orphan drug development guidebook building block u201 · output orphan drug designation best time...

ODDG–BuildingBlockU201–Version1 1

OrphanDrugDevelopmentGuidebook

BuildingBlockU201

ThisdocumentdefinesthecontentoftheBuildingBlockcreatedforeachidentifiedtool,incentives,initiative or practice introduced by public bodies or used by developers to expedite drugdevelopmentinRareDiseases(RDs).

ITEM DESCRIPTION

BuildingBlock(BB)Title

USAOrphanDrugDesignation(US-ODD)

References

https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.htmhttps://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/ucm598062.htm

Description

The Orphan Drug Act (ODA) provides for granting special financial incentives to asponsor developing a drug or biological product (“drug”) to treat a rare disease orconditionuponrequestofthatsponsor.Thisstatusisreferredtoasorphandesignation(orsometimes“orphanstatus”).Ararediseaseorconditionisdefinedasanydiseaseorconditionwhich:

• Affectslessthan200,000personsintheUS,or• Affectsmorethan200,000intheUSandforwhichthereisnoreasonable

expectationthatthecostofdevelopingandmakingavailableintheUSadrugforsuchconditionwillberecoveredfromsalesintheUSofsuchdrug.

TheODA is intendedtoprovide incentives forOrphanDrugdevelopmentandtodefraythe costs of qualified clinical testing expenses incurred in connection with thedevelopmentofdrugsforrarediseasesandconditions.Theproceduretypicalconsistsofareviewcycleofapproximately90days:

• Willeitherreceive: − DesignationLetterOR− DeficiencyLetter• Once designated, sponsor is required to submit annual reports until drug is

approved


Category RegulatoryBuildingBlock

Geographicalscope

UnitedStatesofAmerica

Availability

Applicantsdevelopingmedicinesforrarediseases.

Scope ofuse

ODD,alongwithothertoolsoftheFDAOfficeofOrphanProductsDevelopment(OOPD),allowstoadvancetheevaluationanddevelopmentofproducts(drugs,biologics,devices,ormedical foods)thatdemonstratepromiseforthediagnosisand/ortreatmentofrarediseasesorconditions.

A sponsormay seek orphan designation for a specified rare disease or condition of apreviouslyunapproveddrug,orofanewuseforanalreadymarketeddrug.

Stakeholders

• Theorphandrugdeveloper• OOPD• CBER• CDER

Enablers/Requirements

The disease or condition for which the drug is intended affects fewer than 200,000people in the United States or, if the drug is a vaccine, diagnostic drug, or preventivedrug,thepersonstowhomthedrugwillbeadministeredintheUnitedStatesarefewerthan200,000peryear.

Foradrugintendedfordiseasesorconditionsaffecting200,000ormorepeople,orforavaccine, diagnostic drug, or preventive drug to be administered to 200,000 or morepersonsper year in theUnitedStates, there isno reasonableexpectation that costsofresearchanddevelopmentofthedrugfortheindicationcanberecoveredbysalesofthedrugintheUnitedStates.

Output OrphanDrugDesignation

Besttime toapplyand timewindow

Adevelopermayrequestorphandrugdesignationany timeafterobtainingnon-clinicalproof-of-principle data, until before Biological Licence Application (BLA) submission. Inmost cases, the best time is when you enter clinical phase. ODD granted duringdevelopmentisre-evaluatedandconfirmedatthetimeoftheBLAsubmission.


Experttips

GuidanceonOrphanDrugdesignation,commonissuesinrarediseasesdrugdevelopment,requestingmeetingwithFDA,andothertopicsareavailableontheFDA’sOfficeofOrphanProductsDevelopmentwebsite:https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.htm

InterestedpartiesmayalsorequestmeetingswithOOPDstaff–eitherviaphoneorface-to-faceforadviceonOrphanproductsrelatedprogramsorovercomingissuesstatedinadeficiencyletter.

PROs:

− Orphan designation provides for financial incentives and defraying of costs todrugsponsorsfordevelopmentandmarketingoftheorphandrug.Indetails:

o Market Exclusivity – The first sponsor of a designated orphan drug toobtain FDA marketing approval for the designated rare disease orconditionreceivessevenyearsofmarketingexclusivity.

o Tax credit – A sponsor may claim as tax credits 25% of the qualifiedclinicalresearchcostsforadesignatedorphanproduct.

o WaiverofPrescriptionDrugUserFees–Thesponsor’sfeeasprescribedby the Prescription Drug User Fee Act (PDUFA Fees) at the time ofsubmitting amarketing application to FDA arewaived for a designatedproduct.

o Pediatric Research Equity Act (PREA)Waiver: FDA grants full waiver ofpediatricstudies

CONs:

− Thereareno risks.Therearenocosts to requestingOrphandesignation,andanegative decision does not otherwise undermine the development of the drugforitsintendeduse.



BuildingBlockU202


ITEM DESCRIPTION


HumanitarianDeviceExemption(HDE)

HumanitarianUseDevice(HUD)Program

References

FDAHDE:https://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions/humanitariandeviceexemption/default.htm

FDADesignatingHUD:https://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/designatinghumanitarianusedeviceshuds/default.htm

FDAGuidance:

https://www.fda.gov/industry/designating-humanitarian-use-device-hud/education-and-media-resources-hud-program

Description

In1990, anewprovisionwas created in theUSunder theSafeMedicalDevicesAct tocreateanewregulatorypathwayfordeviceproductsintendedfordiseasesorconditionthataffectsmall(rare)populationsthatdefinedHDEsandHUDs.

AHUDis“medicaldeviceintendedtobenefitpatientsinthetreatmentordiagnosisofadiseaseor condition thataffectsor ismanifested innotmore than8,000 individuals intheUSperyear.”[21CFR814.3(n)].

AnHDE isamarketingapplication foraHUD.AnHDE isexempt fromtheeffectivenessrequirementsoftheFood,DrugandCosmeticAct,andissubjecttocertainprofitanduserestrictions. An HDE is similar to a premarket approval application (PMA) in that theapplicantmustdemonstrateareasonableassuranceofsafety;however,itdiffersfromaPMAinthattheapplicantisexemptfromtherequirementofdemonstratingareasonable


assurance of effectiveness. For safety, a HUD designated device is eligible for HDEapprovalif,amongothercriteria,“thedevicewillnotexposepatientstoanunreasonableorsignificantriskof illnessor injuryandtheprobablebenefittohealthfromuseofthedevice outweighs the risk of injury or illness from its use, taking into account theprobable risks and benefits of currently available devices or alternative forms oftreatment.”[21CFR814.104(b)(2)].

HUD designation is the first step in seeking marketing approval of an HDE and is aprerequisiteforsubmittinganHDEmarketingapplicationtoFDACDRHorCBER.Inorderto obtain HUD designation, an applicantmust provide documentation to demonstratethatthedevicemeetsthepopulationusedefinitionandadescriptionoftherarediseaseorcondition that thedevice treatsordiagnoses.Therequiredcontentsof theHUDaresetforthin21CFR814.102anddescribedindetailintheFDAHUDDesignationGuidance:https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM336515.pdf

HDEsmaybesubjecttosomeconditionsofapproval,including:

• Labeling

• Post-approvalrecord-keepingrequirements

• NamesandaddressestowhichtheHUDwasshipped,IRBrecords

• Mandatoryreporting

• Periodic, post-approval study reports, supplements, annual Medical DeviceReports (MDRs), annual incidence reassessment toensureuse continues to fallbelow8,000patientsperyear

• Post-approvalstudiesmayberequired

• IRBapprovalatthesite,beforetheHDE-approveddeviceisusedatthatsite(butnotforeachpatientatthatsite).AHUD-designateddevicemayonlybeusedinfacilitieswithfunctioningIRBs.

• Maynotbesoldforprofitexceptincertaincircumstances.

• ForPediatricdevices,PediatricAdvisoryCommitteeannualreviewisperformed,whichiscoordinatedthroughFDA’sOfficeofOrphanProducts

Thehumanitarianusedeviceprogramwasestablishedto“encouragethediscoveryanduseofdevicesintendedtobenefitpatientsinthetreatmentanddiagnosisofdiseasesorconditions that affect not more than 8,000 individuals in the US per year.”[21CFR814.100(a).

HUDdesignationrequestapplicationsarereviewedwitha45-daygoaltimeline.


TheHDEreviewgoaldatetimelineis180days,whichisthesameasforaPMA.(Therearenofasttrackorpriorityreviewdesignationsfordevices).


Geographicalscope


Availability

Applicantsdevelopingdevicesintendedforthetreatmentordiagnosisofararedisease.

Scope ofuse

The goal of this building block, along with other tools of the FDA Office of OrphanProducts Development (OOPD) is to advance the evaluation and development ofproducts (drugs,biologics,devices,ormedical foods) thatdemonstratepromise for thediagnosisand/ortreatmentofrarediseasesorconditions.

Device manufacturers may wish to consider HUD designation for their qualifyingproducts.

Stakeholders

• Devicemanufacturer

• FDAOfficeofOrphanProductsDevelopment(OOPD)

• FDAreviewcenter,CDRHorCBER


HUD designation is the first step in seeking marketing approval of an HDE and is aprerequisiteforsubmittinganHDEmarketingapplicationtoFDACDRHorCBER.ForHUDdesignation,anapplicantmustprovidejustificationthatthemedicaldeviceisintendedtobenefitpatientsinthetreatmentordiagnosisofadiseaseorconditionthataffectsorismanifestedinnotmorethan8,000individualsintheUSperyear.DevicesareeligibleforHDE if they are HUD-designated and there is no legallymarketed device for the samediseaseorconditiongrantedunderpremarketnotification(501(k)orPMA.

Output ThefinalproductisanHDEmarketingauthorizationundertheHumanitarianUseDevicepathway.

Besttime toapplyand time

HUDdesignationmustbeobtainedpriortosubmittinganHDEinthepremarketperiod.EarlyconsultationwithOOPDisrecommended.


window

Experttips

Extensiveinformation,guidanceandadviceontheHumanitarianUseDevicepathwayisavailable on FDA OOPD’s website:https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/DesignatingHumanitarianUseDevicesHUDS/default.htm. Interested parties may also requestassistancefromOOPDstaffat(301)796-8660orbyemailat:[email protected]

PROs:

− The main incentive of the HDE is that it is exempt from the effectivenessrequirements for a PMA. Manufacturers ofHUDdevices are exempt from theusualPMArequirementtoprovidereasonableassuranceofeffectiveness inthepremarketperiodforanHDEapproval.

− UserfeesformarketingapplicationsarewaivedforHUD-designateddevices.

CONs:

− There are considerable regulatory burdens and restrictions on profits for HDEdevices. Forexample,prior IRBapprovalandoversightat thesiteatwhichthedevice is used is required, as well as significant reporting requirements. HDEauthorizationmayalsobewithdrawnbyFDAshouldpopulationuserestrictionsbe exceeded (<8,000 patients per year in the US), or another device receivesmarketingauthorizationforthesameindication.



BuildingBlockU203


ITEM DESCRIPTION


FDAExpeditedProgramforseriousconditions-FastTrackDesignation(FDA-FTD)

References

https://www.fda.gov/ForPatients/Approvals/Fast/ucm405399.htm

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf

Description

Processdesignedtofacilitatethedevelopmentandexpeditethereviewofdrugstotreatseriousconditionsandfillanunmetmedicalneed.

FDArecognizes thatcertainaspectsofdrugdevelopment thatare feasible forcommondiseasesmaynotbefeasibleforrarediseasesandthatdevelopmentchallengesareoftengreater with increasing rarity of the disease. Qualifying criteria (i.e., intended to treatserious conditionANDwhereNon-clinical orClinical datademonstrate thepotential toaddress the unmet medical need, OR qualified infectious disease product) does notnecessarily require that the indication meet US definition of rare disease. Fast Trackhoweverisoftenappliedtodrugsdevelopedforraredisease.

The designationmay be rescinded if it no longermeets the qualifying criteria for fasttrack.Adevelopermayalsowithdrawthedesignation.


Geographical



scope

Availability

Applicantsdevelopingmedicinesforrareandnon-rarediseases.

Scope ofuse

The purpose is to facilitate and expedite development and review by the FDA of newdrugsthatpotentiallyaddressunmetmedicalneed.

AdrugthatreceivesFastTrackdesignationiseligibleforsomeorallofthefollowing:

• MorefrequentinteractionswithFDAtodiscussthedrug'sdevelopmentplanandensurecollectionofappropriatedataneededtosupportdrugapproval

• MorefrequentwrittencommunicationfromFDAaboutsuchthingsasthedesignoftheproposedclinicaltrialsanduseofbiomarkers

• Eligibility for Accelerated Approval and Priority Review, if relevant criteria aremet

• Rolling Review (RR), whichmeans that a drug company can submit completedsectionsof itsBiologicLicenseApplication(BLA)orNewDrugApplication(NDA)for review by FDA, rather than waiting until every section of the NDA iscompleted before the entire application can be reviewed. BLA or NDA reviewusually does not begin until the drug company has submitted the entireapplication to the FDA, however the RR gives the applicant the possibility tocheckfordossier/datacompletenessandpotentialweakness.

Stakeholders

• INDSponsor• FDA


Any drug being developed to treat or prevent a serious conditionwith no satisfactoryalternative therapies. When available therapy exists, a new drug must show someadvantageoveravailabletherapy,suchas:

• Havinganeffectona seriousoutcomeof the condition influencedbyavailabletherapy or in patients unable to tolerate or respond to the available therapyHaving an improved effect on a serious outcome(s) of the condition comparedwithavailabletherapy

• Avoidingserioussideeffectsofanavailabletherapy,havingcomparableefficacy

• Improvingthediagnosisofaseriousconditionwhereearlydiagnosisresultsinanimprovedoutcome


• Avoiding significant toxicity or less serious toxicity of an available therapy thatcausesdiscontinuationoftreatmentorreducingharmfuldruginteractions

• Abilitytoaddressemergingoranticipatedpublichealthneed

• The only available therapy was approved under Accelerated ApprovalProgramwithaclinicalbenefitnotverifiedinapostapprovalconfirmatorytrial

Output Designation


FastTrackdesignationmustberequestedbytheSponsoroftheIND.Therequestcanbeearly in development but an INDmust be filed with the Agency to apply. Ideally, therequestshouldbesubmittedwiththeINDorafterandnolaterthanthepre-BLAorpre-NDAmeeting.FDAwillreviewtherequestandmakeadecisionwithinsixtycalendardaysofreceiptoftherequest.

