clinical study design for medical devices
TRANSCRIPT
Clinical Study Design Clinical Study Design for Medical Devicesfor Medical Devices
Greg Campbell, Ph.D.Greg Campbell, Ph.D.Director, Division of BiostatisticsDirector, Division of BiostatisticsCenter for Devices and Radiological Center for Devices and Radiological
HealthHealthU.S. Food and Drug AdministrationU.S. Food and Drug Administration
KitasatoKitasato--Harvard Symposium, October 24Harvard Symposium, October 24--25, 2006, Tokyo25, 2006, Tokyo
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OutlineOutline
•• The nature of medical devices and their The nature of medical devices and their regulationregulation
•• Difference between devices and drugsDifference between devices and drugs•• Therapeutic device design issuesTherapeutic device design issues•• Diagnostic device design issuesDiagnostic device design issues•• Bayesian statistics in medical device trialsBayesian statistics in medical device trials•• ChallengesChallenges
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What Are Medical Devices?What Are Medical Devices?Definition by exclusion: any medical item for use in
humans that is not a drug nor a biological product
intraocular lenses MRI machinesbreast implantssurgical instrumentsthermometers(drug-coated) stents home kit for AIDS diagnostic test kitsbone densitometersartificial hips
PRK lasers pacemakersdefibrillatorsspinal fixation devicesglucometers artificial heartshearing aidslatex glovesartificial skinsoftware, etc
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Cardiovascular DevicesCardiovascular Devices
Bare Metal StentsBare Metal StentsDrug Eluting Stents (DES)Drug Eluting Stents (DES)Balloon angioplastyBalloon angioplastyPacemakersPacemakersDistal protection for AMIDistal protection for AMIHeart valvesHeart valvesVentricular Assist Devices (Ventricular Assist Devices (VADsVADs))Patent foramen Patent foramen ovaleovale (PFO) closure devices(PFO) closure devicesDefibrillators Defibrillators Abdominal aortic aneurysm (AAA) devicesAbdominal aortic aneurysm (AAA) devices
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What is a DrugWhat is a Drug--Eluting Stent?Eluting Stent?Example: Cordis’ Cypher™ Sirolimus-Eluting Coronary Stent
ComponentsStent Platform & Stent Platform & Delivery SystemDelivery SystemCarrier(sCarrier(s))DrugDrug
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The Nature of Medical The Nature of Medical Device StudiesDevice Studies
•• Whereas drugs are discovered, devices Whereas drugs are discovered, devices evolve. evolve.
•• Devices are constantly being Devices are constantly being ““improvedimproved””. . •• Life length of a particular model of a Life length of a particular model of a
device is often 1device is often 1--2 years.2 years.•• Rapidly changing technologyRapidly changing technology
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Devices Not Drugs Devices Not Drugs ----The DifferencesThe Differences
A Trial with a A Trial with a ‘‘ShamSham’’ Control may not be possibleControl may not be possibleMasking (blinding) may be impossible for patients, Masking (blinding) may be impossible for patients, health care professionals, investigatorshealth care professionals, investigatorsBench/Mechanical Testing not PK/PDBench/Mechanical Testing not PK/PDMechanism of Action often well understoodMechanism of Action often well understood–– Effect tends to be localized rather than Effect tends to be localized rather than
systemic, physical not pharmacokineticsystemic, physical not pharmacokineticPrePre--clinical Animal Studies (not for toxicity)clinical Animal Studies (not for toxicity)Implants (skill dependent; learning curve)Implants (skill dependent; learning curve)
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The Differences in the The Differences in the Two IndustriesTwo Industries
Number & Size of Device CompaniesNumber & Size of Device Companies in USin US27,635 registered firms, of which 22,838 are 27,635 registered firms, of which 22,838 are USUSMedian device company sizeMedian device company size----under 50 under 50 employees (Many are new startemployees (Many are new start--up companies.)up companies.)
Many fewer (and generally much larger) Many fewer (and generally much larger) pharmaceutical firmspharmaceutical firms
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Commonalities in Design Commonalities in Design between Pharmaceuticals between Pharmaceuticals and Medical Device Trialsand Medical Device Trials
Superiority trialsSuperiority trialsActive nonActive non--inferiority trialsinferiority trialsMultiple endpointsMultiple endpointsSurrogate endpointsSurrogate endpointsMultiMulti--center trialscenter trialsInterim monitoringInterim monitoringUse of Data Monitoring Committees (Use of Data Monitoring Committees (DSMBsDSMBs) (FDA ) (FDA has a newly released guidance document on DMCs: has a newly released guidance document on DMCs: http://http://www.fda.gov/cber/gdlns/clintrialdmc.htmwww.fda.gov/cber/gdlns/clintrialdmc.htm )). . . . . .
