1. Boehringer Ingelheim Investigator Meeting Study 1230.14 POLO- AML-2 February 23, 2013/Toronto Behbood Sadrolhefazi Therapeutic Area Specialist/ Oncology BI Canada Partners in Quality

2. - Winston Churchill It is no use saying, 'We are doing our best.' 'We are doing our best.' You have got to succeed in doing what is necessary what is necessary Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 2

3. What is GCP? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 3 1.Good Clinical Practice 2.Good Company Practice 3.Good Computer Practice 4.None of the above Q&A Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human subjects

4. What is the aim of GCP? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 4 1.To protect the rights, safety and well-being of trial subjects 2.To assure credibility of clinical trial data 3.To provide clinical trials with a unified standard to support mutual acceptance of data globally 4.All of the above Q&A

5. Partners In Quality Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 5 ICH- GCP IRB/IEC (Section 3) Investigator (Section 4) Sponsor (Section 5) Investigator (Section 4)

6. Investigator Takes a quality management approach to conducting a clinical trial with a focus on three key areas:  Patient  Data / Documentation  Product This approach reflects how you are conducting and supervising the trial! Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 6

7. How Do I do that? Compliance with: Clinical Trial Protocol approved by applicable regulatory authorities and by the IRB/IEC. ICH GCP and applicable regulatory requirements Internal Standard Operating Procedures & Policies By: Putting well-defined processes and monitoring systems in place Assessing your site’s internal performance Responding to sponsor monitor and external audit feedback Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 7

8. Which of the following can be indicators of non-compliance or problems with quality? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 8 Q&A 1.Inconsistent use of the most current Informed Consent form 2.Existing subjects don’t get updated Informed Consent 3.Increased number of subjects withdrawing from trial 4.Protocol violations 5.All of the above

9. Can you enter a patient in a study if they don’t meet all inclusion/exclusion criteria (i.e. protocol waiver)? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 9 Q&A 1.Yes Definitely 2.No – Never 3.It depends on the circumstances

10. Clinical Trial Protocol Compliance Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 10  NO deviations from approved protocol without agreement  Protocol Amendments can only be implemented after IRB/IEC approval EXCEPT: Eliminate hazard to patients Minor logistical / administrative changes MUST be: documented AND submitted to IRB/IEC, Sponsor & Regulatory Authorities (if applicable) ASAP

11. Based on available industry data, how often were protocol- related issues cited as deficiencies in GCP regulatory inspections? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 11 Q&A 1.26% 2.32% 3.51% Important because…. Failure to adhere to the clinical protocol is consistently the most commonly cited deficiency in inspections of clinical investigators each year

12. Who is responsible for ensuring that all site staff are adequately trained and informed of the study prior to starting in the study? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 12 Q&A 1.Investigator 2.Clinical Research Associate (CRA) 3.Ethics Committee 4.Sponsor Project Leader 5.Study Site Coordinator

13. What do I need? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 13 Adequate number of staff - qualified by education, training, and experience to perform their trial- related duties and functions Ability to recruit the required number of suitable subjects Sufficient time to conduct and complete the trial Adequate facilities to conduct the trial properly and safely: Equipment is calibrated and/or properly maintained Area for proper storage of investigational product & documentation Ongoing oversight throughout study to ensure quality & implementation of CAPAs CAPAs = Corrective Action & Preventive Actions

14. According to ICH GCP who is responsible for making trial related decisions for patients in a Clinical Trial? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 14 Q&A 1.Trained study research nurse qualified to work on the trial 2.Qualified physician who is delegated and trained to work on the study 3.CRA that the Sponsor has assigned to that site 4.All of the above 24/7 contact details!

15. Safeguarding the patient: Well-defined processes and monitoring in place to ensure : Informed Consent that is appropriately obtained and documented (ICH GCP 4.8) The safeguard of the rights, safety & well-being of all trial subjects (ICH GCP 2.3 and Section 3) Proper medical oversight (ICH GCP 4.3) Adherence to protocol –Inclusion/exclusion criteria, etc. (ICH GCP 4.5) –Trial procedures Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 15

16. Safeguarding the patient: (continued) Well-defined processes and monitoring in place to ensure : Instruction and monitoring of correct use of investigational product (ICH GCP 4.6) Reporting AE’s and SAE’s according to regulation and sponsor requirements (ICH GCP 4.11) Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 16

17. Should a patient Primary Care Physician be informed of their participation in a Clinical Trial? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 17 Q&A 1.Yes 2.No Important because… Subjects sometimes fail to mention critical clinical information about their medical histories that would preclude enrollment However it is only a recommendation

