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EU CTR Compliance and Success Navigating Updates and Preparing Submissions for the EU CTIS Portal.pptx
- 1. EU CTR Compliance and Success Navigating Updates and Preparing Submissions for EU CTIS Portal
- 2. Our Experts Gina Bennett Senior Clinical Trial Transparency Specialist 5 years experience Utkarsh Suhas Bartakke Clinical Trial Transparency Specialist 6 years' experience Arshi Muhibulla Ghousia Team Lead, Regulatory and Medical Writing 10 Years
- 3. 3 Agenda Topic Duration Presenter/s Introduction 3 mins Gina Navigating document updates: PLPS - What we know so far ā Regulation and Requirements - Developing a PLPS ā Content, Process and Timelines - Challenges we faced - Case study 15 mins Arshi Preparing redacted submissions for CTIS portal - Deferrals - Challenges for Sponsors - Case Studies 20 mins Gina and Utkarsh Roadmap to successful CTIS submission 7 mins Gina
- 4. EU-CTR 536/2014 and CTIS ā¢ The European Union Clinical Trials Regulation (No 536/2014) (EU CTR) replaced the long-standing directive, the European Union Clinical Trial Directive 2001/20/EC (EU CTD) on 31 January 2022 ā¢ The EU CTR aims at creating a favorable environment for conducting interventional clinical trials in the EU with high standards of safety for study participants and increased transparency of clinical trial information ā¢ Clinical Trial Applications (CTA) are submitted by the sponsor via Clinical Trial Information System (CTIS) portal ā¢ New Document Types within CTA requested under EU-CTR (e.g PLPS) ā¢ After decision is issued by MSC (Member State Concerned), lot of clinical data is available to the public (https://euclinicaltrials.eu/search-for-clinical-trials/) ā¢ Sponsors protect data in two ways: ā Apply for Deferral ā Remove CCI and PPD
- 5. Poll Question Have you applied for or provided support for a Clinical Trial application under EU CTR? Yes No
- 6. Navigating Document Updates: Plain Language Protocol Summary
- 7. 7 What Do We Know So Far ā Regulation and Requirements for PLPS Compliance with European Union Clinical Trial Registration 536/2014 (EU CTR) Portray details of clinical study protocols while eliminating most of the technical language Fastens the process of recruitment and development of lay summary results. Public look into vital information Provides protocol information of the study in public domain in lay language Used as a tool in clinical research
- 8. 8 EMA vs MHRA Requirements for PLPS MHRA requires ā¢ ISRCTN registry ā¢ PLPS of ~1000 words EMA: Additional elements beyond EMA requirements would suggest below; UK element Most similar EUCTIS element Background and Study Aims Study rationale and objectives/endpoints Who can participate? Trial population What does the study involve? Trial design and Interventions What are potential risks/benefits? Ethical considerations EMA-European Medical Agency; ISRCTN-International Standard Randomised Controlled Trial Number; UK-United Kingdom; EUCTIS-European Union Clinical Trial Information System; PLPS-Plain Language protocol Synopsis
- 9. 9 Background and Study Aims Who can participate? What does the study involve? What are the possible benefits and risks of participating? Where is the study run from? Duration (Start and End Date) Who is funding the study? MHRA Requirements-PLPS Content MHRA-Medicines and Healthcare products Regulatory Agency
- 10. Developing a PLPS: Points to Consider ā¢ EU CT Number and Protocol Title ā¢ Study rationale ā¢ Primary and Secondary objectives and Endpoints ā¢ Study Design ā¢ Study Population ā¢ Interventions ā¢ Ethical considerations (benefit/risk assessment) ā¢ Maximum of 2 pages EU CT-European Union Clinical Trial
- 11. 11 How Different is PLPS from PIS? PIS ā¢ Longer Document ā¢ Detailed Content (study details, patient details, payment details, questionnaires etc) PLPS ā¢ 2 Page Document ā¢ Concise content PIS-Patient Information Sheet; PLPS-Plain Language Protocol Synopsis
- 12. 12 PLPS: Process and Timelines SCP-Secure Copy of protocol CTIS-Clinical Trial Information System After approval of a developed Protocol Create and Approve PLPS Redaction Translation Populate SCP PLPS Authoring request submitted, writer support begins... Hand off for submission to CTIS Week-19 Week-5 Week-3 Week-0
- 13. Equal to 2 pages More than 2 pages Less than 2 pages Poll Question What is the page limit for a PLPS as per EUCTR requirements?
