Pain Monitor A Direct Way to Measure Pain

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Pain MonitorA Direct Way to Measure Pain

• Inventing Breakthroughs and Commercializing
  Science
• Harvard Business School
• TEAM Beth Leeman1, Melanie Pogach1, Koit
  Saarevet2, Kelly Yedinak2
• AFFILIATIONS 1Harvard Medical School ,
  2Massachusetts Institute of Technology
• INVENTORS David Borsook, Lino Becerra

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What Is It?
Near Infrared Spectroscopy (NIRS) is a
noninvasive, safe optical method that can be used
to assess oxygenation in brain pain center
Full NIRS system for measuring pain
Patient head cap
Computer interface with user
Signal processing
Top view of patients head with prototype cap
Light sources (row)
Detectors (row)
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What Does It Do? How the technology works

• The Pain Monitor solution provides two important
  functions
• An objective determination of patient pain level
• Enables improved anesthesia/analgesia delivery

Software converts the result into a validated
scale
Tactile sensation (brush)
Pain sensation (heat, 46C)
single peak
double peak
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Who Needs It? The Markets
There are (currently) no diagnostic tests that
can determine the quality or intensity of an
individual's pain Current method subjective
scale - patient judgment of their own pain level,
or vital sign assessment
Frost Sullivan report on U.S. Pain Management
Pharmaceuticals Markets, Nov 1, 2002
Operating Room (OR), Post Anesthesia Care Unit
(PACU), and Intensive Care Unit (ICU)
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Steps To Market Remaining Proofs of Concept and
Major Milestones
(6) Multicenter Study
(4 5) Efficacy Outcome
(3) Scale Definition
(2) POC Baseline Pain
(1) POC
Now
2009
2010
2011
2012
2013
2014
2015
2016
2017
Proof of effectiveness with analgesia
Develop universal norms across multiple patient
populations
Demonstrate decreased ICU and PACU stays and/or
prevention of chronic pain
Correlate change in spectra to clear numerical
scale
Determine baseline pain level without stimulus
These steps do not include those required for
veterinary medicine
Pain Monitor - A Direct Way to Measure Acute Pain
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Pain Monitor Funding Profile
(6) Multicenter Study
(4 5) Efficacy Outcome
Analgesia market sales begin
(3) Scale Definition
(2) POC Baseline Pain
Diagnostic market sales begin
(1) POC
Ready for VC funding
Now
2009
2010
2011
2012
2013
2014
2015
2016
2017
Currently funded
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Other Relevant Success Factors
FDA Regulatory pathway ? STRONG, no barriers
foreseen

• NIRS is an FDA approved technology, no exemption
  required
• Less regulated markets may be quicker/easier
  (Military, Veterinary, Clinical Trials)

IP ? STRONG, from 2 positions

• Lack of known infringement concerns
• Strong patents
• Dec 2000 US Patent (broad)
• December 2005 International patent (specific)
  application has been submitted

Reimbursement ? POSSIBLE

• Cost savings to hospitals ? still need to
  demonstrate
• Incorporate into guidelines to be reimbursable
  by 3rd party payers ? goal

Pain Monitor - A Direct Way to Measure Acute Pain
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Summary and Recommendations

• The Pain Monitor has very good market potential
  however it is not recommended to be licensed or
  incorporated as a start-up YET
• A start-up currently appears preferable to
  licensing after Proof of Concept (POC) 2
• Low development costs (primarily software)
• Once all POCs and clinical trials are completed,
  licensing or a joint venture are advisable
• There will be a large initial non-recurring
  engineering (NRE) cost to produce the product at
  high volumes

POC 2 is recommended to be completed with
grants and seed money NIH, DOD, JHACO, ATP (tech
grants)
Pain Monitor - A Direct Way to Measure Acute Pain
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Background Slides
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A Guide To The Background Slides

• Slides 11-23 provide calculations and assumptions
  for market and funding figures
• Slides 24-40 provide background data
• Slides 41-44 provide a summary of published
  studies
• Slides 45-46 provide an overview of IP
• Slides 47-58 provide an overview of interviews

