FDA and the Regulatory PathwayFDA and the Regulatory Pathwayfor Biomaterials infor Biomaterials inMedical DevicesMedical Devices

Steven K. Pollack, Ph.D.Steven K. Pollack, Ph.D.

Director, Division of Chemistry and Materials ScienceDirector, Division of Chemistry and Materials Science

Office of Science and Engineering LaboratoriesOffice of Science and Engineering LaboratoriesCenter for Devices and Radiological HealthCenter for Devices and Radiological Health

Food and Drug Administration Food and Drug Administration

2nd Military Biomaterials Roadmap WorkshopWednesday, November 8, New Brunswick NJ

OverviewOverview

What is a Medical Device?What is a Medical Device? What Do We Do at FDA/CDRH?What Do We Do at FDA/CDRH? Some Insights into Device RelatedSome Insights into Device Related

PropertiesProperties Some ExamplesSome Examples Some War StoriesSome War Stories

Center for Devices andCenter for Devices andRadiological Health MilestonesRadiological Health Milestones

19381938 Federal Food, Drug, and Cosmetic (FD&C) Act isFederal Food, Drug, and Cosmetic (FD&C) Act isenacted.enacted. One of the provisions of the new Act, which One of the provisions of the new Act, whichsupersedes the original Food and Drugs Act of 1906, is tosupersedes the original Food and Drugs Act of 1906, is toextend coverage to devices, making it illegal to sellextend coverage to devices, making it illegal to selltherapeutic devices that are dangerous or marketed withtherapeutic devices that are dangerous or marketed withfalse claims.false claims.

19761976 May 28 May 28 –– Medical Device Amendments to the Food, Medical Device Amendments to the Food,Drug, and Cosmetic Act of 1938 are enacted, to assureDrug, and Cosmetic Act of 1938 are enacted, to assuresafety and effectiveness of medical devices,safety and effectiveness of medical devices, including certainincluding certaindiagnostic and laboratory products.diagnostic and laboratory products.

19971997 Modernization Act mandates the most wide-ranging Modernization Act mandates the most wide-rangingreforms in agency practices since 1938. Provisions includereforms in agency practices since 1938. Provisions includemeasures to accelerate review of devices.measures to accelerate review of devices.

20022002 October - Medical Device User Fee and ModernizationOctober - Medical Device User Fee and ModernizationAct (MDUFMA)Act (MDUFMA)

A medical device definedA medical device defined

• intended for use in the diagnosis of disease orother conditions, or in the cure, mitigation,treatment, or prevention of disease in man, or

• intended to affect the structure or anyfunction of the body of man, and which does notachieve its primary intended purposes throughchemical action within or on the body of man andwhich is not dependent upon being metabolized forthe achievement of its primary intended purposes.”

Section 201, Food DrugSection 201, Food Drug and Cosmetic Actand Cosmetic Act

A medical device definedA medical device defined

• intended for use in the diagnosis of disease orother conditions, or in the cure, mitigation,treatment, or prevention of disease in man, or

• intended to affect the structure or anyfunction of the body of man, and which does notachieve its primary intended purposes throughchemical action within or on the body of man andwhich is not dependent upon being metabolized forthe achievement of its primary intended purposes.”

Section 201, Food DrugSection 201, Food Drug and Cosmetic Actand Cosmetic Act

Cochlear ImplantsCochlear Implants

Office of Device EvaluationOffice of Device Evaluation

Office of In Vitro DiagnosticsOffice of In Vitro Diagnostics

Office of Surveillance and Office of Surveillance and BiometricsBiometrics

Office of ComplianceOffice of Compliance

Office of Management OperationsOffice of Management Operations

Office of Science and Engineering Office of Science and Engineering LaboratoriesLaboratories

Office of Communications, Office of Communications, Educations and Radiation HealthEducations and Radiation Health

