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

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Experience of a MHRA Inspection Aled
ReesSenior LecturerCentre for Endocrine and
Diabetes Sciences
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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

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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 chosenmine!

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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

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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

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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 RD 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)

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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)

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The interview areas covered

• Trial set-up who was involved?
  (Co-investigators, Clinical Trials Pharmacist, St
  Marys Pharmaceuticals Unit)
• Communication with co-investigators
• Co-investigator training (certificates in master
  file)
• Trial set-up difficulties IMP
  shelf-life/stability issues discussed

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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
  Marys of a substantial amendment (in relation to
  batch stability data) accepted by MHRA but
  commented upon in inspection report

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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-investigators decision?
• SOPs for adverse event reporting Trust v
  University and Trust incident form also completed

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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 Marys 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

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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

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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

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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

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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

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Thank you