1. Good Clinical Practice
Hoang Bao Long, M.D.
Clinical Research Coordinator
Oxford University Clinical Research Unit - Hanoi

2. ICE-BREAKING
2

3. IN A NUTSHELL
1. Research ethics
* Research governance and operation
2. Sponsor, IRB and investigator
3. Study documents
4. Obtaining informed consent
5. Adverse events
6. Monitoring
3

4. GAME 1 IS THIS ACCEPTABLE?

5. GAME 1: Is this acceptable?
SITUATION 1
• A study requires patients to come back for follow-up.
• Rate of loss-to-follow-up (LTFU) is high.
• Study team’s solution: keep patients’ insurance card until patients
come back.
5

6. GAME 1: Is this acceptable?
SITUATION 2
• A clinical trial investigating a new therapy.
• A man is asked to join the trial. He is informed that, to date, the
trial is safe; hence, he agrees to participate in the trial. He stays in
the study for some months, then suffers from a severe
complication and dies.
• During his participation, there has been two patients suffering
from serious complications and three mice died in the animal
trial.
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7. GAME 1: Is this acceptable?
SITUATION 3
• A study will compensate for patient’s follow-up visit by paying
their transportation fee.
• An investigator thinks that patients living in a near distance will
be paid with less money. Therefore, to reduce the amount of
payment, he excludes patients living in a farther distance even
when they are eligible.
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8. GAME 1: Is this acceptable?
• Situation 1:
– Patients have the right to withdraw at any time.
– Violation to respect for persons.
• Situation 2:
– The trial appears to be harmful, yet is continued without any
considerations. The patient is not adequately informed.
– Violation to respect for persons and beneficence.
• Situation 3:
– Patients are not chosen by scientific criteria.
– Violation to justice.
8

9. PART 1 RESEARCH ETHICS

10. History of research ethics
Nazi human experimentation:
Nuremberg Code &
Declaration of Helsinki
Tuskegee syphilis
experiment:
Belmont Report
ICH/GCP
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11. Belmont Report
1. Respect for persons: autonomy, informed consent
2. Beneficence: “do no harm”, maximizing benefits, minimizing
risks
3. Justice: fair selection
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12. Belmont Report – Respect for persons
• Autonomy: research participants can themselves make a choice.
• Coercion:
– Threats (losing care if not participating …)
– Undue inducements (too attractive financial compensation …)
• Protection of vulnerable groups:
– Pregnant women, children
– Prisoners
– Poor/unemployed people
– Ethnic minorities
12

13. Belmont Report – Beneficence
• Clear risks  NEVER DO
• Risks/benefits consideration:
– Expected benefits outweigh expected risks
– Unexpected adverse events occur: postpone  evaluate  decide
• Benefactors:
– Participants
– Society/community
– Researcher  avoid exploitation
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14. Belmont Report – Justice
• Selection of participants: based on scientific criteria
• Equal distribution of risks/benefits
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15. Belmont Report
Principles Key issues Process
Respect Autonomy Obtaining informed consent
Beneficence Risks/benefits consideration Design of study protocol
Justice Fair selection Enrollment
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16. ICH/GCP
1. Protect research participants: rights, benefits, safety, & health
2. Ensure high-quality research
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17. INTRO
RESEARCH GOVERNANCE
AND OPERATION

18. Steps to conduct a study
Protocol
design
IRB approval &
funding /
sponsoring
Implementation
• Enrollment
• Data collection
• Analysis
• Monitoring
Close-out:
reports,
publishing

19. Governance vs. Operation
Governance Operation
• Preparing documents:
• Agreements, contracts …
• Regulatory documents
• CRFs, ICFs, patient information
sheets …
• Application for IRB approval
• Filing documents
• Preparing materials & logistics:
• Equipment
• Logistics
• Schedules (training, initiation,
monitoring …)
• Continuous provision of support
to study sites
Research associates Research coordinators
19

