on its transparency rules, via an 8-week public consultation that was launched in May 2023. The objective of this public consultation[2] was to review the transparency rules for CTIS from the point of view of the CTIS user experience, the perceived patient benefit from publication of clinical trial information, and the boost in innovation and access to treatments – which were the founding intentions of the CTIS.

Key responses from the EMA public consultation

By way of this consultation, the EMA explored the needs and priorities of the various stakeholders involved in clinical trials in the EU with targeted questions about the transparency of structured data and documents,  and the mechanisms of deferral and redaction for protection of commercially confidential information (CCI). The response from 204 respondents (>55% of whom were either clinical trial sponsors or Contract Research Organisations (CROs), and the triggered changes to the CTIS transparency rules, are briefly discussed in this article.

Which documents and structured data elements of the CTIS form were voted critically important for publication by the stakeholders?

The structured data elements of the clinical trial applications that were voted the most important for publication were the clinical trial design, details of the trial sponsor, details of the medicinal product used, trial status, recruitment status, and information about temporary halts. The RFIs and responses to RFIs, and notifications of assessments carried out by regulatory authorities were considered the least important for publication.

In the same vein, the documents that CTIS stakeholders were most interested in seeing published were summaries of clinical trial results, subject informed consent documents, clinical trial protocols, clinical study reports and recruitment arrangements. The documents considered least important for publication were supporting documents for trial design, RFIs and notifications, scientific advice, insurance documents and CVs.

Are there compelling reasons to keep the deferral mechanisms in place to protect CCI?

The responses to this query produced divided, though not entirely surprising opinions according to different types of stakeholders. Patients were of the opinion that there are no compelling reasons to keep the deferral mechanisms, some even considering deferrals to have a negative impact on patient safety and trust. On the other hand, commercial and non-commercial sponsors and CROs were keener to retain the deferral mechanism to protect CCI.

Did stakeholders consider redaction alone to be sufficient protection for CCI?

Predictably, commercial and non-commercial sponsors were overwhelmingly of the opinion that redactions alone (i.e., without the added protection of deferral) could not ensure the protection of their CCI, likely due to the CTIS submission task being too burdensome to ensure seamless redactions. CROs on the other hand were a little more optimistic, with more than half voting that redactions alone can be considered sufficient protection for their clients’ CCI.

Most Patients, HCPs and academicians considered reactions alone to be sufficient protection for CCIs.

Outcome of the Public Consultation – changes in CTIS transparency rules

Although patients and sponsors had divergent opinions on deferrals and the sufficiency of redactions to ensure transparency while maintaining confidentiality, there was a general consensus on the need for simplicity and efficiency in the CTIS user experience. Some sponsors commented that the requirements of nearly full transparency by CTIS rules, and the complexity thereof, may discourage clinical trial sponsors from conducting trials in the EU.

It is noteworthy that the extent of clinical trial document and data transparency that has thus far been mandated in the EU is one of the highest in the world. In response to the survey, the EMA has made propositions that strike a fair balance between the transparency needs of different stakeholders by making a few changes to the transparency rules in CTIS. With these changes (discussed below), the EMA aims to simplify the transparency rules to make the system less complex, more efficient and user-friendly, improving the users’ experience, reducing burden for the users and still maintaining public access to clinical trials information.

How do the new CTIS transparency rules change the CTIS users’ experience?

The primary change proposed to CTIS rules is the focused publication of fewer structured data fields and documents in CTIS and removal of deferral mechanisms. The EMA acknowledges that the latter may make the task of  personal protected data (PPD) and CCI redaction by sponsor stakeholders more burdensome, and has therefore proposed that for early phase trials, only key clinical trial information - that patients flagged as being most relevant in the public consultation - is published early. The revised transparency rules will apply after their technical implementation in CTIS which is expected to be finalised in the second quarter of 2024. The effective date of completion of the process and the entry into application of the new rules will be communicated to the users of the system before they become applicable.

