Clinical Trial

Uji Klinik
Abraham Simatupang
Dept. of Pharmacology & Therapeutics
Faculty of Medicine Universitas Kristen Indonesia

Profile
Abraham Simatupang
bram.simatupang@gmail.com

Clinical Pharmacologist
Faculty of Medicine - UKI
oMD FK UKI (1986)
oMKes. FK UGM (1993)
oDr.med. University of Bonn, (1996)
Director Acad. of Physiotherapy (2009 Director of Task Force for HIV & AIDS (20072009)
Head of Dept. of Pharmacology (2004i
n
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y
Director of Research Center (1998-2004)
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Panitia Penilaian Obat Jadi FK UI (2000an
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National Committee Ind. Drug Regulatory

(2000 -

What is Clinical
Trial?
A properly planned and
executed clinical trial is a
powerful experimental
technique for assessing
the effectiveness of an
intervention

Alexander Flemming

Types of Clinical Trials

Open trial
Non-randomized controlled trial
Randomized
controlled
trial: are
An experiment
in which subjects
randomly allocated into groups,
usually called study and control
groups, to receive or not to receive
an experimental preventive or
therapeutic procedure, maneuver, or
intervention. The results are
assessed by rigorous comparison of
rates of disease, death, recovery, or
other appropriate outcome in the
study and control groups,

Core Components of Clinical Trials

Involve human subjects
Move forward in time
Most have a comparison CONTROL
group
Must have method to measure
intervention
Focus on unknowns: effect of
medication
Must be done before medication is part
of standard of care
Conducted early NY/VI
in the
development of
AETC

Other important things

Ethical issues: Research proposal
should pass IRB or Institutional
Ethical Committee (IEC)
Informed consent
Data management & security
Statistical analysis
Sponsor finding, sponsor reporting
Publication planning

Blinding:
The basics design of RCTOne/doubl
Screenin
g,
Inclusion
&
exclusion
criteria

Sampling

Populatio
n

Study
population

e-blind

Grou
pA

Grou
pA

Interventions & measurements

Grou
pB

Grou
pB

Grou
pn

Grou
pn

Random
allocation

Cross-over design
Placebo

Placebo
Grou
pA

Study
population

Wash-out

Grou
pB

Interventions & measurements

Grou
pB
New drug

Wash-out

Grou
pA
New drug

Advantages of RCT
Allows rigorous evaluation of a single
variable (e.g. effect & AEs of drug treatment
vs placebo)
Prospective design
Uses hypotheticodeductive reasoning (seeks
to falsify, rather than to confirm, its own
hypothesis) null hypothesis
Potentially eradicate biases by comparing
two otherwise identical groups
Allows for meta analysis

Disadvantages of RCT
Expensive and time consuming
Many RCTs are either never done, are
performed on too few patients, or are
undertaken for too short a period.
Most are funded by large research
bodies dictate the research agenda
SURROGATE endpoints are often
used in preference to CLINICAL
outcome measures

Scientific Aspects of Clinical Trial

Phases of Clinical Trial

Phase I : First in man safety
Phase II : First in patient dose,
dosage form

Phase III : Efficacy, ADRs

Post marketing surveillance or
Phase IV : Evaluation in the real clinical
setting

Objectives

Phase I

1. To assess a safe & tolerated dose

2. To see if pharmacokinetics differ much from
animal to man
3. To see if kinetics show proper absorption,
bioavailability
4. To detect effects unrelated to the expected action
5. To detect any predictable toxicity

Inclusion criteria
. Healthy volunteers : Uniformity of subjects: age,
sex, nutritional status [Informed consent a must]
. Exception: Patients only for toxic drugs Eg
AntiHIV, Anticancer

Exclusion criteria
. Women of child bearing age, children,

Phase I (contd)
Methods:
First in Man : Small number of healthy
volunteers
First in a small group of 20 to 25
Start with a dose of about 1/10 to 1/5 tolerated
animal dose
Slowly increase the dose to find a safe tolerated
dose
If safe in a larger group of up to about 50 75
No blinding
Performed by clinical pharmacologists
Centre has emergency care & facility for
kinetics study
Performed in a single centre
Takes 3 6 months [ 70% success rate]

Phase II
First in patient [ different from healthy volunteer]
Early phase [20 200 patients with relevant
disease]
Therapeutic benefits & ADRs evaluated
Establish a dose range to be used in late phase
Single blind [Only patient knows] comparison with
standard drug

Late phase [ 50 500]

Double blind
Compared with a placebo or standard drug

Outcomes
Assesses efficacy against a defined therapeutic
endpoint
Detailed P.kinetic & P.dynamic data
Establishes a dose & a dosage form for future trials

Takes 6 months to 2 years [ 35% success rate]

