clinical trial design
TRANSCRIPT
Clinical Trials Design Dr Ritu Budania JR 2 Department of Pharmacology GMC Nagpur
Overview•Introduction
• Clinical Trial Designs
•Challenges
•Application in different phases of trial
•Summary
Clinical Research
All scientific approaches to evaluate medical disease in terms
Prevention Diagnosis Treatment
Humans
Clinical research design
No intervention Intervention
Observational Experimental
Comparison group
NoYes
Analytical study (case control,
cohort)
Descriptive study
Random allocation
Yes No
Randomized controlled trial
Non-Randomised
Types of Clinical trials
Treatment trials
Prevention trials
Quality of life trials
Diagnostic trials
Drug development
Clinical Trial Designs
Designs
Parallel Cross over Factorial Randomized withdrawal approach Adaptive Superiority Non-inferiority
Parallel
• Subjects are randomised to one of two or more arms
• Each arm being allocated a different treatment
• Most commonly used design
Eligibilty assessed
Consent
Control
Test drug
Randomised
Controls in Clinical Trials
1. Placebo
2.No-treatment
3.Active
4. Dose Response
5. External Controls
5 mg
1. Placebo Control• Placebo- inert substance – looks exactly
like test drug but contains no drug
• In trials testing efficacy
• Double blinded
Advantages of Placebo control
• Minimizes bias
• Ability to demonstrate efficacy
When to use placebo?1.In disease in which no prior drug has been
established as - standard therapy2. Minimal risk, short term study3.Add-on design
Disadvantages of Placebo Control: 1.Ethical Issues - Lack of treatment -Serious harm( such as
death or irreversible morbidity) -Declaration of Helsinki – use of standard
treatment as control -Used where minimal risk
2.Patient and physician concerns:-Patients may not enroll-Withdraw
2. No treatment control
• Subjects are randomly assigned to test treatment or to no treatment
• Subjects, investigators are not blind to treatment
• Bias
3.Active control Standard treatment exists
phase III study designs compare “new drug” to standard or compare standard to combination therapy that
involves the standard + “new drug”
• 4.Dose response control• 5.External control
Comparability ?Baseline characteristics?No randomization, blindingBias
Uncontrolled trials
• No controls• When-- Determine pharmacokinetic properties of a
new drug (phase 1 trial)• Limitation- Bias , as no randomization, less
validity than RCT
Run-In Design
• Non-compliance
Run-In Design
Screen & Consent
Placebo Run-In Period
RANDOMIZECompliance Unsatisfactory
Dropped
B
A complianceSatisfactory c
2.Cross over
• Each patient gets both drugs• the order in which the patient gets each drug is randomized• Each patient serves as his own control• Avoids between participant variation in estimating
intervention effect • Requires a small sample size • Assumptions: –The effects of intervention during first period does not carry
over into second period. –Internal and external factors are constant over time
A A
B B
A followed by BB followed by A
ABABAB
ABABBABA
Cross over design with switch-back
C.O. design with double switch-back
Run in
Wash out period
Prerequisites for crossover design
• Disease – chronic (asthma, osteoarthritis) stable
• Effects of drug should develop fully within treatment period (not for Hit and run type drugs)
• Washout periods -sufficiently long for complete reversibility of drug effect
• Wash out period- five half lives of drug
Crossover designs- problems
1.Carryover effect 2.Period effect- patients vary from 1 period to another3.Not useful for acute disease4.Difficulties in assigning adverse events which occur in later
treatment periods to appropriate treatment 5.generally not used in vaccine trials because immune
system is permanently affected (or at least affected for a long time)
Use of cross over design:
• Bioequivalence studies• Phase I
Parallel Crossover
Groups assigned different treatments
Each patient receives both treatments
Shorter duration Longer
Sample size- large Smaller
No carryover effect Carryover effect
Acute cases Not in acute, Chronic,stable
Latin Square Design
A B C
B C A C A B
I II III
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Subjects
Period
Greco-Latin Squares
Effect of treatment & effect of another factor (eg. ancillary Treatment, diet etc)
A B C B C A C A B
I II III
1
2
3
Subjects
Intensive Design: Comparing 2 Tts.(A & B) each subject receives same Tt. several times.
Period I II III IV V VI
Treatment A B B A A B
- For short period of Rx/single dose- For testing efficacy of new compound
3.Factorial design
- two or more interventions- Allows study of interactive effects
2×2 factorial design
B only Neither A nor B
A onlyBoth A and B
Advantages-Two drugs studied at same time-Discover interactions-Test FDC
Disadvantages1.Complexity of trial design2. Complexity of statistical analysis
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Incomplete Factorial DesignEg. depression; if unethical to
do nothing
• A – Desipramine• B – Congnitive therapy• C – Combination of A & B
3 n eligible
A no, B yes
A yes, B no
A yes, B yes
4.Randomized withdrawal approach
Third, the design is particularly useful in determining how long a therapy should be continued (e.g., post-infarction treatments with a beta-blocker
Group 1 Group II
Pt Sex Age IQ Pt Sex Age IQ 1. m 25 95 4 m 25 95 2. f 35 100 5 f 35 100 3. m 45 105 6 m 45 105
5. Matched pairs - Pts. With same characteristics - Expected to respond similarly
Group characteristics
2 males 1 female 2 males 1 female Average age 35 yrs. 35 yrs.Average IQ 100 100 Pt 1. matches with Pt 4
2. 5״ ״ ״
3. 6״ ״ ״ Advantage- Less Variability
Group -I Group-II
Clinical trial design innovations
• Adaptive Design- allows adaptations or modifications to trial
design after its initiation without undermining validity and integrity of trial
1.Maximum Information Design
• interim analyses until the target or maximum information level reached.
