Transcript Study design

臨床試驗
Study design (I)
病人族群、研究設計(一)
2015-3-4
簡國龍老師 [email protected]
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In a randomized trial, the investigator (a) selects a sample from population, (b) measures baseline
variables, (c) randomizes the participants, (d) applies interventions (one should be a blinded
placebo, if possible), (e) follows up the cohort, (f) measures outcome variables (blindly, if
possible)and analyzes the results.
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Experimental vs. observational
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Strength:
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Causality inference
Weakness:
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Expensive
Time-consuming
Address a narrow clinical question
Expose patients to potential harm
Not every question is amenable to clinical trial design
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Clinical trial
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Protocol
Selecting the participants
Measuring baseline variables
Randomizing
Applying the interventions
Follow-up and adherence to the protocol
Measuring the outcome
Analyzing the results
Monitoring clinical trials
Alternatives to the randomized blinded trial
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Principles in clinical trial design
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Randomly assigned
Double blinding
Placebo-controlled
Guideline for procedures
Endpoints
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Primary
 Secondary
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Outline
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Phases of clinical trial
Issues in clinical trial design
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Selection of patients, controls
Randomization
Blinding
Types of designs
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Stages in Testing New Therapies
Preclinical
Studies in Cell Culture and Animals
Phase I
Unblended, uncontrolled studies in a few volunteers
to test safety
Phase II
Relatively small randomized, controlled, blinded trials
to test tolerability and different intensity or dose of the
intervention on surrogate outcomes
Relatively large randomized, controlled, blinded trials
to test the effect of the therapy on clinical outcomes
Phase III
Phase IV
Large trials or observational studies conducted after
the therapy has been approved by the FDA to assess
the rate of serious side effects and evaluate
additional therapeutic uses
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Phases of clinical trial
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Phase I: initial introduction of new drug to humans
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Phase II: first controlled
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Determine metabolic and pharmacologic activities and side
effects in human & PK and PD effects for Phase II
Effectiveness based on clinical endpoints, dosing ranges
IIA: dosing evaluation
IIB: effectiveness
Phase III: expanded
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Effectiveness and safety, adequate basis for labeling
 IIIB: after submission before approval
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Phases of clinical trial
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Phase IV: after approval for marketing
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Adverse reactions, morbidity or mortality, children population,
marked-oriented comparison studies against competitor
products
Phase V: new indications and/or new formulations or
dosage forms
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Issues in study design
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Selection of patients
Selection of controls
Statistical considerations
Randomization
Blinding
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Principles of validity in comparison
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Validity of comparison between the treatment group
and control group
Comparability of population
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Comparability of information
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Are the baseline characteristics of the two groups comparable?
Are the information obtained from the two groups comparable?
Comparability of effects (e.g. placebo, sham
procedures)
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Are the non-therapeutic effects of the treatments comparable?
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Selection of patients
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Representative samples
Define the intended patient population
Select homogeneous as possible
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Patient characteristics and disease severity
Eligibility criteria
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Inclusion
 Exclusion
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Patient selection process
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Single vs. multicenter
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Which site better?
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Individual investigator’s qualification and experience for
disease
Feasibility of the investigator’s site for conducting the
proposal trial
Dedication, education, training, and experience of the
personnel at the site
Availability of certain equipments
Geographic location
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Within the site center, which patients?
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Initial guess of how many patients will meet the eligibility
criteria
Screening based on diagnostic criteria
Patient’s disease change
Concurrent diseases/medications
Psychological factors
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Fear of toxicity
Informed consent
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Selection of controls
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Well-controlled, comparative
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Concurrent control
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Patient characteristics between treatment groups are homogeneous
Placebo concurrent control: placebo effect
Dose-comparison concurrent control: phase II
Active treatment concurrent control: ethical
No treatment concurrent control: available effectiveness & a very short
period of time & negligible placebo effect
Historical control
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High and predictable mortality or self-evident effect
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Table 3.3.3 Conditions for the Ethical Inclusion of a Placebo Concurrent Control
(from Chou & Liu, 1998 )
1. No Standard treatment exists.
2. Standard treatment is ineffective or unproved to be effective.
3. Standard treatment is appropriate for the particular clinical trials.
4. The placebo has been reported to be relatively effective in treating the disease or condition.
5. The disease is mild and lack of treatment is not considered to be medically important.
6. The placebo is given as an add-on treatment to an already existing regimen that is not sufficient to treat patients.
7. Allowing concomitant medicine is one measure of efficacy in these clinical trials.
