regulatory application of exposure- response analyses · pdf fileregulatory application of...

1

Regulatory Application of Exposure-Response Analyses in Dose Selection

Yaning Wang, Ph.D. Deputy Director

Division of Pharmacometrics Office of Clinical Pharmacology

OTS/CDER/FDA

Disclaimer: My remarks today do not necessarily reflect the official views of the FDA

Outline

• Division of Pharmacometrics

• Case studies

– Paliperidone

– Edoxaban

• Summary

2

3

Where Are We at FDA?

US Food and Drug Administration (FDA)

http://www.fda.gov/oc/orgcharts/orgchart.html

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm075128.htm


CDER CFSAN CVM CBER CDRH CTP ORA

OTS OND OSE OPQ OGD …

OCP OB OCS

OFVM OMPT OC OGROP

OIP

OO

DCP4 DCP1 DCP2 DCP3 DCP5 DPM DARS GTTG

OPQ: Office of Pharmaceutical Quality; OCS: Office of Computational Science DARS: Division of Applied Regulatory Science; GTTG: Genomics and Targeted Therapy Group

http://www.fda.gov/oc/orgcharts/orgchart.html



Mission of Office of Clinical Pharmacology and Biopharmaceutics

• To assure that an individual patient receives the right drug, in the right dose at the right time and in the right dosage form.

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/StaffPoliciesandProcedures/ucm073007.pdf

MANUAL OF POLICIES AND PROCEDURES (MaPP): Clinical Pharmacology and Biopharmaceutics Review Template Originator: Office of Clinical Pharmacology and Biopharmaceutics Effective Date: 04/27/04

4

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/StaffPoliciesandProcedures/ucm073007.pdf

Mission of Office of Clinical Pharmacology

5

Pharmacometrics Scope at FDA

• NDA/BLA reviews

• IND reviews

– Dose-Finding trials

– Registration trials

• QT Reviews – Central QT team

• EOP2A

• Model-based drug development tool evaluation

• Research – Disease Models

– Pediatrics

– PBPK

• Knowledge Management

• Evidence of Effectiveness

• Labeling

• Benefit/risk quantification – Dose optimization

– Dose adjustments

• Trial design

Tasks Decisions Influenced

6

7

Case 1: Paliperidone • Indication: schizophrenia

• Extended-Release tablet is already approved (QD regimen)

• New monthly long acting injection formulation

• Regimens studied in phase 3 trials: – 25 mg, 50 mg, 100 mg, 150 mg (day 1, 8, 36, 64)

– 150 mg (day1)+

25 mg (days 8, 36, and 64)

100 mg (days 8, 36, and 64)

150 mg (days 8, 36, and 64)

• Proposed regimen: – 150 mg (day1), 100 mg (day 8) and 75 mg (monthly)

8

Benefit/Risk Assessment

-14

-12

-10

-8

-6

-4

-2

0

0 25 50 75 100 125 150

Maintenance Dose (mg)

Ch

an

ge f

rom

Baseli

ne i

n

PA

NS

S T

ota

l S

co

re

Safety: one death at 150 mg and dose-dependent

increase in body weight and serum prolactin levels

• N160/arm

• All active arms better than placebo

P<0.001

P<0.001

P<0.05

9

Additional Support for 75 mg

19 20 21 22 23 24 25

05

10

15

20

25

30

Time [Week]

Co

nce

ntr

atio

n [n

g/m

L]

Dosing Interval at Steady State (75 mg im. Q 4week)

Median Cmax (6 mg QD ER at steady state)

Median Cmin (6 mg QD ER at steady state)

10

Real Life Challenges

• Dosing window for the 2nd dose

• Dosing window for the monthly maintenance dose

• What to do after missing a dose

• Switching from ER tablet or other antipsychotics

• Dosing regimen for patients with renal impairment

11

PK Simulation for Dosing Window

12

Simulation Based Solutions • Dosing window for the 2nd dose: 4 days

• Dosing window for the monthly maintenance dose: 7 days

• What to do after missing a dose – 2nd dose: 3 re-initiation regimens

– maintenance dose: 3 re-initiation regimens

• Switching from ER tablet or other antipsychotics – Different maintenance doses and starting times

• Dosing regimen for patients with renal impairment – 100 mg (day 1), 75 mg (day 8) and 50 mg (monthly)

13

FDA’s Final Decision on Paliperidone • Unstudied regimen was approved

• FDA’s alternative strategy and individualized maintenance dose were accepted by the sponsor

