FDA and the Regulatory Pathway for Biomaterials in Medical ... · FDA and the Regulatory Pathway...
Transcript of FDA and the Regulatory Pathway for Biomaterials in Medical ... · FDA and the Regulatory Pathway...
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