8. The disease process is characterized by frequent spontaneous exacerbations and remission (e.g., peptic ulcer).
9. “Escape clauses” or points are designed into the protocol.
Source: Spiller (1991).
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Selection of participants
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Entry criteria defining a target population
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Inclusion criteria
 Exclusion criteria
 Optimize
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Rate of primary outcome
Expected effectiveness of the active treatment
Generalizability of findings
Easy of recruitment
Compliance with treatment and follow-up
High risk group
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Strength
Weakness
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Statistical considerations
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Primary and secondary response variables
Criteria for efficacy and safety assessment
Sample size estimation
Interim analysis and data monitoring
Statistical and clinical inference
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Endpoints:
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Response variables: validated
Efficacy assessment: intention to treat, subgroup
analysis (?)
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Parameters to be measured, timing and frequency, normal
values for laboratory, definition of test abnormalities
Safety analysis: at least one dose of treatment
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Incidence of adverse effect
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Sample size estimation
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What design to be used?
What hypotheses are to be tested?
What statistic is to be performed?
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Issues in interim analysis and data
monitoring
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Protection of the overall type I error rate informal
confirmatory clinical trials designed to establish efficacy
Safeguarding of the blinding of a study
Use of interim analyses for administrative or planning
purposes to generate hypotheses for further studies or to
assess safety
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Who will have access to the randomization code?
How the blinding will be broken?
Who will have access to the interim results?
Whether ongoing patients will be included in the analysis?
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Statistical and clinical inference
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Statistical inference as only a part of induction process
Internal validity
External validity: from sample to population
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Age range, childbearing women
Bioequivalence trials: limited validity
Different investigators at different study centers in
different countries
Meta analysis(?)
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Single site versus multi-sites
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Treatment-by-center interaction in more centers
A central laboratory for appropriate and consistent
measures
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Treatment duration
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Typical phases:
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Placebo run-in phase
 Active treatment period
 Follow-up or maintenance phase
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Compliance & missing
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Patient compliance: 20-80%
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Medication event monitor system
 Poor compliance (dose) vs. poor adherence (time)
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Missing value and dropout
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Assumption of missing mechanism
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Randomization and blinding
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Avoid subjective assignment
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1960s gastric freezing
Avoid bias
Random selection of a representative sample from a
targeted patient population
Random assignment of patients in order to study the
medicines
Blinding: open label, single, double and triple blinding
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Randomizing, randomization
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Rationale
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Do a good job of random assignment
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Basis for testing the statistical significance of differences between these
groups in the measured outcome
Mal-distribution effect due to chance
Table of random numbers
Set up a separate randomization facility
Consider special randomization techniques
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Blocked randomization
Stratified blocked randomization
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Randomization models
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Population model
Invoked population model
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Randomization model
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As if a formal sampling procedure performed
Permutation test: nonparametric, Wilcoxin rank sum test
Stratification
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Variability between-strata and within-strata
 Matching, cross-over
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Methods of randomization (1)
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Simple, complete randomization
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Completely binomial design
 Balance?
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Random allocation
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Equal allocation of sample size, restricted
 Randomly select the N/2 out of N without replacement
 Proc PLAN
 Accidental bias
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Methods of randomization (2)
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Permuted-block randomization
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Imbalance in size and covariate
 Time-heterogeneous population
 Block size of 4, six possible permutations
 SAS procedure PLAN
 Stratified randomization
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Adaptive randomization
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Based on previous patient assignment
Treatment, covariates, clinical response
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Table 4.3.1 Unacceptable Methods of Assignment of Patients to Treatment
1. Assignment of patients to treatment according to the order of enrollment,
(every other patient is assigned to one group)
2. Assignment of patients of treatment according to patient’s initial.
3. Assignment of patients of treatment according to patient’s birthday
4. Assignment of patients according to the dates of enrollment
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Response adaptive randomization
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Randomized play-the-winner (RPW) rule
Suitable conditions:
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There is a single outcome or hypothesis of interest