20. PART 2
SPONSOR, IRB AND
INVESTIGATOR

21. Who contributes to a study?
IRB
• Protect study
participants
Sponsor
• Fund
• Equipment
• Human resources
Investigator
• Enrollment
• Data collection
• …

22. Sponsor
• Funding
• Provision of human resources and equipment
• Research governance
• Investigational products
• Monitoring
• Insurance and indemnity
22

23. IRB
• Protect research participants: right, benefits, safety and health
• At least 5 members, with diversities
• Responsibilities:
– Reviewing study protocols
– Monitoring studies
– Making decision regarding studies: delay, request for safety data,
termination …
23

24. Investigator
• Carrying out studies
• Responsibilities:
– Research participants: healthcare, enrollment, obtaining informed
consent
– IRB: providing required documents, providing periodical reports,
monitoring AEs and SAEs and reporting
– Investigational product: management
– Study protocol: procedures, randomization, blinding, CRFs
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25. PART 3 STUDY DOCUMENTS

26. STUDY
DOCUMENTS
1. Regulatory documents
2. Source documents
3. Study protocol
4. Investigational brochure

27. 1 - Regulatory documents
• Prove:
– Study’s existence
– Legality
– Adherence to GCP and regulations
• Documents:
– Delegation log
– Study protocol, CRFs, ICFs, SOPs
– Agreements, contracts
– Correspondence
27

28. 2 - Source documents
• Prove:
– Research participant’s existence
– Data’s accuracy
• Examples: medical records, test results, CRFs
• Requirements: original, preservable
• CRF can be source documents ONLY IF:
– No other sources can be used
– Defined in study protocol
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29. Case Report Form (CRF)
• Data collection
• Two situations:
– Data copied from other documents: define Source documents
– Data written directly onto CRFs: CRF is a source document
• Filling in CRF:
– Easy to read
– Never leave blanks
– Proper correction
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30. Case Report Form (CRF)
30
Filling Proper Improper
1. Write the data inside of the blank.
2. Use “x” or “v” to check.
3. Never leave blanks.
4. Correction: cross over the old data by
ONE cross, write the corrected data next
to the old data, and sign and date below

31. 3 - Study protocol
• Investigators: adhere to study protocol
• What if NOT adhere to protocol?
– Any of these TWO consequences?
• Affecting study participants?
• Affecting data’s quality?
– YES: Protocol violation
– NO: Protocol deviation
31

32. 4 - Investigational brochure
• Purposes:
– Application for IRB approval
– Information for investigators
• Requirements:
– Indications, contraindications, interactions, adverse reactions
– Updated annually, esp. AEs and SAEs
– Simple, easy to understand
32

33. GAME 2
WHEN YOU ARE IN A
RELATIONSHIP WITH
RESEARCH

34. GAME 2: When you are in a relationship with research
• Three groups:
– (Judge): IRB
– (Millionaire): Sponsor
– (Expert): Investigator
• Summary of a study protocol

35. GAME 2: When you are in a relationship with research
IRB
• Who are you?
• What documents do you request?
• What questions do you have?
Sponsor
• What documents do you provide?
• What do you need to prepare?
Investigator
• What do you need to do?
35

36. GAME 2: When you are in a relationship with research
Source documents
• Look at the given CRF.
• What kinds of source documents are required?
36

37. PART 4
OBTAINING INFORMED
CONSENT

38. INFORMED
CONSENT
1. A PROCESS
2. A subject VOLUNTARILY confirms
the willingness to participate
3. After having been INFORMED
4. Documented by a WRITTEN,
SIGNED and DATED informed
consent form.

