Download Immunomodulators and Cancer Risk Assessment

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