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Randomized Controlled Trial

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Randomized Controlled Trial Subodh S Gupta Dr. Sushila Nayar School of Public Health MGIMS, Sewagram Block randomization AABB ABAB ABBA BABA BAAB BBAA Six different ... – PowerPoint PPT presentation

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Title: Randomized Controlled Trial


1
Randomized Controlled Trial
  • Subodh S Gupta
  • Dr. Sushila Nayar School of Public Health
  • MGIMS, Sewagram

2
Type of study Alternate name Unit of study
Observational studies Observational studies Observational studies
Descriptive studies Descriptive studies Descriptive studies
Analytical studies Analytical studies Analytical studies
Ecological Correlational Populations
Cross-sectional Prevalence Individuals
Case-Control Case-Reference Individuals
Cohort Follow-up/ Longitudinal Individuals
Experimental/ intervention Studies Experimental/ intervention Studies Experimental/ intervention Studies
Randomized Controlled Studies Clinical Trial Patients
Field Trial Healthy person
Community Trial Community intervention studies Communities
3
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4
Progression of Study Design Clinical Research
  • 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.

5
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.

6
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

7
Progression of Study Design Community Research
  • Ecological Study
  • Cross-Sectional Study
  • Case-Control Study
  • Cohort Study
  • Randomized Community Trial
  • Meta-Analysis
  • EXAMPLE
  • Lipid - Atherosclerosis Association

8
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)

9
Deciding which one to use
The investigator observes the events without
altering them
10
Deciding which one to use
For observational studies Decision 2 Make
measurements on more than one occasion?
11
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?

12
Randomized controlled trials
  • An epidemiological experiment in which
    subjects in a population are randomly allocated
    into groups, usually called study and control
    groups to receive and not receive an experimental
    preventive or therapetuic procedure, maneuver, or
    interventition
  • John
    M.Last, 2001

13
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.

14
Why RCT?
  • Gold standard in epidemiological research
  • Makes study groups comparable
  • Controls for confounding (known and unknown)
  • Prevents selection bias

15
RANDOMIZED, DOUBLE-BLIND, CONTROLLED TRIAL is
considered as research design par excellence and
GOLD STANDARD amongst research designs with
which results of other studies are often
compared. Deviation from this standard has
potential drawbacks
16
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.)

17
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

18
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
20
Types of Randomized Controlled Trials
  • Clinical Trial
  • Diagnostic, Therapeutic, Prophylactic, Devices,
    Procedures, Regimens, Protocols
  • Preventive Trial
  • Risk Factor Trial
  • Cessation experiments
  • Trial of etiologic agents
  • Evaluation of health system

21
  • 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

22
  • 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

23
  • 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

24
  • 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

25
  • 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

26
MULTICENTER TRIALS
  • Reasons for Multi-center Trials
  • 1. To recruit necessary number of subjects within
    a reasonable time.
  • May assure a more representative sample of the
    study or target population
  • Enables investigators with similar interest and
    skills to work together on a common problem

27
  • 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.

28
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.

29
  • 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.

30
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 drugs risks, benefits,
    and optimal use

35
Phase I
  • 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
  • After useful preclinical information from in
    vitro studies or animal models, important to get
    early data in humans.
  • Safety of the drug
  • Estimate how large a dose can be given before
    unacceptable toxicity is experienced by patients
    maximally tolerated dose (MTD).
  • First, safe dose is extrapolated from animal
    model The dose is gradually stepped- up to
    achieve the MTD
  • Conducted in small number of healthy individuals,
    mostly volunteers

36
Phase II trials Safety and efficacy (SE) trials
  • To evaluate whether the drug has any biologic
    activity or effect and to estimate the rate of
    adverse events.
  • When the development process for a new drug
    fails, this usually occurs during Phase II trials
    when the drug is discovered not to work as
    planned, or to have toxic effects.
  • If the design of phase I trial has not been
    adequate, the investigator may evaluate the drug
    for activity at too low or high a dose. Thus
    phase II depends on the quality and adequacy of
    phase I. The results of phase II will, in turn,
    affect the phase III.

37
SE trials as hypothesis tests
  • Denote response rate of new agent by p
  • Can think of
  • Ho new agent not sufficiently promising
  • Ha new agent sufficiently promising
  • Ho p ? p0 vs Ha p gt p0

38
Phase III trialsComparative Efficacy Trials, CTE
  • Phase III studies are randomized controlled
    multicenter trials on large patient groups
    (3003,000 or more depending upon the
    disease/medical condition studied) and are aimed
    at being the definitive assessment of how
    effective the drug is, in comparison with current
    'gold standard' treatment.

