Post on 17-Sep-2018
Exposure-Response
Analysis –
Regulatory perspectives
Christoffer W Tornøe Quantitative Clinical Pharmacology Novo Nordisk A/S
cwto@novonordisk.com
Slide no 2Exposure-Response Analysis –
Regulatory perspectives Slide no 2May-26-2011
Agenda
•
What does Exposure-Response Analysis Provide?
•
Knowledge of relationship between exposure and favorable
and
unfavorable
effects
•
Exposure: Dose, AUC, Cmax
, Cmin
, conc-time profiles•
Response: Clinical outcome/endpoint, effects on surrogate or remote biomarker
•
What is Exposure-Response Analysis used for in Regulatory Decision-Making?
•
Dose selection through all phases of drug development
•
Evidence of effectiveness
•
Assess impact of new formulations
•
Critical to safe & effective use of drugs (dose recommendations)
•
Dosage and administration instructions in product labeling
Slide no 3
•
Knowledge of relationship between exposure and favourable and unfavourable effects
•
Provides information about
•
Starting dose•
Highest dose
•
Titration steps•
Individualization
•
Dosing in special populations
Slide no 3
↓
Effect
↑
Toxicity
TherapeuticWindow
Rationale for Exposure-Response
Exposure
Resp
on
se
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 4Slide no 4
Regulatory Expectations to Exposure-Response
•
21 CFR 314.125 describes the rules for NDA refusal
•
“There is insufficient information about the drug to determine whether the product is safe for use
under the conditions
prescribed, recommended, or suggested in its proposed labeling
as a basis for refusal”
•
21 CFR 314.126
•
Indicates that a well-controlled dose-response study
may
be one type of study that supports efficacy
•
21 CFR 314.50
•
Call for integrated summaries of safety and effectiveness
that provide evidence to support the dose
and dose interval
recommended, including modifications for gender, age, and racial subgroups
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 5Slide no 5
Several Guidances
Emphasize the Need
1994
1998
2003
2005
2005
2006
2009
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 6Slide no 6
ICH E4 Dose-Response Guidance
•
Knowledge of the relationships
among
dose, drug-concentration, and clinical response
(effectiveness and undesirable
effects) is important for the safe and effective
use of drugs in individual patients
•
Information is used for:
•
Supportive evidence of effectiveness
•
Starting dose, dose adjustments
•
Prepare dosage and administration instructions in product labeling
•
Ideal dose-response study should cover a range that shows a dose with no effect
and
a dose beyond
which no further effect
is
seen
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 7
•
Dose-response can inform effectiveness of doses not tested
•
New dose with similar exposure
can be
concluded effective
on the basis of PK
data alone
•
May be possible to conclude that new dose with different exposure
is effective
based on exposure-response
relationship (and time course) without an additional clinical efficacy trial
•
PK data, together with the well-defined
PK/PD relationship, are used to translate the controlled trial results from one dose to a new dose (e.g. special populations)
Slide no 7
FDA Clinical Effectiveness Guidance
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 8Slide no 8
FDA Exposure-Response Guidance•
Describes the use of exposure-response
studies in regulatory decision-making
•
Encourages integration of assessment of exposure-response relationships into all phases of drug development
•
Exposure-response analysis can
•
Represent a well-controlled clinical study contributing to substantial evidence of effectiveness
•
Add to the weight of evidence supporting efficacy
where mechanism of action is well understood
•
Support approval
of different doses, dosing regimens, or dosage forms, or use
of a drug in different populations
(e.g. pediatrics)
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 9Slide no 9
FDA Premarketing Risk Assessment Guidance•
“Although phase 3 trials do not necessarily need to examine a range of doses, such an examination is highly desirable, particularly when phase 2 studies cannot reasonably be considered to have established a single most appropriate dose”
•
“When a dose is not established in phase 2, more than one dose level should be examined in phase 3 trials of fixed dose products to better characterize the relationship between product exposure and resulting clinical benefit and risk”