Experttips

− ConsidersubmissionwithrequestofInitialIND

− Canserveasafall-backpositionifBreakthroughTherapyrequestisdenied

− ExpeditedProgramsGuidanceAppendix 1 SectionA.3.may serve as a generaltemplateforrequestformat

− SubmiteCTDModuleHeading1.7.1

PROs:

• Early and frequent communication between the FDA and a drug company isencouraged throughout the entire drug development and review process. Thefrequency of communication assures that questions and issues are resolvedquickly,oftenleadingtoearlierdrugapprovalandaccessbypatients.

• Theoretical rationale, mechanistic rationale (based on nonclinical data), orevidenceofnonclinicalactivity,togetherwiththeotherqualifyingcriteria,canbeused todemonstrate thepotentialofanewdrug toaddressanunmetmedicalneed

• Useofnon-clinicaldatadifferentiatesFastTrackfromBreakthroughandthusisadesignationthatmaybeobtainedearlierin3development

CONs:

• Fast Track is much more common than Breakthrough Therapy and lacks theinternal FDA structure and commitment to dedicated resources thatBreakthrough Therapy does. The designation can be less effective, evidence


borne out in average development and review times, to truly expeditedevelopment.



BuildingBlockU204


ITEM DESCRIPTION


FDAExpeditedProgramforseriousconditions-BreakthroughTherapyDesignation(FDA-BTD)

References



Description

Process designed to facilitate the development and expedite the review of drugsintendedtotreataseriousconditionANDpreliminaryclinicalevidenceindicatesthatthedrug may demonstrate substantial improvement over available therapy on a clinicallysignificantendpoint(s).

AnindicationneednotbeararediseasetoqualifyforBTD.However,FDArecognizesthatcertainaspectsofdrugdevelopmentthatarefeasibleforcommondiseasesmaynotbefeasible for rare diseases and that development challenges are often greater withincreasingrarityofthedisease.Regardlessthequalifyingcriteria increasethelikelihoodthat a therapeutic developed for a rare diseasemay qualify for BTD. BTDwill help toexpedite drug development in cases where a substantial improvement over availabletherapycanbesupportedwithpreliminaryclinicalevidence.

AsponsormaywithdrawBTDifthedesignationisnolongersupportedbyemergingdataorthedrugdevelopmentprogramisnolongerbeingpursued.


Geograp UnitedStatesofAmerica


hicalscope

Availability


Scope ofuse

FacilitateandexpeditedevelopmentandreviewbytheFDAofnewdrugsforseriousorlife-threateningconditions.

Toexpeditethedevelopmentandreviewofdrugs intendedtotreataseriousconditionwithpreliminary clinical evidence thatmaydemonstrate substantial improvementoveravailabletherapyonaclinicallysignificantendpoint.

Stakeholders

• INDSponsors• FDA


BreakthroughTherapydesignation requirespreliminary clinical evidence indicating thatthedrugmaydemonstratesubstantial improvementoverexistingtherapiesbasedonaclinicallysignificantendpointthatgenerallyreferstoanendpointthatmeasuresaneffecton irreversible morbidity or mortality (IMM) or on symptoms that represent seriousconsequences of the disease. A clinically significant endpoint can also refer to findingsthatsuggestaneffectonIMMorserioussymptoms,including:

• Aneffectonanestablishedsurrogateendpoint

• Aneffectona surrogateendpointor intermediate clinical endpoint consideredreasonably likely to predict a clinical benefit (i.e., the accelerated approvalstandard)

• Aneffectonapharmacodynamicbiomarker(s)thatdoesnotmeetcriteriaforanacceptablesurrogateendpoint,butstronglysuggeststhepotentialforaclinicallymeaningfuleffectontheunderlyingdisease

• A significantly improved safetyprofile compared to available therapy (e.g., lessdose-limitingtoxicityforanoncologyagent),withevidenceofsimilarefficacy

Ideally, preliminary clinical evidencewouldbederived froma study that compares theinvestigationaldrugtoanavailabletherapyinaclinicaltesting(fromphase1or2trials).

Output Designation.

AdrugthatreceivesBreakthroughTherapydesignationiseligibleforthefollowing:


• AllFastTrackdesignationfeatures

• Intensiveguidanceonanefficientdrugdevelopmentprogram,beginningasearlyasPhase1

• Organizational commitment involving senior managers. A cross-disciplinaryprojectcanbealsoassignedtofacilitatethecoordinationofinternalinteractionandcommunicationwithasponsor


As early as possible, given that the Sponsor feels the required clinical data can besupported.FDAsuggeststhatideally,aBTDrequestshouldbereceivedbyFDAnolaterthan the end-of-phase-2 meetings if any of the features of the designation are to beobtained. FDAwill respond to Breakthrough Therapy designation requests within sixtycalendardaysofreceiptoftherequest.

Experttips

FDAhasastreamlined2-3pagespreliminaryBTDrequestprocesstodeterminepotentialfor eligibility. Sponsors may consider discussing this submission with the RegulatoryProjectManageratFDAasaninitialstep.

Forglobaldrugdevelopers,thePRIME(PRIorityMEdicines)SchemelaunchedbytheEMAin 2016 (Building Block E106) should also be consider since the qualifying criteria aresimilarbetweenthetwoprocedures.

PROs:

• More than FTD, BTD has established that the designation correlates with anoverallabbreviateddevelopmentprogram

• Intensiveguidanceallowsfordiscussionsto incorporatecuttingedgeregulatoryscienceindevelopment(adaptiveprograms,Bayesianstatistics,etc)

CONs:

• FDA expects a very high level of engagement and commitment from an INDsponsor if BTD is granted. Theorganization should beprepared to devote theresources expected fromFDAbefore thedesignation is requested to avoid theriskofwithdrawalanddamagetoreputationtotheAgency

• Forpubliccompaniesinparticular,FDAhasshownawillingnesstowithdrawalaBTDdesignation.WhilewithdrawalispossibleforFTDaswell,BTDwithdrawalisahigherrisk



BuildingBlockU205


ITEM DESCRIPTION


FDAExpeditedProgramforseriousconditions–AcceleratedApproval(FDA-AA)

References



Description

FDA-AA is designed to support the development of drugs that treats serious or life-threateningconditionsANDgenerallyprovidesameaningfuladvantageoveravailable

therapiesANDdemonstratesaneffectonasurrogateendpointthat isreasonably likelyto predict clinical benefit or on a clinical endpoint that can bemeasured earlier thanirreversiblemorbidityormortality(IMM)thatisreasonablylikelytopredictaneffectonIMMorotherclinicalbenefit(i.e.,anintermediateclinicalendpoint)

FDA-AA enables themarketing authorization ofmedicines forwhich there is sufficientevidence to suggest efficacy through the use of surrogate or intermediate clinicalendpoint.Itisintendedforpatientswithanunmetmedicalneed.

The application for the provision does not envisage a dedicatedprocess and thereforedoesnothaveatimeduration.


Geographical



scope

Availability


Scope ofuse

FacilitateandexpeditedevelopmentandreviewbytheFDAofnewdrugsforseriousorlife-threateningconditions.

The accelerated approval pathway has been used primarily in settings in which thediseasecourseislongandanextendedperiodoftimewouldberequiredtomeasuretheintendedclinicalbenefitofadrug.

For drugs granted accelerated approval, post marketing confirmatory trials have beenrequired to verify and describe the anticipated effect on irreversible morbidity ormortality(IMM)orotherclinicalbenefit.

FDA encourages sponsors to communicate with the Agency early in developmentconcerningthepotentialeligibilityofadrugforacceleratedapproval,proposedsurrogateendpoints or intermediate clinical endpoints, clinical trial designs, and planning andconductofconfirmatorytrials.FDAwillnotgrantacceleratedapprovaltoproductsthatmeetstandardsfortraditionalapproval.

Stakeholders

• INDSponsors• FDA


• Serious condition (a disease or condition associated with morbidity that hassubstantialimpactonday-to-dayfunctioning).

• Meaningfuladvantageoveravailabletherapy

• Demonstrateaneffectonanendpointthatisreasonablylikelytopredictclinicalbenefit*.Thetwotypesofendpointsthatcanbeusedasabasisforacceleratedapprovalare:

(1) a “surrogate endpoint” that is a marker (e.g. laboratorymeasurements),orothermeasurethatisthoughttopredictclinicalbenefitbutisnotitselfameasureoclinicalbenefit.

(2) an intermediate clinical endpoint that is a measurement of atherapeutic effect that can bemeasured earlier than an effect onIMMandisconsideredreasonablylikelytopredictthedrug’seffecton IMM or other clinical benefit. A clinical endpoint is acharacteristicorvariablethatdirectlymeasuresatherapeuticeffectofadrug––aneffectonhowapatient feels (e.g., symptomrelief),


functions(e.g.,improvedmobility),orsurvives.

*A clinical benefit is a positive therapeutic effect that is clinically meaningful in thecontext of a given disease. The clinical benefitmust beweighed against a treatment’sriskstodeterminewhetherthereisanoverallbenefitforpatients(i.e.,apositivebenefit-riskprofile).

Output Approval pathway aimed to early patients’ access to treatments for serious conditionsbasedonaneffectonasurrogateendpointoranintermediateclinical

endpointthatisreasonablylikelytopredictadrug’sclinicalbenefit.


AlthoughtheformalrequesttotheAuthoritytoapplytheprovisionoccursatthetimeofNDA/BLA,thebesttimetostartthinkingaboutthispossibilityisattheverybeginningofdevelopment(asthisstrategicandtechnicaldecisionhasasignificantinfluenceoverthedevelopmentofthedrug)andtostartordinarilydiscusswiththereviewdivisionduringthedevelopmentsupporting,forexample,theuseoftheplannedendpointasabasis

for approval and discussing the confirmatory trials, which should usually be alreadyunderwayatthetimeofapproval.

Experttips

• Considerthispossibilitysincethebeginningofdrugdevelopmentdefining(1)thejustification for this development pathway, (2) the surrogate/ intermediateendpoint tobe investigatedbefore approval (and its timingof assessment), (3)the clinically relevant endpoint to be tested in and the duration of theconfirmatory trial, and (4) the justification supporting that the intermediateendpointisreasonablylikelytopredictthefinalclinicaloutcome.

• IfAAispotentiallyapplicable,plantoincludeaspecificquestiononapplicabilityasearlyaspossibleintoyourinteractionswiththeAgency

• If AA is due to the rarity of the condition, consider application as OrphanDesignationasoneofthefirstregulatorysteps

• Consider also the request for other expedite programs available at FDA forseriousmedicalconditions.

PROs:

• Itenablesdevelopmentandapprovalofdrugsotherwisedifficultorimpossibletodevelop andmade available to patients in a reasonable time frame. This is ofparticularrelevancewhenthediseaseisultra-rare,whenpivotalstudiesrequirelong duration (either because of enrollment difficulties or time to endpoint


assessment),andwhenthereisaurgentneedforthetreatmentbypatients.

• It enables for developers to conduct confirmatory studieswhile the product isalready on the market, thus providing financial support to the completion ofdevelopment (thepivotal trial isexpected tobealreadyongoingat the timeofNDA/BLA).

CONs:

• It is a “temporary” authorization, therefore requires commitment to completepivotal development with a risk of having the product withdrawn from themarketincaseofnegativeoutcomeofconfirmatorystudy/-ies.

• Theco-presenceofproductavailableinclinicalpracticeandofclinicaltrial(s)maygenerate issues or limitations in terms of possible designs of the confirmatorystudy/-ies (e.g. acceptability of placebo) and “competition” between the twosettings(e.g.preferenceofpatientsfornormalclinicaluseratherthanbeingpartofacumbersometrial).

• It “certifies” the intrinsic limitationsof theclinicaldatapackagealso in frontofstakeholdersotherthantheFDA.

• To be pursued, it requires appropriate due diligence of the disease, theidentificationofasetofendpointssuitablefortheAAandfortheconfirmatorystudy, and of the relationship (“reasonably likely to predict”) between thesurrogate/ intermediate endpoint and the ultimate clinical benefit in order toprovideasolidandlong-standingjustificationof itsapplicability.Afterapproval,itrequirescontinuousdevelopmentthroughthecompletionoftheconfirmatorystudy.

ODDG–BuildingBlockE1–Version1 1


BuildingBlockU206


ITEM DESCRIPTION


FDAExpeditedProgramforseriousconditions-PriorityReviewDesignation(FDA-PR)

References



Description

APriorityReviewdesignationresultsinanabbreviatedPDUFAmandatedgoaldateforaBiologics License Application (BLA) or a New Drug Application (NDA), from 10months(understandardprocedure)to6months.

Likeotherexpeditedprograms,thequalifycriteriadonotrequirethatthetherapeuticindevelopmenttargetararedisease.

SubmittingaRequestforPriorityReviewhasnocost.PDUFAfilingfees,however,shouldbeassessedcontemporaneously.


Geographicalscope



Availability


Scope ofuse

APriorityReviewdesignationwilldirectoverallattentionandresourcestotheevaluationof applications for drugs that, if approved, would be significant improvements in thesafety or effectiveness of the treatment, diagnosis, or preventionof serious conditionswhencomparedtostandardapplications.

Stakeholders

• INDSponsor• FDA


• Seriouscondition

• Demonstrating the potential to be a significant improvement in safety oreffectivenessas,forexample:

1. evidenceofincreasedeffectivenessintreatment,prevention,ordiagnosisofcondition;

2. eliminationorsubstantialreductionofatreatment-limitingdrugreaction;

3. documentedenhancementofpatientcompliancethatisexpectedtoleadtoan improvement in serious outcomes; or evidence of safety andeffectivenessinanewsubpopulation.

Output DesignationenablingMarketingapplicationreviewprocesswithin6months.


WithoriginalBiologicsLicenseApplication(BLA),NewDrugApplication(NDA),orefficacysupplement(FDArespondswithin60calendardaysofreceiptoftheseapplications).

Experttips

When sponsors receive an expedited drug development designation, they should bepreparedtoproposeacommercialmanufacturingprogramthatwillensureavailabilityofqualityproductatthetimeofapproval.Theproposalshouldconsiderestimatedmarketdemandandthecommercialmanufacturingdevelopmentplan.Theproposalshouldalsoconsider manufacturing facilities and a lifecycle approach to process validation.Additionally, the proposal should include a timeline for development of themanufacturingcapabilitieswithgoalsalignedwiththeclinicaldevelopmentprogram.


NottobeconfusedwithUSFDAPriorityReviewVoucher(PRV)programs.

SponsorsshouldconsiderthattheresourcesrequiredtoexpeditereviewbyFDAshouldbe mirrored by the Sponsor. Net impact being that a sponsor will have less time torespond to InformationRequests,prepare forAdvisoryCommittee,etc in thecaseofaPriorityReview.

