Good Clinical Practice

Hoang Bao Long, M.D.

Clinical Research Coordinator

Oxford University Clinical Research Unit - Hanoi

ICE-BREAKING

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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

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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.

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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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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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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.

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PART 1 RESEARCH ETHICS

History of research ethics

Nazi human experimentation:

Nuremberg Code &

Declaration of Helsinki

Tuskegee syphilis

experiment:

Belmont Report

ICH/GCP

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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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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

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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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Belmont Report – Justice

• Selection of participants: based on scientific criteria

• Equal distribution of risks/benefits

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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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ICH/GCP

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

2. Ensure high-quality research

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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

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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

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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 …

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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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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

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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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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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Case Report Form (CRF)

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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

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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

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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

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?

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GAME 2: When you are in a relationship with research

Source documents

• Look at the given CRF.

• What kinds of source documents are required?

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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

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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

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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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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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Sample of an ICF

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Sample of an ICF

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Sample of an ICF

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Sample of an ICF

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Sample of an ICF

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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?

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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

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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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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

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PART 6 MONITORING

When to monitor?

• Pre-implementation monitoring

• Implementation monitoring:

– Regulatory documents

– Study procedures

– CRFs

– ICFs

– AEs, SAEs

– Data entry

• Post-implementation monitoring

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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

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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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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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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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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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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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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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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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THE END

Thank you for listening!