andy grove's slides on translational medicine
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Translational Medicine: Key to Progress or Bridge to
Nowhere?
Andy Grove
Anti-Medical School
August 31, 2011
Cost of the Great Pyramid
Cost of the Great Pyramid
Cambridge Archaeological Journal, 1996
Cost: ~ $1BTime it took: 20 years
Cost Per NME
Munos B Nat Rev Drug Disc 2009
NM
E c
ost
(U
S$
bill
ion
s)
2.0
1.0
1.5
0.5
01950 1970 1990 2010
Average Drug Development Time
1990
2004
10 years
14 years
Nature Review, 2011
Attrition: High and Growing
Early 1990s
Early 2000s
96%
99.8%
Nature.com/reviews/drug Disc, 2011
The New Age: Cells and GenesWill be Much Harder
• Organic molecules augmented/replaced by genes and cells
• Many targets– Need new manufacturing, systems
• Drug delivery problems compound biology
Technology Integration
• Emerges as key capability and discipline
Example: Implantable Bioartificial Kidney
• Combination of silicon membranes and proximal tubule cells– provides ultrafiltration and cell therapy
• mimics nephron physiology
– “pump-less” operation without need for dialysate• ensures long-term volume/electrolyte balance
– cells are immunoisolated from host• eliminates need for anti-rejection therapy
Silicon Membranes Kidney Cells
Courtesy: The Kidney Project, UCSF (Shuvo Roy, PI)
Example: Growth Factors In Neurodegenerative Disease
• Twenty years in development as therapy
• Animal models questionable
• Brain delivery is invasive (BBB), not well controlled
• Delivery technique (“CED”) developed
Less resource today than 20 years ago
Biotech Seed Investment
• Biologics, combinations and difficult delivery requirements exceed the “bounded rationality” of investors
• Aggressive investments go elsewhere
Biotech <3% of total
Nature, 2003
Science Translational Medicine, August, 2011
Tinkering at the Margins
• Like replacing mud slurry with animal fat
Industry transformation is needed.
TransformationBy analogy to “Phase Transition”
• Discontinuous change of certain characteristics of an industry
• Usually the result of changes in external conditions
Strategic Inflection Points (SIP)
Inflection point
Trying to take advantage
Trying to get by
Transformational Changes Needed to Lower Resistance
1. Move translational boundary, using targeted philanthropy
2. Re-architect regulatory process
1. Move Translational Boundary
• Shift more responsibility for dealing with integration and complexity to the medical centers
Classical Way
Medical Center
(Science)
IP
$
Pharma To patients
Second Way – How it WasCheap venture money pours in; pharma chokes
Medical Center
(Science)
IP
$
Pharma Topatients
Biotechstartup
VC $$$ (cheap venture money)
New Pharma after acquisition
Third Way
Medical Center
(Science)
Early clinical work
IP+
data
$
Pharma To patients
VC $ (lower risk,accepts lower returns)
Biotechstartup
Targeted investments,
early
New Pharma after acquisition
Such a Change Requires...
• Goal orientation by medical center
• Dedication to integration by staff
• Targeted philanthropy
History of the Salk Vaccine
• Ingredients: – A driven physician– A businessman-turned-operational manager,
fully devoted– A President as patient advocate– The March of Dimes
• Alternative: Acres of iron lungs• Result: 2,000,000 children vaccinated in
the first year; polio nearly eradicated in the U.S.
Movie clip: Polio Vaccine Story
Constructive Use of IP
• IP rights are grants of monopoly– Given out for society’s benefit
• Today, they keep products off the market
• Trivial and obvious “inventions” overwhelm the patent system
Will destroy innovation
The Economist, August, 2011
“Patenting the Sun”
2. Re-Architect Regulatory System
Problems of Regulatory System
• Mission creep
• Old technology
• System does not scale sufficiently
FDA Mission Creep
• 1930s– Mandating a pre-market review of the safety of
all new drugs– Banning false therapeutic claims
• 1962– Amendment requiring “substantial evidence” of
the drug’s efficacy for a marketed indication
• Late ’80s on– 137 specific statutes, 18 general statues, 14
executive orders
Meanwhile...