- 14. ā¢ Quick turnover - Drafting in few days ā¢ Incomplete review due to stringent timelines Timelines ā¢ Missing out on data which would need PLPS amendment ā¢ Complex clinical information to be summarized in few pages Data ā¢ Many reviewers per functional role, prolonged review time ā¢ Delay in review ā¢ Technical issue with the tool ā¢ No back up resource for out of office reviewers. Stakeholders Challenges We Faced!
- 15. Case Study: Authoring 5 PLPS for a CTIS Submission in 3 Weeks Timeline ā¢ MMS was awarded with new document type - PLPS ā¢ Scope of work was to submit 5 PLPS for same molecule in single submission ā¢ 5-day timeline, no room for round table with reviewers ā¢ Accommodate all the data from protocol as per the template instructions in 2 pages ā¢ Lack of guidance on choosing content from protocol ā¢ Explaining Trial Design and population in lay language ā¢ Adding primary and secondary objective and endpoints in concise manner Challenge ā¢ Added expertise with lay language along with crisp definitions of scales for the endpoints ā¢ Peer review to fine-tune the details ā¢ Round the clock support to complete the task ā¢ Communication through emails and follow ups for expedited review ā¢ One-person approval was implemented ā¢ Worked on 4 documents in parallel using the first approved PLPS as a model. Solution ā¢ Delivered high quality PLPS(s) in 1 week of time and handover to the Transparency team ā¢ Complex study design with primary and secondary endpoints (ĶĢ“15-18) were simplified using lay language ā¢ Clinical information was accommodated in 3-4 pages ā¢ Repeat Business Outcome
- 16. Preparing Redacted Submissions for CTIS Portal
- 17. Transparency Regulations 17 ā¢ Protocol Data (Summary) ā¢ Results Summary ā¢ Clinical study reports ā¢ Protocol ā¢ SAP ā¢ CRF (eCRF) sample ā¢ Informed Consent (Optional) EU CTR (CTIS) = Increased release of clinical documents to the public ā¢ Protocol data (summary) ā¢ Results summary ā¢ Protocol ā¢ SAP ā¢ CRF template ā¢ CSR body + synopsis + annexes ā¢ + Interim results summary ā¢ + Lay summaries ā¢ + All Inspection Reports (worldwide) ā¢ + Cover letter ā¢ + Data safety monitoring committee charter ā¢ +Scientific advice summary ā¢ + Investigatorās brochure ā¢ + Autorisation of manufacturing and import ā¢ + QP GMP certification ā¢ + IMPD and AMPD ā¢ + Content labelling ā¢ + Proof of payment of fee ā¢ + Proof of insurance cover ā¢ + Investigator CVs and the List of financial interests ā¢ + Recruitment arrangements ā¢ + informed consent ā¢ +Audio/video advertisement ā¢ + Statement of the suitability of the facilities ā¢ + Statement of compliance to GDPR Past Present
- 18. Poll Question Do you prefer a deferral option or redactions to protect CCI in EU-CTIS submissions? Deferral Redaction for CCI
- 19. 19 Deferral Strategy ā¢ Sponsors may apply for deferral of some documents during the CTIS submission of their initial application to delay the publication of certain documents for a set time based on the marketing authorization and phase of the trial ā¢ For deferred documents, EMA expects little to no redaction related to CCIs ā¢ Post deferral period, critical long standing CCI may still be considered CCI Category 1 7 years of end of trial Category 2 5 years of end of trial Category 3 At MAA decision, or within 1 year of end of trial
- 20. 20 Deferral of Publication per Study Type Category 1 (FIH, PK/PD, BE/BA, Bio similarity) Category 2 (Phase II and III) Category 3 (Phase IV) Study protocol, PLPS 7 years after end of trial 5 years after end of trial When summary of results are made public IMPD, IB 7 years after end of trial 5 years after end of trial When summary of results are made public Subject information sheet 7 years after end of trial 5 years after end of trial Time of decision on trial Request for Information (RFI) 7 years after end of trial 5 years after end of trial When summary of results are made public Unexpected events, urgent safety measures When summary of results are made public At the designated time for publication for each notification type Intermediate summary of results 12 months after intermediate analysis date (pediatric) or 30 months after end of trial 12 months after intermediate analysis date Summary of results 6 months after intermediate analysis date (pediatric) or 30 months after end of trial 6 months after end of trial (pediatric) or 12 months after end of trial Layperson summary of results CSR 30 days after marketing authorization decision, or 30 days after withdrawal of MAA
