orphan drug development guidebook building block i401 · scope european union and united states of...

ODDG–BuildingBlockI401–Version1 1

OrphanDrugDevelopmentGuidebook

BuildingBlockI401

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

ITEM DESCRIPTION

BuildingBlock(BB)Title

JointEMA–FDAScientificAdvice(ParallelScientificAdvice–PSA)

References

http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2017/11/WC500239158.pdf

https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/OfficeofInternationalPrograms/UCM557100.pdf

Description

TheEuropeanMedicinesAgency(EMA)andtheU.S.FoodandDrugAdministration(FDA)oftheU.S.DepartmentofHealthandHumanServiceshaveaprogramtoprovideparallelscientific advice (PSA) to sponsors. The goal of the PSA program is to provide amechanism for EMA assessors and FDA reviewers to concurrently exchange withsponsorstheirviewsonscientificissuesduringthedevelopmentphaseofnewmedicinalproducts(i.e.,newhumandrugsandbiologics).

Duetoclinicalparticularitiesofrarediseases, thedevelopmentplanofnewtreatmentsmay deviate substantially from conventional methods and approaches and this mayresult in issues on acceptability of data at the time of marketing authorizationassessment. Regulatory scientific advice may avoid such issues if done early in thedevelopment process, but criteria may diverge between FDA and EMA. Scarcity ofpopulationsdonotallowforseparatedevelopmentsforeachregiontosatisfydifferentcriteria.

Joint FDA-EMA scientific advice allows coordination of the procedure and jointdiscussion,sothatamutuallyrecognizedpositionacceptableinbothregionsisobtained.


Category RegulatoryBuildingBlock

Geographicalscope

EuropeanUnionandUnitedStatesofAmerica

Availability

Applicants developing medicines for rare and non-rare diseases lacking developmentguidelines, or if guidelines do exist, those forwhich EMA’s and FDA’s guidelines differsignificantly.

Scope ofuse

The PSA procedures should focus on sharing information and perspectives. Achievingharmonizationand increased convergence is apotential beneficial outcomeof thePSAprocess. Following PSAmeetings, sponsors should have a clearer understanding of theagencies’respectiverequirementsandperspectivesregardingthedevelopmentprogramdiscussed,andifdivergent,thereasonsforthedivergence.

ThebestcandidatesforPSAincludeimportantmedicinalproducts,especiallythosebeingdevelopedforindicationslackingdevelopmentguidelines,orifguidelinesdoexist,thosefor which EMA’s and FDA’s guidelines differ significantly. In addition, biosimilars,products with significant clinical safety, animal toxicology, or unique manufacturingconcerns that could impede further product development are appropriate PSAcandidates.PreviousPSAshaveinvolvedmedicinalproductsforoncology,anti-infectives,rare diseases, the pediatric population, and cardiovascular disease, as well as post-licensurecommitmentclinicaltrials.

PSA requests should focus primarily on specific questions or issues involving thedevelopmentofamedicinalproduct intendedtobecommercializedinboththeEUandthe USA, and especially if the scarcity of the target population makes it difficult toconduct conventional developments or replicate data to satisfy divergent regionalrequirements, and thus those for which the sponsor desires to have further scientificinputfrombothEMAandFDA.

Stakeholders

• ApplicantsofthePSAprogram

• EMA

• FDA

Enablers/Require

SponsorswishingtonominateaproductforPSAshouldaddressonesingle“RequestforPSA” letter to both [email protected] at EMA and [email protected]. Inthis letter, thesponsorshouldprovidethefollowinginformation: (1) the product in development, (2) why a discussion with the assessors


ments (reviewers) of EMA and FDA would be beneficial to the product’s development, (3)specificquestionsrequiringclarification,(4)thedesiredgoalsforthemeeting,and(5)anexplicit authorization for the agencies’ comprehensive exchange of all informationrelevant to theproduct, including tradesecret information (asdefinedbyU.S. statute).Pursuanttolegallyestablishedauthorities,bothagencieswillmaintaintheconfidentialityofallsuchinformation.

Output Advices from both agencies. The advice of each agencymay still differ after the jointdiscussion. However, both agencies will strive to provide PSA responses that areconvergent.