18. Which of these are required in the Informed Consent according to GCP? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 18 Q&A 1.Subject’s responsibilities 2.Purpose of the trial 3.Anticipated expenses for subject 4.Allowing Sponsor and regulator access to data 5.Foreseeable risks and reasonably expected benefits 6.All of the above are required Important because… A significant number of clinical study sites inspected each year are cited for informed consent issues, including using inadequate informed consent forms

19. Informed Consent - GCP Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 19 Fully informed including disclosure of safety information and risks Given signed copy Personal signing and dating Time for questions & review Completed PRIOR to any study related procedures/change in patients care Vulnerable Patients Face to face discussions Process should comply with local regulatory requirements Clear Language Updates given in a timely manner INFORMED CONSENT

20. According to GCP, who is responsible for investigational products? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 20 Q&A 1.Pharmacist 2.Investigator/Institution 3.Study coordinator 4.All of the above However … Tasks can be delegated to appropriately trained and qualified members of study team (e.g. Pharmacist).

21. Well-defined processes and monitoring in place to ensure investigational product is: Received in proper condition Stored under conditions specified on the product label (especially temperature), in the Investigator Brochure (IB) or the Clinical Trial Protocol Stored in a limited access area Fully traceable for total quantity (maintain records for receipt, dispensing to pts and return from pts, return to sponsor) Used only as specified in the protocol and according the randomization scheme Investigational Products (ICH GCP 4.6) Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 21

22. Procedures & Responsibilities Investigational Product Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 22 Please, help us to ensure the full traceability of the Investigational Product

23. According to GCP, which of the following is correct with respect to study specific records at site? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 23 Q&A 1.Principal Investigator is responsible for accurate, legible & timely data 2.Trial documents must be stored for 20 years after Clinical Trial ends 3.CRF data must be consistent with source documents 4.All of the above 5. (1) and (3)

24. Well-defined processes and monitoring in place to ensure: Essential Documents are maintained (ICH GCP Section 8 and as required by applicable regulations) Controls in place for critical trial updates (e.g. protocol amendments, IC documents, etc.) Documents are readily available and complete for audits, IRB/IEC members and regulatory authorities Plans in place for acceptable methods of recording observations during the trial Documentation (ICH GCP 4.9) Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 24

25. 1.No - there must always be a separate source of all data in the (e)CRF 2.Yes - as long as we remember to transcribe it into the patients notes before the CRA comes to visit 3.Yes – it doesn’t matter where it is entered for the first time Can source data be entered directly into the (e)CRF? Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 25 Q&A Important because…. Must have a source for all data points in the (e)CRF Many sites now enter patient information directly intoelectronic patient notes Important because…. Must have a source for all data points in the (e)CRF Many sites now enter patient information directly intoelectronic patient notes

26. Records & Reports One of the most common audit & inspection findings – inconsistencies between (e)CRF & source data Any changes made (in source notes or CRF) MUST be clear, understandable/explained, signed and dated –Regardless of paper or electronic –This is one reason why sharing of passwords is prohibited - we need to know who has made the entries/changes –Any Sponsor made changes should be endorsed by investigator and copy filed at site Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 26

27. ICH- GCP Partners In Quality Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 27 Investigator (Section 4) Sponsor (Section 5) IRB/IEC (Section 3) IRB/IEC (Section 3)

28. IRB/IEC (ICH GCP Section 3) Composition At least 5 members Responsibilities: Safeguard the rights, safety & well-being of all trial subjects Consider Principal Investigator’s (PI) qualifications Review trial documents within reasonable time & document outcome Conduct annual review of ongoing trials Ongoing review of progress & safety data Establish & document in writing its procedures Maintain records for at least 3 years after completion of trial Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 28

29. According to ICH GCP communication with the Ethics Committee is the responsibility of the Sponsor. Is this statement: Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 29 Q&A 1.True 2.False

30. What does that mean to Investigator? Before the trial – forward documents to the IRB/IEC for review & approval. Protocol and amendment(s) Subject informed consent form / any written subject information Investigator‘s brochure / any other safety information Investigator‘s CV Recruitment materials Other documents required by local regulations During the course of the trial – report the following to the IRB: Relevant deviations from/changes to the clinical trial protocol New safety information Serious and unexpected adverse event information Regular (at least once per year) information about the study Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 30

31. According to ICH GCP approval documentation from IEC/IRB must have : Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 31 1.Study title 2.List of documents reviewed 3.Fee for doing the review 4.Modifications required 5.Decision 6.Date of approval

32. ICH- GCP Partners In Quality Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 32 Investigator (Section 4) Sponsor (Section 5) IRB/IEC (Section 3) Sponsor (Section 5)

33. Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 33 The purpose of a Sponsor audit is to: 1.Scare the Investigator site so they will listen to the CRA! 2.Create more challenges for the Investigator & CRA!! 3.To independently evaluate the trial conduct to ensure compliance with protocol, SOPs and GCP and applicable regulatory requirements 4.Because the Sponsor SOPs state that auditing is required for all studies Q&A