39
  • Because of their size and comparatively long
    duration, Phase III trials are the most
    expensive, time-consuming and difficult trials to
    design and run
  • Randomization

40
Phase IV trialsPost Marketing Surveillance
Trial
  • Phase IV trials involve the safety surveillance
    (pharmacovigilance) and ongoing technical support
    of a drug after it receives permission to be
    sold.
  • Phase IV studies may be required by regulatory
    authorities or may be undertaken by the
    sponsoring company for competitive (finding a new
    market for the drug) or other reasons (for
    example, the drug may not have been tested for
    interactions with other drugs, or on certain
    population groups such as pregnant women, who are
    unlikely to subject themselves to trials).

41
  • The safety surveillance is designed to detect any
    rare or long-term adverse effects over a much
    larger patient population and longer time period
    than was possible during the Phase I-III clinical
    trials.
  • Harmful effects discovered by Phase IV trials may
    result in a drug being no longer sold, or
    restricted to certain uses

42
Steps in conduct of RCT
  • The protocol
  • Selecting reference and experimental populations
  • Randomization
  • Intervention
  • Follow up
  • Assessment

43
  • 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

44
  • 2. Selecting Reference and Experimental
    Populations
  • 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

45
  • Participants must fulfill the following criteria
  • Must give informed consent
  • Should be representative of the population
  • Should be qualified or eligible for the trial

46
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.
47
  • 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

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.
49
  • 4. Manipulation / Intervention
  • Deliberate application or withdrawal or reduction
    of a suspected causal factor
  • It creates an independent variable

50
  • 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

51
  • 6. Assessment
  • Positive results
  • Negative results
  • Biases Subject variation, Observer bias,
    Evaluation bias
  • Can be corrected by blinding

52
Randomized Controlled Trials
53
Example Randomized Controlled Trials
54
Avoidance of bias
  • Use of a control group
  • Blindness
  • Randomization
  • Consent before randomization

55
Control group
  • Placebo
  • Most widely accepted treatment
  • Most accepted prevention intervention
  • Usual care
  • Accepted means of detection

56
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

57
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

58
Randomization
  • We want to assign a group of subjects to one of
    two groupsTreatment A or Treatment B
  • How can we do this in a random manner?

59
Randomization
  • Random assignment
  • Flip a coin
  • HeadsTx A
  • TailsTx B

60
Randomization
  • Random assignment
  • Roll a six-sided dice
  • Even numberTx A
  • Odd numberTx B

61
Randomization
  • Random assignment
  • Table of random numbers
  • Computer generated list

62
Almost Random assignments
  • Random assignment
  • Alphabetical
  • Tx A patients with last name AM
  • Tx B patients with last name NZ
  • 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

63
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

64
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

65
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

66
Block randomization
  • AABB
  • ABAB
  • ABBA
  • BABA
  • BAAB
  • BBAA

Six different ways to arrange two As and two Bs
67
Block randomization
  • Roll a die (16) to determine pattern
  • Each pattern has same probability of being chosen
    (one in six)
  • Guarantees balance after every four patients

68
Potential problems with Simple randomization
(flip a coin)
  • Imbalance on a key variable
  • If study is very small, no guarantee groups are
    comparable
  • Solutionstratify

69
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

70
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

72
Double-Blinded Single-Blinded
73
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74
Types of Randomized Studies
  • Parallel group
  • Sequential trials
  • Group sequential trials
  • Cross-over
  • Factorial designs
  • Adaptive designs

75
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

76
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

77
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

78
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79
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 Placebo Vitamin E Placebo Vitamin A Vitamin E Placebo
Vitamin A Placebo Vitamin E Vitamin A Vitamin E
80
Incomplete/ Partial/ FractionalFactorial Trial
  • Nutritional Intervention Trial
  • 4X4 incomplete factorial
  • Did not look at all possible interactions
  • Not of interest
  • Sample size prohibitive

81
Cross-over Trial
  • Two treatments, two period cross-overs
  • Use each patient as own control
  • Must eliminate carryover effects
  • Need sufficient washout period

82
PERIOD 1
PERIOD 2
INTERVENTION
RANDOM ALLOCATION
SUBJECTS
CONTROL
CROSS OVER DESIGN
83
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

84
Care during analysis
85
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86
Flow diagram of the progress through the phases
of a randomized trial
87
Flow diagram of the progress through the phases
of a randomized trial
88
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.

89
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.

90
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
  • The first two treatments in this list
  • The third treatment (the only one not involving
    an antibiotic) and all the rest combined

91
Exercise 4
  • Refer to Cerebral Palsy data
  • Test whether the addition of rhizotomy has a
    significant effect on motor functions
  • Summarize the effect of adding rhizotomy, giving
    a 95 confidence interval for your summary
    statistics

92
Exercise 5
  • Refer to data given for Norwegian Multicenter
    Study (Table C.8)
  • Construct a separate actuarial life table for
    each treatment group
  • Plot the estimates of cumulative survival
    probability on a graph and interpret the findings
  • Compare the overall survival in the two groups
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