PROs:

− Shorterclockforreviewofmarketingapplication(6monthscomparedwiththe10-monthstandardreview)

− FDAdecidesonthereviewdesignationforeveryapplication

CONs:

− The twomonth“validation”period for someNDA/BLAsubmission isapplied tobothStandardandPriorityReview

− Note that a Priority Review in no way lowers the standard of evidence andquality of data required by FDA. It is possible that a reduced timeframe torespondtoFDAreviewerrequestscanleadtoSponsormediateddelaysorevenacompleteresponse.



BuildingBlockU207


ITEM DESCRIPTION


FDASpecialProtocolAssessment(FDA-SPA)

References

https://www.fda.gov/downloads/Drugs/Guidances/UCM498793.pdf

Description

FDA-SPAisaprocessinwhichsponsorsmayasktomeetwithFDAtoreachagreementonthe design and size of certain clinical trials, clinical studies, or animal studies, todetermineiftheyadequatelyaddressscientificandregulatoryrequirementsforastudythatcouldsupportmarketingapproval.

Specific to Pivotal Study agreement, FDA-SPA can be useful to navigate the inherentcomplexities of rare disease development, including assisting on the selection of thedesignofatrial.

Theproceduretakesaround45daysFDAreviewperiod.


Geographicalscope


Availabili Applicantsdevelopingmedicinesforrareandnon-rarediseases.


ty

Scope ofuse

An FDA-SPA agreement indicates concurrence by FDA with the adequacy andacceptability of specific critical elements of overall protocol design (e.g., entry criteria,doseselection,endpoints,andplannedanalyses)forastudyintendedtosupportafuturemarketing application. These elements are critical to ensuring that the trial conductedunder the protocol can be considered an adequate andwell-controlled study that cansupportmarketingapproval. Feedbackon these issuesprovides thegreatestbenefit tosponsorsinplanninglate-phasedevelopmentstrategy.

Stakeholders

• Drugdevelopers• FDA


Arequestshouldbesubmittedtoasponsor’sexistingIND(InvestigationalNewDrug)foreach protocol the sponsor wants reviewed under an FDA-SPA. A request should notincludemorethanoneprotocol.IfthereisnoINDfortheproduct,FDAwillassignapre-INDnumber so thatameeting to fully informFDAof theoveralldevelopmentplan forthe product can be scheduled. The sponsor can subsequently open an IND after themeetingandthensubmitaRequesttotheIND.

Output Agreement between the FDA and the sponsor on the adequacy and acceptability ofspecificcriticalelementsoftheoverallprotocoldesignforastudyintendedtosupportafuturemarketingapplication.


To allow sufficient time for FDA review and comment, as well as for resolution ofoutstandinghigh-levelissuesbeforetheinitiationoftheproposedtrial.

Experttips

AnFDA-SPAsubmissionmaynotbeappropriateforsuchassessmentif:

• Itcontainsarequesttoevaluatemorethanoneprotocol.Insuchacase,FDAwillaskthesponsortosubmitseparaterequestsforeachprotocol.ThisprocessmaydelaytheinitiationoftheSPAreviews.

• Itcontainsaprotocolforanongoingtrial.

• It containsaprotocol forwhichevaluationandcritical featuresareadequatelydescribedbyexistingguidance(e.g.,conventionalstabilitystudy).

• It does not provide enough content and detail. Content of a Request and


SubmissionMaterials,including:

‒Adetailedprotocol

‒SpecificquestionsforFDAtoaddress

‒ Adequate background documents to support the critical elements ofthe trial design, or to determine whether it can adequately addressscientificandregulatory requirements for thepurpose identifiedby thesponsor

• PriorFDAconcurrencehasnotbeenobtainedfortheanimalmodeltobeusedintheproposedanimalruleefficacystudy.

AsstatedinthePDUFAandBsUFAgoals,thesponsorhasnothadameeting(e.g.,endof-phase2/pre-phase3meeting(orend-of-phase1meeting,ifapplicable)oraBPDType2orType3meeting)withthereviewdivisionatwhichtheregulatorycontextforthestudyortrialthatisthesubjectoftheSPAwasdiscussed(wherethetrialisintendedtosupportefficacyortrialstoprovebiosimilarityand/orinterchangeability).

PROs:

− FDA will also provide advice on other important concerns identified duringreview,evenintheabsenceofaspecificquestion.

CONs:

− Recently updated FDA-SPA guidance further weakened the strength ofagreementswiththeAgencyonaSPA.

− AgreementsmadeonanFDA-SPA,particularlyonclinicalstudiesarenotbindingbyFDA.



BuildingBlockU208


ITEM DESCRIPTION


RarePediatricDiseaseDesignation

References

https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM423325.pdf

Description

The FDA grants rare pediatric disease designation for diseases with serious or life-threateningconditionsthataffectpeoplefrombirthto18yearsofage,thataffectfewerthan200,000peopleintheU.S.

ThepurposeofthisdesignationistoenablelaterapplicationforaRarePediatricDiseasePriority Voucher at the time of drug approval (NDA/BLA). Such a Voucher can beredeemedtograntpriorityreviewofasubsequentmarketingapplicationforadifferentproduct. Vouchers are thus transferred for use in some other program to achieve“priority review” status, thus expediting the regulatory review of this other drugprogram. SuchvouchersaretypicallysoldbytheSponsoroftheRarePediatricDiseasedrug program, to apply to some unrelated drug development program (typically by adifferentSponsor).

https://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/rarepediatricdiseasepriorityvoucherprogram/default.htm



Geographicalscope


Availability

ApplicantsdevelopingmedicinesforRarePediatricDiseases.

Scope ofuse

TheRarePediatricDiseaseDesignationisbasedonvoluntaryrequestsandisnotrequiredfor submitting a Rare Pediatric Priority Review voucher.While such designation is notrequiredtoreceiveavoucher,requestingthisinadvancewillexpediteasponsor'sfuturerequestforapriorityreviewvoucher.Ontheotherhand,ifsponsorschoosetorequestarare pediatric disease designation, they should also submit requests for Orphan DrugDesignationoraFastTrackDesignation.

ToexpeditefutureapplicationsforaRarePediatricDiseasePriorityVoucher.

Stakeholders

• Developers

• TheUSFoodandDrugAdministration(FDA)

• TheOfficeofOrphanProductsDevelopment((BuildingBlock42)

• TheCenterforDrugEvaluationandresearch(CDER)

• TheCenterforBiologicsEvaluationandresearch(CBER)


• Thedrugmustbeintendedforararediseaseorcondition

• The drugmust be intended for a disease or a condition that “primarily affectsindividualsfrom0to18yearsofage”

• Thedevelopeddrugcannotcontainanyactiveingredient(includinganyesterorsaltoftheactiveingredient)ofwhichhasbeenapprovedinanyotherapplication

Output Thefinalproductisadesignation.


Before the FDA has filed for the New Drug Application (NDA) and Biologics LicenseApplication(BLA)forthedrug.


Experttips

NB:Itisnotnecessarytobegranteda“RarePediatricDisease”designationtorequestarare pediatric priority review voucher (Building BlockU208). However, requesting thisdesignation in advance will expedite a sponsor's future request for a priority reviewvoucher.

PROs:

• Designation can expedite future granting of a Rare Pediatric Disease PriorityVoucheruponmarketingauthorization.

• TheVouchercanthenbesoldtootherdrugprograms,providingPriorityReview.

• A relatively straightforward and simple process, that receives relatively rapidreview.

CONs:

• TheDesignationdoesnotguaranteegrantingofafutureVoucher.

• TheDesignationisnotnecessaryforgrantingofafutureVoucher.



BuildingBlockU209


ITEM DESCRIPTION


RarePediatricPriorityReviewVoucher

References

https://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/rarepediatricdiseasepriorityvoucherprogram/default.htm

https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM423325.pdf

Description

This program grants a voucher for priority review from the US Food and DrugAdministration(FDA),whichaimtorenderadecisionwithin6months(incontrastto10fora standard review).Thedevelopeddrug forwhich thevoucher is awardedmustbeintendedforararediseaseorconditionandthatprimarilyaffectindividualsfrom0to18years.Thevouchercanbeutilizedforanyotherdrugdevelopmentprogram.

TheFDAhastorenderadecisionwithin6monthsafterreceiptoftheapplicationandwillestablish the feeamountbefore thebeginningofeach fiscal year.Applicationsmaybeeligibleforexemptionsfromsomefeesiftheyhavereceivedorphan-drugdesignation.


Geographicalscope


Availability

Applicantsdevelopingmedicinesforrarepediatricdiseases.


Scope ofuse

TheVoucherisusedforadifferent(generallynon-orphan)drugprogram.ThegrantingoftheVoucherisafinancial incentivefortheorphanpediatricdrugprogramtowhichit isawarded.

Stakeholders

• Developers


• TheOfficeofOrphanProductsDevelopment(OOPD)

• TheCenterforDrugEvaluationandresearch(CDER)

• TheCenterforBiologicsEvaluationandresearch(CBER)


• Thedrugmustbeintendedforararediseaseorcondition

• The drugmust be intended for a disease or a condition that “primarily affectsindividualsfrom0to18yearsofage”

• Thedevelopeddrugcannotcontainanyactiveingredient(includinganyesterorsaltoftheactiveingredient)ofwhichhasbeenapprovedinanyotherapplication

• FDA reviewof the request for a Rare Pediatric Priority ReviewVoucher canbeexpedited if the pediatric orphan drug is pre-designated as a “Rare PediatricDisease”byFDA

Output The Voucher, when utilized for a different drug development program, expedites FDAreview:6months,comparedto10monthsforastandardapplication.


Atthetimeofmarketingauthorisationsubmission.

Experttips

NB:Itisnotnecessarytobegranteda“RarePediatricDisease”torequestararepediatricpriority review voucher, although previous application and granting of “Rare PediatricDisease”statusmayexpediteFDAreviewforaVoucher.

PROs:

• Providesfinancialincentivesfordevelopingpediatricorphandrugs.


CONs:

• The financial incentives to the orphan drug program are realized once theVoucherissoldtoadifferentprogram.AstheVoucherisnotawardeduntilthemarketingapprovalofthepediatricorphandrug,theincentiveappearsrelativelylateinthedrugdevelopmentpathwayfortheorphandrugtowhichitisgranted.

• Therehavebeenexamplesof‘gamingthesystem’whereadrugapprovedinEUfor common disease, but not approved for any indication by FDA, was takenforward selectively in a rare pediatric indication in the US, in part, due toawardingofaVoucher.



BuildingBlockU210


ITEM DESCRIPTION


NeglectedandTropicalDiseasesPriorityReviewVoucher

References


Description

This program grants a priority review voucher (PRV) from the US Food and DrugAdministration(FDA)tosponsorsofcertaintropicaldiseaseproductapplications(seelistbelow). ThePRVcanbeused toobtainapriority review (PR) fora subsequenthumandrugapplicationafterthedateofapprovalofthetropicaldiseasedrugproduct.FDAaimsto review and act upon a PR NDA or BLA submission within 6 months of submission,ratherthanwithin10monthsforastandardreview.APRVcanbeusedtoobtainaPRforasubsequentapplicationthatwouldnototherwisequalifyforaPR.

Afterapprovaltothetropicaldiseaseproduct,thesponsormayredeemthevouchertoobtainaPRforasubsequenthumandrugapplication(NDAorBLA)ormaytransferthePRVtoanotherparty(e.g.,maysellthevouchertoanotherparty).PRVshavemonetaryvaluethatmaybenefitthesellerofthePRVtoencourageneglectedandtropicaldiseaseproductdevelopment,mostofwhicharerarediseasesintheUS.

ThereisnocosttorequestaPRV.TheNDA/BLAapplicationfeewillstillapplywhenusingapriorityvoucherandrequestingaPR,whichrangesfrom$2-3million.IncaseofOrphandrugdesignation,feeswaiveraccordingtosection736oftheFD&C

For those sponsors who receive a PRV for a qualifying tropical disease, the FDA“anticipate that some tropical disease productsmay qualify for designation as orphan


drugs because the tropical diseases for which these drugs are intended to prevent ortreatmayaffectfewerthan200,000personsintheUnitedStates(seesection526oftheFD&C Act). If a human drug application for a prescription drug product has beendesignatedasadrugproductforararediseaseorcondition,theapplicationisnotsubjecttoanapplicationuserfee,unlesstheapplicationincludesanindicationotherthanforararediseaseorcondition.”


Geographicalscope


Availability

Applicantsdevelopingmedicines fora tropicaldisease.AccordingtotheFDA,a tropicaldiseaseisanyofthefollowing:

• Blindingtrachoma• BuruliUlcer• Chagas• Chikungunyavirusdisease(addedAugust2018)• Cholera• Cryptococcalmeningitis(addedAugust2018)• CuevavirusDiseases• Dengue/Denguehaemorrhagicfever• Dracunculiasis(guinea-wormdisease)• EbolavirusDiseases• Fascioliasis• FilovirusDiseases• HumanAfricantrypanosomiasis• Lassafever(addedAugust2018)• Leishmaniasis• Leprosy• Lymphaticfilariasis• Malaria• MarburgvirusDiseases• Neurocysticircosis• Onchocerciasis• Rabies(addedAugust2018)• Schistosomiasis• Soiltransmittedhelminthiasis• Tuberculosis• Yaws


• ZikaVirusDisease• Any other infectious disease for which there is no significant market in

developed nations and that disproportionately affects poor and marginalizedpopulations,designatedbyorderoftheSecretary

Scope ofuse

The PRVmay be redeemed for any NDA or BLA application submitted to the US FDA.PRVsmayalsobetransferred(sold)toanotherpartyforfutureredemption.

Foranapplicationtoqualify,itmustbeforahumandrug,noactiveingredient(includingany ester or salt of the active ingredient) of which has been approved in any otherapplication.

Stakeholders

• Developers


• TheCenterforDrugEvaluationandResearch(CDER)

• TheCenterforBiologicsEvaluationandResearch(CBER)


• Thedrugmustbe intended forpreventionor treatmentofa tropicalneglecteddisease.

• Thedrugmustotherwisebeeligibleforapriorityvoucher

• Thedrugmustnotcontainanyactive ingredientthathasbeenapproved inanyotherapplication

Output TheFDAwardspriorityreviewvoucherstosponsorsofcertaintropicaldiseaseproduct

Food,Drug,andCosmeticAct(theFD&CAct)(21U.S.C.360n)applicationsthatmeetthecriteriaspecifiedintheFDAguidance.


