CLINICAL TRIAL DESIGN

Sugato Banerjee PhD

banerjeesugato1@gmail.com
 Why conduct a clinical trial

• A clinical trial is a tool for testing a drug, device, or technique

Aim:
• To answer a clinical problem
• To gain new knowledge about a new or established treatment
• To support a “claim”
• for gaining government regulatory approval
• for marketing a drug, device, or technique
 Randomized clinical trial (parallel design)

Intervention 1 Outcome A

Sample
P
Intervention 2 Outcome B
Population

Then compare outcomes A and B (example reduction in triglyceride levels by

Drug X)
 Standard parallel trial design

Advantages:
-Simple as single treatment is given to each group
-Fixed number of patients involved
Appropriate design for studies when
-Treatment is curative
-Duration of treatment is long
-A large number of treatments arms for only one outcome to be
compared
-Number of subjects available for trial are unlimited
 Types of randomized trial designs
• Factorial: Study that tests 2 or more treatments/
interventions/research questions in a single study
• Trial designed to detect an interaction
Treatment A

Treatment B

Sample
P Treatment A+B

No treatment
Population
 • Requirements and advantages of factorial design
-Treatment can be administered without changing dose
-Treatments should have different mechanism of action
-Allows one to determine if there is any interaction between the treatments
-If interactions exist we must be interested in treatment combinations
-Efficient way to answer more than one question in a population of interest
2 disease conditions may be studied in a single study

Beta-carotene No Beta-carotene
Aspirin + beta-carotene Aspirin
Aspirin
Infarction
No Aspirin Beta-carotene

Cancer
Factorial design with 2 different end points
Physicians health study (NEJM 1989)
 Parallel vs factorial design
• Standard design gives one estimate of each intervention. Thus
in comparing two active drugs and one placebo group the
design yields two estimates for 3 treatment assignments.

• Factorial design is more effective as it gives two estimates for

each treatment assignment thus 4 estimates for 4 treatment
groups and also helps us determine any interactions.
 Time series trial

PSample Treatment No treatment Treatment

Population Measure Measure Measure Measure

outcome outcome outcome outcome

In a time series trial outcome is measured before and after each participant
receives the intervention.
Advantage
Thus each participant serves as its own control.
Hence confounding variables like age, gender, race are completely eliminated.

Problems: Learning effect (in cognitive functional studies), carryover effect

(below detection level), random changes (which cannot be determined due to
the absence of control groups) and secular trends (upper respiratory infections
may reduce during follow up as the study started during the flu season, thus this
problem is due to long duration of study)
 Simple crossover design
Treatment A Treatment B

Treatment B Treatment A

Placebo Washout Treatment

Sample
P
Treatment Washout Placebo
Population
Measure Measure Measure Measure
outcome outcome outcome outcome
Parallel design: compares between patient differences
Cross over design: compares within patient differences
Advantages:
Increased efficiency since half the patients are needed
Less variance since within patients compared
Enhanced recruitment (no separate placebo arm)

Disadvantages:
Doubling of study duration
Carryover effect (residual effect of intervention even after
washout)
So may only be used for drugs with fast action and short
half life which gets eliminated fast and only when number of
participants are limited (in case of rare diseases).
 Adaptive design
• Earlier go/no go design: few patients exposed to drug, cost
effective
• Sequential dosing groups
• Terminating some dose groups early based on interim safety
and efficacy; altering randomization ratios to increase
precision in determining the effective dose.

