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EU Clinical Regulation Webinar Slide Deck.pptx

The webinar discusses key changes introduced by the new EU Clinical Trials Regulation that will revolutionize clinical trial transparency in Europe. Some of the major changes include a single application portal, expanded data disclosure requirements, and public access to clinical study documents and results. The new regulation aims to streamline the application process and increase oversight and transparency of clinical trials conducted in the European Union.

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EU Clinical Trials Regulation: The Clinical Trial Transparency Revolution Expert Insights Webinar
2 Our Presenters Kelly Vaillant Senior Director, Center of Excellence and Innovation Karim Ibazatene Associate Director, Transparency Alan Nicolle Senior Director, EU & SA Operations
The European Economic Area (EEA) Brief Reminder
30 Countries in the EEA  European Union = 27 EU Member States* • 1 Single Market = 4 freedoms (free movement of persons, goods, capital and services) • EU Directives and EU Regulations  +3 non-EU Member • EEA = Extension of the EU's single market to 3 non-EU member parties (Norway, Iceland and Liechstentein) • EU rules on medicinal products apply European Medicines Agency (EMA) based in Amsterdam (NL) • Centralized Procedure (mandatory for oncology, HIV, biomedicines…) • 1 Marketing Authorization valid in 30 countries (27 EU countries + 3 EEA countries) • Don’t review CT application National Competent Authority in each Member States • Decentralized and National Procedure (when CP not mandatory) • Review CT applications *Austria, Belgium, Bulgaria, Croatia, Republic of Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden
The EU Clinical Trials Regulation Overview 5
6 New EU Clinical Trials Regulation: What’s New? • Single entry point (article 80): e-Submission via the EU Portal • New scope: Interventional + low-intervention clinical trials • New documents/data to be submitted: – Lay summary, – Interim results, – Statement from the facility director, – Inspection reports in a 3rd Party, – Copies of the advertising material (paper, audio, video…), – Statement on data protection,... • New templates for existing documents: protocol, labellings, IMPD, ICF… • New timing and new Data to be submitted: 1st date of recruitment, end of recruitment, serious breach • New timing for archiving the TMF (article 58): 25 years (for sponsor AND investigators) • New rules regarding GMP, manufacturing & import, labelling: expiry date on the immediate package (primary package)…
• Protocol Data (Summary) • Results Summary • Clinical study reports • Protocol • SAP TODAY TOMORROW • Protocol data (summary) • Results summary • Protocol • SAP • CRF template • CSR body + synopsis + annexes • + Interim results summary • + Lay summaries • + All Inspection Reports (worldwide) • + Cover letter • + Data safety monitoring committee charter • +Scientific advice summary • + Investigator’s brochure • + Autorisation of manufacturing and import • + QP GMP certification • + IMPD and AMPD • + Content labelling • + Proof of payment of fee • + Proof of insurance cover • + Investigator CVs and the List of financial interests • + Recruitment arrangements • + informed consent • +Audio/video advertisement • + Statement of the suitability of the facilities • + Statement of compliance to GDPR
8 New EU Clinical Trials Regulation: What’s New? CT Application CT Application CT Application CT Application CT Application EU Directive 2001/20 1 country = 1 Clinical Trial Application (1 CTA = 1 CA Dossier + 1 EC Dossier) 30 EEA countries = 30 CT Applications CURRENTLY EU Regulation 2014/536 1 Clinical Trial Application only PART I (scientific) + PART II (ethical) CT Application EU PORTAL Single entry point for the submission of clinical data 1 CT Application ↓ Up to 30 CT Authorizations From January 2022
9 EU Portal: An End-to-End Process Every Clinical Step is Managed Through the EU Portal • CT Application (initial dossier, NS and substantial modifications, addition of a New MS) • Assessment Reports (National Competent Authorities, Ethics Committees) • Member States' Decisions • Notifications (Trial dates, Serious breaches, USM…) • Inspection Reports in EU and in Third Countries • CT Results (interim & final results, lay summary, CSR) • Penalties in Case of Non-Compliance CTA Preparation CTA Submission and RFI Start of the Trial Inspection, Serious breach, USM… Start of the Recruitment NS and Substantial Modification End of Recruitment End of Trial Interim Results Restart of Recruitment Restart Temporary Halt Early Termination Results Summary Lay Summary CSR EU PORTAL
10 EU Portal, EU Database and Public Access to Information Source: European Medicines Agency
User Rights Management 11
12 User Right Management – The Hierarchy Inside the EU CT Portal Approves Sponsor High-level administrator (+Backup) Validates CT admin (sponsor, CRO…) Medium-level administrators Approves Approves Approves EMA Submitter • Application Submitter • Notification Submitter • CT Results Submitter • ASR Submitter Request EMA User Account Viewers • Part I Viewer (exc. Q-IMPD) • Part II Viewer • Q-IMPD Viewer • Notifications Viewer • CT results Viewer • ASR Viewer Preparers • Part I Preparer (exc. Q-IMPD) • Part II Preparer • Q-IMPD Preparer • Notification Preparer
Managing the User Rights in the EU CT Portal or Outside? • Registration in the EMA Website ‒ Personal Username & Password ‒ Belongs to the employee, not the sponsor • External User Right management ‒ Business roles limited by the EU Portal (e.g. Part II preparer can access to all Part II) ‒ Limited by the EU Portal functionalities (e.g. no notification email) • If multiple users ‒ Trainings and Monitoring of User Rights ‒ FTE and Resources +++ • New Role for largercompany:User Right Manager ‒ Monitoring the user rights on a daily basis ‒ Monitoring the new hires and the end of contract ‒ Potential breaches of confidentiality Inside the EU CT Portal • Registration at a company level ‒ Only a couple of EMA accounts ‒ User account links to the company accounts • Internal User Right management ‒ Customization of the business roles ‒ No limitation • Process already in place ‒ Slight adaptation ‒ Less FTE and Resources needed • No need of monitoring, no breaches of confidentiality ‒ Account automatically created and deleted ‒ No Potential breaches of confidentiality Outside the EU CT Portal (Through a software technology) VS
Submission of Clinical Trials Application 14