Besttime toapplyand timewindow

Thetoolcanbeusedstartingat thebeginningof theclinicaldevelopmentuntilmarketauthorizationbeingtheoptimaltimetoapplyafterhumanPoC.

Experttips

PROs:

Joint FDA-EMA scientific advice allows coordination of the procedure and jointdiscussion,sothatamutuallyrecognizedpositionacceptableinbothregionsisobtained,orclearreasonsfordivergenceandwaystoapproachthedevelopment if theformer isnotachieved.

CONs:

The development requirements in case of substantial divergence in criteria may beoverall increasedtoreachmutuallyacceptablepositions,andthesemaynotbefeasibletocomplywithoutsubstantialresources,whichmaynotbeavailable.

ODDGTF–BuildingBlockI402–Version11


BuildingBlockI402

This document defines the content of the Building Block created for each identified tool, incentives,initiativeorpracticeintroducedbypublicbodiesorusedbydeveloperstoexpeditedrugdevelopmentinRareDiseases(RDs).

ITEM DESCRIPTION

BuildingBlock (BB)Title

Extrapolationofefficacyandsafetyinmedicinedevelopment(Extrapolation)

References

https://www.ema.europa.eu/documents/scientific-guideline/adopted-reflection-paper-use-extrapolation-development-medicines-paediatrics-revision-1_en.pdf

https://www.ema.europa.eu/en/events/ema-public-workshop-extrapolation-efficacy-safety-medicine-development

ExtrapolationofAdultDataandOtherData inPediatricDrug-DevelopmentPrograms.Pediatrics2011;128;e1242

https://www.ncbi.nlm.nih.gov/pubmed/22025597

ExtrapolationofEfficacyinPediatricDrugDevelopmentandEvidence-basedMedicine:ProgressandLessonsLearned.TherInnovRegulSci2017;2017:1-7.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587157/pdf/nihms901908.pdf

General Clinical Pharmacology Considerations for Pediatric Studies for Drugs andBiologicalProducts:GuidanceforIndustry

https://www.fda.gov/downloads/drugs/guidances/ucm425885.pdf

PediatricRareDiseases-ACollaborativeApproachforDrugDevelopmentUsingGaucherDiseaseasaModel:GuidanceforIndustry

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM587660.pdf


ITEM DESCRIPTION

Description

The EMA describes extrapolation as extending information and conclusions availablefromstudiesinoneormoresubgroupsofthepatientpopulation(sourcepopulation(s)),orinrelatedconditionsorwithrelatedmedicinalproducts,inordertomakeinferencesfor another subgroup of the population (target population), or condition or product,thusreducingtheamountof,orgeneralneedfor,additionalevidencegeneration(typesof studies, design modifications, number of patients required) needed to reachconclusions.

TheFDAstatesthatextrapolationofefficacycanbeconsideredwhenthecourseofthediseaseandtheexpectedresponsetoadrugproductwouldbesufficientlysimilarinthepediatricandreferencepopulation(i.e.,adultorotherpediatricagepopulation).TheFDAemphasizesthatdosingandsafetycannotbeextrapolated;effectsoftherapyonspecificpediatricmanifestations(i.e.growthrate,onsetofpubertyandprogressionofpubertaldevelopment)cannotbeextrapolated.

Coststodevelop/plantheframeworkforextrapolationmayexistbutinthelong-termextrapolationmaysavemoney

Category DevelopmentResourceBuildingBlock

Geographicalscope

Europe,USA

Availability

In rare disease research, due to the small numbers of subjects, it is particularlyimportant to utilise efficiencies. Therefore, it may be appropriate to use availableclinical information in one area to support other aspects of the drug developmentprogramme where modelling and simulation can be used, reducing the burden ofconductingmultipleclinicaltrials.

Scope ofuse

Mainexamplescanbefoundinextrapolatingefficacyfromadultdatatothepaediatricpopulation,potentiallystreamliningthedrugdevelopmentprogramme.

Thereisalsoincreasinginterestinbasketstudies,whereextrapolationbetweengroupsmayberequired.

