Translational ResearchTranslational Research::

University of IowaUniversity of IowaJuly 22, 2013July 22, 2013

Bruce GinglesBruce Gingles

Vice-PresidentVice-President

Cook Medical, IncCook Medical, Inc

bruce.gingles@cookmedical.combruce.gingles@cookmedical.com

Translational ResearchTranslational Research

““Research that benefits at least one person Research that benefits at least one person outside the researcheroutside the researcher’’s laboratory, and s laboratory, and preferably a patientpreferably a patient””

““Research is scientific, translational research Research is scientific, translational research is economicis economic””

R01R01→→ROIROI

Succeeding at researchSucceeding at researchFailing at translation Failing at translation

Four phases of translational research*:Four phases of translational research*:- T1: Phase I and II clinical trials and observational T1: Phase I and II clinical trials and observational

studiesstudies- T2: Phase III clinical trials and observational T2: Phase III clinical trials and observational

studies; evidence synthesis and guidelines studies; evidence synthesis and guidelines developmentdevelopment

- T3: Dissemination research; implementation T3: Dissemination research; implementation research; diffusion research; Phase IV trialsresearch; diffusion research; Phase IV trials

- T4 Outcomes researchT4 Outcomes research

* * Khoury et al. Khoury et al. Genet Med Genet Med 2007; 9(10): 665-6742007; 9(10): 665-674

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MooreMoore’’s law and s law and technologic innovationtechnologic innovation

MooreMoore’’s Law and FDAs Law and FDA

January-July 1999: 17 PMAs and January-July 1999: 17 PMAs and supplements approvedsupplements approved

January-July 2009: 12 approvals, -29%January-July 2009: 12 approvals, -29%

1998 full year: 42 approvals1998 full year: 42 approvals

2008 full year: 24 approvals, -43%2008 full year: 24 approvals, -43%

Impact on CookImpact on Cook

Innovators have increasingly shifted from being Innovators have increasingly shifted from being independent to indentured inventors within a independent to indentured inventors within a changing legal architecture. Manufacturers now changing legal architecture. Manufacturers now frequently negotiate with third parties for property frequently negotiate with third parties for property rights. rights.

Dedicated federal, state and institutional funding Dedicated federal, state and institutional funding intended to result in a larger pool of discoveries intended to result in a larger pool of discoveries and disclosures, to which Cook seeks access.and disclosures, to which Cook seeks access.

Technologies licensed from AMCs have halo Technologies licensed from AMCs have halo effect.effect.

The model for basic research is funded The model for basic research is funded grants, published research, career grants, published research, career advancement and properly staffed medical advancement and properly staffed medical schools competent to perpetuate federal schools competent to perpetuate federal funding, train students and deliver patient funding, train students and deliver patient care. The benefit to society is a stable care. The benefit to society is a stable academic health system.academic health system.

The model for translational research is The model for translational research is invention, patent(s), licensing/royalties (or invention, patent(s), licensing/royalties (or start-ups), with revenue reinvested in the start-ups), with revenue reinvested in the university. The benefit to society is new university. The benefit to society is new cures and advanced medical care. cures and advanced medical care. Discoveries must be unitized, monetized, Discoveries must be unitized, monetized, taxed and exported to achieve optimal taxed and exported to achieve optimal economic utility and public benefiteconomic utility and public benefit..

Why invent?Why invent?

Better patient outcomes and improved Better patient outcomes and improved public healthpublic health

Extends medical impact on patients globallyExtends medical impact on patients globally Intellectually stimulatingIntellectually stimulating RemunerativeRemunerative Academic promotion/Institutional benefit Academic promotion/Institutional benefit

through technology transfer processthrough technology transfer process LegacyLegacy

Why not invent?Why not invent?

