are academic medical center clinical trials going the way of

Are Academic Medical Center Clinical Trials Going

the Way of Oldsmobile?

Cincinnati Innovations in Healthcare Delivery 2006

David Dilts PhD, MBAProfessor & Director, Management of Technology Program, School of EngineeringProfessor & Director, Center for Management Research in Healthcare (www.cmrhc.org)

Owen Graduate School of ManagementVanderbilt University

David.dilts@vanderbilt.edu

2

The will is infinite and the execution confined,The desire is boundless and the act a slave to limit.

Shakespeare, Troilus and Cressida

3

Research Focus

Transfer hard won lessons-learned from one domain to another

Note: Every setting is “special” in some ways, but typical in others

4

Remember When (1970’s)

1970 Corvette Stingray

1970 Toyota Carina

The president warned that Americans were wasting too much energy, that The president warned that Americans were wasting too much energy, that domestic supplies of oil and natural gas were running out– domestic supplies of oil and natural gas were running out– Jimmy CarterJimmy Carter

5

What’s Happened Since

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Two Days in July & August

July 3, 2006: North America Sales– GM Sales ▼26% (37% in light trucks)– Ford Sales ▼6.9%– DaimlerChrysler ▼15%– Toyota Motor ▲14% (22% in passenger cars)– Nissan ▼19%

August 1, 2006– Toyota became the 2nd biggest selling auto company in

the United States Toyota sales ▲16.2%, Ford sales ▼32%

– Honda outsold the Chrysler Group Honda sales ▲10.5%, Chrysler sales ▼31.5%

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Not convinced yet?

August 18, 2006: – Ford to cut 21% of its N.A. production, will

partially shut down at least 10 plants– Ford & GM credit-ratings are five notches below

investment grade (just above junk bond status)

Sept 6, 2006– Bill Ford, jr, resigns as Ford CEO

8

A telling statement

“We are trying to figure out how and how much you advertise new products that are going into (a) segment that may be DOA”

– A Ford SUV manager WSJ, Aug 19-20, 2006, p. A7

9

Development Time in General

41.7

24

56.4

144

0

20

40

60

80

100

120

140

160

1995 2004

Mo

nth

s

New-to-the-world products or services Pharmaceuticals

▼42%

▲155%

10

Question:

Why does it take ~60 months to develop & certify a new jet aircraft but it takes:

38% (~23 months) longer for New Drug Development & Approval Times

– (Tufts CSDD Report 2003, Vol. 5, No. 2)

48% (~29 months) longer for New Biopharmaceutical Development & Approval Times

– (Tufts Center for the Study of Drug Development Outlook 2004)

11

What US Manufacturing Discovered:

U.S.A. was – best in the world, once we started manufacturing– worst in the world, at getting ready to manufacture,

i.e., set-up times When Henry Ford Designed the River Rouge

Factory in 1927 for the Model A:– 95% Direct Labor costs, 5% other costs– From “ore to assembly” – “…easily the greatest industrial domain in the

world” DL Lewis By 1985

– <50% of workers were in direct labor– “World-class” = “Made in Japan”

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Focusing on Setups:The Process Thought-To-Be versus As-Is

Do not assume that the set-up time is fixed Specifically study what is done (not what is

thought to be done) and why each action is done

(Morison, EE 1966 Men, Machines, and Modern Times, MIT Press.)

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Target

Identification

and Validation

↓

Assay

Development

↓

Lead

Generation

LeadOptimization

Pre-Clinical

Develop-ment

Phase I

Phase II

Registra-

tion

Global Launch

Global Optimization

Phase III

$500-600 MM

The Risk/Cost/ Time Development Paradigm Focusing on the “Elbow”

$800 MM

Cumulative Investment

8 – 12 Years

Time

Risk

HypothesisGeneration

ClinicalCandidate Development

Commercialization

$20-60 MM

$200-300 MM

Barker, Anna, TRWG, 2/2006

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What Must Be Done Before Any Clinical Trial

Infrastructure Processes, – i.e., The Dreaded TLAs

IRBs: Institutional Review Boards SRCs: Scientific Review Committees C&Gs: Contracting & Grants Office CTOs: Clinical Trial Offices CRCs: Clinical Research Centers

15

Current Study Settings

Community Groups Vanderbilt-Ingram Cancer Center Affiliates Network (VICCAN)

home office 3 VICCAN member sites

– Memorial, Chattanooga, TN– Central Georgia Hem/Onc (CGHO), Macon, GA– Meharry Medical College (MMC), Nashville, TN

Comprehensive Cancer Center (VICC)–

Academic Medical Center (VUMC)–

Cooperative Oncology Group– Cancer and Leukemia Group B (CALGB)

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Method

Part I: Process Mapping– Extensive visits at each site to document processes, loops and

decisions: Say: What they say they do Should: What policies and procedures say they should do Do: What study chart reviews show they actually do

– Creation of process map Part II: Process Timing

– Identify calendar time for total process and major steps, and potential influencers of the time

Part III: Bottleneck Timing– Using the identified bottleneck process, drill down to discover why

Part IV: Fix the processes Key Aspects:

– What are the bottleneck or constraining processes?– What is the critical path to opening a study?

