2013 ESVB SYMPOSIUM

INNOVATION: FROM IDEA TO DEVICE

THE BIODESIGN CONCEPT AT STANFORD

Thomas M. Krummel, MD School of May 10, 2013

1 “The Doctor,” 1891. Sir Luke Fildes (1844-1927). Tate Gallery, London DISCLOSURE Thomas M. Krummel, MD Past Computer Motion acquired PEAK Surgical acquired SurgRx acquired Current Role Received California Water Services BOD Ownership Interest Cantimer SAB Ownership Interest EarLens --- Ownership Interest eMed SAB Ownership Interest Intervene SAB Ownership Interest Miret Surgical SAB Ownership Interest Procept Biorobotics BOD Ownership Interest PuraCath --- Ownership Interest Relign SAB Ownership Interest Vantage Surgical SAB Ownership Interest Visible Productions SAB Ownership Interest Wadsworth Medical SAB Ownership Interest Wing-Tec SAB Ownership Interest Zipline Medical SAB Ownership Interest 2

INNOVATION: WHY SHOULD WE CARE? Leveraging Medical Knowledge Direct Patient Care

Increasing Health Care Effect

The Entrepreneur 3 Leveraging Medical Knowledge Training Other

Increasing Health Care Effect

The Physician Entrepreneur 4 Leveraging Medical Knowledge Developing New Solutions

Increasing Health Care Effect

WHAT IF WE COULD TEACH THIS? The Physician Entrepreneur 5 TOM FOGARTY

1. Scrub tech in 1960s – witnessed the experts of the day 2. Full leg length incision anteriotomy to extract clot 3. Usually followed by amputation 4. Radical rethinking of approach with balloon catheter was vilified, paper never published Revolutionized endoluminal

6 SURGICAL CLONING THOMAS J. FOGARTY, MD “The Godfather”

1. >100 surgical instrument patents 2. >30 successful startups, bringing great ideas to the bedside 3. ACS Jacobson Innovation Award 4. Lemelson MIT Prize 5. Inductee, National Inventors Hall of Fame 6. Translational Medicine • is not a science fair project • is a product in a box with a 1-800 number for sales and service • gets the surgical patient better • leverages treatment – millions of patients

7 SURGICAL OPERATION Image Manipulation Direct visual 2 hands direct Operative Microscope Video image 2 hands long tools, robots Fluoro cath, stents, etc. US, CT, MR cryo, thermal RIGS radiofrequency PET PDT ESWL NOTES GENE What’s Next? It is up to us 8 BEDSIDE

BENCH TRANSLATIONAL MEDICINE Frequently requires a commercial step

9 TRANSLATIONAL MEDICINE

10 “We believe the process of Innovation can be taught; our goal is to create the next generation of medical device inventors.” -- A 12 year startup

11 Biodesign Leadership

Paul Yock Tom Krummel Founder, Co-Director Tech Tx Director Core Faculty

Ari Chaney Rich Popp Craig Milroy Jan Pietzsch Paul Wang Stefanos Zenios Director Ethics, Policy Collaboratory Reguatory Medicine Business

Fellowship Program Mentors

Josh Makower Todd Brinton Julian Gorodsky Tom Andriacchi Scott Delp Geoff Gurtner Tina Seelig Mentor Fellowship d.School ‘shrink’ Director Co-Founder

12 Global Programs

Stanford-India Singapore-Stanford Biodesign (SIB) Biodesign (SSB)

Raj Doshi Balram Chris Shen Jui Lim Exec Director Bhargava Exec Director Program Director (U.S.) Exec Director (U.S.) (Singapore) (India)

Christine Kurihara Uday Kumar Anurag Mairal Assoc Director, Fellowsh Director, Assoc Director Global Programs Global Programs Global Corporate

13 BIODESIGN INNOVATION FELLOWSHIP

Unique Bay Area confluence of capital – people, university discovery and venture

14 BIODESIGN INNOVATION FELLOWSHIP Timeline -- Year 1

One- or Two-Year Fellowship

July-Aug Innovation Boot Camp Sept-Nov Clinical Immersion and Need Finding d.school Introduction Nov-Dec Market and Intellectual Property Research; Identification of Top 5 Projects Jan-Mar Biodesign Project Course Develop Business Plan Apr-May Business Plan Finalized June Project Presentations; Grant Writing

15 BIODESIGN INNOVATION FELLOWSHIP Timeline -- Year 2

Second year is independent, like post doc • Fellow will choose independent project based on first year experience and future interests • Start-up, VC internship, FDA, large company internship • MS in Bioengineering