• Trial records stored on paper in warehouses, inaccessible for analysis
Activity 800,000 papers 6,100 Phase 3 trials
Pre-clinicalR&D
Regulatorysystem
Drug development
& clinical trials
20
Drug Development & Regulatory System
GAO “New Drug Development” Report, 2006
Activity 800,000 papers 6,100 Phase 3 trials
Pre-clinicalR&D
Regulatorysystem
Drug development
& clinical trials
20
200
61,000 Phase 3 trials
Can it Scale10X?
Scaling 10X
5,000 patients* x 20 = 100,000 patients/year
Per drug out drugs out/year
of Ph 3)
5,000 patients* x 200 = 1,000,000Per drug out drugs out/year patients/year
of Ph 3)
*5,000 patients/drug: GAO report New Drug Development, 2004
• Recruitment of patients is already the limiting factor
• 50% of trials miss schedules
• 90% of time is due to patient recruiting
Eur Respir J, 1992McKinsey, 2002
~$300M cost
A Year’s Delay
R&D Directions, 2008
It Will Get Worse
• Post-marketing monitoring
• Comparative effectiveness research
• Additional complexity due to biologics
Reminiscent: Bell Labs Late 1940s
• Traffic growth– Actual and projected
• Switching manually done• Electronic technology unreliable• Started solid state effort• Transistor discovered• Electronic switching• Direct dialing allows scaling
Bell System bet & won.
Survived.
Trial Architecture
• Designed with technical environment circa 1960
• Today’s technical environment is dramatically different
Comparison of Technical Environments (estimate)
1960 2011
IC cost/cycle 10-4 10-38
DB cost/stored byte 103 $/MB 10-4 $/MB
BW (103 b/sec) (107 b/sec)
Comparison of Technical Environments (estimate)
Cost to download 1998 2011
a movie $270 $0.05
Regulatory System is Based On
This... instead of this
Footprints in the Snow
“A New Bargain for Drug Approvals”
“Returning the FDA to its earlier mission of ensuring safety and leaving proof of efficacy for post-approval”
WSJ, p. A15, July 27, 2011
Free To Choose
www.heartland.org
Note: “Drug Repositioning”
• A way to lower costs of drug development
• Attacking the lesser of two obstacles
New Trial System
• N = 1• Virtual cohorts• “Zero” cost to scale• Open for research• “Progressive approval”• Other approaches:
– Adaptive trials– Registry-based– “Free to Choose”
How Do We Stimulate Action?
Learning From Corporate Transformation
• More difficult in the absence of an emergency
• Response to recognition: experimentation
• “Let chaos reign, then rein in chaos”
• In corporations, central leadership and control can do both
Industry-Wide Change:
• Experimentation can take place absent central stimulus
• Guiding/reigning-in cannot
• The only central force is the State
• Philosophical objections to industrial policy
The Unstated Role of the Regulatory System
• Provides rule-based denial of reimbursement
• Puts doctor in a quandary
“The doctor’s dilemma
is the nation’s problem.”
Fuchs, NEJM 8, 2011
Who Will Drive Change?
• Politicians?
• Insurance companies?
• Medical professions?
Are the professions up to it?
If not, here are four ways to slow medical progress even further
1. Invest more in science. Delivery is best left for UPS.
2. Use fruit flies. They are really cheap, help save $.
3. Be nice to everyone. They may be reviewing your next paper.
4. Sue the patent office to allow you to patent placebo. But first, test to make sure it is safe.
Appendix
What Does “Translational Medicine” Mean for Us?
The practice of developing new drugs, devices and clinical practices motivated by need and using cost, scalability and efficacy as the principal metrics governing the process.
“There is an almost complete lack of understanding of how much it costs to deliver patient care, much less how those costs compare with the outcomes achieved.”
Robert A. Kaplan and Michael E. PorterHarvard Business Review, September 2011
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