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THE UNIQUE ROLES OF IRB THE UNIQUE ROLES OF IRB IN MEDICAL DEVICE IN MEDICAL DEVICE CLINICALL TRIAL CLINICALL TRIAL

Chiu Lin, Ph.D.Chiu Lin, Ph.D.

CITI, May, 2009CITI, May, 2009

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The World of Medical Device IndustryThe World of Medical Device Industry

Venture OrientedVenture Oriented Diverse Diverse - > 20,000 firms world wide > 20,000 firms world wide - Produce > 80,000 brand productsProduce > 80,000 brand products

Rapidly ExpandingRapidly Expanding Becoming very innovative and high-Becoming very innovative and high-

techtech

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Medical Device Industry Medical Device Industry Exponential GrowthExponential Growth

0

2000

4000

6000

8000

10000

12000

14000

16000

1998 1999 2000 2001 2002 2003 2004

Ophthalmic

Eletromedical

X-Ray

Dental

Surgical

Instruments

Diagnostics

Dun & Bradstreet Medical Device Firm Data

Number of Manufacturers by YearNumber of Manufacturers by Year

44

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DEVICES ARE NOT DRUGSDEVICES ARE NOT DRUGSDEVICES ARE NOT DRUGSDEVICES ARE NOT DRUGS

DDRUGS ARE RUGS ARE DISCOVEREDDISCOVERED

DDEVICES ARE EVICES ARE DDESIGNEDESIGNED

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Development of Products -Development of Products -Clinical InvestigationsClinical Investigations

Development of Products -Development of Products -Clinical InvestigationsClinical Investigations

DEVICES DEVICES (IDE)(IDE)( >> 20% clinical trials)( >> 20% clinical trials)

- EffectivenessEffectiveness and/or and/or safetysafety pivotal trial pivotal trial (one phase)(one phase)

DRUGS AND BIOLOGICS DRUGS AND BIOLOGICS

(100% clinical trials) (100% clinical trials) (IND)(IND)

- Dose limiting toxicity Dose limiting toxicity (Phase I)(Phase I)

- SafetySafety and and efficacy efficacy (Phase (Phase II & Phase III)II & Phase III)

The complexity and need for clinical data is growing…

Embolic protection Embolic protection devicesdevices

Vascular anastomosis

devices for CABG

Image-guided Image-guided bronchoscopesbronchoscopes

Combination Combination productproduct Glaucoma shuntsGlaucoma shunts

Daily wear contact lenses

CPAP devices for apnea

… … requiring more in-depth requiring more in-depth assessment of safety andassessment of safety and

effectiveness…….effectiveness…….

… … requiring more in-depth requiring more in-depth assessment of safety andassessment of safety and

effectiveness…….effectiveness…….

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Perspectives of Device Clinical Perspectives of Device Clinical Trials – Compared to DrugsTrials – Compared to Drugs

Perspectives of Device Clinical Perspectives of Device Clinical Trials – Compared to DrugsTrials – Compared to Drugs

Devices vary greatly on type, intended use Devices vary greatly on type, intended use population, and risk posedpopulation, and risk posed

FDA device regulation recognizes these FDA device regulation recognizes these differences by classifying devices into 3 differences by classifying devices into 3 classes: classes: Class IClass I (low risk), (low risk), Class IIClass II (intermediate risk), and (intermediate risk), and Class IIIClass III (high risk) (high risk)

FDA does not automatically require clinical FDA does not automatically require clinical trials as part of its approval process for all trials as part of its approval process for all devices (only about 20% devices require devices (only about 20% devices require clinical trials)clinical trials)

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Premarket Submission Premarket Submission Requirements of Medical DevicesRequirements of Medical Devices

Premarket Submission Premarket Submission Requirements of Medical DevicesRequirements of Medical Devices

Premarket Notification [510(k)] Premarket Notification [510(k)] –Class I & Class II–Class I & Class II

Premarket Approval (PMA) Premarket Approval (PMA) – Class III– Class III

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PREMARKET PREMARKET

NOTIFICATION 510(K)NOTIFICATION 510(K)Data to demonstrate the new device is Data to demonstrate the new device is

as safe and effective (as safe and effective (substantially substantially equivalent, equivalent, SESE) as a legally market ) as a legally market

(predicate) device(predicate) device

Only in few cases, a clinical data is Only in few cases, a clinical data is needed to support SE determination.needed to support SE determination.

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PREMARKET APPROVAL PREMARKET APPROVAL (PMA)(PMA)

PREMARKET APPROVAL PREMARKET APPROVAL (PMA)(PMA)

The most stringent marketing applicationThe most stringent marketing application

PMA must contain sufficient information PMA must contain sufficient information to reasonably assure the to reasonably assure the safetysafety and and effectivenesseffectiveness of the proposed device. of the proposed device.