- 21. Any information contained in the clinical documents submitted to the Agency by the applicant/MAH that is not in the public domain or publicly available and where disclosure may undermine the legitimate economic interest of the applicant/MAH CCI Personal information about individuals that encompasses both direct and indirect identifiers that may increase the risk of reidentification of an individual if they are disclosed to the public PPD 21 Protecting Non-Deferred Documents: PPD and CCI ā¢ Excipients quantitative composition ā¢ Synthesis/ manufacturing details of the active substance ā¢ Future development plans ā¢ New biomarkers or novel methodologies not yet qualified ā¢ Innovative analytical methods Indirect Identifiers ā¢ Age ā¢ Race and/or ethnicity ā¢ Gender Direct Identifiers ā¢ Participant IDs ā¢ Medical History ā¢ Names/signatures
- 22. Common Pitfalls During Submission 22 Process ā¢Evolving regulation ā¢Document updates (SOPs, GD, WP) ā¢New document types ā¢Stakeholder management Strict Timelines ā¢Request For Information (RFIs) ā¢Resource planning Translation ā¢Vendor qualification ā¢Documents in-scope for translation ā¢Quality Certificates CCI Handling ā¢Over-redaction ā¢Trainings ā¢Consistency across other submissions of same drug molecule
- 23. 23 Process Considerations During CTIS Submission Start is critical New set of documents Collaboration within the sponsor and vendor teams ā¢ Starting well in advance ā¢ Scoping of documents- Trackers-TOC-CCI trackers ā¢ Working on Part I and II documents simultaneously ā¢ CTIS being a collaborative effort, a streamlined work transition between various teams plays a key role. ā¢ Roles, POC, and responsibilities should be clearly communicated ā¢ Documents like PLPS, IB, DMC charter etc getting published in public domain ā¢ Understanding the document level CCI ā¢ Work as per the criticality of the document
- 24. 24 CCI Handling Over redaction Lack of training Co-relating Submissions CTIS/P0070/HC ā¢ Blanked redaction vs Targeted redaction ā¢ Study level vs Submission level CCIs ā¢ Once released on CTIS unredacted no longer a CCI for any other submission ā¢ Temporary vs long term CCIs ā¢ Training on CCI ā¢ Public domain and Sponsor document searches ā¢ Stat team and IP Law team CCI approaches
- 25. Case Study on Streamlining CCI Identification and Submission Process: 25 An Ongoing EU CTR Redaction Project from small pharma ā¢ Helped sponsor with identification of document types in-scope for CTIS ā¢ Strategy support to identify upcoming tasks for CTIS (transition trials, prospective studies) ā¢ Collaborated with sponsor on necessary redactions by defining PPD rulesets, QC checklists, CCI tracker Sponsor Unfamiliar with CTIS Requirements ā¢ MMS provided project management support to sponsor ā¢ Identified key responsibilities for transparency team and sponsor reviewers ā¢ Aligned efficiencies to identify standard and expedited timelines Aid Sponsor With Ad-hoc Resource Requirements ā¢ Collaborated with sponsor experts on identification of CCI ā¢ Cross functional communication between sponsor and MMS teams for CCI alignment ā¢ Understanding EMA criteria for CCI acceptance based on deferral rules Partner for CCI Handling
- 26. 26 Timelines for CTIS submissions Over redaction Lack of training Co-relating Submissions CTIS/P0070/HC ā¢ RFI response time is limited: ā¢ 10 calendar days to respond when received during the validation period ā¢ 12 calendar days to respond during Part I and Part II assessment periods ā¢ Multiple rounds of RFI ā¢ Authoring updates - Writing, Biostats, Legal ā¢ Submission updates - Regulatory ā¢ Redaction updates ā Transparency ā¢ Translation updates ā Translation vendor ā¢ Reducing timelines ā¢ Expedited requests ā¢ One person approvals
- 27. ā¢ Lack of resources to address the RFI ā¢ Lack of expertise to track down the changes and provide updated documents ā¢ received RFI over RFI ā¢ Timeline was further reduced only to a couple of days with subsequent RFIs Sponsor was unprepared for RFIs ā¢ MMS provided project management support to sponsor ā¢ Conducted RFI alignment meeting ā¢ Alerted MMS global team ā¢ Global team worked on the document round the clock to get the submission done on time Aid Sponsor with timely submission ā¢ MMS carefully assessed the situation to understand the RFI requirements ā¢ The time to response was as low as 48 hours. MMS a reliable partner Case Study on RFI Support A project on RFI responses for a sponsor with minimal experience in CTIS 27