39. Why to obtain informed consent?
• Evidence for respect for research participants
• Historical examples:
– Henrietta Lacks – HeLa immortal cell line
– Thalidomide – from miscarriage prevention to birth defects
– GlaxoSmithKline – 2004-2012: vaccine experiments on poor children,
orphanage children and soldiers
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40. What needs to be done?
1. Inform potential candidates about the study
– “This is a research”
– Study procedure, investigational products (up-to-date)
– Risks/benefits, compensation/reimbursement, confidentiality
– Contact information
2. Spend time for questions
3. Ask for agreement
4. Sign and date in 2 copies of informed consent form (ICF)
5. Provide a copy of ICF
40

41. Special situations
• Children
– Legal representative
– Assent form (age 12-<18)
• Illiterate subjects
– Thumbprint
– Independent witness
• Subjects with cognitive impairment/coma
– Legal representative
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42. What is called “RESPECT”?
• No coercion
– “You’ll receive more of my cares if you join the study” ~ “You’ll
receive less of my cares if you don’t join the study”
– “We’ll give you very much money if you join the study”
• No concealing
– Risks and adverse events
– Future use of samples
• Voluntary participation = voluntary withdrawal
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43. Sample of an ICF
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44. Sample of an ICF
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45. Sample of an ICF
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46. Sample of an ICF
46

47. Sample of an ICF
47

48. GAME 2: When you are in a relationship with research
• An investigator is to obtain informed consent
• IRB and sponsor: Is the process properly performed?
48

49. PART 5 ADVERSE EVENTS

50. ADVERSE
EVENTS
Any signs / symptoms / diseases /
abnormal lab tests
• New
• Worsening
During the study

51. Severe vs. serious
• Serious:
– Death
– Life-threatening
– Hospitalization (initial / prolonged)
– Disability – significant / persistent
– Congenital anomaly
– Emergency intervention required
• Severe: depending on the scale to each individual condition
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52. Severe vs. serious
• Severe but not serious:
– Severe headache (VAS 10)
– Generalized rash, but not with respiratory failure or shock
• Serious but not severe:
– Mild chest pain but requires hospitalization
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53. Expected vs. unexpected
• Expected: documented
• Unexpected adverse events:
– Assess relativeness to investigational product:
• Definite
• Likely
• Possible
• Probable
• Unlikely
– Reporting: sponsor, IRB, other study sites, research participants
53

54. PART 6 MONITORING

55. When to monitor?
• Pre-implementation monitoring
• Implementation monitoring:
– Regulatory documents
– Study procedures
– CRFs
– ICFs
– AEs, SAEs
– Data entry
• Post-implementation monitoring
55

56. Why to monitor?
• Research participants:
– Informed consent
– Risks/harms of study procedures
– Sample collection, transfer and storage
• Data quality
– Data collection
– Data entry
• Confidentiality: data storage, data transfer …
• Logistics
56

57. Monitoring vs. Auditing vs. Inspection
Monitoring Auditing Inspection
Who? Monitor: sponsor,
CRO
Auditor: sponsor,
IRB
Inspector: regulatory
agencies
What? Participants, study
procedures
Study procedures,
monitoring
Suspected problems
Frequency Optional Once throughout
the study
Depending
Report to Sponsor Sponsor, IRB Regulatory agencies
Friendly Serious Punishment
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58. GAME 2: When you are in a relationship with research
Situation 1
A patient comes to you on day 3 for follow-up. She doesn’t have
any significant health problems, and just wants to come early.
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59. GAME 2: When you are in a relationship with research
Situation 2
Look at this CRF and find out errors in the CRF.
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60. GAME 2: When you are in a relationship with research
Situation 3
The research nurse takes 10 mL of blood and separates into 2 tubes.
He sends one tube to one research lab unit for the study lab tests,
and the other tube to another lab unit for another study which
investigates only on blood specimens.
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61. GAME 2: When you are in a relationship with research
Situation 4
The pharmacy assistance reveals to the evaluation investigator that
the current patient is in the placebo group.
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62. GAME 2: When you are in a relationship with research
Situation 5
A new research nurse doesn’t remember the exact follow-up
duration and makes an appointment with a new patient earlier than
the follow-up days in the protocol. The patient comes back earlier
and is examined. The follow-up CRF is filled in and a blood sample
is taken.
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63. GAME 2: When you are in a relationship with research
Situation 6
Look at this ICF and find out errors in the ICF.
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64. THE END
Thank you for listening!