Paediatrics,basketstudies,modellingandsimulation

Stakeholders

Drugdevelopers,regulatoryauthorities


ITEM DESCRIPTION

Enablers/Requirements

Scientific advice with the Central and National Regulatory Authorities is stronglyrecommendedregardingtheacceptabilityofextrapolationproposals

Output Componentofthedrugdevelopmentpathway

Best timeto applyand timewindow

Early in the development plan so that the approach can be factored into the overallapproachestosupportmarketingauthorization.

Experttips Considerearly inthedevelopmentpathway,considermodellingandsimulation(M&S)questionandanswersorotherregulatorysupport

https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/clinical-pharmacology-pharmacokinetics/modelling-simulation-questions-answers

PROs:

• Canspeedupthedrugdevelopmentandreducetheneedforclinicaltrials

CONs:

• Approachshouldbeagreedbyseekingscientificadvicefromregulators



BuildingBlockI403


ITEM DESCRIPTION


NationalScientificAdvicewithHTAbodies(NSAw/HTA)

References

https://ec.europa.eu/health/sites/health/files/technology_assessment/docs/2018_mapping_npc_en.pdf

https://ec.europa.eu/health/sites/health/files/technology_assessment/docs/2018_mapping_methodologies_en.pdf

http://www.cirsci.org/wp-content/uploads/2016/10/cirs-rd-briefing-60-early-scientific-advice-from-hta-agencies_sept-2016.pdf

Palkmets O, Nagda N, Sear R. Early HTA Advice In European Countries: Scope AndAssociatedCosts.ValueinHealth2017;20(9):A695.

Description

In Europe, pricing and reimbursement decisions are a national/regional responsibility,and aremadebasedon a process of appraisal by nationalHealth technologyAgencies(HTA) that includes value assessment and economic considerations, amongst others.Regional and national HTA bodies provide recommendations on medicines and otherhealth technologies that can be financed or reimbursed by the healthcare system in aparticularMember State or region. The assessment criteria used by HTA bodies differbetweenMemberStates,inaccordancewithregionalandnationallegislation.

At the request of Sponsors, Regional and national HTA bodies can providerecommendations on the data to be submitted at the time of application for pricing,fundingorreimbursementofmedicinesandotherhealthtechnologiesbythehealthcaresysteminaparticularMemberStateorregion.

National advice can be sought by sponsors during clinical development, in order to


advancewhichwillbethelikelycriteriaforvalueassessmentthatwilldrivethepriceandreimbursementdecision,andwhetherthedatacollectionthathasbeenplannedbythesponsorforpivotaltrialswillbeappropriateandsufficienttoinformtheprocess.

The advice received can be used to timely implement changes to the clinicaldevelopmentplantoensurethatalltherequiredinformationisavailableatthetimeofauthorization,sothatanydelaysinaccessduetolackofdatacanbeavoided.

The process of National Scientific Advice with HTA bodies is applicable to any kind ofproduct, thus not restricted to rare diseases, butmay be especially relevant for drugsintended for rare diseases with anticipated high prices per treatment, becausesubstantial differencesmay occur across countries in the criteria for appraisal, due todifferencesinstandardsofmedicalandsocialcare,aswellasintheaffordabilityofhighpricesfornewdrugs.


Geographicalscope

Procedureisdoneatthenationallevel,relevantmainlyforEurope.

Availability

Applicantsdevelopingmedicinesforrareandnon-rarediseases.

Scope ofuse

Clinicaldevelopmentismainlyfocusedonregulatoryapprovalofmarketingauthorizationapplications,andthecriteriaforapprovaloforphandrugsinEuropeisappliedatasupranational level. However, the competence for pricing and reimbursement decision inEuropereliesonNationalauthorities.WhileEuropeancountriesshareregulatorycriteria,they diverge inwealth, economic systems and healthcaremodels, so that funding andpubliccoveragemaybesubstantiallydifferent.

Because of that, despite a common positioning may be reached from supranationalconsultation through coordinated procedures involvingmany HTAs (see BB on parallelconsultationofHTA),itmaystillberequiredtogatheropiniononparticularrequirementsforagivencountry.

