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

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

3. 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

4. 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

5. 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

6. TASC Organisational Structure

7. TCTU Organisational structure

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

9. TCTU and externally sponsored studies

10. 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

11. 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

12. 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

13. 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

14. MHRA Findings
Critical
Major
Other

15. 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

16. 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.

17. 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

18. MHRA Findings
Study specific
TCTU Processes
TASC Process

19. 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

20. 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

21. 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

22. 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)

23. 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

24. 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

25. 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)

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

27. 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?

28. 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