Learn-Apply Paradigm:Re-configuring Drug Development Goals

Joga Gobburu

Division of Pharmacometrics

OCP/OTS/CDER/FDA1Gobburu

• Industry, regulators and academia are all in this together.

• This talk is not about Pharmacometrics – but it is about the fundamental R&D goals. Excessive focus on ‘confirmation’ is curtailing innovation. I propose an alternative here for your consideration.

Gobburu 2

Gobburu 3

“Currently, the practical goal of drug development is (regulatory) approval. This goal drives the intellectual focus: demonstrating (confirming) efficacy. Thus, understanding confirmatory study design (primarily how to avoid confounding) and devising and evaluating test statistics are seen as the intellectually challenging tasks as, indeed, a glance at the contemporary clinical trial or biostatistics literature will confirm.”

Learning versus confirming in clinical drug developmentLB Sheiner, CPT, 1997

Gobburu 4

Kola I, Landis J. Nat.Rev.Drug.Disc. Aug 2004.

Gobburu 5

• PLAN - Establish the objectives and processes necessary to deliver results in accordance with the expected output.

• DO - Implement the new processes.

• CHECK - Measure the new processes and compare the results against the expected results to ascertain any differences.

• ACT - Analyze the differences to determine their cause. Each will be part of either one or more of the P-D-C-A steps.

Deming

Gobburu 6

Learn

• Disease

• Drug

• Trial

Apply• Approval,

Labeling• Confirm

effectiveness

• Trial design• Dose selection

• Go, No-go

7Gobburu

Gobburu, Pharmacometrics 8

DiseaseModel

TrialModel

FDA Data

DiverseExpertise

Physiology

Drug Model

MoleculeScreening

Trial DesignEndpointsPolicy

Patient Selection

Dose Selection

9Gobburu

• Sponsor was developing a drug for a life-threatening condition.

• Few approved drugs available in US

• 3 Registration trials conducted

– ~600 patients, 3 doses

– Mild, severe baseline disease patients

– All 3 trials failed to meet primary endpoint

Gobburu 10

Case#1

Gobburu 11

0 5 10 15 20 25 30

Dose, mg

-40

-20

0

20

40

60

80

Pla

ce

bo

-Su

btr

acte

d C

ha

nge

In S

co

re A

at

We

ek 1

2

0 5 10 15 20 25 30

Dose, mg

-40

-20

0

20

40

60

80

Pla

cebo-S

ubtr

acte

d C

hange

In S

core

A a

t W

eek 1

2

Mild Baseline Disease(Unlikely Responders)

Severe Baseline Disease(Likely Responders)

Case#1

Gobburu 12

• M 50%

• S 50%1• M 60%

• S 40%2

• M 60%

• S 40%3

Q1 Q2 Q3 Q4Yr1 Yr2 Yr3 Yr4

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

Yr5Q1

M=MildS=Severe

Case#1

Gobburu 13

Case#1

Confirm mode

• 3 Failed trials

• Drug not approved

• Development time prolonged

• More trials needed for approval

Learn-Apply mode

• Analysis of data beyond primary analysis could have identified enrichment opportunities

• Trials #2, #3 could have served a primaries; Trial#1 supportive.

• Cost and time could have been saved

Learn

• Disease

• Drug

• Trial

Apply• Approval,

Labeling• Confirm

effectiveness

• Trial design• Dose selection

• Go, No-go

14Gobburu