Noapplicationisrequired,butsponsorscanrequestconsiderationforaPRVatthetimeofmarketing application submission. FDAwill award PRVs at the timeof approval forqualifyingapplications.

Expert “It is possible that a drug productmeeting the requirements of a tropical disease alsomayqualify fordesignationasanorphandrug. Ifdesignatedasanorphandrug,sucha


tips drug productmay be eligible for orphan drugmarketing exclusivity and tax credits forqualified clinical testing as well as fee exemptions. For information regarding theseorphandrugincentives,potentialsponsorsshouldcontacttheOfficeofOrphanProductsDevelopment(OOPD).Forinformationregardinguserfeeexemptions,potentialsponsorsshould contact the User Fee staff in the Center for Drug Evaluation and Research’s(CDER’s)OfficeofManagement.”

PROs:

• A PRV is expected to result in monetary advantages for the recipient, eitherthrough a faster review and action upon a future application for the drugsponsor,orthroughsaleofthevouchertoanotherparty.

• The PRV program is intended to provide an incentive to sponsors for thedevelopmentandmarketingoftropicaldiseaseproducts.



BuildingBlockU211


ITEM DESCRIPTION


RegenerativeMedicineAdvancedTherapy(RMAT)Designation

References

https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm585414.pdf

Description

The RMAT Designation is analogous to the Breakthrough Designation designed fortraditionaldrugcandidatesbutappliestoregenerativemedicinetreatments,andallowscompaniesto interactwiththeFDAmorefrequentlyduringtheclinicaldevelopmentofthetherapy.AnRMAT-designatedtherapy iseligibleforpriorityreviewandacceleratedapproval.

“Regenerativemedicineisarapidlyexpandingfieldthathasthepotentialtotreatseriousconditions, particularly in patientswith unmetmedical needs. The Center for BiologicsEvaluation and Research (CBER) recognizes the importance of regenerative medicinetherapiesandiscommittedtohelpingensuretheyarelicensedandavailabletopatientswithseriousconditionsassoonasitcanbedeterminedthattheyaresafeandeffective.Thisisintendedtofacilitatedevelopmentandreviewofregenerativemedicinetherapiesintendedtoaddressunmetmedicalneedinthosewithseriousconditions.”

Allmatters related to regenerativemedicines (FDA-CBER definition) intended to treat,modify, reverse or cure a serious condition especially at early stage of productdevelopment.ManycandidatetherapiesindevelopmentfororphandiseasesalsoqualifyfortheRegenerativeMedicineAdvancedTherapydesignation.

CBERwillnotifythesponsor60daysafterreceiptoftherequest.IncaseofOrphandrug


designationgranted,feeswaiveraccordingtosection736oftheFD&C.


Geographicalscope


Availability

Applicantsdevelopingregenerativemedicinetherapies,whichcomprise:

“Celltherapies,therapeutictissueengineeringproducts,humancellandtissueproducts,and combination products using any such therapies or products. Additionally, genetherapies,includinggeneticallymodifiedcellsthatleadtoadurablemodificationofcellsor tissuesmaymeet the definition of a regenerativemedicine therapy. A combinationproduct(biologic-device,biologicdrug,orbiologic-device-drug)canbeeligibleforRMATdesignationwhen thebiologicalproduct componentprovides thegreatest contributiontotheoverallintendedtherapeuticeffectsofthecombinationproduct(i.e.,theprimarymode of action in the combination product is conveyed by the biological productcomponent)”

Scope ofuse

Frequent interactionswith FDA for discussions e.g. study design, extent of safety datarequiredtosupportapproval,dose-responseconcerns,anduseofbiomarkers.

Stakeholders

• Sponsors

• TheCenterforBiologicsEvaluationandResearch(CBER)


AninvestigationaldrugiseligibleforRMATdesignationif:

•Itmeetsthedefinitionofregenerativemedicinetherapy

•Itisintendedtotreat,modify,reverse,orcureaseriouscondition;and

•Preliminaryclinicalevidenceindicatesthattheregenerativemedicinetherapyhasthepotentialtoaddressunmetmedicalneedsforsuchcondition.

In order to apply for RMAT designation, a developer should submit a request to CBEReitherwithanew investigationalnewdrugapplication (IND)or in an INDamendment.CBER will not accept requests for RMAT designation for INDs that are inactive or onclinicalhold.

− Productsintendedtotreat,modify,reverse,orcureaseriouscondition.


− Preliminaryclinicalevidenceindicatingpotentialtoaddressunmetmedicalneedsforseriousdiseasesorconditions.

− UnlikeBTD (BuildingBlockU204),RMATdesignationdoesnot requireevidenceindicatingsubstantialimprovementoveravailabletherapies.

Output The output is a designation which grants access for Priority Review Designation andAcceleratedApproval.


EitherwiththeINDrequestorafter,oncethereisclinicalevidenceofthedrugefficacy.Nolaterthanendofphase2.

Experttips

RMAT, especially when the product is also eligible for Priority Review, may greatlyexpedite the timeframeforaqualifyingproduct toobtainmarketingauthorization.Theearly and more frequent interactions with FDA also help de-risk the development ofproductsthatareoftenfacingnoveldevelopmentchallengesintheregenerativespace.

PROs:

- Guaranteed interactions with the FDA resulting in intensive FDA guidance onefficientdrugdevelopment

- Flexibility in thenumberof clinical sitesusedand thepossibility tousepatientregistry data and other sources of “real-world” evidence for post-approval


studies(pendingFDAapproval)

- Eligibleforpriorityreview

- Eligibleforacceleratedapproval

CONs:

- Restrictedtoregenerativemedicines

- RMAT is not available for human cell and tissue products that are minimallymanipulatedandareintendedforhomologoususe,andeither:

(1) have no systemic effect or do not depend onmetabolic activity oflivingcells,or

(2)are forautologous,allogenic (to first-or second-degreerelatives)orreproductiveuse.

- RMAT designation has significant overlap with BTD, so it is not easy todisaggregatetheeffectofeachoneindividually



BuildingBlockU212


ITEM DESCRIPTION


FDAMilestonesmeetings–TypeB

References

https://www.accessdata.fda.gov/cder/sb-navigate/topic3/topic3/da_01_03_0110.htm


Description

TypeBmeetingsarealsoknownasmilestonemeetings.

PertheDraftGuidanceforFormalMeetingsBetweentheFDAandSponsorsorApplicantsofPDUFAProducts,examplesoftypeBmeetingsinclude:

1) Pre-investigationalnewdrugapplication(pre-IND)meetings.

2) Pre-emergencyuseauthorizationmeetings

3) Pre-new drug application (pre-NDA)/pre-biologics license application (pre-BLA)meetings

4) Post-actionmeetingsrequested3ormoremonthsafteranFDAregulatoryactionotherthananapproval(suchasissuanceofacompleteresponseletter).

5) Meetings regarding risk evaluation andmitigation strategies or post-marketingrequirements that occur outside the context of the review of a marketingapplication.

6) Meetingsheldtodiscusstheoveralldevelopmentprogramforproductsgranted


breakthrough therapy designation status. Subsequent meetings forbreakthrough therapy designated productswill be considered either Type B orpossiblyTypeAmeetings ifthemeetingrequestmeetsthecriteriaforaTypeAmeeting.

Thedefaultdrugdevelopmentprogram includes threemilestones,orTypeBmeetings.Theearliest is thePre-INDMeeting, the second is theEndof Phase2 (EOP2)Meeting,andthethirdmilestoneisthePre-NDAMeeting.

Under the Prescription Drug User Fee Act (PDUFA), meeting management goals havebeenestablishedtoassist requesterswhoseekadvicerelatingtothedevelopmentandreview of investigational new drugs and biologics, and drug or biological productmarketing applications. Type Bmeetings apply to all drugs in development, includingthoseintendingtotreatrarediseases.

After requesting themeeting, FDAwill confirm the schedulingwithin 21 days, and themeetingwilltakeplacenolaterthan60dayslater.OfficialminutesofthemeetingwillbeissuedbyFDAwithin30daysofthemeeting.


Geographicalscope


Availability

Applicants who can be based in a public, non-profit, university, or private companydevelopingmedicinesforrareandnon-rarediseases.

Scope ofuse

Helps address specific regulatory concerns between a sponsor and the FDA at keymilestonepointsinthedevelopmentprogram.ThePre-INDmeetingreviewstheclinicaldevelopmentplans,theEOP2meetingreviewsthePhase3programplans,andthePre-NDAmeetingdeterminesifthedatapackagewarrantssubmissionofanNDAorBLA.

Utilize a type B meeting to discuss the topics raised in description above at keymilestonesduringdevelopment.

Stakeholders

• FDA

• Drugdevelopers

Enablers/

Tosubmitameetingrequest,perthereferenceaboveyoumust include“Theproposedmeeting format, […] The date the meeting background package will be sent by the


Requirements

requester.[…]Abriefstatementofthepurposeofthemeeting.[…]Alistofthespecificobjectivesoroutcomestherequesterexpectsfromthemeeting.[…]Aproposedagenda,including estimated times needed for discussion of each agenda item. […] A list ofplanned attendees from the requester’s organization, including their names and titles.[…]AlistofrequestedFDAattendeesand/ordisciplinerepresentative(s).”

Per the above reference, you should include “The application number (if previouslyassigned). […] The product name […] The chemical name, established name, and/orstructure. […] The proposed regulatory pathway (e.g.; 505(b)(1), 505(b)(2). […] Theproposed indication(s)or contextofproductdevelopment. […]Themeeting typebeingrequested […]Pediatric studyplans, ifapplicable. […]Combinationproduct information[…] Suggested dates and times (e.g., morning or afternoon) for the meeting that areconsistent with the appropriate scheduling time frame for the meeting type beingrequested[…]Alistofproposedquestions,groupedbyFDAdiscipline.

Output ClarityaboutFDA requirements inorder tobeable toproceedsuccessfully to thenextstepinthedevelopmentprocess.Meetingminuteswillbeissuedtotherequesterwithin30calendardaysafterthemeeting.


Varies,basedonissuesraised/stageofdevelopmentasoutlinedindescriptionoftypesofTypeBmeetingsabove.

Experttips

ContactFDAandseekinputearly.

PROs:

− Obtain clear input from the FDA on navigating the regulatory issues at variousstagesoftherapeuticdevelopment.

CONs:

− CommunicationswithFDAshouldnotbelimitedtomilestone,typeB,meetings.



BuildingBlockU213


ITEM DESCRIPTION


FDATypeC,Ameetings

References


Description

PerReferenceabove:

TypeAMeeting:

“Type A meetings are those that are necessary for an otherwise stalled productdevelopmentprogramtoproceedortoaddressanimportantsafetyissue.ExamplesofaTypeAmeetinginclude:

-Dispute resolutionmeetingsasdescribed in21CFR10.75,312.48and314.103and in the guidance for industry and review staff Formal Dispute Resolution:SponsorAppealsAbovetheDivisionLevel.

-Meetingstodiscussclinicalholds:(1)inwhichtherequesterseeksinputonhowtoaddress thehold issues;or (2) inwhicha response tohold issueshavebeensubmitted,andreviewedbytheFDA,buttheFDAandtherequesteragreethatthedevelopmentisstalledandanewpathforwardshouldbediscussed.

-Meetings that are requested after receipt of an FDA Nonagreement SpecialProtocolAssessmentletterinresponsetoprotocolssubmittedunderthespecialprotocolassessmentproceduresasdiscussedintheguidanceforindustrySpecial


ProtocolAssessment.

-Post-actionmeetingsrequestedwithin3monthsafteranFDAregulatoryactionotherthananapproval(i.e.,issuanceofacompleteresponseletter).

-Meetingsrequestedwithin30daysofFDAissuanceofarefuse-to-fileletter.Tofileanapplicationoverprotest,applicantsmustavailthemselvesofthismeeting(21CFR314.101(a)(3)).”

TypeCMeeting:

“ATypeCmeetingisanymeetingotherthanaTypeA,TypeB,orTypeB(EOP)meetingregardingthedevelopmentandreviewofaproduct,includingmeetingstofacilitateearlyconsultationsontheuseofabiomarkerasanewsurrogateendpointthathasneverbeenpreviously used as the primary basis for product approval in the proposed context ofuse”.

Under the Prescription Drug User Fee Act (PDUFA), meeting management goals havebeenestablishedtoassist requesterswhoseekadvicerelatingtothedevelopmentandreview of investigational new drugs and biologics, and drug or biological productmarketingapplications.


Geographicalscope


Availability

Applicants, who can be based in a public, non-profit, university, or private companydevelopingmedicinesforrareandnon-rarediseases.

Scope ofuse

UtilizeatypeAortypeCmeetingtodiscussthetopicsraisedasoutlinedindescriptionabove.IthelpsaddressspecificregulatoryconcernsbetweenasponsorandtheFDA.

Stakeholders

• FDA

• Drugdevelopers.


Tosubmitameetingrequest,perthereferenceaboveyoumust include“Theproposedmeeting format, […] The date the meeting background package will be sent by therequester.[…]Abriefstatementofthepurposeofthemeeting.[…]Alistofthespecificobjectivesoroutcomestherequesterexpectsfromthemeeting.[…]Aproposedagenda,including estimated times needed for discussion of each agenda item. […] A list of


planned attendees from the requester’s organization, including their names and titles.[…]AlistofrequestedFDAattendeesand/ordisciplinerepresentative(s).”

Per the above reference, you should include “The application number (if previouslyassigned). […] The product name […] The chemical name, established name, and/orstructure. […] The proposed regulatory pathway (e.g.; 505(b)(1), 505(b)(2). […] Theproposed indication(s)or contextofproductdevelopment. […]Themeeting typebeingrequested […]Pediatric studyplans, ifapplicable. […]Combinationproduct information[…] Suggested dates and times (e.g., morning or afternoon) for the meeting that areconsistent with the appropriate scheduling time frame for the meeting type beingrequested[…]Alistofproposedquestions,groupedbyFDAdiscipline.

Output Meeting minutes will be issued to the requester within 30 calendar days after themeeting.


Per reference “Before submittinga TypeAmeeting request, requesters should contactthereviewdivisionorofficetodiscusstheappropriatenessoftherequest.”

Experttips

ContactFDAandseekinputearly.

PROs:

− Obtain clear input from the FDA on navigating the regulatory issues at variousstagesoftherapeuticdevelopment.



BuildingBlockU214


ITEM DESCRIPTION


Pre-InvestigationalNewDrug(IND)interactions

References

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm362746.htm


Description

Apre-INDmeeting isanFDAmilestonemeetingalsoknownasTypeBmeeting (seeBBU212). In thesemeetings thedrugsponsorseeksFDA feedbackabout thequality,non-clinicalandclinicaldevelopmentplan.ThePre-INDmeetingsarenotmandatory.

