Randomized Controlled

TrialSubodh S Gupta

Dr. Sushila Nayar School of Public Health

MGIMS, Sewagram

Type of studyType of study Alternate nameAlternate name Unit of Unit of studystudy

Observational studiesObservational studiesDescriptive studiesDescriptive studies

Analytical studiesAnalytical studies EcologicalEcological CorrelationalCorrelational PopulationsPopulations

Cross-sectionalCross-sectional PrevalencePrevalence IndividualsIndividuals

Case-ControlCase-Control Case-ReferenceCase-Reference IndividualsIndividuals

CohortCohort Follow-up/ Follow-up/ LongitudinalLongitudinal

IndividualsIndividuals

Experimental/ intervention StudiesExperimental/ intervention Studies Randomized Randomized Controlled Controlled Studies Studies

Clinical TrialClinical Trial PatientsPatients

Field TrialField Trial Healthy personHealthy person

Community TrialCommunity Trial Community intervention Community intervention studiesstudies

CommunitiesCommunities

Isolated Case Reports Case Series Cross-Sectional study Case-Control Study Cohort Study Randomized Clinical Trial Meta-Analysis

EXAMPLE: The role of oxygen in retrolental fibroplasia RLF among

premature infants.

Progression of Study Design: Clinical Research

First Case - Feb. 14, 1941, Dr. Clifford, Boston Case Series - 1941 (Silverman 1980) Ca-Co Study (53 RLF Children, 298 Normal Children) Association was observed. Still, it was postulated that

poor health of infants necessitated longer hours of oxygen. Poor health and not oxygen use caused RLF.

Progression of Study Design: Clinical Research

Cohort Studies: Contradictory Results I RCT: Gallinger Muncipal Hospital, Washington, DC II Collaborative Multi-centre Trial Confirmed the role of oxygen in the etiology of

Retrolental Fibroplasia

Progression of Study Design: Clinical Research

Ecological Study Cross-Sectional Study Case-Control Study Cohort Study Randomized Community Trial Meta-Analysis

EXAMPLE:Lipid - Atherosclerosis Association

Progression of Study Design: Community Research

Analysis of Death Rates from CAD according to per capita fat consumption in 20 countries Hypothesis of L-A association.

CS Studies: Framingham and Evans County Heart Studies (Dawber et al 1971, Cassel 1971)

Case-Control Studies confirmed Association. Cohort Studies (Truett et al 1967, Tyroler et al 1971) Community Based Controlled Trials of Lipid Reduction

(Lipid Research Clinics Program)

Progression of Study Design: Community Research

Deciding which one to useThe investigator observes the events without altering them

Decision # 1Alter the events under study?

The investigator applies an intervention, & observes the effect on the outcome

NO

Yes

Observational study

Experimental study

Example: Comparing the history of needle sharing among IV drug abusers

who have HIV antibodies with those who do not

Example: Impact of health education on needle sharing habits

Deciding which one to use

For observational studiesDecision # 2

Make measurements on more than one occasion?

Each subject is examinedon only one occasion

Each subject is followed overA period of time

NO

Yes

Cross-sectional study

Longitudinal study

Example: Study of needle sharing habits and HIV antibodies measured at the

same time

Example: Cohort study that assesses current needle sharing habits of group of

IV drug abusers and observes who subsequently develop HIV antibodies

Deciding which one to use Can you alter the events under the study? How strong is the hypothesis? How common is the disease or health event which is to

be studied? How common is the exposure/ determinants of the

health event? Do you want to study the different factors/

determinants of a health event or disease? Or; Do you want to see the multiple effect of an exposure?

How much resources do you have?

Randomized controlled trials

””An epidemiological experiment in which An epidemiological experiment in which subjects in a population are randomly subjects in a population are randomly allocated into groups, usually called study and allocated into groups, usually called study and control groups to receive and not receive an control groups to receive and not receive an experimental preventive or therapetuic experimental preventive or therapetuic procedure, maneuver, or interventition” procedure, maneuver, or interventition”

John M.Last, 2001John M.Last, 2001

Randomized Controlled Trial

• A true experiment• Key features– the classic way to evaluate efficacy or

effectiveness of drugs (or exercise, diet, counseling)

– patients are followed over time (prospective)• Properly done, an RCT can be used to

determine cause and effect.

