MHRA Inspection – 100 questions for Chief, Principal and ...



MHRA Inspection – Questions for CI – PI – Subinvestigators

The majority of questions were collated from real MHRA inspections across NHS Trusts and Universities between 2006 and 2010; Southampton University Hospitals NHS Trust (SUHT) would like to thank the University of Edinburgh, NHS Lothian (Scotland), the Royal National Orthopaedic Hospital Stanmore and West Hertfordshire Hospitals NHS Trust for sharing those. Some questions were added as they arose during inspection preparations.

Please be aware that this is by no means a complete set of questions and the MHRA will ask additional or differently phrased questions.

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Staff should bring their updated training record to the preparation interview.

About you

1. What is your clinical background?

2. Tell me about your experience on clinical trials (% non-commercial, % commercial)

3. How many active CTIMPs and other studies at the moment?

4. What type of GCP training have you had? (provider, what topics were covered, UK Clinical Trial Regulations included?) Why is there no record of GCP training on your CV?

5. Have you done any other research training? (e.g. MCA/paediatric consent, designing CRF/PIS)

6. Do you initiate your own studies?

7. Are you aware of recent changes to the UK legislation around CTIMPs?

8. What type of contract do you have with the NHS? (substantive, honorary, Research Passport)

9. How long have you been involved with this trial? (since beginning?)

About this clinical trial

10. How did this study come about?

11. Who was involved in the development of the protocol? (R&D, Research Design Service, Uni, Funding body?)

12. How did you decide on the key headings throughout the protocol?

13. Was this study written for an academic degree?

14. What type of statistical advice was taken for the study? (Medical or University statistician?)

15. Do you have a formal statistical plan or is it in the protocol?

16. What type of IMP is this? (chemical, biological, off-licence, unlicensed)

17. As far as the IMP is concerned, did you work out what you wanted or did you ask pharmacy what they could provide?

18. Were you given any support, for example, with the drug information?

19. How were Information Sheet, Consent Form and Case report Forms designed? Did anyone guide you?

20. How is this study managed? (CTU, trial coordinator, monitor involved?)

21. Who is managing the Trial Master File/ the Investigator Site File?

22. How does general correspondence, e.g. emails etc. get into the file?

23. Who obtained the regulatory approvals?

24. There were grounds for non-approval with the first submission to the MHRA. What was that about?

25. What is the sequence of getting approvals? Did you apply for ethics before or after R&D?

26. Which documents to you have to supply for R&D approval?

27. The University has an insurance policy. Does that cover this study?

28. What do R&D require from you during the study?

29. Do you as the Chief Investigator receive copies of local approvals/progress and which are these? (R&D approval, site initiation, mtg minutes/summary)

30. What duties were delegated to you by the Sponsor? (Is there a document that spells out what the Trust does and what the investigator does?)

31. How do you know which these are?

32. What documents/instructions did you get back from R&D with the R&D approval letter?

33. How do you manage this trial, are there overarching SOPs/policies from the Sponsor/Trust/University?

34. Who are the Principal Investigators on the other teams?

35. How where the other sites chosen?

36. Is any of the PIs/Research Nurses covering more than one site?

37. How are you as CI informed about progress at the other sites?

38. What information do you as CI regularly send out to the other sites?

39. What duties were delegated to the research team by the Chief/Principal Investigator?

40. Who sets up and signs the delegation log?

41. Are you responsible for any training on this trial? Where is this documented?

42. Who is on the local team?

43. Are standard clinical ward/rotational staff contributing to this trial?

44. How much are they trained for this study? Are they GCP trained?

45. What duties were delegated to you by the PI and how is this documented?

46. Was there specific training for this trial? (e.g. how to take consent, clinical procedures, lab analyses procedures, procedures or data analyses)

