Inspection Readiness, Inspection readiness for clinical trial site..pptx

Inspection readiness for clinical trial site.

1. Inspection Readiness What to Expect During a (GCP) Regulatory Inspection

2. Agenda Purpose and Expectations of Regulatory Inspections When the Inspection is announced The Inspection Process Post Inspection Expectations How to Behave during an Inspection Communication during an Inspection Wrap Up / Q&A

3. Purpose of Inspections

4. Purpose of Inspections

5. Purpose of Inspections Type of Regulatory Inspections: Clinical Trial Inspections (EU) / Pre Marketing Approval (FDA) after a Marketing Authorisation / New Drug Application (MAA / NDA) Quality System Inspections (EU) / Surveillance (FDA) For Cause Scope of Regulatory Inspections: Comprehensive evaluation of the regulated party (Quality) System-based Limited to specific clinical trial and/or issue/area

6. Purpose of Inspections

7. Expectations of Regulatory Inspections You can expect an inspection to be built up as follows: Formal opening meeting with inspectors and key site staff To share inspection expectations (inspection scope, references against which will inspected, etc) Interviews, document review and facility tours Formal inspection closure To share inspection conclusion / feedback / any findings Was it not documented, did not happen

8. Expectations of Regulatory Inspections Inspectors are to: Assure that trial records will comply with applicable regulatory requirements Assure the accuracy, completeness and credibility of reported trial results – supported by data to the source data level Assure no selective reporting to authorities (e.g. withholding relevant safety information, protocol deviations, serious breaches) Assure trial data are not altered, omitted or fabricated Assure that trial documentation supports evidence that procedures and protocol are followed Review your decisions and may ask for supporting data for justifying these decisions

9. Expectations of Regulatory Inspections

10. When the Inspection is announced….

11. Inspections may be: Announced Unannounced Inspectors may enter the workplace at any time during business hours (FDA: FDA Form 482 (Notice of Inspection) Note: Foreign inspectors may need to announce their intention to perform an inspection in another country to the country MOH / inspectorate Announcement of Regulatory Inspections

12. Inspection Notification: FDA: FDA-482 (Notice of Inspection) EMA: Announcement Letter Announcement of Regulatory Inspections

13. Announcement of Regulatory Inspections Don’t wait until the inspector knocks at your door to prepare Be inspection Ready…Any Time Periodical reviews of: Investigator Site Files Access to medical records ( including archived records) Overall organization and compliance of the site / trial Establish an inspection site team representing the site as Subject Matter Experts (SMEs)

14. Typical composition of inspection site team: Lead coordinator and Principal Investigator (PI) Subject Matter Experts of study team Scribe : M aintains inspection history and takes (often literate) notes of interviews and questions/requests Escort : Site staff member who escorts inspectors during their visit Runner : Conveys document requests to answer any inspector questions/requests Documentation Manager : Document Reviewer/ Quality team Note: CRA/CRO/Sponsor will/can support with the inspection facilitation Announcement of Regulatory Inspections

15. Preparing for the inspection Make sure that (pre-)requested documentation is provided (complete and in a timely manner) Know your job and be prepared to explain this to an inspector! Deviations and mistakes occur, but be prepared to show documentation of (prompt and the right) corrective/preventive actions taken Define the tasks of the i nspection site team and make sure everyone understands his/her role Plan an inspection “strategy” (dry run?) Anticipate on document requests and prepare documentation Book the days and the required facilities (including a quiet room for the inspectors) Announcement of Regulatory Inspections

16. Announcement of Regulatory Inspections When an inspection has been announced / inspectors arrive unexpectedly: Follow site visitor procedures, if any, but in any case request inspectors’ credentials Immediately notify CRA / Sponsor Make sure institute staff / departments (e.g., EC, IRB, QA) are immediately notified per institute instructions Organize the inspection (as relevant for the scope of inspection), including: Notify and set up the inspection site team Arrange introduction and interviews of SMEs of study team (as requested by inspector) Arrange tour of the facilities (as requested by inspector) Make sure all documentation is readily available upon inspector request (including archived documentation)

17. The Inspection Process

18. Usual inspection approach: Formal opening meeting with inspectors and key site staff To introduce inspectors / key site staff To share inspection expectations (inspection scope, references against which will inspected, etc) To agree on inspection arrangements (e.g. department visits) Interviews, document review and facility tours Daily wrap-ups may be part of the inspection (ask for it!) Formal inspection closure To share inspection conclusion / feedback / any findings The Inspection Process