So what changes for clinical trial sponsors, exactly?

Sponsors can now prepare for the following changes that are applicable under the new CTIS transparency rules:

1. Fewer, more targeted[3] structured data fields of interest and clinical trial documents will be published (see Table below).
2. The deferral mechanism will be removed under every trial category.
3. Key clinical trial documents that were originally deferred will be published much earlier – i.e. at the time of decision in case they are part of a clinical trial application dossier or at the time of submission into the database, as applicable (Annex 1 of the revised CTIS transparency rules)[4].
4. Due to the simplified and focused publication rules, CTIS users will find the experience and navigability of the system less complex and burdensome.

Targeted structured data fields for publication under the new CTIS rules.

Targeted documents for publication under the new CTIS rules.

How should sponsors protect CCI and PPD while complying with the applicable new transparency rules before the new CTIS system is up in the second quarter of 2024?

The revised Q&A document[5] on the protection of CCI and PPD while using CTIS (v1.3) guides that in the period of time from adoption of the revised rules (Oct 2023) until their technical implementation in the system (estimated to be Q2 2024), sponsors may already follow the principles of the revised rules for initial clinical trials applications.

1. For the documents in scope of the revised transparency rules sponsors may provide a redacted version ‘for publication’ and an unredacted version ‘not for publication’ - the latter for assessment by the Member States
2. For documents not in scope of the revised transparency rules, sponsors may upload the unredacted version ‘not for publication’. With this, sponsors may upload a single document in the slot ‘for publication’ containing the following wording suggested in Annex I to this Q&A: “The present document is no longer subject to publication in line with revised CTIS transparency rules. Further information is provided in section 4 of the ‘Q&A on the protection of Commercially Confidential Information and Personal Data while using CTIS’ published on the ACT EU website – Implementation of the Clinical Trials Regulation”
3. For documents produced by the Member States that are not in scope of the revised transparency rules (e.g. assessment reports, decision letters, etc.), the same wording suggested in Annex I to this Q&A (see bullet 2) should be used in the documents slot ‘for publication’.
4. In structured data fields for RFI and RFI responses, which are now public but will not be published upon implementation of the revised rules, CCI and PPD should still be protected as these cannot be redacted.

For historical trials ((i.e. all trials submitted to CTIS before the new transparency rules are implemented):

1. The structured data fields for all trials’ categories of historical trials will be published on the new CTIS public website in line with the timelines and principles of the revised transparency rules.
2. All documents contained in applications submitted to CTIS before the implementation of the technical changes will not be published on the new CTIS public website. Publication of redacted documents in scope of the revised rules will occur only when included in applications submitted after the revised rules are in place, in line with the timelines and principles of the new rules.

How sponsors can prepare for document redactions under the new transparency rules and publication on the new CTIS system