47. Who conducted the training and how is this documented?

48. How do you assess that your team are competent to complete their delegated tasks? (documented anywhere?)

49. What happens after the regulatory approvals are in place?

50. Did you have a site initiation meeting? What did this involve? (documented where?)

51. Do you have update meetings with the Chief Investigator? (discussions documented?)

52. Are there any committees for this trial (Data Management, safety, trial steering, how independent?)

53. Who are the members?

54. Locally, do you have regular team meetings?

55. What do you usually cover in those meetings and are these minuted?

56. How many participants do you have (recruited, on treatment in follow-up)

57. How do you identify patients? Describe your recruitment strategy.

58. Do you use adverts? (radio, posters) and have these been approved?

59. Who identifies the patients?

60. How do you approach patients?

61. Who tells participants about this trial and consents them?

62. Can all participants consent on their own? Do all parents have the capacity to consent? (what happens if not)

63. Talk me through the consenting procedure?

64. Do both parents sign consent?

65. Are there any things that you need to do before consenting? E.g. fasting, questionnaire, standard clinical samples

66. How have other clinicians been informed trained about this trial? (documented?)

67. What information are the participants given?

68. What about the side effects of the drug – who explained them to your participants?

69. Where do you store the Information sheets and consent forms? (ISF and/or different sets of medical notes)

70. You have consented the patient, what is the next step?

71. Against which criteria was inclusion/exclusion decided? Are any tests done to confirm eligibility?

72. Who decided on eligibility of the patient and is this documented anywhere?

73. What scores did you use? (e.g. Pain score, or DASH Disability of Arm, Shoulder and Hand/upper limb functionality score)

74. How do you liaise with any other medics/GP/health care teams about the medical history?

75. At what point are GP/Health carers contacted? How often?

76. What quality systems do you have supporting this trial? (QA, SOPs, monitoring)

77. How frequently and what do PIs report to the Chief Investigator?

78. What method was used for randomisation? Where is this information in the Trial Master File?

79. What do the IMP and comparator, placebo look like? Could I see exemplary bottles?

80. Have any errors occurred during randomisation? (if yes, what corrective/preventative action, how documented?)

81. Do you get a copy of the randomisation list/code, or are you just told which randomisation arm?

82. Where are the unblinding codes kept?

83. What happens in an emergency?

84. If double-blinded trial, who is allocated to do the unblinding and how can they be contacted (24h emergency tel, during the night)?

85. What is the procedure for breaking the code and where is this documented? (difference between day and night procedure?)

86. Was this ever tested? (procedure, night access)

87. There are many versions of the information sheet. How do you ensure that the correct version is used?

88. How did you decide who supplies the drug?

89. Is there a contract in place for the IMP supply?

90. Who designed the drug label?

91. Was there a single, large IMP stock supply, or multiple across several batches?

92. What amount is given to patients? How is this recorded (against batch no?)

93. Is there a recall procedure? Have you already used or tested it?

94. Who keeps the accountability log?

95. Who signs the IMP prescriptions? (Is there a log?)

96. Who does the weight calculation for the prescription? Who counter-checks this calculation?

97. How are the drugs transferred from pharmacy to the participants? (How do you get IMP to the Ward? Who takes prescription down?)

98. Did participants pick up themselves from Pharmacy?

99. Was there any interim storage? How far in advance is this sent from Pharmacy?

100. Did the IMP have any particular storage conditions? (temp, humidity and access controlled)

101. Did you receive/give any training on IMP storage? (documented?)

102. For temperature log deviations, what happened, what were your corrective/preventative actions?

103. Did you track the amounts of IMP taken? (how about self-administered drugs which participants took home, what happens to empty phials/packages)

104. Did you capture IMP administered/not taken on Case Report Forms (CRF)?

105. In percent, how good would you say is compliance of drug administration (esp. if taken at home)?

106. Any problems in compliance and why?

107. How many visits are there for each patient?

108. Where are these held (a good consulting room on ward, in Research Facility/Centre? Any issues with room booking/availability?)

109. Do participants show a photo ID when they attend?

110. On an ongoing basis, who sees patients?

111. Are all participant visits documented in the patient medical records/notes?

112. What is your source data, the medical notes or the case report forms?

113. What tests/interventions are conducted at these visits?

114. What happens at visit 1?

115. What will I see in the files for the data acquisition for healthy volunteers?

116. Where are these tests/measurements recorded?

117. Who has medical oversight?

118. Who provides medical cover if the PI is absent?

119. How do you monitor dosage and blood results?

120. How do you decide whether or not the patient should continue with treatment (IMP/placebo) and how do you manage this?

121. Talk me through the number of samples that are being taken.

122. Where are samples being analysed? (local lab, sent externally?)

123. When do you get lab results?

124. Who checks and signs off lab results as OK?

125. If external analyses etc – is there a contract/an agreement?

126. Do patients have a trial detail/emergency contact card to carry round?

127. What do you do if one of your participants gets pregnant? (assume excluded from protocol)

128. Have there been any deviations from the protocol and what type? (missed visits, follow-up calls, different dosing, missed tests, IMP storage deviations)

129. How have these deviations been logged/documented?

130. Who has made the impact assessment and how?

131. Any persistent deviations/breaches of GCP? (what is your definition of persistent, serious?)

132. How do you know that something is an adverse event?

133. How are general AEs recorded and what do you do about them?

134. What would you consider a reaction against the drug/intervention?

135. How do you capture reactions against the IMP? What info is captured?

136. How do other clinicians on this/other wards know that a patient is on a CTIMP?

137. Can they access the research file 24h?

138. Have there been any allergic reactions?

139. What would you consider serious reaction? Is there a grading scale?

140. What do you do when one happens? When do you do your report/timelines?

141. (How) Does the protocol permit for any non-escalated SAEs?