15 Initial Application: Timelines (60 - 106 Days) CT Application 1 single Part I = Scientific Part • Administrative data • EU application form • Clinical documents (Cover letter, Scientific Advice, Protocol, IB, IMPD, AMPD, Labellings,…) Part I Part II BE Part II DE Part II FR Part II PL Part II = Ethical Part (x4 Member States) • Recruitment arrangements • ICF • Investigators CV, list of financial interests • Suitability of facilities • Insurance • Financial arrangements • Proof of payment of fees • Data protection statement 1 Decision per MSc Harmonized assessment Assessment by each Member states Validation phase: 10 days – 25 days Decision 5 days Part 1 Part 2 (x4) Total 45 days /+31/+5 RFI - clock stop 12 days Ethical assessement 45 days Consolidation 19 days Single Decision RMS review Initial AR 26 days MSc review 12 days RFI - clock stop 12 days Consolidation 7 days Decision 5 days Total 45 days /+31/+5 Consolidation 19 days 31 days 45 days 1 Single Dossier is Submitted
16 Initial Application: Need of Coordination +++ Sending of a dossier with erroneous information • Validation rejected • + 10 days Submission of CTA freezes any other processes until the decision on Part I • No addition of new Member States possible. – Delay 60-106 days (initial application) + the review duration of Part II by the Member States (52-83 days) – If a country miss the first application, 112 to 189 days to wait a CTA • Submission of substantial amendments not possible during the Part I review • Sequential process. Each submission freezes the next one during the review Not answering on time? Huge consequences. • Request for information (RFI) must be answered within 12 days – Late answer for Part I? The CTA is deemed lapsed  Re-submission from the beginning + disclosure of the dossier for the first attempt – Late answer for Part II? The country is lost. Need to resubmit with a second wave + disclosure of the dossier for the first attempt
17 Adding a Member State After the Initial Application (52 - 83 Days) CT Application 1 Decision per MSc Irish Health Authorities agrees or disagrees Assessment by each Member State Decision 0 days Part 1 Part 2 (x4) Total 52 days/ +31 RFI - clock stop 12 days Ethical assessement 52 days Consolidation 19 days Part II for Ireland is Submitted Part I Part II BE Part II DE Part II FR Part II PL New Part II For Ireland • Recruitment arrangements • ICF • Investigators CV, list of financial interests • Suitability of facilities • Insurance • Financial arrangements • Proof of payment of fees • Data protection statement Part II IE
18 Key Take Aways *(+60 days possible for Advanced Therapy) Initial CTA Process frozen until Part I Decision Substancial Modification Process frozen if modification on Part I Adding a New Member State (Only Part II) Process stay open during the review 60 – 106 days* 49 – 95 days* 52 – 83 days
Trial Notifications (Trial dates, Serious Breach, USM,…) 19
20 Trial and Recruitment Date (Article 36 and 37) • Type of dates – Start Date = Date of the First act of recruitment (e.g. advertisement) – Start of recruitment = Date of First Signed Consent (FVFP) – Temporary halt: Date of temporary halt – Date of restart: Date of the first act of restart – Restart of recruitment: Date of the first consent after the temporary halt. – End of recruitment: Date of the end of recruitment + Date of the end of the studies • Entering the dates within 15 days • Non compliance can be prosecuted
21 Trial Notifications Unexpected events (Article 53) • All unexpected events which affect the benefit-risk balance of the clinical trial, but are not suspected unexpected serious adverse reactions • Notification without undue delay but no later than 15 days Urgent Safety Measure (Article 54) • Where an unexpected event is likely to seriously affect the benefit-risk balance, the sponsor and the investigator shall take appropriate urgent safety measures to protect the subjects • Notification without undue delay but not later than 7 days Serious Breach (Article 52) • A breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial • Notification without undue delay but not later than 7 days
Inspections and Extra-Jurisdictional Powers 22
23 Inspections Inspection of the clinical trial by Member States (Article 78) • Inspection reports will be redacted and disclosed by the responsible inspectorate Inspection by a third country authority = outside EEA (Article 53) • Inspection reports must be translated by the sponsor in English • Sponsor must also redact the personal data • Original and redacted version must be submitted via the EU Portal • Redacted version is made public
24 Studies Supporting a CTA Must Be ICJME Compliant (Article 25) ALL INTERVENTIONAL STUDIES • must be registered in primary registry (eg. clinicaltrials.gov) • BEFORE the first recruitment Yes Study rejected by Health Authorities Can not be used to support the CTA Registered before the FVFP Study supporting a CTA (ex: Phase 1 in US only) When started the study? Registered on primary registry? Study accepted by Health Authorities Can be used to support the CTA Yes Results in medical journals? Registered on primary registry? Yes No No No No Yes Before 2022* After 2022* * +1 year with transition period ONLY PHASE 2-4 • must be registered in clinicaltrials.gov • Within 21 days AFTER the first recruitment
Full and Immediate Disclosure of Clinical Trials Results 25
26 Interim Results (Article 37) Interim Results • MUST be posted on the EU Portal within 1 year after the intermediate data analysis date • No deferral for phases 2-4 • Deferral of 30 months after the intermediate data analysis date for phases 1 Challenges • Tracking interim analysis dates – Potential linkage to CTMS? – Can push this interim analysis date to the Disclosure Team • Provide the results summary within 1 year (impact to Medical Writing) • To be integrated in the publication plan (impact to Medical Affairs) SOLUTIONS • TrialAssure Beacon: Can be configured to automatically pull dates from CTMS into TrialAssure Registry • TrialAssure Registry: Workflow configuration and compliance tool can trigger initiation of disclosure activities
27 Final Results Summary (Article 37) Results Summary • MUST be posted on the EU Portal within 1 year after the end of study (LVLP) • No deferral for phases 2-4 • Deferral of 30 months after the end of the study for phases 1 Challenges • Similar to EudraCT requirements. Current process can potentially be adapted • Tracking LVLP – Via CTMS – Push this date to the Disclosure Team • Provide the results summary within 1 year Solutions • TrialAssure Beacon: Can be configured to automatically pull dates from CTMS to TrialAssure Registry • TrialAssure Registry: Workflow configuration and compliance tool can trigger initiation of disclosure activities
