GOOD CLINICAL PRACTICE (GCP)

INFORMED CONSENT
Dr. Jarir At Thobari, DPharm, PhD
1Dept. Pharmacology & Therapy Div. Pharmacoepidemiology, Pharmacovigilance & Pharmacoeconomic

2Clinical Epidemiology and Biostatistic Unit (CEBU) 2Indonesia Cochrane Center (ICC)

Faculty of Medicine, Public Health & Nursing Universitas Gadjah Mada

 Learning Objectives

Describe how to
Define the role
Explain obtain informed
of the EC and
Explain the need challenges in consent from
Define informed investigator in
for informed obtaining vulnerable
consent (what) relation to the
consent (why) informed participant (how
informed
consent – for vulnerable
consent
subject)

2
 What is Informed Consent?

a decision to participate in research

made by a competent individual
who has received the necessary information,
has adequately understood the information,
and after considering the information
has arrived at a decision, without having been subjected to
coercion, undue influence, inducement or intimidation

3
Why we need to do Informed Consent?

• Ethical principles
• Autonomy/respect for persons
• Beneficence
• Justice

Respect for person’s autonomy

It is their choice to decide for themselves whether to participate
in clinical research or not.
 1. Disclosure – provision of adequate
information
2. Comprehension – understand and
Elements of valid seek clarification
Informed Consent • Capacity & Competence
process 3. Decision making
• Voluntariness, free from coercion,
undue influence, inducement or
intimidation

5
1. Disclosure – Provision of Information

• Give the information and make sure the potential participant

understands all information shared
• Information should be
• In a language understandable by the subject
• Clear, unambiguous and non-technical
• Delivered in the most effective manner
What is the essential information to be
provided to the potential participants?
 Trial treatment,
Statement that the
Purpose of the trial randomization
study is research
probability

Contents of Description of
Experimental part of
Informed procedures including Subject’s responsibility
the trial
Consent all invasive procedures

Foreseeable Alternative procedures

risk/inconveniences to Expected benefits or treatment available
subjects with risks and benefit
 Compensation or
treatment available in
Voluntary nature, right
case of trial related Confidentiality
to refuse/ withdraw
injuries and anticipated
expenses, if any

Content Access to original Will be informed in a Contact person for

Informed medical records to
monitors, auditors, IRBs
timely manner, of all
information relevant to
further information on
trial, rights, trial related

Consent and Regulators participation injuries

Foreseeable
Approximate number of
circumstances that the Expected duration of
subjects involved in the
subject’s participation participation
trial
may be terminated

9
 Technical statement...

This study is about the ‘antiaromatase

neoadjuvant therapy’ for adenocarcinoma
Awareness of treatment can confound
of the sigmoid colon demonstrating the
results; therefore, the research is
EGFR receptor mutation
randomized and blinded to avoid ‘Bias’

10
 Media for Pamphlets, advertisements,
information on internet
disclosure of Patient information sheets
information audio-visual presentations
charts/diagrams
photographs
Truth, nothing but the truth...
 2. Comprehension

Provide the potential participant / participant’s legally acceptable

representative ample time and opportunity to inquire about
details of the trial and to decide whether to participate in the trial.
All questions about the trial should be answered to the
satisfaction of the subject or the subject’s legally representative
(GCP 4.8.7)
 Open-ended questions:

• "Describe in your own words the purpose of the study."

• "What more would you like to know?"
• "What is the possible benefit of participating in this
study?
Has the potential • What are the possible risks?"
• "Can you describe the alternatives to participation in
participants this study?”
understood? Do not ask Closed-ended questions:
How to check?
• "Do you understand?"
• "Do you have any questions?"
• "Do you see that there are some risks to taking this
drug?"
3. Decision Making

• Allow participants to decide.

• Do not coerce, induce, unduly

influence or intimidate to
participate
 When is Informed Consent obtained?
Consent is “ a process” not a “one time event”

new risk
information study
initial
extension
consent loss/gain of end of study
subject
capacity
recruitment
process

