MP-7 Investigator Meeting January 31, 2011

1. MP-7 Investigator MeetingJanuary 31, 2011 Responsibilities of Investigator Kamila Novak

2. Investigator’s Responsibilities Safety Reporting Medical Care of Trial Subjects Communication with IRB/IEC Essential documents Informed Consent Adequate Resources IP Site Non- compliance Compliance to GCP and reg. requirements Source documents Protocol Compliance Records and reports

3. Adequate Resources Adequate number of qualified staff, adequately informed about the protocol, IP and their duties Adequate resources • Sufficient Time (competing trials) • Motivation • Adequate facilities • Adequate equipment and support functions Potential for recruiting the required number of suitable subjects ICH GCP Chapter 4.2

4. Medical Care • A qualifiedphysician (or dentist), who is an investigator • or a sub-investigator, should beresponsible for all trial • relatedmedical (dental) decisions • Investigator should ensure that adequatemedical care • is provided to a subject for ANYadverse events, • including clinically significant laboratory values • With subject’s agreement it is recommended for the • investigatortoinform the subject’s primary physician • about the subject’s participation in the trial • Investigator should make a reasonable effort to • ascertain the reasonfor subject’s withdrawing • prematurely from a trial Medical care ICH GCP Chapter 4.3

5. Сompliance with GCP Compliance with GCP Investigator should: • Be aware of and should comply with GCP and the applicable regulatory requirements ICH GCP Chapter 4.1.3

6. Сompliance with Protocol Investigator should: • Review the protocol • Be thoroughly familiar with the IP as described in the protocol, current Investigator’s Brochure, and the product information Compliance with protocol ICH GCP Chapter 4.1.2

7. Two Roles: Physician and Investigator Routine Medical Care Conduct of a Clinical Trial Person with symptoms is looking for physician to diagnose and treat the illness Investigator is looking for subjects with diagnosis eligible for the clinical trial Investigator collects and reviews, per protocol, relevant info to select eligible subjects Physician collects and reviews, per medical practice, relevant information to make a diagnosis Physician makes diagnosis and gives standard treatment/therapy of choice Investigator enters eligible subject into trial and is obliged to give IP per protocol

8. Two Roles: Physician and Investigator Routine Medical Care Conduct of a Clinical Trial Physician may change dose, route, administration of drug or drug itself and allow concomitant medication according to standard treatment Investigator follows protocol for dose, route and administration of IP and use of concomitant medication may be restricted Physician performs examinations and procedures to determine Diagnosis and evaluates outcome of treatment Investigator performs examinations and procedures per protocol to obtain data for efficacy and safety evaluation of IP Physician determines schedule of events for each patient Investigator follows schedule of events per protocol Treatment ends when satisfactory outcome is achieved Subject participation in trial is complete per protocol

9. Compliance with Protocol • The Investigator should sign the protocol (signature page) to confirm his/her agreement to conduct the trial in compliance with the approved protocol Compliance with protocol • The Investigator should not implement any deviation from the protocol without agreement of the sponsor and prior review and approval/favourable opinion of the IRB/IEC EXCEPT ... ICH GCP Chapter 4.5.1, 4.5.2

10. Compliance with Protocol • Where necessary to eliminate an immediatehazard totrial subjects • When changes involve only logisticalor administrativeaspects EXCEPT ... • The investigator should • document and explain any deviation from the protocol • document, explain and report such deviation • to IRB/IEC for review and approval • to sponsor for review ICH GCP Chapter 4.5.2, 4.5.3

11. Noncompliance Sponsor should act promptly to secure compliance (e.g. corrective action plan) Non- compliance Noncompliance with protocol, SOPs, GCP and/or applicable regulatory requirements Sponsor should terminate investigator’s participation If serious and/or persistent Noncompliance is identified by auditors and/or monitor Sponsor should notify RA promptly ICH GCP Chapter5.20

12. Deviations from Protocol - Reports to IRB/IEC • Deviations from, or changes of the • protocol to eliminate immediate • hazards to trial subjects • Changes increasing the risk to • subjects and/or affecting • significantly study conduct • All adverse drug reactions that • are both serious and unexpected • New information that may affect • adversely the safety of subjects No deviation from, or change of protocol without sponsor’s agreement, IEC/IRB approval * * * except when necessary to eliminate an immediate hazard(s) to subjects or in case of administrative changes ICH GCP Chapter 3.3.8, 4.5.4

13. Informed Consent (IC) of Trial Subjects • The voluntary confirmation of a subject’s willingness to participate in a particular • trial, after having been informed of all • aspects of the trial relevant to his/her • decision to participate in the trial • Documented by means of • a written, signed and dated • informed consent form • (by subject and investigator) Informed Consent Informed Consent Form Signature Date ICH GCP Chapter 1.28