28 Lay Summary (Article 37) Lay Summary • MUST be posted on the EU Portal within 1 year after the end of study (LVLP) – Concurrent with Final Results Summary Posting • MUST be translated in all languages of participating Member States (up to 26 languages of the EEA) • No deferral for phases 2-4 • Deferral of 30 months after the end of the study for phases 1 Challenges • Same Timelines as Results Summaries • Translation in EEA languages • Integrating lay persons and Patients Advocacy Group in the review • Distribution of Lay Summaries Solutions • TrialAssure Link: – Workflow configuration and compliance tool can trigger initiation of disclosure activities – Potential for automated content population (Auto pre-population) – Potential for automated translation (Auto pre-translation)
29 Clinical Study Report (Article 37) Clinical Study Report of a Trial Supporting a Marketing Authorization in EEA • MUST be posted within 30 days of marketing authorization decision (or withdrawal)on the EU Portal • CSR Body (+ ALL annexes ?) • Disclose immediately • For Centralized Procedure (EMA) and Decentralized Procedures (National Competent Authorities) • For initial MA and any type of variation supported by a clinical trial performed in the EEA Challenges • No proactive review by Health Authorities prior to public release ≠ EMA Policy 0070 • No CCI allowed (cf Recital 68 of the EU CTR) ≠ EMA Policy 0070 • CSR body + All annexes or only the CSR body? The entire CSR in theory. To be clarified. • Integration with the Policy 0070 (EEA studies + Non-EEA Studies)? Solutions • For PPD: Privacy by Design • For CCI: Transparency by Design
Transparency
31 Transparency and Privacy by Design • Adoption of an enterprise Transparency & Disclosure Policy and GDPR strategy • Definition and Configuration of Disclosure rules and scenarios • Adaptation of Clinical Document Templates and Authoring Approach (e.g., Structured Content Management – SCM and Lean Authoring) • Development of a comprehensive Transparency End-to-end process • Important to move away from thinking of Disclosure & Transparency as compliance activities • Move toward thinking about Disclosure & Transparency as value added activities across the entire Development Pipeline Lifecycle Protecting Personal Data • Minimizing the volume of personal data in document • Avoiding personal identifiers (when possible) • Pro-active/Prospective Anonymization Privacy by Design General Writing strategy • Minimizing inclusion of confidential information • Disclosure of interim results, lay summary, final results and CSR • Education and Training Transparency by Design
32 Public View of the EU CT Portal (Article 81)
33 Defining & Assigning Disclosure Rules at the Beginning, Once for All • Disclosure starts at the time of decision (or time of the posting when there is no review by Member States) • Deferral of the disclosure is possible for certain document and data • It must be selected before some part of the submission • No possible change in the deferral selection after the CTA • Must be selected document per document. • Justification will be assessed. Deferral could be refused • Early termination of the deferral with the Marketing Authorization
Timing of Publication, Now or Later? Data/Documents Phase 1 Phase 2 & 3 Phase 4 & LI trials Main characteristic of trial Deferral up to 30 months after LVLP No deferral Cover letter Details regarding the investigators and the site (CVs, List of Financial interests, statement on the suitability of the site) Serious breach, inspection reports, notification including USM, unexpected events Interim results, Summary results and Lay summary Protocol 7 years 5 years 1 year Investigator Brochure IMPD Efficacy and Safety Parts) Response to RFI ICFs Dates (decision, FVFS, end of trial…) No deferral Member States decision (Request to sponsor, Assessment reports, Conclusion Part I and II, Member State Decision) Clinical Study Report Up to 30 days after Marketing Authorization
Penalties
36 Penalties (Article 94) Lack of compliance can be prosecuted • Non-compliance on submission of information intended to be made publicly available • Non-compliance on subject safety Sanctions depending on the Member States legislation Example: France (article L1126-12 of the Public Health Code) • Non compliance can be sanctioned by 1 year of jail +15,000 euros fine • Results disclosure (Interim results, final results, lay summary, CSR) • Reporting of the date for the End of study, Temporary halt and early termination • Reporting of suspected unexpected serious adverse reactions • Annual safety reporting • Data Protection
Transitional Arrangements
38 Transition Period (Article 98) New Studies starting after January 2022 EU CT Directive EU CT Regulation for New Studies starting after January 2023 January 2022 EU CT Regulation becomes applicable January 2023 End of Transition Period On-going Studies after January 2022 EU CT Directive EU CT Regulation - for On-going studies started during the Transition Period - For On-going studies started before January 2022 January 2022 EU CT Regulation becomes applicable January 2023 End of Transition Period for New Studies January 2025 End of Transition Period for on-going studies
Preparing the EU CT Regulation
40 Preparing for the EU CT Regulation with MMS Monitoring • Compliance metrics • KPI EU Portal Approach • In-house • Full or partial outsourcing (EU portal leader/support) IT System • TrialAssure software • Client system integration Implementation • Corporate governance • SOPs and clinical documents • User rights managements • Change management • Transparency and disclosure policy • Trainings
41 EU Clinical Trials Regulation: Our Services SME (Subject matter Expert) EU Task Forceand Governance Supportingprocessadaptation and development.Gap analysis for SOPand process. Actionplans and monitoringof the complianceimplementation Transparency and Privacy Transparency and Privacy by design. Redaction and Disclosure strategy to protect patient privacy and confidential information. Disclosure of results User Right Management Single POC for the User rights management. Supporting the development of a user right matrix. Super Trainer Program Training of Client teams on the EU CT Regulation and the EU CT Portal EU Portal Leader Single point of contact for the entire clinical trials lifecycle (CTA preparation and submission, RFI, Maintenance, Notifications, Results) Change management Implementation of Technology and Supporting organizational and procedural changes to comply with the new requirements. Clinical Documents Gap analysis, revision or creation of clinical documents to integrate EU CTR specifics, Translation services EU Portal Support Full or Partial outsourcing to support Client’s activities (CTA Preparer, CT maintenance and notification, CT Results submitter) PM and Strategy Planning and strategy for the submission of Part I and Part II.