16 SURGICAL FELLOWS

Venita Chandra, MD Russell Woo, MD Stanford Kevin Chao, MD Andy Rink, MD Stanford 2006-2008 2003-2004 Stanford Northwestern 2008-2010 2012-2013

Dan Riskin, MD David Boudreault, MD UCLA Greg Magee, MD, MS Tiffany Chao UCSF – East Bay Yale/Stanford MGH 2004-2005 2007-2009 2008-2010 2013-2014

Carlos Mery, MD Ronald Jou, MD • Victor McCray, MD Brigham & Women’s Stanford • UCSF-Fresno 2005-2007 2007-2009 • 2010-2011

Bilal Shafi, MD, MSE Nandan Lad, MD Penn Stanford/ Dan Azagury, MD Geneva Univ Hospital 2005-2008 Univ of Chicago 2007-2009 2011-2012

Tatum Tarin, MD Jake Brenner, PhD, MD Stanford Univ of Pittsburgh • Swami Gnanashanmugam, MD 2008-2010 2006-2007 • Northwestern • 2011-2012

Matthew Callaghan, MD Insoo Suh, MD James Wall, MD UCSF UCSF UCSF 2008-2010 2006-2008 2011-2012 2012-2013 2nd Year Fellows

Dan Azagury, MD Swami Gnanashanmugam, MD Jasmine Zia, MD 2012-2013 1st Year Fellows Specialty Red Team Fellows

Emma Essock-Burns, PhD Andy Rink, MD Ivan Tzvetanov, MS Justin Williams, BS Rush Bartlett, PhD Cottrell Innovation Fellow CTSA Fellow St. Jude Fellow Fogarty Fellow Cottrell Specialty Fellow White Team

John Paderi, PhD Vijaykumar Rajasekhar, MS Kate Rosenbluth, PhD Tahel Altman, MD Ryan Van Wert, MD Grube Fellow Khosravi Fellow CTSA Fellow Lucile Packard Fellow Cottrell Specialty Fellow

BIODESIGN STRUCTURE Year One

Clinical Concept Concept Boot Camp Brainstorming ImmersionNeed Statement Selection Development

19 NEED STATEMENT

• Need Statement – A phrase that focuses on the goal or endpoint not the problem – “The genetic code of your solution”

“A“ Abetter better method method to do to a do CABG” a CABG” “A better method to revascularize the heart”

20 PROTOTYPING - a multi-functional laparoscopic tool

Failing to Success 21 2007-09 RED TEAM: EXTERNAL FETAL MONITORING Wires – Tethered to bedside, source of liability for the hospital

Sensors – Posion sensive, roune procedures cannot be performed safely

Straps – Uncomfortable, obstruct access for epidural and c-secon

-confidential- 22 OPPORTUNITY

Market Opportunity $300 M +

Competitive Advantage Experienced Team Intellectual Property Wireless Dermal Patch Adjustment-free Disposable Patient-centric Research & Design

-confidential- 23 EXTERNAL FETAL MONITORING

PVDF Sensors • Formal Patent (in progress)

• Alpha Prototype

• Feasibility trial

-confidential- 24 PARTNERSHIP

-confidential- 25 REAL LIFE EXPERIENCE

James Wall • Four clinical needs addressed in 2006-07 • Finalists, Stanford Business Plan Competition • 3 Provisional Patents, 1 Utility Patent filed • $20K NCIIA grant for concept development Zachary Malchano • One company started with a $100K NSF SBIR award Follow on $500K SBIR Award • $500K Investment lined up for a validated concept Kenneth Wu • Venture Capital internship – Kleiner Perkins • James Wall, Bioengineering Masters - Medical Waste Management Steve Eichmann

26 EPIDURAL ANESTHESIA

Regional Anesthesia à Local Pain Block Does not affect patient (or unborn child) systemically

Spinal cord, Cerebrospinal Fluid (CSF) expecting woman in labor Dura Ligamentum Flavum

Catheter Epidural space (potential space) with anesthetic

anesthesiologist

Tuohy needle

2-6 cm 2-4 mm Confidential27 TRADITIONAL EPIDURAL ACCESS PROCEDURE

expecting woman in labor

Stop!

