Post MHRA Inspection What next? TASC Seminar 25 January 2017 Dr Fiona Hogarth Co-Director TCTU

Preparation for the inspection Inspection itself MHRA report and Findings TCTU response and actions Actions completed so far

Timelines 22 January 2016: TCTU notified of inspection within the next 6 months 19 February: TCTU submitted dossier and trial list 27 May: MHRA confirmed dates of inspection (18-22 July) 7 July: MHRA issued draft inspection plan 15 July: MHRA added another study added to the inspection 18-22 July: inspection week 12 August: MHRA issue inspection report 19 September: TCTU send response 6 October: MHRA accept TCTU response

TCTU Dossier and at Inspection We aimed to demonstrate: The relationship between TASC and TCTU TCTU functions – what we do and do not do Definition of a TCTU badged study

Relationship between TASC and TCTU TASC is a joint UoD-NHST collaboration created in 2010 to provide oversight and governance for all clinical research projects carried out in Tayside TASC is not a legal entity but is governed by a MoU All contracts are with either the UoD and/or NHST Local studies are co-sponsored by UoD/NHST Roles of co-sponsors are managed by the R&D office, operational unit of TASC. TCTU is an operational unit of TASC TCTU supports locally and externally sponsored studies

TASC Organisational Structure

TCTU Organisational structure

TCTU and locally sponsored studies Statement of Support TM DM Stats IWRS Sponsorship Agreement CI responsibilities CI UoD NHST   TCTU Co-Sponsor

TCTU and externally sponsored studies

What TCTU does not do Activities managed by TASC R&D office Sponsor approval Legal advice, contract negotiation Not contracting authority R&D approval (commercial and non-commercial) Pharmacovigilance including DSUR Monitoring

TCTU Governance All TCTU activity is to TASC and/or external sponsor SOPs. All TCTU activity is to TASC and TCTU Working Instructions Definition of a TCTU Badged study: TCTU is providing the CI with, in addition to trial design or management advice, one or more bespoke TCTU services such as data management system and/or statistical advice and/or a randomisation system

Inspection preparation Notified everyone we could think of TASC/TCTU review meetings every two weeks Engaged external consultant for advice and mock interviews Reviewed TCTU processes – not to change but to confirm Worked with study teams to prepare them, TMF, file notes etc. Worked with TASC: R&D office, legal, CRC, Biorepository, Clinical Trial Pharmacy, Tayside Pharmaceuticals Dealt with serious breach Maintained work as normal

Inspection week 08:00 to 18:00 each day Set interview times: study teams, TCTU and TASC Ad hoc meetings at request of MHRA Ad hoc document review Review meeting at the end of each day to guide next day Advice and guidance throughout Verbal report at the end Cake

MHRA Findings Critical Major Other

Critical Findings a) Where evidence exists that significant and unjustified departure(s) from applicable legislative requirements has occurred with evidence that: i) the safety or well-being of trial subjects either has been or has significant potential to be jeopardised, and/or ii) the clinical trial data are unreliable and/or iii) there are a number of Major non-compliances (defined in (c) and (d)) across areas of responsibility, indicating a systematic quality assurance failure, and/or b) Where inappropriate, insufficient or untimely corrective action has taken place regarding previously reported Major non-compliances (defined in (d) and (e)) c) Where provision of the Trial Master File (TMF) does not comply with Regulation 31A 1-3, as the TMF is not readily available or accessible, or the TMF is incomplete to such an extent that it cannot form the basis of inspection and therefore impedes or obstructs inspectors carrying out their duties in verifying compliance with the Regulations

Major and Other Findings Major: d) A non-critical finding where evidence exists that a significant and unjustified departure from applicable legislative requirements has occurred that may not have developed into a critical issue, but may have the potential to do so unless addressed, and/or e) Where evidence exists that a number of departures from applicable legislative requirements and/or established GCP guidelines have occurred within a single area of responsibility, indicating a systematic quality assurance failure. Other: f) Where evidence exists that a departure from applicable legislative requirements and/or established GCP guidelines and/or procedural requirement and/or good clinical practice has occurred, but it is neither Critical nor Major.

MHRA Report No Critical Findings 3 Major Findings Data Management Project Management Monitoring 9 Other Findings Computer systems, PV, Medical Writing, QA, QS, REC, Serious Breach Reporting, Statistics Training

MHRA Findings Study specific TCTU Processes TASC Process

Study specific actions Unsigned protocols File notes Data cleaning Database unlock and lock Review of monitoring plans Review of monitoring reports Review of Statement of Support

TCTU Processes Data Management - immediate Review of existing and introduction of new WIs: Delete data from DMS (new WI) Updated existing WI for data lock and granting access rights Requesting of unbinding codes from randomisation system (new WI) Data management plan to be in place before DMS started

TCTU Processes Data Management- ongoing Introduce risk assessment for every change to DMS Detailed test plans for every change to DMS Processes for data verification at start and throughout study SAE reconciliation process

TCTU Processes Project Management - ongoing Review of existing and introduction of new WIs: Update pre-award TCTU process WI (risk assessment, budget) TRuST user guide and training (new WI) TMG charter and template agenda Update post award management WI Identification and recording protocol breaches Peer review of study documentation (new WI)

TCTU Processes Other – immediate and ongoing Migrate TRuST to new server UAT for TRuST Change management process for TRuST Formal validation of new versions of OpenClinica New WI and/or SOP to cover statistical activity including sample size calculations, DMCs, data transfer and archiving

TASC Processes Review of existing and introduction of new SOPs Update of SOP for locking databases Update (or combine) data management SOPs Update monitoring SOPs Update serious breach SOP

TASC Processes Monitoring Update of monitoring reports to help sites prioritise Process for TCTU to input into TASC monitoring plan Process for review of monitoring reports Review of SAE reconciliation process (new SOP)

TASC Processes Other Standardise pre-award process for approvals and budget preparation Review and new SOPs to cover statistics Review of training logs

Where next Record all actions addressed in response to MHRA inspection, with dates (prevents a Critical Finding in future) Informed MHRA of specific actions required by end of December 2016 Continue to review and improve TCTU processes Work with TASC to ensure TCTU and TASC processes are complementary Prepare for next MHRA inspection – 2017?

Some big thank yous.... CIs and study teams TASC: Jacob, Graeme, Catrina, Anna, Val and a lot of others UoD and NHST Dr Allan Gaw Biggest thank you is to my colleagues in TCTU who I hope are very proud of what they have achieved