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Ankur Barua

At the end of the session, the learner will be able to:

Understand the importance of obtaining Ethical Committee clearance, Informed Written Consent, Registration in Clinical Trial Registry.

Interpret and apply the concepts of Randomization, Blinding and Cross-over technique.

Ethical Committee clearance, Informed Written Consent, Registration in Clinical Trial Registry
Procedure of Randomization

Procedure of Blinding
Cross-over technique

Autonomy (right of patients for self-governance) To exercise this right, a patient must be informed on the benefits and potential risks of the new treatment/procedure (related to the requirement of obtaining informed consent from patients).

Beneficence is the patients right to be benefited from therapy, and the physicians duty not to harm the patient.
Justice or fairness of distribution of the burdens and benefits of the research. For example, testing on poor people or minorities, and then distributing to the privileged would be in direct violation of this principle.

Clearance from Ethical Committee of

the institution or organization.

Informed Written Consent for all

human experiments.

Registration in Clinical Trial Registry.


Moher D, Hopewell S, Schulz KF, Montori V, Gtzsche PC, Devereaux PJ, CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.

Moher D, Hopewell S, Schulz KF, Montori V, Gtzsche PC, Devereaux PJ, CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869.

Clearly stated objectives. Well-defined endpoints or quantifiable measures derived

from these objectives.

A priori stated decision rules for success or failure of the

experimental treatment based involving these endpoints. on statistical tests


necessary, a clearly presented calculation of the sample size and its associated power. patient screening and randomization.

Well-described patient inclusion and exclusion criteria, and

A system of data monitoring; this includes: Safety and efficacy monitoring, possibly by an external body (e.g., a Data Safety Monitoring Board or DSMB), with possibly explicit rules for early study termination. Data quality monitoring and error correction.
All examinations, tests, and evaluations described in detail along with a schedule of when they are to be performed.

A data collection system which is based on data collection instruments called Case Report Forms (CRFs) as well as a system of digital data entry.



Not controlled


Not randomised


Not blinded

True experiments (randomized controlled trials) are contrasted with non randomized controlled trials and observational studies.

In non randomized controlled trials, the control group is predetermined (without random assignment) to be comparable to the program group
Non randomized controlled trials are also called quasi experiments.



randomized participants who -





1) volunteer to join the study 2) reside geographically close to the study site 3) conveniently turn up (at a clinic, school) while the study is being conducted

the study groups are opportunistically rather than randomly composed, study group characteristics (age, sex) may not be balanced before the study begins. differences confound the results. between groups may


Typical confounding variables include age, educational level, motivation, severity of illness, social structure, and income.
Evaluation researchers worry that study groups in nonrandomized trials will differ from one another at baseline, and the studys findings will be compromised. They aim to create study groups that are as similar to one another as possible (equivalent) at baseline or before treatment. Among the strategies commonly used to ensure equivalence is one called matching.


Matching requires selecting pairs of participants or clusters of individuals who are comparable to one another on important variables.
A researcher who is interested in comparing the acuity of vision

among smokers and non smokers can try to balance the two groups by selecting pairs of smokers and non smokers who are same age, sex and have the same medical history.

Statistical methods such as analysis of covariance and propensity score analysis are sometimes used to deal with the problem of confounding after the data are collected for the study.


Time-series Designs Time-series designs are longitudinal studies that enable the researcher to monitor change from one time to the next.
They are sometimes called repeated measures analyses.

Interrupted or Single Time-series The interrupted or single time-series design without a control group involves repeated measurement of a variable (e.g., reported crime) before and after implementation of a program.
The goal is to evaluate whether the program has

"interrupted" or changed a pattern established before its implementation.


Self-Controlled or Pretest-Post Test Designs Each participant is measured on some important program variable and serves as his or her own control.
Participants are usually measured twice (at baseline and

after program participation), but they many be measured multiple times afterward as well.

Historical Controls Investigators compare outcomes among participants who receive a new program with outcomes among a previous group of participants who received the standard program.


Involves some action, intervention or manipulation such as deliberate application or withdrawal of suspected cause.

Drawing up a protocol

3. 4. 5. 6. 7.