34. Sponsor – ICH GCP Section 5 Investigator Selection Select qualified investigators Obtain agreement with Investigator to conduct trial according to ICH GCP and applicable regulatory requirements Investigational Product Manufacturing, packaging, labelling & coding Supply & handling Quality Assurance & Quality Control Implement & maintain quality systems with written SOPs Ensure direct access to trial sites & source data Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 34

35. Noncompliance Noncompliance to: Protocol SOPs GCP Law by Investigator OR sponsor staff requires prompt action to secure compliance If persistent or serious noncompliance identified at investigator site: Termination of participation in trial & Notify regulatory authorities Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 35

36. Sponsor – How do we do that? Partner & Support you throughout Provide the tools needed to conduct the trial –Clinical Trial Protocol, Investigational Product, IB, Training, etc. Monitor Through Quality Control and Quality Assurance –Via ongoing site monitoring, audits –Applying new processes for addressing compliance issues Provide assistance in the event of regulatory inspection –Training on what to expect and how to respond to findings –Help with preparation Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 36

37. Regulatory Inspections Why? Approval process for new drugs/new indications Routine Legal requirements Targeted It is the site being inspected – not the sponsor Updated: FINAL 23 Sept 11 37 MCG-125 GCP slides for Investigator Meeting PPT

38. Regulatory Inspections What to expect: Opening and closing meetings Inspector Interviews of all team members – always the PI –PI oversight Detailed data review so ALL study documents & patients notes must be available Time for preparation, conduct and follow up of actions Potential impact if there are findings: –Time to follow up on findings –Monetary fines –Legal action –Disqualifications 38 MCG-125 GCP slides for Investigator Meeting 38 MCG-125 GCP slides for Investigator Meeting PPT Updated: FINAL 23 Sept 11

39. Regulatory Inspections Advise on conduct  Be sure you understand the question. –Do not be afraid to ask for clarification –Never guess an answer  Do NOT respond to questions that are improper or outside your area or expertise.  Don’t delay providing records.  Stay friendly and courteous – do not become defensive! Updated: FINAL 23 Sept 11 39 MCG-125 GCP slides for Investigator Meeting PPT

40. Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 40 The following GCP areas have the MOST Sponsor AUDIT findings:AUDIT Q&A 1.IRB / IEC 2.Regulatory Authorities 3.Informed Consent 4.Adverse Event and Safety Reporting 5.Source Documents / Documentation 6.Management of Investigational Trial Drug 7.CRF Issues and Source Data Verification 8.Adherence to Clinical Trial Protocol 9.Adequacy of Investigator Facilities 10.Investigator’s Qualifications & Resources

41. MCG-125 GCP slides for Investigator Meeting PPT 41 QUESTIONS ? Updated: FINAL 23 Sept 11

42. As a partner in quality with the IRB/IEC and Sponsor you can be successful by: Summary Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 42 Taking a quality management approach to conducting a clinical trial focusing on patients, data and investigational drugs Putting well-defined processes and monitoring systems in place to ensure quality of every aspect of the trial Continually assessing your site’s internal performance

43. Trainers notes ADD PARTICIPANTS LEADER BOARD IF DOING A QUIZ Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 43

44. Following are back up slides for the optional AUDIT part – these can be modified as per local audit findings (if used) Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 44

45. Sponsor Quality Assurance Audits Informed Consent Issues: Patient has not personally dated the Informed Consent Not used the most current Informed Consent form Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 45

46. Sponsor Quality Assurance Audits Adverse Event and Safety Reporting Issues: Adverse Event/Serious Adverse Event not reported Serious Adverse Event report delayed Source information not used Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 46

47. Sponsor Quality Assurance Audits Source Document Issues: Source documents missing or inadequate Documentation in Source Documents according to protocol not complete Discrepancies or wrong values within Source Documents not explained Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 47

48. Sponsor Quality Assurance Audits Source Documentation : Requirements differ for data to be reported on the CRF in terms of whether a paper CRF or an electronic CRF is used Paper: Refer to the clinical trial protocol for data which needs to be derived from the source documents Electronic: All data needs to be derived from the source documents Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 48

49. Sponsor Quality Assurance Audits Case Report Form (CRF) and Source Data Verification Issues: Adverse Event not reported Concomitant therapies not reported Major entries, e.g. primary endpoints not adequately reported Concomitant diagnoses, medical history not reported Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT 49

50. Quality Assurance and GCP Clinical Trial Protocol Compliance Issues: Enrollment of subjects who do not meet eligibility criteria Study visits outside of prescribed windows Use of restricted medications Clinical Trial Protocol required tests not conducted Updated: FINAL 23 Sept 11 MCG-125 GCP slides for Investigator Meeting PPT Protocol 50