Why RCT?

• ”Gold standard” in epidemiological research

• Makes study groups comparable– Controls for confounding (known and unknown)– Prevents selection bias

““RANDOMIZED, DOUBLE-BLIND, CONTROLLED RANDOMIZED, DOUBLE-BLIND, CONTROLLED TRIAL” TRIAL” is considered as research design is considered as research design par excellence and “par excellence and “GOLD STANDARDGOLD STANDARD” ” amongst research designs with which amongst research designs with which results of other studies are often results of other studies are often compared. Deviation from this standard compared. Deviation from this standard has potential drawbackshas potential drawbacks

Advantages

• Most efficient for investigating causality• Ensure ‘ONLY ONE’ factor is different:

confounding factors do not confuse the results• Ensure that treatments are compared efficiently• Look for effects of combinations of treatments,

interaction between treatments and personal characteristics

• Only study design which can help us evaluate a new treatment (medicine, other procedures etc.)

Disadvantages

• Share many of the disadvantages of cohort study

• Ethical concerns• It may not be possible for all kinds of

questions that we have• Intervention studies screen out ‘problem’

subjects, such as the very young, the elderly and pregnant and lactating women

Ethical Considerations

• Major issue for ‘Randomized Controlled Trial’• Proper information to all the study subjects• Informed consent• The trial is conducted ethically• Avoid bias in results• Sample size is adequate to give the results• What if, before the study is completed, there is

evidence that one treatment is better than the other one

19

ETHICS

IMPORTANT ISSUE IN CLINICAL TRIALS

ETHICAL CLEARANCE

* INSTITUTIONAL REVIEW BOARDS

* ETHICAL COMMITTEES

* ICMR GUIDELINES

* FEDERAL/STATE GUIDELINES

1. Clinical Trial: Diagnostic, Therapeutic, Prophylactic, Devices, Procedures, Regimens, Protocols

2. Preventive Trial3. Risk Factor Trial4. Cessation experiments5. Trial of etiologic agents6. Evaluation of health system

Types of Randomized Controlled Trials

Types of Randomized Controlled Trials:

1. Clinical Trial- Concerned with evaluating therapeutic

agent, mainly drugs eg. Evaluation of beta-blockers in reducing

cardiovascular mortality- Not all clinical trials are susceptible to being

blinded

21

2. Preventive Trials:- Trial of primary preventive measures eg.

Vaccines

- Analysis of preventive trials must result in clear statement about benefits to community, risk involved and cost to health

22

3. Risk Factor Trials:- Investigator intervenes to interrupt the usual

sequence in the development of disease for those individuals who have risk factor for developing the disease

- Primary prevention of CHD using clofibrate to lower serum cholesterol

23

4. Cessation Experiment:

- An attempt is made to evaluate the termination of a habit which is considered to be causally related to disease

- Cigarette smoking and lung cancer

24

5. Trials of Etiological Agents:- To confirm or refute an etiological hypothesis

6. Evaluation of Health Services:- Domiciliary treatment of PTB was as effective

as more costlier hospital or sanatorium treatment

25

26

MULTICENTER TRIALS

Reasons for Multi-center Trials :

1. To recruit necessary number of subjects within a reasonable time.

2. May assure a more representative sample of the study or target population

3. Enables investigators with similar interest and skills to work together on a common problem

CLINICAL TRIALS• Prospective study comparing the effect and value

of one of more interventions against a control in human subjects with a given medical condition.

• Measures causality in terms of the effect of an intervention: If one alters the risk factor, does one alter the occurrence of the event/injury?

• "...the most definitive tool for evaluation of the applicability of clinical research.“

WHAT IS CLINICAL TRIAL

• A clinical trial is defined as a prospective study comparing the effect and value of interventions against a control in human beings

• Study participants must be followed forward in time. They need not all be followed from an identical calendar date.

• Must contain a control group against which the intervention group is compared.

• At baseline, the control group must be sufficiently similar in relevant respects to the intervention group so that differences in outcome may reasonably be attributed to the action of the intervention.

• Most often a new intervention is compared with best current standard therapy.

