10/22/2015

1

Causes and Effects of Paradigm Shifts in Clinical Research

Why the Drug Development Paradigm is Why the Drug Development Paradigm is

Failing and a Compelling Path ForwardFailing and a Compelling Path Forward

Ken Getz, MBA

Director, Sponsored Research Program, Associate Professor

CSDD, Tufts University School of Medicine

November 2015

10/22/2015

2

Agenda

• Our Traditional Drug Development Paradigm

• Why Drug Development Optimization Remains Elusive

• Compelling Value Proposition of a New Paradigm

3

Drug Pipeline Activity

4,8855,482

6,476 6,531

8,0108,617

9,349

10,150

2000 2002 2004 2006 2008 2010 2012 2014

Source: FDA

10/22/2015

3

30

35

2724

1721

31

18 1816

2119

15

2628

24

30

7

3

25

7

6

5

24

2

4 7

6

9

11

3

11

98 99 2000 01 02 03 04 05 06 07 08 09 2010 11 12 13 14

NDAs BLAs

Source: FDA

Year

Number of New Drug

and Biologics Approvals

Productivity as Measured by Annual Approvals

Overall Drug Development Durations(Cycle Time in Years from IND Filing to NDA Approval)

6.3 6.8 7.25.9 6.0 6.1 6.3 6.8 6.7

2.92.6 2

1.4 1.21.75 1.6

1.5 1.4

87-89 90-92 93-95 96-98 99-01 02-04 05-07 08-10 11-13

Mean Clinical Time Mean Approval Time

Source: Tufts, CSDD

10/22/2015

4

Actual Study Enrollment Cycle Times

Multiplier of Planned Study

Duration to Reach Target

Enrollment

Overall 1.9

Cardiovascular 2.0

CNS 2.2

Endocrine/Metabolic 2.1

Oncology 1.7

Respiratory 1.9

Source: Tufts CSDD, 2012

* Does not include screen failure rates

$33.9

$54.6

$94.2

$127.4

$142.2

1995 2000 2005 2010 2015P

Source: EvaluatePharma

Total Global R&D Spending

CAGR

7.4%

$ US Billions

10/22/2015

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High and Rising Development Risk

21.3%

19.1%

16.4%

11.3%

1980s 1990s 2000s 2010s to date

Clinical Success Rates (IND Filing to Approval)

Source: Tufts CSDD, 2015

Capitalized Cost to Develop a Successful Drug

$179

$413

$1,044

$2,558

1970s 1980s 1990s 2000s

(US Millions in 2013 $s)

CAGR

9.3%

Source: Tufts CSDD, 2015

10/22/2015

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Cost per NME -- Total Annual Spend per Annual Approval

2.7

2.2 2.3

3.43.7

4.6

4.2

3.7

4.9

3.8 3.7

5.1

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

($US Billions)

Source: EvaluatePharma; PwC

10-Year Average -- $3.8 Billion/Drug

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Why is Performance Optimization So Elusive?

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Why is Performance Optimization So Elusive?

1. Protocol design complexity

2. Collaboration and Integration Inefficiencies

3. Regulatory burden

4. Poor public and patient engagement

Trends in Protocol Design Practices

Scientific Characteristics

A Typical Phase III Protocol 2002 2012

Total Number of Endpoints 7 13

Total Number of Procedures 106 167

Total Number of Eligibility Criteria 31 50

Average number of Major Amendments 2.3 3.6

Proportion of procedures that are ‘Non-Core’ 18% 31%

Source: Tufts CSDD ; (* Medidata Solutions)

10/22/2015

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Trends in Protocol Design Practices

Operating Characteristics

A Typical Phase III Protocol 2002 2012

Total Number of Countries 11 34

Total Number of Investigative sites 124 196

Total Number of Patients Randomized 729 597

Total number of data points collected* 494,236 929,203

Source: Tufts CSDD ; (* Medidata Solutions)

Impact of Complexity on Performance

(All TAs, Phases II-III) ‘High’ Complexity

Compared with ‘Low’

Complexity Protocols

Study volunteer screen to completion

rate

-50%

Time from Protocol Ready to FPFV

(median)

+12%

Time from Protocol Ready to LPLV

(median)