Pre-Clinical Applications

Post-Market Monitoring

Manufacturing/Actions

Labeling/Human Factors

Consulting/Research

CDRH Mission TodayCDRH Mission Today

ProtectPromote

CDRH CDRH promotespromotes and andprotectsprotects the health of the health ofthe public bythe public byensuring the safetyensuring the safetyand effectiveness ofand effectiveness ofmedical devices andmedical devices andthe safety ofthe safety ofradiological productsradiological products

SafetySafety

““There is reasonable assuranceThere is reasonable assurancethat a device is safe when it can bethat a device is safe when it can be

determined based on determined based on validvalidscientific evidencescientific evidence that the that the

probable benefits to health fromprobable benefits to health fromuse of the device use of the device for its intendedfor its intended

uses and conditions of useuses and conditions of use, when, whenaccompanied by accompanied by adequateadequate

directionsdirections and warnings against and warnings againstunsafe use, outweigh the probableunsafe use, outweigh the probable

risks.risks.””

21 CFR 860.7 21 CFR 860.7

EffectivenessEffectiveness

““There is reasonable assurance thatThere is reasonable assurance thata device is effective when it can bea device is effective when it can be

determined, determined, based upon validbased upon validscientific evidencescientific evidence, that in a, that in a

significant portion of the targetsignificant portion of the targetpopulationpopulation, the use of the device for, the use of the device forits intended uses and conditions ofits intended uses and conditions of

use, use, when accompanied bywhen accompanied byadequate directions for use andadequate directions for use and

warnings against unsafe usewarnings against unsafe use, will, willprovide provide clinically significant resultsclinically significant results..””

21 CFR 860.721 CFR 860.7

We Regulate Devices,We Regulate Devices,Not MaterialsNot Materials

Two important points:Two important points:

… we don’t regulatemedical procedures

(aka “practice ofmedicine”).

We regulate MedicalDevices…

Risk-Based Classification ofRisk-Based Classification ofMedical DevicesMedical Devices

Class I: simple, low riskClass I: simple, low riskdevicesdevices General controlsGeneral controls Most exempt from premarketMost exempt from premarket

submissionsubmission

Class I:Class I:General Controls SufficientGeneral Controls Sufficient

General Controls include:General Controls include:-Prohibition against adulterated or-Prohibition against adulterated or

misbranded devicesmisbranded devices-Premarket notification (-Premarket notification (510(k)510(k)))

requirementsrequirements-Banned devices-Banned devices-Good Manufacturing Practices (-Good Manufacturing Practices (GMPsGMPs))-Listing of device types-Listing of device types-Record keeping-Record keeping-Repair, replacement, refund-Repair, replacement, refund

Class I ExemptionsClass I Exemptions

All Class I Devices are exempt All Class I Devices are exempt exceptexcept:: Those intended for a Those intended for a ““use which is ofuse which is of

substantial importance in preventingsubstantial importance in preventingimpairment of human health, orimpairment of human health, or

Those that present a potential unreasonableThose that present a potential unreasonablerisk of illness or injuryrisk of illness or injury

Examples:Examples:Ammonia test systemAmmonia test systemDental Dental handpiecehandpiece and accessories and accessoriesProtective restraintProtective restraint

Risk-Based Classification ofRisk-Based Classification ofMedical DevicesMedical Devices

Class II: more complex, higherClass II: more complex, higherriskrisk Special controlsSpecial controls Premarket Notification [Premarket Notification [510(k)510(k)]] Substantial equivalenceSubstantial equivalence 10-15% require clinical data10-15% require clinical data 90 total FDA days to review90 total FDA days to review

Class II:Class II:Special Controls SufficientSpecial Controls Sufficient

Special Controls include:Special Controls include: LabelingLabeling GuidanceGuidance TrackingTracking Design ControlsDesign Controls Performance StandardsPerformance Standards Postmarket SurveillancePostmarket Surveillance

Risk-Based Classification ofRisk-Based Classification ofMedical DevicesMedical Devices