• Whenever the pre-specified target information level is reached, the patient recruitment is stopped.
2.N-Adjustable Design
3. Group sequential design
prematurely terminating trial based on the results of interim analyses
• Early-efficacy stopping• Early futility stopping
(4) Drop-Losers Design
- allows dropping of treatment arm(s) during study based on interim analysis results
-trial starts with several treatment groups; at each stage, interim analyses are performed
- losers (inferior groups) are dropped based on prespecified criteria.
-best arm(s) will be retained. -used in a phase-II/III combined trial
5.Adaptive Randomization Design
• Response-adaptive randomization (RAR) -allocation probability is based on response of previous patients.
• The purpose is to provide the patients with a better chance of being assigned to the better/best treatment
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Superiority Trials
Show that new treatment is better than control or standard (maybe a placebo)
• Examples:Placebo-controlled efficacy trials
Active controlled
Non-Inferiority Trials
-Show that new treatmentIs not worse that the standard by more than
some margin-Active control equivalence trial -Placebo not used-Better tolerated, less dosing
X is non inferior
Placebo Active ControlDELTA
Multicentric trials
1. Large sample size needed- in less time2. Availability of eligible patients is a constraint3. Role of Racial/ Ethnic factors to be studied
• Strict protocol compliance by Investigators at all centres
• Central monitoring committee• Phase III trials
Challenges in Design:
Control of bias (Randomization, Blinding )
Bias
Prejudice Deviation from truth Selection/Allocation bias Observer bias
Good study design - minimizing all possible sources of bias
Randomization
-Assigns patients to treatment arms by chance-Eliminates selection bias
Pseudo randomization
Randomization methods
1. Simple randomization
2. Block Randomization
3. Stratified Randomization ( age, gender, stage, severity)
Tossing coin Dice
Random number table Computer generated
Randomized controlled trials
• Gold standard• Minimize bias• Costly, time consuming
Allocation Concealment
• Preventing next assignment in clinical trial from being known
• procedure for protecting randomization process so that treatment to be allocated is not known before the patient is entered into the study
Methods of Allocation concealement
• Sequentially numbered, opaque, sealed envelopes,
• Pharmacy-controlled allocations • Coded identical containers or kits • Central randomisation systems
Blinding
• ensuring that neither patients, healthcare providers, nor researchers know to which group specific patients are assigned
Reasons for blinding-Patients on active treatment - adhere Placebo- do not adhere - Observer’s bias- Principal investigator-more vigorously examine active group
Blinding types
• Open label• Single blind• Double blind• Triple blind • PROBE (Prospective Randomized Open with
Blinded End point Assessment)
No standard definitionShould be specified who is blinded and how
Double dummy technique
Randomise
Placebo
Placebo
Blinding not possible when
• Surgery with non–surgical treatment• Types of dialysis [hemodialysis versus
peritoneal dialysis]
Application of various designs in phases of clinical trial
Phase I (Human Pharmacology)Aims:
– To find safe dose range – Pharmacokinetics of drug– Drug food interaction– First in man study
Sample:• Healthy volunteers • Drug -too toxic (cancer, HIV): patients Sample size- 20-50
Phase I contd
Design Open label Non-randomized Dose escalation Uncontrolled
Randomized 2 way crossover study of one dose level of drug under fasting and fed conditions
6004/11/2023
Phase II (Therapeutic exploratory) IIa IIb
II a- Proof of conceptSample – PatientsSample size- 40-100 subjectsPlacebo control preferrednot- multi centered
Phase II b- Dose range finding• To find optimal dose response range• 300-400 patients• Placebo/ active control• Multicentric
Phase III
Confirmatory trials- confirm drug is safe and effective• Sample- 1000-3000 patients• Active controlled• Randomized• Double blinded• Parallel• Non-inferiority• Multicentric
Phase IV
Post- marketing surveillance• Detect long term ,rare side effects• Pharmacoeconomics• New indication
UncontrolledObservationalNew drug status-
4 years
Bioequivalence studies
• For generic drug submission• ANDA- Abbreviated new drug application• RLD- Reference listed drug• Parallel-Group Design •Even number of subjects in two groups •Each receive a different formulation
Single dose,two way crossover
fasting
Single dose,two way crossover
fed
Single dose parallel fasting
Multiple dose, crossover fasting
Microdosing (Phase 0)
• Candidate drugs fail- suboptimal human pharmacokinetics
• FDA- 100 mcg drug or < 1/100 th of pharmacological dose
determined from animal models• LCMS
Hierarchy of EvidenceRCT
Open label,Cohort studies
Case control studies
Case series
Case reports
SummarySuccess of clinical trial- appropriate clinical
design, control group
RCT – gold standard
Blinding, randomization- minimize bias
References
1.ICH E8 ,9,10 Guidelines : General consideration for clinical trials, Current Step 4 version, 1997
2. Lawrence J. Appel. Primer on the Design, Conduct, and Interpretation of Clinical Trials. Clin J Am Soc Nephrol 1: 1360–1367, 2006
3.Shein-Chung Chow and Mark Chang. Adaptive design methods in clinical trials – a review .Orphanet Journal of Rare Diseases 2008, 3:11
4.Kenneth F Schulz, David A Grimes. Blinding in randomised trials: hiding who got what. THE LANCET 2002 ,359:2
5.New Movement in Drug Development Technology – Micro-dosing and its challenges, QUARTERL REVIEW No.40 / July 2011
6.Thereasa A , Clinical pharmacology ; Goodman and Gilmans, Pharmacological basis of therapeutics; 12;1731-50; 2010.
7.HL Sharma and KK Sharma, Clinical pharmacology , Principles of Pharmacology;2;871-91;2010