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Summary Of Market Feasibility
5 Strong Position
1 Weak Position
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Market Calculations
Diagnostic Markets (US)
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Market Calculations
Analgesic Monitoring Markets (US)
Market OR, PACU, ICU
ICU Total Revenue 8B - 17.5B
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Market Calculations
NB Average time for hospital to recoup fixed
costs of devices 4 years Inflation
rates 2-3 not included Average 10 in
maintenance costs/year not included
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Market potential--customers

• Operating room
• One local university hospital performed gt 1200 OR
  cases in 2007
• Particular populations?trauma, obstetric, cardiac
  surgery
• Intensive care unit
• Oversedation and analgesia leads to prolonged
  time on ventilators and increased morbidity and
  mortality in the ICU
• Underanalgesia and undersedation contributes to
  PTSD and significant patient morbidity
• 30 acute care hospital costs
• 180 billion per year health care spending
• 
  (American Hospital Association)

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Market potential--customers

• ? Veterinary medicine
• ? Large market
• ? Trial in rats planned
• ? Clinical Trials
• ? Objective outcome measure
• to assess efficacy of new
  drugs
• ? Military Hospitals
• ? Large numbers of acute trauma, surgery
• ? For use in transport and monitoring
• ? Is a setting with less direct nursing
  care/available staff for the wounded
• ? More automated method for detecting pain
  would
• improve patient care

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Market potential--customers

• Additional consumers
• Neuro-intensive care
• Nonverbal patients?stroke, dementia, vegetative,
  locked-in, autism
• Dentistry
• Death row
• Use of same system across domains increases
  options for funding

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OR Monitoring Market

• Nearest market category for envisioned
  application
• Yearly revenues of 140 million
• Less than 2 growth
• Average unit price of roughly 20K (similar to
  the Aspect Medical BIS system)
• The NIRS system is at least an order of magnitude
  more expensive per unit!

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OR Monitoring Market

• Improbable but not impossible
• Need to show ability to reimburse cost
• Bill to patients insurance
• Show clear ability to improve patient care
• Other markets may be more promising!
• ICU
• Pain Clinics
• Life Science Pharmaceuticals Research

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Potential Reimbursement

• Regulatory processes
• ? FDA
• ? Insurance
• Non-regulatory processes
• ? Veterinary markets
• ? Clinical trials

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Potential Partners/Licensees
Major Players (Market Share 2008)
Johnson Johnson (13.7) General Electric Co.
(10.0) Medtronic, Inc. (8.5) Baxter
International, Inc. (7.1) Covidien Ltd.
(6.4) Other (54.3) e.g. Boston
Scientific, T2 Biosystems
Adapted from IBISWorld Industry Report, June
2008
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Projected Medical Device Industry Growth

• -0.1
• 2009 5.3
• 2010 6.8
• 2011 4.5
• 2012 4.7

Percent Growth
Year
Integra Information, Dec. 2008
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Guidelines

• VA Guidelines
• The fifth vital sign

• New JHACO GuidelinesJanuary, 2000
• All accredited facilities must provide
  appropriate pain assessment tools
• Assessment of pain must be documented
• If a facility does not have the tools to
  adequately manage a patients pain, the patient
  must be transferred to another hospital
• Institutions graded on pain assessment for
  accreditation

Medtech Insight, LLC (2006)
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A direct way to measure acute pain

• Near infrared spectroscopy
• Noninvasive
• No injections
• No radiation
• Moves beyond current subjective methods of pain
  monitoring
• Uses in operating/recovery rooms, intensive care
  units, veterinary medicine facilities
• Benefits patients
• Reduce health care spending
• For acute care
• Avoid under- and over-analgesia
• Decrease PACU and ICU length of stay
• By reduction of chronic pain due to improved
  acute pain management

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Pain

• The estimated economic impact of pain in the U.S.
  100 billion annually
• Money spent on various forms of pain management
  
