RltRegulatorychllhallenges for registration of novel vaccines · RltRegulatorychllhallenges for...

R l t h ll fRegulatory challengesforregistration of novelregistrationofnovel

vaccines

D N D ll iDr.NoraDellepianeFondationMerieux,LesPensières‐ Annecy22‐ 24June 2015

Dr.NoraDellepiane‐ ConsultantonQuality andRegulation ofBiological Products

Public Health ObjectivePublicHealthObjective

AccessforallMemberStatestovaccinesneededtofightinfectiousdiseasesofpublichealthrelevanceataffordableprices This requires enough availability and sustainableprices.Thisrequiresenoughavailabilityandsustainablesupplyofvaccinesofassuredquality,safetyandefficacymeetingtheprogrammaticneedsofcountries,particularlythose which are less resourcedthosewhicharelessresourced.


Access to priority vaccinesAccesstopriorityvaccines• Vaccineregistration/marketingauthorizationisa

i i i d i iprerequisitetointroductioninanycountry• Theevaluationofvaccinesformarketingauthorization,particularlythatofnovelvaccinesmaybechallengingp y y g g

• Authoritiesinproducingcountriesandinhighincomecountriesusuallyhavetherequiredinfrastructureandresources for a proper reviewresourcesforaproperreview

• Authoritiesinmostoftheusercountries,particularlyinlessresourcedcountriesmaynothavetherequiredconditionstoconductameaningfulevaluationofsuchcomplexproducts


Regulatory process during vaccinedevelopmentdevelopment

IND‐like process:Early communicationbetween sponsorandregulators to discuss expectations and sharing of productregulators todiscuss expectationsandsharingofproductdevelopment planincluding theclinical development plan.Scientificadvice applied inEurope:Asanexample,EMAaddresses specific questions from product developers andaddresses specific questionsfrom product developers andguidesthem inthedevelopment planEstablishmentoftesting capacity bytheNRAincollaborationwith the sponsor Transfer of testing methods for future lotwith thesponsor.Transferoftesting methods forfuturelotreleasePre‐submission meetingstodiscuss submission requirements,legal considerations of the application etclegal considerations oftheapplication,etcPediatric InvestigationPlan(PIP)incaseofvaccinestargetingthis age groupis arequirement inEurope


Regulatory process formarketingauthorizationauthorization

Pre‐submission meetingsI t ti t b it li ti fIntentiontosubmit orapplicationformMarketingauthorization application.Requirements mayinclude:• Submission ofProductdossier;usually CTDformat• Testing ofsamples (some authorities)I ti f d ti f iliti (if i d)• Inspectionofproductionfacilities (ifrequired)

• Review ofsamples,labellingandinserts/Summary ofProductCharacteristics

• InfoonPharmacovigilancesystem• Risk ManagementPlan


Common Technical Document (CTD)CommonTechnical Document(CTD)


Increased complexity inproductp y pdevelopment

Novelvaccinesrequireproductspecificexpertiseandunderstandingofdiseaseburden,morbidityandmortalityrates in areas where the disease is prevalentrates,inareaswherethediseaseisprevalent,

Manyaretargetedtocountriesinregionswithoutenoughdevelopmentofregulatoryagencies

Clinicaltrialstobeconductedincountrieswherethediseaseisprevalent,requirecapacityfortheregulationofclinical trialsclinicaltrials

Useofnewproductiontechnologiesrequiresspecificexpertiseformeaningfulreview


Supportfortheregulation ofclinicalpp gtrials

TWOIMPORTANTTOOLSAVAILABLE

NetworkingNetworking• Tojointly develop common procedures andforms fortheapproval andmonitoringofclinical trialsandfortheevaluation ofclinical data

• Tosupporteach other forthereview andapproval ofCTapplications• Tobenefit from thesupportbyregulators from robust NRAs andfromWHOpp y g

TheAfrican VaccineRegulatory Forum(AVAREF)is agoodexampleTheDeveloping CountryVaccineregulators Network(DCVRN)isanother goodexampleJointreviewmeetings

• Supportoffered byWHOtoassist regulators mostly inAfrica toreview CTapplications

• Forhighpriority vaccines,such asmalariaandebola candidates


Increased complexity ofvaccineproductsimplies increased complexity in regulatoryimplies increased complexity inregulatoryapproaches

Review ofnewvaccineproducts requires among others

• Specific expertise in the product and in the technology used forSpecific expertiseintheproduct andinthetechnology used forproduction

• Specific expertiseforreview ofnon‐clincal andclinical dataforthespecific vaccineinquestion

• Risk benefit assessment as part of product evaluationRisk benefit assessment aspartofproduct evaluation• Review ofrisk managementplans• Specific pharmacovigilancecommitments orphaseIVstudies• Ability toassess thepotential PublicHealthImpactparticularly forvaccines for which efficacy may be lower than generally observedvaccinesforwhich efficacy may be lower than generally observed