Dilts and Sandler (2006) “The Invisible Barriers to Opening Clinical Trials, J Clin Onc, 24(28), xxx

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Investigator-Initiated Clinical Trials At VICC – Level 0 Diagram

Set-up Steps

Clinical Trial Steps

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Steps to activate a study

– Opening a study requires the additional steps shown previously And both come before the 1st patient on study

30 ft x 5 ft in 8 pt font

Process Map at CALGB

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To open or activate a study…

Number of … VIC

CA

N

VIC

C

CA

LGB

Processing Steps < 60 > 110 >370

Groups / Individuals Involved 13 - 27 < 27 > 30

Signatures Required 4 - 12 13 - 27 > 70

Decision Points n/a n/a 42

Processing Loops n/a n/a 29

Dilts et al. (2006) “Processes to Activate Phase III Clinical Trials in a Cooperative Oncology Group, the case of CALGB”, J Clinical Oncology, 24(28), xxx.

Note: Some signatures take less than a minute to obtain…

… others take up to 60 days

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More In-Depth Look at VICC IRB

8 Primary Participants 3 Secondary Participants

12 Value-Added Activities

9 Stopping Points

1 Study Approved

26 Paperwork29 Approvals

21

Some Statistics

11746%1513-6Regulatory and Clinical Research Center

131054%1113-4SRC

361352%1314-6IRB Amendments

392332%261237IRB

Sub-Process Level

14-64-1375%1-56-151-83VICCAN Member Sites (range of 3 sites)

12370%37-3VICCAN Main Office

121375%5151611VICC

Accept Or N/ADecline

Decision Points

% Value Added

Non-Value Added

Value Added

OtherPrimaryLevel 0 (Macro Process Level)

Outcomes---------Steps----------Participants

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Part II TimelinesKey Issue: What is the bottleneck or constraining process?

39

47

78.5

70

172

34

217

0 50 100 150 200 250

Days

Start to First Process

IRB

Contract & Grants

SRC

Receipt to Open

Open to First Pt

Receipt to First Pt

Median Times

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Median= 784 days

CIRB Review111 days

Activation7 days

Concept Development193 days

Concept Review

126 days

Concept Review 16 days

Concept Voting 2 days

Concept Approval 7 days

Study Team Teleconference 16 days

Grant Development222 days

FDA Review100 days

Regulatory Affairs Development350 days

Forms / Database Development434 days

CDE Compliance Review240 days

Protocol Develoment477 days

Protocol Review277 days

Major Processing Activities

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Results of Expediting

Note: In the studies investigated, expedited studies were only opened 15 days faster than nonexpeditied studies

0.0

20.0

40.0

60.0

80.0

100.0

120.0

0% 5% 10%

15%

20%

25%

30%

35%

40%

45%

50%

55%

60%

65%

70%

75%

80%

85%

90%

95%

100%

% of Studies Expedited

Nu

mb

er

of

Stu

die

s O

pe

ne

d in

5 y

rs

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

% o

f S

tud

ies

Re

qu

irin

g R

ev

isio

n

Studies Opened % Revisions

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Timing At VICC:studies received between 1/1/01 to 12/31/05:

27-657172 (159-182)188.6 (101.80)211All

62-594191 (119-269)218.6 (127.65)18 VICCAN27-657171 (158-182)185.8 ( 98.99)193 VICC

By Manager (p=.192)

62-475197.5 (155-259)221.4 (115.18)14 Other27-657120 ( 97-147)141.6 ( 96.07)58 Oncology Coop Group

158-449230 (158-449)239.1 ( 95.44)8 Internal41-614179 (167-195)208.8 ( 97.00)131 Company

By Sponsor Type (p<.001)

62-228120.5 ( 80-160)127.9 ( 45.49)10 Other54-657157 (138-175)173.2 ( 99.64)50 III57-238174 ( 57-238)154.9 ( 67.68)7 II/III41-594181 (166-204)200.2 (104.31)91 II27-356174.5 (123-235)178.2 ( 81.16)20 I/II27-614176.5 (131-249)204.9 (125.82)28 I

