Adaptive Research in Practice:

Running Tighter, Faster Studies

Michael Rosenberg, MD, MPH

CEO/President

Health Decisions Inc

2

Disclaimer

• The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (―DIA‖), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated.

• These PowerPoint slides are the intellectual property of the presenter’s organization and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners.

3

What is Adaptive?

ADAPTIVE

STUDY CYCLE

Results achieved

earlier in

study cycle

TRADITIONAL

STUDY CYCLE

Kn

ow

led

ge

Time

4

Adaptive: Continuous Measurement and Refinement

• Immediate, actionable information

• Role-specific:

the right information, to the right eyes, at the right time

• Focus on decision making, on multiple levels

Data & Status Collection

InterpretationAction

Adaptive

Design

5

Adaptive Design plus Adaptive Operations

Design adaptations

Study Timeline

Traditional

Adaptive

Design

6

Adaptive Design plus Adaptive Operations

Design adaptations

Operational adaptations

Study Timeline

TraditionalAdaptive

Design &

Operations

7

Traditional Process

Adaptive/Agile Process

8

Managing Information

9

Managing Information

10

Common Pain Points

Traditional Agile

Enrollment (% on time) 15% 76%

Database lock (weeks) 10+ <2

Monitoring (# visits) X X/2

Waste (queries/100 fields) 5-7 web; 15+ paper 1

11

Real Results

• Rescue (renal)

– Target of 140 pts; in 6 mo, 14 enrolled

– Agile was implemented with new systems; in 6 mos, 140 pts

• Pivotal (CNS / Alzheimer’s)

– Study run under Agile completed ~1 yr ahead of companion

study run under conventional program—avg 96 pts/mo

• Registration (Oncology / mBrCa)

– Product brought to marked one year ahead of schedule

– Main contributors were speed of enrollment (31.7 pts/mo), SSRE

• Registration (device)

– 4,000 subjects completed three months ahead of schedule

12

A Simple Adaptation: Sample Size Re-Estimation

• Planning is done with estimates that are always wrong—

only question is how much off

• Implications are profound, ranging from failure of study

to overbuilding and wasted resources

• SSRE allows size to be checked during study using

actual data to date

13

The Cost of Not Doing SSRE

δ less

δ less

δ equal

δ equal

δ greater

δ greater

No SSRE

SSRE

0.33

0.33

0.33

OUTCOMERelative

to SSRE

COST(m)

Probability

weighted

Failure

Success

Success

- $5

- $1

- $2

- $1.65

- $0.34

- $0.66

- $2.7

Total

Success

Success

Success

$5

$5

$5

$5

$4

$3

0.33

0.33

0.33

Assumes study cost $5m, 20% buffer in non-SSRE, fixed and linear subject cost, 20% difference in δ

14

$0.0

$1.0

$2.0

$3.0

0 0.1 0.2 0.3

Probability of Effect Size (δ) Differing from Planned by >20%

Ad

dit

ion

al

co

st

of

no

SS

RE

(m

)The Cost of Not Doing SSRE

15

Operational Design Typical Range

Safety• Rapid decision

cycles• CRM 35% 15 – 80%

Dose Finding

• Rapid enrollment

• Centralized

monitoring

• Reduced rework

• Rapid DB lock

• SSRE/Bayesian

• Adaptive

randomization

• Pruning

• Seamless

transition

25% 10 - 35%

Confirmatory

• Rapid enrollment

• Centralized

monitoring

• Reduced rework

• Rapid DB lock

• SSRE/Bayesian

• Pruning30% 10 – 25%

Submission • Early start 20% 10 – 40%

Adaptive Savings over Traditional

16

Trial & Program Time Savings (months)

17

Getting Started with Agile

• Get informed on adaptive options

• Design RFP to encourage better approaches

• Leverage CRO expertise in creating a

customized trial

• Demand transparency at operational level; it

means control and your ability to make better,

faster decisions

• Build capabilities progressively; can start slowly

18

An Unprecedented Opportunity

• Adaptive, agile tools are here today, tested, and

robust

• The opportunities are enormous; greater than

ever experienced in our industry

• Adaptive design elements as appropriate;

adaptive operational elements are universal

• Bottom line are for consistent time and cost of

projects—10-50% reduction

19

If you want the same results,

keep doing the same thing.