Implementing Adaptive Clinical Trials

Clinovo

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Implementing Adaptive Clinical Trials

Webinar – Wednesday, November 16th, 9 AM PST

2© 2011 Clinovo. All Rights Reserved.

The contents of this document are confidential and proprietary to Clinovo

Clinovo’s free webinar series

Every month, Clinovo hosts several webinars covering various topics:

� Medidata Rave® Advanced Use

� Open Source For Clinical Trials

� CDISC® Data Conversion

� Adaptive Clinical Trials



Joe Laver

Senior Director of Biometrics

Clinovo

Pascal Royet

VP of Business Operations

Clinovo

Today’s Speakers



� Introduction

� When should we use adaptive clinical trials?

� Key benefits

� Planning ahead for an adaptive clinical trial

Today’s Agenda



Definition

� Adaptive clinical trials allow pre-planned modifications to

the study when opportunities arise

• Adaptive randomization design

• Group sequential design

• Sample size re-estimation design

• Drop-the-loser design

• Adaptive dose-finding design

• Biomarker-adaptive design

• Adaptive treatment-switching design

• Hypothesis-adaptive design

• Adaptive seamless phase II/III design

• Multiple-adaptive: two or more of the above design

Some types of adaptive

designs



Some Facts

Mentioned in Oxford University Press’ Biometrika December 1933

Work on sequential clinical trials 1940’s - 1950’s

Declared an “urgent need” in the FDA’s Critical Path Initiative 2004

Among the FDA’s Critical Path Opportunities Report 2006

US PhRMa working group on adaptive trials reports 2006

Guidance for Industry on Adaptive Design Clinical Trials for Drugs and

Biologics issued by the FDAFebruary 2010

“A study that includes a prospectively planned opportunity

for modification of one or more specified aspects of the

study design and hypotheses based on analysis of data

(usually interim data) from subjects in the study.”

Definition of adaptive design from the FDA Guidance



Why Adaptive Clinical Trials

� Clinical trials have become increasingly complex….

38%

49%54% 58%

-21%-30%

-40%

-20%

0%

20%

40%

60%

80%

Unique Procedures Total Procedures Execution Burden Total Eligibility

Criteria

Volunteer Enrollment

Rates

Volunteer Retention

Rates

Change in Clinical Trials: Resources, Length and Participation,2000-03 to 2004-07

Source: 2011 profile, PhRMA Pharmaceutical Industry

Pharmaceutical study, Jan 22,2011. New York Times



Why Adaptive Clinical Trials

� … Expensive …

$19.0$22.7

$26.0$29.8 $31.0

$34.5$37.0

$39.9 $43.4$47.9 $47.4 $46.4

$49.4

$0

$10

$20

$30

$40

$50

$60

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Source: 2011 profile, PhRMA Pharmaceutical Industry

Pharmaceutical study, Jan 22,2011. New York Times

High failure rates: 50-75% in late stage

Total R&D as a percentage total sales: 17%

PhRMA Member Companies’ R&D Expenditures (Billions of Dollars)

� … and Risky



Agile Clinical Development

� Enhance study performance

� Improve speed

� Minimize risks

Characteristics of Adaptive Design

Adaptive

Design Dynamic

Sequential

learning

Simulation

Robust

Real-TimeBayesianIntegrity

Validity

Cost-efficient

Systematic

Data-Driven

Optimized

Flexible

Streamlined

Decision-

Oriented



When should we use adaptive design?

� When is it most appropriate to run an adaptive clinical trial?

When you have a lot to learn about the drug and the

disease in your target population

You do not have the time or money to simply recruit

enough subjects in a simple way to answer your

questions

And there are outcomes early enough in treatment to

adapt to




� When in a drug's development is the most appropriate time

to conduct an adaptive clinical trial?

� Any phase where there is significant uncertainty over the drug

behavior




� What indications particularly lend themselves to the use of

adaptive clinical trials?

� Quick response (<25% of recruitment period)

� Range of doses available

� Subjects are expensive

0

50

100

150

200

250

300

350

1 2 3 4 5 6 7 8 9 10 11 12 13 14

# S

ubje

cts

/ Res

pons

es

Months into trial

Example Cumulative Subjects and Responses

Monthly recruitment

Total Recruitment

2 Month Response




What indications particularly lend themselves to the use of


Stroke, Alzheimer's, Schizophrenia

Diabetes, cholesterol lowering

Cancer

Orphan indications




� What indications don’t lend themselves to the use of


� Very long time to final response

� Very swift recruitment

� Population change over duration of trial

� Subjects are cheap

� Want to learn equally about all treatment arms



Key Benefits of Adaptive Design

� Savings in every phase of development

� Shorter timelines

� Higher probability of success

� Improved flexibility

� Responsiveness

� The right drug to the right patient

Sources: Health Decision Webinar “Top 10 Benefits of Adaptive Design”, Jan 25, 2011

Mark Chang, “Enhancing the quality of clinical trials”, Pharma Focus Asia



The right drug to the right patient

� Better characterization of the drug efficacy and toxicity

� More data on the dose of interest

� Better characterization of the dose behavior

� Faster/smarter overall development through better targeted

trials

� Optimization of dose allocation



Other Benefits

� Better Ethics

� Fewer subjects allocated to ineffective or over-toxic treatment arms

� Fewer subjects used in studies that fail

� Better Science

� Can try more doses

� Explore other dimensions – combinations, indications, sub-

populations

� Better Business

� Swifter curtailment of failing compound

� Better information -> better decisions at the next phase



Impact on the development program

� Consider trial in whole development program

� Need to think about the next trial earlier and longer

� Need to integrate the development team



Advanced Technology

� Need more powerful forecasting systems

� To simulate trial scenarios & patient enrolment

� To project time-phased patient demand for clinical supplies

� Need for advanced technology to manage the clinical trial

� Central randomization

� Dynamic treatment allocation

� Automated dose titration



Challenges

� Longer Design Time

� Need to identify candidate trial

� Design less “off-the-shelf”

� Design needs interaction with clinical team

� Design needs simulation and optimization

� More Integrated Trial Management System

� Quick capture of key responses

� Frequent modification of randomization

� Drug Supply

� Need to be able to deliver more doses

� Need to be able to use central randomization



Contact us

Pascal Royet

VP of Business Operations

[email protected]

Joe Laver

Senior Director of Biometrics

[email protected]

Upcoming webinars

Open Source Technologies for Clinical Trials November 17th, 9:00 AM PST

Medidata Rave Custom Functions November 23rd, 9:00 AM PST

CDISC SDTM Conversion November 30th, 9:00 AM PST

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Implementing Adaptive Clinical Trials

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