Randomized Controlled Trials

(RCT)
 Study Designs
OBSERVATIONAL Exposure NOT manipulated by Investigator

Analytic Descriptive
• Cohort • Case-series
• Cross-sectional
• Case-control
• Ecological

EXPERIMENTAL Exposure manipulated by Investigator

• Clinical trials
 Association

The results of any epidemiological study

may reflect the true effect of an exposure
on the development of disease
It is also possible that the findings may
have an alternative explanation !

Three possibilities ??
 Three possibilities

• Chance
• Bias
• Confounding
 Bias in epidemiological studies

Bias is systematic error (or non-random error) that

introduces distortion in estimates/results of study

• Selection bias
• Information bias
• Confounding bias
 Randomized Controlled Trials (RCT)

• The methodologic standard of excellence

for scientific experiments

• ‘RCT has probably contributed more than

any single scientific discovery to the
improvement in medical care’ ( Lancet, 1987)
 Randomized Controlled Trials

• One of the main scientific advances in methods of

clinical research in the 20th century

• RCT is considered as the Gold standard for

demonstrating therapeutic efficacy for a

pharmaceutical agent

• Efficacy is not transferable from one goal to another

( e.g. Lowering of blood glucose and
prevention of vascular complications)
 RCT
A clinical trial is a planned experiment designed to
assess the efficacy of a treatment in humans by
comparing the outcomes in a group of patients treated
with a test treatment with those observed in a
comparable group of patients receiving a control
treatment where patients in both groups are enrolled,
treated and followed over the same period.
Curtis L Meinert: Clinical Trials, Oxford Univ Press, 1986
 RCT
“ A scientific research activity undertaken to define

prospectively the effect and value of prophylactic /

diagnostic / therapeutic agents, devices, regimens,

procedures etc. applied to human subjects.

It is essential that the study be prospective and that

intervention of some sort occur”

NIH (1980)
 RCT Paradigm

Population of Interest
Child <5 year presenting at
hospital with severe malaria

Randomize

Tx Placebo

Outcome Assessment
Death within 7 days
Randomized (controlled) clinical trials
are described often as Phase III clinical
trials

•Phase I Clinical Trial is usually carried out in ‘normal’

•human volunteers to examine clinical pharmacology

of a new drug. This phase is concerned with Safety of
the drug in humans, and studies

• - Drug metabolism, Bio-availability

• - Dose ranging and Multiple Doses

 Phases of trial

Phase I • Clinical pharmacology & toxicity

• Human volunteers
• Hospital study

Phase II • Initial clinical investigation for treatment effects

• Patients
• Hospital study

Phase III • Full-scale evaluation

• Patients
• Hospital study

Phase IV • Post-marketing surveillance

 Phase I Clinical Trials

• Usually carried out in ‘normal’ Human volunteers to

examine clinical pharmacology of a new drug

• Concerned with Safety of the drug in humans, and

studies Drug metabolism, Bio-availability, Dose
ranging and Multiple Doses
 Phase II Clinical Trials

It evaluates

• Effectiveness of a drug based on Clinical Endpoints

• Dosing Ranges and Doses for Phase III trial

• Common Short-term Side Effects and Risks

associated with the drug

 Phase III Clinical Trials

• The final stage in testing a new treatment in humans

• Is primarily concerned with assessment of efficacy

and safety studied under controlled conditions

 Phase IV trials

• Post-marketing trials assess incidence of

adverse reactions and effect on morbidity
and mortality in the population
 Classification of RCT
Based on Classification