Class III: most complex,Class III: most complex,highest riskhighest risk Premarket Application [Premarket Application [PMAPMA]] Establish safety andEstablish safety and

effectivenesseffectiveness Bench - Animal - HumanBench - Animal - Human May include post-approvalMay include post-approval

study requirementsstudy requirements 320 total FDA days to review320 total FDA days to review

Class IIIClass IIIGeneral and Special ControlsGeneral and Special Controls

are not sufficientare not sufficient

Devices for which insufficient informationDevices for which insufficient informationexists to determine that general andexists to determine that general andspecial controls are sufficient to providespecial controls are sufficient to providereasonable assurance of the safety andreasonable assurance of the safety andeffectiveness of such devices andeffectiveness of such devices and

Such devices are:Such devices are: life sustaining of life supportinglife sustaining of life supporting substantial importance in preventingsubstantial importance in preventing

impairment of human health; orimpairment of human health; or present unreasonable risk of illness or injurypresent unreasonable risk of illness or injury

??How do we decide which pathway is theHow do we decide which pathway is theright one for a particular device?right one for a particular device?

510k or PMA?510k or PMA?

Classified in the Code of FederalClassified in the Code of FederalRegulations (CFR)Regulations (CFR)

PrecedentPrecedent Previously found SE Previously found SE →→ 510(k) 510(k) Previously found NSE Previously found NSE →→ PMA/HDE or PMA/HDE or

““de novode novo”” if low-risk device if low-risk device Previously approved PMA Previously approved PMA →→ PMA PMA

513(g) Request513(g) Request

Medical DeviceMedical DevicePrimary Pathways to MarketPrimary Pathways to Market

510(k) Submission Required510(k) Submission RequiredWhen:When:

Introducing a device to the marketIntroducing a device to the marketfor the first timefor the first time

Change in intended use for aChange in intended use for amarketed devicemarketed device

Making significant modification to aMaking significant modification to amarketed device (aka Special 510k)marketed device (aka Special 510k)

A Device is SubstantiallyA Device is SubstantiallyEquivalent (SE) if:Equivalent (SE) if:

In comparison to a legallyIn comparison to a legallymarketed device, it:marketed device, it: Has the same intended use,Has the same intended use,

andand Has the same technologicalHas the same technological

characteristics as thecharacteristics as thepredicate device, or:predicate device, or:

SE (cont.)SE (cont.)

Has the same intended use, andHas the same intended use, and Has different technologicalHas different technological

characteristics and thecharacteristics and theinformation in the 510(k):information in the 510(k):

Does not raise new types ofDoes not raise new types ofquestions of safety andquestions of safety andeffectiveness, andeffectiveness, and

Demonstrates it is as safe andDemonstrates it is as safe andeffective as the predicateeffective as the predicate

Medical DeviceMedical DevicePrimary Pathways to MarketPrimary Pathways to Market

Four stages of PMA reviewFour stages of PMA review

Filing ReviewFiling Review Substantive ReviewSubstantive Review

Includes one or more cyclesIncludes one or more cycles May also include a prior module reviewMay also include a prior module review

Panel ProcessPanel Process Closeout ProcessCloseout Process

PMA Review Process:PMA Review Process:FilingFiling

PMA Filing ReviewsPMA Filing Reviews Filing MeetingFiling Meeting

Expedited or not?Expedited or not? First discussion of panel meetingFirst discussion of panel meeting Division or Office level signoff?Division or Office level signoff?

Filing Review MemorandumFiling Review Memorandum Refuse to File/File LetterRefuse to File/File Letter

Only FILED PMAs count towards MDUFMA goalsOnly FILED PMAs count towards MDUFMA goals

PMA Review Process:PMA Review Process:Substantive ReviewSubstantive Review

The The ““gutsguts”” of the PMA process of the PMA process Communication is keyCommunication is key

Between team membersBetween team members With the firmWith the firm With management (whenWith management (when

needed)needed)

The first BIG questionThe first BIG question

Do we need to takeDo we need to takethe PMA to Panel?the PMA to Panel? First-of-a-kindFirst-of-a-kind Data raises issues forData raises issues for

PanelPanel

Preliminary decisionPreliminary decisionby day 60by day 60

The second questionThe second question

Are theAre thedeficienciesdeficienciessignificant enoughsignificant enoughto warrant ato warrant aMajor DeficiencyMajor DeficiencyLetter?Letter?