follow-up
before
screening
changes in research
(procedures, visits, etc)
 Consent is given by a person who is
legally & factually capable of
consenting
• Competence (refers to a legal state)
• Capacity (refers to a medical/mental state)
in making decisions
Who can give
consent? If a person is incompetent/
incapable, consent must be
obtained from the parent, legal
guardian or legally acceptable
representative (LAR) in accordance
with the law of the country
Vulnerable population
• Children
• Mentally Challenged
• Institutionalized Individuals
• Subordinates/ Staff/ employee
• Students
• Prisoners • Not to include unless the study demands
• Pregnant/ Lactating women special groups
• Disease/condition
• Where applicable, informed consent from
• Poor the Legally Acceptable Representative
• Military
• Informed consent from the individuals
• Tribals wherever possible
• Uneducated
• Assent from minors
• Ethnic minorities/refugees
• Homeless/frail and old • Respect their right to refuse participation
• Emergency situation
 • Age differs from country to country
Age of • Usually 18, unless local law states
differently
consent • Age 12 -17
• Parent or guardian can make decision
for them if agreement of the
potential subject to participate in the
research - Assent
• Age <12
• automatically not competent
 A literate adult, who is independent of the
trial, cannot be unfairly influenced by people
involved with the trial
Impartial Attends the informed consent process if the
Witness subject or the subject’s Legally Acceptable
Representative (LAR) cannot read and write

Signs & dates along with subject/investigator

This indicates that consent is voluntary and

freely given without any force, or undue
influence
 Use the latest version of consent form
that has been approved by the Ethics
How is Committee

Informed The informed consent documentation

should clearly identify the person who
Consent performed the informed consent.
documented? Signed & dated by the subject and by
the person who conducted the
process (and make 2 copies)
 Drafting information sheet & consent form

• Investigator/sponsor
RESPONSIBILITY?

Review/approve

• IRB/IEC
WHOSE

Obtaining consent

• Investigators/designee who has full knowledge of

the study and listed in the delegation log
• Overall responsibility vests with the PI
 Challenges
Participant factors Researcher factors

• Poor literacy rates • Complex and lengthy forms

• Intimidation/stress
• Confusion about the
consent process – Doctors
are ‘God’ and can make the
decision
• Some notions are not easy to
explain, like randomization,
blinding
• Time limitations
• Wrong assumptions about
participant understanding
 Privacy and Confidentiality

Privacy is... Confidentiality...

• About people • Is about identifiable data
• A right to be protected • Is an agreement about maintenance
• Is in the eye of the participant, not and who has access to identifiable
the researcher or the IRB data
 Study procedures done in designated areas that
allows privacy;

Only authorised study staff will do the study

related procedures
How to ensure
privacy & Use of codes and numbers as identifiers no
names;
confidentiality
Protection of records that could identify
participant; stored cabinets under lock and key;

Inform participants of the limits and possible

consequences of breaches of confidentiality
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 Summary

Essentially Informed Consent is A Process’ ‘and not an administrative Act

Informed consent is an ongoing process of education and information exchange;

Starts prior to recruitment, continues throughout the person’s participation in the

research, and may extend until the completion of the research

The more explicit the consent process, the more robust it is!
 GOOD CLINICAL PRACTICE (GCP)
RECRUITMENT
Dr. Jarir At Thobari, DPharm, PhD
1Dept. Pharmacology & Therapy Div. Pharmacoepidemiology, Pharmacovigilance & Pharmacoeconomic

2Clinical Epidemiology and Biostatistic Unit (CEBU) 2Indonesia Cochrane Center (ICC)

Faculty of Medicine, Public Health & Nursing Universitas Gadjah Mada

 Case Study 1

Inclusion Criteria
• A trial protocol limits participation to the age group of 18 to 65
• In a site an investigator asks to be allowed to screen a patient
who is not yet 18 but will be in a week when randomization
occurs.

What do you think?

 Are all inclusion & exclusion criteria essential to
Patients’ safety? Rigor of protocol?

At the
Remember – the more inclusion & exclusion criteria
Protocol
Planning
Stage
The tougher recruitment

The less representative the study population

When selecting Patients

• No exceptions and no deviations!

• No bias by “taking a second chance”
• Repeating laboratory analysis because of “borderline”
results
• Re-screening a patient
• When a 3rd party holds the clues
• Referred patients, duration or severity of disease
 the more subjective the criterion the better
documentation from a referring physician needed
After Randomization

• Protocol defines course of action

Violation of a
• If no protocol provisions, decision is driven by
criterion detected what is best for the patient

Remember – Whatever the protocol

states Patients’ Safety is first

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Case Study #2

• Patient XYZ enrolled into a trial about the safety and efficacy of an anti-TB
combination regimen conducted in a rural area of a developing country.
• The study period is 24 months including 6 months directly-observed treatment (DOT)
in the TB clinic. The patient was lost to follow-up at month 9.
• Further tracing of the patient revealed that the patient moved to a big city to find a
job.

How to prevent loss to follow-up at the beginning of the trial when participants are
recruited?

