Randomized Trials

Dr. Waqar Ali

HoD, Community Medicine
Vice Principal Research
PhD Scholar, MBBS, MPH, MNCH, QMIH (Germany),HRHM (U.K)

1
2
Objectives
• By the end of the lecture, the learners would be able to:

• Distinguish between experimental and observational studies

• Identify the design elements of a clinical trial
• Understand Types of Clinical Trial
• Discuss the issues in the design and conduct of a clinical trial

3
Objectives
• By the end of the session the learner would be able to understand:

• Randomized Trial
• Basic Design and Terminologies Of A Randomized Trial
• Types of Randomized Trial

4
Uses of Epidemiology
1. Investigate the etiology of disease and modes of transmission
2. Determine the extent of disease problems in the community
3. Study the natural history of disease
4. Evaluate new preventive and therapeutic measures and modes of
health care delivery*
5. Provide a foundation for developing public policy and regulatory
decisions

DR WAQAR ALI, CHS 5

Randomized Trials

Also known as
• Clinical Trials
• Randomized Clinical Trials
• Randomized Controlled Trials

6
Study Types
STUDY TYPES

Descriptive Analytical

Experimental/
Individual based Population based Observational
Interventional

Case studies Ecological Case-control RCT’s

Quasi-
Case series cohort
Experimental

Cross-
sectional
7
 History*
• A planned trial was described by the Scottish surgeon James Lind in
1747.(scurvy in British seamen)

8
Interventions that Can Be Evaluated
• New drugs and new treatment of diseases
• New medical and health care technology (Robotic surgery)
• New methods of primary prevention (Use of mobile)
• New programs for screening (Cervical screening)
• New ways of organizing and delivering health services (Mobile Units)
• New community health programs (Incentive for Pregnant Women)
• New behavioral intervention programs (Involvement of personalities )

9
Comparison Groups in an Experimental Study

• Therapy vs. no therapy

• Therapy vs. placebo
• Therapy A vs. Therapy B

10
The Basic Design Of A Randomized
Trial

11
Studies without Comparison
• No comparison is made with an untreated group or with a group that
is receiving some other treatment.

• Comparison is important because we want to be able to derive a

causal conclusion regarding the relationship of a treatment and
subsequent outcome.

12
Quiz
• Researchers enrolled 41,837 women in 1986 and collected exposure
and lifestyle information to assess the relationship between these
factors and subsequent occurrence of cancer, is an example of:
A. Experimental
B. Cohort
C. Case-control
D. Clinical trial

13
Section B
Randomized Clinical Trials

14
Randomization
• Randomization is the process by which allocation of subjects to
treatment groups is done by chance, without the ability to predict
who is in what group

15
Randomized Clinical Trial
• A trial is an experiment

• A randomized clinical trial is a clinical trial in which participants are

randomly assigned to separate groups that compare different
treatments

16
Design of a Randomized Clinical Trial

METHODS OF
RANDOM
ALLOCATION?

17
Purpose of Randomization
• Primary purpose
• Prevent bias in allocating subjects to treatment groups (avoid
predictability)

• Secondary purpose
• Achieve comparability between the groups (there is no guarantee)

18
Gold Standard of Study Designs

• Randomized trials are gold standard of study designs

because the potential for bias (selection into treatment
groups) is avoided.

19
Difference of Randomzation
Results of a Trial of BCG Vaccination

Data from Levine MI, Sackett MF: Results of BCG immunization in New York City. Am Rev
Tuberculosis 53:517–532, 1946. DR WAQAR ALI, CHS 20
Results of a Trial of BCG Vaccination

Data from Levine MI, Sackett MF: Results of BCG immunization in New York City. Am Rev
Tuberculosis 53:517–532, 1946. DR WAQAR ALI, CHS 21
Non-randomized Study

22
DATA COLLECTION ON SUBJECTS

TREATMENT
• Assigned and received

OUTCOMES
• Including beneficial and adverse effects

PROGNOSTIC PROFILE AT ENTRY

• Age

23
Masking or Blinding

• Masking or blinding is used to increase the neutrality of the persons

dealing with the randomized study (& to prevent discrimination).

24
Level of masking/blinding
• Single Blinding
• Double Blinding
• Triple Blinding

Single Double Triple

Subject X X X
Researcher -------- X X
Data Analyst -------- -------- X
= Blind with respect to subject’s allocation
x
= Aware of subject’s allocation
----
How can subjects be masked? 25
Quiz
The major purpose of random assignment in a clinical trial is to:
a. Help ensure that study subjects are representative of general population
b. Facilitate double blinding (masking)
c. Facilitate the measurement of outcome variables
d. Ensure that the study groups have comparable baseline characteristics
e. Reduce selection bias in the allocation of treatment

26
Placebo

• An inert substance that looks, tastes, and smells like the active agent
but which has no therapeutic value

• Use of a placebo does not automatically guarantee that the patients

are masked (blinded).

27
 Placebo and Side Effects

Side effect results from the Women’s Health study

Ridker PM, et al. (2005). A randomized trial of low dose aspirin in the primary prevention of cardiovascular disease in women.
28
NEJM 352(13):1293.
Compliance

• Compliance is the willingness of the participants to carry out the

procedures according to the established protocols (adherence).

• Drop-outs are the participants who do not adhere to the

experimental regimen during follow-up.

• Drop-ins are the participants who do not adhere to the control

regimen during follow-up.

29
Dealing with Non-Compliance

• Monitor compliance
• Observe treatment directly.
• Count pills.
• Conduct blood or urine tests to confirm compliance.

• Use of “run-in” period

• Run-in period is a period before a clinical trial is commenced when
no treatment is given.

30
Randomized Trials: Study Designs

• Concurrent Parallel Study Design

• Crossover
• Planned crossover
• Unplanned crossover

• Factorial
31
Planned Crossover

32
Continue..

33
Advantage?

Each patient can serve as his or her own control, holding constant the variation between
individuals in many characteristics that could potentially affect a comparison of the
effectiveness of two agents.
34
Concern
1. Carryover
• There must be a washout period to be sure none of therapy A, or its
effects, remains.

2. Patients may react differently to the first therapy

given in a study as a result of the enthusiasm that is
often accorded a new study

35
Unplanned Crossover

Original study design.

36
Continue..

37
Continue..

If we want to carry out an intention to treat analysis, we would compare the patients
according to their original assignments following randomization.

38
Factorial Design Trial
• Assuming that two drugs are to be tested, the anticipated outcomes
for the two drugs are different, and their modes of action are
independent.

• One can economically use the same study population for testing both
drugs.

39
Example Of A Factorial Design
Physicians’ Health Study (PHS)

Objectives of the Physicians’ Health Study

1. Does aspirin prevent first myocardial infarction?

2. Does beta carotene prevent cancer?

40
Quiz
• A total of 300 newly diagnosed patients with laryngeal cancer are
allocated to treatment with either surgical excision alone or surgical
excision plus radiation treatment. What is the study design?
a. Case series report
b. Case-control study
c. Clinical trial
d. Cohort study
e. Case report

41
Design of a
randomized controlled trial.

42
43
Reference
• K-Park

44
THANK YOU
&
QUESTIONS

45