Presentation on theme: "Monitoring and Auditing"— Presentation transcript:
1 Monitoring and Auditing Dr Ruben E. KeaneTrinity Centre, St James Hospital, Dublin30 January 2015
2 Whats my responsibility as investigator? Monitoring and Auditing are Sponsor responsibilitiesSo why does the investigator have to think about them?Investigator/sponsorAcademic institutions as sponsorsSponsor can delegate responsibilites‘The investigator/ institution should permit monitoring and auditing by the sponsor and inspection by the approprite regulatory authority(ies)’(ICH GCP 4.1.4)If sponsor responsibility why do investigators have to think about them.Well, as we will see Academic institutions are only coming to grips with the idea of academic sponsorship
3 What is Monitoring?The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded and reported in accordance withThe protocolStandard Operating Procedures (SOPs)Good Clinical Practice (GCP) andthe applicable regulatory requirements(ICH GCP 1.38)You as Investigator probably wrote the protocol – if you deviate from it consider amending it!
4 Why Monitor? ICH GCP and ISO14155 requirement. To verify that:the rights and well being of participants are protectedthe reported clinical trial data are accurate, complete and verifiable from source documentsThe conduct of the trial is in compliance withThe currently approved protocol/ammendment(s)With Good Clinical PracticeWith applicable regulatory requirements(ICH GCP 5.18.)Note – currently approved protocol – ensure amendments are done if procedures change.Applicable regulatory requirements – Regulations EU , ISO 190Devices directives etc.–
5 Who should Monitor? Monitors should be appointed by the Sponsor. Monitors should be appropriately trained and have the scientific and/ clinical knowlege needed to monitor the trial adequately.Need to be familiar with IMP, Protocol, GCP etc.(ICH GCP )Science, Nursing or Medical qualifications.Training in ICH-GCP, regulations, monitoring techniquesTraining in Therapeutic area and protocolSponsor may delegate the responsibility for appointing a monitor to the PI.
6 Who Currently Monitors academic trials? A member of the study teamContract Research Organisations (CRO)Freelance Contract monitorsHRB Clinical Research Facilities – Monitoring resources – Reciprocal monitoring - ICTRN
7 Nature and extent of Monitoring: ‘ Adequately monitored’ (ICH-GCP )This depends on the purpose, nature, complexity of design, size, risk to patients, endpoints, experience of PI and study site personnel.Traditionally Gold standard monitoringon site visits every 4- 8 weeks100% Source Document VerificationTraditional monitoring – onsite visit ever 4-8 weeks Move towards risk based central data monitoring – more targeted use of resources – fewer on site visits
8 Move toward Risk Based Central Data Monitoring: FDA guidance doc (2013) and EMA reflection paper (2011)Maximise use of resources , increase efffectiveness– more scrutiny of data, centrally and fewer onsite visits.Some data anomalies more easily detected by central monitoring techniques.Effective remote monitoring enabled by technology:Electronic CRFReal time data entrySKYPE remote ‘visits’Traditional monitoring – onsite visit ever 6-8 weeks Move towards risk based central data monitoring – more targeted use of resources – fewer on site visits
9 Types of on site Monitoring Visits Site SelectionSite initiationOngoing monitoring – routine or targeted visitsClose out visitMonitor= main communication link between sponsor and investigatorMonitoring report to sponsor and follow up letter to PI after each visitSite selection – verify suitability of the investigator and siteDo they have the necessary facilities and personnel and time to carry out the study.Targeted visit – if issues identified at site by remote data monitoring, by monitor , by Sponsor etc
10 Site SelectionPurpose: Verify the suitability of the investigator and the siteInvestigator and study staff qualifications and experienceClinical trial experience, experience in therapteutic areaAdequate site resources and facilitiesAny specialised equipment needed,storage and dispensing of IMPAdequate patient populationSite selection – verify suitability of the investigator and siteDo they have the necessary facilities and personnel and time to carry out the study.
