140712 fsh presentation - good clinical practice hoang bao long

Good Clinical Practice

Hoang Bao Long, M.D.

Clinical Research Coordinator

Oxford University Clinical Research Unit - Hanoi

ICE-BREAKING

2

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

GAME 1 IS THIS ACCEPTABLE?

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


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.

6


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.

7


• 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

PART 1 RESEARCH ETHICS

History of research ethics

Nazi human experimentation:

Nuremberg Code &

Declaration of Helsinki

Tuskegee syphilis

experiment:

Belmont Report

ICH/GCP

10

Belmont Report

1. Respect for persons: autonomy, informed consent

2. Beneficence: “do no harm”, maximizing benefits, minimizing

risks

3. Justice: fair selection

11

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

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

13

Belmont Report – Justice

• Selection of participants: based on scientific criteria

• Equal distribution of risks/benefits

14

Belmont Report

Principles Key issues Process

Respect Autonomy Obtaining informed consent

Beneficence Risks/benefits consideration Design of study protocol

Justice Fair selection Enrollment

15

ICH/GCP

1. Protect research participants: rights, benefits, safety, & health

2. Ensure high-quality research

16

INTRO RESEARCH GOVERNANCE

AND OPERATION

Steps to conduct a study

Protocol

design

IRB approval &

funding /

sponsoring

Implementation

• Enrollment

• Data collection

• Analysis

• Monitoring

Close-out:

reports,

publishing

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

PART 2 SPONSOR, IRB AND

INVESTIGATOR

Who contributes to a study?

IRB

• Protect study

participants

Sponsor

• Fund

• Equipment

• Human resources

Investigator

• Enrollment

• Data collection

• …

Sponsor

• Funding

• Provision of human resources and equipment

• Research governance

• Investigational products

• Monitoring

• Insurance and indemnity

22

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

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

24

PART 3 STUDY DOCUMENTS

STUDY

DOCUMENTS

1. Regulatory documents

2. Source documents

3. Study protocol

4. Investigational brochure

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

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

28

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

29

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

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

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

GAME 2 WHEN YOU ARE IN A

RELATIONSHIP WITH

RESEARCH

GAME 2: When you are in a relationship with research

• Three groups:

– (Judge): IRB

– (Millionaire): Sponsor

– (Expert): Investigator

• Summary of a study protocol


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


Source documents

• Look at the given CRF.

• What kinds of source documents are required?

36

PART 4 OBTAINING INFORMED

CONSENT

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.

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

39

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

Special situations

• Children

– Legal representative

– Assent form (age 12-<18)

• Illiterate subjects

– Thumbprint

– Independent witness

• Subjects with cognitive impairment/coma

– Legal representative

41

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

42

Sample of an ICF

43

Sample of an ICF

44

Sample of an ICF

45

Sample of an ICF

46

Sample of an ICF

47


• An investigator is to obtain informed consent

• IRB and sponsor: Is the process properly performed?

48

PART 5 ADVERSE EVENTS

ADVERSE

EVENTS

Any signs / symptoms / diseases /

abnormal lab tests

• New

• Worsening

During the study

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

51

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

52

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

PART 6 MONITORING

When to monitor?

• Pre-implementation monitoring

• Implementation monitoring:

– Regulatory documents

– Study procedures

– CRFs

– ICFs

– AEs, SAEs

– Data entry

• Post-implementation monitoring

55

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

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

57


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.

58


Situation 2

Look at this CRF and find out errors in the CRF.

59


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.

60


Situation 4

The pharmacy assistance reveals to the evaluation investigator that

the current patient is in the placebo group.

61


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.

62


Situation 6

Look at this ICF and find out errors in the ICF.

63

THE END

Thank you for listening!

140712 fsh presentation - good clinical practice hoang bao long

Health & Medicine

study documents

study participants

highquality research

study protocols

intro research governance

management study protocol

source documents

regulations documents