Phase III

Large scale, Randomised, Controlled trials

Target population: 250 1000 patients
Performed by Clinicians in the hospital
Minimises errors of phases I and II
Methods
Multicentric Ensures geographic & ethnic
variations
Diff patient subgroups Eg pediatric, geriatric, renal
impaired
Randomised allocation of test drug /placebo /
standard drug
Double blinded:
Cross over design
Vigilant recording of all adverse drug reactions
Rigorous statistical evaluation of all clinical data

Takes a long time: up to 5 years [25% success]

Cross over design

GroupWeek 1 Week2 Week3
I
Standard Placebo Test
II
Placebo Test Standard
III
Test Standard Placebo
* A wash out period of a week
between two weeks of therapy

Phase IV or Post marketing

Surveillance
No fixed duration / patient
population
Starts immediately after marketing
Report all ADRs
Helps to detect
rare ADRs
Drug interactions
Also new uses for drugs [Sometimes
called Phase V]

The drug story

Pre-clinical
studies

Clinical
studies (I-III)

Registratio
n

Not-approved

Marketi
ng &
Selling

PMS (Phase
IV)

withdrawal

How to read medical articles

CONSORT
(Consolidation for Reporting Trials)
Paper section &
topic

Item

Description

TITLE & ABSTRACT

How participants were allocated to

intervention (e.g. random
allocation), ranoomised or
randomly assigned

INTRODUCTION
Background

Scientific background and

explanation of rationale

METHODS
Participants

Eligibility criteria for participants and

the settings and locations where the
data were collected

Interventions

Precise details of the interventions

intended for each group and how and
when they were actually
administered

Objectives

Specific objectives and hypotheses

Outcomes

Clearly defined primary and

secondary outcome measures and,

CONSORT (continued)
Paper section &
topic

Item

Description

Sample size

How sample size was determined

and, when applicable, explanation of
interim analyses and stopping rules

Randomization
Sequence generation

Method use to generate the random

allocation sequence , including
details of any restriction (e.g.
blocking, stratification)

Randomization
Allocation
concealment

Method used to implement the

random allocation sequence (e.g.
numbered containers or central
telephone), clarifying whether the
sequence was concealed until
interventions were assigned

Randomization
Implementation

10

Who generated the allocation

sequences, who enrolled
participants, and who assigned
participants to the groups

Blinding (masking)

11

Whether or not participants, those

administering the intervention, and

CONSORT (continued)
Paper section &
topic
Statistical methods

Item

Description

12

Statistical methods used to compare

groups for primary outcomes;
Methods for additional analyses,
such as subgroup analyses and
adjusted analyses

Participant flow

13

Flow of participants through each

stage (a diagram is strongly
recommended). Specifically, for each
group report the numbers of
participants randomly assigned,
receiving intended treatment,
completing the study protocol, and
analysed for the primary outcome.
Describe protocol deviations from
study as planned, together with
reasons.

Recruitment

14

Dates defining the periods of

RESULTS

CONSORT (continued)
Paper section &
topic

Item

Description

Numbers analysed

16

Number of participants
(denominator) in each group
included in each analysis and
whether the analysis was by
intention to treat. State the results
in absolute numbers when feasible
(e.g. 10/20, not 50%)

Outcomes and
estimations

17

For each primary and secondary

outcome, a summary of results for
each group, and the estimated effect
size and its precision (e.g. 95%
confidence interval)

Ancillary analyses

18

Address multiplicity by reporting any

other analyses performed, including
sub group analyses and adjusted
analyses, indicating those prespecified and those exploratory

Adverse events

19

All important adverse events or side

CONSORT (continued)
Paper section &
topic

Item

Description

DISCUSSION
Interpretation

20

Interpretation of the results, taking

into account study hypotheses,
sources of potential bias or
imprecision and the dangers
associated with multiplicity of
analyses and outcomes.

Generalizability

21

Generalizability (external validity) of

the trial findings

Overall evidence

22

General interpretation of the results

in the context of current evidence

e A, Sabin C. Medical statistics at a glance. 2012. Wiley-Blackwell, West Sussex,

Sy power in
The pyramid of
ste
Evidence Basema
Medicine (EBM)
tic
rev
ie
w/
me
ta
an
aly
sis
Cohort studies

RCTs

Case series
Case reports
Editorials & Opinions
Lab studies & Animal research

Level of Evidence
Level I: Evidence obtained from at least one properly
designed randomized controlled trial.
Level II-1: Evidence obtained from well-designed controlled
trials without randomization.
Level II-2: Evidence obtained from well-designed cohort or
case-control analytic studies, preferably from more than one
center or research group.
Level II-3: Evidence obtained from multiple time series with
or without the intervention. Dramatic results in uncontrolled
trials might also be regarded as this type of evidence.
Level III: Opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert
committees.