1

Definition 2

 Standard structure for representing the planned

sequence of events and the treatment plan of a trail.

 Plan for a precise procedure to be followed in a

clinical trail, including timing of events, choice of
control group, method of allocating treatments,
blinding methods.
Study Design 3
 The choice of design depends on the goal of the trial

 Choice also depends on the population, knowledge of the

intervention

 Choose mentor wisely

 Get an epidemiologist/ statistician on board at start

 Should be Flexible, appropriate, efficient, economical

 Should give smallest experimental error & high reliability &

validity
Phase I Design 4

Typical/Standard Design
 Based on tradition, not so much on

 statistical theory

 Dose escalation to reach maximum tolerated

 dose (MTD)

 Dose escalation often based on Fibonacci Series

1 2 3 5 8 13 . . . .
Typical Scheme 5

1. Enter 3(5) patients at a given dose

2. If no toxicity, go to next dosage and repeat step 1

3. a. If 1 patient has serious toxicity, add 3 more

patients at that dose (go to 4)
b. If 2/3 have serious toxicity, consider MTD

4. a. If 2 or more of 6 patient show toxicity, MTD

reached (perhaps)
b. If 1 of 6 has toxicity, increase dose and go back
to
step 1
Standard Phase I Design 6

Designed to find dose where 1/3 of patients

experience dose limiting toxicity (DLT)
Therapeutic Index for a new 7
drug
Toxic Dose

Dose Therapeutic Index

Minimally Effective Dose

Phase II Design 8

 Goal
 Screen for therapeutic activity
 Further evaluate toxicity
 Test using MTD from Phase I
 If drug passes screen, test further
Phase II Design 9

 No control
 Goal is to reject ineffective drugs ASAP

Decision I: Drug is unlikely to be effective in  x% of

patients

Decision II: Drug could be effective

in  x% of patients
Phase III Introduction 10

 Use of proper control group necessary due to:

 Natural history of most diseases
 Variability of a patient's response to intervention

 No comparison groups needed when results dramatic:

 Penicillin for pneumococcal pneumonia
 Rabies vaccine
Phase III Design 11

 Comparative Studies

 Experimental Group vs. Control Group (Placebo

/ Comparator)

 Placebo made to look like a study drug

 Randomized Control Trial (RCT) is the gold

standard
 Eliminates several sources of bias
Purpose of Control Group 12

 To allow discrimination of patient outcomes caused by

experimental intervention from those caused by other factors
 Natural progression of disease
 Observer/patient expectations
 Other treatment

 Fair comparisons
 Necessary to be informative
Choice of Control Group 13

 Goals of Controlled Clinical Trials

 Types of Control Groups

 Significance of Control Group

 Assay Sensitivity
Considerations in Choice of 14
Control Group
 Available standard therapies

 Adequacy of the control evidence for the chosen design

 Ethical considerations
Significance of Control 15

Group
 Inference drawn from the trial
 Ethical acceptability of the trial
 Degree to which bias is minimized
 Type of subjects
 Kind of endpoints that can be studied
 Credibility of the results
 Acceptability of the results by regulatory
authorities
 Other features of the trial, its conduct, and
interpretation
Randomized Control Clinical Trial 16
 Patients assigned at random to either treatment(s) or control

 Each patient has the same chance of receiving any of the treatments
under study

 Allocation of treatments to participants is carried out using a chance

mechanism so that neither the patient nor the physician know in
advance which therapy will be assigned
Randomization 17
Advantages of RCT 18

 Considered to be “Gold
Standard”

 Randomization
"tends" to
produce comparable groups

 Randomization produces valid

statistical test
 Disadvantages RCT 19

1. Recruitment
 Twice as many new patients

2. Acceptability of Randomization Process

 Some physicians will refuse
 Some patients will refuse

3. Administrative Complexity
Treatment Studies 20

 Randomized controlled trial

 Non-blind trial
 Single-blind randomized trial
 Double-blind randomized trial
 Triple-blind randomized trial

 Nonrandomized trial (quasi-experiment)

 Interrupted time series design (measures on a sample
or a series of samples from the same population are
obtained several times before and after a manipulated
event or a naturally occurring event) - considered a
type of quasi-experiment
 Non-Blind Trial / Open Trial 21
 Researchers as well as patients know full details
of the treatment
 Usually this kind of study design is used in
bioequivalence studies

 Single-Blind Trial
 Researchers know the detail of treatment but
patient does not
 Since the researcher knows, it is possible for the
researcher to treat the patient differently or to
subconsciously hint to the patient important
treatment-related details, thus influencing the
outcome of the study
 Double-Blind Trial 22
 Neither research staff nor study subjects know
the detail of treatment
 Double-blind trials are preferred, as they tend
give the most accurate results

 Triple-Blind Trial
 Subject, researcher and person administering
treatment (often a pharmacist/ statistician) are
blinded
 it connotes an additional layer of security to
prevent undue influence of study results by
anyone directly involved with the study
 Cluster Randomization Designs
23
• Groups (clinics, communities) are randomized to treatment
or control