14. Investigator’s Responsibilities • Consent the subject prior to participation in a trial and before ANY trial procedure, including blood tests for screening unless it’s part of normal clinical practice • Ensure the subject is fully informed • Ample time and opportunity to ask questions must be given • Should not unduly influence a subject to participate ICH GCP Chapters4.8.8, 4.8.5, 4.8.7, 4.8.3

15. Investigator’s Responsibilities • Document the consent procedure in source documents • Give the subject a copy of the signed and dated ICF • Obtain written approval from IEC/IRB on ICF and all changes to ICF • Ensure the language is understandable to the subjects ICH GCP Chapter 4.8.11, 4.8.1, 4.8.2, 4.8.6

16. “Special” ICF Procedures • Witnessed consent by impartial witness • e.g., if subject is unable to read • Legally acceptable representative • e.g., pediatric trials, mentally ill subjects • Emergency situations • e.g., unconscious subjects ICH GCP Chapter 4.8.9, 4.8.15

17. Vulnerable subjects Individuals whose willingness to volunteer is influenced by the expectation of benefits of participation, or of response from senior members of hierarchy: * medical students * patients with incurable disease * hospital/laboratory personnel * persons of nursing homes * armed forces * unemployed/homeless * people under detention * pharmaceutical industry * patients in emergency cases employees * ethnic minorities * incapable to give IC ICH GCP Chapter 1.61

18. Investigational Product IP A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use ICH GCP Chapter 1.33

19. IP – Investigator Responsibilities • Receipt of IP only by authorised staff • Dispensing, handling and appropriate use of IP according to protocol • IP given only to trial subjects, used package and unused IP returned • Explanation of the correct use of IP to each subject to ensure compliance with protocol • Storage as specified by the sponsor (temperature regimen, proper conditions/times) • Secure, safe and appropriate storage with limited access by investigator and authorised staff IP IP ICH GCP Chapter 4.6.2, 4.6.6, 4.6.4, 4.6.3

20. IP – Records at the Site • Maintain records of IP delivery, inventory, use by each subject and the return to sponsor/destruction • Dates and amounts received from sponsor • Confirmation IP received by authorised person • Dates and amounts dispensed to/used by patients • Dates and amounts returned to sponsor • Expiry dates (if applicable) • Unique code numbers assigned • Dosesused by subjects • IP accountability-RECEIVED = USED + UNUSED IP IP ICH GCP Chapter 4.6.3

21. IP – Randomization & Unblinding IP • Investigator should: • follow the trial’s randomization procedures • ensure that the code is broken only in accordance with the protocol • promptly document and explain to the sponsor any premature unblinding IP ICH GCP Chapter 4.7

22. IP - Flow of Events Investigational Product Q/sponsor/vendor IP receipt docs Received at Site IP dispensed to subjects IP accountability docs IP returned by patient IP returned to sender IP Reconciliation docs Destruction of IP

23. Adverse Event Any untoward medical occurrence in a patients or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment Safety reporting ICH GCP Chapter1.2

24. Why Are AEs Important? • Medical Reasons • Regulatory Reasons

25. Adverse Event-Recording WHERE ? Adverse Event Page in the CRF At each visit if AE occurred WHEN ? ! All AEs must be assessed by investigators and documented in the source documents first and then transferred to CRF ! ICH GCP Chapter 4.9.2

26. Adverse Event Page Protocol: Site Nr: Investigator: Subject Initials: Subject Nr: Randomisation Nr: Visit Nr: Visit Date: Treatm. given Outcome Serious- ness Adverse Event Trial Drug Duration Intensity/ Severity Causality Investigator Signature ____________________ Date ___________________

27. Recording AEs • What information is generally collected: • Adverse Event • Dates of Onset and Resolution • Severity: • Mild = aware but tolerable • Moderate = interferes with activities • Severe = unable to do normal activities • Causality: • Not related • Unlikely • Possible • Probable (AE stops when drug stopped) • Highly probable (AE stops when drug stopped and restarts when drug is reintroduced)

28. Recording AEs • What information is generally collected: • Outcome • Resolved • Resolved with sequelae • Ongoing • Death • Action Taken with Study Drug (dose) • None • Reduced or increased • Interrupted (means temporarily) • Discontinued (means permanently) • Requirement for Treatment – Concomitant Medication • Seriousness

29. Adverse Drug Reaction (ADR) New medicinal product Marketed medicinal product A causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out May occur at ANY DOSE! A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or treating diseases or for modification of a physiological function ICH GCP Chapter1.1

30. Unexpected Adverse Drug Reaction (UADR) An adverse reaction, the nature and severity of which is not consistent with the applicable product information It is not as you said it would be ! ICH GCP Chapter1.60

31. Serious Adverse Event (SAE) Any untoward medical occurrence that at any dose results in: • death • life-threatening • inpatient hospitalization or • prolongation of existing hospitalization • persistent or significant disability/incapacity • congenital anomaly/birth defect ICH GCP Chapter 1.50