• projected to by 4-14.5 per year
• Most common reason for seeking medical care
• 50 of office visits in the U.S.
• Longer duration of stay
• Longer recovery times
• Poorer outcomes
• 80-85 of those gt65 years have health problems
  that predispose to pain

Medtech Insight, LLC (2006)
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Acute Pain

• 25 million people per year experience acute pain
  due to injury/surgery
• Acute post-operative pain leads to chronic pain
  in 10-50 of patients
• After common operations, e.g. CABG, hernia
  repair
• Severe in 2-10
• 50 acute pain is undertreated

Medtech Insight, LLC (2006)
Kehlet et al. (2006)
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Chronic Pain

• gt50 million people suffer from chronic pain in
  U.S.
• 3,800 pain management programs/practitioners in
  the U.S. in 2006
• gt50 of those who develop chronic pain become
  disabled
• 25 leads to anxiety/depression
• 14 of workforce have absences due to pain

Medtech Insight, LLC (2006)
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Analgesic Monitoring Device

• Estimated economic impact of pain in the U.S. ?
  100 billion
• 25 million people per year experience acute pain
  due to injury/surgery
• After common surgeries, acute post-operative pain
  is followed by persistent (chronic neuropathic)
  pain in 10-50 (Kehlet et al., Lancet 2006)
• 14 of workforce have absences due to pain
• VA Guidelines ? Pain is the fifth vital sign
• JHACO Guidelines, 2000 ?All accredited facilities
  must provide appropriate pain assessment tools
  
  Medtech Insight, LLC (2006)
  
  

The problem Currently ? no way to objectively
measure pain

• The proposal
• An objective way to measure acute pain
• Noninvasive
• Near infrared spectroscopy
• Assess change in blood oxygen level in brain
  pain centers

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Analgesic Monitoring Device
Steps to market 1. Fills unmet need? 2. Proof of
concept How long/expensive? Will end result be
qualitative or quantitative? How validated are
the end points? 3. Regulatory pathways 4. IP 5.
How reimbursed/source of payment for services
funding, investors
Determine the Business plan
Licensing vs. Start-up?
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NIRS Pain Monitor
2. Proof of concept ? INCOMPLETE

• Does this technology work? YES
• Can distinguished pain from other stimuli
• Data correlates to fMRI

• What more still needed?
• Market specific proof of concept
• Demonstrate absence of/change in pain
  spectra with analgesia
• Trials in OR (pending), ICU, veterinary
  medicine
• Technical issues remain
• Real time assessment (underway)
• Correlate change in spectra to clear
  numerical scale or image (children)
• Determine baseline pain level without
  stimulus
• Universal norms (specific age groups
  populations, i.e. chronic pain)
• Demonstrate efficacy and outcomes
• Decrease ICU and PACU stays, lower costs,
  prevent chronic pain/costs

funding? seed money, grants, investors
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NIRS Pain Monitor
3. Regulatory pathway ? STRONG, no barriers
foreseen

• NIRS is an FDA approved technology
• Need approval for proposed application
• Initial discussions with FDA ? Class 1 device,
  no investigational
• device exemption (IDE) needed for studies

4. IP ? STRONG

• Patent search yielded
• No direct competition for proposed application
  of NIRS
• (2002-present, international)
• Dec. 2000 U.S. patent ? broad, sets precedent
• Dec. 2005 International application is specific

5. How reimbursed ? CHALLENGE

• Cost savings to hospitals? still need to
  demonstrate
• Benefit to patient ? decrease over/under
  sedation, reduce frequency of chronic pain
• Reduce costs on medications, ventilator time,
  ICU and PACU time
• Costs of chronic pain
• To be reimbursable by 3rd party payers ?should
  be goal
• Support from societies/ guideline of societies
• Critical care, Surgery, Anesthesia,
  Veterinary medicine, JHACO support
• Non-FDA regulated markets
• Pharma, military, veterinary

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NIRS Pain Monitor
Summary / Recommendations