Current Federal law requires that a drug be the subject of an approved marketingapplicationbefore it is transportedordistributedacross state lines.Becausea sponsorwillprobablywanttoshiptheinvestigationaldrugtoclinicalinvestigatorsinmanystates,itmust seekanexemption from that legal requirement. The IND is themeans throughwhich the sponsor technically obtains this exemption from the Food and DrugAdministration(FDA).

Apre-INDmeetingmaybe requested for issues related todataneeded to support therationale for testing a drug in humans; the design of nonclinical pharmacology andtoxicology studies including design and potential uses of any proposed treatment inanimalmodels;datarequirementsforanINDapplication;initialdrugdevelopmentplans,regulatoryrequirementsfordemonstratingsafetyandefficacyandotheraspectsofthedevelopmentprogram.

Intermsofduration,itisscheduledwithin60daysofwrittenrequest.



Geographicalscope


Availability


Scope ofuse

The Pre-Investigational NewDrug Application (IND) Consultation Program fosters earlycommunications between sponsors and the Center for Drug Evaluation and Research(CDER)newdrugreviewdivisionstoprovideguidanceonthedatanecessarytowarrantINDsubmission.

All programs can be reviewed in a Pre-INDmeeting, including those intending to treatrarediseases.Thepre-INDfeedbackcanhelpidentifystudiestosupporttheinitiationofclinical trials and canprovide insight as towhetherdevelopment canbeeligible for anorphandrugdesignation.

Stakeholders

Anysponsor-investigatorwhoispreparingand/orsubmittingcompleteINDapplicationstotheCDERandtheCenterforBiologicsEvaluationandResearch(CBER)attheFDA.

(Asponsor-investigatorisanindividualwhobothinitiatesandconductsaninvestigation,and under whose immediate direction the investigational drug is administered ordispensed. The term, as defined in FDA regulations, does not include any entity otherthananindividual.)


Inorder tobenefit frompre-IND interactionswith theCDER, sponsorsmust fill an INDapplication.

Output ClarityaboutFDA requirements inorder tobeable toproceedsuccessfully to thenextstepinthedevelopmentprocess.Meetingminuteswillbeissuedtotherequesterwithin30calendardaysafterthemeeting.


The pre-INDmeeting has to be considered well ahead of the original IND submissiondate, so that there is enough time to generate and complete the original IND dossierrequirements.


Experttips

• Pre-INDmeetingsarenotmandatory;however,theyarehighlyrecommendedtominimizetheriskofholduponINDoriginalsubmission.

• Thelistofproposedquestionsisthemostimportantelementintheagenda.Eachquestion should be precise. For each question, there should be a briefexplanationofthecontextandpurposeofthequestion.

• Youcanask tomeet face-to-face, tohavethemeetingvia teleconferenceor toreceivewrittenfeedback.

PROs:

• Obtain clear input from the FDA on navigating the regulatory issues at variousstages of therapeutic development. Particularly useful for small sponsors withlimiteddrugdevelopmentexperience.

CONs:

• YoucanonlyhaveonePre-INDmeetingperapplication.



BuildingBlockU215


ITEM DESCRIPTION


Productspecific–pre-approvaladvisorycommittee

References

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079765.pdf

https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm125650.pdf

Description

Advisorycommittees(AC)provideindependentadviceandrecommendationstheUSFDAon scientific and technical matters related to the development and evaluation ofproducts regulated by the FDA. Through the AC system, FDA is able to secureindependent professional expertise in accomplishing its mission and maintaining thepublictrust.AlthoughtheACprovidesrecommendationstoFDA,finaldecisionsaremadebyFDA.

TheUSFDAconvenesadvisorycommitteemeetings foravarietyofdifferentpurposes,someofwhich includepre-approvalmeetingsformarketingapplicationsubmissionsforNDAs,BLAs,andsupplicationsupplements.Meetingswilldifferdependingontheissuesrelevanttotheapplicationunderreview,butmayincludeissuesrelatedtotheproduct’sefficacy, safety,manufacturing or characteristics, and labeling or intended use, amongothers.

ACs are not specific to Rare Diseases, but are frequently convened for novel products(e.g.,newclassesofdrugsorinnovativetherapies),forscientificquestions(suchasnon-traditional trial designs or small clinical development programs), or to provide expertadviceondifficultquestions. Thesesituationsarenotuncommoninrarediseasesdrugdevelopmentandthus,ACsarelikelytobeconvenedformanyrarediseaseproducts.


ACstypicallyoccurwithinthelast60-90daysofaproductreviewcycle.ACstypicallylast0.5-2days,dependingonscopeofissuestobediscussed.


Geographicalscope


Availability

Advisory committee meetings may occur for any product and or not specific to rarediseases;however,novelclassesofdrugs,noveltreatmentapproachesorfirst-in-diseasedrugsare frequently thesubjectadvisorycommitteemeetings,whichhaveapplicabilitytoorphandrugdevelopment,reviewandapproval.

Scope ofuse

The goal of this building block is to assist product developers in anticipating andpreparing foranFDAadvisorycommittee,shouldonebeconvened. ACsalsogenerallyhaveanOpenPublicHearingportionatwhichanymemberof thepublicmayapply tospeak, including patients, caregivers and other interested parties in the rare diseasecommunity. Written comments may also be submitted to the AC by members of thepublic.

Stakeholders

• Productdevelopers

• FDACDER,CBER

• ExternalexpertswhocomprisetheindependentAdvisoryCommittee


Advisory Committee meetings are convened at the request of FDA, who may seekexternalexpertinputintoissuesrelatedtoproductsunder-goingrevieworoversight.

Output ThereareseveraloutputsforanAC:

• Publicpostingofthemeetingshalloccurapproximately60daysinadvanceofanAC

• Briefing documents prepared in advance of an AC are compiled by the drugsponsorandbytheFDAreviewdivisionwithregulatoryoversightfortheproduct.BriefingpackagesaregenerallypublishedontheFDA’swebsitewithin7daysof


anACmeeting

• Foranopenmeeting,sponsorandFDApresentationswillbemadeduringtheACas well as discussions and voting on individual questions on the applicationbeforethecommittee.Closedmeetingsarenotopentothepublic,andwrittenmaterialsrelatedtoaclosemeetingwillnotbemadepublicallyavailable.

• Ameetingtranscript,minutes,andallmeetingmaterialswillbepublishedontheFDAwebsitegenerallywithin90daysafterameeting.


FDAstaffconveneameetingandthereisnoapplicationprocess.AsponsormayrequestthatanACbeheld,whichtypicallywouldoccurduringproductreviewofanNDA,BLAorsupplement; however, an AC may be convened at any time should issues requiringindependentadvicearise(e.g.,asafetyconcerninthepost-marketingperiod).

Experttips

ConsulttheFDAACwebsiteforadditionalinformation:https://www.fda.gov/AdvisoryCommittees/default.htm

Developersmay also request assistance for preparing for ameeting from FDA AC andreviewdivisionstaff.



BuildingBlockU216


ITEM DESCRIPTION


FDAPediatricsAdvisoryCommittee

References

https://www.fda.gov/advisorycommittees/committeesmeetingmaterials/pediatricadvisorycommittee/default.htm

https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/ucm116525.htm

https://www.fda.gov/scienceresearch/specialtopics/pediatrictherapeuticsresearch/ucm123229.htm

Description

ThePediatricAdvisoryCommittee(PAC)isacommitteeofauthoritiesknowledgeableinpediatric research, pediatric subspecialties, statistics, and/or biomedical ethics whoadviseandmakerecommendationstotheFDAregarding:

1)pediatricresearchbeingconducted,

2) identification of research priorities related to pediatric therapeutics and theneedforadditionaltreatmentsofspecificpediatricdiseasesorconditions,

3) The ethics, design, and analysis of clinical trials related to pediatrictherapeutics,

4) Pediatric labeling disputes per the Best Pharmaceuticals for Children Act(BPCA)

5)PediatriclabelingchangesperBPCA,


6)Post-marketingadverseeventreviewsfordrugsgranted-pediatricexclusivity,

7)anyotherpediatricissueorlabelingdispute,

8)researchinvolvingchildrenassubjects,

9) Any other matter involving pediatrics for which FDA has regulatoryresponsibility.

Most serious disorders involving children are rare, thus some of the issues broughtbeforethePACarelikelytoinvolverarediseasedrugdevelopment.

PACmeetingslast1-2daysandhappenfourtimesperyear.


Geographicalscope


Availability

PAC meetings may occur for any product or issue relevant to pediatrics, and or notspecifictorarediseases;however,itislikelyanumberofissuesputtothePACwillhaveapplicabilitytoorphandrugdevelopment,reviewandapproval.

Scope ofuse

ACsare convenedby the FDA inorder to receive scientificor technical advice fromanindependent panel of experts relating to the review andoversight of products for andresearchconductedinpediatricpatients.

The goal of this building block is to assist product developers in anticipating andpreparingforanFDAadvisorycommittee,shouldonebeconvened,andtobeawareofissuesbeingbroughtbeforethecommittee.PublicparticipationviarequeststospeakorwrittencommentsmaybesubmittedtothePAC.

Stakeholders

• FDACDER,CBER,OfficeoftheCommissionOfficeofPediatrics,OfficeofOrphanProductsDevelopment

• ExternalexpertswhocomprisetheindependentAdvisoryCommittee

• Membersofthepublic

Enablers/Require

ThePACisastandingcommitteethatisconvenedbytheFDAapproximately4timesperyear.


ments

Output • PublicnoticeforthemeetingshallbepostedonFDA’swebsiteapproximately60daysinadvanceofaPAC

• Meeting materials including agendas, meeting rosters, briefing materials,presentations,meetingminutesandmeeting transcript shallbepostedprior toandwithinabout90daysafterthemeetinghasoccurred.


Typically occurs when matters of interest to pediatric drug review and oversight areneeded.

Experttips

InterestedpartiesmayalsocontactFDAstaffat:

• theOfficeofPediatricTherapeutics:https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/officeofscienceandhealthcoordination/ucm2018186.htm

• TheCDERDivisionofPediatricandMaternalHealth:https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm621895.htm

PROs:

− Childrenareaspecialresearchpopulationforwhomadditionaloversightandindependentadviceareappropriate

CONs:

− Publicairingofunsettledorcontroversialissues



BuildingBlockU217


ITEM DESCRIPTION


Stakeholderinteraction–ProfessionalaffairsandCommunityEngagement

References

Example:

https://www.researchgate.net/publication/303831422_Stakeholder_cooperation_to_overcome_challenges_in_orphan_medicine_development_The_example_of_Duchenne_muscular_dystrophy

The Express EURORDIS summer school (patients and academics are pupils and areeducatedaboutdrugdevelopmentandtheregulatorysystem).

Description

There are different stakeholders in drug development: patients, academics, industry,regulators and payers. For rare diseases with no available therapy often multi-lateraleducationisrequired:regulatorsandpayersarenotawareofthecurrentstateoftheartofthatspecificdiseaseresearch,oroftheimpactandburdenofthediseaseondailylifeofthepatients.Atthesametimeacademicsandpatientsareoftennotawareofthewaytheregulatorysystemworks. Initiatingthedialoguebetweenthesestakeholders isbestdonenotforaspecificdrug,butforaspecificdiseaseordiseasegroups.

Interaction of the stakeholders and multilateral education at an early stage ofdevelopment will facilitate drug development (e.g. ensuring outcome measures forclinical trials are developed that are meaningful for patients, are acceptable to theregulators,andareacceptabletopayers).



Geographicalscope


Availability

Applicantsdevelopingmedicinesforrarediseases.

Scope ofuse

Early interaction between stakeholders will ensure outcome measures are developedthatmeasurewhatisimportanttopatientsandareacceptabletoregulatorsandpayers

Stakeholders

• Academics: develop relevant and regulatory compliant outcome measures,prepareforgapsinknowledge/toolsforregulatoryapproval

• Regulators: learnabout the stateof theartofa specific rarediseaseand learnaboutthepatients’need

• Patients:relevantoutcomemeasures,smootherdrugdevelopmentprocess

• Payers:learnaboutthepatients’needsandburden(cost)ofthedisease


Someoneneedstoinitiatethedialogue(generallypatientsoracademics).

Output Moreawarestakeholdersandbetteroutcomemeasures.


The regulatorswill not have time to have a dialogue for each rare disease all at once.However,whenpreclinicalworklookspromisingitisbesttostartadialoguetoavoidtheset-upofsuboptimaltrials.

Companies should get educated on the disease burden and patient experience beforedesigningclinicaltrials.

Experttips

DO:

• Workwithin the patient community to have an open dialoguewith companiesandregulatorsaboutdiseaseexperienceanddiseaseburden.


• Identify if clinical outcomes are suitable, and if these are not availablecollaboratewithacademicsandindustryindevelopingclinicaloutcomemeasuresbeforeclinicaltrialsstart.

• Seekadviceonhowtocollaboratewiththeindustryandlearntoseethemasapartner.

DON’T:

• Relyonlyonacademicstohelpyoudesignclinicaloutcomesandotherimportantelements of drug development. These are specific science fields that requireindustryandregulatorsfeedbackandoftencollaboration.



BuildingBlockU218


ITEM DESCRIPTION


Stakeholderinteractions–PatientAffairsStaff(PAS)

References

https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/ucm589472.htm

https://www.fda.gov/downloads/Drugs/NewsEvents/UCM604544.pdf

Description

AttheFDA,thePatientAffairsStaff(PAS)isdevotedtosupportingcross-cuttingpatientengagementactivitiesacross theFDA. Itsmission is tocoordinateandsupportpatientengagementactivitiesacrossFDAtofacilitateawarenessandcollaborationwithpatients,theiradvocatesandtheFDA.Objectivesinclude:

1. Create and assist with public and private collaborations and partnerships todiscussregulatorytopicsofinterest

2. Lead cross-center programs and activities that can leverage best practices andenhancepatientengagement

Enhance the FDA’s external communication platforms to expandpublic awareness andhelp patients, caregivers, and advocates navigate FDA engagement activities and theregulatoryprocess.

WhilePAScanbecontactedforanydisease-ordrug-relatedreason,rarediseasesdrugdevelopment frequently relies upon, and may be led by, rare diseases patients andadvocacygroups.ItislikelythatmanyrarediseasesgroupswillfindPASinteractionsandprogramsuseful.