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Types of Controls for Types of Controls for Device StudiesDevice Studies•• Randomized control (RCT)Randomized control (RCT)•• NonNon--randomized concurrent controlrandomized concurrent control•• Historical controlHistorical control
Pseudo twoPseudo two--treatment comparative study treatment comparative study –– OneOne--arm study, compared to historical controlarm study, compared to historical control–– PatientPatient--level data of historical control is available and level data of historical control is available and
used in treatment comparison.used in treatment comparison.–– Propensity score statistical analysisPropensity score statistical analysis
SingleSingle--arm study against a fixed target value arm study against a fixed target value –– Compared to a fixed target valueCompared to a fixed target value obtained from multiple obtained from multiple
historical trials historical trials
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Regulatory Differences in US Regulatory Differences in US Between Drugs and DevicesBetween Drugs and Devices
Different law and regulations for devices Different law and regulations for devices due to the nature of devicesdue to the nature of devicesDifferent Alphabet SoupDifferent Alphabet SoupIDE IDE ---- IInvestigational nvestigational DDevice evice EExemptionxemptionPMA PMA ---- PPrereMMarket arket AApprovalpproval510(k) 510(k) ---- Substantial EquivalenceSubstantial Equivalence------not not bioequivalencebioequivalenceA Single Confirmatory Trial (not 2).A Single Confirmatory Trial (not 2).Usually donUsually don’’t use Phase I, IIA, IIB, III, IVt use Phase I, IIA, IIB, III, IVFDA guidance for international officials FDA guidance for international officials http://http://www.fda.gov/cdrh/manual/ireas.htmlwww.fda.gov/cdrh/manual/ireas.html
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Diagnostic DevicesDiagnostic Devices
Can be used for Can be used for –– DiagnosisDiagnosis–– ScreeningScreening–– Monitoring disease or medical conditionMonitoring disease or medical condition
Types of devicesTypes of devices–– In vitroIn vitro diagnostic devicesdiagnostic devices–– Imaging devicesImaging devices–– OthersOthers
Combination therapeuticCombination therapeutic--diagnostic devicediagnostic device–– Example: implantable cardioverter defibrillator Example: implantable cardioverter defibrillator
(ICD)(ICD)
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Diagnostic DevicesDiagnostic Devices
Diagnostic devices require a Diagnostic devices require a completely different approachcompletely different approachFDA Statistical Guidance on Reporting FDA Statistical Guidance on Reporting Results from Studies Evaluating Results from Studies Evaluating Diagnostic Tests; Draft Guidance for Diagnostic Tests; Draft Guidance for Industry and FDA ReviewersIndustry and FDA Reviewershttp://www.fda.gov/cdrh/osb/guidance/1428.htmlhttp://www.fda.gov/cdrh/osb/guidance/1428.html
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Some Design Issues in Some Design Issues in DiagnosticsDiagnostics
Plan the type of study design; more than Plan the type of study design; more than one design is possible. Potential problem is one design is possible. Potential problem is that FDA usually does not require an that FDA usually does not require an Investigational Device Exemption (IDE) for Investigational Device Exemption (IDE) for a diagnostic test.a diagnostic test.The Randomized Clinical Trial (the premier The Randomized Clinical Trial (the premier design for therapeutics) is of limited use in design for therapeutics) is of limited use in many diagnostic evaluations of tests.many diagnostic evaluations of tests.It is generally more efficient to use patient It is generally more efficient to use patient as his/her own control if new test is as his/her own control if new test is compared to a reference method. compared to a reference method.
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Bayesian InitiativeBayesian Initiative
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Why FDAWhy FDA’’s Bayesian Initiative s Bayesian Initiative in Medical Device Trials?in Medical Device Trials?Mechanism of action is often physical and local.Mechanism of action is often physical and local.
Often a great deal of prior information on very similar Often a great deal of prior information on very similar devices often exists: clinical trials overseas, data devices often exists: clinical trials overseas, data registries, historical controls and pilotsregistries, historical controls and pilots
Use of good prior information can appreciably reduce Use of good prior information can appreciably reduce the size and perhaps the length of a trial. One can the size and perhaps the length of a trial. One can arrive at the same decision in a much more timely arrive at the same decision in a much more timely manner. manner.
A Bayesian approach has some appeal to clinicians since A Bayesian approach has some appeal to clinicians since the focus is on the patient.the focus is on the patient.
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Bayesian Statistics in Device TrialsBayesian Statistics in Device Trials
Use available prior informationUse available prior informationPrior planning of the design and analyses stages Prior planning of the design and analyses stages is crucial in a Bayesian paradigm. is crucial in a Bayesian paradigm. Identify the source of prior information before Identify the source of prior information before current experiment begins.current experiment begins.In addition, there is a need to agree upon the In addition, there is a need to agree upon the weight of the prior evidence. weight of the prior evidence. Not a substitute for good science. Still need Not a substitute for good science. Still need randomization, blinding, precision, low bias randomization, blinding, precision, low bias
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Bayesian Draft GuidanceBayesian Draft Guidance
““Draft Guidance for the Use of Draft Guidance for the Use of Bayesian Statistics in Medical Device Bayesian Statistics in Medical Device TrialsTrials””, released in May, 2006, released in May, 2006http://www.fda.gov/cdrh/osb/guidance/1601.htmlhttp://www.fda.gov/cdrh/osb/guidance/1601.html
Public meeting in Rockville MD in July, 2006Public meeting in Rockville MD in July, 2006http://www.fda.gov/cdrh/meetings/072706 http://www.fda.gov/cdrh/meetings/072706
bayesian.htmlbayesian.html for document and slides from for document and slides from meeting presentations.meeting presentations.