anesthesiologist

Confidential28 EARLY PRODUCT VISION

First in human - April 2009 Clinical Trial in UK - present Confidential29 From a student Biodesign team…

draft

30 INVENTION AWARDS: AN INEXPENSIVE PORTABLE VENTILATOR Popular Mechanics, May 28, 2010

Matt Callaghan, MD

How OneBreath Works: Software calculates how much air is in the patient’s lungs based on data from a sensor, and then directs a compressor to deliver more air through a valve system. Paul Wootton

31 CLINICAL NEED

1. Pandemic will happen – SARS++ 2. No way to stockpile, transport, or surge ventilator equipment 3. Minimal ventilator capacity in Developing Nations 4. Overwhelming need for simple, safe, cheap (down market) ventilator 5. Critical concept - duality

32 PROTOTYPE PROGRESS

33

OneBreath One World…One Breath

• What is the “product” that would result from completion of the entire program • One or two slides MAXIMUM to describe the TECHNOLOGY being used in this project

34 COMPANIES FROM BIODESIGN TRAINEES 1. NEEDS FINDING 2. NEEDS SCREENING AND SPECIFICATION 1.2 1.3 Need 2.3 1.1 Strategic Observation & 2.1 Statement Stakeholder 2.5 Needs Focus Problem Disease State Development Analysis Filtering Identification Fundamentals

IDENTIFY IDENTIFY 2.2 2.4 Need Need Treatment Market Statement Specification Options Analysis

3. CONCEPT GENERATION 4. CONCEPT SELECTION

3.2 4.1 4.5 Early 3.1 4.3 4.6 Concept Concept Intellectual Stage Design Brainstorming Regulatory Selection Screening Property & Prototyping

INVENT 4.4 Final Multiple 4.2 Concept Concepts Business Reimbursement Models & Prototype

5. DEVELOPMENT STRATEGY 6. DEVELOPMENT PLAN

5.3 6.1 R&D / 6.4 6.7 5.1 Regulatory Engineering Operating Plan Business Plan IP Strategy Strategy 5.6 Competitive Plan & Milestones Development Advantage & Value 5.4 5.2 Proposition 6.5 Financial Stakeholder / 6.2 Business Reimbursement Modeling & Political Clinical Trial Plan Strategy Proxy Strategy Design Competitive Validation Advantage IMPLEMENT IMPLEMENT Statement 5.5 Clinical & 6.3 Marketing 6.6 Sales & Strategy Funding Marketing Sources Plan 36 BIODESIGN INNOVATION PROGRAM A Work in Progress

1. More than 700 invention disclosures, patents 2. Multiple abstracts, posters, chapters, manuscripts published and/or presented 3. Real world funding successes – NCIIA, SBIR, Angels, VC 4. 24 startups; 4 more in pipeline, 291 jobs created 5. 500 new jobs created 6. 94 grads, 8 rookies 7. Birthed 18 other Biodesign Programs - worldwide 8. More than 150,000 patients treated

37 OUR REAL “PRODUCT” June 2012 38 39

The Art of is not yet perfect and advancements now unimaginable are still to come.

May we have the wisdom to live with this with grace and humility.

William Stewart Halsted

40 41 The abdomen, the chest and the brain will forever be shut from the intrusion of the wise and humane surgeon.

SIR JOHN ERIC ERICKSEN Surgeon-Extraordinaire to Queen Victoria. 1837

42 “The Doctor,” 1891. Sir Luke Fildes (1844-1927). Tate Gallery, London CLINICAL PERFORMANCE

FUNCTIONALITY OneBreath LTV1200 Impact 73x Magellen Pediatric & adult Yes Yes No No ventilation Assisted weaning mode Yes Yes Yes No High flow (to 100 LPM) Yes Yes No Yes Low pressure O2 source Yes Yes No No

Internal battery life 10hrs 1hr 6hrs N/A Designed for unfamiliar Yes No No No users Simple field repair Yes No No No Price ~$1000 $15,000 $4000-60 $5000-70 00 00

43 HISTORY OF SURGERY Progress is Always About Innovation whether diagnostics, supportive care, monitors, tools, devices, technologies or surgical procedures

Iron Cautery Rods Temperature Controlled From Pompeii Sealing via Nanofilms

79 AD 2008

44 45 Leveraging Medical Knowledge Supervising Other Providers

Increasing Health Care Effect

The Physician Entrepreneur 46 MEDTECH = BIOPHARMA

medtech biopharma

FDA 2-8 years 6-12 years

Investment $20-100M $500M – 1B

Innovation needs- discovery Process driven plus need

WHAT ELSE DO WE DO? Biodesign Innovation Class: University-wide BioE 374, ME 374, MED 272, OIT 384

Stefanos Zenios 48