19. The Inspection Process Remember that Regulatory Inspectors have a broad power and: May enter the workplace anytime during business hours (i.e., FDA Form 482) May speak with employees and management May observe the operation of processes, (computerized) systems, equipment, facilities May review historical data (incl. access to medical records) Need to confirm adherence to Legislation / Protocols / SOPs

20. Remember that Regulatory Inspectors have a broad power and: May require access to and production of documents (and retain copies) May take photographs May take samples as relevant for the scope of inspection The Inspection Process

21. Interviews: Inspectors may want to speak with any staff member / management as deemed relevant Inspectors may ask the same questions to different individuals to confirm consistency of work / responses How to behave: Try to remain calm and polite, under any circumstances Further trips & tricks to follow … The Inspection Process

22. The Inspection Process Tour of Facilities: Tour of Inspectors may perform a tour of the facility depending on the scope of inspection for key risks to trial subjects and clinical trial data, for example: Outpatient / Inpatient clinic where study procedures are performed Pharmacy Clinical Laboratories used (blood/urine lab, MRI/ ECG department) Document storage / archiving facilities Don’t forget to take notes and follow up on requests!

23. The Inspection Process Document review: The inspector is permitted to (and will) review Procedures / Protocols (directly/indirectly) relating to clinical trial activities ISF (Investigator Site File) Source records (medical records, patient diaries, results, etc ) Case Report Forms and Databases Documents that – in principle- cannot be reviewed during inspections: Reports of audits Financial records of the site (unless relating to the clinical trial) Personnel records other than training

24. The Inspection Process Inspection Feedback and Conclusion: Daily wrap up meetings may be scheduled to share any findings, concerns and/or outstanding requests Take notes and ask questions if anything is unclear! Don’t assume that the inspector will not longer require a particular document or answer, when it is not mentioned during wrap-up! Contact your CRA / Sponsor to inform of the results of these wrap up meetings (in case they are not on site) Inspection will be concluded with a close out meeting to share the inspection outcome (findings) Form FDA483 may be issued by FDA Ask for next steps, if not clear from the conversation Take notes and ask questions if anything is unclear! Contact your CRA / Sponsor to inform of the result of the close out meeting (if they are not on site)

25. Post Inspection Expectations

26. Post Inspection Expectations Don’t assume the inspection has ended! Based on inspector feedback / Form FDA483, PI to agree with CRA/Sponsor on corrective / preventive action plan, to start immediately after inspection Share copy of any Form FDA483 with CRA/CRO/Sponsor PI, CRA and Sponsor will agree on how to answer immediately after the inspection (FDA483 or outstanding requests) or upon receipt of report Contact CRA and Sponsor as soon as you receive any news / report from Inspectors! Don’t Be Late

27. How To Behave during an Inspection…..

28. How to behave – Be organized Team organization is crucial in locating documents, presenting information, and answering the inspectors’ questions: Identify SMEs of study / site team Have documentation readily available Documentation should be reviewed prior to taking it into the Inspection room Be aware that response time may be monitored Be an expert on the project/documentation and be able to represent it confidently Make sure that any requests/questions/issues are shared within the team to see if anyone can address them Support satellite sites / departments: Make sure they are prepared in case of any requests

29. How to behave – Preparing for interviews If you are called as an SME of the study / site team during an inspection: Do not enter the inspection room directly unless specifically instructed, but report to the inspection facilitator of the inspection site team The inspection site team, with support of CRA/Sponsor, will provide you further instructions Once briefed, you will proceed to the inspection room

30. How to behave - FAQ What happens if an inspector finds something “wrong”? Answer: Make sure you fully understand what the inspector understands. There should be no misconceptions. Ask questions if necessary. If, for whatever reason, you feel that a finding is not justified, be sure to explain the situation/observation and provide evidence (evidence is here essential!) At the end of each day, request a verbal list of any observations At the conclusion of the inspection, the inspector will verbally present any significant findings at the closing meeting (and the FDA might leave the Form FDA 483)

31. How to behave - FAQ What happens if an inspector finds something “wrong”? Answer (continued): If the findings are insignificant, an inspector may opt to do nothing except verbally advise the PI / site staff The PI will respond in writing with a corrective / preventive action plan CRO and Sponsor will assist you during the development of the responses and the corrective action plan

32. How to behave - FAQ What happens if an inspector finds something “wrong”? Answer (continued): Corrective / Preventive Action Plan should address: Specific observations Systemic corrections / actions And reasonable time frames for implementing corrective (and/or preventive) actions The Plan should address all findings and be realistic