Selecting reference and experimental population

Randomization Blinding Manipulation or intervention Follow- up Assessment of outcome

Clinical Trials: Phases


EXPERIMENTAL STUDY DESIGNS (Randomised or Non-randomised trials)

Salient Features

Study Unit
1st group - Intervention 2nd group Control - Done on animals or experiments under lab conditions 1st group - Intervention 2nd group Control - Done on diseased individuals (patients) 1st group - Intervention 2nd group Control - Done on apparently healthy individuals 1st group - Intervention 2nd group Control - Done on community as a unit


Lab or Animal Trials (Phase-I trial) (a) Laboratory Experiments (b) Animal Experiments (c) Drug trials with small number of patients
Clinical Trials with large number of patients (Phase-II trial) (a) Preventive (Vaccine / Drug trials) (b) Therapeutic ( Drug trials) Field Trials (Phase-III trial) (a) Preventive (Vaccine & Nutritional Supplementation trials) Community Trials (Phase-IV trial) Also known as Post-Marketing Trials (a) Preventive (Vaccine & Nutritional Supplementation trials)

Comparison / Control group is chosen after Randomisation, following informed consent, wherever feasible. Studies could be multicentric when >2 centres are involved. Application of Statistical Tests of Significance is mandatory. These follow-up studies are conducted for demonstration of cause & effect relationships.




D E s i G N
o F

Selection by defined criteria Potential participants (Meet selection criteria) Invitation to participate Participants Randomization & double blinding Experimental group Control group Manipulation, Follow up & Assessment

Non-participants (do not meet selection criteria) Non-participants (do not give consent)


The CONSORT Flow Chart JAMA. 2001;285:1987-1991

Random Allocation
known chance receiving a treatment cannot predict the treatment to be given

Eliminate Selection Bias

Similar Treatment Groups

Randomization tries to ensure that ONE factor is different between two or more groups. Observe the Consequences Attribute Causality

Standard ways:
Random number tables Computer programs

NOT legitimate:
Birth date Last digit of the medical record number Odd/even room number

Statistical Properties of Randomization

A. Sampling-Based Population Model B. Randomization Model

Population a y~G(y|a)

Population b y~G(y|b)

Study Sample

Sample at Random

Sample at Random

na patients yaj~G(y|a)

nb patients ybj~G(y|b)

n = nb + nb patients


na patients

nb patients

Simple Blocked Randomization

Stratified Randomization

Randomize each patient to a treatment with a known probability

Corresponds to flipping a coin

Could have imbalance in proportion or group or trends in group assignment Could have different distributions of a trait like gender in the two arms

Insure the proportion of patients assigned to each treatment is not far out of balance Variable block size
An additional layer of blindness

Different distributions of a trait like gender in the two arms possible

To improve balance between treatment assignments we can use permuted blocks. Within each block, the two treatments are balanced, and the order of treatment allocation is changed (permuted) from block to block. At the end of each block both treatments are balanced. Permutation number Within-block assignment 1 2 3 4 1 A A B B 2 A B A B 3 A B B A 4 B B A A 5 B A B A 6 B A A B

A prioritize certain factors likely important (e.g., Age, Gender). Randomize so different levels of the factor are balanced between treatment groups. Cannot evaluate the stratification variable.

For each subgroup or strata perform a separate block randomization Common strata
Clinical center, Age, Gender

Stratification MUST be taken into account in the data analysis Subgroup Analysis.

Every prognostic factor or prognostic factor combination (in the case of multiple prognostic factors) is made into a separate stratum. Treatment assignment is then balanced in each stratum yielding balanced representation of each stratum in each treatment. Then the blocks shown in the previous table, can be allocated at random into each stratum (thus balancing treatment allocation into each stratum). For example, Treatment assignment w/ a block size of 6

1 Old male Young male A A 2 A B 3 A B 4 B B 5 B A 6 B A

Old female Young female







Randomization is used to -

Control the variability of clinical outcome. Combat treatment selection bias (where a certain type Create homogeneous risk strata.
Stratification is used to -

of patient maybe more likely to be selected for one treatment versus the other).

Balance known risk factors between the treatments under


Parallel Group Sequential Trials

Group Sequential trials

Cross-over Factorial Designs

Randomize patients to one of k treatments

Measure at end of study Delta or % change from baseline Repeated measures Function of multiple measures

Randomised Parallel Group

Participants satisfying entry criteria Randomly allocated to receive A or B

Participants followed up exactly the same way

Example: Digoxin vs Placebo DIG study

Not for a fixed period Terminates when

One treatment shows a clear superiority or It is highly unlikely any important difference will

be seen

Special statistical design methods

Popular Analyze data after certain proportions of results available Early stopping
If one treatment clearly superior Adverse events

Careful planning and statistical design

Cross-over Trial
A cross-over trial is one in which subjects are given sequences with the object of studying differences between individual treatments.

(C)Stephen Senn


Two-period, two-treatment cross-over trial

Participants satisfying entry criteria sometimes followed by run-in period

Randomised to A followed by B or vice-versa

Usually washout in between

Example: Aspergesic (A) vs ibuprofen (B) in rheumatoid arthritis.


