Al Mann's innovations

8/9/2019 Al Mann's innovations

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October 2007October 2007

Innovation in Healthcare:Innovation in Healthcare:

Balancing Patient RiskBalancing Patient Riskand Rewardsand Rewards

Alfred E. MannAlfred E. MannChairman and CEO, MannKind CorporationChairman and CEO, MannKind Corporation

Chairman and coChairman and co--CEO, Advanced Bionics CorporationCEO, Advanced Bionics Corporation


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Balance Between Risk and Reward

Current considerable debate in many countries over the effects oCurrent considerable debate in many countries over the effects offpublic policypublic policyin particular governmental regulationsin particular governmental regulationsfor thefor the

development of innovative pharmaceuticals and medical devicesdevelopment of innovative pharmaceuticals and medical devices Regulators must balance patient access to therapies with theRegulators must balance patient access to therapies with the

safety of drugs and technologysafety of drugs and technology

The consequences of decision making can be dire:The consequences of decision making can be dire:

If access is promoted at the expense of safety, a dangerousIf access is promoted at the expense of safety, a dangerousproduct can cause incalculable harmproduct can cause incalculable harm

Conversely, if safety is overConversely, if safety is over--emphasized at the expense ofemphasized at the expense ofaccess, patients can suffer from the absence of lifeaccess, patients can suffer from the absence of life--saving andsaving andlifelife--enhancing medications and technologyenhancing medications and technology


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2006 Global Life Expectancy US is 32nd

76 77 78 79 80 81 82 83

JapanHong KongIceland

SwitzerlandAustralia

SpainSweden

IsraelMacau

FranceCanada

Italy

New ZealandNorway

SingaporeAustria

NetherlandsMartinique

GreeceBelgium

MaltaUnited Kingdom

GermanyU.S. Virgin Islands

FinlandGuadeloupe

Channel IslandsCyprus

Republic of IrelandCosta Rica

Puerto RicoLuxembourg

United Arab EmiratesSouth Korea

Chile

DenmarkCubaUnited States

40

45

50

55

60

65

70

75

80

1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2004

Average US Life Expectancy 1900Average US Life Expectancy 1900 -- 20042004

Average

LifeExpec

tancy

Average

LifeExpec

tancy

In spite of increasing US life expectancy, in 2006 the US is 32In spite of increasing US life expectancy, in 2006 the US is 32ndnd behind Japan,behind Japan,Canada and most of Western EuropeCanada and most of Western Europe

Global lifeGlobal lifeexpectancyexpectancy

Source:Source: United Nations World Population Prospects: 2006 revision,United Nations World Population Prospects: 2006 revision, USUS National Center for Health StatisticsNational Center for Health Statistics Source: Centers for Disease Control and Prevention, National VitSource: Centers for Disease Control and Prevention, National Vital Statistics Reportal Statistics Report


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Global Harmonization

Accomplishments of the 5 GHTF Study Groups under the Steering CoAccomplishments of the 5 GHTF Study Groups under the Steering Committeemmitteeinclude harmonized guidance documents on:include harmonized guidance documents on:

Premarket approval and harmonized product labeling requirementsPremarket approval and harmonized product labeling requirements

Adverse event reportingAdverse event reporting

PostPost--market surveillancemarket surveillance Quality systems requirementsQuality systems requirements

Regulatory auditing of quality management systemsRegulatory auditing of quality management systems

Evidence of clinical safetyEvidence of clinical safety

GHTF is ensuring the transformation and alignment of policies esGHTF is ensuring the transformation and alignment of policies essential for safesential for safeand effective outcomes that can be evaluated and regulated withand effective outcomes that can be evaluated and regulated with predictablepredictableconsistencyconsistency

Reach consensus internationally on the regulatory infrastructureReach consensus internationally on the regulatory infrastructure that guide ourthat guide ournations to streamline the process of innovationnations to streamline the process of innovation

Ultimately, we must expedite the time to deliver costUltimately, we must expedite the time to deliver cost--effective safe and effectiveeffective safe and effectiveclinical solutions to patientsclinical solutions to patients

The efforts of Global Harmonization are moving towards ensuringThe efforts of Global Harmonization are moving towards ensuring the safety,the safety,effectiveness and quality of medical devices promoting technologeffectiveness and quality of medical devices promoting technologicalicalinnovation and facilitating international trade.innovation and facilitating international trade.


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Timeline of Alfred E. Mann Companies


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Development of PacemakersPacesetter Increases Average Life from 18 months to 25 years

19691969 Became involved in medical devices through theBecame involved in medical devices through theJohns Hopkins connection from the aerospace programJohns Hopkins connection from the aerospace program

1972 Medtronic pacemaker: Average life of 18 months1972 Medtronic pacemaker: Average life of 18 months 1973 First Pacesetter pacemaker: Average life > 25 years1973 First Pacesetter pacemaker: Average life > 25 years

1977 Programmable pacemaker with 21977 Programmable pacemaker with 2--way telemetryway telemetry

1985 Programmable lithium iodine shrinking 50% in size1985 Programmable lithium iodine shrinking 50% in sizeby 1995.by 1995.