1. Sponsors will now have to increase focus on CCI and PPD redaction preparedness. This may be achieved by the following approaches:
   1. Early document-level preparedness: Most clinical trial sponsors are now familiar with the scope of CCI and PPD redactions. However, the omission of the added layer of protection afforded by deferral mechanisms means that CCI will need to be protected by redaction alone. This would require more foresight and disclosure-preparedness than what has served the purpose thus far. At minimum, sponsors will need to mark out or strategically minimise CCI in documents during the draft stage, and plan for cross-functional teams and resources to confirm and redact CCI within the allotted timelines.
   2. Upstream process-level preparedness: Most sponsors have already started building a disclosure and transparency group within their organisation to provide expertise on an organizational and departmental level. Sponsors will have to increasingly engage with cross-functional teams to not just track CCI in existing documents but also develop upstream processes, templates, strategy and checklists to standardize and minimize CCI and PPD in clinical trial documents, and maintain exhaustive lists of terms and phrases that are confidential to the sponsor organisation. This cross-functional effort will be even more valuable when preparing clinical reports for EMA policy 0070, now that the EMA has revived the policy and has expressed the intention to align EU CTR and EMA policy 0070 guidance on redaction of CCI and anonymization of PPD.
2. Reduced burden of CTIS-related redactions: A CTIS package for a late phase multi-centre trial could easily edge up to 300-500 documents for submission. The new transparency rule significantly reduces the number of CTA-related documents and structured fields that are required to be published, therefore reducing the content to be redacted. This will reduce the amount of redaction-related pre-submission effort in the brief time window between clinical trial document finalization and CTIS upload. In particular, PPD and CCI-heavy documents like the IB, IMPD, some investigator and site-related documents, and administrative forms and charters are no longer required to be published, significantly reducing the time and resource allotted to future CTIS packages.
3. Removal of deferral will now mean more CCI, and mean more thorough redactions – While the volume of documents for publishing had reduced, the removal of deferral mechanisms has hastened the publication of previously delayed documents, highlighting the need for a thorough assessment and application of CCI before CTIS submission. One must be mindful that to reap the optimal benefit of the reduced burden of publishing redacted documents, sponsors will need to build the redaction task into disclosure-ready processes and checklists (as suggested above) to mitigate and tackle the potentially increased density of CCI in documents for publishing. In addition, the efficiency of the actual redaction task becomes a key consideration. Sponsor companies will need to consider allocating dedicated trained resources and fit-for-purpose automated tools that would increase the efficiency, timeliness and compliance of the redaction process and outcomes. For many sponsors this will mean either leaning on an artificial intelligence (AI)-proficient redaction service provider, or leveraging in-house AI capabilities. As a redactor with several years of experience in clinical document redaction, I cannot overstate the value of automation and fit-for-purpose AI technology when working to consistently and predictably redact documents in different formats, with or without character recognition, and with several layers of inconsistencies in terminology.
4. EU CTR will now present a less confounding question of compliance: While the removal of deferral mechanisms might increase the volume and sophistication of PPD and CCI redactions required, it makes the upstream planning, process and timelines much simpler. To aid this, the EMA has swiftly defined a clear path forward5 for CTIS submissions in the interim period of the few months, until the rules become applicable in Q2 of 2024. making it much easier to be compliant and plan ahead. Knowing that we are now working without the added layer of protection offered by deferrals, sponsors may plan to track and mark CCI and PPD ahead of time in the focused list of documents that will be published under the new transparency rules.

Conclusion

With these upcoming changes, the EMA aims to strike a balance between transparency of information and protection of CCI, and the diverse needs of the CTIS stakeholders. In favor of patient needs, key clinical trial information that patients flagged as being most relevant for them will be published early. The upcoming process simplifications would make the CTIS experience more efficient and less painstaking for clinical trial sponsors, and more intuitive for patients and caregivers. It is anticipated that these changes will make the CTIS system more user-friendly, navigable, relevant, engaging and transparent for all stakeholders.

About the Author

Simin is a Sr. Principal Medical Writer at Parexel International. She has been a Regulatory Medical Writer for almost 15 years, and has experience across most therapeutic areas and Phases, and in most document types. Simin serves as a mentor for medical writers, a program lead for enterprise projects, and an SME for transparency and disclosure activities and RWE studies. Simin is also a trainer at Parexel Academy for the IUBH MBA class (2022 and 2023), where she teaches the Medical Writing course. She is a member of the Good Transparency Practices working group at PhUSE. Simin has a personal interest in health information accessibility since her years in dental practice, and remains passionate about balancing data transparency and privacy.

References

[1] https://health.ec.europa.eu/latest-updates/clinical-trials-eu-survey-implementation-clinical-trial-regulation-2023-01-23_en.
[2] https://www.ema.europa.eu/en/documents/other/revised-ctis-transparency-rules_en.pdf. 
[3] Revised CTIS transparency rules, Interim period & Historical trials: Quick guide for users (europa.eu).
[4] Revised CTIS transparency rules (europa.eu).
[5] ACT EU_Q&A on protection of Commercially Confidential Information and Personal Data while using CTIS (europa.eu)

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