Thank you! Any questions? email media@mmsholdings.com visit www.mmsholdings.com
Backup Slides
44 6 Key Takeaways New Processes Numerous procedures are impacted. Numerous SOPs needs to be created or updated. Informed Consent Reinforced Children and incapacitated subjects must be involved in each step. Their dissent must be respected. Safety Portal New Module of the EudraVigilance Database. Sponsor is required to submit SUSARs and ASRs. EU Portal as a Single Entry Point Harmonized e-submission and assessment process for clinical trials conducted in EU. Transparency Everywhere All data and document which enter in the EU Portal will be made public (with few exceptions). CT Notifications and CT Results Sponsors shall submit various notifications (such as key milestones, important safety information) and various CT results.
45 ICF - New Provisions (Article 28-35) New Provisions 1. Risk threshold and degree of distress 10. Minor involvement in ICF procedure 2. Secondary use of data for scientific purpose 11. Minor assent / agreement 3. Use of data before withdrawal 12. Minors refusal or withdrawal 4. ICF format 13. Benefit for the minor population 5. ICF content 14. CT scope for incapacitated subjects 6. ICF readability 15. ICF in emergency situations 7. Checking if the understanding of ICF information 16. ICF in pregnant or breastfeeding women 8. Summary of results in lay language 17. ICF in cluster trials 9. Specific patient populations
46 Implication of the Minor in the Consent Procedure Minors must be actively involved in the consent procedure, adapted for his/her age • Informed Consent Form should be developed with parents or Patients Organization • Systematic presence of the minor in each step of the consent procedure. Consent of parents/legal representative is not sufficient. • Minor (capable of forming an opinion and assessing the information) shall also assent to participate to a CT • Refusal or withdrawal from a minors is respected
47 ICF in Minors? The Cartoon Project! • To improve and facilitate the readability and the understanding • Different cartoon templates according the different class of age • Need to develop collaborations with Patients’ Organizations https://www.pediatricpain.eu/patients-and-families/ 2-5 Years Old 6-9 Years Old 10-18 Years Old
48 Corrective Measures and Union Control Corrective measures to be taken by a Member State (art. 77) • Revocation of the CTA, suspension of the trial, action to be taken by the sponsor to modify any aspect of the clinical trial. • Notice of corrective measures will be made public via the EU Portal at the time of the decision. Union Control (art. 79) • ExtraTerritorial Jurisdiction if sponsor use data generated by clinical trials outside EU to support a CTA • EU Commission may verify that equivalent EU requirements applies to the clinical trials outside EU: – Rights and safety of the subject – Reliability and robustness of the data generated • Final report of a Union Control is made public via the EU Portal
49 Safety Portal (Article 40-44) Safety Portal = New Module of the EudraVigilance Database • Suspected unexpected serious adverse reactions (SUSAR) • Annual Safety Reporting (ASR) submission and assessment Annual Safety Reporting (ASR) submission and assessment • Submission of DSUR by the sponsors via the Safety Portal • Assignment of safety assessment MS (saMS) to lead and provide recommendations to RMS and MSc • Assessment by the MSs (including Request for information) SUSAR reporting, rerouting and assessment • Reporting of SUSARs via the new Safety Portal • Re-routing of SUSARs to the MSs based on CT number and active ingredient • Assessment of SUSARs by the MSs • Safety Portal don’t use the EU Database • Disclosure rules will follow the rules of EudraVigilance Database. Not the disclosure rules of the EU Portal/EU Database
50 ICF Readability • EU CT Regulation go further and introduce the concept of layperson • ICF must be comprehensive, concise, clear, relevant and understable to a layperson • Lay person means readability of ICF should be between 6th-8th grade • Verification of the CT information understanding has to be performed. May be verified during inspections • EU trial number must be available for the subject in ICF • Sponsor should inform that: – Clinical trial results are available in the EU Portal – A summary in understandable terms to a layperson are available on the European Portal
51 Others Initiatives Source: Pediatric Clinical Trials | Pfizer (pfizerclinicaltrials.com) Pfizer ICFs in Minor Boston Children’s Hospital (in partnership with the Children’s Hospital of Philadelphia and Cincinnati Children’s Hospital)

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EU Clinical Regulation Webinar Slide Deck.pptx

  • 1.
    EU Clinical TrialsRegulation: The Clinical Trial Transparency Revolution Expert Insights Webinar
  • 2.
