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