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© Copyright 2015 Quintiles
Pharmacokinetic / pharmacodynamic modeling and
simulation in the design and analysis of Randomized
Concentration-Controlled Trials (RCCTs)N. Seth Berry, PharmD
Senior Scientific Advisor
Quantitative Decision Strategies & Analytics
2
• The Causal Chain in Clinical Pharmacology
• What is a Randomized Concentration-Controlled Trial (RCCT)?
› How does it differ from a fixed-dose, randomized dose-response controlled trial
(RDCT)?
› What is the difference between Concentration-Response (C-R) and Dose-Response
(D-R) analyses?
• What impact does PK variability have on response?
› High vs. Low PK variability
› Minimizing Confounding Overlap
• What is the role of a RCCT in a Drug Development Program?
Overview
3
Carl Peck, MDThe Champion of the Randomized Concentration-Controlled Trial
4
Dose
• Represents the basic amount of drug being administered to a patient
• Often a static assignment that does not change over time
Concentration
• The amount of drug that is observed in the body
• Varies within a subject over time due to the effect of absorption, distribution, metabolism, and elimination (ADME) of the drug
• Additionally can vary between subjects due to differences in the ADME
Response
• In basic clinical pharmacology receptor theory, the effect the drug has on the body.
• Varies within a subject over time due to the concentration of drug available to elucidate an effect
• Additionally can vary between subjects due to differences in the receptors / genetics
• Is not always quantifiable
Clinical Endpoint
• The observed patient outcome or assessment.
• Can vary both within and between patients over time.
The Causal Chain
Copyright 2014 - Quintiles
From Dose to Clinical Endpoint
23 October 2015
5
• Create Basic Structural Model
› 1-, 2-, 3-Compartment
› Route of Administration (Oral, IV)
› Estimate PK Parameters
» Absorption Rate Constant
» Volume of Distribution
» Clearance
• Create Error Model
› Between Subject Variability
» Exponential Error Model
› Within Subject Variability
» Proportional Error Model
» Additive Error Model
Population PK ModelsNonlinear Mixed Effects Modeling
0 6 12 18 24 30 36 42 48
Time After Dose (hr)
0
100
200
300
400
500
600
Concentr
ation (
mg/L
)
Source: Example developed from analysis of a large, proprietary, de-identified illustrative data set.
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• Terminology
› RDCT (Randomized Dose - Controlled Trial )
» Objectives: Dose-Response; Effectiveness
» Design: Randomization to 2+ fixed doses (including placebo)
– Parallel or cross-over
» Analysis: Relationship between the assigned fixed-doses and the observed effect(s) is analyzed
› RCCT (Randomized Concentration - Controlled Trial)
» Objectives: Concentration-Response; Effectiveness
» Design: Randomization to 2+ pre-defined concentration ranges (including zero)
– Achieved, if necessary, via adaptively individualized doses
» Analysis: Relationship between the achieved concentrations and the observed effect(s) is
analyzed
› Concentration Drives Clinical Response (R)
» A Concentration-Response (C-R) relationship always exists somewhere
» Concentration is a confirmed measure of exposure in contrast to uncertain exposure after
assigned dosage in a Dose-Response (D-R) analysis
What is a
Randomized Concentration-Controlled Trial (RCCT)?
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• Dose-Response
• Concentration-Response
Dose- vs Concentration-Response
Copyright 2014 - Quintiles
Design and Analysis
23 October 2015
D1 D2O
C1 C2O
R
R
X
X
X
X
D1
D2
O (Placebo)
D3
C1
C2
O (Placebo)
C3
8
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10
Dose (mg)
Re
sp
on
se
Dose vs Response
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 100 200 300 400 500 600 700 800 900 1000
Maximum Concentration (mcg/L)
Re
sp
on
se
Maximum Concentration vs Response
Implications of Low PK Variability in a RDCT
Copyright 2014 - Quintiles
Low PK Variability = No Confounding or Little Overlap
23 October 2015
0
100
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1000
0 1 2 3 4 5 6 7 8 9 10
Dose (mg)
Ma
xim
um
Co
nc
en
tra
tio
n (
mc
g/L
)
Dose vs Maximum Concentration
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Implications of High PK Variability in a RDCT
Copyright 2014 - Quintiles
High PK Variability = Confounding Overlap
23 October 2015
0
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1000
0 1 2 3 4 5 6 7 8 9 10
Dose (mg)
Ma
xim
um
Co
nc
en
tra
tio
n (
mc
g/L
)
Dose vs Maximum Concentration
0.0
0.1
0.2
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1.0
0 100 200 300 400 500 600 700 800 900 1000
Maximum Concentration (mcg/L)
Re
sp
on
se
Maximum Concentration vs Response
0.0
0.1
0.2
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0.4
0.5
0.6
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1.0
0 1 2 3 4 5 6 7 8 9 10
Dose (mg)
Re
sp
on
se
Dose vs Response
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Implications of High PK Variability in a RDCT
Copyright 2014 - Quintiles
Confounding Overlap Worse in Narrow Dose Range
23 October 2015
0.0
0.1
0.2
0.3
0.4
0.5
0.6
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0.8
0.9
1.0
0 100 200 300 400 500 600 700 800 900 1000
Maximum Concentration (mcg/L)
Re
sp
on
se