33
 Prevalence of the disease in the region where
the site is

What are the Prior situation analysis on disease burden

Factors influencing e.g., hospital list of attendance by patients,
disease reports, surveillance reports from
the Recruitment health office, CDC, etc.
Rate?
Patients with target disease (rare vs. common
disease)

Patients eligible to enter studies (protocol

reflect the reality)

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What are the Factors influencing the Recruitment Rate?
Patient detected / approached by
the investigator
Referral system: how the patients
gets referred to the recruitment
site
Patient willing to enter the study
Trust of patient into the research
and clinical trials
Benefits and risks
Projected burden of study
protocol (e.g., number of visits,
blood draws)
35
 Recruitment tools

Recruitment software
Leveraging the Doctor referral (in- used by health centres
Attendance logs /
“normal” flow of and out-patients clinic, (requires EHRs –
document related
patients health centres, etc.) Electronic Health
Records)

Social networks &

Patients’ organizations
web-based push & pull Advertising etc.
& advocacy groups
postings
Specific Recruitment Challenges
Investigator related:
• Unrealistic recruitment goals
• Inadequate recruitment
strategies
• Inclusion/exclusion criteria
too tight
• Materials that are inaccurate
or “oversell” the study
Participant related:
• Study’s relevance
• Benefits (or harms)
• History of research abuses
• Respect (the “guinea pig”
effect)
37
 Ethical Principles in the Recruitment Process
Respect for Persons:
• Accurate information
provided to the participant
to allow him / her to make
an informed, and voluntary
decision to enroll and
withdraw, without
coercion or inappropriate
inducement
Beneficence:
• The recruitment process
should ultimately describe
all the steps to maximize
the study’s benefit (if any)
and minimize or avoid
undue risk(s).
Justice:
• The study should be seen
by the participant as fair in
that it’s open to all or
those in the trial who
would stand to enjoy the
possible benefits of the
study. That the risks and
benefits are interpreted by
the participant as
equitably distributed.
 GOOD CLINICAL PRACTICE (GCP)
SAFETY MANAGEMENT
Dr. Jarir At Thobari, DPharm, PhD
1Dept. Pharmacology & Therapy Div. Pharmacoepidemiology, Pharmacovigilance & Pharmacoeconomic

2Clinical Epidemiology and Biostatistic Unit (CEBU) 2Indonesia Cochrane Center (ICC)

Faculty of Medicine, Public Health & Nursing Universitas Gadjah Mada

Learning objectives
Define adverse event (AE), adverse drug reaction (ADR) and
serious adverse event (SAE)

Familiarize with terminologies related to causality assessment

Recognize the importance of reporting adverse events

Be aware of the reporting requirements, format and process

Why Monitor Safety?

To contribute
Participant To capture to early toxicity To contribute
safety is safety-related profile, alert to labelling
Paramount! data sponsor of information
safety issues
Definitions…. (ICH-E6)

Adverse Event (AE)

•Any untoward medical occurrence in a patient

or clinical investigation participant administered
a pharmaceutical product and which does not
necessarily have a causal relationship with this
treatment
Untoward medical occurrence – what does it mean?

Signs such as changes in

Symptoms such as nausea,
pulse rate, temperature or
diarrhea, fever
skin rashes

Lab value that is abnormal Inter-current illness

i.e., beyond the reference occurring while on study,
range or described as even if unrelated to the
significant/critical in the test medication; e.g., Viral
protocol fever, UTI
 • Temporal association
What is most • Condition detected/ diagnosed
after study drug
important?
Study drug start

1 day after drug bronchitis/ ulcer

is diagnosed
 Adverse Drug Reaction (ADR)

A causal relationship
All noxious and unintended
between a medicinal product
responses to a medicinal
and the event is at least a
product related to any dose
reasonable possibility, i.e. the
should be considered adverse
relationship cannot be ruled
drug reactions.
out
Investigator’s Brochure (IB)

Compilation of Describes
Provides guidance
clinical and Pharmacokinetics,
on the recognition
nonclinical data on bioavailability,
and treatment of
the investigational interactions, safety
possible ADRs
product(s) and efficacy
 Case Study 1
What is the event?

BBL 013, participant has On way to the clinic for

been enrolled in a the third dose, he falls
Clinical Trial (CT) has down from a motor bike
received 2 doses of the and sustains a muscle
trial product. sprain.
 Case Study 2
What is the event?