    2 Our Presenters Kelly Vaillant SeniorDirector, Center of Excellence and Innovation Karim Ibazatene Associate Director, Transparency Alan Nicolle Senior Director, EU & SA Operations
  • 3.
    The European EconomicArea (EEA) Brief Reminder
  • 4.
    30 Countries inthe EEA  European Union = 27 EU Member States* • 1 Single Market = 4 freedoms (free movement of persons, goods, capital and services) • EU Directives and EU Regulations  +3 non-EU Member • EEA = Extension of the EU's single market to 3 non-EU member parties (Norway, Iceland and Liechstentein) • EU rules on medicinal products apply European Medicines Agency (EMA) based in Amsterdam (NL) • Centralized Procedure (mandatory for oncology, HIV, biomedicines…) • 1 Marketing Authorization valid in 30 countries (27 EU countries + 3 EEA countries) • Don’t review CT application National Competent Authority in each Member States • Decentralized and National Procedure (when CP not mandatory) • Review CT applications *Austria, Belgium, Bulgaria, Croatia, Republic of Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden
  • 5.
    The EU ClinicalTrials Regulation Overview 5
  • 6.
    6 New EU ClinicalTrials Regulation: What’s New? • Single entry point (article 80): e-Submission via the EU Portal • New scope: Interventional + low-intervention clinical trials • New documents/data to be submitted: – Lay summary, – Interim results, – Statement from the facility director, – Inspection reports in a 3rd Party, – Copies of the advertising material (paper, audio, video…), – Statement on data protection,... • New templates for existing documents: protocol, labellings, IMPD, ICF… • New timing and new Data to be submitted: 1st date of recruitment, end of recruitment, serious breach • New timing for archiving the TMF (article 58): 25 years (for sponsor AND investigators) • New rules regarding GMP, manufacturing & import, labelling: expiry date on the immediate package (primary package)…
  • 7.
    • Protocol Data(Summary) • Results Summary • Clinical study reports • Protocol • SAP TODAY TOMORROW • Protocol data (summary) • Results summary • Protocol • SAP • CRF template • CSR body + synopsis + annexes • + Interim results summary • + Lay summaries • + All Inspection Reports (worldwide) • + Cover letter • + Data safety monitoring committee charter • +Scientific advice summary • + Investigator’s brochure • + Autorisation of manufacturing and import • + QP GMP certification • + IMPD and AMPD • + Content labelling • + Proof of payment of fee • + Proof of insurance cover • + Investigator CVs and the List of financial interests • + Recruitment arrangements • + informed consent • +Audio/video advertisement • + Statement of the suitability of the facilities • + Statement of compliance to GDPR
  • 8.
    8 New EU ClinicalTrials Regulation: What’s New? CT Application CT Application CT Application CT Application CT Application EU Directive 2001/20 1 country = 1 Clinical Trial Application (1 CTA = 1 CA Dossier + 1 EC Dossier) 30 EEA countries = 30 CT Applications CURRENTLY EU Regulation 2014/536 1 Clinical Trial Application only PART I (scientific) + PART II (ethical) CT Application EU PORTAL Single entry point for the submission of clinical data 1 CT Application ↓ Up to 30 CT Authorizations From January 2022
  • 9.
    9 EU Portal: AnEnd-to-End Process Every Clinical Step is Managed Through the EU Portal • CT Application (initial dossier, NS and substantial modifications, addition of a New MS) • Assessment Reports (National Competent Authorities, Ethics Committees) • Member States' Decisions • Notifications (Trial dates, Serious breaches, USM…) • Inspection Reports in EU and in Third Countries • CT Results (interim & final results, lay summary, CSR) • Penalties in Case of Non-Compliance CTA Preparation CTA Submission and RFI Start of the Trial Inspection, Serious breach, USM… Start of the Recruitment NS and Substantial Modification End of Recruitment End of Trial Interim Results Restart of Recruitment Restart Temporary Halt Early Termination Results Summary Lay Summary CSR EU PORTAL
  • 10.
    10 EU Portal, EUDatabase and Public Access to Information Source: European Medicines Agency
  • 11.
  • 12.
    12 User Right Management– The Hierarchy Inside the EU CT Portal Approves Sponsor High-level administrator (+Backup) Validates CT admin (sponsor, CRO…) Medium-level administrators Approves Approves Approves EMA Submitter • Application Submitter • Notification Submitter • CT Results Submitter • ASR Submitter Request EMA User Account Viewers • Part I Viewer (exc. Q-IMPD) • Part II Viewer • Q-IMPD Viewer • Notifications Viewer • CT results Viewer • ASR Viewer Preparers • Part I Preparer (exc. Q-IMPD) • Part II Preparer • Q-IMPD Preparer • Notification Preparer
  • 13.
    Managing the UserRights in the EU CT Portal or Outside? • Registration in the EMA Website ‒ Personal Username & Password ‒ Belongs to the employee, not the sponsor • External User Right management ‒ Business roles limited by the EU Portal (e.g. Part II preparer can access to all Part II) ‒ Limited by the EU Portal functionalities (e.g. no notification email) • If multiple users ‒ Trainings and Monitoring of User Rights ‒ FTE and Resources +++ • New Role for largercompany:User Right Manager ‒ Monitoring the user rights on a daily basis ‒ Monitoring the new hires and the end of contract ‒ Potential breaches of confidentiality Inside the EU CT Portal • Registration at a company level ‒ Only a couple of EMA accounts ‒ User account links to the company accounts • Internal User Right management ‒ Customization of the business roles ‒ No limitation • Process already in place ‒ Slight adaptation ‒ Less FTE and Resources needed • No need of monitoring, no breaches of confidentiality ‒ Account automatically created and deleted ‒ No Potential breaches of confidentiality Outside the EU CT Portal (Through a software technology) VS
  • 14.
