DIAS 4 Investigator Meeting January 2011 Are you ready for inspection? Quiz

1. DIAS 4 Investigator MeetingJanuary 2011Are you ready for inspection?Quiz

2. Question 1 (warm-up)What are you going to do after the end of today’s meeting? • I will have a walk to stretch my legs • I will think about how to optimise patient recruitment • I will be hungry and have a snack • I will be quite exhausted and just have a rest The correct answers will be marked in green and respective references will be given!

3. Question 2 What is the Latin name of the Vampire Bat? • Demodus smorundus • Demodus smotundus • Desmodus rotundus • Desmodus sotundus Desmoteplase is a protein from the saliva of the vampire bat Desmodus rotundus living in South America

4. Question 3 “The objective of this ICH GCP Guideline is to provide unified standards for _______ to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.” Which regions must be entered instead of the ______? • USA, Europe, Japan • USA, European Union, Japan • USA, Europe, Asia • USA, European Union, Asia Please refer to the introduction of GCP: The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.

5. Question 4 Select ALL of the following rights that are granted to a sponsor’s monitor by the term “Direct Access” • Direct access allows the monitor to inspect other medical records within the institution where the records are located • Direct access allows the monitor to examine, analyze, verify, and reproduce any records or reports deemed important to evaluation of the trial • Direct access allows the monitor to access all of a study subject’s personal health information • Direct access allows the monitor to publish reports of observations made during the inspection in public domains 1.21 Direct Access Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects' identities and sponsor’s proprietary information.

6. Question 4 Select ALL of the following rights that are granted to a sponsor’s monitor by the term “Direct Access” 1 Direct access allows the monitor to inspect other medical records within the institution where the records are located 2 Direct access allows the monitor to examine, analyze, verify, and reproduce any records or reports deemed important to evaluation of the trial 3 Direct access allows the monitor to access all of a study subject’s personal health information 4 Direct access allows the monitor to publish reports of observations made during the inspection in public domains

7. Question 4 - answer Select ALL of the following rights that are granted to a sponsor’s monitor by the term “Direct Access” 1 Direct access allows the monitor to inspect other medical records within the institution where the records are located 2 Direct access allows the monitor to examine, analyze, verify, and reproduce any records or reports deemed important to evaluation of the trial 3 Direct access allows the monitor to access all of a study subject’s personal health information 4 Direct access allows the monitor to publish reports of observations made during the inspection in public domains 1.21 Direct Access Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects' identities and sponsor’s proprietary information.

8. Question 5 Which medical occurrence is not a Serious Adverse Event? 1 An occurrence resulting in death 2 A birth defect 3 Pregnancy 4 Prolongation of hospitalisation

9. Question 5 - answer Which medical occurrence is not a Serious Adverse Event? 1 An occurrence resulting in death 2 A birth defect 3Pregnancy 4 Prolongation of hospitalisation 1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR) Any untoward medical occurrence that at any dose: • results in death, • is life-threatening, • requires inpatient hospitalization or prolongation of existing hospitalization, • results in persistent or significant disability/incapacity,or • is a congenital anomaly/birth defect (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting)

10. Question 6 What can serve as a source document? 1 Hospital records 2 Subjects’ diaries 3 eCRF 4 1 and 3 5 1 and 2 and 3

11. Question 6 - answer What can serve as a source document? 1 Hospital records 2 Subjects’ diaries 3 eCRF 4 1 and 3 5 1 and 2 and 3 1.52 Source Documents Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial).

12. Question 7 ICH-GCP ensures 1 Protection of the rights, safety and wellbeing of the trial subjects 2 Investigational Products should be manufactured according to GMP 3 Study protocols are scientifically sound and clear 4 1 and 3 5 1 and 2 and 3

13. Question 7 - answer ICH-GCP ensures 1 Protection of the rights, safety and wellbeing of the trial subjects 2 Investigational Products should be manufactured according to GMP 3 Study protocols are scientifically sound and clear 4 1 and 3 5 1 and 2 and 3 2.3 The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. 2.12 Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol. 2.5 Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

14. Question 8 What is weighed against each other for the subject before the clinical trial as well as throughout the conduct of the trial? 1 Risks against Costs for society 2 Benefits against Costs for society 3 Risk against Benefits 4 Risks and Costs for society against Benefits

15. Question 8 - answer What is assessed for the subject before the clinical trial as well as throughout the conduct of the trial? 1 Risks against Costs for society 2 Benefits against Costs for society 3Risk against Benefits 4 Risks and Costs for society against Benefits 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.