National advice would allow for timely planning of data collection (I ex: related todifferentclinicalpracticesinagivencountry)and/orspecificstudies(Iex:comparisontodifferentstandardsofcare)thatmightberequiredbytheHTA inordertoappraisethenewproduct.

The BB is to be used by sponsors in preparation of the post-authorization process ofpricing and reimbursement, in order to anticipate that all the relevant data needed to


supportapplicationforpricingandreimbursementiscollectedtimelyandappropriately,in order to satisfy the HTA procedures for value assessment and criteria for drugappraisal.

Stakeholders

• Sponsors of products intended for marketing authorization application andfutureapplicationforpricingandfunding/reimbursement.

• NationalHealthTechnologyAgenciesreceivetheapplicationsandissueopinionsonthequestionsraisedbytheSponsors.


The Sponsor of a given clinical development should identify the strategic need orconvenience of a national scientific advice with HTA, and the best moment forconsultation.TheSponsor contacts theHTA for requirements,preparesdocumentationandsubmitsapplication.

TheHTAreviewsthematerialsandpreparesanswers.Theformatofconsultationcanbein writing or in the form of a face to face meeting, depending on HTA internalprocedures.

Output TheHTAissuesopinioninwritingorintheformofafacetofacemeeting,dependingonHTAinternalprocedures.Theopinionisgenerallykeptconfidential.


The tool can be used starting from product discovery until market access being theoptimal times toapply rightbeforeFirst inHumanReady,afterhumanPoCandbeforemarketauthorization.

Experttips

A description of the European HTAs can be found here:https://ec.europa.eu/health/sites/health/files/technology_assessment/docs/2018_mapping_npc_en.pdf

A summary of the different methodologies European HTAs apply:https://ec.europa.eu/health/sites/health/files/technology_assessment/docs/2018_mapping_methodologies_en.pdf

• The Sponsor of a given clinical development identifies the need for a nationalscientificadvicewithHTA,ideallybytheendofphaseII,beforebeginningofphaseIII.

• The number of HTAs and the selection of which HTA to approach is an strategicdecisionof the sponsor, thatmay varydependingon thedegreeof uncertaintyonthecountryprocedures,clinicaldifferencesinthestandardsofcarefortheindication


soughtforthenewtreatment,andstrategicconsiderationsofthecompany,amongstotherfactors.

• Thenameoftheproceduremaybedifferentineachcountry(HTAScientificAdvice,pre-submissionmeeting,Technicalconsultation,amongstothers).

• TheSponsor contactswith the selectedNationalHTA to request advice, andwhicharetherequirementsfortheprocedureandfeesoftheHTA,whereapplicable.

• A product briefing document is produced that is shared with the HTA ahead ofdiscussions. The document includes a summary of product data and a list ofquestionswithbackgroundsupportandproposedsponsorpositioningregardingthepotentialresponse.

• The HTA reviews the briefing document and prepares answers to the Sponsor’squestions.Theanswers includewhetherthesponsorpositioning isendorsedornotacceptable, and if an alternative positioning is hold by the HTA. Answers may beissued in writing or verbally during a face to face meeting with the sponsor; thenumberofmeetingsmayvarybetweenHTAdependingontheirinternalprocedures.

• Also depending on the HTA, a final report with recommendation may beissued,orcompanyminutesofthefacetofacemeetingarecirculated.

PROs:

GenerallynationalscientificadvicewithHTAisamoredirect,shorterandagileprocedurethanafullparallelconsultationprocessthroughEUnetHTA.Also,maybeafirstapproachto obtain initial opinions to prepare a future parallel consultation procedure throughEMA/EUnetHTA,includingapreliminaryselectionofpreferredparticipating/leadingHTAsinthemultistateprocedure.

When issues on lack of predictability are limited to one singular country, the directconsultationwith theconcernedHTAmaybeagileandmayallow the sponsorand theHTA todefinemutually agreed solutions tobe implementedonly at thenational level,withnoinvolvementofotherterritorieswhereamorestandardapproachcanbedone.Also, if higher exigencies ormore strict policies are expected, these canbehandled inisolation, avoiding generalization of theworst scenario to HTAs in other countries if aparallelconsultationwithregulatorsandhealthtechnologyassessmentbodieswasdoneinvolvingtheconcernedHTA.

