Transcript Slide 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 protected]
The will is infinite
and the execution confined,
The desire is boundless
and the act a slave to limit.
Shakespeare, Troilus and Cressida
2
Research Focus
 Transfer hard won lessons-learned
from one domain to another
Note: Every setting is “special” in some ways, but
typical in others
3
Remember When (1970’s)
1970 Corvette Stingray
1970 Toyota Carina
The president warned that Americans were wasting too much energy, that
domestic supplies of oil and natural gas were running out– Jimmy Carter
4
What’s Happened Since
5
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

–
Honda outsold the Chrysler Group

6
Toyota sales ▲16.2%, Ford sales ▼32%
Honda sales ▲10.5%, Chrysler sales ▼31.5%
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
–
7
Bill Ford, jr, resigns as Ford CEO
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

8
WSJ, Aug 19-20, 2006, p. A7
Development Time in General
160
144
140
Months
120
▲155%
100
80
60
56.4
41.7
40
▼42%
24
20
0
1995
New-to-the-world products or services
9
2004
Pharmaceuticals
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
–
10
(Tufts Center for the Study of Drug
Development Outlook 2004)
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
–
–
11
<50% of workers were in direct labor
“World-class” = “Made in Japan”
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.)
12
The Risk/Cost/ Time Development Paradigm
Focusing on the “Elbow”
Hypothesis
Generation
Clinical
Candidate Development
Commercialization
$800 MM
Cumulative Investment
Target
Identification
and Validation
↓
Lead
Assay
Optimization
Development
↓
Lead
Generation
$500-600 MM
PreClinical
Development
Phase
I
Phase
II
Phase Registra- Global
tion
III
Launch
Global
Optimization
$200-300 MM
$20-60 MM
Risk
Time
13
8 – 12 Years
Barker, Anna, TRWG, 2/2006
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
14
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
–
15
Cancer and Leukemia Group B (CALGB)
Method

Part I: Process Mapping
–
Extensive visits at each site to document processes, loops and
decisions:



–

Identify calendar time for total process and major steps, and potential
influencers of the time
Part III: Bottleneck Timing
–


Creation of process map
Part II: Process Timing
–

Say: What they say they do
Should: What policies and procedures say they should do
Do: What study chart reviews show they actually do
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
16
Investigator-Initiated Clinical Trials
At VICC – Level 0 Diagram
Clinical Trial Steps
Set-up Steps
17
Process Map at CALGB
 Steps to activate a study
30 ft x 5 ft in 8 pt font
–
Opening a study requires the additional
steps shown previously

18
And both come before the 1st patient on study
Processing Steps
CA
LG
B
VIC
C
Number of …
VIC
C
AN
To open or activate a study…
< 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
Note: Some signatures take less than a minute to obtain…
… others take up to 60 days
Dilts et al. (2006) “Processes to Activate Phase III Clinical Trials in a Cooperative Oncology Group, the
19 case of CALGB”, J Clinical Oncology, 24(28), xxx.
More In-Depth Look at VICC IRB
29 Approvals 8 Primary Participants
20
3 Secondary Participants 26 Paperwork
12 Value-Added Activities
1 Study Approved
9 Stopping Points
Some Statistics
Participants
Level 0 (Macro Process
Level)
Primary
Other
---------Steps---------Value
Added
NonValue
Added
Outcomes
%
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
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
Sub-Process Level
21
Part II Timelines
Key Issue: What is the bottleneck or constraining process?
Median Times
217
Receipt to First Pt
34
Open to First Pt
172
Receipt to Open
70
SRC
78.5
Contract & Grants
47
IRB
39
Start to First Process
0
50
100
150
Days
22
200
250
Major Processing Activities
Protocol Develoment
477 days
Protocol Review
277 days
CIRB Review
111 days
Concept
Review
126 days
Concept Development
193 days
Forms / Database Development
434 days
CDE Compliance Review
240 days
Grant Development
222 days
Concept Review
16 days
Concept Voting
2 days
Regulatory Affairs Development
350 days
FDA Review
100 days
Concept Approval
7 days
Study Team Teleconference
16 days
23
Median= 784 days
Activation
7 days
Results of Expediting
120.0
100.0
90.0
100.0
60.0
60.0
50.0
40.0
40.0
% of Studies Requiring Revision
70.0
80.0
30.0
20.0
20.0
10.0
%
0%
10
95
%
90
%
%
85
80
%
75
%
70
%
%
%
65
60
55
%
50
%
%
45
40
%
35
%
30
%
%
%
25
20
15
10
%
0.0
5%
0.0
0%
Number of Studies Opened in 5 yrs
80.0
% of Studies Expedited
Studies Opened
% Revisions
Note: In the studies investigated, expedited studies were only opened 15 days
24
faster than nonexpeditied studies
Timing At VICC:
studies received between 1/1/01 to 12/31/05:
N
By Phase (p=.151, excluding N<11)
Pilot
I
I/II
II
II/III
III
Other
Mean (Std Dev)
Median (95%CI)
Min-Max
5
28
20
91
7
50
10
250.0
204.9
178.2
200.2
154.9
173.2
127.9
( 60.15)
(125.82)
( 81.16)
(104.31)
( 67.68)
( 99.64)
( 45.49)
231 (189-344)
176.5 (131-249)
174.5 (123-235)
181 (166-204)
174 ( 57-238)
157 (138-175)
120.5 ( 80-160)
189-344
27-614
27-356
41-594
57-238
54-657
62-228
By Sponsor Type (p<.001)
Company
Internal
Oncology Coop Group
Other
131
8
58
14
208.8
239.1
141.6
221.4
( 97.00)
( 95.44)
( 96.07)
(115.18)
179 (167-195)
230 (158-449)
120 ( 97-147)
197.5 (155-259)
41-614
158-449
27-657
62-475
By Manager (p=.192)
VICC
VICCAN
193
18
185.8 ( 98.99)
218.6 (127.65)
171 (158-182)
191 (119-269)
27-657
62-594
All
211
188.6 (101.80)
172 (159-182)
27-657
25
Part III: Drilling Down on
Contracts & Grants at VUMC
Dependent Variable: Time from Receipt to Signature (days)
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
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
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
Medical Device (p=.001)
Phase or Study Type
(p=.986)
26
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%
>20
17.2%
25.0%
3.2%
14.3%
3.9%
8.5%
14.3%
9.8%
3.7%
27.3%
12.4%
If insufficient patients are accrued, then all process steps are non-value added!
27
CALGBPhase
Phase
Accruals
foratTrials
Investigated
IIIIII
Accrual
Rates
CALGB
5000
4500
4000
15% of all studies activated in a 5 year
period resulted in no accruals
3500
Accrual
3000
2500
2148
2000
1500
1000
732
513
500
369
238
212
152
67
63
42
41
15
1
May-05
Apr-04
0
May-02
Oct-03
Jun-04
Dec-03
Dec-03
Dec-02
Apr-05
May-02
Jan-04
Mar-04
Dec-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
Accruals
28
Expected Accrual
Phase III- More and Deeper