    Submission of ClinicalTrials Application 14
  • 15.
    15 Initial Application: Timelines(60 - 106 Days) CT Application 1 single Part I = Scientific Part • Administrative data • EU application form • Clinical documents (Cover letter, Scientific Advice, Protocol, IB, IMPD, AMPD, Labellings,…) Part I Part II BE Part II DE Part II FR Part II PL Part II = Ethical Part (x4 Member States) • Recruitment arrangements • ICF • Investigators CV, list of financial interests • Suitability of facilities • Insurance • Financial arrangements • Proof of payment of fees • Data protection statement 1 Decision per MSc Harmonized assessment Assessment by each Member states Validation phase: 10 days – 25 days Decision 5 days Part 1 Part 2 (x4) Total 45 days /+31/+5 RFI - clock stop 12 days Ethical assessement 45 days Consolidation 19 days Single Decision RMS review Initial AR 26 days MSc review 12 days RFI - clock stop 12 days Consolidation 7 days Decision 5 days Total 45 days /+31/+5 Consolidation 19 days 31 days 45 days 1 Single Dossier is Submitted
  • 16.
    16 Initial Application: Needof Coordination +++ Sending of a dossier with erroneous information • Validation rejected • + 10 days Submission of CTA freezes any other processes until the decision on Part I • No addition of new Member States possible. – Delay 60-106 days (initial application) + the review duration of Part II by the Member States (52-83 days) – If a country miss the first application, 112 to 189 days to wait a CTA • Submission of substantial amendments not possible during the Part I review • Sequential process. Each submission freezes the next one during the review Not answering on time? Huge consequences. • Request for information (RFI) must be answered within 12 days – Late answer for Part I? The CTA is deemed lapsed  Re-submission from the beginning + disclosure of the dossier for the first attempt – Late answer for Part II? The country is lost. Need to resubmit with a second wave + disclosure of the dossier for the first attempt
  • 17.
    17 Adding a MemberState After the Initial Application (52 - 83 Days) CT Application 1 Decision per MSc Irish Health Authorities agrees or disagrees Assessment by each Member State Decision 0 days Part 1 Part 2 (x4) Total 52 days/ +31 RFI - clock stop 12 days Ethical assessement 52 days Consolidation 19 days Part II for Ireland is Submitted Part I Part II BE Part II DE Part II FR Part II PL New Part II For Ireland • Recruitment arrangements • ICF • Investigators CV, list of financial interests • Suitability of facilities • Insurance • Financial arrangements • Proof of payment of fees • Data protection statement Part II IE
  • 18.
    18 Key Take Aways *(+60days possible for Advanced Therapy) Initial CTA Process frozen until Part I Decision Substancial Modification Process frozen if modification on Part I Adding a New Member State (Only Part II) Process stay open during the review 60 – 106 days* 49 – 95 days* 52 – 83 days
  • 19.
    Trial Notifications (Trial dates,Serious Breach, USM,…) 19
  • 20.
    20 Trial and RecruitmentDate (Article 36 and 37) • Type of dates – Start Date = Date of the First act of recruitment (e.g. advertisement) – Start of recruitment = Date of First Signed Consent (FVFP) – Temporary halt: Date of temporary halt – Date of restart: Date of the first act of restart – Restart of recruitment: Date of the first consent after the temporary halt. – End of recruitment: Date of the end of recruitment + Date of the end of the studies • Entering the dates within 15 days • Non compliance can be prosecuted
  • 21.
    21 Trial Notifications Unexpected events(Article 53) • All unexpected events which affect the benefit-risk balance of the clinical trial, but are not suspected unexpected serious adverse reactions • Notification without undue delay but no later than 15 days Urgent Safety Measure (Article 54) • Where an unexpected event is likely to seriously affect the benefit-risk balance, the sponsor and the investigator shall take appropriate urgent safety measures to protect the subjects • Notification without undue delay but not later than 7 days Serious Breach (Article 52) • A breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial • Notification without undue delay but not later than 7 days
  • 22.
  • 23.
    23 Inspections Inspection of theclinical trial by Member States (Article 78) • Inspection reports will be redacted and disclosed by the responsible inspectorate Inspection by a third country authority = outside EEA (Article 53) • Inspection reports must be translated by the sponsor in English • Sponsor must also redact the personal data • Original and redacted version must be submitted via the EU Portal • Redacted version is made public
  • 24.
    24 Studies Supporting aCTA Must Be ICJME Compliant (Article 25) ALL INTERVENTIONAL STUDIES • must be registered in primary registry (eg. clinicaltrials.gov) • BEFORE the first recruitment Yes Study rejected by Health Authorities Can not be used to support the CTA Registered before the FVFP Study supporting a CTA (ex: Phase 1 in US only) When started the study? Registered on primary registry? Study accepted by Health Authorities Can be used to support the CTA Yes Results in medical journals? Registered on primary registry? Yes No No No No Yes Before 2022* After 2022* * +1 year with transition period ONLY PHASE 2-4 • must be registered in clinicaltrials.gov • Within 21 days AFTER the first recruitment
  • 25.
    Full and ImmediateDisclosure of Clinical Trials Results 25
  • 26.
    26 Interim Results (Article37) Interim Results • MUST be posted on the EU Portal within 1 year after the intermediate data analysis date • No deferral for phases 2-4 • Deferral of 30 months after the intermediate data analysis date for phases 1 Challenges • Tracking interim analysis dates – Potential linkage to CTMS? – Can push this interim analysis date to the Disclosure Team • Provide the results summary within 1 year (impact to Medical Writing) • To be integrated in the publication plan (impact to Medical Affairs) SOLUTIONS • TrialAssure Beacon: Can be configured to automatically pull dates from CTMS into TrialAssure Registry • TrialAssure Registry: Workflow configuration and compliance tool can trigger initiation of disclosure activities
  • 27.