ConsultingConsultingreviews due dayreviews due day80/70: need to80/70: need todecide soon afterdecide soon after

Major Deficiency LetterMajor Deficiency Letter

Major DeficiencyMajor Deficiency Significant new or updated dataSignificant new or updated data Significant previously omitted dataSignificant previously omitted data Resets 180 day clockResets 180 day clock

MDUFMA requirementsMDUFMA requirements Must issue within 150 days on first cycleMust issue within 150 days on first cycle Must issue within 120 days on second cycleMust issue within 120 days on second cycle

PMA Review Process:PMA Review Process:Panel ProcessPanel Process

Must begin planning earlyMust begin planning early Coordinate with Panel Exec SecCoordinate with Panel Exec Sec Selection of panel membersSelection of panel members Panel pack due out Day 100/90Panel pack due out Day 100/90

Review memosReview memos Company infoCompany info Panel questionsPanel questions

Medical Device Advisory PanelsMedical Device Advisory Panels

Provide broad clinical and scientific expertise toProvide broad clinical and scientific expertise toevaluate safety and effectivenessevaluate safety and effectiveness PMAs, PDPs, 510(k)s Device classification/reclassification General issues (e.g. guidance documents, standards) Homework assignments

7 voting members, non-voting industry &7 voting members, non-voting industry &consumer representativesconsumer representatives

Provide Provide recommendationsrecommendations only only

CDRH Medical DevicesCDRH Medical DevicesAdvisory Committee PanelsAdvisory Committee Panels

Anesthesiology and RespiratoryAnesthesiology and Respiratory

Circulatory SystemCirculatory System

Clinical ChemistryClinical Chemistry//ToxicologyToxicology

Dental ProductsDental Products

Ear, Nose & ThroatEar, Nose & Throat

GastroenterologyGastroenterology//UrologyUrology

General & Plastic SurgeryGeneral & Plastic Surgery

General HospitalGeneral Hospital//Personal UsePersonal Use

HematologyHematology//PathologyPathology

ImmunologyImmunology

Medical Devices DisputeMedical Devices DisputeResolutionResolution

MicrobiologyMicrobiology

MolecularMolecular//Clinical GeneticsClinical Genetics

NeurologicalNeurological

ObOb//GynGyn

OphthalmicOphthalmic

Orthopedic & RehabilitationOrthopedic & Rehabilitation

RadiologicalRadiological

PMA Review Process:PMA Review Process:Closeout:Closeout:

The BIGGESTThe BIGGESTquestion:question: What is the finalWhat is the final

decision?decision?ApprovalApprovalApprovableApprovableNot ApprovableNot ApprovableDenialDenial

PatientPatientprotection andprotection andclinical studyclinical studydesigndesignconsiderationsconsiderations

Investigational Device Exemptions (IDE)Investigational Device Exemptions (IDE)

Allows investigational devices to be used inAllows investigational devices to be used inclinical studies to support PMA, 510(k)clinical studies to support PMA, 510(k)

Exempts from certain provisions of FD&C ActExempts from certain provisions of FD&C Act Requirements for informed consent, labeling,Requirements for informed consent, labeling,

monitoring, records/reportsmonitoring, records/reports Requires approval by Institutional Review BoardRequires approval by Institutional Review Board

(IRB) and, for significant risk devices, FDA(IRB) and, for significant risk devices, FDA 30-day review period 30-day review period –– if no action by FDA in 30 if no action by FDA in 30

days, it is days, it is ““deemed approveddeemed approved””

IDEIDE

Polymers for Medical DevicesPolymers for Medical Devices

PrimaryPrimary Properties are critical to the function ofProperties are critical to the function of

the devicethe device IOLsIOLs Resorbable suturesResorbable sutures HemostaticHemostatic polymers polymers