33. How to behave – General Inspection Conduct Act as follows during an inspection: Inspector(s) should be accompanied at all times by a site staff member All Inspectors are required to abide by any relevant safety (e.g., EHS) procedures (provide instructions!) In case Inspector(s) receive direct access to an electronic system, make sure (a brief and focused) training is provided Inspectors expect that staff are working, so don’t stop performing your job unless specifically requested

34. How to behave – General Inspection Conduct Act as follows during an inspection (continued): Limit conversations in the office area, hallways, rest rooms, etc. to only essential information Be cognizant of the presence of Inspectors when discussing any information pertaining to clinical trials Don’t assume that inspectors do not speak the country language (or any other language you use in internal conversations)! There is no such thing as an “off the record” conversation with an inspector Be aware that if Inspector(s) will be onsite multiple days, conversations outside of the immediate area/building should not involve company business - Inspector(s) might be around

35. Communication during an Inspection

36. Communication during an Inspection What Can We Expect The Inspector To Be Like? Methodical Intelligent Familiar with processes Well versed in Quality Systems Usually easy to converse with

37. Language: Verbal: ~7% Paralinguistic ~38% Non-Verbal ~55% Communication during an Inspection

38. Communication during an Inspection As an inspectee : Be Professional, Polite and Cooperative Be Informed Be Responsible Be Truthful Be Organized Be Respectful, Accepting, and Humble When interacting with an Inspector, act as the expert: Demonstrate knowledge and confidence in your quality system (if any), study-related procedures, manuals and the protocol

39. Communication during an Inspection When interacting with the inspectors: Listen to questions carefully Answer only what is asked. Do not embellish an answer. Clarify what you don’t understand before answering the question When a question is too broad, ask for specifics If you don’t know the answer, say so (but follow up!) If you are not the SME for a question asked, explain to Inspector and get the right person.

40. Communication during an Inspection If they use a closed question, answer as much as expected Never guess! Don’t fill in what an Inspector needs, unless it is absolutely obvious Do not volunteer information / issues / concerns If you think that the inspector has misunderstood something… Share this with the inspector (where necessary after confirmation with the inspection site team) Explain why, in a professional manner (and provide evidence to support this where feasible)

41. Communication During an Inspection Stick to the facts not opinions. Phrases to refrain from: I think … I’m not sure but … In my opinion, it should … What you are saying is not true… Honestly… Usually… Typically… As I recall…

42. Communication During an Inspection The DON’Ts during an Inspection: It is not productive to argue with the Inspector when responding to a question or an observation Don’t challenge the Inspector (too much). It only motivates curiosity and more questions. Don’t offer what you think should be an observation Do not stand around making faces and looking worried. Act confident and proud (not arrogant), not defensive .

43. Communication During an Inspection The DON’Ts during an Inspection: Never guess or give false data, always tell the truth If the Inspector asks you for information, do not: Make them ask for it again Wait to see if they forget about the request There are some “tricks” used to pull information from you during the inspection (interrogation tactics) Be aware of what you are saying and doing The “dome of silence” The “Hmmm… factor”

44. Communication During an Inspection The DON’Ts during an Inspection: Do not interrupt the Inspector or other employees when they are speaking Do not talk loud when the Inspector is trying to concentrate, read or review documentation Be professional Be courteous with cell phones

45. The Art of Inspections… Thought Exercise

46. The Art of Inspections You are a cast member at Walt Disney Land/World. A park guest asks “What time is the parade?” How do you, the cast member, respond? What if the Investigator asks you a similar question, how do you respond?

47. Wrap Up …

48. Remember The ultimate goal of the regulatory authorities is to protect the trial subjects and data submitted to the agency in support of a marketing application (and as such protect the patient who will might receive the drug in the future) Be inspection Ready…Any Time Records should demonstrate compliance and should therefore be in place, easily retrievable, complete and correct (ALCOA+) to avoid any findings

49. Remember As soon as you receive an Inspection notification, contact your CRA / Sponsor representative Prepare your team / site for the inspection During the inspection, be p rofessional, polite and cooperative Take notes and ask questions during the inspection Ask for daily wrap up meetings Note down any findings communicated by the Inspectors (and share with CRA / Sponsor representative)

50. Remember PI, CRA and Sponsor will agree on how to answer/act after the inspection Corrective / Preventive Action Plan should address: Specific observations Systemic corrections / actions And reasonable time frames for implementing actions Remain calm during the entire process: You are the expert, and the inspectors are humans Always contact CRA and Sponsor!!!

51. “Ethical behavior is doing the right thing when no one else is watching...” -Aldo Leopold