Clinical trials: from European perspective to National implementation. CTFG / FAMHP / pharma.be. Brussels, 19 November 2010

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1 Clinical trials: from European perspective to National implementation CTFG / FAMHP / pharma.be Brussels, 19 November 2010 Safety in clinical trials: From detection to decision How safety events are captured and treated by promoters and NCA s CTFG - NCA s view Elke Stahl, Ph.D. CTFG Safety Subgroup

2 Overview European Commission: Draft guidance on adverse reaction reports from clinical trials, CT-3 CTFG s view on the CT-3 draft guidance CTFG s support to facilitate and harmonize safety monitoring in clinical trials Introduction to CT-3 Review Draft Guidance Draft detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use ( CT-3 )* Replaces: o CT3 o CT4: Detailed guidance on the European database of SUSARs (Eudravigilance Clinical Trial Module, EV-CTM) o Question & Answers to adverse reaction (AR) reporting in clinical trials (CTs) Goal: Short term improvement and clarification of rules for safety reporting prior revision of the Clinical Trial Directive 2001/20/EC (CTD) 2

3 Scope of CT3 Legal basis on the Clinical Trial Directive (CTD) Applies to Clinical Trials at least performed in 1 Member State (MS) Valid for all stakeholders in CT A concerned MS is a MS where the trial is authorised by NCA (national competent authority) and positive opinion by EC (ethic commission) Covers adverse reaction o Reporting on IMPs (Investigational Medicinal Product) o Eudravigilance database: EV-CTM (Clinical Trial Module) Serious Adverse Events and Suspected Unexpected Serious Adverse Reaction (SAE - SUSAR) Investigator needs to report SAEs immediately to sponsor except those specified in protocol or investigators brochure (IB) o Time line for immediate reporting <48h for non immediate reporting appropriate time, for non-sae with critical safety issues time specified in protocol Sponsor needs to o Report SUSAR fast to NCA and EC o Inform investigators o Input SUSAR into EV-CTM With regard to definitions reference is made to ICH E2A 3

4 SUSAR Obligation to report SUSARs in CT for all IMPs according to CTD only! Independent of marketing authorization (MA) status or usage (comparator, placebo)! SUSAR Assessment Seriousness o Responsibility of the sponsor, judgement delivered by investigator Causality o Responsibility of the sponsor, assessment by investigator o Sponsor not to downgrade investigator o reasonable causal relationship to IMP should be given (ICH E2A) Expectedness o Responsibility of the sponsor, assessment by investigator! o Sponsor should take investigator opinion into account, no downgrade o Assessment based on applicable reference 4

5 SUSAR Assessment Reference Applicable reference: CTD: Product information CT 1 guidance: Reference safety information (RSI) - Latest IB version approved by NCA or equivalent e.g. SmPC SUSAR Reporting Which Reporting if the CT is performed in at least 1 MS o SUSARs in that CT, no matter where occurred o SUSARs related to active compound outside EU if same sponsor, part of sponsor or development agreement SUSAR reporting obligation is not finished with end of trial 5

6 No SUSAR Reporting Adverse Reaction not to be reported: o For a Non-IMP (NIMP) if not related to interaction with IMP o If SUSAR occurs in EU and sponsor is not the sponsor of this trial of occurance o No SUSAR within definition, but Relevant for safety of participants, e.g. NIMP Observation which requires protection of subjects (ICH E2A) These may require other actions (see CT1): - Urgent safety measures - Substantial amendment - Early termination of trial SUSAR Reporting To Whom Addressee of sponsor report o NCA of MSs concerned and EV-CTM o EC which issued single opinion in the MS where event occurred o Investigators shall be informed, periodical line listing together with safety profile of IMP preferred 6