Stages of experimentation

– Phase I: dose-finding– Phase II: preliminary evidence of efficacy– Phase III: comparisons to standard therapy– Phase IV: post-marketing surveillance

31

PHASES OF TRIALS

Phase I Trials:

• Initial studies to determine the metabolism and pharmacologic actions of drugs in humans, the side effects associated with increasing doses, and to gain early evidence of effectiveness; usually conducted on healthy volunteers

32

PHASES OF TRIALS

Phase II Trials:

• Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with disease or condition under study and to determine the common short-term side effects and risks

33

PHASES OF TRIALS

Phase III Trials:

• Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug

34

PHASES OF TRIALS

Phase IV Trials:

• Post-marketing studies to delineate additional information including the drug’s risks, benefits, and optimal use

1. The protocol2. Selecting reference and experimental

populations3. Randomization4. Intervention5. Follow up 6. Assessment

Steps in conduct of RCT

1. The Protocol- Rationale- Aims and objectives, Research questions- Design of the study: selection of patients, drugs

and doses, assessment, withdrawals, data analysis, data discharge

- Ethics: patient consent, adverse events - Documentation- Procedure

43

2. Selecting Reference and Experimental Populations

a. Reference or target population - population to which the findings of the trial, if found successful, are expected to be applicable (eg. drugs, vaccines, etc.)

b. Experimental or study population - actual population that participates in the experimental study

44

Participants must fulfill the following criteria:

- Must give informed consent

- Should be representative of the population

- Should be qualified or eligible for the trial

45

SAMPLE SIZE

Clinical trials should have sufficient statistical power to detect differences between groups considered to be of clinical interest. Therefore, calculation of sample size with provision for adequate levels of significance and power is essential part of planning.

3. Randomization- Heart of the control trial- Procedure: Participants are allocated into

study and control groups- Eliminates bias and allows comparability- Both groups should be alike with regards to

certain variables that might affect the outcome of the experiment

- Best done by using table of random numbers

47

48

RANDOMIZATION

Randomization tends to produce study groups comparable with respect to known as well as unknown risk factors, removes investigator bias in the allocation of subjects and guarantees that statistical tests will have valid significance levels.

4. Manipulation / Intervention

- Deliberate application or withdrawal or reduction of a suspected causal factor

- It creates an independent variable

49

5. Follow Up- Implies examination of the experimental and

control group subjects at defined intervals of time, in a standard manner, with equal intensity, under the same given circumstances

- Attrition: Inevitable losses to follow up

50

6. Assessment- Positive results- Negative results

- Biases: Subject variation, Observer bias, Evaluation bias

- Can be corrected by blinding

51

Randomized Controlled Trials

Example: Randomized Controlled Trials

Avoidance of bias

• Use of a control group• Blindness• Randomization• Consent before randomization

Control group

• Placebo• Most widely accepted treatment• Most accepted prevention intervention• Usual care• Accepted means of detection

Randomization: Definition

• Not a random sampling• Random allocation– Known chance receiving a treatment – Cannot predict the treatment to be given

• Eliminates selection bias• Similar treatment groups

Only one factor is different

• Randomization tries to ensure that ONLY ONE factor is different between two or more groups

• Observe the consequences• Attribute Causality

Randomization

• We want to assign a group of subjects to one of two groups—Treatment A or Treatment B– How can we do this in a random manner?

Randomization

Random assignment• Flip a coin– “Heads”—Tx A– “Tails”—Tx B

Randomization

Random assignment• Roll a six-sided dice– Even number—Tx A– Odd number—Tx B

Randomization

Random assignment• Table of random numbers• Computer generated list

‘Almost’ Random assignmentsRandom assignment• Alphabetical– Tx A = patients with last name A–M– Tx B = patients with last name N–Z

• Telephone number/social security number– Tx A = last digit odd– Tx B = last digit even

• Sequential– Tx A = morning patients– Tx B = afternoon patients

• Bed number– Tx A = odd bed number– Tx B = even bed number

‘Almost Random’ assignments

There are potential problems in the “Almost Random” assignment scheme– Do you see a potential problems with these

‘Almost Random’ assignment scheme

Potential problems with Simple randomization (flip a coin)

Randomize individuals to one of two treatments• If n is big, works great• If n is small– May be imbalanced with respect to . . .

