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ImmunomodulatorsandCancerRisk Assessment TheTNFInhibitorHistoryIllustratesthe Scientific&RegulatoryChallenges DanMellon,Ph.D. PharmacologyToxicologySupervisor DivisionofAnesthesia,Analgesia,andAddictionProducts CenterforDrugEvaluationandResearch U.S.FoodandDrugAdministration October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 1 Disclaimer Thecontentofthistalkdoesnot necessarilyreflecttheviewsofthe FDA,andisentirelybasedonmy ownobservationsandviewpoints. October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 2 CancerRiskAssessment ICHS1A‐ 1995 • CancerRiskAssessment • “Carcinogenicitystudiesshouldbeperformedforany pharmaceuticalwhoseexpectedclinicaluseiscontinuous foratleast6months(SeeNOTE1)” – “Note1:Itisexpectedthatmostpharmaceuticals indicatedfor3monthstreatmentwouldalsolikelybe usedfor6months.” October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 3 CancerRiskAssessment ICHS6‐ 1997 • “Standardcarcinogenicitybioassaysaregenerally inappropriateforbiotechnology‐derivedpharmaceuticals. However,product‐specificassessmentofcarcinogenic potentialmaystillbeneededdependingupontheduration ofclinicaldosing,patientpopulationand/orbiological activityoftheproduct(e.g.,growthfactors, immunosuppressiveagents,etc.)…” – Norecommendationsonhowtodothisfor immunosuppressiveagents October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 4 CancerRiskAssessment ICHS6(R1)‐ 2011 • Carcinogenicity – Product‐specificassessments – “Strategycouldbebasedonaweightofevidenceapproach...” – Possibledatasources: • Publisheddata(e.g.,informationfromtransgenic,knock‐outoranimal diseasemodels,humangeneticdiseases),informationonclasseffects, detailedinformationontargetbiologyandmechanismofaction,in vitrodata,datafromchronictoxicologystudiesandclinicaldata. • “Insomecases,theavailableinformationcanbesufficienttoaddress carcinogenicpotentialandinformclinicalriskwithoutadditional nonclinicalstudies.” October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 5 CancerRiskAssessment ICHS6(R1)– 2011– ImpactofWOE • IfWOEsupportsconcern,rodentbioassaysarenotwarranted – Labelandmanagerisk • IfWOEisunclear,proposestudiesthatcouldmitigatethe mechanismbasedconcern • Ifinsufficientknowledge,doamoreextensiveassessment – Understandthetargetbiology – Includeadditionalendpointsintoxicologystudies • IfWOEdoesnotsupportconcern,nofurthertesting recommended • TheProduct‐SpecificAssessmentisusedto: – Communicaterisk – Provideinputforriskmanagementplanwithlabelingproposals, clinicalmonitoring,post‐marketingsurveillance,oracombination oftheseapproaches October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 6 ICHS1(R1) Whycan’twedothesame? Howtohandleimmunomodulators? October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 7 CommunicatingRisk:Labeling 21CFR§201.57 13Nonclinicaltoxicology 13.1Mutagenesis,carcinogenesis,impairmentof fertility • “…muststatewhetherlongtermstudiesin animalshavebeenperformedtoevaluatethe carcinogenicpotentialand,ifso,thespeciesand results” October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 8 21CFR§201.57 13.1…carcinogenesis • “…anyprecautionarystatementonthesetopics mustincludepractical,relevantadvice tothe prescriberonthesignificanceoftheseanimal findings. • Humandatasuggestingthatthedrugmaybe carcinogenic…asdescribedinthe‘Warningand Precautions’section,mustnot beincludedinthis subsectionofthelabeling.” October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 9 Wheredophysiciansandpatients havetolookforcarcinogenicityinfo? • Boxedwarning • 5WarningsandPrecautions – “Immunosuppression”or“Malignancies” • 6AdverseEvents – “Malignancies” • 13NonclinicalToxicology • 17PatientCounselingInformation October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 10 Typicalnonclinicalcontributionfor biologic immunomodulatorytherapeutic • 13NONCLINICALTOXICOLOGY • 13.1Carcinogenesis,Mutagenesis,ImpairmentofFertility • Long‐termanimalstudieshavenotbeenperformedtoevaluate thecarcinogenicpotentialof_______. October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 11 Typicalnonclinicalcontributionfor smallmolecule immunomodulatorytherapeutic • 13NONCLINICALTOXICOLOGY • 13.1Carcinogenesis,Mutagenesis,ImpairmentofFertility • Long‐termanimalstudieshavebeenperformedinmiceandrats toevaluatethecarcinogenicpotentialof_______.Tumors/No tumorswerenotedasx‐foldthemaximumhumandailydose. October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 12 5FDA‐approvedAnti‐TNF‐products • • • • • REMICADE® (infliximab)approvedAug1998 ENBREL® (etanercept)approvedNov1998 HUMIRA® (adalimumab)approvedDec2002 CIMZIA® (certolizumab)approvedApr2008 SIMPONI® (golimumab)approvedApr2009 October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 13 OriginalInfliximabLabel (c.1998) Precautions: Malignancy/Infection • PatientswithlongdurationofCrohn’sdiseaseand chronicexposuretoimmunosuppressant therapiesaremorepronetodeveloplymphomas andinfections.Theimpactofinfliximabtreatment onthesephenomenaisunknown. Carcinogenesis… • Long‐termstudiesinanimalshavenotbeen performedtoevaluatethecarcinogenicpotential … October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 14 KeyInfliximabLabelingUpdates • 2002: Carcinogenesis sectionupdated – 6‐monthrepeat‐dosetoxicitystudyinmice givencV1qanti‐mouseTNF‐ (mouseanalog). • Dosed2‐8timeshumandose(mg/kgbasis)oncea week • “ResultsindicatedthatcV1qdidnotcause tumorigenicityinmice.” October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 15 KeyInfliximabLabelingUpdates • 2004:Warnings:Malignancyupdated – Lymphoma casesinRApatientsreported • 2006: BoxedWarningUpdated – HepatosplenicT‐celllymphomas(rare)inadolescentandyoung adultpatientsonconcomitanttreatmentwithazathioprineor6‐ mercaptopurine • 2009: BoxedWarningUpdated – “Lymphomaandothermalignancies,somefatal,havebeen reportedinchildrenandadolescentpatientstreatedwithTNF blockers,includingREMICADE.” October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 16 KeyInfliximabLabelingUpdates 2013:Warnings:MalignanciesUpdated • Lymphomas • HepatosplenicT‐celllymphoma • SkinCancer– Added“MelanomaandMerkelcellcarcinoma”have beenreportedinpatientswithTNFblockertherapy • OtherMalignancies Why did nonclinical not predict ultimate clinical labeling? What could nonclinical do better to characterize potential risk? Can nonclinical data help with the interpretation of the human findings? If ICH S1 is revised…what do we do with the immunomodulators? October 20 & 21, 2014 Mellon: ILSI/HESI FDA Workshop 17