Participant gives Few hours post-

Blood sample is
consent to participate phlebotomy
drawn for performing
in the study, not yet complains of pain at
some screening tests.
enrolled the site.
 Case Study 3
What is the event?

Child (NLH 056), enrolled in trial, has two episodes of loose

stools following vaccine administration; there are no signs
during physical examination.

These symptoms are described as common events in the

Investigator Brochure.
Unexpected Adverse Drug Reaction

An adverse reaction, the nature or severity of which is

not consistent with the applicable product information
- Investigator’s Brochure/ Summary of product
characteristics/ Literature
 Serious Adverse Event (SAE)
Any untoward medical occurrence that at any dose

Requires inpatient
hospitalisation or
Results in death Is Life-threatening
prolongation of
existing hospitalisation

Results in persistent or
Is a congenital Otherwise a significant
significant disability/
anomaly/birth defect medical
incapacity
Event which The cause of
results in death is the SAE
DEATH

“Fatal” is the
outcome
 An adverse event that places the
patient or subject, in the view of the
Investigator, at immediate risk of
Life- death from the adverse drug event as
threatening it occurred.

It does not include an adverse drug

event which hypothetically might have
caused death if it were more severe
Hospitalisation

 Event which results in or prolongs

Hospitalisation
• report the diagnosis and NOT the procedure
• hospitalization - detained for observation
and/or treatment
 Planned surgery prior to the patient
When entering the study e.g., Cataract,
BPH
hospitalization
is not an SAE?
Hospitalisation for insurance, social
or convenience purposes

Only involving treatment in the

emergency room and no admission
as an inpatient (Chest pain - CAD,
Nebulised for Asthma)
 An adverse event that
Disability substantially disrupts a person’s
ability to conduct normal life
functions. E.g., Stroke - hemiplegic

The extent of the disability does

not need to be permanent
Congenital
anomaly/birth defect

Congenital anomaly diagnosed in the

offspring of a subject who received
drug

Pregnancy is not an SAE

 Important medical events that may not

• result in death,
‘other’ • be life-threatening or
significant • require hospitalization
medical event but, based upon appropriate medical
judgment, may jeopardize the subject
and may require medical or surgical
intervention to prevent one of the
other outcomes listed in this definition
 Case Study 4
What is the event?

• AMH 305 enrolled in the study and is

currently on trial medication.
• Had developed wheeze and was taken
to the hospital at 9 pm.
• He was kept in nursing care at the
hospital overnight as limited transport
facility is available during the night.
 A Clinical Trial (CT) participant has
completed trial medication.

Case Study 5
What is the On way to the clinic for follow up, he is
involved in a motor vehicle accident.
event?

He is admitted in the Emergency Unit

where a parietal cranial fracture is
diagnosed.
 MLA 037, enrolled into the study; hospitalized for
administration of trial medication;

Case Study 6 While in hospital, patient developed nausea,

What is the vomiting and loss of appetite, physical examination
showed an enlarged liver. ALT was 1200 and AST 820
event? IU; baseline AST and ALT were normal

Treated with intravenous fluids and concomitant

medication; Hospitalization was extended by
further one week
 Seriousness is “regulatory definition”

Serious Vs Severity refers to “Intensity” of event i.e.

Severe mild, moderate, severe.

Not synonymous e.g., severe headache need

not be serious, myocardial infarction does
not have to be severe to qualify for
“Seriousness”.
Grading the Severity - Toxicity tables
AE Grade Intensity

pain 0 absent
1 minor reaction to touch
2 cries/protests on touch
3 cries when limb is moved
or spontaneous painful

general AE 0 normal

1 tolerate easily, causing minimal discomfort

and not interfering with daily activities
2 sufficiently discomforting to interfere with
normal daily activities
3 prevent normal daily activities
eg. prevent attendance at school
would the patent seek medical advice
 Grading Severity

GENERAL AE
• PAIN • Grade 1:
• Grade 1: absent tolerate easily, causing minimal discomfort and
• Grade 2: minor reaction to touch not interfere daily activities
• Grade 3 : cries/protests on touch • Grade 2:
• Grade 4 : cries when limb is moved sufficiently discomforting, interfere normal daily
• Grade 5 : spontaneous painful activities
• Grade 3 :
prevent normal daily activities
 Suspected All adverse drug reactions
Unexpected (ADRs) that are both
Serious - serious and
Adverse Reaction
- SUSAR - unexpected
Causality assessment

Unrelated Clearly not related

Possible May be related

Most probable Clearly related

 Case study 7
• MUM 078 35 years, male is enrolled in a clinical trial; he is
admitted to the hospital on June 1st 2021 for administration of
12 doses of intravenous drugs (study product) at one dose per
day; IV cannula is changed every fourth day;
• On the 5th day he complains of pain in the arm (at the site)
where he received the first four doses of intravenous injection;
• The next day, the physician observes a mild swelling at the site;
Case study 7
• Two days afterward patient develops high fever and inability
to move the arm; examination of the arm reveals swelling
and intense redness at the same site;
• Patient is treated with antibiotics (Cephalosporin) for 5 days
after which the event resolved
• How many events?
• What is the event?
• Causality?
What are Investigator responsibilities?