Geographicalscope


Availability


Scope ofuse

The goal of this building block is to raise awareness in the patient and advocacycommunityonopportunitiesforengagement,support,communicationandtransparencywith the FDA. PAS provides a venue for contacting FDA about any product of drugdevelopmentissue.

Stakeholders

• FDA PAS staff and other patient engagement groups throughout FDA reviewcenters,CBER,CDER,CDRH

• Patientsandadvocates

• Membersofthepublic


MembershipCriteria:

• Patientswhohavepersonaldiseaseexperience• Caregiverswho support patients, such as a parent, child, partner, other family

member, or friend, and who have personal disease experience through thiscaregiverrole

• Representatives from patient groups who, through their role in the patientgroup,havedirectorindirectdiseaseexperience

Output Outputwillvarydependingonthequestionsandconcernsofthepatientsandadvocatescontacting PAS. FDAwill respond to questions or issues put before them, and providematerialsandresourcescurrentlyavailable(e.g.,guidance,policy)tothepublic.

Besttime toapplyand time

Anytime throughout the lifecycle of medical product development and regulatorydecision-makingformattersunderFDA’spurview.


window

Experttips

PAS staffmay also be contacted by email: [email protected] or by calling (inUS):301-796-8460

PROs:

− FDA staff devoted entirely to facilitating and enhancing patient and advocacycommunicationwithFDA.Canbecontactedatany timeand foranydiseaseorproductrelatedarea.



BuildingBlockU219


ITEM DESCRIPTION


FDAQualificationPrograms-DrugDevelopmentTools(DDTs)

References

https://www.fda.gov/drugs/development-approval-process-drugs/drug-development-tool-qualification-programs

Description

TheFDAQualificationprograms,orDrugDevelopmentTool(DDT)qualificationprogramsprovides a framework for interactions between FDA and DDT requestors to guide thecollectionofdatatosupportaDDT’sprospectivelyspecifiedcontextofuse.Theguidancedescribestheprocess forqualifyingdrugdevelopmenttools intendedforpotentialuse,over time, in multiple drug development programs. DDTs are methods, materials, ormeasuresthataiddrugdevelopment.

DDTsinclude,butarenotlimitedto,

• Biomarkers: qualification-programs: https://www.fda.gov/drugs/drug-development-tool-qualification-programs/cder-biomarker-qualification-program

• Clinical outcome assessments (COAs): https://www.fda.gov/drugs/drug-development-tool-qualification-programs/clinical-outcome-assessment-coa-qualification-program

• Animal models for drug development under the Animal Rule:https://www.fda.gov/drugs/drug-development-tool-qualification-programs/animal-model-qualification-program

This guidance provides a framework for interactions between the Center for DrugEvaluationandResearch (CDER)andtheentityproposingtheDDTforqualification (the


submitter). It also explains the kinds of data that should be submitted to supportqualificationofaDDTandcreatesamechanismforCDER’sformalreviewofthedatatoultimatelyqualifytheDDT.


Geographicalscope


Availability


Scope ofuse

• To qualify and make DDTs publicly available for a specific context of use toexpeditedrugdevelopmentandreviewofregulatoryapplications

• Toprovide a framework for early engagement and scientific collaborationwithFDAtofacilitateDDTdevelopment

• TofacilitateintegrationofqualifiedDDTsinregulatoryreview• ToencouragedevelopmentofDDTsforcontextsofusewithunmetneeds• To encourage the formation of collaborative groups to undertake DDT

development programs to increase the efficiency and lessen the individualresourceburdenincumbentwithDDTdevelopment

• Toencourageinnovationindrugdevelopment• To create a shared learning environment for exchanging information on DDT

development

Stakeholders

A person, group, organization (including the federal government), or consortium thattakes responsibility for and initiates a DDT qualification proposal.


The qualification process includes three submissions: the Letter of Intent (LOI), theQualification Plan (QP), and the Full Qualification Package (FQP). Anyone interested inentering the qualification program should submit an LOI.

Output Thequalification is a conclusion thatwithin the stated context of use, theDDT canberelied upon to have a specific interpretation and application in drug development andregulatoryreview.Oncequalified,DDTswillbepubliclyavailabletobeusedinanydrugdevelopmentprogramfor thequalifiedcontextofuse.Additionally, thequalifiedDDTcanbeincludedinIND,NDA,orBLAsubmissionswithoutneedingFDAtoreconsiderandreconfirmitssuitabilityaslongas:


• Therearenoseriousstudyflaws• TherearenoattemptstoapplytheDDToutsidethequalifiedcontextofuse• There are no new and conflicting scientific facts not known at the time the

qualification was determined


Assoonaspossibleduringtheearlydrugdevelopmentphasewhenyouareconsideringusingnotvalidatedtoolstoinvestigateprimaryandsurrogateendpoints.

Experttips

• ADDTcanbeusedinadrugdevelopmentprogramwithoutitgoingthroughthequalificationprogramsandisthereforenotmandatory.Theuseofnon-qualifiedDDTswillbereviewedbytherelevantFDAcenter(s),division(s),andoffice(s)aspart of IND, NDA, or BLA reviews.

PROs:

• Having qualifiedDDTs that can be used bymany sponsors helps optimize drugdevelopmentandevaluation.

• ADDTthathasthepotentialtobeusedinmultipledrugdevelopmentprogramsmay be considered for qualification. Qualification may reduce duplication ofefforts, allow resource and information sharing, and facilitate regulatoryacceptanceoftheDDTforfutureapplicationsutilizingthesamecontextofuse.

• These qualification programs promote a collaborative setting where multipleinterestedpartiesmaypoolresourcesanddatatodecreasecost,expeditedrugdevelopment, and facilitate regulatory review. Increased public availability ofqualified DDTs for specific contexts of use is anticipated to benefit the publichealth through (1) increased availability of effective drugs, (2) earlier access tomedical therapies and (3) an enhanced knowledge of the drug underdevelopment.

CONs:

• DDT acceptance in the drug development and regulatory review process haspreviously been on a sponsor-by-sponsor, drug-by-drug basis. Drug sponsorsseeking tousespecificDDTshave typicallydevelopedenoughdata to justify itsuseonlyinthatonesetting.GeneralizedapplicabilityofDDTsacrossvarieddrugdevelopmentprogramsisoftenleftundeterminedtherebypotentiallylimitinganexpandeduseofthetool.

• The resources needed to develop a DDT for a more generalized use is often


beyondthecapabilitiesofasingleentity.FDAencouragesformingcollaborativegroups,suchasapublic-privatepartnership(PPP).



BuildingBlockU220


ITEM DESCRIPTION


RighttoTryAct(RtT)

References

https://www.fda.gov/patients/learn-about-expanded-access-and-other-treatment-options/right-try

Description

TheRight toTryActwas signed into lawonMay30,2018.This law isanotherway forpatientswhohavebeendiagnosedwithlife-threateningdiseasesorconditionswhohavetriedallapprovedtreatmentoptionsandwhoareunabletoparticipateinaclinicaltrialtoaccesscertainunapprovedtreatments.

Thelawdefineseligibilitycriteriaforthepatientandfortheinvestigationaldrug:

(1) Aneligiblepatienthas:- Life-threateningdiseaseorcondition- Exhaustedapprovedtreatmentoptions- Unabletoparticipateinaclinicaltrialwiththedrug

Alltheaboveiscertifiedbyaphysician

(2) Investigationaldrugcanonlybeprovidedifit- Isnotapprovedorlicensedforanyuse- Hascompletedaphase1trial- Iseither:

o ThesubjectofanNDAorBLAwithFDA,oro Isunder investigation inaclinical trial that“is intendedtoformthe

primarybasisofaclaimofeffectiveness”


- Isactivelybeingdevelopedandnotonclinicalhold

FDAdoesnotrevieworapproverequestsforRighttoTryActuse.FDA’sroleislimitedtoreceiptandpostingofcertaininformationsubmittedundertheRighttoTryAct.FDAwillreceiveannualsummariesfrommanufacturersorsponsorsonuseofaneligibleinvestigational drug under the Right to Try Act. FDA will post a consolidated annualsummaryreportofRighttoTryActuse.Individual Right to Try Act requests do not require IRB review or approval; however,eligibleinvestigationaldrugsundertheRighttoTryActmustmeetcertaincriteria.The physician is responsible for getting written informed consent from the eligiblepatientortheirlegallyauthorizedrepresentativeforRighttoTryActuse.TheRighttoTryActdoesnotrequireasponsortoprovideaneligibleinvestigationaldrugtoaneligiblepatient.Right-to-trylegislationalso

1) spellsouttheregulatoryexemptions,2) whichregulationsmuststillbefollowed,3) andaddsarequirementfortheinvestigationalproductsponsor.

The regulatory exemptions include: some labeling requirements, interstate commerceregulations,recordkeepingtoensureGCPcompliance,partsoftheINDregulations,andpartsoftheIRBregulations.There are some regulations thatmust still be followed. These include: some labelingrequirements,prohibitiononanysortofpreapprovalpromotion,andlimitationsoncosttothepatient.The limitations on cost to the patient are actually determined by the FDA expandedaccessregulations,andlimitthecosttorecoverytothemanufacturingcosts.Thenewrequirementisthattheinvestigationalproductsponsormustprovideanannualreport to FDA that minimally includes the number of doses supplied, the number ofpatientstreated,andanyknownseriousadverseevents(SAEs).ItisnotclearatthispointwhatFDAissupposedtodowiththereports.


Geographicalscope


Availability

Patientswhohavebeendiagnosedwithlife-threateningdiseasesorconditionswhohavetriedallapprovedtreatmentoptionsandwhoareunabletoparticipateinaclinicaltrialtoaccesscertainunapprovedtreatments.


Scope ofuse

• Alleviating the administrative burden for seriously ill patients to gain access toinvestigationalproducts.

• Reducingtheriskforsponsorcompaniesinprovidingpatientswithaccess.(Manysponsors are concerned both about their liability resulting from a negativeclinical outcome and the impact of a negative clinical outcome on continueddevelopmentoftheproduct.)

Stakeholders

Thepatientsufferingfromaseriouslylife-threateningdiseaseorcondition,thephysicianwhodiagnoseandvalidatetherequestforaccesstoanunapprovedinvestigationaldrugunder the right-to-try act, the sponsor/manufacturer who provides information aboutwhether the drug or biological productmeets the criteria to be considered an eligibleinvestigationaldrugforuseundertheRighttoTryAct.(FDAdoesnotrevieworapproverequestsforRighttoTryActuse. FDA’srole is limitedtoreceiptandpostingofcertaininformationsubmittedundertheRighttoTryAct).


The Physician validating the patient’s diagnosis consults with the sponsor of theinvestigationaldrugorbiologicalproduct.

The sponsor is in the best position to provide information aboutwhether the drug orbiologicalproductmeetsthecriteriatobeconsideredaneligibleinvestigationaldrugforuseundertheRighttoTryAct(i.e.,phase1data).

Output This law is another way for patients who have been diagnosed with life-threateningdiseases or conditions who have tried all approved treatment options and who areunabletoparticipateinaclinicaltrialtoaccesscertainunapprovedtreatments.


AfterphaseIclinicaldataareavailableandbeforetheproductisregistered.

Experttips

• AkeydifferencebetweenEarlyAccessProgram(EAP)andRight-to-TryisthatwithEAPthereisstilloversightbyFDA.TheEAPFDAregulationshavebeendevelopedoverthelast30yearstoallowearlyaccesswhilereducingrisktothepatientandensuringsystematicimplementation.

PROs:

• Alleviating the administrative burden for seriously ill patients to gain access toinvestigationalproducts


• Reducingtheriskforsponsorcompaniesinprovidingpatientwithaccess.

CONs:

• Therearestillsomequestionsthatremainaboutpatienteligibility:o Itisnotclearhoweligibilityandinformedconsentwillbedocumentedo whoisresponsibleformaintainingthatdocumentation.o It is also unclear who would provide information about the risks and

benefitsoftheinvestigationalproducttothepatientwhichisneededinorderforthepatienttoprovideinformedconsent.

o There are also questions about whether the product sponsor or theinvestigator/physician is responsible for administering these processes.

• Therearenoincentivesforproductsponsorstoparticipate.• Nocostsreimbursementisallowedbeyondthemanufacturingcosts.• Manyoftheseproductsaremanufacturedbysmallbiotechcompanies,andthey

simplydonothaveextraproducttogivetopatientsunderRight-to-Try.• Thelegislationofferssomelimitationsinliabilityforproductsponsors,however,

theseassurancesdonot appear tobeenough to convincemost investigationalproduct sponsors toprovide theirproductunderRight-to-Try. (If this continuesto develop, it may provide sponsors with more assurance. Clinical outcomesassociatedwiththeuseofaninvestigationalproductwillnotbeusedtodelayoradverselyaffecttherevieworapprovaloftheproductunlessthoseoutcomesarecriticaltodeterminingthesafetyoftheproduct,suchasaseriousadverseevent).

• Grantingverysickpatientsearlyaccesstoinvestigationalproductswithreducedregulatoryoversightmaybemorelikelytoharmpatientsthanhelpthem.

• Providingaccesstoinvestigationalproductoutsideofcontrolledclinicaltrialscandelay thegenerationofdataneeded tomakeevidenced-baseddecisionsaboutapprovalanduseofnewdrugs.

• Itismoreimportantinmostproductsponsors’mindstogettheirtherapeuticstothemarketquicklywheretheywillbeavailabletoallpatientsthatneedit,ratherthangettingtheproducttoafewpatientsnow.

• DependingontheStateofresidence,patientsmayloosehospicecoverage,maybedeniedhomehealthcarecoverage,may losehealth insurance, insurersmaydenycoveragefortreatmentofharmcausedbyinvestigationalproduct.



BuildingBlockU221


ITEM DESCRIPTION


Patient-focuseddrugdevelopmentprogram

References

Patient-focuseddrugdevelopment:https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm347317.htm

Externally-ledpatient-focuseddrugdevelopment:https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm453856.htm

Description

ThePatient-focusedDrugDevelopment(PFDD)programwasinitiatedatFDAfrom2012-2017underCongressionalMandate(PDUFAV)tomoresystematicallyobtainthepatientperspective on specific diseases and their treatments. PFDD meetings provide keystakeholdersanopportunitytohearthepatient’svoice.

From 2012-2017, 24 disease-area FDA-sponsored PFDD meetings were conducted fordiverse disease areas, including common and rare diseases. In approx. 2017, theprogram was expanded to include Externally Led (EL)-PFDD meetings, where patientorganizations undertook identifying and organizing patient-focused collaborations togeneratepublicinputonadditionaldiseaseareas,usingtheprocessestablishedthroughthePFDDmodel.

