Practical Effective Steps to Improve Trial QUALITY from Audit/Inspections findings Cancer Clinical Trials Unit Scotland A NCRI Accredited Cancer Trials Unit Stirling Management Centre Friday, 14th November 2014

Dr Klimt Research & Development Bernini NHS Trust Daphne Street LONDON NW1 2DC 1 st April 2015 Dear Dr Klimt Re: Advance Notice of MHRA Statutory Routine GCP Inspection The Medicines and Healthcare Products Regulatory Agency (MHRA) Statutory GCP Inspection programme commenced in May 2004, in accordance with the Statutory Instrument 2004:1031. Your organisation has been provisionally scheduled for a routine GCP inspection between 1 st June 2015 and 30 th June To this end, please provide the GCP Inspection Dossier requested for planning purposes within 30 days of the date of this request.

How to best use our audit findings to improve trial quality?

1. What are our ‘classic’ findings? 2. How can we improve the quality of the trial to prevent the findings happening again? 3. How do we look for ‘relevant’ findings? To have a real impact on the quality?

Our ‘classic’ findings?

1.Lack of ‘OVERSIGHT’ PI oversight CI oversight CTU oversight Sponsor oversight

Newest kind of ‘lack of oversight’ finding: Lack of oversight on the Central monitoring systems. Documents are requested from sites and checked. However, there is NO log to document that the checks have been carried out by the CTUs requesting these documents. i.e. NO ‘oversight’ of this central System.

2.Quality systems: SOPs are in draft Uncontrolled templates are used It is not documented that SOPs have been read by staff SOPs are not implemented and do not reflect the practice There is no audit carried out to assess if the SOPs are being implemented ‘Classic’ findings:

3.IMP (s) Shipping records Temperature records Labelling ( CTU TMF contains a number of templates with no version numbers on them and it is unclear which has been submitted to MHRA) Accountability records Dose records Prescription ‘Classic’ findings:

‘Classic’ findings 4. No unblindind SOP or The existing unblinding SOP has not been tested out. Or If it was tested out, it was not documented.

5. Consent form Wrong version Gone missing Wrong date Investigator signing the consent is not on the delegation log ‘Classic’ findings:

6. Eligibility criteria Inclusion criteria not verified example: Medical notes ‘Classic’ findings:

7. PV Wrong SmPC is being used Different SmPc in the Pharmacy file and the site file Not clear, who is in charge of checking if the SmPc has been updated? CTU? When PIs are delegated to assess expectedness, they often do not realise that this needs, to be done by looking at the SmPC ‘Classic’ findings:

8.Computer validation system No evidence of validation This is a finding for all organisations: CTU, site, sponsor ‘Classic’ findings:

9. Discrepancy between the protocol and the CRF ‘Classic’ findings:

How can we prevent these findings happening again?

Being aware of our weaknesses is a start

1. Lack of oversight?  We need to better document what we already do: e.g.: PIs by large, do meet with their teams. All they need to do is document these meetings. CIs need to: be made aware of the outcome of the CTU and sponsor’s risk assessments. be involved/be made aware of the mitigations and monitoring plans by the CTU. CTUs: When substantial amendments are submitted, document that re-risk assessing the trial was considered. CTUs carry a lot of checks while collecting the data. Design logs to documents all the checks carried out as part of the central monitoring system and data collection.  At the costing stage: Funders to better fund monitoring, audits

2.Quality systems 3.IMP 4.Unblinding SOP 5.Consent 6.Eligibility 7.PV 8. Computer validation 9. Protocol/ CRF Better documentation but also, time, training which means added resources

How can we prevent these findings re-occurring again? 1.Risk assess the trials to effectively allocate resources 2.Better risk assessment criteria for better assessments 3.Maintain a tracker of Corrective And Preventative Actions (CAPA) for monitoring, audit, and inspection reports 4.Re-audit to check/demonstrate that the findings are not re-occurring 5.To minimise human error: training, sufficient staff

How do we look for ‘relevant’ findings?

From a QA perspective, what is our ‘END product’?

MHRA inspection(s) What do they look at? SYSTEMS To pre-empt the inspection findings we need to focus on the same scope to carry out our audits : Audit our SOP folders on a regular basis Audit our Training folders on a regular basis Prioritise SOP implementation audits instead of TMF/site files audits

Questions?