19731973

19751975

19771977197919791985198519951995

Pacesetter grew to be the number two pacemakerPacesetter grew to be the number two pacemakercompany, and is now the major part of St. Jude Medicalcompany, and is now the major part of St. Jude Medical

TodayToday


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Diabetes Therapy InnovationDiabetes Therapy Innovation

Insulin Pump andGlucose Sensor

1.

InsulinPump

Continuous

Glucose Sensor

2.


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HiResolution

Bionic Ear System

RF Powered 16 Independent Stimulation Channels

90,000 Pulses Per Second DSP Control

HiRes 90K ImplantHiRes HarmonyProcessor


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Precision

Spinal Cord Stimulator

Smaller IPG sizeGreater patient comfort Increased placement options

Rechargeable Battery Longevity designed to surpass

existing systems

Competition


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Miniature implantable singleMiniature implantable single--channel neurostimulatorchannel neurostimulator

~ 2.7 cm length and 3 mm diameter~ 2.7 cm length and 3 mm diameter

Fully programmableFully programmable

BiBi--directional telemetrydirectional telemetry RechargeableRechargeable

bion


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Innovative Functional ElectricalInnovative Functional ElectricalStimulation (FES) andStimulation (FES) andneuromodulation devices for physicalneuromodulation devices for physical

rehabilitationrehabilitation

Exoskeletal neuroprosthetics stimulateExoskeletal neuroprosthetics stimulatesensory and motor nerves tosensory and motor nerves to

rehabilitate and restore limb functionrehabilitate and restore limb function

Maintaining or increasing range ofMaintaining or increasing range ofmotionmotion

PreventingPreventing or retarding atrophy ofor retarding atrophy offunctionfunction

A pipeline of exoskeletal andA pipeline of exoskeletal andimplantable productsimplantable products


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Without the L300 With the L300

L300L300


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Implanted integrated hearing

system requiring only minorsurgical procedure

Uses miniature acousticdevices, hermetic implantedelectronics, and tissue-integrating bio-compatiblematerials

Designed for individuals withmild to moderately severe

hearing losses

Implanted integrated hearingImplanted integrated hearing

system requiring only minorsystem requiring only minorsurgical proceduresurgical procedure

Uses miniature acousticUses miniature acousticdevices, hermetic implanteddevices, hermetic implantedelectronics, and tissueelectronics, and tissue--integrating biointegrating bio--compatiblecompatiblematerialsmaterials

Designed for individuals withDesigned for individuals withmild to moderately severemild to moderately severe

hearing losseshearing losses

Implanted IntegratedHearing System


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Fully and partially implantableFully and partially implantabletissuetissue--specific drugspecific drug--deliverydelivery

systemssystems

Founded in 2004Founded in 2004

Neuroprotective drugs to treatNeuroprotective drugs to treattinnitus, Mtinnitus, Mninire's Disease,re's Disease,progressive hearing loss andprogressive hearing loss andmaintain nerve function followingmaintain nerve function following

surgery or other traumasurgery or other trauma

Novel strategies for sustainedNovel strategies for sustaineddelivery of unstable therapeuticsdelivery of unstable therapeutics


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Percutaneous accessPercutaneous accessdevices incorporatingdevices incorporatingnew tissuenew tissue--integratingintegratingbiobio--compatible materialscompatible materialspermitting safe repeatedpermitting safe repeatedaccess to the bodyaccess to the body

The first product forThe first product for

hemodialysis is serving thehemodialysis is serving theneeds of 300,000 critically illneeds of 300,000 critically illpatientspatients


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Second SightMedical Products, Inc.

Argus I Patient

Implantable visual prosthetics to enableImplantable visual prosthetics to enableblind individuals achieve greaterblind individuals achieve greaterindependenceindependence

Target patients with retinitis pigmentosaTarget patients with retinitis pigmentosa

Argus II Retinal prosthesisArgus II Retinal prosthesis

Using implantable electronics to restoreUsing implantable electronics to restoresight to the blindsight to the blind

Novel electrode with over 20x surfaceNovel electrode with over 20x surfacearea of standard platinum electrodesarea of standard platinum electrodeswhich allows much smaller array.which allows much smaller array.