189-344231 (189-344)250.0 ( 60.15)5 PilotBy Phase (p=.151, excluding N<11)

Min-MaxMedian (95%CI)Mean (Std Dev)N

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Part III: Drilling Down on Contracts & Grants at VUMC

93812298.00172.250192303.03Total

818115433.00232.8277454.14Other/Device

93812236.00216.68749291.37Evaluative

59813304.00160.94228277.50Phase 3

73029312.50162.16528309.46Phase 2

40913249.50113.84612235.83Phase I

72640314.00138.49768315.59Preclinical

MaximumMinimumMedianStd. DevNMeanPhase or Study Type (p=.986)

93812298.00172.250192303.03Total

88133334.00236.43129370.83Yes

93812294.00156.046163290.96No

MaximumMinimumMedianStd. DevNMeanMedical Device (p=.001)

93812298.00172.250192303.03Total

73012279.50166.84178289.53Yes

93829305.00175.984114312.26No

MaximumMinimumMedianStd. DevNMeanMaster contract (p=.164)

Dependent Variable: Time from Receipt to Signature (days)

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One Other Disturbing Statistic:

12.4%27.3%9.8%14.3%8.5%25.0%17.2%>20

3.7%3.9%14.3%3.2%6.9%16-20

11.0%9.1%11.8%10.6%15.0%13.8%11-15

19.3%9.1%33.3%19.6%20.2%10.0%27.6%5-10

33.0%18.2%16.7%27.5%71.4%35.1%40.0%31.0%1-4

20.6%36.4%50.0%27.5%0.0%22.3%10.0%3.4%0

TotalOtherPILOTIIIII/IIIIII/IIIAccrual Per

Trial

Percent of Studies by Phase with Accruals Range

If insufficient patients are accrued, then all process steps are non-value added!

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CALGB Phase III Accruals for Trials Investigated

2148

732513

369238 212 152 67 63 42 41 15 1

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

May-02 Oct-03 Jun-04 Dec-03 Dec-03 Dec-02 Apr-05 May-02 Jan-04 Mar-04 Dec-04 May-05 Apr-04

Breast GU GU Leuk GI* GI GU Resp* GU GU Transp Lymp GU*

40101 90206 80303 10201 80203 80101 90401 30102 90202 90104 100104 50303 90106

Ac

cru

al

Accruals Expected Accrual

Phase III Accrual Rates at CALGB

15% of all studies activated in a 5 year period resulted in no accruals

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Phase III- More and Deeper

2nd Major NCI Grant– Study Settings:

Eastern Cooperative Oncology Group (ECOG) 4 Comprehensive Cancer Centers Cancer Therapy Evaluation Program (CTEP)

– Studying CTEP is equivalent to being allowed to study how the IRS makes its decisions.

– Outcomes Individual process maps for each group Timing data study for all sites

Projected Phase IV– Major roundtable to dramatically improve the system

Other activities:– EDRN – early detection research network– CTWG –clinical trials working group– TRWG – translational research working group– & pharmaceutical firms are becoming interested

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What Drug Companies are Doing

“29% of our clinical trials are now done abroad, we expect that figure to jump to 50% in two years.”

– Tadataka Yamada, GlaxoSmithKline’s Chairman of R&D Discussing a post-marketing clinical trial for two cardiovascular drugs – involving

46,000 patients in 1,250 hospitals in China – cost $3 million. “Could you do it in Europe? I don’t think so.”

Tom McKillop, Former CEO of AstraZeneca (quoted in WSJ, 2/14/2006) “For a Phase II trial, the cost for 100 patients in China could be as low as $25,000, while

in the U.S. or Europe, it could range from $500,000 to $1 million Dr. Ikeguchi, Medidata Solutions (quoted in WSJ 2/14/2006)

FDA-approved investigational drug studies (all phases)

U.S. Clinical trial sites

U.S. PI’s

Year

Some Statistics

15%4,5003,900

-6%48,00051,000

-16%21,00025,000

20032001

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Don’t look to the government to bail out AMCs

“NIH Budget Falls for the First Time in 36 Years” AAAS R&D Funding update

– http://www.aaas.org/spp/rd/nih06f.htm

“If the knives are going to come out, now is when it will happen” National Journal Group, 04-15-2006

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Think It Can’t Happen Here?

So did they:– Oldsmobile

One of the original car companies (1874) After 107 years, 35.2 million cars, Ceased production in 2004

– Winchester Founded in 1860 “The Gun that Won the West.” No longer made in America after March, 2006.