+73%

Source: Tufts CSDD16

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Frequency of Amendments

Source: Tufts CSDD, 2010

2

2.6

3.6

2.3

Phase I Phase II Phase III Phase IIIb/IV

Mean Number of

Amendments per Protocol

Phase I

New and Modified Safety

Assessment

(15.4% of Total)

Phase IIChange in Eligibility Criteria

(17.2%)

Phase IIIChange in Eligibility Criteria

(15.2%)

Phase IIIb/IVChange in Eligibility Criteria

(17.9%)

Top Reasons for Amendments

The Cost of Implementing Protocol Amendments

43%

52%

37%

30%

38%

Overall Phase I Phase II Phase III Phase

IIIb/IV

Proportion Occurring Before

First Patient First Dose

Source: TCSDD 2010 analysis of 3,596 amendments

• Results in 2 months of

unplanned time and $497,500 in

unplanned direct costs to

implement

• 37% of all amendments are

deemed avoidable

– A significantly higher

percentage of avoidable

amendments observed

before FPFDose

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74.9

17.0

91.5

66.0

15.8

82.0

70.2

16.4

86.5

Clinical Phase* Approval Phase** Total Phase***

Mo

nth

s

Interrupted Uninterrupted All

* p=0.0131; ** p=0.4147; ***p=0.0116

The Impact of Collaboration and Risk-Sharing (2000-2011)

Source: Tufts CSDD 2013; N=289 drugs approved between 2000 – 2011

2011/12 Collaboration Assessments

• 22% of 89 sponsors had terminated

an integrated alliance

• 30% of 81 sponsors reported that

alliances were failing to deliver

expected cost and time savings

• 48% of 81 sponsors reported that

CROs can’t work collaboratively

– 60% of 57 CROs said the same

of their Sponsors 2%

45%

17%

70%

Very Satisfied Somewhat Satisfied

Satisfaction with

Relationship Quality and

Effectiveness

Sponsors CROs

Sources: Vantage Partners, Avoca, TCSDD

10/22/2015

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Growing Reliance on Outsourcing

$33.9

$54.6

$94.2

$127.4

$142.2

$3.8$10.4

$24.3

$43.1

$59.7

1995 2000 2005 2010 2015P

R&D Spend Spend on Contract Preclinical and Clinical Services

20-year

CAGR

7.4%

14.8%

Source: EvaluatePharma; William Blair & Wells Fargo Securities

$ US Billions

The Incidence of Change Orders

1.1

2.3

4.1

2.4

Phase I Phase II Phase III Phase IV

1.1

2.5

5.3

2.2

Phase I Phase II Phase III Phase IV

Integrated Alliances(Average Number per Study)

Transactional Relationships(Average Number per Study)

Source: Tufts CSDD, 2012; N =138 studies

10/22/2015

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Foundational Factors

Outsourcing Practice Culture

• Inconsistency

• Poor execution

• Legacy and New

Juggling Act

• Distrust

• Risk Aversion

• Commodity view of

External providers

• Protocol Complexity

• Poor Site

Management

• Poor Patient

Engagement

Barriers to Realizing Relationship Potential

Total Active Investigators World Wide

18,608

28,24629,883

34,959

39,791

1997 2001 2005 2009 2013

Unique 1572 filers

Source: Tufts CSDD analysis of FDA’s Bioresearch Monitoring Information System File (BMIS)

10/22/2015

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Site Enrollment Achievement

Fail to Enroll a Single

Patient

11%

Under EnrollUnder Enroll

37%37%Meet Enrollment Meet Enrollment

TargetsTargets

39%39%

Well Exceed

Enrollment Targets

13%

(N= 15,965 sites participating in 153 global phase II and III clinical trials)

Source: START Study Tufts CSDD-goBalto, 2012

Clinical Trial Process Inefficiencies

Phase II/III Programs Coefficient of Cycle

Time Variances

Study Design and Approval .8

Site Identification .9

Pre-Visit to Contract/Budget Sent to Site 1.1

Contract/Budget Sent to Site to Contract Execution 1.0

Contract Execution to Site Initiation 1.2

Site Initiation to FPI 1.4

LPLV to Data Lock .8

Source: Tufts CSDD, 2012

10/22/2015

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111

139

266

245

263254

278

2001 2003 2005 2007 2009 2011 2013

Complaints for Non-Compliance and Fraud

Source: FDA CDER Office of Compliance

Limited Connection and Relevance

27%

63%

10%

'Yes' 'No' 'Not Sure'

Percent ‘Somewhat’ and ‘Very’

Willing to Participate

Source: CISCRP 2013 N=5,701; Research!America, 2010; N=1,000 – 2,000 Adults;

87%93%

58%64%

73%

Overall North

America

Europe South

America

Asia

Pacific

Percent of the Public that

Can Name a Living Scientist

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Who makes a greater contribution to human health?