Maximum Concentration vs Response
0
100
200
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700
800
900
1000
0 1 2 3 4 5 6 7 8 9 10
Dose (mg)
Ma
xim
um
Co
nc
en
tra
tio
n (
mc
g/L
)
Dose vs Maximum Concentration
0.0
0.1
0.2
0.3
0.4
0.5
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0.9
1.0
0 1 2 3 4 5 6 7 8 9 10
Dose (mg)
Re
sp
on
se
Dose vs Response
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11
• RDCT
• RCCT
Concentration-Response Analysis:The Confounding Effect of High Correlation between PK and Response
A RCCT Protects Against the Disease and
Pharmacokinetic Confounders That Cause the Down Bias
D1
D2
O (Placebo)
D3
C1
C2
O (Placebo)
C3
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 100 200 300 400 500 600 700 800 900 1000
Maximum Concentration (mcg/L)
Re
sp
on
se
Maximum Concentration vs Response
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 100 200 300 400 500 600 700 800 900 1000
Maximum Concentration (mcg/L)
Re
sp
on
se
Maximum Concentration vs Response
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• RDCT: valid D-R analysis may be biased by
› High PK variability
» Reduces power unless fixed doses are far apart
› High correlation between PK and R
» May downwards bias D-R relationship unless covariate analysis is employed
• RDCT: valid post-hoc C-R analysis relies on
› Low PK variability
» High PK variability reduces power
› Low correlation between PK and R
» High correlation downwards biases C-R relationship
• RCCT: valid C-R analysis
› Independent of PK variability
» High PK variability is controlled via individualized dosing
› Resistant to downwards bias due to high correlation between PK and R
» Further benefits from covariate modeling
Consequences of High PK Variability
and/or PK-R Correlation in D-R & C-R Analyses
13
• Efficient, unbiased estimation of the C-R Relationship1-3
• Establishment of Effectiveness4-6 of a Drug with
› Narrow Therapeutic Range, and/or
› High PK Variability
• Safe trial of a drug with a narrow therapeutic index w/serious toxicities &/or serious
consequences of under-exposure7-9
• Examples:1. Hale, Michael D, and Russell Reeve. “Planning a randomized concentration controlled trial with a binary response (Mycophenylate mofetil).”
Proceedings of the Biopharmaceutical Section, 1994 Joint Statistical Meetings
2. Reeve, Russell and Michael D Hale. “Results and efficiency of Bayesian dose adjustment in a clinical trial with binary endpoint.” Proceedings of
the Biopharmaceutical Section, 1994 Joint Statistical Meetings
3. Hale, Michael D, et al “The pharmacokinetic-pharmacodynamic relationship for mycophenolate mofetil in renal transplant,” Clin Pharmaco
Ther, 64, pp. 672-683
4. Fletcher CV, Anderson PL, Kakuda TN, Schacker TW, Henry K, Gross CR, Brundage RC. “Concentration-controlled compared with conventional
antiretroviral therapy for HIV infection.” AIDS. 2002 Mar 8;16(4):551-60.
5. Pledger, GW, et al. “Flunarizine for treatment of partial seizures : Results of a concentration-controlled trial.” Neurology, Vol. 44, No. 10,
10.1994, p. 1830-1836.
6. BHAT β-Blocker Study Group. “A Randomized Trial of Propranolol in Patients With Acute Myocardial Infarction: I. Mortality Results.” JAMA.
1982;247(12):1707-1714.
7. Vozeh S, Kewitz G, Perruchoud A, Tschan M, Kopp C, Heitz M, Follath F. “Theophylline serum concentration and therapeutic effect in severe
acute bronchial obstruction: the optimal use of intravenously administered aminophylline.” Rev Respir Dis. 1982 Feb;125(2):181-4.
8. Bever, CT, et al. “The effects of 4‐aminopyridine in multiple sclerosis patients: Results of a randomized, placebo‐controlled, double‐blind,
concentration‐controlled, crossover trial.” Neurology June 1994; 44(6): 1054.
9. Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui C-H. “Conventional versus individualized chemotherapy for childhood acute
lymphoblastic leukemia.” New Engl J Med 1998; 21: 435-437,
•
The Uses of a Randomized Concentration-Controlled Trial
14
• When Should a RCCT NOT be Applied?
› Wide Therapeutic Range
› Low Inter-individual PK Variability
› Very Large PD Variability
› No correlation between PK and Clinical
Response
• When Should a RCCT be Considered?
› Usually in Phase I/II
» To Define the Therapeutic Range /
Therapeutic Index
– Concentration – Effect Reduction
Relationship
– Concentration – Adverse Reaction
Frequency/Severity Relationship
» To Undertake a Safe Trial
(if ADR = severe)
› In Phase III (rarely)
» If Therapeutic Drug Monitoring (TDM) is
Contemplated
» If Dose Adjustment is the Only Way to
Achieve Safe and effective Exposures in
the Effective Range
» If C-R information is required by a
regulatory agency which is concerned
about high PK variability or safety
Randomized Concentration-Controlled Trials in Drug Development
15
• Demanding Design
› Complex Dose-Concentration Titration
Procedures
› Blinding / Drug Packaging
› Drug Product / Dosage Forms
› More Costly, Possibly Longer Trial
• Opportunities
› Mobile web applications to help guide
PK concentration assignments via
Bayesian dosing adjustments
› Large molecules with narrow
therapeutic windows
• Labeling
› Could Lead to a Requirement for
Concentration Monitoring
(Therapeutic Drug Monitoring)
Randomized Concentration-Controlled Trials in Drug Development
Other Factors
16
Questions?