    27 Final Results Summary(Article 37) Results Summary • MUST be posted on the EU Portal within 1 year after the end of study (LVLP) • No deferral for phases 2-4 • Deferral of 30 months after the end of the study for phases 1 Challenges • Similar to EudraCT requirements. Current process can potentially be adapted • Tracking LVLP – Via CTMS – Push this date to the Disclosure Team • Provide the results summary within 1 year Solutions • TrialAssure Beacon: Can be configured to automatically pull dates from CTMS to TrialAssure Registry • TrialAssure Registry: Workflow configuration and compliance tool can trigger initiation of disclosure activities
  • 28.
    28 Lay Summary (Article37) Lay Summary • MUST be posted on the EU Portal within 1 year after the end of study (LVLP) – Concurrent with Final Results Summary Posting • MUST be translated in all languages of participating Member States (up to 26 languages of the EEA) • No deferral for phases 2-4 • Deferral of 30 months after the end of the study for phases 1 Challenges • Same Timelines as Results Summaries • Translation in EEA languages • Integrating lay persons and Patients Advocacy Group in the review • Distribution of Lay Summaries Solutions • TrialAssure Link: – Workflow configuration and compliance tool can trigger initiation of disclosure activities – Potential for automated content population (Auto pre-population) – Potential for automated translation (Auto pre-translation)
  • 29.
    29 Clinical Study Report(Article 37) Clinical Study Report of a Trial Supporting a Marketing Authorization in EEA • MUST be posted within 30 days of marketing authorization decision (or withdrawal)on the EU Portal • CSR Body (+ ALL annexes ?) • Disclose immediately • For Centralized Procedure (EMA) and Decentralized Procedures (National Competent Authorities) • For initial MA and any type of variation supported by a clinical trial performed in the EEA Challenges • No proactive review by Health Authorities prior to public release ≠ EMA Policy 0070 • No CCI allowed (cf Recital 68 of the EU CTR) ≠ EMA Policy 0070 • CSR body + All annexes or only the CSR body? The entire CSR in theory. To be clarified. • Integration with the Policy 0070 (EEA studies + Non-EEA Studies)? Solutions • For PPD: Privacy by Design • For CCI: Transparency by Design
  • 30.
  • 31.
    31 Transparency and Privacyby Design • Adoption of an enterprise Transparency & Disclosure Policy and GDPR strategy • Definition and Configuration of Disclosure rules and scenarios • Adaptation of Clinical Document Templates and Authoring Approach (e.g., Structured Content Management – SCM and Lean Authoring) • Development of a comprehensive Transparency End-to-end process • Important to move away from thinking of Disclosure & Transparency as compliance activities • Move toward thinking about Disclosure & Transparency as value added activities across the entire Development Pipeline Lifecycle Protecting Personal Data • Minimizing the volume of personal data in document • Avoiding personal identifiers (when possible) • Pro-active/Prospective Anonymization Privacy by Design General Writing strategy • Minimizing inclusion of confidential information • Disclosure of interim results, lay summary, final results and CSR • Education and Training Transparency by Design
  • 32.
    32 Public View ofthe EU CT Portal (Article 81)
  • 33.
    33 Defining & AssigningDisclosure Rules at the Beginning, Once for All • Disclosure starts at the time of decision (or time of the posting when there is no review by Member States) • Deferral of the disclosure is possible for certain document and data • It must be selected before some part of the submission • No possible change in the deferral selection after the CTA • Must be selected document per document. • Justification will be assessed. Deferral could be refused • Early termination of the deferral with the Marketing Authorization
  • 34.
    Timing of Publication,Now or Later? Data/Documents Phase 1 Phase 2 & 3 Phase 4 & LI trials Main characteristic of trial Deferral up to 30 months after LVLP No deferral Cover letter Details regarding the investigators and the site (CVs, List of Financial interests, statement on the suitability of the site) Serious breach, inspection reports, notification including USM, unexpected events Interim results, Summary results and Lay summary Protocol 7 years 5 years 1 year Investigator Brochure IMPD Efficacy and Safety Parts) Response to RFI ICFs Dates (decision, FVFS, end of trial…) No deferral Member States decision (Request to sponsor, Assessment reports, Conclusion Part I and II, Member State Decision) Clinical Study Report Up to 30 days after Marketing Authorization
  • 35.
  • 36.
    36 Penalties (Article 94) Lackof compliance can be prosecuted • Non-compliance on submission of information intended to be made publicly available • Non-compliance on subject safety Sanctions depending on the Member States legislation Example: France (article L1126-12 of the Public Health Code) • Non compliance can be sanctioned by 1 year of jail +15,000 euros fine • Results disclosure (Interim results, final results, lay summary, CSR) • Reporting of the date for the End of study, Temporary halt and early termination • Reporting of suspected unexpected serious adverse reactions • Annual safety reporting • Data Protection
  • 37.
  • 38.
    38 Transition Period (Article98) New Studies starting after January 2022 EU CT Directive EU CT Regulation for New Studies starting after January 2023 January 2022 EU CT Regulation becomes applicable January 2023 End of Transition Period On-going Studies after January 2022 EU CT Directive EU CT Regulation - for On-going studies started during the Transition Period - For On-going studies started before January 2022 January 2022 EU CT Regulation becomes applicable January 2023 End of Transition Period for New Studies January 2025 End of Transition Period for on-going studies
  • 39.
