Pharmaceutical R&D needs a paradigm shift to improve the 50% success rate of late phase clinical trials. I propose the \'Learn-Apply\' paradim which calls re-configuring drug deveopment goals to expand beyond \'confirmation\'.

1. Learn-Apply Paradigm: Re-configuring Drug Development Goals
JogaGobburu
Division of Pharmacometrics
OCP/OTS/CDER/FDA
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Gobburu

2. •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
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3. Gobburu
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“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 development
LB Sheiner, CPT, 1997

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

5. Gobburu
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•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

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7. Learn
•Disease
•Drug
•TrialApply
•Approval, Labeling
•Confirm effectiveness
•Trial design
•Dose selection
•Go, No-go
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Gobburu

8. Gobburu, Pharmacometrics 8
Disease
Model
Trial
Model
FDA Data
Diverse
Expertise
Physiology
Drug
Model
Molecule
Screening
Trial Design
Endpoints
Policy
Patient
Selection
Dose
Selection

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Gobburu

10. •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
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Case#1

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0 5 10 15 20 25 30
Dose, mg
-40
-20
0
20
40
60
80
Placebo-Subtracted Change
In Score A at Week 12
0 5 10 15 20 25 30
Dose, mg
-40
-20
0
20
40
60
80
Placebo-Subtracted Change
In Score A at Week 12
Mild Baseline Disease
(Unlikely Responders)
Severe Baseline Disease
(Likely Responders)
Case#1

12. Gobburu
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•M 50%
•S 50%
1
•M 60%
•S 40%2
•M 60%
•S 40%
3
Q1
Q2
Q3
Q4
Yr1
Yr2
Yr3
Yr4
Q1
Q2
Q3
Q4
Q1Q2Q3
Q4
Q1
Q2
Q3
Q4
Yr5
Q1
M=Mild
S=Severe
Case#1

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Case#1
Confirm mode
•3 Failed trials
•Drug not approved
•Development time prolonged
•More trials needed for approvalLearn-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

14. Learn
•Disease
•Drug
•TrialApply
•Approval, Labeling
•Confirm effectiveness
•Trial design
•Dose selection
•Go, No-go
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Gobburu