7 SUSAR Content Minimum reporting criteria: Only relevant information Relevance by medical judgement o Administrative information o Information needed to assess the benefit/risk Reporting time o fatal or life-threatening SUSAR by sponsor within 7 days initial and 8d for follow up report o non life-threatening SUSAR initial 15 days Format o Should be (follow) ICSR (individual case safety report; ICH E2B, EMA guidances new February 2011) For direct reporting: o Sponsor should provide EV-MPD (medicinal product dictionary) information o English Blinded IMPs Investigator should break blind only if relevant to safety of CT participant Sponsor should break blind only for that participant and only for person need to get unblinded data. Groups of people more specified In case of high morbidity or mortality disease change of unexpectedness to expectedness is allowed if a serious outcome is the efficacy endpoint. An independent data management committee (DMC) should be set up and composition and operation must be described in the protocol Case management see ICH E2A 7

8 EVCTM - single platform EV-CTM is the transmission tool for reporting SUSAR to MS concerned Input one mode provided by MS: o Direct input by sponsor, concerned MSs are notified by EV-CTM o Indirect input by NCA of MS where SUSAR occurred, NCA informed by sponsor, other concerned MSs notified by EV- CTM o Sponsor may chose input modus o If direct input not possible by sponsor (resources, experiences) also delegation to partner involved, outsourcing or use of indirect reporting possible Transition Phase To attain this single database in Europe: Capabilities needs to be improved to reach enhanced functionalities! Transition phase reporting in parallel to all o SUSARs in that CT, no matter where occurred reported to all concerned MS o SUSARs of active compound outside EU if same sponsor, part of sponsor or development agreement reported to all concerned MS o SUSARs occurred in a third country and trial also in EU, reported directly or a concerned MS selected for indirect reporting o SUSARs occurred in a third country only, reported directly or a MS selected for indirect reporting Member state where SUSAR occurred is in charge of ensuring input into EV-CTM direct or indirect. 8

9 Suspected Serious Adverse Reaction (SSAR) Yearly reporting of SSARs: Annual safety report will be succeeded by DSUR: Development Safety Update Report (ICH E2F, coming into operation September 2011) EV-CTM Purpose: o Supervision CT in whole EU and in each MS o Facilitation of reporting to NCA and of communication between NCA, Agency and Commission (EC no access to EV-CTM) Basic functionalities o Direct reporting of ICSR* o Reports integrating traditional and quantitative methods of signal detection by filtering main information o Queries for number of adverse reactions by IMP/s, age or indication, one CT (EudraCT#), case line listings o Monitoring reports for certain MPs or active compounds 9

10 EV-CTM Enhanced functionalities o Daily messages on new SUSAR relevant for MS including essential information o Alerts of SUSARs with certain properties MS is interested in o Reports based on range of ICH E2B fields including EudraCT number; Some customization and storage of these queries and reports, some selection of output format Overview European Commission: Draft guidance on adverse reaction reports from clinical trials CT-3 CTFG s view on CT-3 Draft guidance CTFG support to facilitate and harmonize safety monitoring in clinical trials 10

11 CTFG NCA s view on CT3 Roles and responsibilities of all stakeholders needs to be more specified: Investigator-Sponsor-NCA-EC-EMA Clarification is needed for responsibilities of NCA and EC o NCA responsible to assess safety in CT NCA have to ensure public health NCA supervise CT as e.g. they have access to EV-database, suspend/stop or inspect CT o EC responsible for ethical aspects Receive SUSARs only from CTs they gave opinion and which occurred in their MS now as case reports, old CT3 as case line listing, no access to EV-database Responsibilities Guidance is mainly dealing with sponsor s responsibilities Sponsors responsibilities specified details needed o We recommend to keep the old section 4.2. Ongoing safety evaluation Prompt notifications to all concerned bodies SOP for quality of trial Evaluation and reporting of AE/SUSAR Investigator o Informed by sponsor if safety issue from ICSR or from reviewed aggregated data only communication of analyzed data Periodically line listing and summary of safety profile recommendation: quarterly o Should assess causality! o Not to assess expectedness 11