Source: CISCRP 2013 N=5,701

46%

33%

12%9%

Organ Donor Blood Donor Financial Donor CT Volunteer

Little Recognition and Appreciation

Failure to Engage Health Providers

• 23% of volunteers report that they

learned about clinical trials from their

primary/specialty care physician (CISCRP,

2015)

– Greater disparities among minority

patients given low physician

involvement

• 60% of physicians report referring

patients into clinical trials with a typical

referral rate of <1% of community served (Tufts CSDD, 2015)

– 87% of physicians who have conducted clinical

research in the past report regularly referring

their patients

Medical

Doctors

Pharmacists Nurses Auto

mechanics

Perceived Honesty and Integrity

Source: Gallup Survey, 2010

Percent of Public

Rate Very High/High

26%

66%71%

81%

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Paradigm Shift to Optimize Performance

‘Product-Centric’ ‘Patient-Centric’

Linear, Sequential Multi-directional, iterative

Compartmentalized Open

Insular Integrated

Centralized Ownership and Risk Shared Ownership and Risk

Rigid Flexible/Adaptive

Proprietary Clinical Data at the core Patient experience at the core

Focus on Great Science Focus on Great and Feasible Science

Participant as Subject Participant as Partner

(Key Characteristics)

Ernst & Young: Shift to Pharma 3.0

From

Pharma 2.0

To

Pharma 3.0

Business Model Product-Centric Consumer-Centric

Value Drivers Revenue, profitability Heath outcomes

Brand Value Product profile Consumer experience

Go-to-Market Strategy Pitching Listening and co-creating

Inorganic Growth M&A Innovative Partnerships

Innovation Spark Product differentiation Collaborative models

Information Assets IP and approval based

on clinical data

IP, approval and

reimbursement based on

real world evidence

Source: E&Y, 2013

10/22/2015

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Forming a New ‘Learning Health Care Ecosystem’

• Patient-empowered & centered drug

development and health care

• Democratization of health data and

information (EHR, mobile devices)

• Boundaries blurred between care

providers, payers, federal agencies and

research sponsors under integrated,

learning health systems

Engagement Objectives

1. Relevance

2. Feasibility

3. Convenience

4. Ownership

Parallel Developments

Regulatory Agencies

Quasi-Regulatory;

Public-Private

Clinical Research Conduct

• Individual company

initiatives; policies

and practices

• Service and

technology

solutions to

improve

convenience

• Engagement meetings

with select patient

communities to

define better

endpoints

• Guidelines on

‘acceptability’ and

‘use’

• CTTI; PCORI; MRCT;

IOM; TransCelerate;

NHC; EUPATI

• Frameworks

• Standard practices

and processes

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Proliferation of Piloted and Planned Initiatives

• Real world, pragmatic trials

• Home nursing networks

• Telemedicine

• Wearable ePRO devices

• E-Consent

• Integrated clinical & EHR data

• Lay-summary risk management

• Lay-summary clinical trial results

• Protocol feasibility review committees

• Patient advisory boards

• Professional panels

• Advocacy group involvement

• Open design and crowdsourcing

• Adaptive designs and licensing

• Real-time data collection

• Direct-to-patient clinical trials

The Value Proposition

of Patient Centered Drug Development

LevelLevel of Improvementof Improvement Cycle TimeCycle Time Success RateSuccess Rate

5% $102 million $153 million

10% $250 million $384 million

25% $390 million $486 million

Source: Tufts CSDD

Savings on Capitalized Costs in 2013 $s

10/22/2015

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Ken Getz, Director of Sponsored Research and Associate Professor

CSDD, Tufts University School of Medicine

617-636-3487

Kenneth.getz@tufts.edu

Q&A and Thank You!