1. Surviving CTIMPs and MHRA inspections Kim Gooding Diabetes and Vascular Medicine UEMS and Exeter CRF Exeter Clinical Research Facility

2. My CTIMP history Principal Investigator (PI) on 2 investigator led studies – Both out of licence use of the IMP (drug) – One low risk, mechanistic study – Acute, clinical setting Non-commercial studies, both sponsored by R&D Both selected for inspection by MHRA

3. Is the proposed study a CTIMP?

4. How do you check whether it is a CTIMP? Talk to people, eg other researcher, R&D Send protocols for clintrialhelpline@mhra.gsi.gov.uk MHRA Algorithim – https://www.gov.uk/government/uploads/system /uploads/attachment_data/file/317952/Algothrim.pdf

5. Algorithm

6. Is it CTIMP? MHRA interested in studies looking at safety, efficacy and new indications for drugs. Tend not to be interested in mechanistic studies Are you testing the drug or using it as a research tool? Is it clear from your research question / aim that you are using the drug as a research tool?

7. Research question Interested in whether an abnormal peak skin blood flow response is induced by inflammation. Does the Salmonella typhi vaccination induces a abnormal peak reactive hyperaemic response in healthy individuals? To examine whether an acute inflammatory challenge induces abnormal vascular response in healthy individuals.

8. Study Development Talk to people

9. Study development Ensure that protocol is agreed with all relevant parties prior to submission, includes study team, sponsor and the clinical trials pharmacy team. IMP pathway Source data Safety reporting

10. Delegation of responsibilities Between Co-sponsors eg Trust and University Between sponsors and CI / PI Between CI and PI

11. Clinical trials authorisation Submitted at the same time as Research Ethics submission. Can be difficult to information before you are in system.

12. During the study Keep your site file up to date – Delegation logs – Summary product of characteristics Ensure that all relevant information is signposted. Document everything – Document phone calls by confirmation emails or files notes. Easier and more accurate to do it as you go along

13. My inspection experience

14. Panic!!!!!!!

15. Preparation for MHRA inspection Ensure site folder is up to date, signposted and complete Use file notes to complete the story Ensure all CRFs are appropriately completed Hospital notes contain all relevant details.

16. Lots of paperwork and communication with the research team and Trust, including a last minute audit Take advantage of all training / preparation eg I attended the Trust run courses: Inspection readiness and Mock interview Keep the study team informed Preparation for MHRA inspection

17. Ensure all process are in place, including – SOPs – Risk assessments – Freezer monitoring – All equipment under appropriate QC – GCP and training records – Honorary contracts

18. Prior to inspection Submitted site files, all CRFs and hospital notes, CVs of PI and CI Submitted information on training processes Training records of staff members performing assigned assessments /procedures.

19. During the inspection Attended the initial open briefing by Inspector Underwent my scheduled interview. Be prepared to supply additional information as required. – Ensure that you have time available or a runner Be prepared to attend a second interview Attended the final, close out meeting

20. Interview They use a variety of techniques, for example silence and double questioning. Main advice – Know your study – Know your study role – Be honest Ask questions, use it as a learning experience

21. Main feedback from first inspection Insufficient documentation Training: documented proof of training and competency. Delegation log is not sufficient. – Certificates – Training records Calibration / QC data: Evident that we are performing robust calibrations and QC checks but the documentation of this is not sufficient.

22. Documenting QC / calibration data Each individual machine needs a dedicated QC sheet. The sheet should reference relevant SOP. It should also include information on acceptable values. Should be signed and dated by operator. Should also be ultimately be signed off / reviewd by a competent individual.

23. Equipment / software etc Is everything validated? Does it fulfil IQ OQ PQ – IQ: Installation quality installed correctly? – OQ: Operational quality working correctly? – PQ: Performance quality performing as expected? – Cross Equipment verification

24. Take home messages Is the proposed study a CTIMP? Talk to people from the outset – Pharmacy, R&D, Sponsors, study team …….. – Team endeavour Document everything – File notes are wonderful things!

25. Don’t be put off from doing a study if it is a CTIMP.

26. Acknowledgements Diabetes and Vascular Medicine Research Team Stroke Research Team Pharmacy Clinical Trials Unit R&D