• Unmet clinical need
• Large size and multiple markets
• Difficult to quantify monetarily
• Reduced ventilator time, PACU stay
• Reduce patient morbidity
• Reduce frequency of chronic pain
• Improve quality of care
• No existing competitive market
• Strong IP
• Regulatory pathway smooth
• Nonregulatory market alternatives
• Much work remains on POC, technology

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Timeline

• Analgesia POC evaluate pain in adults in OR
  based on multiple types of anesthesia (Funded)
  Jan 2009 Jan 2010
• Concurrent technical issues
• Making machine smaller, fewer sensors with
  real-time data presentation
• Baseline pain w/o stimulus POC includes a second
  machine (in order to do in parallel) Resources
  tech, pilot study 20 subjects, IRB approval,
  300K price tag (Unfunded) Jan 2009 Jan 2011
• Define a clear scale for level of pain in healthy
  population, correlate with existing methods of
  measurement (vital signs, etc.) with larger
  sample size 150 subjects (possible to include in
  step 1) Jun 2009 Jan 2012
• Proof of efficacy show ability to adjust
  analgesia based on a numerical pain level, small
  single center study of 20 50 subjects, FDA
  support needed (Unfunded) Jan 2012 Jun 2013
• Show outcome effect ability to reduce time in
  ICU, PACU, improve patient care, small single
  center study of 20 50 subjects (Unfunded)
  Extension of previous study Jul 2013 Jan 2014
• Multicenter study get universal norms based on
  large sample, demonstrate outcome effect on a
  large scale 500 1000 subjects (Unfunded) Jan
  2014 Jan 2017

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Timeline
Instructions for 3 Part 1 Record patient NIRS
information throughout an OR procedure
(pre-anesthesia through recovery) without
stimulus Instructions for 4 Part 1 Awake
patient not in pain or sedated Record NIRS pain
level between VAS 3 and 7 with recorded level of
stimulus Part 2 Give anesthesia/analgesia, apply
recorded levels of stimulus that correlate to
previous VAS 3 and 7, and record new VAS levels.
Should show reduction in VAS levels with same
level of stimulus
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How device works

• Measures changes in total/ratio of oxy to deoxy
  hemoglobin levels in the brain
• Pain perception is converted into a digital scale
• A graph/AUC of absorption spectra correlates with
  a digital read out representing pain level
• Amount of anesthesia or analgesia adjusted for
  goal level lt 3
• Transportable and affordable

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• Physical sensation increased activity in brain
• Increased activity need for more oxygen
• Body sends in fresh, oxygen-rich blood
• NIRS can detect oxygen levels in blood

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690 nm HbR 830 nm HbO
(Slide adapted from Lino Becerra, PhD)
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How device works

• Tactile sensation
• (brush) single peak

• Pain sensation
• (heat, 46C) double peak

Somatosensory cortex (average, 10 subjects)
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VAS (visual analog scale) pain scale

• Validated pain scale
• Pain scores 7 ? significant pain
• Pain scores 3 ? acceptable/tolerable level
• With NIRS device, spectra loses second peak when
  VAS score 3
• Preliminary data
• Group results robust
• Individual results give multiple stimuli, use
  averaging phenomena