Type of intervention Therapeutic; Preventive

Unit of randomization Individual ;Community

Design Parallel; Cross-over; Factorial

Sample Size Fixed; Sequential

Randomization Fixed; Adaptive (Number, Baseline,

Outcome); Blocking

Masking Single, Double, Triple,…

 Assures Comparability

• In observational studies, statistical

methods allow investigators to control
for confounding factors

• Must be measured
 Randomized Trials Require
Methodological Rigor

• Improperly conducted RCTs yield biased

results

• Researchers must devote assiduous

attention to design and conduct of RCTs

• Only properly conducted RCTs will fulfill their

promise of minimizing bias
 Advantages of Randomized Trials

• First and foremost, the only effective method

known to control selection bias

• Controls confounding bias without adjustment

• Facilitates effective blinding in some trials

• Theoretically attractive -many statistical

methods assume random assignment

• Maintains advantages of cohort studies

 Disadvantages of Randomized Trials
• May be complex and expensive

• Prohibitively difficult and expensive with low

incidence outcomes

• May lack representativeness - volunteers may

differ from population of interest

• Ethical challenges of experimental research

• Sometimes impossible or impractical to

conduct
Study outcome measures

• Quantitative

• Qualitative

• Primary

• Secondary
Study outcome measures (contd.)

• Multiple outcomes

• Intermediate endpoints

• Misclassification
• We deal mostly with Phase III trials

• Comparative or Controlled trials

• Variations are kept under control

• Groups differ only with respect to “treatment”

• Integration of statistical ideas and methodology

• Elimination of bias at Design and Analysis Stages

 Steps in RCTs
• Define purpose of the trial
(General – Specific objectives)
• Design the trial
(Written protocol, Work instructions etc.,)
• Conduct the trial (Good organization)
• Interim analyses (Stopping rules)
• Analyse the data
(Descriptive statistics, Test the hypothesis)
• Draw conclusions
• Publish results
Interventions amenable to
be studied using clinical
trials
• Life style
• Diet
• Drugs
• Operational factors
• Surgical procedures
• Rehabilitation
 Specific issues

• Sample selection • Randomization

• Sample size • Blind assessment

• Control groups • Length of follow-up

• Uncertainty principle:Definite indications

and contraindications
Specific issues (cont)

• True effect may not be

ascertained for many years
• Study power is dependent
on number of events
observed during the study
• Random allocation
Definition of levels of evidence and grading
of recommendation
Level Type of evidence available from Grade
Ia Meta-analysis of RCTs
A
Ib At least one RCT
IIa At least one well-designed controlled study without
randomization
IIb At least one other type of well-designed quasi-
B
experimental study
III Well-designed non-experimental descriptive
studies
IV Expert committee reports or opinions and/or clinical
C
experience of respected authorities
 Good Clinical Practices (GCP)

GCP are international ethical and

scientific standards
setting the minimum requirements
for the development,conduct,
performance,
monitoring, auditing, recording,
analysis and
reporting of clinical trials that
involve the
participation of human subjects
 GCP standards are established by:
• International Conference on Harmonization

• US Food and Drug Administration

• Guidelines for Clinical Trials on

Pharmaceutical Products in Indonesia (GCP,
National Drug Regulatory Agency)
 GCP Synopsis
• Regulations for informed consent
• Regulations for Institutional Ethics
Committees
• Defining the responsibilities of the
sponsor and investigator
• Control of investigational product
• Required elements of the investigator’s
brochure
• Essential documents
Patients, Treatment and Comparison (or
Evaluation) are the three key words in
the above definitions
•Patient has to be representative of a targeted
population under study. The results must be
generalisable to the study population. Healthy
individuals are the experimental units in
prophylactic studies
•Treatment may be a Placebo or a Drug or a
Compound (low dose aspirin + Beta carotene) or
a Diet, or a Surgical Procedure, a Medical
Device, a Diagnostic test , or even no Treatment:
Patients, Treatment and Comparison (or
Evaluation) are the three key words in
the above definitions (contd.)
• e.g.– Radio Therapy + Surgery for Breast Cancer
• – Antiarrythmic agent + defibrillator
• – MRI with or without a contrast imaging
agent
•Evaluation: Efficacy; safety (adverse
experience). Recent years have seen evaluation
encompass
Assessment of Quality of Life, Cost-effectiveness
and Cost- Benefit
 Designing a Controlled Clinical
Trial (RCT)

