Are Academic Medical Center Clinical Trials Going the Way of Oldsmobile?
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Transcript of Are Academic Medical Center Clinical Trials Going the Way of Oldsmobile?
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
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The will is infinite
and the execution confined,
The desire is boundless
and the act a slave to limit.
Shakespeare, Troilus and Cressida
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Research Focus
Transfer hard won lessons-learned from one domain to another
Note: Every setting is “special” in some ways, but typical in others
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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
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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
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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
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Development Time in General
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1995 2004
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New-to-the-world products or services Pharmaceuticals
▼42%
▲155%
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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)
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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
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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 …
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
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Some Statistics
Participants ---------Steps---------- Outcomes
Level 0 (Macro Process Level)
Primary Other Value Added
Non-Value Added
% Value Added
Decision Points Decline
Accept Or N/A
VICC 11 16 15 5 75% 13 2 1
VICCAN Main Office 3 - 7 3 70% 3 2 1
VICCAN Member Sites (range of 3 sites)
3 1-8 6-15 1-5 75% 4-13 4-6 1
Sub-Process Level
IRB 7 3 12 26 32% 23 9 3
IRB Amendments 6 - 14 13 52% 13 6 3
SRC 4 - 13 11 54% 10 3 1
Regulatory and Clinical Research Center
6 - 13 15 46% 7 1 1
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Part II TimelinesKey Issue: What is the bottleneck or constraining process?
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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
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120.0
0% 5% 10%
15%
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% of Studies Expedited
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Studies Opened % Revisions
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Timing At VICC:studies received between 1/1/01 to 12/31/05:
N Mean (Std Dev) Median (95%CI) Min-Max
By Phase (p=.151, excluding N<11)
Pilot 5 250.0 ( 60.15) 231 (189-344) 189-344 I 28 204.9 (125.82) 176.5 (131-249) 27-614 I/II 20 178.2 ( 81.16) 174.5 (123-235) 27-356 II 91 200.2 (104.31) 181 (166-204) 41-594 II/III 7 154.9 ( 67.68) 174 ( 57-238) 57-238 III 50 173.2 ( 99.64) 157 (138-175) 54-657 Other 10 127.9 ( 45.49) 120.5 ( 80-160) 62-228
By Sponsor Type (p<.001)
Company 131 208.8 ( 97.00) 179 (167-195) 41-614 Internal 8 239.1 ( 95.44) 230 (158-449) 158-449 Oncology Coop Group 58 141.6 ( 96.07) 120 ( 97-147) 27-657 Other 14 221.4 (115.18) 197.5 (155-259) 62-475
By Manager (p=.192)
VICC 193 185.8 ( 98.99) 171 (158-182) 27-657 VICCAN 18 218.6 (127.65) 191 (119-269) 62-594
All 211 188.6 (101.80) 172 (159-182) 27-657
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Part III: Drilling Down on Contracts & Grants at VUMC
Master contract (p=.164) Mean N Std. Dev Median Minimum Maximum
No 312.26 114 175.984 305.00 29 938
Yes 289.53 78 166.841 279.50 12 730
Total 303.03 192 172.250 298.00 12 938
Medical Device (p=.001) Mean N Std. Dev Median Minimum Maximum
No 290.96 163 156.046 294.00 12 938
Yes 370.83 29 236.431 334.00 33 881
Total 303.03 192 172.250 298.00 12 938
Phase or Study Type (p=.986)
Mean N Std. Dev Median Minimum Maximum
Preclinical 315.59 68 138.497 314.00 40 726
Phase I 235.83 12 113.846 249.50 13 409
Phase 2 309.46 28 162.165 312.50 29 730
Phase 3 277.50 28 160.942 304.00 13 598
Evaluative 291.37 49 216.687 236.00 12 938
Other/Device 454.14 7 232.827 433.00 115 818
Total 303.03 192 172.250 298.00 12 938
Dependent Variable: Time from Receipt to Signature (days)
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One Other Disturbing Statistic:
Percent of Studies by Phase with Accruals Range
Accrual Per Trial I I/II II II/III III PILOT Other Total
0 3.4% 10.0% 22.3% 0.0% 27.5% 50.0% 36.4% 20.6%
1-4 31.0% 40.0% 35.1% 71.4% 27.5% 16.7% 18.2% 33.0%
5-10 27.6% 10.0% 20.2% 19.6% 33.3% 9.1% 19.3%
11-15 13.8% 15.0% 10.6% 11.8% 9.1% 11.0%
16-20 6.9% 3.2% 14.3% 3.9% 3.7%
>20 17.2% 25.0% 8.5% 14.3% 9.8% 27.3% 12.4%
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)
Some Statistics
Year 2001 2003
U.S. PI’s 25,000 21,000 -16%
U.S. Clinical trial sites 51,000 48,000 -6%
FDA-approved investigational drug studies (all phases) 3,900 4,500 15%
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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 databaseSource: 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
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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?
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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
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Bottleneck in the Bottleneck
Mean Median
1 e-contract & protocol received 4% 1%
2 1st revisions to sponsor 5% 3%
3 Sponsor Disagrees 10% 6%
4 Sponsor Agrees 17% 13%
5 1275 form (budget) sent to Finance 43% 47%
6 Required Dept Signatures 8% 4%
7 Required Contracts Signatures 1% 0%
8 Required Sponsor Signatures 12% 6%
% 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)
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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
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The Traditional USA Way
• Very large, tightly integrated, monolithic plants• Extremely efficient when they operate• Terribly expensive to start, stop or change
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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