Educate Ask for and assess the

subjects/parents to AE if any, during each
report all AE visit of the subject

Record all information

Be on the look out for an on hospital records/
AE turning into a Serious source documents for
Adverse Event onward transmission to
the Data management
 Prime responsibility of the PI and team
Management
AE/SAE Administer the best possible care appropriate
to patient’s need and by qualified personnel

Monitor/Follow up until

• Event resolution
• Condition stabilizes or is otherwise explained
• Patient is lost to follow-up
When should AEs be collected?

An event from study drug administration until the protocol specified period

Last dose of Protocol defined

Screening
Study Drug period
Consent study drug

Report AEs/SAEs
When should AEs be collected?
What about events before study drug administration?

Last dose of
study drug
Follow-up
Study drug Protocol defined
visit
Initiation period

Screening Related to product

Consent
Events related to study participation
 All SAEs occurring during study and
protocol defined follow-up period,
whether or not related to study drug

When to Aany SAEs that are related to study

report SAEs? participation

within 24 hours from being aware

 Fill out the SAE form as completely as possible

Record ‘diagnosis’ if known; otherwise record

How to individual signs/symptoms

Report Causality (must be assessed by investigator)

SAEs?
Fax / scan and e-mail

File the original

 Report SAEs immediately to the
sponsor. Alert should be followed
promptly by detailed, written
reports
SAE report-
Investigator
responsibilities Comply with the applicable
regulatory requirement(s) related to
the reporting of unexpected serious
adverse drug reactions to the
IRB/IEC and the regulatory authority
 Complete picture –
Well documented,
Legible, no
accurate reports
abbreviations

What does
the sponsor No missing data or Follow up questions
inconsistencies answered on time
want?

An SAE report which seems

insignificant at the time of
reporting, could become an
important safety signal requiring
reporting to Regulators!!
 Sponsor should promptly notify all
Sponsor’s concerned investigator(s)/institution(s)
responsibilities and the regulatory authority of findings
that could
• affect adversely the safety of subjects,
• impact the conduct of the trial,
• alter the IRB/IEC's approval to
continue the trial.
Investigator Notification

If an Adverse Event is:

‘serious’
‘unlabelled’ not specified in the IB
‘suspected’ of being related to trial drug
an Investigator Notifications (IN) is issued to all concerned
investigator(s)/ institutions(s), IRB/ IEC, where required, and to the
regulatory authority by the Sponsor
 Determine whether all serious adverse events
are appropriately reported within the time
periods required by GCP, the protocol, the
IRB/IEC, the sponsor, and the applicable
regulatory requirement(s).
responsibility
Monitor’s

Ensure that Investigator notifies IRBs/IECs

according to IRB/IEC requirements
Common issues

SAE not
SAE not
documented in SAE reported late
SAE not identified appropriately
the source or not at all
managed
documents

Incomplete data
Inconsistency of
on CRF/Source,
SAE data between Not followed up
e.g., concomitant
CRF and SD
medications
 Data and Safety Monitoring Board (DSMB)

01 02 03
provide safety review and evaluate provide independent,
monitoring during the clinical efficacy and competent, and
conduct of safety data collected timely review of the
biomedical research during the study safety of the on-going
studies
 Early phases of novel intervention
with very limited information on
clinical safety
When is Studies where interim analyses of
DSMB safety and efficacy are essential to
ensure the safety of trial participants.
required? Randomized and blinded trials
specifically focused on clinical efficacy
and safety of new intervention
 Regulatory
Sponsor
Authorities

Clinical
Teams Key Players in Drug Safety IEC/IRB

Investigator DSMB
 AEs - Any Untoward medical occurrence, whether or not
related to the product

ADR - event likely related to the product

Serious Adverse event – death, life threatening,

disability, hospitalization or any other event

Summary
Seriousness Vs Severity

Grading, documentation, management and follow up of

AE

Management, documentation and reporting of SAE