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How it works Loss of second peak (contralateral
side) when VAS score 3 compared to 7
Ipsilateral side
Contralateral side
Red 7/10 Blue 3/10
Pain sensation (heat, avg 3 subjects)
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CAN NIRS DISTINGUISH BETWEEN PAIN AND NON-PAINFUL
STIMULI? Slater et al. (2006) ? Heel lance
in infants elicits NIRS response ? No response
to non-painful stimuli ? Greater response when
awake ? Response increases with age Becerra et
al. (2008) ? Brush vs. noxious heat in
adults ? NIRS detects single peak for
non-painful stimuli and double peak for
painful stimuli
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SENSITIVE TO TREATMENT OF PAIN? FOR USE IN
CLINICAL TRIALS? Bucher et al. (1995) ?
Sucrose shown to reduce crying after heel lance
in infants ? Cerebral blood volume
measured by NIRS decreased in 5/14 infants
after sucrose and in 6 /14 infants after
placebo BUT not clear that sucrose was
effective treatment  
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CAN SIGNAL BE OBTAINED IN THE OR? Kussman et
al. (2005) ? Infants undergoing cardiac
surgery ? Cerebral oxygen saturation measured
with NIRS After induction of
anesthesia Before, during and after CP
bypass With deep hypothermic circulatory
arrest Lee et al. (2008) ? Adults undergoing
spinal surgery ? Cerebral NIRS significant
predictor of plasma Hgb
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DOES THE RESPONSE CORRELATE WITH OTHER MEASURES
OF PAIN? Slater et al. (2008) ? Heel lance
in infants ? NIRS measures correlate with ?
Infant pain profile (PIPP) score r.57,
p0.001 ? Facial expression r.74,
plt0.0001 Becerra et al. (2008) ? NIRS
response similar to that seen with fMRI
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IP Patents and Applications

• US Patent 6,907,280. Method and apparatus for
  objectively measuring pain, pain treatment and
  other related techniques. Filed Dec 2000, issued
  Jun 2005Broad coverage of the technology.
• International Patent Application WO 2006/071891
  A2. Evaluating Central Nervous System. Filed
  12/23/2005.Specific, detailed coverage of the
  technology.
• US Patent Application 20060074298. CNS assay for
  prediction of therapeutic efficacy for
  neuropathic pain and other functional illnesses.
  Filed Sep 2005.Specific coverage for drug
  efficacy testing application.
• International search for patents owned by third
  parties yielded no signs of direct competition,
  thus, we consider IP strong.
• Coverage through 2025 - 8 years after clinical
  trials completed.

Pain Monitor - A Direct Way to Measure Acute Pain
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Patent Application WO 2006/071891 A2 Claims

• Claims 1-11 measuring central nervous system
  (CNS) activity in a subject experiencing pain
• Claims 12-23 identifying therapeutic
  interventions for neurological conditions (incl.
  testing efficacy of pain treatment drug
  candidates)
• Claims 24-41, 65-69 using the measurement
  results to adjust the amount of medication, both
  for acute and chronic pain treatment
• Claims 47-64 evaluating pain or analgesia

Pain Monitor - A Direct Way to Measure Acute Pain
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Interviews
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Arthur Buzz DimartinoTechEn

• Prototype cost is 170K
• The TechEn NIRS system is custom made
• Potentially high NRE tooling cost to go to large
  scale production
• Savings of roughly 30 can be achieved with
  quantity, but overhead and distribution costs
  would roughly equal that

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Peter Clardy, M.D.Director, Medical Intensive
Care Unit, Beth Israel Deaconess Medical Center,
Boston

• How we currently assess pain remains rather
  primitive despite use of validated tools and
  scaleswe still often under and over dose
• Clinical need for such a device exists
• Ideally would be noninvasive, no interference
  with other equipment
• Would need FDA approval/IRB approval for use
• If could assess consciousness and pain together
  would be even more useful

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Wiley Hall, MDDirector, Neurocritical
CareUniversity of Massachusetts, Worcester

• To assess pain, we look at vital signs. NIRS
  would be useful.
• Patients in the ICU are intubated, they dont
  speak, so you dont really know if they are in
  pain.
• Would use it for surgical patients as they have
  bigger pain issues.
• Use of NIRS may allow for better management of
  vital signs
• In SAH Because they are in pain and good
  analgesia would make blood pressure easier to
  control
• In the OR If theres not enough analgesia in
  the OR, and they need more sedation, and then
  blood pressure is harder to control

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Edward George, MD, Ph.D.Department of
AnesthesiaMassachusetts General Hospital, Boston

• The recovery room costs 1000 per hour. If
  theres increased pain, the patient stays there.
• You want to decrease costs by decreasing time in
  the OR if better pain control, can use less
  sedating drugs
• Use for high risk cases 1. trauma 2.
  cardio-pulmonary bypass 3. obstetrics

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Adam MuzikantInotek Pharmaceuticals

• Starting with a prototype idea, must build proof
  of concept
• Most companies want answers to such questions
• Is there real unmet need? Talk to end users.
• Is the use reimbursable? How long and how
  expensive to obtain POC, mechanism in humans
• Is the end point qualitative or quantitative?
• How validated will the end points be?
• Assess IP.
• Would need more POC studies in humans, which
  leads to significant increase in product value.