2nd Major NCI Grant
–
Study Settings:



–
Outcomes



Individual process maps for each group
Timing data study for all sites
Projected Phase IV
–

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.
Major roundtable to dramatically improve the system
Other activities:
–
–
–
–
29
EDRN – early detection research network
CTWG –clinical trials working group
TRWG – translational research working group
& pharmaceutical firms are becoming interested
What Drug Companies are Doing
Some Statistics
Year
2001
2003
U.S. PI’s
25,000
21,000
-16%
U.S. Clinical trial sites
51,000
48,000
-6%
3,900
4,500
15%
FDA-approved investigational drug studies (all phases)



“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)
30
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
31
Think It Can’t Happen Here?
 So did they:
–
Oldsmobile



–
Winchester



–
Founded in 1860
“The Gun that Won the West.”
No longer made in America after March, 2006.
RCA Victor



32
One of the original car companies (1874)
After 107 years, 35.2 million cars,
Ceased production in 2004
World’s largest manufacturer of phonographs
(Victrola)
Introduced the 33 1/3 RPM
Died as a manufacturer, circa 1970
Importance of the Problem:
the Cancer Burden
Iceland
1,000 / 500
Canada
138,000 / 66,000
United States
of America
1.4M / 566,000
7.6 million
people
died of cancer
in 2005
Sweden
43,000
/ 22,000
Norway
21,000 / 11,000
Estonia
5,000 / 3,000
Ireland
Germany
13,000 / 8,000
408,000 / 218,000
United Kingdom
277,000 / 156,000
Austria
37,000 / 19,000
Japan
521,000 / 311,000
China
2.2M / 1.6M
Switzerland
35,000
/ 17,000
France
269,000 / 149,000
Korea
109,000 / 62,000
Republic of
Singapore
10,000 / 6,000
Australia
86,000 / 37,000
Cancer Incidence / Mortality per year
Source: Derived from International Agency for Research on Cancer, GLOBOCAN 2002 database
33
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
–

Then:
–

And a typical drug requires three phases
~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
34
ALL BECAUSE OF PAPERWORK
Thank you
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?
36
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
37
Bottleneck in the Bottleneck
% of total time
1 e-contract & protocol received
2 1st revisions to sponsor
3 Sponsor Disagrees
4 Sponsor Agrees
5 1275 form (budget) sent to Finance
6 Required Dept Signatures
7 Required Contracts Signatures
8 Required Sponsor Signatures
38
Mean Median
4%
1%
5%
3%
10%
6%
17%
43%
8%
13%
47%
4%
1%
12%
0%
6%
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
–
39
(2006 Nanomedicine, Device & Diagnostic Report, National Health Information, LLC)
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
–
40
DamlierChrysler cuts 14% of workforce
The Traditional USA Way
• Very large, tightly integrated, monolithic plants
• Extremely efficient when they operate
• Terribly expensive to start, stop or change
41
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-Americanworker" 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.

42
Fairclough, F (2006 July 12), WSJ, D5