Drop inferior arms

Randomization with Observe and Response adaptive
or stop trial or
(5 initial arms) predict response randomization
adjust sample size
(surrogate markers)
(Might be left with
just 2 arms which
goes to phase 3)
 Pilot clinical trial
• To acquire the right dose, duration of action, potential
adverse effects and feasibility of recruiting, randomizing and
maintaining participants in the trial usually a pilot study is
conducted.
• It helps to determine the feasibility, time required and cost of
recruiting adequate number of eligible participants for study,
if they are willing to accept randomization and can comply
with the intervention.
• Another important reason to perform pilot study is to
determine the sample size based on effect size (outcome) and
statistical variability of the outcome.
• A good pilot trial makes it more likely that the actual trial will
be successful.
 Stages of Clinical trial
• Preclinical: Studies in cell culture and animals
• Phase I: Unblinded, uncontrolled studies in a few volunteers
to test safety with single or multiple doses (20-80 volunteers)
• Phase II: Relatively small randomized blinded trials to test
tolerability and different intensity or dose of the intervention
on the surrogate or clinical outcomes (100-300 patients)
• Phase III: Relatively large randomized blinded trials to test the
effect of the therapy on the clinical outcome on a larger
cohort. (more than 1000 patients)
• Phase IV (post marketing surveillance): Large trials or
observational studies conducted after the therapy has been
approved to assess the rate of serious side effects and
evaluate additional therapeutic uses
 Phase I

 Determine maximum tolerated dose (MTD)

 Characterization of pharmacokinetics (ADME)
a) Single dose escalation study (single dose given to a group
and if they don’t show adverse effects dose is escalated in
the next group of participants)
b) Multiple dose escalation study (multiple small doses given to
group of people. If they don’t show adverse effects doses
are escalated in the next group of participants)
 Determine if there is any food effects
 Subject group usually normal
 No control group
 Pharmacokinetic parameters: AUC (area under the plasma
concentration time curve) Half life, Tmax, Cmax
 Determine pharmacological proof assuming there is a
Biomarker-a characteristics that is measured and evaluated as a measure of
normal biological function, pathogenic process or pharmacological
response to a therapeutic intervention. Earlier assessment of efficacy,
determine best earlier in the process (cost-effective), quicker feedback to
discovery, better dose selection by use of biomarker in PK/PD models.
Surrogate end point: A biomarker accepted by regulatory agencies as a
substitute for clinical end point. Like increased bone density (arthritis) or
decreased cholesterol (lipid profile studies) or decreased viral load (HIV
studies)
Clinical end point: A characteristics or variable that determines how the
patient feels, functions or survives. example reduced fracture rate,
decreased coronary artery disease or increased survival
 Selection of dose range and regimen for Phase 2A studies
 Phase II

Phase 2A:
• Intervention studied in patients with disease
• Proof of concept (how well the drug works)
• Define dose and concentration response for Biomarker activity/ efficacy
• Continues to monitor toxicity to larger number of patients (MTD).
• Early go/no go decision trials (if this phase does not work trial may be
stopped)
Phase 2B:
• Confirm evidence of efficacy
• Understand PK/PD relationships (pharmacokinetic and
pharmacodynamic)
• Understand totality of the data (including safety)
• Validate end points.
Phase III
• Intended to gather additional information to evaluate the
overall benefit-risk relationship of the drug on larger patient
population
• Randomization, double blinding, multicenter
• Drug-drug interaction
• Bioequivalence study- Comparing the safety and efficacy of
the new drug with an established/drug of choice.
• Dose proportionality study comparing with established/drug
of choice
• Pharmacokinetics and safety studies on special population.
example: renal impairment, elderly, pediatrics
Phase IV
Post approval activities
New clinical indications monitored
New dosage forms and formulations may be explored
• Randomization of matched pairs: Match pairs on age,
gender disease severity and then randomized to intervention.
• Can also be applied within an individual
One arm, eye, or foot receives one treatment , the other
receives the other treatment
Disadvantage: Relevant factors to be matched not always known
before initiation of the study
• Group/cluster randomization: Assign groups or clusters
of participants to an intervention instead of assigning
individually.
Example: Assign players randomly from 120 college football
teams (not all the students from these colleges) for an anti-
spit tobacco study. So half of the players were given some
intervention to stop taking spit-tobacco. Then the whole
group (players receiving intervention+ players who did not
receive intervention) is studied to see if the intervention
group had significantly lower tobacco use.