 Outcomes are ascertainable in a short period of time
 The study has important public health consequences, but the diseases
are not life-threatening
 The study has an adequate sample size and the composition of the
sample is not likely to change over time
 The participants in the study have the resources to logistically
implement the randomization procedure
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Limitations: complex outcomes, multiple visits
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Implementation of randomization
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Standard operating procedure, SOP
Appropriate method of randomization and related logistic
issues for implementation
Quality assurance (QA) procedures
Laboratory evaluation
Central administrative telephone-based assignment
system
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Generalization of controlled randomized trials
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Internally vs. externally
Efficacy or safety
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Population vs. individual
Average efficacy versus. Variability of efficacy
Individual efficacy: N-of-1 randomized trial
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Theophylline efficacy, N pairs
Patient-by-treatment interaction
Limitation: short time, hard endpoint or irreversible
Guyatt G, et al. Determining optimal therapy—Randomized trials in
individuals patients. New Engl J Med 1986;314:889-92
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Blinding
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Various groups of individuals involved with the trial are
withheld from the knowledge of treatments
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Patient, study center or investigator (two teams), sponsor
Masking
4 types
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Types of blinding
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Open-label
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Single-blind
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All of health care personnel
Triple-blind
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Patient unaware of his/her assignment
Double-blind
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Ethical: phase I dose-escalating studies in oncology, pre-marketing,
post-marketing surveillance
Highest degree for the validity
Maintain the blindness throughout the entire course
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Matched placebo, identical container
Multiple-placebo, double dummy
To ask both to guess
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Design types of clinical trial
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Parallel designs
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Parallel-group designs
 Matched pairs parallel designs
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Cross-over designs
Titration designs
Enriched designs
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Parallel designs
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Simple, universally accepted, applicable to acute
conditions
Matched
Run-in period
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Establish comparability
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R
Patients
U
N
I
N
R
A
N
D
O
M
IZ
A
TI
O
N
Test
Control A
Control B
Figure 5.2.1 Parallel-group design
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Crossover designs
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p x q: p sequences of treatment in q different time
periods
Benefits:
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Within-patient comparison between treatment
 Remove inter-patient variability
 Best unbiased estimates
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Washout period: carryover effects
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Cross-over design (vs. parallel design)
treatment
treatment
Group I
A
(wash-out period )
B
Group II
B
(wash-out period )
A (Three or more groups are possible)
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Advantages of cross-over design
 Minimize confounding, -Smaller number of patients required
Disadvantages of cross-over design
 Potential carry-over effects (depends on the pharmocokinetics of drugs)
 Underlying disease process has to be stable (i.e. not applicable to all diseases)
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Suitable situations for cross-over
designs
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Objective measures and interpretable data
Chronic and relatively stable disease
Prophylactic drugs with short half-life
Short treatment periods
Baseline and washout periods are feasible
Adequate number of patients to allow carryover effect
and expected dropouts
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Patients
RA
N
D
O
MI
ZA
TI
O
N
Period
I
Sequence 1
Test
Sequence 2
Control
II
W
AS
H
O
UT
Control
Test
Figure 5.3.1 Standard two-sequence, two-period crossover design.
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Higher-order crossover designs
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Handle carryover effects and intra-subject variability
Extended-period design
Replicated design: doubled standard 2x2
Williams designs
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More than two treatments
 Variance-balanced designs
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Balanced incomplete block designs
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Patients
R
A
N
D
O
M
IZ
A
TI
O
N
Period
II
I
Sequence 1 Test
Sequence 2 Control
W
AS
H
O
UT
III
W
AS
H
O
UT
Control
Test
Control
Test
Figure 5.3.2 Two-sequence dual crossover design.
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Table 5.3.1 Higher-Order Crossover Designs
I. Balaam’s design
AA
BB
AB
BA
II. Two-sequence dual design
ABB
BAA
III. Doubled (replicated) design
AABB
BBAA
IV. Four-sequence design
AABB
BBAA
ABBA
BAAB
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Table 5.3.2 Williams Designs
I. Williams’s design with three treatments
ACB
BAC
CBA
BCA
CAB
ABC
II. Williams’s design with four treatments
ADBC
BACD
CBDA
DCAB
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Table 5.3.3 Balance Incomplete Block Designs
I. Four treatments with two periods
AB
BC
CD
AC
BD
DB
CA
AD
DC
CB
BA
II. Four treatments with three periods
BCD
CDA
DAB
ABC
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Examples of crossover design
Study
Purpose
Sample Size
Chan et al.
(1993)
Effects on lipids
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Nagi and
Yudkin
(1993)
Effects on
lipids and
risk factors for
cardiovascular
disease
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Elkeles
(1991)
Effects of lipids
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Duration
(Period 1 +
Washout +
Period 2)
4 wk + 0 wk + 4 wk
12 wk + 2 wk + 12 wk
3 mo + 6 wk + 3 mo
Primary
Endpoint
Metabolic and
Hemodynamic
index
Insulin resistance
Glycemic control
Cardiovascular risk
Serum lipids
Lipoproteins Blood
glucose Glycosylated
hemoglobin
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Titration designs
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Phase I safety and tolerance studies
Maximum tolerable dose, MTD
Pre-specified proportion: 1/3
Up-and-down design
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Enrichment designs