• PK simulation led to recommendations for dosing window, strategy for handling missing dose, switching from prior treatments, dosing regimen for special patients

• All these model based recommendations are included in the product label

14

Case 2: Edoxaban • Indication: reduction in the risk of stroke and

systemic embolism in nonvalvular atrial fibrillation

• Mechanism of action: direct and reversible inhibitor of serine protease FXa which catalyzes the transformation of prothrombin to thrombin

• In healthy subjects with normal renal function, renal clearance accounts for 50% of the total clearance of edoxaban

• Phase 3 trial: two doses met NI margin relative to warfarin on efficacy, superior on major bleeding

• Regulatory issue: inferior efficacy relative to warfarin in the normal renal function subgroup for both dose regimens on ischemic stroke

Edoxaban Sponsor’s slide from AC meeting: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM421613.pdf

15

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM421613.pdf




NI margin: 1.38 retention of 50% of treatment effect of warfarin

16




Clarification on NI Margin • DR. TEMPLE:

• Page 213: “There's a long history of how we reached that, and it's not entirely satisfactory because these are terrible events. You don't want to be inferior at all really, but you couldn't do the trial to rule out any inferiority, it would be hundreds of thousands of people so you can't really do that unless you're better.”

• Page 272: “They said it should be -- you should rule out a difference of 25 percent. So we ran the numbers, did the calculations, and that would needed a study of 55,000 people. So we said, okay, 50 percent will do. Because you wanted the study, and of course, that's the upper bound of what the difference can be, you also get a point estimate to look at.”

17 AC meeting’s transcript: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM457033.pdf




FDA’s AC Comments on Two Doses*

For the primary endpoint, the high dose was thus nearly superior to warfarin, whereas the low dose was nearly significantly worse, although both clearly met the NI threshold. As there was no marked bleeding excess and bleeding rates were still well below warfarin, it seems hard to support use of a dose < 60 mg.

Edoxaban FDA’s questions for AC meeting: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM421609.pdf

*: Not supported by statistical review team

18





19




20 Edoxaban FDA’s slide from AC meeting: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM421612.pdf




Edoxaban FDA’s slide from AC meeting: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM421612.pdf

21




FDA AC Primary Question

1. DISCUSSION: Please comment on your interpretation of the primary efficacy endpoint, ischemic stroke, and bleeding results in the various subgroups based on renal function in the ENGAGE AF trial. Do you believe the observed differences in outcomes among the renal function subgroups represent the play of chance or differences in exposure? How did you reach your conclusion, and how confident are you in your conclusion?

Edoxaban FDA’s questions for AC meeting: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM421609.pdf

Primary efficacy endpoint (Stroke/SEE)

Ischemic strokes only

22




Different Opinions • Sponsor

– Seeking only high dose (60/30) as it was studied

• FDA

– Statistical team

• Both high (60/30) and low (30/15) doses should be approved

• 60 mg dose appeared effective in eCrCL>80 mL/min subgroup

– Medical and clinical pharmacology teams

• Only high dose should be approved

• 60 mg dose in eCrCL>80 mL/min subgroup should NOT be approved

Edoxaban Sponsor’s and FDA’s slides from AC meeting: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM421613.pdf http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM421612.pdf

23








warfarin-normal




AC Members’ Opinions • Eight AC members commented on this

question (5 true, 3 chance finding)

• DR. DAVIS (MD, PhD, Professor of Biostatistics, page 288): “To me this question of the subgroup analysis is a little bit complicated. Normally, I would say I would dismiss it totally, and I still think that there's a good deal of play of chance here… So I am somewhat confident that it's the play of chance, but not completely.”

AC meeting transcript: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM457033.pdf

26




AC Members’ Opinions (Cont’) • DR. BORER: (MD, page 290): “…the apparently unimpressive

result of 60 milligrams in patients with normal renal function, really may well be due to chance alone. I say that because there are so many secondary analyses just as Dr. Davis said, and prior analyses, et cetera, et cetera… Remember, we saw several times the apixaban results. One big bar jumped out and wow, we were willing to accept that as an outlier. That just is meaningless… I believe this is -- the renal function versus outcome result is more likely to be due to chance than to reality…. isn't it unusual that patients with mild renal dysfunction did the best… But when I look at all these numbers and see them jumping around as they were, and look for biological plausibility, it's hard to find”

AC meeting’s transcript: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM457033.pdf

27




AC Members’ Opinions (Cont’)

• DR. SCOTT (MD, Industry Rep, Page 296): “I think part of what makes the subgroup analysis compelling to people is biological plausibility, and I just wanted to quote from somebody else who's spoken frequently in this room. You said that, "The road to Hell is paved with biological plausibility.“…So overall, I thought that the sponsor had proven their case.”