- 28. 28 Translations Requirements for CTIS Submissions Translation vendor management Identification of documents Quality certificates ā¢ Active facilitator between Sponsor and Translation vendor ā¢ Communication on document requirements ā¢ Timelines for translation ā¢ Review of the documents ā¢ Authenticity of the translation ā¢ Successful audit ā¢ Identification of the correct set of documents (redaction needed /not needed) ā¢ Confirming with local sites for availability of the translated versions ā¢ Multiple language requirements of the document
- 29. Case Study on Translation of In-scope Documents 29 An EU CTR Redaction Project from sponsor dealing with first CTIS submission ā¢ 1st submission ā¢ 4 studies active simultaneously with no prior information ā¢ Expedited timelines ā¢ Rush Services from translation partner on a case-by-case basis ā¢ No prior planning Translation requirements with no clear process ā¢ MMS provided project management support to sponsor ā¢ Identified key process steps between MMS/Translation partner and sponsor. ā¢ MMS helped to align the communication between the stakeholders, manage the process and get the documents translated on time. MMS as a Liaison ā¢ MMS scrutinized the in-scope documents for actual translation needs. ā¢ Bringing down the number of document for translation to only 3 from previously projected 160 documents in CTAs ā¢ MMS helped the sponsor to save significant cost on translation services Cost effective guidance
- 30. Partnering with an Experienced CRO ā A win-win scenario
- 31. 31 CTIS submissions: A Collaborative Effort Regulatory Operations Sponsor Data and Documents Regulatory Strategy Medical Writing Transparency Translation Vendor Submission Strategy, countries selection, data, RFIs Authoring and Document Generation Public Anonymized Document Generation Translation of Original and Anonymized Documents Content Plan, Document Publishing, CTA Compilation, QC, and submission Sponsor Review and Approval
- 32. 32 Utilizing Cross Functional Teams to Streamline Processes ā¢ Regulatory Affairs to guide sponsor on document submission ā Develops better understanding of process and what is needed when uploading these documents to the portal ā Help make transitions for sponsors better ā¢ Medical writers knowledgeable in ālean writingā ā Educate submission medical writers on PPD and CCI and how to avoid when authoring documents: ā Limit the amount of necessary CCI ā If possible, refrain from adding any unpublished information ā Refrain from adding any PPD such as subject IDs
- 33. 33 Utilizing Cross Functional Teams to Streamline Processes ā¢ Transparency to educate Sponsors on protection of CCI and PPD ā Identification of temporary vs long standing CCI ā¢ Data can be maintained on an electronic database; sponsor can start making a list of the documents and keep them ready to upload well in advance of the submission ā Ideal time would be three months in advance to begin the redaction work and assessment of the documents ā The documents can be prioritized as per the page and data complexity
- 34. Roadmap to Successful CTIS Submission 34
Editor's Notes
- Thank you for the introductions. Our team is excited to share our experiences with EU CTR CTIS submissions. For those who may be somewhat unfamiliar , EU CTR stands for the European Union Clinical Trials Regulation which began replacing the former EU CTD or European Union Clinical Trial Directive on Jan 31 2022. Sponsors had one year to take part in voluntary submissions under the new regulation before it became required of all sponsors submitting new trial applications as of January 31 2023 Ā EU CTR is a searchable public website that aims at creating a more favorable environment for conducting interventional trials in the EU with high standards of safety for study participants and increased transparency of clinical trial information
- Before we move on, letās take a minute to conduct a quick poll to find out how many of you attending today have provided support in any fashion for a Clinical trial application under EU CTR? We will pause and give everyone a chance to respond. Thank you for your responsesā¦.