To identify the patients is likely to be beneficial, specific
population
Two phases

Enrichment phase: open-label with a titration design to class
patients into groups
 Randomize and double-blind phase
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Examples: best dose
Screening process further to a small selective group
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Further topics in clinical trial designs

Multi-center trial
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Active control trial
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Treatment-by-center interaction
Primary objectives
Combination trial

Fixed-combination prescription drugs
 Multi-level factorial design
 Global superiority of combination drug
 Method of response surface
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Equivalence trial
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(a) No Interaction
treatment A
treatment B
1
Center
2
(b) Quantitative Interaction
treatment A
treatment A
treatment B
Center
treatment B
Center
(c) Quantitative Interaction
treatment A
treatment B
Center
Figure 6.2.1 Treatment-by-center interaction.
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Figure 6.2.3 Mean seated diastolic blood pressures versus study site.
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Summary: randomized, double-blind,
controlled trials
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Treatment group and control group
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Randomization

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Concurrent controls, Self controls, Historical controls, and
Literature controls
Assignment of treatment through a random process
Blinding/ masked

Both the patient and outcomes assessor do not know the
treatment assignment
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Shein-Chung Chow & Jen-Pei Liu
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In a randomized trial,
the investigator (a)
selects a …
<Design and Analysis of Clinical Trials: Concepts and Methodologies> 3rd. Edition, p.15-16 /
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Wiley, October 2013http://as.wiley.com/WileyCDA/WileyTitle/productCd-0470887656.html
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<Design and Analysis of Clinical Trials: Concepts and Methodologies> 3rd. Edition, p.90 /
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Validity of comparison
between the treatment
group and control
group….Well-controlled,
comparative
<Design and Analysis of Clinical Trials: Concepts and Methodologies> 3rd. Edition, p.94-97 /
Shein-Chung Chow & Jen-Pei Liu
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Simple, complete
randomization…
Permuted-block
randomization
<Design and Analysis of Clinical Trials: Concepts and Methodologies> 3rd. Edition, p.124126 / Shein-Chung Chow & Jen-Pei Liu
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<Design and Analysis of Clinical Trials: Concepts and Methodologies> 3rd. Edition, p.124 /
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<Design and Analysis of Clinical Trials: Concepts and Methodologies> 3rd. Edition, p.140 /
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<Design and Analysis of Clinical Trials: Concepts and Methodologies> 3rd. Edition, p.180 /
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Shein-Chung Chow & Jen-Pei Liu
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Shein-Chung Chow & Jen-Pei Liu
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<Controlled Clinical Trials> 23卷 <The method of minimization for allocation to clinical
trials. a review>
Scott NW1, McPherson GC, Ramsay CR, Campbell MK.
Control Clin Trials. (2002), p.662-674
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<Controlled Clinical Trials> 23卷 <The method of minimization for allocation to clinical
trials. a review>
Scott NW1, McPherson GC, Ramsay CR, Campbell MK.
Control Clin Trials.(2002), p.662-674
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