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Kevin L. Ohashi, The Vertical GroupDevice
Venture Company

• Regarding how advanced the technology must be
  before a VC would consider investing? depends on
  the VC firm. Some focus on early stage
  technology, like this company.
• Considerations for potential interest
  includeshowing a clear unmet clinical need,
  identifying initial beach heads, assessing
  hurdles, i.e. business, regulatory pathways,
  management of founding teams.
• How will the diagnostic device get reimbursed?
  If it is just to save moneyneed to prove this3rd
  party reimbursement potential is superior.
• Device has a wide spectra of applications, need
  to demonstrate savings to customers, and ideally
  be reimbursable by 3rd party payers.

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Zaffer SyedClinical marketing group for Pain
Management Boston Scientific

• Clinical marketing group for Pain Management at
  Boston Scientific
• Targeted specifically at a spinal treatment for
  chronic pain
• His challenge Assessing the mitigation of pain
  is subjective
• Its difficult to prove the validity of a
  treatment without an objective measurement
• An objective measurement could further increase
  adoption of the therapy
• His customers are neuroscientists and pain
  clinicians.
• It is very much an interest of Boston Scientific
  to support clinical research
• Boston Scientific bought the start up company
  that is now their Pain Management group
• He sees an opportunity for this system to become
  a standard of care
• Could either replace or supplement the subjective
  VAS method

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Wolf Sapirstein, MD, MPH,FACS Medical Officer,
FDADivision of Cardiovascular Devices, Office of
Device Evaluation Center for Devices and
Radiological Health
? Devices are categorized into classes
Class 1 simple, noninvasive, do not induce
treatment effect Class 2 not implantable,
but more invasive than class 1 Class 3
implantable devices, increased risk to patients
This device would most likely be class 1. ?
What would be required for FDA approval of
proposed application/technology? In vitro
studies showing how the device works, information
on which to base labeling and indications for
use. Must demonstrate the device can indeed
measure differences in acute pain. ? What
regulation is needed to initiate clinical
studies? Since likely Class 1, would not require
IDE (investigational device exemption). Would
need hospitals IRB approval. However, prior to
beginning the study, recommend pre-approval
meeting with FDA to learn FDA thoughts,
suggestions regarding the clinical trial.
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Rahul DhandaDirector of Marketing, T2
Biosystems, Inc.

• Monitoring pain directly is its own company.
• Sounds solid what is the comparator? We
  know there is nothing.
• Potential uses
• Everythings subjective, pain management
  centers where subjectivity forces decisions
  regarding narcotics, the clinical trials world,
  people want indications for pain.
• CROs would have a leg up.
• A recent study by a large biotech company
  examined pain with stents - was difficult to
  conduct, as there was no quantifiable outcome
  measure for pain.

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Marko PoolametsHead of Quality ManagementOriola
(a Finnish distributor of healthcare products)

• Hospitals in Estonia are skeptical about new
  devices, but would buy Pain Monitor after it is
  widely in use in Finland, Sweden and Germany.
• I also see potential market in outpatient
  surgery, cosmetic surgery and dental surgery, as
  anesthesia there is less deep and precise
  monitoring is more critical than in the case of
  long operations.
• I would predict the sales of ca 100 units in
  Estonia, assuming that the price is reasonable.

Pain Monitor - A Direct Way to Measure Acute Pain
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Additional Interviews and Resources

• Marisa Fox, RNDepartment of Public Health
• Denise A. LaGasseLicensing ManagerPartners
  Healthcare Systems
• Gary Leeman, MBA, CPA, PC
• Direct access to anesthesiologists
• Direct access to FDA