Experience of a MHRA Inspection Aled Rees Senior Lecturer Centre for Endocrine and Diabetes Sciences

Timelines Trust informed June 2007 Pre-inspection dossier submitted July 2007 Informed early October that my trial had been chosen A Randomised, Double Blind, Placebo-Controlled Study Of The Effects Of Dehydroepiandrosterone Replacement On Vascular Function In Patients With Primary And Secondary Adrenal Insufficiency. Eudract No 2005-000115-10 SAE list for all trials sent late October Inspection visit 3rd – 7th December 2007

Why me? MHRA chooses 5-6 trials to inspect Unlikely a random process and will be chosen to best test the range of systems involved e.g. a multi-centre study, investigator-initiated single centre etc 1 University-sponsored trial chosen…mine!

The weeks leading up to the inspection OR ? Neither Plan: Familiarise myself with all regulations pertaining to clinical trials Ensure the trial master file was as good as it could be

Reference resources accessed GCP training update (Tanya Symons course) July 2007 Useful up-to-date information on ICH-GCP, EU Clinical Trials Directive and subsequent amendments, ethics committees, informed consent, pharmacovigilance & reporting requirements etc National research ethics service (www.nres.npsa.nhs.uk) MHRA clinical trials (www.mhra.gov.uk) Draft records management guidance Cardiff University CU/Trust SOP for trial master file Cardiff University RACD site SOPs, especially reporting of research related adverse events Data protection guidance for researchers (Trust guideline) Clinical trials toolkit website (www.ct-toolkit.ac.uk) Others

The interview Day 4 Interview 17 – DHEA 3294E Interviewed in the Clinical Research Facility 1 and a quarter hours Present: Me (obviously!), Senior GCP Inspector, Trust R&D Co-ordinator (to take notes) Co-investigator/nurse not interviewed for my trial but interviewed separately for all others (University sponsored and Trust being inspected)

The interview – areas covered Job history & research experience GCP training of trial staff and when undertaken (also CVs) Training in study specific techniques, calibration records discussed Archiving & retention of data Where will final data be stored? Discuss roles and responsibilities of CI and PI (both as a single centre study)

The interview – areas covered Trial set-up – who was involved? (Co-investigators, Clinical Trials Pharmacist, St Mary’s Pharmaceuticals Unit) Communication with co-investigators Co-investigator training (certificates in master file) Trial set-up difficulties – IMP shelf-life/stability issues discussed

The interview – areas covered What is the difference between a substantial and non-substantial amendment? Any amendments to the study and how dealt with? (change to washout period & approved by sponsor) I brought up the delay in submission from St Mary’s of a substantial amendment (in relation to batch stability data) – accepted by MHRA but commented upon in inspection report

The interview – areas covered Pharmacovigilance – AE and SAE reporting What would you do if an SAE occurred? What is an SAE? Who do you report to? Timelines of SUSAR reporting etc What if a co-investigator decided an adverse event had occurred? Could he make a decision? What if CI/PI was on leave? Could you override co-investigator’s decision? SOPs for adverse event reporting – Trust v University and Trust incident form also completed

The interview – areas covered Unblinding – emergency and end-of-study Envelope storage, on-call pharmacist, protocol for emergency unblinding in TMF Pharmacy issues and St Mary’s – accountability logs, delegation of responsibilities End of study unblinding ‘SOP’ discussed Data storage – where held? Identifiable information? Back up. Source data verification and archiving facilities End of study statistical plans

The interview – areas covered Trial steering committee? Risk assessment at study planning Master file and 5 case notes (list provided by MHRA a week or so before inspection) available for review but I believe may not have been looked at as insufficient time

The aftermath Attended end of inspection report on the Friday afternoon Trust – 1 critical and 4 major findings later downgraded to 0 critical and 4 major findings

The aftermath Inspection report issued to the Trust February 28th 11 page summary! Findings pertaining to DHEA 3294E (Minor/Other) 3.3.2 Data management and statistics There was no documented process for database lock and unblinding of blind codes for both …. & DHEA study

Conclusions Do not underestimate the importance of the inspection Be familiar with all the important regulatory documents Ensure your site file is spot on Be honest & remember this is an inspection of systems not really of individual trials The individual trials are picked to test that appropriate systems are in place and that these are running well

Thank you