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  • Side note: my wife (a certified horticulturist) & I both talk about plants but her’s are hibiscus or dieffenbachia, while mine are steel or automotive
  • In early WWII, armaments were in short supply, the British made use of every field piece possible. Anything mobile was moved to coastal defense after the fall of France. A time & motion expert was asked to watch a five man gun crew practice loading, aiming & firing. For every firing, 2 men ceased all activity and came to attention for a 3-second interval extending throughout the discharge of the gun. When he showed pictures to a WW-I artillery officer, he was also puzzled. Then, when seeing the pictures again, he said “Ah, I have it. They are holding the horses.”
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    • 1. Are Academic Medical Center Clinical Trials Going the Way of Oldsmobile? Cincinnati Innovations in Healthcare Delivery 2006 David Dilts PhD, MBA Professor & Director, Management of Technology Program, School of Engineering Professor & Director, Center for Management Research in Healthcare (www.cmrhc.org) Owen Graduate School of Management Vanderbilt University [email_address]
    • 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) The president warned that Americans were wasting too much energy, that domestic supplies of oil and natural gas were running out– Jimmy Carter 1970 Corvette Stingray 1970 Toyota Carina
    • 5. What’s Happened Since
    • 6. 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 2 nd 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%
    • 7. 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 ▼ 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”
    • 12. 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.)
    • 13. The Risk/Cost/ Time Development Paradigm Focusing on the “Elbow” $800 MM Cumulative Investment Risk Hypothesis Generation Clinical Candidate Development Commercialization $20-60 MM $200-300 MM Barker, Anna, TRWG, 2/2006 Target Identification and Validation ↓ Assay Development ↓ Lead Generation Lead Optimization Pre-Clinical Develop-ment Phase I Phase II Registra- tion Global Launch Global Optimization Phase III $500-600 MM 8 – 12 Years Time
    • 14. 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)
    • 16. 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
    • 17. Investigator-Initiated Clinical Trials At VICC – Level 0 Diagram Set-up Steps Clinical Trial Steps
    • 18.
      • Steps to activate a study
        • Opening a study requires the additional steps shown previously
          • And both come before the 1 st patient on study
      Process Map at CALGB 30 ft x 5 ft in 8 pt font
    • 19. To open or activate a study… 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
    • 20. More In-Depth Look at VICC IRB 8 Primary Participants 3 Secondary Participants 12 Value-Added Activities 9 Stopping Points 1 Study Approved 26 Paperwork 29 Approvals
    • 21. Some Statistics 1 1 7 46% 15 13 - 6 Regulatory and Clinical Research Center 1 3 10 54% 11 13 - 4 SRC 3 6 13 52% 13 14 - 6 IRB Amendments 3 9 23 32% 26 12 3 7 IRB Sub-Process Level 1 4-6 4-13 75% 1-5 6-15 1-8 3 VICCAN Member Sites (range of 3 sites) 1 2 3 70% 3 7 - 3 VICCAN Main Office 1 2 13 75% 5 15 16 11 VICC Accept Or N/A Decline Decision Points % Value Added Non-Value Added Value Added Other Primary Level 0 (Macro Process Level) Outcomes ---------Steps---------- Participants
    • 22. Part II Timelines Key Issue: What is the bottleneck or constraining process?