28




AC Members’ Opinions (Cont’)

• DR. LINCOFF: (MD, AC Chair, 6): we've heard this dismissed as a subgroup of a subgroup a lot of times. I think it's not. It's a subgroup. It's a big subgroup. And it's a subgroup that Dante's Inferno notwithstanding, does have biological plausibility and has been the basis for a lot of drug dosage adjustments with a lot of other agents…. I believe this could well be real.”


29




Alternative Way of Presenting Subgroup Analysis Results

• Without any knowledge about the relative efficacy relationship between normal and mild before the trial (uninformative prior), what is the probability of the following two events after the trial data were observed (Bayesian posterior probability)?

Scenario Chance finding Real Probabilistic translation

1 Normal is at least as effective as mild

Normal is worse than mild P(HRnormal<=HRmild) or 1-P

2 Edoxaban is at least as effective as warfarin in normal

Edoxaban is worse than warfarin in normal

P(HRnormal<=1) or 1-P

3 Edoxaban is no worse than warfarin by 1.38 (NI for HR) in normal

Edoxaban is worse than warfarin by at least 1.38 (NI for HR) in normal

P(HRnormal<=1.38) or 1-P

30

Scenario Chance finding Real

1 Normal is at least as

effective as mild

Normal is worse than mild

P=0.06% P=99.94%

2 Edoxaban is at least

as effective as

warfarin in normal

Edoxaban is worse than

warfarin in normal

P=1.59% P=98.41%

3 Edoxaban is no worse

than warfarin by 1.38

(NI for HR) in normal

Edoxaban is worse than

warfarin by at least 1.38

(NI for HR) in normal

P=25.24% P=74.76%

A Response with A Quantitative Probability

31 Endpoint: ischemic strokes

For Hardcore Frequentists

• Similar numbers can be generated

Scenario Assumed Truth Probability of Observing

HR>=1.58 (Chance finding)

1 Edoxaban is more

effective than

warfarin in normal

(HRtrue=0.9)

0.018%

2 Edoxaban is same as

warfarin in normal

(HRtrue=1)

0.097%

32

Endpoint: ischemic strokes

FDA’s Final Decision on Edoxaban • Only high dose was approved

• 15mL/min<CrCL<=50mL/min 30 mg once daily

• 50mL/min<CrCL<=95mL/min 60 mg once daily

• BOXED WARNING (A) REDUCED EFFICACY IN NONVALVULAR ATRIAL FIBRILLATION PATIENTS WITH CREATININE CLEARANCE (CRCL) > 95 ML/MIN

• SAVAYSA should not be used in patients with CrCL > 95 mL/min. In the ENGAGE AF-TIMI 48 study, nonvalvular atrial fibrillation patients with CrCL > 95 mL/min had an increased rate of ischemic stroke with SAVAYSA 60 mg once daily compared to patients treated with warfarin. In these patients another anticoagulant should be used

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316s002lbl.pdf

33

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316s002lbl.pdf

34

Summary • Precision medicine is the core of clinical

pharmacology

• Exposure-response analysis plays an important role in dose selection

• Rigorous analyses led to

– Rational dosing regimen

– Unnecessary trials avoided

– Faster access of medication for patients

– Strategy to handle real life issues

• Routine practice in drug development and regulatory review

35

Acknowledgments

• Scientists from the sponsor

• Melanie Blank, M.D.

• Tzu-Yun McDowell, Ph.D.

• Martin Rose, M.D.

• Norman Stockbridge, M.D.

• Robert Temple, M.D.

• Justin Earp, Ph.D.

• Jeffry Florian, Ph.D.

• Divya Menon-Andersen, Ph.D.

• Rajnikanth Madabushi, Ph.D.

• John Lawrence , Ph.D.

• Jim Hung, Ph.D.

• Hao Zhu, Ph.D.

• Kofi Kumi, Ph.D.

• Raman Baweja, Ph.D.

• Jing Zhang , M.D.

regulatory application of exposure- response analyses · pdf fileregulatory application of...

Documents