• Sample size• Other variable

Unequal sample sizes• If study has very small sample size, there is no

guarantee two groups will have equal sample size using simple randomization

Block Randomization

• Ensure that # of patients assigned to each treatment is not far out of balance

• Variable block size (permuted)– An additional layer of blindness

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

Block randomization

• AABB• ABAB• ABBA• BABA• BAAB• BBAA

Six different ways to arrange two As and two Bs

Roll a die (#1–6) to determine pattern• Each pattern has same probability of being

chosen (one in six)• Guarantees balance after every four patients

Block randomization

Imbalance on a key variable• If study is very small, no guarantee groups are

“comparable”• Solution—stratify

Potential problems with Simple randomization (flip a coin)

Stratified randomization

• A priori 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

Stratified randomization

• Stratify, then do block randomization

Male; 25-44 yrs ABBA BBAA BABA ABAB BAAB

Female; 45-60 yrs AABB ABBA BBAA BABA ABAB

71

BLINDING

•UNBLINDED, OPEN TRIAL

•SINGLE BLIND

•DOUBLE BLIND

•TRIPLE BLIND

Double-Blinded Single-BlindedDouble-Blinded Single-Blinded

Types of Randomized Studies

• Parallel group• Sequential trials• Group sequential trials• Cross-over• Factorial designs• Adaptive designs

Parallel Group

• Randomize patients to one of k treatments• Response– Measure at end of study– Delta or % change from baseline– Repeated measures– Function of multiple measures

Sequential trials

• Not for a fixed sample size/ period• Terminates when– One treatment shows a clear superiority or – It is highly unlikely any important difference will

be seen– Special statistical design methods

Group Sequential Trials

• Popular• Analyze data after certain proportions of

results are available• Early stopping– If one treatment clearly superior– Adverse events

• Careful planning and statistical design

Factorial design

• Each level of a factor (treatment or condition) occurs with every level of every other factor

• Vitamin A and Vitamin E for prevention of Hypertension:

Vitamin A PlaceboVitamin E Placebo

Vitamin AVitamin E Placebo

Vitamin A PlaceboVitamin E

Vitamin AVitamin E

Incomplete/ Partial/ FractionalFactorial Trial

• Nutritional Intervention Trial• 4X4 incomplete factorial• Did not look at all possible interactions– Not of interest– Sample size prohibitive

Cross-over Trial

• Two treatments, two period cross-overs• Use each patient as own control• Must eliminate carryover effects– Need sufficient washout period

82

INTERVENTION

SUBJECTS

CONTROL

RANDOM

ALLOCATION

PERIOD 2

CROSS OVER DESIGN

PERIOD 1

Adaptive designs

• Smaller overall sample size (potential)• Run-in; then analyze data continuously or

fixed intervals• Act like group sequential design• Close an arm early• Re-estimate sample size based on variance

Flow diagram of the progress through the phases of a randomized trial

Flow diagram of the progress through the phases of a randomized trial

Exercise 1

• A multicentric randomized double blind study to assess the efficacy of Probiotics for reduction of risk of sepsis among neonates

• Five sites have been selected for this study. • Describe a suitable method for allocating

hospital patients to intervention groups.

Exercise 2

• A study planned to assess the desirability, and overall impact on the health services of day surgery

• Several hospitals agree to take part in the study. • Two groups will be compared using various

subjective criteria (self-assessed health) and factual criteria

• Describe a suitable method for allocating hospital patients to intervention groups. Assume that a list of day surgeries have already been established.

Exercise 3• In a study of four treatments for eradication of H.

pylori, Tham et al. report the following eradication results (expressed as ratios of eradication to number treated)– Omeprazole + Amoxycillin + Metronidazole – 6/20– Ranitidine + Amoxycillin + Metronidazole – 8/20– Omeprazole + Placebo – 0/20– Omeprazole + Clarithromycin – 4/20

• Test whether there is a significant difference between:i. The first two treatments in this listii. The third treatment (the only one not involving an

antibiotic) and all the rest combined

Exercise 4

• Refer to Cerebral Palsy data:

i. Test whether the addition of rhizotomy has a significant effect on motor functions

ii. Summarize the effect of adding rhizotomy, giving a 95% confidence interval for your summary statistics

Exercise 5

• Refer to data given for Norwegian Multicenter Study (Table C.8)

i. Construct a separate actuarial life table for each treatment group

ii. Plot the estimates of cumulative survival probability on a graph and interpret the findings

iii.Compare the overall survival in the two groups