EL-PFDDmeetingsaresimilarinintenttoPFDDs,asopportunitiesforkeystakeholderstohear the patient’s voice, and should target disease areas where there is an identifiedneed for patient input on topics related to drug development. Some considerations inplanninganEL-PFDDinclude:

• An identified need to better understand the patient perspective for drugdevelopmentpurposes


• Diseaseareasthatarechronic,symptomatic,affectfunctioningand/oractivitiesofdailyliving

• Forwhichaspectsofthediseasearenotformallycapturedinclinicaltrials

• Forwhichtherearecurrentlynoorveryfewtherapies,oravailabletherapiesdonotdirectlyaffecthowapatientfeels,functionsorsurvives

• That have a severe impact on identifiable subpopulations (e.g., children, theelderly)

The patient perspective is critical in helping FDA understand the context in whichregulatory decisions aremade for new drugs. While applicable to all diseases, this isespeciallyrelevanttorarediseasesbecauserarediseasestendtobepoorlyunderstood,have little to no clinical trials or outcome assessment precedent, and the clinicalmanifestationsoftherarediseaseareoftenhighlyheterogeneousandcapturingthefullrangeofpatientexperienceisofsubstantialimportance.

Most meetings typically last 1 day, however the planning process could take about 1year.

Category RegulatoryBuildingBlock,DevelopmentPractices

Geographicalscope


Availability

EL-PFDDsmayoccur foranydiseasearea,commonor rare,andmaybeundertakenbykeystakeholders.EL-PFDDsarehighlyrelevanttorarediseasesgiventheneedtobetterunderstand thepatientvoice indiseaseprogression, characteristics, andaspectsof thediseaseofimportancetopatients.

Scope ofuse

Thegoalofthisbuildingblockistoadvanceevaluationanddevelopmentofproductsforrarediseases,especiallydiseasenaturalhistory,potentialoutcomemeasures,andareasof clinical impact that are of particular importance to patients, through hearing thepatient’svoiceandunderstandingthepatientperspectiveindisease-specificareas.

The Voice of the patient has tremendous value in rare diseases drug development inprovidingpatientperspectivesonaspectsof thedisease that important to thepatient.This information can contribute as a brief/partial cross-sectional natural history andprovideinformationtoidentifyoutcomemeasuresorareasforendpointandclinicaltrialdesigndevelopment,aswellasengagingthepatientcommunityinthedrugdevelopmentprocessforindividualrarediseases.


Stakeholders

• Patientgroups

• FDApolicyandreviewdivisionstaff

• SMEs,diseaseexperts


EL-PFDD are convened and executed by patient groups in collaborationwith their keystakeholders. For FDA attendance at these meetings, FDA recommends submitting aLetterof Intent(LOI)toFDAapproximately1yearbeforetheanticipatedmeetingdate.The LOI should be no more than 5 pages and communicate the importance of themeetinginthecontextofthediseasearea,andimportantdetailsregardingthemeetingplan.

Guidelinesfordevelopingaletterofintentareavailablehere:https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM453857.pdf.

Thefirstof4planneddraftguidancesonconductingPFDDsavailableare:

• Guidance1,Collectingcomprehensiveandrepresentativeinput:https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM610442.pdf

• Guidance2&3arecurrentlythesubjectofpublicworkshops,Methodstoidentifywhatisimportanttopatients&select,developormodifyfit-for-purposeclinicaloutcomesassessments:https://www.fda.gov/downloads/Drugs/NewsEvents/UCM620707.pdf

• Guidance4isforthcoming

MeetingmaterialsfromapublicworkshopondevelopmentPFDDguidancefromDecember2017isavailablehere:https://www.fda.gov/Drugs/NewsEvents/ucm574725.htm

Output ThemainoutputfromEL-PFDDmeetingsis“theVoiceofthePatient”report,thatsummarizestheresultsofthemeeting.AdditionaldeliverablescouldincludeWebcastrecordings,ameetingtranscript,andmeetingmaterials(agenda,slides).LinkstocompletedEL-PFDDsarelistedonFDA’swebsite:https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm368342.htm

Meetinginformationfromtheoriginal24FDA-sponsoredPFDDsarealsopublicallyaccessibleonFDA’swebsiteandincludeameetingsummary,backgroundmaterialsandmeetingrecordings:


https://www.fda.gov/forindustry/userfees/prescriptiondruguserfee/ucm347317.htm


ForFDAparticipation inanEL-PFDD,patientgroupsareadvised toengagewithFDAatleast1yearinadvance.AnEL-PFDDmaybeconvenedatanytimeinthediseaseresearchprocess.

Experttips

ThereisabundantinformationonpastmeetingsandthePFDDmodelthatareaccessibleonFDA’swebsite,includingsummaryreports,backgrounddocuments,recordingsandotherinformation:https://www.fda.gov/forindustry/userfees/prescriptiondruguserfee/ucm347317.htm

PatientgroupsmayalsocontactFDAstaffinthePatientAffairsStaffofficeforassistanceinmeetingplanning:https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/ucm589472.htm

PROs:

− Perusesectionabove,providesauniqueanddetailedcross-sectionofthepatients’voiceforclinicalmanifestations,diagnosis,clinicaltrialdesignandoutcomemeasureassessmentanddevelopment.

CONs:

− Resourceintensivewithprolongedplanningtime(~1year).



BuildingBlockU222


ITEM DESCRIPTION


INTERACTMeetings(InitialTargetedEngagementforRegulatoryAdviceonCBERproducts)

References

https://www.fda.gov/vaccines-blood-biologics/industry-biologics/interact-meetings-initial-targeted-engagement-regulatory-advice-cber-products

Description

Developmentofinnovativeinvestigationalproductscanintroduceuniquechallengesdueto unknown safety profiles, complex manufacturing technologies and issues,incorporationofinnovativedevices,andtheuseofcutting-edgetestingmethodologies.

Through a CBERINitialTargetedEngagement forRegulatoryAdvice onCBER producTs(INTERACT)meeting, sponsorscanobtain initial,nonbindingadvice fromFDAregardingchemistry,manufacturingandcontrols,pharmacology/toxicology,and/orclinicalaspectsofthedevelopmentprogram.Thisinformalmeetingcan:

1) assist sponsors conducting early product characterization and preclinical proof-of-conceptstudies;

2)initiatediscussionfornewdeliverydevices;

3)informsponsorsaboutoverallearly-phaseclinicaltrialdesignelements;and

4) identify critical issues or deficiencies for sponsors to address in the development ofinnovativeproducts.

ACBERINitialTargetedEngagementforRegulatoryAdviceonCBERproducTs(INTERACT)


meetingenablessponsorstoobtainpreliminaryinformalconsultationwiththeAgencyatan early stage of development prior to a pre-IND meeting (see BB #214), subject toAgencyresourceconstraints.

To requests for INTERACT meetings should be forwarded [email protected]. Inorder toassess the request,pleaseprovide:1) a summaryof theproduct and disease being treated, 2) information about the product development todateandfuturedevelopmentplans, ifappropriateand3)questionsthesponsorwishesto have addressed. Sponsorswill receive a response regarding the scheduling of theirrequested meeting from the responsible office within 21 calendar days ofreceipt. AlthoughCBERwill do its best to hold INTERACTmeetingswithin 90 calendardays of receiving requests, resource constraints may limit scheduling within thistimeframe.


Geographicalscope


Availability


Scope ofuse

An INTERACT meeting is not intended to take the place of a pre-IND meeting (seeBB#214),whichoccurspriortothesubmissionofanINDtodiscussthescopeanddesignof planned initial studies, design of animal studies needed to support human clinicaltesting,andtheformatfortheIND.1Conversely,anINTERACTmeetingalsoisnotavenueto provide advice to sponsors who have yet to initiate any product developmentactivities.

Products that are further along the development pathway should be discussed in thecontext of a pre-IND meeting. Pre-IND submissions typically include a description ofproduct manufacturing and testing; summaries of completed and planned preclinicalstudies;andaPhase1clinicalstudydesignorprotocol.Eachoftheseelementsmaybefurtherrefinedafterthepre-INDmeeting,tosupportanIND.

The INTERACT program is also intended for such occasions when development ofinnovativeinvestigationalproductsintroducesnewsafetyconcernsduetotheunknownsafetyprofilesresultingfromtheuseofcomplexmanufacturingtechnologies,innovativedevices,orcutting-edgetestingmethodologies.

StakeholAny sponsor-investigator who is preparing and/or submitting complete pre-INDapplicationstotheCenterforBiologicsEvaluationandResearch(CBER)attheFDA.


ders


Prior to requesting an INTERACTmeeting, a sponsor needs to have selected a specificinvestigationalproductoraproduct-derivationstrategytoevaluateinaclinicalstudy.

Output The INTERACTprogramgenerally consists of one consultationon issues that a sponsorneedstoaddress,oftenthisispriortomovingforwardwiththesubmissionofapre-INDmeetingrequest.

CBER advice given during INTERACTmeetings is informal and non- binding. Therefore,officialmeetingminuteswillnotbeissuedtothesponsor.

In accordance with 21CFR10.65(f), the sponsor, or other meeting participant, mayprepareandsubmittoCBERamemorandumsummarizingtheirunderstandingof issuesdiscussed at themeeting. Since INTERACTmeetings are informal and non-binding, thismemorandum, ifprovided,willnotbe reviewedbyCBER inanymanner,noevaluationwillbeperformed tosee if thememorandum isaccurate.SponsormeetingminutesdonotalterCBER’spre-meetingcommentsprovidedinwritingorbyverbalcommunicationandtheyarenottheofficialminutesofthemeeting.


The INTERACTprogramgenerally consists of one consultationon issues that a sponsorneedstoaddress,oftenthisispriortomovingforwardwiththesubmissionofapre-INDmeetingrequest,suchaschoiceofappropriatepreclinicalmodelsornecessarytoxicologystudies.

Experttips

• INTERACT meetings are not mandatory and they may be subject to Agencyresourceconstraints.

PROs:

• PurposeandprocessforINTERACTmeetingsmuchclearernowvs.priorpre-preINDprocess

• UsefulexamplesprovidedintheSOPPfortypesofquestionstopose• Freeexchangeofideas–opendialogue• Provision of written responses in advance of meeting very helpful; should be

adoptedaspartofSOPP• Valuableactionableadviceprovidedtosponsors

CONs:


• NeedtohavetheactualproductcandidatefortheINTERACTmeetingo timinganissueespeciallyforseveralsmallcompanieso groupofpotentialproduct candidates,pickoneor solicit FDA feedback

andperspectiveontheplatform• Uncertaintyaboutmeetingrequestbeinggranted

o Needed clear examples about the level of data that would support anINTERACTmeetingand inwhat instanceswould themeetingbedeniedorapre-INDmeetingwouldbedeemedmoreappropriate

o CheckboxcriteriafornotgrantinganINTERACTmeeting• ClarityofwhentohaveanINTERACTmeeting

o It is needed to specify in the SOPPwhat ismeant by “premature” and“too advanced” so sponsors can determine timing of an INTERACTmeeting

o Provideexamples• AbilitytosendbriefingmaterialsthroughFDAgateway



BuildingBlockU223


ITEM DESCRIPTION


NCATSToolkitforPatient-FocusedTherapyDevelopment

References

https://ncats.nih.gov/toolkit

https://rarediseases.info.nih.gov/toolkit

Description

The NCATS Toolkit for Patient-Focused Therapy Development (Toolkit) was developedthrough a collaboration betweenNCATS and rare diseases patient groups. The patientgroupshadexpressedaninterestinexchangingknowledgeandsharingbestpracticesintherapydevelopment.TheToolkitprovidesacollectionofonlineresourcesthatcanhelppatient groups advance through the process of therapy development and provide thetoolstheyneedtoadvancemedicalresearch.Asaliving,onlineresourcecontainingtoolsfor and by patient groups, aswell as other reliable sources of information, the Toolkitincludesinformationsuchashowto:

• Establishapatientregistryandnaturalhistorystudydatabase;• Advancepatient-focuseddiscoveryandpre-clinicalresearchanddevelopment;• WorkwithNIHandtheFoodandDrugAdministration(FDA);and• Assistwithpost-marketsurveillance.

ATherapyDevelopmentRoadMapThe Toolkit is organized into five areas to address where users may be in thedevelopmentprocess:

• Getting Started — Describes how therapies are developed, how to prioritizeactivities,whypatient involvement is important andhow tobuild relationshipswithotherstakeholders.

• Discovery — Explains how potential therapies often are discovered, how toparticipate early in the discovery anddevelopment process, andhow to “grow


your field” of research interest through collaborations, patient registries andnaturalhistorystudydatabases,fundingsourcesandtranslationaltools.

• Preparing for Clinical Trials — Describes the testing process and how patientgroupscancollaboratewith researchersand industrypartnersonstudydesign,preparationandparticipation.

• ClinicalTrialsandFDAReview—ProvidestoolsthatcanhelppatientsconnecttoclinicaltrialsandtakepartintheFDAregulatoryreviewprocess.

AfterFDAApproval—Provideshelpwithintegratingnewtreatmentsintoclinicalcare.

Category DevelopmentalResourcesBuildingBlock

Geographicalscope


Availability


Scope ofuse

Developed by the rare diseases community to facilitate therapeutics research anddevelopment, the Toolkit offers many tools that may be useful to patient advocacygroups for both rare and common diseases and conditions. The working groupthoroughly evaluated the tools to make sure they met the team’s criteria of beinguseable, accessible and practical. The group also identified gaps in the types of toolsavailable and discussed how those gaps could be addressed. Patients and patientadvocateshelpeddesignandtesttheToolkitwebsiteforusabilityandfunctionality.

NCATSwillcontinuetopartnerwiththepatientcommunitytoaddnewtools;ensurethatexistingcontentisaccurate,timelyandrelevant;andidentifygapssothatnewtoolscanbedeveloped.

Stakeholders

ThissitewasdevelopedbytheNIH,NationalCenterforAdvancingTranslationalSciencesfor patient groups in conjunction with academic, government, industry and advocacypartners.


Internetaccesstoawealthofrecoursesorganizedfortheuser.

Output Aseriesoflinkstodevelopment-stageassociatedresourcesandtools.



Thetoolhasitsuseimmediatelyandshouldberevisitatprogressinglevelsoftherapeuticdevelopment,asitisalivingsitewithupdatedtoolsandresources.

Experttips

Awonderfulfreeresourcewithexcellentlinksthataredevelopment-stagespecific.ItisaIRDiRCRecognizedResource.

PROs:

− Awonderfulsetofresourcelinksthatfacilitatetherapeuticdevelopment.