• Examples:
• Community trials on fluoridization of water
• Breast self examination programs in different clinic setting

• Advantages
• Sometimes logistically more feasible
• Avoid contamination
• Allow mass intervention, thus “public health trial”

• Disadvantages
• Effective sample size less than number of subjects
• Many units must participate to overcome unit-to-unit variation,
thus requires larger sample size
• Need cluster sampling methods
Commonly used Phase III 24
Design
Open label trial
 Parallel trial
 Cross over trial
 Randomized control trial
 Cohort study
 Prospective study
 Retrospective study
 Replicate design
 Factorial design
Fundamental Design 25

Yes Yes R
Eligible Consent
A
N A
D
No No O
M
I A
Z
Dropped Dropped E
Open label trial 26

 The situation when both the researcher and the

participant in a research study know the treatment the
participant is receiving.

 Open-label trials may be appropriate for comparing

two very similar treatments to determine which is most
effective.

 An open-label trial may be unavoidable under some

circumstances, such as comparing the effectiveness of a
medication.

 Open-label trials may also be uncontrolled, with all

participants receiving the same treatment.
Parallel Study 27

 A parallel designed clinical trial compares the results of a

treatment on two separate groups of patients

 Measures the standard deviation of repeated

observations in the same individual

 Advantage
 Simple, General Use
 Valid Comparison

 Disadvantage
 Require greater sample size
Parallel Design 28
Screen
Treatment A

Treatment B
Randomize

Study Treatment A vs. Treatment B in different groups

E.g. CAST (Cardiac Arrhythmia Suppression Trial ) DCCT
(Diabetes Control and Complications Trial )
Crossover Study 29

 A crossover study compares the results of a two

treatment on the same group of patients

 Crossover designs are generally not used in

vaccine trials because the immune system is
permanently affected (or at least affected for a
long time). Thus, carry over effects are always
present

 Measures the standard deviation of the

difference between two measurements in the
same individual
Cross Over Design 30

Scheme
Period
Group I II
AB 1 TRT A TRT B
Washout
BA 2 TRT B Period TRT A

 Advantage
 Each patient their own control
 Smaller sample size

 Disadvantage
 Not useful for acute disease
 Disease must be stable
 Assumes no period carry over
 If carryover, have a study half sized
(Period I A vs. Period I B)
 Cross-over Design 31

Population Intervention Washout Placebo

Sample Randomization

Placebo Washout Intervention

Outcome Outcome
Run-In Design 32

Problem:

 Non-compliance by patient may seriously impair

efficiency and possibly distort conclusions

Possible Solution: Drug Trials

 Assign all eligible patients a placebo to be taken for a

“brief” period of time. Patients who are “judged”
compliant are enrolled into the study. This is often
referred to as the “Placebo Run-In” period.
 Can also use active drug to test for compliance
 Run-In Design 33

R
A
Screen & Run-In Satisfactory N A
Consent Period D
O
M B
Unsatisfactory I
Z
E
Dropped

Note: It is assumed that all patient entering the run-in

period are eligible and have given consent
Examples of Run-In Trials 34

 Cardiac Arrhythmia Suppression Trial (CAST)

 Diabetes Control and Complications Trial (DCCT)

 Physicians Health Study (PHS)

Cohort Study 35
 A cohort is a group of people who share a common
characteristic or experience within a defined period e.g are
exposed to a drug or a vaccine together

 The comparison group may be the general population from

which the cohort is drawn, or it may be another cohort of
persons thought to have had little or no exposure to the
substance under investigation, but otherwise similar.
Alternatively, subgroups within the cohort may be compared
with each other.

 Cohort studies are expensive to conduct & take a long

follow-up time to generate useful data. Some cohort studies
track groups of children from their birth, and record a wide
range of information (exposures) about them.

 The value of a cohort study depends on the researchers'

capacity to stay in touch with all members of the cohort.
Some of these studies have continued for decades.
Graphical illustration of 36
cohort study
Advantages of cohort study 37

 Study design does not require strict random assignment

of subjects.

 As in the case of smoking vs. non-smoking cohort study,

random assignment is not a feasible or ethical
alternative. (Who wants to be assigned to a smoking
group if he/she is non-smoker?).

 Appealing and useful technique because it is highly

flexible.

 In some instances, a cohort analysis can be less

expensive than experiments or surveys.
Disadvantages of cohort study
38
 To assess whether associations between cohort and dependent
variables derived from the studies are of a causal nature or not.

 Threats to validity: influence of factors over which the investigators

most often do not have full control.

 Because of the lack of randomization in the cohort design, the two

groups may differ in ways other than in the variable under study.

 For e.g., if the subjects who smoke tend to have less money than
the non-smokers, and thus have less access to health care, that
would exaggerate the difference between the two groups.