CONs:

Asking for individual advice toall concernedHTAs is timeand resource consumingandinefficient.

Also, risksof individualadvicewithnomultistatecoordination includedivergentadvice


from several national HTA for a single product. Inconsistencies betweenrecommendationsmay pose a difficult scenario to Sponsors, whowill have to deviatefrompartoftheadvicereceived.Askingforadviceisnotbinding,butanydeviationfrompreviously received recommendations will require justification and may becomeproblematicatthetimeofapplication.Becauseofthat,generallyaparallelconsultationprocedureismoresensiblethanseveralnationalprocedures.

Waiting for advice before closing the designs of phase III trialsmay represent a delay.Outcomesoftheadvicemayrequirechangingkeyfeaturesoftheclinicalplan,leadingtostrategic discussions on clinical positioning, objectives and goals of the clinicaldevelopmentplan.Thiscanbedifficulttomanagewithinthesponsorteam.



BuildingBlockI404


ITEM DESCRIPTION


Crowdfunding

References

Multiplewebsites/platformsprovidecrowdfundingservicesordescribeshowtoinitiatecrowdfundingforrarediseases,e.g.,

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818677/

https://www.raredr.com/news/crowdfunding-and-rare-disease-therapy

Description

The internet and social networking havemade crowdfunding a realistic avenueforindividualsandgroupshopingtofundmedicalandresearchcauses,includingpatients in need of whole exome genetic sequencing (WES), as well as R&Dprojects.

Traditionally,themainfundingsourcesforrarediseasesandorphandrugR&Daregovernment,pharmaceuticalcompanies,andventurecapitalists.

Inrecentyears,crowdfundingisbecominganewfundingsourceviasocialnetworksandtheinternet.

Category FundingBuildingBlock

Geographicalscope

International


Availability


Scope ofuse

ToraisefundingtofundrarediseasediagnosisandR&D.

Stakeholders

Twoparties:

• stakeholders in rare disease diagnosis and R&D (Patients and families. Patientgroups.Foundations,Researchers,orR&Dcompanies),and

• thepublic


Statethecauseandjustifytheamounttoberaisedandthetargetraiseamount.

Output Funding


The best time to apply is at very early stage of R&D.While private funding is possiblethroughout the development life cycle, public funding usually lasts until the end ofhumanPoC.

Experttips

Beastransparentaspossibleastohowthefundsareused

Donotmisusepublicdonations.

PROs:

− Leverageonpubliccontribution

− Promotepublicawareness

CONs:

− Maynotalwaysmeetthetargetraiseamount

− May not always meet the project timing (i.e., when you need the money toaddressthescientificquestion)



BuildingBlockI405


ITEM DESCRIPTION


Nationalprogramsforearlyaccess

References

USA:

https://www.fda.gov/news-events/public-health-focus/expanded-access

https://www.fda.gov/media/85675/download

Europe:

http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/Timely_Access/2018_09_CUP_27-6-18.pdf

Description

Sometimes called “compassionate use”, expanded access is a potential pathway for apatientwithan immediately life-threateningconditionorseriousdiseaseorconditiontogainaccess toan investigationalmedicalproduct (drug,biologic,ormedicaldevice)for treatment outside of clinical trials when no comparable or satisfactory alternativetherapyoptionsareavailable.Patient access tomedicines during their developmentmay be seen as a necessity forthosewhohaveadiseasewithnosatisfactoryauthorisedtherapiesandwhocannotwaituntiltheireventualapproval.Clinicaltrials(CT)offeraccesstomedicinesforpatientswhilehighqualityknowledgeonthe effects and safety ofmedicines is produced.However, CT are not always availableeverywhereand/orthetrialmaynotbeintendedtoincludeallpatients.In the USA, expanded access refers to the use of an investigational drug when theprimarypurposeistodiagnose,monitor,ortreatapatient’sdiseaseorconditionratherthan to obtain the kind of information about the drug that is generally derived from


clinical trials. FDA has a long history of facilitating expanded access to investigationaldrugs for treatment use for patients with serious or immediately life- threateningdiseasesorconditionswholacktherapeuticalternatives. UnderFDA’scurrentregulations,therearethreecategoriesofexpandedaccess:

• Expanded access for individual patients, including for emergency use (21 CFR312.310)

• Expanded access for intermediate-size patient populations (generally smallerthan those typical of a treatment IND or treatment protocol — a treatmentprotocol is submitted as a protocol to an existing IND by the sponsor of theexistingIND)9(21CFR312.315)

• Expanded access for widespread treatment use through a treatment IND ortreatment protocol (designed for use in larger patient populations) (21 CFR312.320)

IntheEuropeanUnionandtheEEA,earlyaccessprogrammesareanoptionforaccessingmedicines before approval. There are roughly two different ways for using anunauthorisedmedicineoutsideaCT:- cohort access (compassionate use programmes, CUPs) under the provisions of theArticle83oftheRegulation(EC)No726/2004,and- individual access (named patient programmes) under the Article 5(1) of Directive2001/83/EC.Both CUPs and named patient use are governed by national legislation and rules. TheindividualNCAdecidewhetherornottheyincludearegulatoryframeworkforCUPsandnamed patient use in their legislation. Moreover, the conditions for application andapprovalofsuchprogramsaredefinedatnationallevel.In addition to national regulations there is a procedure to request the opinion of theCHMPinplaceunderArticle83ofRegulation(EC)No726/2004.

Early access programs have a focus on patient access. However, there may beopportunities to collect real world data to supplement the knowledge base of theproductstillunderinvestigation.


Geographicalscope

International(EuropeanUnionandUnitesStatesofAmerica)

Availability

Applicantsdevelopingmedicines inareasofunmetmedicalneed for rareandnon-rarediseases.


Scope ofuse

Considerationofrequirementsandneedforearlyaccessshouldbeprospectivelyplannedinthedevelopmentprogram.

Engage with individual EU member states or FDA on the requirements – for an EUoverviewseetablesinthelinkbelow:

http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/Timely_Access/2018_09_CUP_27-6-18.pdf

Stakeholders

USA:

even if the patientmeet the criteria under the law and FDA regulations, thelicensed physician, the Institutional Review Board (IRB), and the company allneed to agree that expanded access is appropriate for this patient in order toreceive the investigationalmedicalproduct. Inaddition, theremaybecostsnotcoveredbythird-partypayerssuchasprivateinsuranceorMedicare.

EU:

• Sponsors,

• Nationalcompetentauthorities,

• Healthcareprofessionalsandhealthsystems,

• Patients


Individualnationalcompetentauthorities/FDAmayhaveaspecificregulatoryframeworkforearlyaccess intheir legislation.Oftentheconditionsforapplicationandapprovalofsuchprogramsaredefinedatanationallevel.

Output Patientaccess inadvanceofamarketingauthorizationwiththepotentialtocollectrealworldevidence,asappropriate.Infewcases,areimbursementoftheinvestigationdrugisenvisaged(i.e.,ATUinFrance,648/96lawinItaly)


The tool has its best use later in developmentwhen data on the benefits and risks ofusingthemedicinesareavailableandbeforetheproductisplacedonthemarket.


Experttips

Canbeausefulwaytoprovidepatientaccessandsimultaneouslycollectrealworlddatatosupportregulatorydecisionmakinge.g.futurecommissioningdecisions.

PROs:

− Fulfillingpatientneed

− EngagementwithKOLinthehealthsystems,healthsystemsalsogainexperienceofusingthemedicine

− Potentialtocollectrealworldevidence

− Reimbursementofthedrugcostsinfewcases

CONs:

− Different member states have different rules and procedures, may beburdensomeapplicationprocesses

− Therearefinancialcostsandresourcesneeded(e.g.pharmacovigilancesystems)inordertorunaschemeandforsupplyingthemedicinestopatients



BuildingBlockI406


ITEM DESCRIPTION


TissueChipforDrugScreeningprogramandConsortium

References

https://ncats.nih.gov/tissuechip or several publications, such as DOI:10.1039/c6lc01554a

Description

NCATS, in collaborationwith otherNIH Institutes and Centers and theFood andDrugAdministration(FDA), is leadingtheTissueChipforDrugScreeningprogramtodevelophumantissuechipsthataccuratelymodelthestructureandfunctionofhumanorgans—suchasthelungs,liverandheart—tohelppredictdrugsafetyinhumansmorerapidlyand effectively. During the program’s inception, it has focused on developingphysiologicallyrelevantmodelsfortoxicitytesting.Thecurrentfocusoftheprogramisondiseasemodellingandefficacytesting.