11 Site InitiationPurpose: To ensure site is ready to begin entering patientsInvestigational Medicinal product on siteClinical supplies on siteTraining on Protocol , GCP, study specific proceduresData CollectionAE/ SAE reportingInformed consentInvestigator site file - documentationSite selection – verify suitability of the investigator and siteDo they have the necessary facilities and personnel and time to carry out the study.Site initiation-IMP on site, site personnel training , delegation log, Essential documents ready to start – green lightOngoing routine monitoring- check informed consents, CRFs, Do SDV (%) , check IMP storage and accountability, Essential documents. SAE reportingClose out visit- Any outstanding data queries, drug accountability and destruction, Essential documents complete, archiving arrangements for sample storage,
12 Ongoing- Routine Monitoring Monitor will focus on key study processes and documents:Informed consent process and documents – often 100% reviewEssential documents –including Approvals from Ethics Committee and Regulatory authorities, Insurance, Sponsor agreement etcQualifications, experience and training of site personnelPatient data - Study endpointsEligibility pf patients– Inclusion and exclusion criteriaSafety data -Adverse events (AE, SAE) documentation,reporting and follow up.Some errors are more important than others!
13 Key processes and documents (Continued) Investigational Medicinal product or device – handing, storage, accountabilityCompletion of Case Report forms – accurate and timelySample Collection and handlingSource document verification for % of participantsData management procedures – data capture and query resolution
14 Close out visitPurpose: To ensure that all documentation is complete, queries resolved and IMP accounted for.Review the Investigator site fileDiscuss ArchivingIMP – final accountability and destruction/return.Sample storage/ destructionSite selection – verify suitability of the investigator and siteDo they have the necessary facilities and personnel and time to carry out the study.Site initiation-IMP on site, site personnel training , delegation log, Essential documents ready to start – green lightOngoing routine monitoring- check informed consents, CRFs, Do SDV (%) , check IMP storage and accountability, Essential documents. SAE reportingClose out visit- Any outstanding data queries, drug accountability and destruction, Essential documents complete, archiving arrangements for sample storage,
15 Monitoring planWho will monitor ?– consider qualificaitons and experienceHow often?Remote or onsite?What will be monitored? - some errors are more important than others…What % of source document verification?Quality by Design- build quality into the planning phase.Some errors more important than others – consider an error in e.g patient height compared to an error in measuring a study endpoint or not reporting an SAE
16 AuditA sytematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported accordingto the protocol,sponsors standard operating procedures (SOPs),Good Clinical Practice (GCP) ,and the applicable regulatory requirements.(ICH GCP 1.6)
17 Monitoring versus Audit Ongoing review of qualitySnap shot of complianceFocus on data and daily activities of siteFocus on Processes and systemsMonitor is part of study teamAuditor is independentFlag issue and suggest remedial actionEvaluate if remedial action is workingMonitoring report + follow up letterAudit report noting non compliancesReply to follow up letterCorrective and Preventive action plan (CAPA)
18 If monitoring is done well, why audit? Objectivity- Auditor is not part of the study teamAudit is more process focussedAudit -Overview -Looking at the forest versus the tree!Audit -Can assess the effectiveness of monitoringMonitoring may trigger an audit – systemic problemAudit can support the monitor in getting compliance from unresponsive sitesAudit can support study site in preparing for regulatory inspection
19 Academic studies wrt monitoringand auditing: Challenges:Resources - Lack of experienced monitors and auditors on the study teamCosts- no cconsideration of Monitoring and Auditing costs in grant applicationsClarity re who is responsbile for monitoring -Who takes on this sponsor responsibility?Monitoring multicentre studies – language/culture/travelOpportunities:Clinical research facilities -Monitoring capabilities – reciprocal monitoring - ICTRNAwareness to factor in Monitoring and Auditing in grant application/costingsQuality by desing- Monitoring/ Quality Plan at early planning stage.Increased clarity around sponsorship responsibilities.
20 UCC sponsored HPRA studies Sponsor (UCC) Green light procedureBefore study can start recruiting QRM visits site to review documentation and processes. CRRO signs off green light.Quality Plan drawn up by Investigator and QRM at this visit:Who will monitor and how oftenQualifications and experience of monitorWho will do PharmacovigilanceWho will do Data managementWho will Audit and how oftenWho’s SOPs will be usedArchiving arrangements
21 Monitoring + Auditing – Synergy - addative effect on Quality Both are vital components in the sponsors Quality Assurance and Quality Control Processes.Monitoring and Audit are support functions who share your objectivesof ensuring patient rights and safetyensuring data is accurate and crediblegetting good quality clinical research done wellhelping you prepare for inspections