1. Starting point for a Controlled Clinical Trial is a

clear statement of the Research Question. It is
advisable to have a single Primary Research
Question addressed in the trial. There may be
Secondary questions also. The trial will be
planned to answer the Primary Question with
adequate Power.
 Designing a RCT
2. The Primary Research Question will determine the
Study Objective (s) and will help us to set up
appropriate hypotheses for evaluation
• e.g Sample Statement of Objectives:
• Evaluate the efficacy of several lipid-influencing drugs in the long-
term therapy of CHD in men ages 30 through 64 with evidence of
previous myocardial infarction
• State type of patients, class of treatments; But ambiguous on
outcome

3. The next step would be to prepare a well-organised

written protocol of the clinical trial
 Contents of Protocol for Clinical Trials
1. Study Background
2. Statement of objectives
3. Primary objective – with a Concise and Precise
statement of pre-specified hypotheses based on
clinical responses for evaluation of the drug.
(Patients to be studied, treatment, and outcome )

4. Secondary objective (s)

(Sometimes sub-group analyses may be stated)
Contents of Protocol for Clinical Trials
3. Study plan
- Study design
- Should permit valid Statistical Inference
- Describe Patient and Control groups with rationale
for choice
- Single centre or Multi-centric study
- Patient Inclusion and Exclusion criteria
Unambiguous to define the targeted population
-Method of Randomisation & Blinding
- Study Subject withdrawal
Contents of Protocol for Clinical Trials

4. Study Drugs

• Dose and Route of administration and Duration

• Method of Dispensing (Package and labeling included)

• Method of Administration

• Any Concomitant medications / procedures

Contents of Protocol for Clinical Trials
5. Measurements and observations
• Response variable
– Valid and Reliable measurement;
- measurement schedule
- Surrogate response variable
• Intermediate end point like CD 4 in AIDS or
mortality in HIV +ve reduces period of follow up
Impact on sample size ( Continuous Vs Qualitative
variable)
• Caution  Should truly reflect the Clinical outcome
and be acceptable to study patients
• Adverse effects of intervention may be incompletely
Contents of Protocol for Clinical Trials

6. Statistical methods
• Sample size; Handling Dropouts, Missing Data,
• Measurement of Covariates, Sub-group analyses
planned
• Interim analysis (Termination), Analytical tools to
be used
7.Adverse events (Side-effects…) Reporting
Clinical / laboratory supported
8. Institutional Review / Ethics Committee approval
 Ethical issues in clinical trials
1. Ethics of Doing and not Doing a clinical trial
2. No harm to participants
3. Not missing opportunity to benefit society
4. If drug known to be better – no control group
5. Alternative treatment as a control (unrelated treatment
also)

6. Efficacy of drug must be truly unknown Study Validity

should be ensured – Sample size, Allocation, Blinding etc.
 Ethical issues in clinical trials

3. Informed consent Understand requirements for

participation in trial. Must be clearly explained
procedures to be performed.

Should consent to receiving a placebo. Should be free

to refuse to participate or withdraw

4. Stopping rule to be stated before start of trial

- Clinical efficacy of test treatment
- Toxicity of test treatment
- External ( independent ) experts to do this
 Randomisation procedures
1.Fixed numbers to treatment regimens
a) Simple randomisation
b) Blocked randomisation
c) Stratified allocation
2. Adaptive Randomisation
- to ensure desired allocation ratio
- to ensure comparability of baseline
characteristics
- outcome adaptive  not desirable
 Bias

• Selection  Incomplete review; of literature also

• Observation  Exposure and outcome

• Statistical procedure  Analysis / Interpretation

• Publication
 Conclusions

• RCT is the standard but not the only approach

• Rigorous scientific assessment – absolutely

essential

• Involve researchers and practitioners in the

concerned system of medicine

• Ethics and human rights