- Today, we want to focus on the role of Transparency as well as interdepartmental collaboration in EU CTR submissons. Letās begin with why and how it is important to protect your trial data
- EU Clinical Trial Regulation that went live on January 31st, 2022. Itās Clinical Trials Information System (CTIS) is being presented as a one-stop shop for clinical trial applications, regulatory review, and public access to trial information. For the first year of rollout, stakeholders can use CTIS, but existing application frameworks will still exist. From January 2023, all new clinical trial applications will go through CTIS. Beginning 2025, all new and ongoing trials must go through the platform. What is the impact for Transparency? More clinical trial documents will be made public. EU-CTR 536/2014 is to provide a single, unified portal and database, which is the Clinical Trials Information System (CTIS), available for both trial sponsors and regulatory authorities of each Member State. The CTIS will be a centralized, paperless, integrated, single-entry point for submission, evaluation of data, authorizing, supervising, and reporting any trial-related information between the relevant Member States. The EMA will set up and manage the CTIS, in collaboration with the Member States and the European Commission.{5} The purpose of this system is to considerably facilitate the process of clinical trial conduct across EU, starting from the initial submission to authorization, providing corrective measures, inspection information, and publication of relevant documents for the general public. Itās use will be mandatory for new clinical trials after January 31, 2022 with a one year transition period where applicants can choose to file under the existing clinical trials directive or under the new regulation.
- Before we move on, letās take a minute to conduct a quick poll to find out how many of you attending today have provided support in any fashion for a Clinical trial application under EU CTR? We will pause and give everyone a chance to respond. Thank you for your responsesā¦.
- So, what is deferral? Sponsors may apply for deferral of some documents during the submission of their initial application Deferral delays the publication of certain documents for a set time period based on the marketing authorization and phase of the trial For deferred documents, CTIS expects little to no redaction Only PPD andĀ very limited pieces ofĀ criticalĀ long standing CCI that may still be considered CCI after the deferral period has lapsed CTIS quote: Using simultaneously both CCI redaction and deferral requests for the same document, or set of documents, equates to over redaction and would not be acceptable. In this context it is acknowledged that, in limited situations, some pieces of information (of quality nature in the trial protocol, for example) may still be considered CCI even after the deferral period elapses and consequently would be redacted even in documents subject to deferral requests.Ā
- Not all documents can be deferred. This table from this slide is taken from EMA EU CTR guidance and outlines what documents fall under this option: See table The category and phase of the trial also play into how long the deferral period may last Category 1: pharmaceutical development trials Category 2: therapeutic exploratory and confirmatory trials Category 3: therapeutic use trials
- Another way to protect your data in all submitted documents is the use of redaction; PPD (read slide definition) and includes indirect identifiers such as (age, race/ethnicity and gender to name a few) and Direct identifiers such as participant IDs, safety case numbers, names and handwritten signatures to name a few) Here you see what the redacted overlay for PPD would look like in the public domain Ā CCI (read definition) this could include any of the following (read banner) as a few examples
- This process flow depicts the functional lines integration that is needed forĀ CTIS.Ā Data and Documents are collected from the sponsor.Ā RO will drive the submission process that typically includes content plan creation, data and document collection, document publishing and submission related activities such as compilation, QC, and dispatching.Ā ā ā As any other regulatory submission, weāll need to do this hand-in-hand with RS team with inputs on submission such as countries selection, data, and responses toĀ RFIs.Ā Ā Partner with MW on procuring the correct document and any responses toĀ RFIs.Ā Transparency is built into the design withĀ CTIS.Ā As you have heard multiple times today most data and documents will be made publicly available one time or the other.Ā Hence coordination with TS team on public/anonymized documents will be needed at each and every step of the submission.Ā Ā Lastly, we will also be able to coordinate the translation of documents with our preferred vendor.Ā ā ā
- Most Part I documents can be accepted in English
- Missing RFI deadlines may result in the CTA being deemed as lapsed and an automatic withdrawal of the application in all Member States
- Identifying CCI in clinical data can bring its own unique set of challenges and is something that as transparency experts we should take time to educate Sponsors about best practices. Some of our best practice tips include: (bullet points on slide) Public Domain Searchesā - European Public Assessment Reports - FDA Summary Basis of Approval,Ā Advisory Committee materialsā - Trial registries (eg, ClinicalTrials.gov, EudraCT), company websitesĀ etc.ā ā Sponsor PublicationsĀ ā - Abstracts, posters and journal articles etc.ā - Documents/publications available with the sponsor to be shared with the transparency team. ThisĀ helps to locate CCIā quickly.
- 31 January 2023 : All new initial clinical trial applications became subject to EU CTR