••––••–––•––– -––•MassMassachachuusesettstts InInssttiittuutte of Technole of TechnoloogygyHaHarvarvarrd Md Meedicadicall SScchohoololBrBrigighaham am annddWWoomemenn’’s Hs HoossppitalitalVA BVA Boossttonon HeHealalthcthcaare Sre Syysstteemm22..7782J82J//33.9.961J61J//BEH.45BEH.4511JJ//HST5HST52424JJSUMMARY OF FEDERALSUMMARY OF FEDERAL REGULATORY ISSUESREGULATORY ISSUES AND CLINICAL TRIALSAND CLINICAL TRIALSM. SpecM. Specttor,or, PPhh.D..D.FDAFDA • • • • • • NNaame ofme ofdevicedeviceDescriptiDescriptioon ofn of devicedevice– IndicIndicaation and intetion and intendended used use– PerformanPerformancce cle claimsaimsFDA claFDA classissificficaatitiononPreclPrecliinniiccalal testesttiinngg:: funcfunctitiononalal andandbibiolologogiiccalal testesttiinngg– TestsTests– WhWhichich compcompononenentsts of thof the de deevviice toce to bbeeevaluevaluaatteedd bbyy eacheach testesttmethmethodod– Form ofForm of ththee cocompmpononenent to bt to bee tteessttededIDEIDE proprottococolol– IInncluclussionion critecriterriia fora for ppaatientientsts ttoo bbee enenrorolledlled inin ththe se sttuuddyy– Controls?Controls?– Number of patients; statisticsNumber of patients; statistics-powpoweer cr caalclculationulation (http://(http://calculatcalculators.stat.uclaors.stat.ucla..ededuu/)/)– Outcome vaOutcome variariabblesles– IInnformedformed conconssenent formt formBenefiBenefit/rist/riskk rraattiiooPage 1Biocompatibility Flow Chart for the Section of Toxicity Tests for 510(k)s Page 2 Source: U.S. FDAPage 3 Source: U.S. FDAPage 4 Source: U.S. FDAU.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) May 2001 This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations. Page 5 Source: U.S. FDAFDA CLINICAL TRIAL GUIDANCEFDA CLINICAL TRIAL GUIDANCEPurpose of Control GroupPurpose of Control GroupControl groups have one major purpose: to allowControl groups have one major purpose: to allow discrimination of patient outcomes (for example, changesdiscrimination of patient outcomes (for example, changes in symptoms, signs, or other morbidity) caused by thein symptoms, signs, or other morbidity) caused by the test treatest treatment from outcomes caused by other factotment from outcomes caused by other factorrs,s, such as the natural prosuch as the natural proggression of the disease, observerression of the disease, observer or patient expectations, oror patient expectations, or other treatment. The controother treatment. The controll group experience tells us whgroup experience tells us what wat woould have hauld have happened toppened to patients if they had notpatients if they had not receireceived thved the test tre test treatment or ifeatment or if they had received a differenthey had received a different treatment known to bet treatment known to be effectiveffective.e.FDA CLINICAL TRIAL GUIDANCEFDA CLINICAL TRIAL GUIDANCE••Purpose of Control GroupPurpose of Control Group––RandomizRandomizationation––BlindingBlinding••Types of ControlTypes of Control––Placebo Concurrent ControlPlacebo Concurrent Control––NoNo--treatment Concurrent Controltreatment Concurrent Control––DoseDose--response Concurresponse Concurrent Controlrent Control––Active (PositivActive (Positive) Concurrent Controle) Concurrent Control ––External Control (InclExternal Control (Including Historical Control)uding Historical Control)––MultMultiple Control Groiple Control GroupsupsPage 6FDA CLINICAL TRIAL GUIDANCEFDA CLINICAL TRIAL GUIDANCEPurpPurposes ofoses of CliniCliniccal Trial Triaallss and Relatedand Related IssuesIssues••Evidence of EfficacyEvidence of Efficacy••CompComparatiarativve Ee Effffiicacy ancacy and Safetd Safetyy••Fairness ofFairness of ComCompparisarisonsons––DoseDose––Patient PopulationPatient Population––Selection and Timing of EndpointsSelection and Timing of EndpointsFDA CLINICAL TRIAL GUIDANCEFDA CLINICAL TRIAL GUIDANCEGuidance for IndustryGuidance for IndustryE6 Good ClinicalE6 Good Clinical Practice:ConsolidatedPractice:ConsolidatedGuidGuidanceance••Good clinGood clinical practiical practice (ce (GGCP) is an inteCP) is an internationrnationaal el etthicahical al andnd scientific quality standard for designing, conducting, recordingscientific quality standard for designing, conducting, recording,, and reporting trials thand reporting trials that involve the participat involve the participation of humanation of human subjects.subjects.••ComplianceCompliance wwiith this standardth this standard provides public assurance thatprovides public assurance thatthe rights, safety, and wthe rights, safety, and weellbeingllbeing of trial subjects are protecteof trial subjects are protected,d, consistent wconsistent wiith the principlesth the principles that have theirthat have their origorigin in thin in thee Declaration of Helsinki, and thatDeclaration of Helsinki, and that the clinicathe clinicall ttrriaial data arl data aree credcredible.ible.••The objective of this ICH GCP guThe objective of this ICH GCP guidance is to provide a unifiedidance is to provide a unifiedstandard for the European Union (standard for the European Union (EEU), Japan, and the UnitedU), Japan, and the UnitedStates to faStates to facilitacilitate the mutualte the mutual acceptance of clinical data by tacceptance of clinical data by thehe regulatory authorities inregulatory authorities in these jurisdictions.these jurisdictions.Page 7•––•-––•POWER CALCULATIONPOWER CALCULATIONSAMPLE SIZE DETERMINATIONSAMPLE SIZE DETERMINATIONTyType I Erpe I Errroorr (False(False PositivePositive))• Alpha (Alpha (αα) is the probabilit) is the probability thay thatt the testthe testwillwill lelead to thead to the rejerejecctition ofon ofththe he hyyppootthhesesiistestedtested wwhhen thaen thatt hyhypothesis ispothesis is ttrrue.ue.– HypothHypothesisesis: The: Themmeedidical devcal deviicece reresultssults inin an ian immpprroved outcooved outcommee..αα=0.05 m=0.05 meeans that thans that thereere is only a 5is