• Understanding ofQuality bydesignconceptforwell characterizedproducts

• Understanding ofadaptiveclinical trialsconcept


Regulators worldwide arechallenged

Thereis consensusamong regulators globally,particularly fromwell developed regulatory agencies,that notasingleagency hastherequired resources toaddress alltherelevantregulatory aspectsforallproduct categories;andtherefore collaboration,informationh i d k h i b ti lsharingandworksharing become essential.Avoidance ofunnecessary testing is considered criticalAvoidance of redundant inspections of manufacturing facilities isAvoidance ofredundant inspectionsofmanufacturing facilities isconsidered criticalTrendis tofocusonrisk benefit equation,potential publichealthimpact of the intervention and measures to monitor safety andimpactoftheinterventionandmeasures tomonitorsafety andminimize risk


Supportfortheevaluation ofMAppapplications

Vaccines supplied through centralized procurement Vaccines supplied through direct procurementVaccinessupplied through centralized procurement(e.g.UN)

Vaccinessupplied through directprocurement(notnecessarily prequalified byWHO)

MarketingAuthorization (MA)grantedin country of origin

MarketingAuthorization (MA)may ormay not have been granted in countryincountryoforigin

Prequalification by WHO: ensures that

may nothavebeengranted incountryoforigin

Prequalification byWHO:ensures thatvaccinemeets theneeds oftheprogrammeintarget countries

MarketingAuthorization (MA)mayhavebeengranted inthird countries

Afacilitated MAprocess expected inreceiving countries:Expedited

d f h i f i d

Fullresponsibility forevaluation lieswith NRAinprocuring country,unless

i i f li h


procedure forthereview ofimportedprequalified vaccines.Now revised toCollaborativeprocedure between WHOandNRAs fortheassessment and

provisionsforreliance onotherregulators areinplace

Supportfortheevaluation ofMAppapplications

Vaccinessupplied through directprocurement(notnecessarily prequalified byWHO)

MarketingAuthorization (MA)may or Supportnationalreview ofMAmay nothavebeengranted incountryoforigin

evaluation with MAincountryoforigin(CPP)and/orinthird countriesconsidered asreference authorities

U f i d fMarketingAuthorization (MA)mayhavebeengranted inthird countries

Useofown expertiseandresources forreview ofMAapplications

Useofbilateral agreements with otherNRAs to assist evaluation process

Fullresponsibility forevaluation lieswith NRAinprocuring country,unless

NRAs toassist evaluation process UseofNetworkinginitiativestoassist

evaluation process


gprovisionsforreliance onotherregulators areinplace

CONSTRAINTSCONSTRAINTSV i li d th h t li d Wh t d t b i lVaccinessupplied through centralizedprocurement (e.g.UN)

What needs tobe inplace

MarketingAuthorization (MA)grantedin country of origin Adequate regulatory framework withincountryoforigin

Prequalification by WHO: ensures that

Adequate regulatory framework withprovisionsforreliance onother NRAs orWHOPQ

Defined and transparent process forPrequalification byWHO:ensures thatvaccinemeets theneeds oftheprogrammeintarget countries

Defined andtransparentprocess formarketingauthorization,with clearrequirements,steps andtimelines forapproval

Afacilitated MAprocess expected inreceiving countries:Expedited review

d f C ll b i d

pp Alignment ofrequirements betweencountriesandregions

Technical/scientific expertiseforproper


procedure forCollaborativeprocedurebetween WHOandNRAs fortheassessment andaccelerated registrationofprequalified medicines

assessment oftheapplication

CONSTRAINTS Inadequate regulatory frameworkwith provisions for reliance on other Frequently seenwith provisionsforreliance onotherNRAs orWHOPQ

Notwell defined andnon‐transparent process for marketing

constraints that impairordelay implementationoftheexpedited orll b i d

REMAINTOBEtransparentprocess formarketing

authorization,without clearrequirements,steps andtimelinesforapproval

collaborativeprocedure;andleadtounpredictable timelinesfor registration

ADDRESSED

Lack ofalignment ofrequirementsbetween countriesandregions

Limitedtechnical/scientific

forregistration

Supportprovided byWHO and collaborating ALREADY

expertiseforproper assessment oftheapplication

WHOandcollaboratingregulatory agenciesSupportprovided basedon bilateral agreements

BEINGADDRESSEDMORENEEDEDonbilateral agreements

between countries,etcNEEDED


POTENTIALLYUSEFUFULINTERVENTIONSINTERVENTIONS

Availabilityofguidancedocuments(modelregulatoryframework,modelprocessforregistration),

d d f l l f h d Trainingprovidedtofacilitateimplementationoftheguidance, Furthereffortstowardsalignmentandharmonizationofrequirements, Collaborationbetweenregulators(relianceandrecognitionincludingg ( g g

mutualrecognition)throughnetworkinginitiatives Technical/scientificexpertiseprovidedjointreviewactivities,twining

betweenNRAsandothermeans Scientificguidanceprovidedthroughexpertcommittees(e.g.SAGE)on

riskbenefitanalysis,potentialpublichealthimpactofintervention,etc;availabletoNRAstoassistinregistrationprocess

StrengtheningofNationalImmunizationTechnicalAdvisoryGroups(NITAGs)toassistdecisionmakingatcountrylevel


Dr. Nora Dellepiane

Consultant on Quality and Regulation of Biological Products

Tel. (41) 79 475 5460E-mail: [email protected]

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