16. Question 9 Patient and investigator signed on the respective part of the IC but did not time and date. The study nurse noted this and dated and timed it on behalf of the investigator and patient. Is this correct according to GCP? 1 Yes, this is correct. 2 No, not correct; investigator and patient should date and time the IC retrospectively 3 No, not correct; in this case you must document what happened and let the patient (or witness or legal representative) confirm that the written informed consent was given and signed on the date and time noted and this comment should again be signed and dated by the investigator and the patient or the respective person. 4 No, not correct: the IC consent should in this case be left blank and correct time and date of the IC procedure should only be documented in the medical records enabling inspectors/auditors to verify correctness of obtaining IC

17. Question 9 - answer Patient and investigator signed on the respective part of the IC but did not time and date. The study nurse noted this and dated and timed it on behalf of the investigator and patient. Is this correct according to GCP? 1 Yes, this is correct. 2 No, not correct; investigator and patient should date and time the IC retrospectively 3No, not correct; in this case you must document what happened and let the patient (or witness or legal representative) confirm that the written informed consent was given and signed on the date and time noted and this comment should again be signed and dated by the investigator and the patient or the respective person. 4 No, not correct: the IC consent should in this case be left blank and correct time and date of the IC procedure should only be documented in the medical records enabling inspectors/auditors to verify correctness of obtaining IC 2.10 All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.

18. Question 10 The study protocol must be approved by the 1 Investigator and Sponsor 2 Sponsor and Subject 3 Investigator and IRB/IEC 4 Sponsor and IRB/IEC

19. Question 10 - answer The study protocol must be approved by the 1 Investigator and Sponsor 2 Sponsor and Subject 3 Investigator and IRB/IEC 4 Sponsor and IRB/IEC 3.1.2 The IRB/IEC should obtain the following documents: trial protocol(s)/amendment(s), … and any other documents that the IRB/IEC may need to fulfil its responsibilities. The IRB/IEC should review a proposed clinical trial within a reasonable time and document its views in writing, clearly identifying the trial, the documents reviewed and the dates for the following: approval/favourable opinion;…

20. Question 11 If a subject withdraws prematurely from the trial… 1 you are not allowed to ask the subject for his/her reasons 2 you should make a reasonable effort to ascertain the reasons 3 you should make every effort to ascertain the reasons 4 you should not accept this until at least a withdrawal visit was conducted

21. Question 11 - answer If a subject withdraws prematurely from the trial… 1 you are not allowed to ask the subject for his/her reasons 2 you should make a reasonable effort to ascertain the reasons 3 you should make every effort to ascertain the reasons 4 you should not accept this until at least a withdrawal visit was conducted 4.3.4 Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights.

22. Question 12 Responsibility for the investigational product accountability at the trial site rests with the 1 Investigator 2 Sponsor 3 Monitor 4 1 and 2

23. Question 12 - answer Responsibility for the investigational product accountability at the trial site rests with the 1 Investigator 2 Sponsor 3 Monitor 4 1 and 2 4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution.

24. Question 13 In DIAS 3/4 and in accordance with ICH-GCP the informed consent… 1 Always needs to be signed by the patient 2 Should be given verbally in case the patient is physically not able to sign and an impartial witness must sign the informed consent 3 Can be signed by a legally acceptable representative if patient is not able to 4 2 and 3

25. Question 13 - answer In DIAS 3/4 and in accordance with ICH-GCP the informed consent… 1 Always needs to be signed by the patient 2 Should be given verbally in case the patient is physically not able to sign and an impartial witness must sign the informed consent 3 Can be signed by a legally acceptable representative if patient is not able to 4 2 and 3 Please refer to chapter 4.8 of GCP

26. Question 14 If – following a protocol amendment – a new version of the Patient Information was issued, this version must be used immediately after being approved by the sponsor to inform future potential study subjects! 1 No, not correct; at first the regulatory authorities have to assess the changed risk benefit ratio before the new IC version can be used 2 Yes, correct; only this process ensures quick turn-around of latest safety information 3 No, not correct; at first IRB/IEC should approve the new version before it is used to inform potential study subjects 4 Cannot be answered generally, since regulations are different among regions

27. Question 14 - answer If – following a protocol amendment – a new version of the Patient Information was issued, this version must be used immediately after being approved by the sponsor to inform future potential study subjects! 1 No, not correct; at first the regulatory authorities have to assess the changed risk benefit ratio before the new IC version can be used 2 Yes, correct; only this process ensures quick turn-around of latest safety information 3No, not correct; at first IRB/IEC should approve the new version before it is used to inform potential study subjects 4 Cannot be answered generally, since regulations are different among regions 4.8.2 The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised written informed consent form, and written information should receive the IRB/IEC's approval/favourable opinion in advance of use. The subject or the subject’s legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject’s willingness to continue participation in the trial. The communication of this information should be documented.