 Time consuming so tend to change over the course of the study

(People die, move away, or develop other conditions, new and
promising treatments arise, and so on.)
Prospective study 39
 A prospective study is a cohort study that follows over
time a group of similar individuals who differ with
respect to certain factors under study, in order to
determine how these factors affect rates of a certain
outcome.

 For eg, middle-aged truck drivers who vary in terms of

smoking habits, in order to test that after 20-year
incidence rate of lung cancer will be highest among
heavy smokers, followed by moderate smokers, and
then nonsmokers.

 The prospective study is important for research on the

etiology of diseases and disorders in humans.

 It can be more expensive.

Prospective Cohort Study Design 40

The Present The Future

Population

Risk Factor Disease No Disease

No Risk Factor Disease No Disease

Sample
Advantages
 Prospective cohort study data is the longitudinal 41
observation of the individual through time, and the
collection of data at regular intervals, so recall error is
reduced.
 Temporal relationship established
 Multiple outcomes can be studied
 Good choice for rare exposure situation
 Investigator defines and applies outcome criteria

Disadvantages
 Hard to select and maintain a “non-exposed” group
 Loss to follow-up problem for long induction times
 Expensive
 Changes can take place over time in both exposure and
outcome assessment
Retrospective trial 42

 Retrospective means to take a look back at

events that aleready have taken place (like pt’s
medical history)

 Also called a historic cohort study, is a medical

research study in which the medical records of
groups of individuals who are alike in many
ways but differ by a certain characteristic.

 For example, Long-Term Mortality after Gastric

Bypass Surgery
Retrospective Cohort Study 43
Design
The Past
The Present

Population

Risk Factor Disease No Disease

No Risk Factor Disease No Disease

Sample
 44
Advantages of Retrospective Study

 Inexpensive
 Uses existing records
 Allows study of rare occurrences
 Easier to assess conditions where there is a
long latency between exposure and disease
 Can generate hypothesis that is then tested
prospectively (quality improvement initiatives)
 45
Disadvantages of Retrospective Study

 Relies on accuracy of written record or recall of

individuals
 Important data may not be available
 Difficult to control bias and confounders: no
randomization, no blinding
 May be impossible to access important
information (restricted by statute or institutional
regulations)
 Difficult to establish cause and effect
 Results are, at best, hypothesis-generating
Replicate design 46

 The experiment should be repeated more than once,

thus each T/t is many experimental units instead of
one.

 Typically four-period design

Each product administered twice Period Period Period Period
1 2 3 4

 Intra-subject variability
Sequence T R R T
1
 Different approaches possible Sequence R T T R
 Average bioequivalence 2
 Individual bioequivalence Sequence T T R R
3
Sequence R R T T
4
 47

Advantages
 More information available
 Different approaches to assessment possible

Disadvantages
 Biggercommitment for volunteers
 More administrations to healthy volunteers
 More expensive to conduct
Factorial design 48
 Designs which include multiple independent variables are
known as factorial designs.

 If we were looking at GENDER and ,TIME OF EXAM, these

would be two independent factors
 GENDER would only have two levels: male or female
 TIME OF EXAM might have multiple levels, e.g. morning,
noon or night

 Depends on three pieces of information:

 The number of independent variables
 The number of levels of each independent variable
 The kind of independent variable
 Between Groups
 Within Subjects (or Repeated Measures)
 If there is only one independent variable then
49
 The design is a one-way design (e.g. does coffee drinking influence
exam scores)

 If there are two independent variables

 The design is a two-way design (e.g. does time of day or coffee
drinking influence exam scores).

 If there are three independent variables

 The design is a three-way design (e.g. does time of day, coffee drinking
or age influence exam scores).

E.g.: When patients are being treated with a combination of drugs, as is

current practice for HIV infection, a new drug may be evaluated by
testing it in combination with other drugs rather than by itself. A
factorial design trial may be used for this purpose. A simple factorial
design would have one group testing therapy A, another testing
therapy B, a third group testing A and B combined, and a control
group testing neither A nor B.
 Factorial Design 50

Int A and Int B Outcome

Population
Int A and Pbo B Outcome

Sample
Pbo A and Int B Outcome

Pbo A and Pbo B Outcome

Advantages 51
 A greater precision can be obtained in estimating the
overall main factor effects.
 Interaction between different factors can be explored.
 Additional factors can help to extend validity of
conclusions derived.
 Factorial designs are considered an efficient way to test
medicines in combination, but their results are not
always easy to interpret.

Disadvantages
 Experimental error like replicated
 Lesser attractive
 More subjects
 More expensive
 Other Types of trial 52

 Superiority trials are designed to demonstrate that one treatment is

more effective than another.

 Non-inferiority trials are designed to demonstrate that a treatment

is at least not appreciably worse than another.
 Would have beaten placebo if a placebo arm had been included
(regulatory)
 The question is whether new (easier or cheaper) treatment is as
good as the current treatment

 Equivalence trials are designed to demonstrate that one treatment is

as effective as another by more than some margin

 A longitudinal study research subjects over two or more points in

time; by contrast, while a cross-sectional study assesses research
subjects at one point in time.
53