•
“Dose-response data from phase 3 trials with multiple dose levels
will help to
better define the relationship of clinical response to dose for both safety and effectiveness”
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 10Slide no 10
ICH E14 QT Guidance•
Analysis of relationship between drug exposure and QT/QTc
interval change
under near worst case clinical exposure
scenario
•
Exposure-response
analysis assists in
the planning
and interpretation
of
studies assessing cardiac repolarization
Write informative label for drug that prolongs QTc
Adjust doses for drug-interactions, special populations, poor CYP metabolizers
Labeling
Support the primary endpoint (E14)
Predict QTc risk at different dose levels
Evaluate assay sensitivity
Thorough QT Study
Waive TQT study for drug that prolongs QTc
Assess drug effect on QTc when TQT study cannot be conducted
Select doses based on Benefit-Risk assessment
Clinical Development
Garnett et al., Concentration-QT Relationship Play a Key Role in the Evaluation of ProarrhythmicRisk During Regulatory Review, JCP
48:13-18 (2008)
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 11Slide no 11
EMA Pediatrics
Guideline•
“If similar exposure in adult and paediatric patients can be assumed to produce similar efficacy, PK data alone
can be used to
extrapolate efficacy”
•
“If a similar relationship between concentration and clinical efficacy cannot be assumed paediatric PK/PD
(biomarker)
data can be used to extrapolate efficacy”
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 12Slide no 12
FDA EOP2A Meeting Guidance
•
The overall purpose of an EOP2A meeting is to discuss options for trial designs, modeling
strategies, and
clinical trial simulation scenarios to improve the quantification of the exposure-response information from early drug development.
•
The goal of these meetings is to optimize dose selection
for
subsequent trials to improve the efficiency of drug development.
•
The exposure-response data
discussed might be pertinent to evaluation of efficacy outcomes
or
adverse outcomes.
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 13
Case Studies
1.
AC Meeting on Community-Acquired Pneumonia
2.
AC Meeting on Rivaroxaban
for VTE prophylaxis
3.
Argatroban
Injection in pediatrics
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 14
Case Study 1
FDA Advisory Committee on Community-Acquired Pneumonia
http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4343b1-01-FDA.pdf
http://www.fda.gov/ohrms/dockets/ac/08/slides/2008-4343s1-01-FDA-corepresentation.ppt
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 15
Background
•
Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality in the world
•
Recent FDA effort to justify the non-inferiority margins used in active control studies of antibacterial products
•
Particular problem for diseases such as CAP where antibacterial use became the standard of care long before careful placebo-controlled or dose-response studies became accepted practice during drug development
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 16Slide no 16
Can exposure-response analysis contribute to the discussion of a non-inferiority margin for studies of Community-Acquired Pneumonia (CAP)?
a) What is the exposure-response derived treatment effect against Streptococcus pneumoniae
in patients with mild-moderate CAP?
b) Can exposure-response analysis support the choice of non-
inferiority margin in CAP trials?
Key Question
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 17Slide no 17
Y-intercept as “Placebo”
Response Estimate
Forrest A et al. Pharmacokinetics and pharmacodynamics
of oral grepafloxacin
in patients with acute bacterial exacerbations of chronic bronchitis. J Antimicrob
Chemother. 1997;40 Suppl
A:45-57.
Grepafloxacin
against AECB
Treatment Effect
“Untreated/Placebo”
Response
AUC/MIC
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 18Slide no 18
Pre-clinical Information Supports Approach
Craig WA, Andes DR. Correlation of the Magnitude of the AUC24
/MIC for 6 Fluoroquinolones
against Streptococcus pneumoniae
with survival and bactericidal activity in an animal model. In Abstracts of the 40th ICAAC, Toronto, Canada, Sept. 17-20, 2000. Abs-289.
Ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and sitafloxacin
Free AUC/MICFree AUC/MIC
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 19Slide no 19
0.0
0.2
0.4
0.6
0.8
1.0
50 100 200 500 1000
| | |N=5 N=69
Free AUC/MIC
Pro
babi
lity
of C
linic
al R
espo
nse
GarenoxacinGatifloxacinGemifloxacinLevofloxacin
0.0
0.2
0.4
0.6
0.8
1.0
50 100 200 500 1000
| | |N=5 N=69
Free AUC/MIC
Pro
babi
lity
of C
linic
al R
espo
nse
GarenoxacinGatifloxacinGemifloxacinLevofloxacin
60%
97%
Estimated Treatment Effect of 37% (95%CI -6;80%) for Fluoroquinolones
in CAP against S. Pneumoniae
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 20Slide no 20
Key Questions (Revisited)
•
What is the exposure-response derived treatment effect against Streptococcus pneumoniae
in patients with mild-
moderate CAP?•
37% (95%CI -6;80%)
•
Can exposure-response analysis support the choice of non-inferiority margin in CAP trials?
•
Very likely, but more data (with low free AUC/MIC ratios) are needed to precisely quantify the treatment effect
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 21
Case Study 2
NDA 22406 Rivaroxaban, VTE Prophylaxis
Special populations
FDA AC meeting: http://www.fda.gov/ohrms/dockets/ac/09/slides/2009-4418s1-06-FDA-Tornoe.pdf
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 22
•
Is there Evidence of Dose/Exposure-Response for Effectiveness and Safety?
•
Shallow dose-response for composite efficacy endpoint
•
The risk of major bleeding increases with increasing rivaroxaban
dose/exposure
•
Which Special Populations are at Risk for Clinically Relevant Increases in Exposure?
•
Moderate-severe hepatic patients
•
Concomitant use of strong CYP3A4/P-gp inhibitors
•
Mild-moderate renal impairment + moderate CYP3A4/P-gp inhibitors
•
What are the Strategies to Address Increased Exposure Risk of Bleeding in Special Populations?
•
Lower dose is the best option and help larger patient population
to receive this treatment
Key Questions
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 23
0
10
20
30
0 10 20 30 40
25% 11% 9% 14% 6%15%
Pro
porti
on o
f Pat
ient
s w
ith D
VT,
PE
, or D
eath
(%)
Shallow Dose-Response Relationship for Composite Efficacy Endpoint
Enox
40 mg
Dose (mg)*The error bars represent the 95% confidence interval of the mean proportions
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 24
Increasing Risk of Major Bleeding with Increasing Dose and Exposure
0
2
4
6
8
10
12
0 10 20 30 40
1.9% 0.7% 5.3% 5.2% 6.1%2.4%
Ris
k of
Maj
or B
leed
ing
(%)
Enox40 mg
Dose (mg) Steady-state AUC (mg*hr/L)
0
2
4
6
8
10
12
0 2 4 6 8 10
2.2%2.5%
3.8%4.6%
5.7%
p<0.01
40 mg
30 mg
20 mg10 mg
5 mg
*The error bars represent the 95% confidence interval of the mean proportions
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 25
•
Is there Evidence of Dose/Exposure-Response for Effectiveness and Safety?
•
Shallow dose-response for composite efficacy endpoint
•
The risk of major bleeding increases with increasing rivaroxaban
dose/exposure
•
Which Special Populations are at Risk for Clinically Relevant Increases in Exposure?
•
Moderate-severe hepatic patients
•
Concomitant use of strong CYP3A4/P-gp inhibitors
•
Mild-moderate renal impairment + moderate CYP3A4/P-gp inhibitors
•
What are the Strategies to Address Increased Exposure Risk of Bleeding in Special Populations?