2 treatments: crossover


Use each patient as own control Must eliminate carryover effects

Need sufficient washout period

Each level of a factor (treatment or condition) occurs with every level of every other factor Selenomethionine and Celecoxib Gastroenterology 2002; 122:A71

Placebo Placebo Placebo Celecoxib

Selenium Placebo Selenium Celecoxib

Factorial design
Participants satisfying entry criteria
Participants randomly allocated to one of four groups. 2x2 factorial design

Example: Heart Protection Study. =Vitamins; =Placebo


The simplest way to randomize patients in two

treatments is by flipping a coin (the first treatment takes the heads and the second treatment the tails). However, there is no guarantee of equal number of subjects assigned to the two treatments. For example, for N=100, the probability of equal treatment allocation is about 8% only.

Single blind trial: Here, the participant is not aware whether he belongs to study group or control group. Double blind trial: Here, neither the administrator of intervention (doctor / nurse) nor the participant are aware of the group allocation and the treatment received.

Triple blind trial: Here, the participant, the administrator of intervention (doctor / nurse) and the analyzer (statistician) are all blind.

(1) p { Type I error } = , (2) p { Type II error } = ,

less p { type I error } more subjects less p { type II error } more subjects, More power (1-)


True False


Accept Reject

Correct action

Type II error ()
Correct action

Type I error ()

Probability of committing {Type I error} = = level of significance (Rejecting a true null hypothesis)
Probability of committing {Type II error} = (Accepting a false null hypothesis) (1 - ) = Power of the test. It is Probability of not committing a type II () error or ability of a test to reject a false null hypothesis.


level of power ( 1- )
effect size (d)


significance level ()


Sample size determination

1. level of power (1- )

1. What level of power is required?

A rule of thumb is that the power of a test should be at least 1 4, e.g. for a 5% significance level the power of the test should be at least 80%. = 1- (4X 0.5) = 0.8 This means that there is an 80% chance of detecting the required order of difference b/t population means.

Sample size

d = The effect size (i.e clinically

important differences or important

d = PA-PB
PA = proportion expected in the treatment group
PB = proportion expected in the control group

Sample size

Lehrs formula

m = 16 (1- )/(PA-PB)2 = (PA-PB)/2

Treatment group = 0.05 Placebo group = 0.2

= (PA-PB)/2

= (0.05-0.2)/2 = 0.15/2 = 0.075

m = 16 (1- )/(PA-PB)2 = 16 X 0.075 ( 1-0.075)/0.0752 = 74


Sample size determination

1. level of power ( 1- )

2. Effect size

3. Statistical significance

Difference between means 2. The effect size (i.e clinically important differences or

important difference)

d = T C

= SD of the populations that the two samples are taken C mean

(assuming that it is the same for both)

T = mean
of the treatment group; of the control group

3. Significance level of 5% (i.e = 0.05)


Sample size determination

For a 2 sided significance level of 5% & power

of 80%
m = 16/d

m = the number required in each group

Source: MJ Campbell, SA Julious & DG Altman (1995). Estimating sample sizes for binary, ordered categorical, and continuous outcomes in two group

comparisons, BMJ:311:1145-1148.


Sample size determination


If we wish to detect a difference in means of 5 mm Hg between the group with antihypertensive drug & those with placebo. The systolic BP of the drug group = 136 mm Hg The systolic BP of placebo group = 144 mm Hg Assume SD of BP in each group = 17 mm Hg = 17

d = t C
d = 5/17 = 0.294 For 80% power, using a significance level of 5% m = 16/d2 = 16/0.2942
= 185


Sample size required per group at the 2 sided 5% significance for the difference value of effect size & power

MJ Campbell, S AJulious, D GAltman (1995). Estimating sample sizes for binary, ordered categorical, and continuous outcomes in two group comparisons, BMJ; 311: 1145-1148. 55

Sample size to detect a difference between two proportions at the

5% significance level with 80% power

MJ Campbell, S AJulious, D GAltman (1995). Estimating sample sizes for binary, ordered
categorical, and continuous outcomes in two group comparisons, BMJ; 311: 1145-1148. 56


Should be random assignment

Each individual has the same chance of

receiving each possible treatment.



Some examples of random allocation I.

Random number table: as each subject enrolled, assigned a number from the random number table; assign even numbers to treatment A and odd to treatment B Toss a coin for each subject: heads=A, tails=B



Some examples of Non-random allocation I.

Alternate assignment of treatments

Assignment by day of the week



Triple blind Randomized

with adequate

allocation concealment
Parallel groups

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