Valid scientific evidenceValid scientific evidence must be provided must be provided to demonstrate that the device is safe and to demonstrate that the device is safe and effective for its intended use.effective for its intended use.

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Valid Scientific EvidenceValid Scientific Evidence(21 CFR 860.7)(21 CFR 860.7)

Well-controlled clinical investigationWell-controlled clinical investigation

Partially controlled clinical studiesPartially controlled clinical studies

Studies and objective trials without Studies and objective trials without matched controlmatched control

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Regulation of Medical Device Regulation of Medical Device Clinical InvestigationClinical Investigation

Regulation of Medical Device Regulation of Medical Device Clinical InvestigationClinical Investigation

21 CFR Part 812 - Investigational Device 21 CFR Part 812 - Investigational Device Exemption, Exemption, IDE (IND – 21 CFR Part 312)IDE (IND – 21 CFR Part 312)

21 CFR Part 50 - Informed consent 21 CFR Part 50 - Informed consent – – drugs, devices, and biologicsdrugs, devices, and biologics

21 CFR Part 56 - Institutional Review Boards 21 CFR Part 56 - Institutional Review Boards (IRB) (IRB) – – drugs, devices, and biologicsdrugs, devices, and biologics

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Clinical Investigations Clinical Investigations Subject to IDE RegulationSubject to IDE Regulation

To support marketing application [PMA, To support marketing application [PMA, or 510(k)]or 510(k)]

Collection of safety and effectiveness Collection of safety and effectiveness information for unapproved deviceinformation for unapproved device

Sponsor-investigatorSponsor-investigator studies studies

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Clinical Investigation Under IDEClinical Investigation Under IDE

To determine To determine safetysafety and and effectivenesseffectiveness of an of an investigational device investigational device

NoNo phasesphases in clinical investigation in clinical investigation Distinction between Distinction between significant risksignificant risk (SR) (SR)

devices and devices and non-significant risknon-significant risk (NSR) (NSR) devices in approval processdevices in approval process

Different approval procedures for SR and Different approval procedures for SR and NSR studiesNSR studies

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Significant Risk (SR) InvestigationSignificant Risk (SR) InvestigationSignificant Risk (SR) InvestigationSignificant Risk (SR) Investigation

A study that presents a potential for serious A study that presents a potential for serious risk to the health, safety, or welfare of a subjectrisk to the health, safety, or welfare of a subject

Require FDA and Require FDA and IRBIRB approval before clinical approval before clinical investigation can begininvestigation can begin

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Examples of SR DevicesExamples of SR Devices Cardiac cathetersCardiac catheters Surgical tissue adhesivesSurgical tissue adhesives Vascular and arterial graft Vascular and arterial graft

prothesesprotheses Dental endosseous implantsDental endosseous implants Cochlear implantsCochlear implants Implantable infusion pumpsImplantable infusion pumps Implantable pacemakerImplantable pacemaker

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Examples of NSR Devices Examples of NSR Devices (Require only IRB approval for investigation)(Require only IRB approval for investigation)

Bio-stimulation lasers for treatment of painBio-stimulation lasers for treatment of pain Daily wear contact lensesDaily wear contact lenses Glucose monitorGlucose monitor Blood pressure monitorBlood pressure monitor Magnetic resonance imaging (MRI) Magnetic resonance imaging (MRI) Pulse oximeterPulse oximeter Ob/Gyn diagnostic ultrasoundOb/Gyn diagnostic ultrasound

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Approving Clinical Approving Clinical Investigation of Medical Investigation of Medical

Devices by IRBDevices by IRB(21 CFR 812 Subpart D – IDE (21 CFR 812 Subpart D – IDE

Regulation)Regulation)

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IRB Review and ApprovalIRB Review and Approval

§ 812.60 – IRB composition, duties, and § 812.60 – IRB composition, duties, and functionfunction

- An IRB reviewing and approving An IRB reviewing and approving investigation shall comply with investigation shall comply with requirements of Part 56 in all respects, requirements of Part 56 in all respects, including its composition, duties, and including its composition, duties, and functionfunction

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IRB Review and ApprovalIRB Review and Approval

§ 812.62 – IRB Approval§ 812.62 – IRB Approval

- An IRB shall review and have authority to An IRB shall review and have authority to approve, require modifications, or approve, require modifications, or disapprove all investigations under IDE.disapprove all investigations under IDE.

- If FDA finds that an IRB’s review is If FDA finds that an IRB’s review is inadequate, a sponsor should submit an inadequate, a sponsor should submit an IDE application to FDA.IDE application to FDA.