•
Lower dose is the best option and help larger patient population
to receive this treatment
Key Questions
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 26
Case Study 3
Argatroban
Injectionin pediatrics
(birth to 16 yrs)
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm071734.pdf
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM193136.pdf
Match PD
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 27
Argatroban
(Anti-coagulant)
•
Indications •
Heparin-induced thrombocytopenia (HIT)
•
Adult dosing•
Start and Max dose: 2 ug/kg/min and 10 ug/kg/min
•
Titrated to 1.5 –
3 times baseline aPTT
•
Pediatric
dosing•
Use concentration –
aPTT
relationship and PK model to
explore competing dosing schemes
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 28
1. Establish PK/PD Relationship
ModelsPK/PD
DemographicsBaseline aPTT
Dosing0.25-10 ug/kg/minin increments of0.25 ug/kg/min
Starting Dose Simulations
Generate conc. &aPTT
data in
10.000 peds
ateach dose
AnalysisCount % patients:
Below TargetAchieving TargetExceeding Target
Titration SchemeSimulations
Patients < Target ateach dose are giventhe next higher dose
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 29
0
50
100
150
200
0.1 1 10 100 1000 10000Argatroban Concentration, ug/L
aPTT
, sec
onds
Pediatric Patients - Old DataHealthy AdultsMeanPediatric Patients - New Data
1. Establish PK/PD Relationship Concentration-aPTT
relationship is similar between adults
(healthy) and pediatrics
(patients)
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 30
2. Explore Optimal Pediatric
Starting Dose
ModelsPK/PD
DemographicsBaseline aPTT
Dosing0.25-10 ug/kg/minin increments of0.25 ug/kg/min
Starting Dose Simulations
Generate conc. &aPTT
data in
10.000 peds
ateach dose
Target: 1.5-3 times baseline aPTT
and < 100 seconds.
Titration SchemeSimulations
Patients < Target ateach dose are giventhe next higher dose
AnalysisCount % patients:
Below TargetAchieving TargetExceeding Target
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 31
2. Explore Optimal Pediatric
Starting Dose Adult Starting Dose of 2 ug/kg/min is Too High for Pediatrics
0
20
40
60
80
100
0 1 2 3
Dose, ug/kg/min
% R
each
ing
targ
et a
PTT
0
5
10
15
20
% E
xcee
ding
targ
et a
PTT
Pediatric Adult
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 32
3. Select Incremental Pediatric
Dose
ModelsPKPD
DemographicsBaseline aPTT
Dosing0.25-10 ug/kg/minin increments of0.25 ug/kg/min
Starting Dose Simulations
Generate conc. &aPTT
data in
10.000 peds
ateach dose
AnalysisCount % patients:
Below TargetAchieving TargetExceeding Target
Target: 1.5-3 times baseline aPTT
and < 100 seconds.
Titration SchemeSimulations
Patients < Target ateach dose are giventhe next higher dose
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 33
3. Select Incremental Pediatric
Dose 0.25 ug/kg/min with no additional anti-coagulation
beyond 3 ug/kg/min (compared to 10 ug/kg/min for adults)
0
20
40
60
80
100
0 1 2 3
Dose, ug/kg/min
% B
elow
targ
et a
PTT
First DoseNext Dose
20 of the 39/100
non-respondersat 0.75 ug/kg/min respond whentitrated to 1.0 ug/kg/min.
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 34Slide no 34
Summary
•
What does Exposure-Response Analysis Provide?
•
Knowledge of relationship between exposure and favorable
and
unfavorable
effects
•
Exposure: Dose, AUC, Cmax
, Cmin
, conc-time profiles•
Response: Clinical outcome/endpoint, effects on surrogate or remote biomarker
•
What is Exposure-Response Analysis used for in Regulatory Decision-Making?
•
Dose selection through all phases of drug development
•
Evidence of effectiveness
•
Assess impact of new formulations
•
Critical to safe & effective use of drugs (dose recommendations)
•
Dosage and administration instructions in product labeling
Exposure-Response Analysis –
Regulatory perspectives May-26-2011
Slide no 35
Take Home Messages
•
Little regulation on exposure-response but clear guidance and long history
•
Exposure-response information is needed for dosing recommendations but selection is complex
•
Exposure-response is the strongest form of evidence of effectiveness
•
Totality of evidence is used to write informative product labelling
Exposure-Response Analysis –
Regulatory perspectives May-26-2011