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MannKind: Pulmonary Insulin fromthe Patients Perspective

MannKindMannKind Pfizer/NektarPfizer/Nektar

MannKind Insulin System.A proprietary dry powderinhaled into the deep lungusing hand held inhaler

believed to facilitatepatient compliance

Super rapid delivery ofcharge masked monomeric

insulin to the deep lung

MannKind Technosphere

Insulin SystemCompetition


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Technosphere/Insulinand Research Results

11 mm

0

20

40

60

80

100

120

140

160

-30 0 30 60 90 120 150 180 210 240 270

Time from Mea l Onset (min)

Blood

Insulin

(uU/m

L)

14 IU SC48 U T/I

100

120

140

160

180

200

220

240

260

-30 0 30 60 90 120 150 180 210 240 270

Time from Meal Onset (min)

Blood

Glucose

(m

g/dL

)

14 IU SC

48 U T/I

Insulin LevelsInsulin Levels Glucose LevelsGlucose Levels

TechnosphereTechnosphere/Insulin Mimics Early Insulin Secretions/Insulin Mimics Early Insulin Secretions

Post Prandial Synchronization


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Post Prandial SynchronizationTechnosphere Insulin vs.

Subcutaneous Insulin

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0 100 200 300 400 500 600

Time from Dosing (min)

24 IU sc

48 U T/I

180 min180 min

GlucoseLo

weringActivity

ApproximatingApproximatingthe earlythe earlyinsulin secretionsinsulin secretions

increases glucoseincreases glucosecontrol at thecontrol at thebeginning of a mealbeginning of a mealand reduces excessand reduces excessinsulin followinginsulin followingdigestiondigestion

With T/IWith T/I With SubWith Sub

Glucose lowering activity within 180 minutes following start ofGlucose lowering activity within 180 minutes following start of mealmeal 74%74% 18%*18%*

*Over 15 hours; 29% over 9 Hours*Over 15 hours; 29% over 9 Hours


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Solutions to Major Insulin Issues

Technosphere Insulin can:Technosphere Insulin can:

1.1. Reduce postprandial glucose excursions to normal levelsReduce postprandial glucose excursions to normal levels2.2. Virtually avoid causing hypoglycemiaVirtually avoid causing hypoglycemia

3.3. Require no complex meal titrationRequire no complex meal titration

4.4. Reduce the need for mealtime glucose measurementsReduce the need for mealtime glucose measurements

likely just to infrequent fasting glucose measurementslikely just to infrequent fasting glucose measurements

5.5. Cause no weight gainCause no weight gain

6.6. Eliminate prandial injectionsEliminate prandial injections


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The FDA Critical Path Initiative

Objective is to reduce uncertainty about product performanceObjective is to reduce uncertainty about product performancethroughout the product life cycle using updated scientificthroughout the product life cycle using updated scientificresearch techniquesresearch techniques

Collaborative model conceived to bridge the gap with a focus onCollaborative model conceived to bridge the gap with a focus ondownstream product development concerns.downstream product development concerns.

Critical Path Initiative presents 76 major opportunities likelyCritical Path Initiative presents 76 major opportunities likely totomodernize and transform the development and use ofmodernize and transform the development and use ofmedicines and technologymedicines and technology

Should increase predictability in the development andShould increase predictability in the development andperformance of the regulated productsperformance of the regulated products

Physicians and patients would be also be given improvedPhysicians and patients would be also be given improvedinformation about product use to maximize its benefit and minimiinformation about product use to maximize its benefit and minimizezeside effectsside effects


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Molecular Metamorphosis in Medicine

Transition from the micro level to the molecular levelTransition from the micro level to the molecular level

Enhanced understanding of the disease processEnhanced understanding of the disease processAndrew von Eschenbach has termed this transitionAndrew von Eschenbach has termed this transitionthethe molecular metamorphosis in medicinemolecular metamorphosis in medicine

As our knowledge and performance measurementAs our knowledge and performance measurementtools evolve, we may be positioned to intervene attools evolve, we may be positioned to intervene atthe molecular levelthe molecular level

Potential results are personalized, predictive,Potential results are personalized, predictive,preemptive and participatory medicinepreemptive and participatory medicine

Critical Path Initiative May


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Critical Path Initiative MayExpedite Development Times

For verification of clinical efficacy and drug toxicityFor verification of clinical efficacy and drug toxicityUse of data mining and computer modelingUse of data mining and computer modeling

Development of innovative clinical trial designs forDevelopment of innovative clinical trial designs forsmaller but smarter clinical trialssmaller but smarter clinical trials

Ability to use modern imaging technologies to trackAbility to use modern imaging technologies to trackoutcomes measures.outcomes measures.

Identification of biomarker sets with increasedIdentification of biomarker sets with increasedpredictability of clinical risks and/or benefits overpredictability of clinical risks and/or benefits oversingle markers.single markers.