CONs:

− None



BuildingBlockU224


ITEM DESCRIPTION


USExpandedAccessProgram

References

https://www.fda.gov/downloads/drugs/guidances/ucm351261.pdf

https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm351264.pdf

Description

This FDA program allows early access to drugs and medical devices before marketingapproval, under regulatory oversight with collection of safety data, to patients withserious or immediately life-threatening diseases or conditions who lack therapeuticalternatives. The program is designed to protect patient safety and avoid interferencewith the development of the investigational drug for marketing under approvedapplications.

The Program allows patients with serious rare diseases to have access to pre-marketdrugsanddevices,iftheSponsoragreestothisundertheirexpandedaccesspolicy.Thepurpose of a protocol under this program is to diagnose,monitor or treat a patient’sdiseaseor condition rather thanobtain information about adrug, as is derived fromaclinical trial. However, the protocol is conducted under IND and IRB oversight, withreportingofadverseevents.


Geographical



scope

Availability

Applicantsdevelopingmedicinesforrareandnon-rarediseases.Morespecificallyto:

− treatinglicensedphysicianinvestigatorswithagreementfromthedeveloper− developersfilinganewIND,oramendmenttoexistingIND− appropriate patients and caregivers interested in access to pre-market

drugs

Scope ofuse

• whenadrughasbeenwithdrawn for safety reasons,but thereexists apatientpopulation forwhomthebenefitsof thewithdrawndrugcontinue tooutweightherisks;

• use of a similar, but unapproved drug (e.g., foreign-approved drug product) toprovidetreatmentduringadrugshortageoftheapproveddrug;

• use of an approved drug where availability is limited by a risk evaluation andmitigationstrategy(REMS)fordiagnostic,monitoring,ortreatmentpurposes,bypatientswhocannotobtainthedrugundertheREMS;

• toprovidedrugbetweenendofthetrialandcompletionofFDAreview;or

• useforotherreasons.

Stakeholders

• Sponsors

• Patients/guardians

• Physicians

• FDA


• SponsormustagreetoprovidedrugandfileanIND,orprotocolamendmenttoexistingIND

• IRB approval must be obtained in advance (except in case of emergencyexpandedaccessuseforanindividualpatient,seeBuildingBlockU225)

• Licensedphysicianinvestigatormustagreetoprescribethedrugandreportadverseeventsperprotocol

• Informedconsentfromthepatient/guardianmustbeobtained


Output Provisionofcareunderapprovedexpandedaccessprotocol


AnexpandedaccessprotocolsubmissionforexpandedaccessshouldbeusedonlyifthesponsorseekingexpandedaccesshasanexistingINDineffect—typically,suchasponsorisacommercialsponsorwithanexistingINDunderwhichthesponsorisdevelopingthedrugformarketing.WhenthereisanexistingINDineffect,FDAgenerallyencouragesthesubmission of an expanded access protocol, rather than a new expanded access IND,becausehavingallexpandedaccessuseandclinicaltrialuseconsolidatedunderasingleINDmayfacilitateidentificationofsafetyconcerns,maymaketheadministrativeprocesslessburdensomeforsponsorsandFDA,andmayhelpinproductreview.

Anewexpandedaccess INDsubmissionforexpandedaccessgenerallyshouldbeusedwhen(1)thereisnoexistingINDineffectforthedrugor,morecommonly,(2)thereisanexisting IND ineffect forthedrug,butthesponsoroftheexisting IND10declinestobethesponsoroftheexpandedaccessuse(e.g.,foranindividualpatientuse,thesponsorofthe existing IND may prefer that a patient’s physician take on the role of sponsor-investigatorandsubmitaseparateindividualpatientIND).

Experttips

TherearethreecategoriesofexpandedaccessINDsandINDprotocolamendments:

• A protocol may be filed by the Sponsor or an intermediate size patientpopulation,

• OrformorewidespreaduseasatreatmentIND/protocol.

• Individual(orsingle)patientexpandedaccessprotocolssubmittedbya licensedphysician(physician-investigator).

PROs:

− Providesaccesstopre-marketdrugs

CONs:

− Requiressafetymonitoring,IRBoversight

− Costofdrugandstudybornebythedeveloperor,withFDAauthorization,maybechargedtoapatientorthird-partypayor



BuildingBlockU225


ITEM DESCRIPTION


SinglePatientExpandedAccess

References

https://www.fda.gov/downloads/drugs/guidances/ucm351261.pdf

https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm351264.pdf

Description

This FDA program allows early access to drugs and medical devices before marketingapproval,underregulatoryoversightwithcollectionofsafetydata,toindividualpatientswithseriousorimmediatelylife-threateningdiseasesorconditionswholacktherapeuticalternatives.Thisincludesemergencyandnon-emergencyexpandedaccess.

TheProgramallowsindividualpatientswithseriousrarediseasestohaveaccesstopre-market drugs and devices, if the Sponsor agrees to this under their expanded accesspolicy.


Geographicalscope


Availability

Applicantsdevelopingmedicinesforrareandnon-rarediseases.Morespecificallyto:

− treatingphysicianswithagreementfromtheSponsor


− patientsandfamiliesinterestedinaccesstopre-marketdrugs

Scope ofuse

• whenadrughasbeenwithdrawnforsafetyreasons,butthereexistsapatientforwhomthebenefitsofthewithdrawndrugcontinuetooutweightherisks

• use of a similar, but unapproved drug (e.g., foreign-approved drug product) toprovidetreatmentduringadrugshortageoftheapproveddrug

• use of an approved drug where availability is limited by a risk evaluation andmitigationstrategy(REMS)fordiagnostic,monitoring,ortreatmentpurposes,byapatientwhocannotobtainthedrugundertheREMS;or

• useforotherreasons.

Stakeholders

• Sponsors

• Patients/guardians

• Physicians

• FDA


• Sponsormustagreetoprovidedrug

• PhysicianmustfileanINDagreetoprescribethedrug,andreportadverseeventsperprotocol(seenotesonemergencyusebelow)

• Informedconsentfromthepatient/guardianmustbeobtained

Output Provisionofcareunderapprovedexpandedaccessprotocol.


WhenaphysicianwantstosubmitaSinglePatientExpandedAccessrequesttoobtainanunapprovedinvestigationaldrugforanindividualpatient,heorshemustfirstensurethatthemanufactureriswillingtoprovidetheinvestigationaldrugforexpandedaccessuse.Ifthemanufactureragreestoprovidethedrug,thephysicianshouldfollowthestepsbelowtosubmitanInvestigationalNewDrugApplication(IND)totheFDA.

Experttips

• PhysicianmayfileanindividualpatientIND

• SponsormaysubmitaprotocolforindividualpatientusetoanexistingIND

• FDAmayauthorizeexpandedaccess foran individualpatientwithoutawrittensubmission if there is “an emergency that requires the patient to be treated


beforeawrittensubmissioncanbemade.”Inthiscase,expandedaccesstothedrugmaybeginuponauthorization(usuallyprovidedbytelephoneorotherrapidmeansofcommunication)bythereviewingFDAofficial.Thelicensedphysicianorsponsor, however, must agree to submit an expanded access IND or protocolwithin15workingdaysofFDA’sauthorizationoftheuse.

• Inthecaseofanemergencyexpandedaccess,itisnotnecessarytowaitforIRBapproval to begin treatment. However, the IRB must be notified of theemergencyexpandedaccessusewithin5workingdaysofemergencyuse.

PROs:

− Provides access to pre-market drugs for patients without therapeuticalternatives.

CONs:

− Requiressafetymonitoring,IRBoversight.

− Cost of drug and study borne by Sponsor or, with FDA authorization, may bechargedtoapatientorthird-partypayor.



BuildingBlockU226


ITEM DESCRIPTION


NIHfundedprogramsandresources

References

https://grants.nih.gov/grants/oer.htm

Description

NIHisthelargestpublicfunderofbiomedicalresearchintheworld,investingmorethan$32billionayeartoenhancelife,andreduceillnessanddisability.

Category DevelopmentOpportunityBuildingBlock

Geographicalscope


Availability


Scope ofuse

Toprovidefundsfordifferentphasesofdrugdevelopment.

Stakeholders

• NIH,


• Developer(publicorSME)


Enablersdependsoneachspecificfundingapplication.

Output A successful funding application both results in a research proposal and themeans toconducttheresearch.


Thetoolhasitsbestuseatveryearlyphasesofdrugdevelopment

Experttips

Startapplyingforfundingwellinadvance,andalsoconsideralternativefundingoptions.

PROs:

− Allows a substantial amount of funding, when obtained, especially for earlyphasesofdrugdevelopment.

CONs:

− High commitment is required from participants,while only a part of proposalsgetsgranted.



BuildingBlockU227


ITEM DESCRIPTION


TheNIHRareDiseaseClinicalResearchNetwork(CRN)

References

https://ncats.nih.gov/rdcrn

Description

TheOfficeofRareDiseasesResearch (ORDR)within theNational Center forAdvancingTranslationalSciences(NCATS)alongwithNationalCancerInstitute(NCI),NationalHeart,Lung, and Blood Institute (NHLBI), National Institute of Allergy and Infectious Diseases(NIAID), National Institute of Arthritis andMusculoskeletal and Skin Diseases (NIAMS),Eunice Kennedy Shriver National Institute of Child Health and Human Development(NICHD), National Institute of Dental and Craniofacial Research (NIDCR), NationalInstitute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the NationalInstituteofNeurologicalDisordersandStroke(NINDS).

TheRDCRNismadeupofmultipleindividual,RareDiseaseClinicalResearchConsortium(RDCRC) and a Data Management and Coordinating Center (DMCC). The RDCRCs areintendedtoadvancethediagnosis,management,andtreatmentofrarediseaseswithafocus on clinical trial readiness. Each RDCRCwill promotes highly collaborative,multi-site, patient-centric, translational and clinical research with the intent of addressingunmetclinicaltrialreadinessneeds.

Todatethisprogramhassuccessfullysupported31 individualconsortia thatconductedresearchon238individualdisorders,leadingtoagreaterunderstandingofrarediseases.

Eachconsortiummuststudyat leastthreedifferentrarediseaseandmusthavepatient


advocacy groups or patients must be engaged in a significant manner within theconsortia.

Eachconsortiumaimsconductinglongitudinal/naturalhistorystudiesandhasafocusonclinicaltrialreadiness(e.g.,biomarkers,outcomemeasures).


Geographicalscope

UnitedStatesofAmericaandInternational

Availability


Scope ofuse

Informational, potential research collaborators, potential clinical research studies forpatients

Stakeholders

• Researchers,

• Clinicians,

• PatientAdvocacyGroups,

• Patients,families,caretakers


Webaccess.

Output Specificresearchstudies


TheRDCRNas a network is recompetedonce every five years (last competition 2019).Applicants must be within the United States however; international collaborators areallowed.

The consortia are open to collaborations with other rare disease researchers andcommunicationwiththenetworkorindividualconsortiaareencouraged.


Experttips

PROs:

− Excellentassembledresource

CONs:

− None



BuildingBlockU228


ITEM DESCRIPTION


Discovering New Therapeutics Uses for Existing Molecules (NTU) program, NationalCenterforAdvancingTranslationalSciences(NCATS)

References

https://ncats.nih.gov/ntu

Description

The NTU program aims to improve the process of developing new treatments fordiseasesbyfindingnewusesforexistingtherapiesthatalreadyhaveclearedseveralkeystepsalongthedevelopmentpath.Existingorpartiallydevelopedtherapeuticcandidatescan be repurposed for use in new disease indications. The program aims to bringtogetherassetsfrompharmaceuticalcompanies(pharma)andnewideasfromacademicresearchersthatcouldproducenewtreatmentsmorequicklythanstartingfromscratch.

NTUcanbeusedforapotentialnewuseofanexistinginvestigationaltherapyforarareor common disease. NTU seeks to repurpose existing therapeutic candidates towarddisease targets forwhich theymay hold promise, thereby potentially reducing time todevelopmentofatherapeuticcandidateregardlessofindication.


Geographicalscope



Availability


Scope ofuse

The goal of this building block is to advance the evaluation and development of drugproducts that are partially developed or developed for a different indication. Thepurpose is to produce new treatments more quickly than starting from a novelcompound.

TheNTUprogrambrings togetherassets fromparticipatingPharmacompaniesand theacademic biomedical research community. Pharma partnerships (per the website:https://ncats.nih.gov/ntu/about) include: AstraZeneca, MedImmune, AbbVie, Bristol-MyersSquibb,EliLilly&Co,GlaxoSmithKline,JanssenPharma,MeroeBioPharma,Pfizerand Sanofi. Participating Pharma companies must meet inclusion criteria per thepublishednotice:https://grants.nih.gov/grants/guide/notice-files/NOT-TR-14-001.html

Investigators may propose testing new therapeutics uses for experimental drugs orbiologics across a broad range of human diseases in adult and pediatric populations.Strong applications will include scientific evidence that modulation of a drug forrepurposingwillhaveapositiveimpactonthedisease/condition.

Investigatorswithaproposalconsistingofstrongscientificevidencethatmodulationofadrugforrepurposingwillhaveapositive impactonthedisease/conditionmayconsiderapplying. Please consult published FOAs for additional information regarding scope ofthespecificawards:https://ncats.nih.gov/ntu/funding

Stakeholders

• NIHNCATS

• ParticipatingPharmacompanies

• Academicbiomedicalresearchers


Current open funding opportunity announcements (FOAs) are available here:https://ncats.nih.gov/ntu/funding. FOAs vary in scope and target applicants, andpotentialapplicantsareurgedtoreadtheopenannouncementscarefully.

Output TheNTUprogramassistswithsupportingCooperativeAgreements(e.g.,U01s,U34s)toenableNTUof candidate therapeutics. Cooperativeagreements support testingof thecandidatetherapeuticsatvariousclinicalandpre-clinicalphasesofstudy.

Besttime to

FOAs are open for varying lengths of time – please consult the website for specifics:


applyand timewindow

https://ncats.nih.gov/ntu/funding

Experttips

Please consult the NCATS NIH website for additional information, templates, FOAs,availablePharmaassetsandapplicationprocess:https://ncats.nih.gov/ntu/about

NCATSstaffmayalsobeconsultedforadditionalassistance.

PROs:

− Availablefundingfortestingofcandidatetherapeuticsforrepurposinginabroadrangeofdiseases/conditions.

CONs:

− Limited funding/opportunities available through peer-review process. Time lagand submission requirements for available FOAs are resource intensive andfundingisnotguaranteed.

orphan drug development guidebook building block u201 · output orphan drug designation best time...

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