    • 23. Major Processing Activities Median= 784 days
    • 24. Results of Expediting
      • Note: In the studies investigated, expedited studies were only opened 15 days faster than nonexpeditied studies
    • 25. Timing At VICC: studies received between 1/1/01 to 12/31/05: 27-657 172 (159-182) 188.6 (101.80) 211 All 62-594 191 (119-269) 218.6 (127.65) 18 VICCAN 27-657 171 (158-182) 185.8 ( 98.99) 193 VICC By Manager (p=.192) 62-475 197.5 (155-259) 221.4 (115.18) 14 Other 27-657 120 ( 97-147) 141.6 ( 96.07) 58 Oncology Coop Group 158-449 230 (158-449) 239.1 ( 95.44) 8 Internal 41-614 179 (167-195) 208.8 ( 97.00) 131 Company By Sponsor Type (p<.001) 62-228 120.5 ( 80-160) 127.9 ( 45.49) 10 Other 54-657 157 (138-175) 173.2 ( 99.64) 50 III 57-238 174 ( 57-238) 154.9 ( 67.68) 7 II/III 41-594 181 (166-204) 200.2 (104.31) 91 II 27-356 174.5 (123-235) 178.2 ( 81.16) 20 I/II 27-614 176.5 (131-249) 204.9 (125.82) 28 I 189-344 231 (189-344) 250.0 ( 60.15) 5 Pilot By Phase (p=.151, excluding N<11) Min-Max Median (95%CI) Mean (Std Dev) N
    • 26. Part III: Drilling Down on Contracts & Grants at VUMC Dependent Variable: Time from Receipt to Signature (days) 938 12 298.00 172.250 192 303.03 Total 818 115 433.00 232.827 7 454.14 Other/Device 938 12 236.00 216.687 49 291.37 Evaluative 598 13 304.00 160.942 28 277.50 Phase 3 730 29 312.50 162.165 28 309.46 Phase 2 409 13 249.50 113.846 12 235.83 Phase I 726 40 314.00 138.497 68 315.59 Preclinical Maximum Minimum Median Std. Dev N Mean Phase or Study Type (p=.986) 938 12 298.00 172.250 192 303.03 Total 881 33 334.00 236.431 29 370.83 Yes 938 12 294.00 156.046 163 290.96 No Maximum Minimum Median Std. Dev N Mean Medical Device (p=.001) 938 12 298.00 172.250 192 303.03 Total 730 12 279.50 166.841 78 289.53 Yes 938 29 305.00 175.984 114 312.26 No Maximum Minimum Median Std. Dev N Mean Master contract (p=.164)
    • 27. One Other Disturbing Statistic: If insufficient patients are accrued, then all process steps are non-value added! 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 Total Other PILOT III II/III II I/II I Accrual Per Trial Percent of Studies by Phase with Accruals Range
    • 28. CALGB Phase III Accruals for Trials Investigated Phase III Accrual Rates at CALGB 15% of all studies activated in a 5 year period resulted in no accruals
    • 29. Phase III- More and Deeper
      • 2 nd 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
    • 30. 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% 4,500 3,900 -6% 48,000 51,000 -16% 21,000 25,000 2003 2001
    • 31. 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
    • 32. 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
    • 33. Importance of the Problem: the Cancer Burden Canada 138,000 / 66,000 United States of America 1.4M / 566,000 Australia 86,000 / 37,000 China 2.2M / 1.6M Austria 37,000 / 19,000 France 269,000 / 149,000 Germany 408,000 / 218,000 Switzerland 35,000 / 17,000 Iceland 1,000 / 500 Ireland 13,000 / 8,000 Japan 521,000 / 311,000 Korea 109,000 / 62,000 Norway 21,000 / 11,000 Estonia 5,000 / 3,000 Republic of Singapore 10,000 / 6,000 Sweden 43,000 / 22,000 United Kingdom 277,000 / 156,000 Source: Derived from International Agency for Research on Cancer, GLOBOCAN 2002 database Cancer Incidence / Mortality per year 7.6 million people died of cancer in 2005
    • 34. 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 PAPERWORK
    • 35. 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 % of total time 6% 12% Required Sponsor Signatures 8 0% 1% Required Contracts Signatures 7 4% 8% Required Dept Signatures 6 47% 43% 1275 form (budget) sent to Finance 5 13% 17% Sponsor Agrees 4 6% 10% Sponsor Disagrees 3 3% 5% 1st revisions to sponsor 2 1% 4% e-contract & protocol received 1 Median Mean
    • 39. 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 3 rd turn around in 5 years)
          • Conceded 2 nd 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 &quot;Japanese&quot; company, but a &quot;pro-American-worker&quot; 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