The Critical Path Initiative has the potential toThe Critical Path Initiative has the potential toaddress industryaddress industry--wide initiatives;wide initiatives;


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FDA Decisions and User Fees

04-06 2006 2005 2004Number FDA

decisions-3% 37 39 38

Ave FDAdecision days

-8% 252 273 273

P

MAsandPMA

PanelTrack

Supplements

Ave total

elapsed days -30% 353 416 504Number FDA

decisions-8% 3198 3222 3463

Ave FDAdecision days

-22% 57 58 73510(k)s

Ave totalelapsed days

-10% 89 88 99

User fees have doubled in 5 years

FDA has review times

Manufactures have theirtheir responsetimes

Average FDA decision days = ave# days

for FDA to review the applications

(FDA time only)

Average total elapsed days = ave# of

days from receipt to final approval

decision (FDA time + manufacturer time).

$1,500

$2,000

$2,500

$3,000

$3,500

$4,000

$4,500

2003 2004 2005 2006 2007

$150,000

$175,000

$200,000

$225,000

$250,000

$275,000

$300,000

510(k) User Fees

PMA User Fees

PMA FeesPMA Fees

510(k) fees510(k) fees


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Increasing Drug and Device User Fees

User fees make up an increasing part of the drug and device reviUser fees make up an increasing part of the drug and device review budgetew budget An increasing concern is voiced about the significant portion ofAn increasing concern is voiced about the significant portion of FDA funding thatFDA funding that

comes from the drug and device companies the FDA is chartered tocomes from the drug and device companies the FDA is chartered to regulate.regulate.

$0$0

$50$50

$100$100

$150$150

$$200200

20032003 20042004 20052005 $0$0

$125$125

$250$250

$375$375

$500$500

MDUFMAMDUFMA(Millions)(Millions)

16% 17%21%

53%59%

57%

PDUFAPDUFA(Millions)(Millions)FDA Congress-Allocated Funds FDA Congress-Allocated Funds

MDUFMA User Fees PDUFA User Fees


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Delayed Approval Denies Access

Terminal patients request access to investigationalTerminal patients request access to investigationaldrugs and devices and are consistently denieddrugs and devices and are consistently denied

Advocacy alliances push for access to drugs withAdvocacy alliances push for access to drugs withcompleted animal testing, positive Phase I and incompleted animal testing, positive Phase I and insome cases moresome cases more--advanced Phase II or Phase IIIadvanced Phase II or Phase IIItrialstrials

A few examples of drugs with delayed approvalA few examples of drugs with delayed approval Gleevec/Glivec: Chronic myelogenous leukemiaGleevec/Glivec: Chronic myelogenous leukemia

Eloxatin: Advanced colorectal cancerEloxatin: Advanced colorectal cancer

Erbitux: Head and neck and colorectalErbitux: Head and neck and colorectalcancercancer

Tykerb: Breast cancerTykerb: Breast cancer


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Post Market Surveillance

Need to address the culture of risk aversion that unnecessarilyNeed to address the culture of risk aversion that unnecessarilydelays product approvalsdelays product approvals

The FDA could contract out product reviewsThe FDA could contract out product reviewsa process whicha process whichhas been highly successful in pilot programshas been highly successful in pilot programs

Congress could create extraCongress could create extra--governmental mechanism forgovernmental mechanism for

product oversightproduct oversight

A regulatory approach, which treats the device developmentA regulatory approach, which treats the device developmentprocess as a continuum beginning with initial use extending intoprocess as a continuum beginning with initial use extending intoroutine use would provide a more realistic framework to addressroutine use would provide a more realistic framework to address

issues of safety and efficacy.issues of safety and efficacy. EU contracts out product reviews by thirdEU contracts out product reviews by third--parties in the privateparties in the private--

sector (notified bodies) that test products, inspect manufacturisector (notified bodies) that test products, inspect manufacturingngsystems and ultimately verify that EU standards have been metsystems and ultimately verify that EU standards have been met


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Balancing Patient Risks and Rewards

1.1. More prudent tolerance for risk to gain benefitsMore prudent tolerance for risk to gain benefits

2.2. Expedited and less costly drug regulatory processesExpedited and less costly drug regulatory processes

3.3. Global reciprocity across regulatory agenciesGlobal reciprocity across regulatory agencies

4.4. Greater reliance on independent evaluation companiesGreater reliance on independent evaluation companies

5.5. Balance between preBalance between pre-- and post market controland post market control

6.6. Emphasis on contraindications for patient classesEmphasis on contraindications for patient classes

7.7. Approval process for off label useApproval process for off label use

8.8. Compassionate care useCompassionate care use9.9. Greater focus on reality rather than processGreater focus on reality rather than process

10.10. Realistic patent extensionRealistic patent extension

Recommendations for regulatory evolution:Recommendations for regulatory evolution:


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Imagine the Possibilities

Documents

Al Mann's innovations