– RCA Victor World’s largest manufacturer of phonographs

(Victrola) Introduced the 33 1/3 RPM Died as a manufacturer, circa 1970

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Importance of the Problem:the Cancer Burden

Canada138,000 / 66,000

United States of America

1.4M / 566,000

Australia86,000 / 37,000

China2.2M / 1.6M

Austria37,000 / 19,000

France269,000 / 149,000

Germany408,000 / 218,000

Switzerland35,000 / 17,000

Iceland1,000 / 500

Ireland13,000 / 8,000

Japan521,000 / 311,000

Korea109,000 / 62,000

Norway21,000 / 11,000

Estonia5,000 / 3,000

Republic of Singapore

10,000 / 6,000

Sweden43,000 / 22,000

United Kingdom277,000 / 156,000

Source: Derived from International Agency for Research on Cancer, GLOBOCAN 2002 database

Cancer Incidence / Mortality per year

7.6 millionpeople

died of cancer in 2005

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Bottom-line

With: – Setup for each clinical trial phase taking

2.1 years for a cooperative group, then ~5 ½ months for a comprehensive cancer center

– And a typical drug requires three phases

Then:– ~7.8 years are spent in setup paperwork

Therefore:– For Pharmaceutical Firms:

A nearly 8 years of sales are lost, along with those profits– For physicians & patients:

~11 million new cancer patients in the US alone will not have the best treatment possible

~4.4 million cancer deaths will not be prevented or delayed

ALL BECAUSE OF PAPERWORKALL BECAUSE OF PAPERWORK

Thank you

36

Does It Only Work For Manufacturing?

– IBM Credit went from 7-days to 4-hours without an increase in headcount

– Ford Accounts Payable had 500 people to do the same work that Mazda did with 5

– (Hammer & Champy (1993) Reengineering the Corporation)

– Southwest Airlines 10 minute turn-around time “Ticketless” travel No Assigned seating

Can we use the same techniques in Clinical Trials?

37

Composition of Development Time

Typical Reported Phases– Clinical Phase– FDA Approval Phase

But can a study start once a LOI is submitted? Or must you wait? If you wait, what are you

waiting on? Setup processes, all of which take time But setup is not typically measured

38

Bottleneck in the Bottleneck

6%12%Required Sponsor Signatures8

0%1%Required Contracts Signatures7

4%8%Required Dept Signatures6

47%43%1275 form (budget) sent to Finance5

13%17%Sponsor Agrees4

6%10%Sponsor Disagrees3

3%5%1st revisions to sponsor2

1%4%e-contract & protocol received1

MedianMean

% of total time

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And the problem is getting worse

In the 1990s, the FDA approved 38 new agents for treatment of cancer and cancer-related indications, more than the preceding 40 years

The more than 100 claims approved for treatment indications during the 1990s far exceeded the total of those granted in the proceeding 40 years

– (Rothenberg ML, Carbone DP, Johnson DH, Improving the evaluations of new cancer treatments: challenges and opportunities. Nature Rev Cancer 2003;3:303-9)

In one new area: nanotechnology– Understanding of cancer at the molecular level is progressing exponentially– Nano-based devices and drugs for cancer and all diseases are increasing

68% increase in the clinical pipeline from 2005 130 nanotech-based drugs and delivery systems 125 devices or diagnostic tests

– (2006 Nanomedicine, Device & Diagnostic Report, National Health Information, LLC)

40

And remember the automobile industry (Part 2)

September 15, 2006– Ford

called for 44,000 job cuts– (The 3rd turn around in 5 years)

Conceded 2nd place in the US to Toyota Does not expect to make a profit in NA until 2009

– Chrysler Group Would report a loss for this summer of $1.5

billion, more than double that anticipated

September 20, 2006– DamlierChrysler cuts 14% of workforce

41

The Traditional USA Way

• Very large, tightly integrated, monolithic plants• Extremely efficient when they operate• Terribly expensive to start, stop or change

42

And remember the automobile industry (Part 1)

“In the mid-1970s, anybody found driving a Japanese car in Michigan was in danger of ending up with a tire slashed or a door keyed. Today, mention one of the Big Three U.S. auto-makers -- GM, Ford or DaimlerChrysler -- at a blue-collar Midwestern honky-tonk and you'll hear groans. Everybody in the Midwest these days is begging Honda to come into their hometown. It is no longer viewed as a "Japanese" company, but a "pro-American-worker" corporation flush with jobs, jobs, jobs.”

Douglas Brinkley, D (2006, July 18) “Hoosier Honda”, WSJ, A14

SHANGHAI -- Nanjing Automobile (Group) Corp., a Chinese state-owned car maker, said it is joining with two U.S. investment funds to build MG cars at a new plant in Oklahoma.

Fairclough, F (2006 July 12), WSJ, D5