12 Other Safety Issues Events not falling into SUSAR definition according ICH E2A o May need prompt communication since may influence benefit risk of IMP or CT (ICH E2A), like increased frequencies of SESARs, lack of efficacy, major non clinical or quality safety issue, reaction to misuse or error administration, NIMP o May not lead to other activities (see CT1), like urgent safety measures, substantial amendment, or early termination Expedite reporting of these events to NCA needed also see old o For example in case of a NIMP, it might even not be covered by any guidance! SUSAR Assessment Reporting only SUSARs o With reasonable causal relationship to IMP - investigator and/or sponsor o Expectedness should be assessed by sponsor, he should has best knowledge of his IMP o Unexpectedness is also given if specificity or severity of SESARs changes (ICH E2A) o Unblinded SUSARs o For certain CTs with high morbidity or mortality endpoints DSMB shall be appointed 12

13 SUSAR Reporting Minimum criteria for initial reporting and relevant information need to be in accordance with current ICSR Same reporting for life-threatening or non-life-threatening SUSAR, except time line Indirect EV-CTM reporting mode via (concerned) MS o Acceptable for non commercial sponsor and small enterprises o Same holds for reporting of SUSAR from 3rd countries during transition phase Annual Safety Report ASR/DSUR o Only reference given to ICH E2F o Applies to all sponsors commercial and non-commercial o Clarification with regard to RSI needed o If RSI changes for next DSUR period it needs to be approved by NCA via substantial amendment o Discussion on content which might be needed for signal assessment ongoing 13

14 Reference Safety Information Clarification is needed for RSI selection for SUSAR assessment o IMP not authorized or used outside authorization: IB, same in all MS concerned o IMP authorized within terms and conditions: SmPC, the most appropriate for the CT, same in all MS concerned, Clearly identified in protocol and cover letter of CT application o Language acceptable o Changes to RSI need to be accepted in all MS concerned prior implementation o RSI is crucial basis for assessment of unexpectedness (CT1, ICH E2A); Expected adverse reactions should clearly be describe Reference Safety Information Additional section in guidance: Safety assessment section in protocol proposed o As guidance for investigator for collection, assessment, reporting of AE o Issues to be covered needs to be specified 14

15 Reference Safety Information Differentiation between RSI for a CT or for a DSUR period o CT Needs to be changed for safety information (GCP) Basis for expectedness Introduce in IB a list of expected adverse reaction o DSUR RSI in DSUR reporting period should not change Best is to keep reporting rules for SUSAR for period An alternative? - under discussion EV-CTM A single CT safety database in EU is supported A mandatory use only if all parties are able to use it Improvement of EV-CTM functionalities needed o Basic and enhanced functionalities should cover the needs as defined by and going to be further specified by NCAs o Timeframe for implementation needed EVCTM should have an interface with EudraCT or be linked to it EV-MPD should be populated - best starting with early phase CT 15

16 EV-CTM Usage by all sponsors o Simplification of registration procedure and costs o Mandatory courses on EV-CTM online o Easy completion form e.g. EV-MPD, CTA, loaded from EudraCT Overview European Commission: Draft guidance on adverse reaction reports from clinical trials CT-3 CTFG s view on CT-3 Draft guidance CTFG support to facilitate and harmonize safety monitoring in clinical trials 16

17 CTFG activities to facilitate and harmonize safety monitoring in clinical trials Assist in improving and interpretation of regulatory framework Building on a safety assessor network SUSAR o EV-CTM functionalities First defined needs to proper assessment of SUSAR provided to EMA and Commission Standard queries and reports needed Specifications for a functioning database (EV-CTM / EV-DAS / EV-MPD; EudraCT) defined by user (NCA - via CTFG) compiled in cooperation with EMA o Assist in simplifying EV-CTM training CTFG support to facilitate and harmonize safety monitoring in clinical trials ASR / DSUR o Work-sharing process o Limited internal pilot to check process started o Concept paper on procedures of DSUR work-sharing, including assessment template ongoing 17

18 Improvements by Harmonization o Interpretation of regulatory framework (CTD, CT1, CT3, DSUR ) o Assessment of safety information o Actions by NCA and coordination of decision o Interaction with EC on a national base Simplifications o Single platform(s) for submission and multinational assessment e.g. SUSAR, DSUR, RSI, IB, protocol, CTA repository o Signal detection? THANKS! 18