Fear of being fleeced, ignored or Fear of being fleeced, ignored or corruptedcorrupted

Loss of academic or professional Loss of academic or professional reputationreputation

Poor understanding of the processPoor understanding of the process

Common Expectations of Common Expectations of Inventors by IndustryInventors by Industry

Product design inputProduct design input Assistance with regulatory applicationsAssistance with regulatory applications Perform/advise clinical evaluationPerform/advise clinical evaluation Publication/presentation in peer-reviewPublication/presentation in peer-review Patents/licensing Patents/licensing PatronagePatronage

Common Expectations of Common Expectations of Industry by InventorsIndustry by Inventors

Timely product development cycleTimely product development cycle Prompt and honest communicationPrompt and honest communication Financial support of development, research Financial support of development, research

and presentation costsand presentation costs Strong marketing effortStrong marketing effort Upgrade/modify product as neededUpgrade/modify product as needed CompensationCompensation

RoyaltiesRoyalties

Paid for the life of licensed patents, 20 yearsPaid for the life of licensed patents, 20 years May be paid in the absence of patents, for May be paid in the absence of patents, for

defined periods of time, typically 6-10 year defined periods of time, typically 6-10 year intervalsintervals

Customary rates range from 1Customary rates range from 1½-8% of net ½-8% of net sales, with an average of 3%. May be paid sales, with an average of 3%. May be paid quarterly or annuallyquarterly or annually

Conflicts of InterestConflicts of Interest

Simply, if you receive royalties, research grants, Simply, if you receive royalties, research grants, salary or professional fees (FFS), $COI existssalary or professional fees (FFS), $COI exists

Misconduct is more important than COI. Misconduct is more important than COI. Presumption of innocence? (PPSA)Presumption of innocence? (PPSA)

Perception is a fallible standard Perception is a fallible standard

Royalties not paid on sales to inventorRoyalties not paid on sales to inventor’’s hospitals hospital

Type I and Type II risk and error Type I and Type II risk and error

Relationships with IndustryRelationships with Industry

Industry possesses resources and expertise Industry possesses resources and expertise indispensible to the development and indispensible to the development and commercialization of technologic innovationcommercialization of technologic innovation

Technologic innovation depends on close Technologic innovation depends on close working relationships between inventors and working relationships between inventors and manufacturersmanufacturers

These relationships are ethical, professional These relationships are ethical, professional and as altruistic as FFSand as altruistic as FFS

Typical Development CycleTypical Development Cycle

Idea submitted under non-disclosureIdea submitted under non-disclosure Reviewed for acceptance based on Reviewed for acceptance based on benefit to benefit to

patientspatients, total economic value, ROI, total economic value, ROI Coding and reimbursement are issues todayCoding and reimbursement are issues today FDA filing fees: 510(k) FDA filing fees: 510(k) $4,158$4,158 /PMA /PMA $281, 600 $281, 600

MDUFMA, 2002. CE markMDUFMA, 2002. CE mark IRBIRB→→Prototype evaluationPrototype evaluation Quality system design reviewQuality system design review→p→productionroduction Market release (average 510(k) cycle time: 35m, Market release (average 510(k) cycle time: 35m,

PMA: 70m)PMA: 70m)

How to BeginHow to Begin

Identify corporate partner: web pages, Identify corporate partner: web pages, medical symposia exhibitions, sales medical symposia exhibitions, sales representatives, phone corporate product representatives, phone corporate product development, referral from colleagues, development, referral from colleagues, http://i2iconnect.orghttp://i2iconnect.org..

Resources vs. bureaucracyResources vs. bureaucracy Agree on expectations up frontAgree on expectations up front

Common Expectations by Common Expectations by UniversitiesUniversities

Technology TransferTechnology Transfer*: Royalties typically divided 35% to *: Royalties typically divided 35% to PI, 15% to PIPI, 15% to PI’’s lab, 15% to the department, 30% to the s lab, 15% to the department, 30% to the school and 5% to the university.school and 5% to the university.