    Preparing the EUCT Regulation
  • 40.
    40 Preparing for theEU CT Regulation with MMS Monitoring • Compliance metrics • KPI EU Portal Approach • In-house • Full or partial outsourcing (EU portal leader/support) IT System • TrialAssure software • Client system integration Implementation • Corporate governance • SOPs and clinical documents • User rights managements • Change management • Transparency and disclosure policy • Trainings
  • 41.
    41 EU Clinical TrialsRegulation: Our Services SME (Subject matter Expert) EU Task Forceand Governance Supportingprocessadaptation and development.Gap analysis for SOPand process. Actionplans and monitoringof the complianceimplementation Transparency and Privacy Transparency and Privacy by design. Redaction and Disclosure strategy to protect patient privacy and confidential information. Disclosure of results User Right Management Single POC for the User rights management. Supporting the development of a user right matrix. Super Trainer Program Training of Client teams on the EU CT Regulation and the EU CT Portal EU Portal Leader Single point of contact for the entire clinical trials lifecycle (CTA preparation and submission, RFI, Maintenance, Notifications, Results) Change management Implementation of Technology and Supporting organizational and procedural changes to comply with the new requirements. Clinical Documents Gap analysis, revision or creation of clinical documents to integrate EU CTR specifics, Translation services EU Portal Support Full or Partial outsourcing to support Client’s activities (CTA Preparer, CT maintenance and notification, CT Results submitter) PM and Strategy Planning and strategy for the submission of Part I and Part II.
  • 42.
  • 43.
  • 44.
    44 6 Key Takeaways NewProcesses Numerous procedures are impacted. Numerous SOPs needs to be created or updated. Informed Consent Reinforced Children and incapacitated subjects must be involved in each step. Their dissent must be respected. Safety Portal New Module of the EudraVigilance Database. Sponsor is required to submit SUSARs and ASRs. EU Portal as a Single Entry Point Harmonized e-submission and assessment process for clinical trials conducted in EU. Transparency Everywhere All data and document which enter in the EU Portal will be made public (with few exceptions). CT Notifications and CT Results Sponsors shall submit various notifications (such as key milestones, important safety information) and various CT results.
  • 45.
    45 ICF - NewProvisions (Article 28-35) New Provisions 1. Risk threshold and degree of distress 10. Minor involvement in ICF procedure 2. Secondary use of data for scientific purpose 11. Minor assent / agreement 3. Use of data before withdrawal 12. Minors refusal or withdrawal 4. ICF format 13. Benefit for the minor population 5. ICF content 14. CT scope for incapacitated subjects 6. ICF readability 15. ICF in emergency situations 7. Checking if the understanding of ICF information 16. ICF in pregnant or breastfeeding women 8. Summary of results in lay language 17. ICF in cluster trials 9. Specific patient populations
  • 46.
    46 Implication of theMinor in the Consent Procedure Minors must be actively involved in the consent procedure, adapted for his/her age • Informed Consent Form should be developed with parents or Patients Organization • Systematic presence of the minor in each step of the consent procedure. Consent of parents/legal representative is not sufficient. • Minor (capable of forming an opinion and assessing the information) shall also assent to participate to a CT • Refusal or withdrawal from a minors is respected
  • 47.
    47 ICF in Minors?The Cartoon Project! • To improve and facilitate the readability and the understanding • Different cartoon templates according the different class of age • Need to develop collaborations with Patients’ Organizations https://www.pediatricpain.eu/patients-and-families/ 2-5 Years Old 6-9 Years Old 10-18 Years Old
  • 48.
    48 Corrective Measures andUnion Control Corrective measures to be taken by a Member State (art. 77) • Revocation of the CTA, suspension of the trial, action to be taken by the sponsor to modify any aspect of the clinical trial. • Notice of corrective measures will be made public via the EU Portal at the time of the decision. Union Control (art. 79) • ExtraTerritorial Jurisdiction if sponsor use data generated by clinical trials outside EU to support a CTA • EU Commission may verify that equivalent EU requirements applies to the clinical trials outside EU: – Rights and safety of the subject – Reliability and robustness of the data generated • Final report of a Union Control is made public via the EU Portal
  • 49.
    49 Safety Portal (Article40-44) Safety Portal = New Module of the EudraVigilance Database • Suspected unexpected serious adverse reactions (SUSAR) • Annual Safety Reporting (ASR) submission and assessment Annual Safety Reporting (ASR) submission and assessment • Submission of DSUR by the sponsors via the Safety Portal • Assignment of safety assessment MS (saMS) to lead and provide recommendations to RMS and MSc • Assessment by the MSs (including Request for information) SUSAR reporting, rerouting and assessment • Reporting of SUSARs via the new Safety Portal • Re-routing of SUSARs to the MSs based on CT number and active ingredient • Assessment of SUSARs by the MSs • Safety Portal don’t use the EU Database • Disclosure rules will follow the rules of EudraVigilance Database. Not the disclosure rules of the EU Portal/EU Database
  • 50.
    50 ICF Readability • EUCT Regulation go further and introduce the concept of layperson • ICF must be comprehensive, concise, clear, relevant and understable to a layperson • Lay person means readability of ICF should be between 6th-8th grade • Verification of the CT information understanding has to be performed. May be verified during inspections • EU trial number must be available for the subject in ICF • Sponsor should inform that: – Clinical trial results are available in the EU Portal – A summary in understandable terms to a layperson are available on the European Portal
  • 51.
    51 Others Initiatives Source: PediatricClinical Trials | Pfizer (pfizerclinicaltrials.com) Pfizer ICFs in Minor Boston Children’s Hospital (in partnership with the Children’s Hospital of Philadelphia and Cincinnati Children’s Hospital)