28. Question 15 In DIAS 3/4 the MRI/MRA or CT/CTA can be done before the subject has signed the informed consent? 1 This is true for MRI/MRA, but not for CT/CTA due to the radiation 2 This is true only if the imaging sequences required by the study protocol are the same as the routine imaging sequences used at the respective site to diagnose stroke patients 3 This is generally true 4 This is generally false

29. Question 15 - answer In DIAS 3/4 the MRI/MRA or CT/CTA can be done before the patient has signed the informed consent? 1 This is true for MRI/MRA, but not for CT/CTA due to the radiation 2 This is true only if the imaging sequences required by the study protocol are the same as the routine imaging sequences used at the respective site to diagnose stroke patients 3 This is generally true 4 This is generally false 4.8.8 Prior to a subject’s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion.

30. Question 16 The investigator will give access to all patient data to 1 The sponsor’s monitor 2 The sponsor’s auditors 3 Only inspectors from the country the site is based in 4 Inspectors from all over the world 5 All monitors independent of the company they represent 6 1 and 2 and 4 7 1 and 2 and 3

31. Question 16 - answers The investigator will give access to all patient data to 1 The sponsor’s monitor 2 The sponsor’s auditors 3 Only inspectors from the country the site is based in 4 Inspectors from all over the world 5 All monitors independent of the company they represent 6 1 and 2 and 4 7 1 and 2 and 3 4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should make available for direct access all requested trialrelated records.

32. Question 17 What is not the duty of the investigator? 1 Quality assurance to ensure proper conduct of a trial 2 Reviewing ECG and lab results 3 Keeping detailed patient notes 4 Maintaining an investigator trial master file

33. Question 17 - answer What is not the duty of the investigator? 1 Quality assurance to ensure proper conduct of a trial 2 Reviewing ECG and lab results 3 Keeping detailed patient notes 4 Maintaining an investigator trial master file 5.1.1 The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).

34. Question 18 In which chapter of ICH GCP are essential documents listed? 1 5 2 6 3 7 4 8

35. Question 18 - answer In which chapter of ICH GCP are essential documents listed? 1 5 2 6 3 7 4 8 8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL

36. Question 19 Study files are kept at the sponsor AND at the site. However not all documents are maintained in both locations. Which of the following documents should be filed in both locations? 1 Signed Informed Consent Forms 2 Final Trial Close-Out Monitoring Report 3 Investigational Product Accountability at Site 4 Subject Identification Code List

37. Question 19 - answer Study files are kept at the sponsor AND at the site. However not all documents are maintained in both locations. Which of the following documents should be filed in both locations? 1 Signed Informed Consent Forms (8.3.12; only site) 2 Final Trial Close-Out Monitoring Report (8.4.5; only sponsor) 3Investigational Product Accountability at Site(8.4.1; site and sponsor) 4 Subject Identification Code List (8.3.21; only site)

38. Question 20 When the site has no bed scales available to measure the subject’s weight the patient cannot be included! 1 This is true; a bed scale must be available 2 The weight of the patient will not be captured in the eCRF if a bed scale is not available 3 If a bed scale is not available the weight of the patient will have to be estimated or relatives have to be asked for the weight

39. Question 20 - answer When the site has no bed scales available to measure the subject’s weight the patient cannot be included! 1 This is true; a bed scale must be available 2 The weight of the patient will not be captured in the eCRF if a bed scale is not available 3If a bed scale is not available the weight of the patient will have to be estimated or relatives have to be asked for the weight Common sense: The weight of the patient must be known to calculate the volume of desmoteplase solution to be administered. If a bed scale is not available the weight of the patient can be estimated or the relatives can be asked for it. This procedure mirrors the daily practice.

40. Question 21 In DIAS 3/4 we distinguish between asymptomatic and symptomatic ICHs (the latter means a worsening of >4 point on the NIHSS). What is correct in terms of safety reporting? 1 Both types of ICHs are medically significant events and need to be reported like any other SAE 2 aICH is not even an AE and sICH is an SAE (medically significant event) 3 aICH is an AE and sICH is an SAE (medically significant event) 4 aICH is an AE. sICH is also an AE since it does require a prolongation of hospitalisation

41. Question 21 - answer In DIAS 3/4 we distinguish between asymptomatic and symptomatic ICHs (the latter means a worsening of >4 point on the NIHSS). What is correct in terms of safety reporting? 1 Both types of ICHs are medically significant events and need to be reported like any other SAE 2 aICH is not even an AE and sICH is an SAE (medically significant event) 3aICH is an AE and sICH is an SAE (medically significant event) 4 aICH is an AE. sICH is also an AE since it does require a prolongation of hospitalisation Protocol 9.1.1 Specific definition of adverse events: Symptomatic ICH (SAE) – will be defined as an intracranial haemorrhage confirmed by appropriate diagnostic imaging which results in a worsening of ≥4 points on the NIHSS. A symptomatic ICH is a medically significant event and therefore an SAE Asymptomatic ICH – An intracranial haemorrhage confirmed by appropriate diagnostic imaging, which does not fulfil the criteria for a symptomatic ICH