MIT faculty and alumni alone have founded more than MIT faculty and alumni alone have founded more than 4,000 companies and these generate more than $230 4,000 companies and these generate more than $230 billion in annual sales, ranking as the 23billion in annual sales, ranking as the 23rdrd largest economy largest economy in the world.ªin the world.ª

• * Read, * Read, The Research Brass Ring, The Research Brass Ring, Patrick A. Gilbert, Hopkins Health, Fall, 2004Patrick A. Gilbert, Hopkins Health, Fall, 2004• ª Read, ª Read, As the Future catches You, As the Future catches You, Juan EnriquezJuan Enriquez

Patents granted by USPTO in 1985Patents granted by USPTO in 1985

Argentina 12Argentina 12 Venezuela 15Venezuela 15 Brazil 30Brazil 30 Mexico 35Mexico 35 South Korea 50South Korea 50

Patents granted by USPTO in 2003Patents granted by USPTO in 2003

Venezuela 20Venezuela 20 Argentina 70Argentina 70 Mexico 92Mexico 92 Brazil 180Brazil 180

South Korea South Korea 4,1324,132

Real wages in South Korea multiplied ninefold Real wages in South Korea multiplied ninefold between 1960 and 1990between 1960 and 1990

Real minimum wage in Mexico was Real minimum wage in Mexico was unchanged between 1960 and 2000unchanged between 1960 and 2000

South KoreaSouth Korea’’s real economic growth was eight s real economic growth was eight times larger than Mexicotimes larger than Mexico’’s between 1990 s between 1990 and 1998and 1998

20032003

17 countries generated 95% of all US 17 countries generated 95% of all US patentspatents

188 other countries generated the other 5%188 other countries generated the other 5%

The University of California alone spends 21 The University of California alone spends 21 percent more on R&D than the entire percent more on R&D than the entire country of Mexico……country of Mexico……

…………and generates six times as many US and generates six times as many US patentspatents

In 2004, Pfizer spent over $7.4B on R&DIn 2004, Pfizer spent over $7.4B on R&D

Three essential Three essential elements of innovation:elements of innovation:

Invention: Concept, prototype, validation Invention: Concept, prototype, validation (including research), regulation, production(including research), regulation, production

Education: Understand indications, Education: Understand indications, contraindications, potential complications, contraindications, potential complications, patient selection, interactions, timing, patient selection, interactions, timing, technique, references, etc. CMEtechnique, references, etc. CME

Commercialization: Innovation must be Commercialization: Innovation must be accessible to be useful. Adoption accessible to be useful. Adoption

““Invention-driven research is vastly Invention-driven research is vastly superior to research-driven superior to research-driven inventioninvention””

Why medical devices?Why medical devices?

Shorter time to market than drugsShorter time to market than drugs Longer patent life and royalties than drugsLonger patent life and royalties than drugs Requires fewer capital resources than drugsRequires fewer capital resources than drugs High direct involvement by the inventor, High direct involvement by the inventor,

throughout the product lifecyclethroughout the product lifecycle Rich EBM, CER and research opportunities*Rich EBM, CER and research opportunities*

** RO Darouiche et al. A comparison of two antimicrobial-impregnated central venous catheters. N Engl RO Darouiche et al. A comparison of two antimicrobial-impregnated central venous catheters. N Engl

J Med 1999;340:1-8J Med 1999;340:1-8

Industry-sponsored Industry-sponsored research funding research funding

Early-stage product R&DEarly-stage product R&D Clinical research fundingClinical research funding Physician training and educationPhysician training and education HTA, CER and economic research- priorityHTA, CER and economic research- priority Intake forms and complianceIntake forms and compliance Inter-organizational familiarityInter-organizational familiarity→ → projectsprojects

Two whopping barriers Two whopping barriers to device innovationto device innovation

(FDA-cleared/approved) clinical prototype (FDA-cleared/approved) clinical prototype evaluation, performed by the inventorevaluation, performed by the inventor

Commercial adoption at the inventorCommercial adoption at the inventor’’s hospitals hospital

““The best way to predict the The best way to predict the

future is to invent itfuture is to invent it””

--Alan Kay, 1971Alan Kay, 1971