142. Have you had any SUSAR or USADE (Unanticipated Serious Adverse Device Effect)?

143. How do you assess whether something is a SUSAR? (expectedness)

144. What is your definition for a SUSAR for this specific trial?

145. How do you assess an expected reaction if drug used outside the licence?

146. Who assesses SUSARs?

147. If there is discrepancy, can the CI overturn SAR/SUSAR assessment?

148. Within how many days do you report SUSAR or SAE to the Sponsor/hosting R&D?

149. What are the reporting requirements for SUSAR to the MHRA? (7 days, unblinded)

150. Would CI report to MHRA if SUSAR?

151. What is the system to capture all AEs or only ARs (only Serious AE/AR?) from other sites in the TMF?

152. How do you communicate SUSAR/SAE to other research sites?

153. Did you have a system set up to deal with SAEs along the way or is it something that has developed due to having the first SAE?

154. What does R&D/your Sponsor do with SAEs/SUSAR/Safety Reports?

155. Where do you send the Annual Safety Report?

156. Who is responsible for writing/sending the Annual safety Reports and how do you know?

157. What is an urgent safety measure and how would you implement it? (3 days to submit substantial amendment, inform CI, PIs, Sponsor, R&D)

158. How would you define a serious breach and how report it? (when?)

159. Who monitors this trial?

160. Was it already monitored and what was the outcome?

161. What happens with all the data on the CRFs?

162. Is there electronic data capture?

163. Is there interim data analysis, signal trend analysis?

164. What type of database/software analysis is used?

165. What type of Quality Control processes do you have for the data? (cross-checking, double entry, avoid transcription errors)

166. Is there any data back-up?

167. At what point/stage was the trial data unblinded? (before or after stats analysis?)

168. Where any Annual Safety Reports submitted and who does this?

169. Who tracks the annual reports and Investigator Brochure/SPC updates are done?

170. What is the outcome of the trial so far? Any benefits for using XYZ? (interim analyses?)

171. What is the current trial status (number enrolled, post-dosing follow-up, completed, withdrawn/died)

172. How was this number of patients manageable?

173. What amendments have been made to the protocol?

174. Do you need to get these approved (by whom?)

175. What did you do with non-substantial amendments?

176. How and to whom were amendments communicated? (documented?)

177. What support do you get from Pharmacy? Does all IMP come via Pharmacy?

178. Are there specialist pharmacies (e.g. oncology, radio)

179. What are Pharmacy’s responsibilities for this trial?

180. How is the IMP supplied to the other sites?

181. How does pharmacy know who is authorised to prescribe/release the IMP?

182. What is the end of this trial? (last patient last visit?)

183. Is there a procedure for locking the database?

184. Who is involved in reviewing the data results?

185. Where was/will the information be published?

186. What is the Trust’s role in reviewing publications?

187. What happens to the study material and patient medical notes at the end? (archiving arrangements, who, where, how long)

188. What happens with the archiving for the other sites?

189. What will be forwarded for the TMF for archiving?

Ward /clinical area questions

190. Which of this equipment is specific to CTIMPs?

191. When was this equipment (screen, scales etc) last calibrated and can we see the certificate?

192. How quickly could you supply a calibration certificate if we asked for it in 14 years’ time for this particular trial?

193. Who determines the calibration frequency?

194. Are internal or external calibration services used?

195. How is the decision made into which of the 4 currently active CTIMPs on this ward to recruit a patient?

196. Describe the interaction/frequency of contact between clinical and research staff on this ward.

197. Where are the standard ward drugs and where the CTIMP drugs stored on the ward?

198. Is the IMP storage access and temperature controlee? If yes, how?

199. Can I do a quick check on expiry dates for IMP and also for some sample collection test tubes?

200. Who prepares the sample packs with the relevant test tubes?

201. How often do you check expiry dates? Where is this documented?

202. Who calculates the amount of drug per patient and how?

203. Is this calculation checked by another staff member?

204. How is shift handover managed and documented?

205. What is your source data and where do you record it?

206. How can you see if someone amended source data? (eCRF entry via web)

207. Who is present for study drug administration?

Any question you would like to ask yourself or your R&D Department to forward to an MHRA Inspector?

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