委托协议书(职业健康体检类)

Tysabri®(natalizumab)BiogenIdecInc.BLA125104/15PeripheralandCentralNervousSystemDrugsAdvisoryCommitteeGaithersburg,MarylandMarch7-8,2006AliceHughes,M.D.DivisionofNeurologyProductsCenterforDrugEvaluationandResearchPeripheralandCentralNervousSystemDrugsAdvisoryCommitteeMarch7-8,20062ReviewofNon-PMLSafetyIssuesPeripheralandCentralNervousSystemDrugsAdvisoryCommitteeMarch7-8,20063Outline•InfectionsotherthanPML•Immunogenicityandhypersensitivityreactions•Carcinogenicity•Post-marketingreportsofseriousadverseevents•SummaryofmajorsafetyconcernsPeripheralandCentralNervousSystemDrugsAdvisoryCommitteeMarch7-8,20064•Natalizumab-andplacebo-treatedpatientshadsimilarincidencesof:–infectionsoverall:73.7%vs.73.9%(natalizumabvs.placebo)–seriousinfections:2.4%vs.2.3%•Natalizumab-andplacebo-treatedpatientshadsimilarincidencesof:–upperrespiratorytractinfections:59.6%vs.59.8%–UTIs:21.5%vs.21.4%•seriousUTIs:0.6%vs.0.5%–gastroenteritis:9.1%vs.9.0%InfectionsotherthanPML:Placebo-controlledMSstudiesPeripheralandCentralNervousSystemDrugsAdvisoryCommitteeMarch7-8,20065InfectionsotherthanPML:MSstudies•Incidencesofspecificinfectionsinplacebo-controlledstudies:–alllowerrespiratorytractinfections:13.3%vs.12.2%(natalizumabvs.placebo)•seriouspneumonias:0.4%vs.0.2%–vaginalinfections:7.5%vs.6.2%–allherpesinfections:7.0%vs.6.1%–gingivalinfections:1.1%vs.0.5%•Atypicalinfections•cryptosporidialgastroenteritiswithprolongedcourse(inmonotherapyStudy1801)•acuteCMVinfectionwithtransaminitis(inopen-labelStudy1808)PeripheralandCentralNervousSystemDrugsAdvisoryCommitteeMarch7-8,20066InfectionsotherthanPML:Placebo-controlledCDstudies•Incidenceofinfectionsoverall:–40.4%vs.35.8%(natalizumabvs.placebo)•Incidenceofseriousinfections:–2.5%vs.2.6%•Incidencesofselectedinfections:–URIs:27%vs.21%–UTIs:2.9%vs.2.0%–vaginalinfections:2.1%vs.1.6%–allherpesinfections:1.6%vs.1.0%–perianalabcesses:1.1%vs.0.6%–seriousviralmeningitides:0.2%(2)vs.0–seriousUTIs:0.2%(2)vs.0•OneseriousCMVinfection(CMVcolitis)–PatientalsoreceivingazathioprinePeripheralandCentralNervousSystemDrugsAdvisoryCommitteeMarch7-8,20067InfectionsotherthanPML:Long-termCDstudiesAtypicalInfections•Sixseriousatypicallowerrespiratorytractinfections–Pneumoniawithlungabscess–Pulmonaryaspergillosis–Pneumocystiscariniipneumonia–Varicellapneumonia–Mycobacteriumaviumintracellularecomplexpneumonia–Burkholderiacepaciainfection•Possibletuberculosisinfection•Unclearroleofconcomitantimmunosuppressive/immunomodulatoryagentsandintercurrentillnessesPeripheralandCentralNervousSystemDrugsAdvisoryCommitteeMarch7-8,20068Immunogenicity•Anti-natalizumabantibodyformationassessedevery12weeksinPhase3MSStudiesandselectedCDstudies–10%ofpatientshadapositiveantibodytiteratleastonce•4%ofpatientsweretransientlypositiveand6%werepersistentlypositiveinMSStudies•Incidenceofanti-natalizumabantibodyformationwashigherinStudy1802(12%)thanin1801(9%)–Intermittent(irregular)infusionsmayleadtohigherincidenceofantibodyformationPeripheralandCentralNervousSystemDrugsAdvisoryCommitteeMarch7-8,20069Immunogenicity•Anti-natalizumabantibodyformationstronglyassociatedwithinfusionreactionsandhypersensitivityreactions–Infusionreactionsoccurredin77%ofpersistentlyantibody-positivepatientsvs.20%ofantibody-negativepatientsinMSStudies1801and1802•Mostfrequentinfusionreactionsinantibody-positivepatients:rigors,nausea,headache,urticaria,flushing,pruritus,dyspnea–Anaphylactic/anaphylactoidreactionsoccurredin5.3%ofantibody-positivepatientsvs.0antibody-negativepatientsinMSStudies1801and1802–Anaphylactic/anaphylactoidreactionsoccurredin1.3%ofantibody-positivepatientsvs.0antibody-negativepatientsinselectedCDstudiesPeripheralandCentralNervousSystemDrugsAdvisoryCommitteeMarch7-8,200610Immunogenicity•MSrelapsesreportedmorefrequentlyasadverseeventsinantibody-positivepatients(vs.transientlypositiveandantibody-negativepatients)–57%vs.35%(antibody-positivevs.antibody-negativepatients)•Incidenceofinfectionslowerinantibody-positivepatients(vs.transientlypositiveandantibody-negativepatients)–OverallinfectionsinMSpatients:69%vs.82%(antibody-positivevs.antibody-negativepatients)–HerpesinfectionsinMSpatients:2.7%vs.8.4%PeripheralandCentralNervousSystemDrugsAdvisoryCommitteeMarch7-8,200611Hypersensitivityreactions•Anaphylactic/anaphylactoidreactions–MSplacebo-controlledstudies:0.4%(6)vs.0.2%(2)[natalizumabvs.placebo]–CDplacebo-controlledstudies:0.1%(1)vs.0–Long-termCDstudies:1additionalcaseofanaphylaxis(duringfirstinfusioninCD251;300daysafterreceiving4infusionsinpriorCDstudy)•SkinandsubcutaneoustissuedisorderinfusionreactionsinMSplacebo-controlledstudies:4.6%vs.1.9%•Urticaria:1.6%vs.0.3%•Delayedhypersensitivityevents•Mosthypersensitivityeventsoccurredduringorimmediatelyaftersecondinfusion;someoccurredlater–Onecaseofanaphylaxisassociatedwith13thinfusionPeripheralandCentralNervousSystemDrugsAdvisoryCommitteeMarch7-8,200612Carcinogenicity:MSstudies–Malignanciesbalancedinnatalizumab-andplacebo-treatedpatientsinplacebo-controlledstudies(0.7%natalizumabvs.1.3%placebo)–Typesofmalignanciesobserve