SecondarySecondary Properties are convenientProperties are convenient

Housings on electronic devicesHousings on electronic devices Components in non-implant devicesComponents in non-implant devices

Physical PropertiesPhysical Properties

ThermoplasticityThermoplasticity ReactivityReactivity TransparencyTransparency Mechanical StrengthMechanical Strength ToughnessToughness TribologicalTribological Properties Properties Interfacial PropertiesInterfacial Properties

Biocompatibility/BiostabilityBiocompatibility/Biostability

BiocompatibilityBiocompatibility Lack of toxicity/Lack of toxicity/immunogeniticyimmunogeniticy Minimal inflammatory responseMinimal inflammatory response Controlled encapsulationControlled encapsulation Non-Non-thrombogenicthrombogenic

BiostabilityBiostability Long term stability in the presence ofLong term stability in the presence of

high moisturehigh moisture Resistance to Oxidation andResistance to Oxidation and

Environmental Stress CrackingEnvironmental Stress Cracking

Devices are Made of MultipleDevices are Made of MultipleMaterialsMaterials

Wear Leads to ProblemsWear Leads to Problems

PolyethylenePolyethylene

PolyethylenePolyethylene

UHMWPEUHMWPE

UHMWPEUHMWPE

UHMWPEUHMWPE

UHMWPEUHMWPE

PolypropylenePolypropylene

PolycarbonatePolycarbonate

Cardiotomy reservoir

PolycarbonatePolycarbonate

PolyethyleneterephthalatePolyethyleneterephthalate

PolyurethanesPolyurethanes

PolyurethanesPolyurethanes

SiliconeSilicone

SiliconesSilicones

SiliconesSilicones

SiliconesSilicones

BioresorbableBioresorbable Polymers Polymers

and H

BioresorbableBioresorbable Polymers Polymers

TeflonTeflon

Wear particles led to severe bone loss

CellulosicsCellulosics

Storage of the Hollow Fiber DialyzerAt Elevated Temperatures Led toDepolymerization and Release ofNeurotoxic Oligosacharrides

Non Non ““Off-The ShelfOff-The Shelf”” Polymers Polymers

No device historyNo device history Use in different deviceUse in different device Use for different indicationUse for different indication WE DONWE DON’’T APPROVE MATERIALST APPROVE MATERIALS

Sponsor must address theSponsor must address thesafety/efficacy of the Device.safety/efficacy of the Device.

Biocompatibility from earlier device canBiocompatibility from earlier device canbe sited, but use in different tissuesbe sited, but use in different tissues(neurological versus bone) will certainly(neurological versus bone) will certainlyraise new safety questions.raise new safety questions.

An Example ofAn Example ofDevice EvolutionDevice Evolution

Ball ValveBall Valve

Silicone

Dacron

Ex Vivo ViewEx Vivo View

PyrolyticPyrolytic Graphite Disc Valve Graphite Disc Valve

Dacron

Pyrolitic Carbon(derived from PAN)

In ActionIn Action

PyrolyticPyrolytic Graphite Graphite

Fixed Porcine Fixed Porcine XenographXenograph Valve Valve

Porcine Porcine EndocardiumEndocardium

Polyurethane Tricuspid ValvePolyurethane Tricuspid Valve

WhatWhat’’s Next?s Next?

NanophaseNanophase Materials Materials Conducting Polymers inConducting Polymers in

Electrophysiological ApplicationsElectrophysiological Applications Tissue Engineered Medical ProductsTissue Engineered Medical Products

with Synthetic Polymer Scaffoldswith Synthetic Polymer Scaffolds New New BioresorbableBioresorbable Polymers Polymers

DCMS’s FUTURE HOME

AcknowledgementsAcknowledgements

Dr. Donna-Bea Tillman, Director, ODEDr. Donna-Bea Tillman, Director, ODE Dr. Dan Schultz, Director, CDRHDr. Dan Schultz, Director, CDRH