32. Planned Hospitalization • Per project requirements, a hospitalization planned prior to a subject’s inclusion in the trial might not be considered an SAE • If a hospitalized subject has an AE that prolongs that hospitalization, then that AE would become an SAE

33. Pregnancy and Subjects • Most sponsor companies will request that all pregnancies are reported in the same way as serious adverse events i.e., immediately, and using the SAE report form or Pregnancy Notification Form • Upon consent pregnancies are followed until delivery of the child • Child is assessed at birth for any congenital anomaly/birth defect and possibly longer

34. What is what? AEs ADRs SAEs UADRs

35. Immediately may mean 24 hours Serious Adverse Event - Flowchart Episode of Myocardial Infarction Complete AE Page YES Is it an Adverse Event ? Is it a Serious Adverse Event ? NO Y E S • Notify the Sponsor/CRO • Complete SAE Report Form • Notify IRB/IEC and RA

36. Communicationwith IRB/IEC Written, dated approval/favourable opinion (before initiating) Ongoing applications of trial documents (during the trial) Ongoing Safety Reporting (during the trial) Progress/annual reports (during the trial Notification about trial completion, early termination (end of the trial) Communication with IRB/IEC ICH GCP Chapter 3.1.2, 3.1.4, 3.3.8, 4.4.1, 4.4.3, 4.10.1, 4.10.2, 4.12.1, 4.13

37. Prompt Reports to IRB/IEC • Deviations from, or changes of, the protocol to • eliminate immediate hazards to the trial subjects • Changes increasing the risk to subjects and/or • affecting significantly the conduct of the trial • All adverse drug reactions (ADRs) that are both • serious and unexpected • New information that may affect adversely the safety • of the subjects or the conduct of the trial Progress Reports ICH GCP Chapter 3.3.8

38. What are Source Documents (SD)? • Original documents, data and certified copies of original records necessary for trial evaluation and reconstruction SDs ICH GCP Chapter 1.52

39. Source Documents Include, But Are Not Limited To.... • Medical records/clinical charts/subject's file • Laboratory results • Subject diaries/cards • Pharmacy drug dispensing records • Recorded data from automated instruments ICH GCP Chapter 1.52

40. Source Documents Include, But Are Not Limited To.... • Microfilm or magnetic media, x-rays, etc • Records kept at pharmacy, at labs and medico- technical departments • Electronic records • Electronic signatures ICH GCP Chapter 1.52

41. Case Report Form (CRF) A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject CRF ICH GCP Chapter 1.11

42. Minimum Requirements for SD • Signed and dated Informed Consent form • source notes indicating that the subject has signed and dated the consent prior to any study procedure • Subject Identification/Demographic data • Unique study identifier (screening/randomization number) • Medical history including diagnosis of the condition under study • Physical examination

43. Minimum Requirements for SD (cont.) • Entries for each visit including screening, scheduled, and unscheduled, to include: • Dates • Health status • Medical observations • Changes to medications with reasons • IP dispensing and accountability • Adverse events • Efficacy measures • Study procedures (both done and not done with reasons)

44. Minimum Requirements for SD (cont.) • Concomitant medication • Concurrent medical conditions • Reports and printouts, radiology, x-ray, laboratory, ECG, MRI, EEG, etc. • Date of completion or withdrawal from study with reasons stated • Follow-up • Contacts with patients

45. Investigator’s Responsibilities • Consistency of CRFs with SDs • Up-to-date Source Documents maintained • Accuracy, completeness, legibility and timeliness of data collected, recorded and reported • Follow minimum requirements for recording data in Medical Records • Direct access to all trial documents for monitor, auditor, IRB/IEC, RA • Changes/corrections to CRFs dated, initialed • Discrepancies explained (if necessary) Source documents must not be altered to match the CRF ICH GCP Chapter 4.9.1, 4.9.2, 4.9.3

46. Data Correction • Proper procedure for correcting CRFs • Single line through error • Legibly print correct data adjacent to error • Initial and date correction • Never back date • Avoid pencil use • Never use correction fluid or tape ICH GCP Chapter 4.9.3

47. Source Document Verification (SDV) • Process of checking data consistency in the CRF with source data, performed to maintain subject safety • Requirements for data consist ency: • accuracy • completeness • explanation and documentation of discrepancies ICH GCP Chapter 5.18.4k, 5.18.4m, 5.18.4n

48. General Reminders • Source documents/data must be maintained individually for each subject and identifiable to the subject • Only authorised personnel are to make entries into source documents • All entries should be signed and dated by the personnel responsible for entries

49. Essential Documents Documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced Records • May include: • CRFs • Patients Medical Notes • SDs • Investigator Site File Essential Documents ICH GCP Chapter 1.23, 8.1

50. Retention of Essential Documents Records • At least 2 years after last Marketing Application approval in an ICH region and there are no pending or contemplated MAs in ICH regions • At least 2 years after discontinuation of clinical development • Sponsor responsible for informing investigator when no longer required ICH GCP Chapter 4.9.5