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ChallengesChallenges
Adaptive trialsAdaptive trialsCombination products and the use of Combination products and the use of biomarkers using advances in imaging, biomarkers using advances in imaging, genomics, proteomicsgenomics, proteomicsPostPost--market concernsmarket concernsGlobal development and Global development and internationalizationinternationalization
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Changes in Device TrialsChanges in Device Trials
Modifications during the course of the Modifications during the course of the trial to the protocol in terms of trial to the protocol in terms of –– Inclusion/exclusion criteriaInclusion/exclusion criteria–– EndpointsEndpoints–– Control groupControl group–– Statistical analysis planStatistical analysis plan
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Adaptive TrialsAdaptive Trials
Monitor sequentially and possibly stop Monitor sequentially and possibly stop early for success or futility.early for success or futility.Increase the sample sizeIncrease the sample sizeChange the randomization ratioChange the randomization ratioThe important point is that to be The important point is that to be successful, one needs to plan for successful, one needs to plan for adaptation at the start of the trial.adaptation at the start of the trial.
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Combination ProductsCombination Products
Drug Eluting StentsDrug Eluting StentsHeart ValvesHeart ValvesCardiovascular devices that both detect a Cardiovascular devices that both detect a condition and deliver a therapy (ICDs)condition and deliver a therapy (ICDs)Diagnostic tests for pharmacogenomics to Diagnostic tests for pharmacogenomics to guide the use of cardiovascular drugsguide the use of cardiovascular drugsFDA Drug/Diagnostic CoFDA Drug/Diagnostic Co--development development Concept Paper Concept Paper www.fda.gov/cder/genomics/pharmacoconceptfn.pdfwww.fda.gov/cder/genomics/pharmacoconceptfn.pdf
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Postmarket ActivitiesPostmarket Activities
INTERMACS InterINTERMACS Inter--agency Registry for agency Registry for Mechanically Assisted Circulatory SupportMechanically Assisted Circulatory SupportA joint effort by NHLBI, CMS and FDA to A joint effort by NHLBI, CMS and FDA to provide comprehensive post market national provide comprehensive post market national registry on all patients receiving mechanical registry on all patients receiving mechanical circulatory support therapy in the US circulatory support therapy in the US beginning in 2006.beginning in 2006.www.intermacs.orgwww.intermacs.org
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International OpportunitiesInternational Opportunities
Global Harmonisation Task Force Global Harmonisation Task Force GHTFGHTF–– Similar to ICHSimilar to ICH
Goal:Goal: To harmonize regulation of To harmonize regulation of medical devices among members.medical devices among members.
GHTF website: GHTF website: www.ghtf.orgwww.ghtf.org
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““Harmonization by DoingHarmonization by Doing””
One important program to meet the One important program to meet the increasing public health challenges of the increasing public health challenges of the 2121stst centurycenturyIt involves FDA and MHLW as well as It involves FDA and MHLW as well as industry and academia in US and Japan.industry and academia in US and Japan.Market approval goal: to conduct Market approval goal: to conduct simultaneous clinical studies in Japan and in simultaneous clinical studies in Japan and in US in order to obtain regulatory market US in order to obtain regulatory market approval at the same time.approval at the same time.
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FDAFDA’’s Critical Path s Critical Path Opportunities ListOpportunities List
#1 Biomarker Qualification#1 Biomarker Qualification–– One of five questions is One of five questions is ““What types and What types and
levels of evidence are needed to accept a levels of evidence are needed to accept a biomarker as a surrogate endpoint for biomarker as a surrogate endpoint for product efficacy?product efficacy?””
#6 Surrogates Outcomes for #6 Surrogates Outcomes for Cardiovascular Drug Eluting StentsCardiovascular Drug Eluting Stents#23 Imaging Biomarkers in #23 Imaging Biomarkers in Cardiovascular DiseaseCardiovascular Disease
http://www.fda.gov/oc/iniatitives/criticalpath/reports/opp_list.http://www.fda.gov/oc/iniatitives/criticalpath/reports/opp_list.pdfpdf
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Total Product Life Cycle Total Product Life Cycle (TPLC) for Devices(TPLC) for Devices
““Ensuring the Health of the Public Throughout the Total Product LEnsuring the Health of the Public Throughout the Total Product Lifecycle ifecycle . . . It. . . It’’s Everybodys Everybody’’s Businesss Business””
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CDRHCDRH’’s Vision of the Pipelines Vision of the Pipeline