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IRB Review and ApprovalIRB Review and Approval

§ 812.64 – IRB’s Continuing Review § 812.64 – IRB’s Continuing Review

- The IRB shall conduct its continuing The IRB shall conduct its continuing review of an investigation in accordance review of an investigation in accordance with Part 56.with Part 56.

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Determination of SR/NSR StudyDetermination of SR/NSR Study(21 CFR 812.66)(21 CFR 812.66)

Determination of SR/NSR StudyDetermination of SR/NSR Study(21 CFR 812.66)(21 CFR 812.66)

Sponsor presents protocol to IRB and a Sponsor presents protocol to IRB and a statement why investigation does not pose statement why investigation does not pose significant risk (NSR study)significant risk (NSR study)

If IRB agrees the study is NSR & approves the If IRB agrees the study is NSR & approves the study, then, no formal IDE submission for FDA study, then, no formal IDE submission for FDA approval is needed. Investigation can begin approval is needed. Investigation can begin ((Abbreviated IDE requirementsAbbreviated IDE requirements).).

If IRB disagrees, then, submit IDE application to If IRB disagrees, then, submit IDE application to FDA for approval (SR Investigation with full FDA for approval (SR Investigation with full requirements)requirements)

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Abbreviated IDEAbbreviated IDE

No formal FDA IDE approval is neededNo formal FDA IDE approval is needed

IRB is required to meet all aspects of:IRB is required to meet all aspects of:

- 21 CFR Part 50 (protection of human subjects) – 21 CFR Part 50 (protection of human subjects) – Informed consentInformed consent

- 21 CFR Part 56 (IRB)21 CFR Part 56 (IRB)

Labeling requirementsLabeling requirements

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Comparison Between Device Comparison Between Device and Drug/Biologics Trialsand Drug/Biologics Trials

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Regulatory DistinctionsRegulatory Distinctions

Device Classification – risk based Device Classification – risk based

- Class IClass I

- Class IIClass II

- Class IIIClass III

Drug and Biologics Drug and Biologics

- All high riskAll high risk

- No Class I, II, and III classificationNo Class I, II, and III classification

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Regulatory DistinctionsRegulatory Distinctions

* Devices: “Investigator agreement” generated * Devices: “Investigator agreement” generated by the sponsor [per 21 CFR 812.43(c)]by the sponsor [per 21 CFR 812.43(c)]

* Drugs: “Statement of Investigator” - Form * Drugs: “Statement of Investigator” - Form 15721572

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Regulatory DistinctionsRegulatory Distinctions

Adverse EventsAdverse Events DevicesDevices: investigators shall submit the : investigators shall submit the

adverse effect report to the adverse effect report to the sponsorsponsor and and IRBIRB [21 CFR 812.150(a)(1)] [21 CFR 812.150(a)(1)]

Drugs/BiologicsDrugs/Biologics: investigators shall : investigators shall submit the adverse effect report to the submit the adverse effect report to the sponsorsponsor [21 CFR 312.64(b)] [21 CFR 312.64(b)]

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Regulatory DistinctionsRegulatory Distinctions

Device – Significant vs. non-significant Device – Significant vs. non-significant risk trialsrisk trials

Drug – All significant risksDrug – All significant risks

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Research DistinctionsResearch Distinctions Device Studies (Device Studies (vsvs. drug trials). drug trials)- Small subject population (mostly 100s)Small subject population (mostly 100s)

- OneOne phase trial phase trial

- Blinding study is not commonBlinding study is not common

- ““Controls” varyControls” vary

Can not do placebo Can not do placebo

Sham, active, historical controls are commonSham, active, historical controls are common

- CI trainingCI training is critical (Human Factors) is critical (Human Factors)

- IRBs play critical roleIRBs play critical role

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Regulatory SimilaritiesRegulatory Similarities

21 CFR 50: Informed consent21 CFR 50: Informed consent

21 CFR 54: Financial Disclosure of 21 CFR 54: Financial Disclosure of clinical investigatorclinical investigator

21 CFR 56: IRB21 CFR 56: IRB

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Regulatory SimilaritiesRegulatory Similarities

FDA approval required FDA approval required

IDE or INDIDE or IND

FDA regulations specify sponsor and FDA regulations specify sponsor and

clinical investigator responsibilitiesclinical investigator responsibilities

21 CFR 812 and 21 CFR 31221 CFR 812 and 21 CFR 312

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CONCLUSIONCONCLUSION

The role of IRB in approving medical The role of IRB in approving medical device clinical trial is identical to device clinical trial is identical to approving drug investigationapproving drug investigation

Additional role in medical device trial is Additional role in medical device trial is the differentiation of SR and NSR the differentiation of SR and NSR investigationinvestigation

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THANK YOU FOR YOUR THANK YOU FOR YOUR ATTENTION !!ATTENTION !!

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