Oncedevelopedandintegrated,researcherscanusethesemodelstopredictwhetheracandidatedrug,vaccineorbiologicagentissafeortoxicinhumansinafasterandmoreeffectivewaythancurrentmethods.

TheultimategoaloftheprogramandConsortiumistoacceleratethetranslationofbasicdiscoveries intotheclinic.Bycreatinganintegratedhumanbody-on-a-chip,researcherscantestthevariedpotentialeffectsofasubstancesuchasadrugacrosstheentirebodybeforeanytestinginhumans.

Category DevelopmentOpportunityBuildingBlock


Geographicalscope

International

Availability


Scope ofuse

Thisbuildingblock canbeused in theearlyphasesofdrugdevelopment, fromdiseaseknowledgediscoverytoproductdiscovery. Itcanalsobeusedduringearlyclinicaltrialstoinformpatient-relevantdecision-making.

Interestedparties(academic/industrydrugdevelopers,patientadvocacygroups)canmakecontactwithfundedinvestigatorswithintheTissueChipConsortiumandpotentiallyformcollaborationswiththem.TheTissueChipConsortiumdatabase(https://mps.csb.pitt.edu/) hasconsolidatedinformationgleanedfromtheprojectswithintheConsortiumandisanotheraspectoftheprogramthatcanbeutilizedbybiomedicalresearchers.

Stakeholders

• FundedTissueChipConsortiuminvestigators

• NCATSprogramstaffwhomanagetheTissueChipprogram


A collaboration with Tissue Chip Consortium investigators or the database; users mayneed iPSCs or donor samples of tissue, or other relevant sources of data, e.g. clinicaldata.

Output AcollaborationwithTissueChipConsortiuminvestigatorstoenablefurtherresearchintothe disease or body system, e.g. creation of an in vitro tool to test multiple drugsefficiently.


The toolhas itsbestuse in theveryearlyphasesofdrugdevelopment, inparticular inbasicresearchorpreclinicaldevelopmentstage.

Experttips

Contactprogramstafftofindoutmore([email protected]).

Differentorgansandtissuesareatdifferentstagesofmodelingontissuechips,sotheremaynotbeavailabletissuechipsyet,ortheymaybeatveryearlystagesofdevelopment.


PROs:

Efficientwayto testefficacyandsafetywithout involvinganimalsorvulnerablepatientpopulations, thereby reducing development cost, while accurately modeling thestructureandfunctionofhumanorgans.

CONs:

TissueChipsfordrugdevelopmentarestillarelativelynewtool,thereforeknowledgeontheiruseissomewhatlimited.

ODDGTF–GalaxyGuide_BuildingBlockFactSheet–December12-13,20181

OrphanDrugDevelopmentGuidebookTaskForce

GalaxyGuidefordrugdevelopmentBuildingBlockFACTSHEETFORMcontent

This document defines the content of the FACT SHEET to be created for each identified tool,incentives, initiative or practice (the Building Block) introduced by public bodies or used bydeveloperstoexpeditedrugdevelopmentinRareDiseases(RDs).

ITEM DESCRIPTION

BuildingBlock(BB)Title DataMining

References https://www.ncbi.nlm.nih.gov/pubmed/28129139

DescriptionTheunderstandingofrarediseasesremainslimitedatatimewhenthecapacity togeneratedatacontinues togrow.Theseunprecedentedlylargeamountsofdata–fromraretonon-raretocommondiseases–have challenged researchers trying tomake sense of it. Meanwhile,data-sharing initiatives also opens up access to new types of dataincluding patient records and other real-world data. These data areripe for analyses using big data techniques, including computationalmodels that unveil molecular mechanisms and similarities amongclinical phenotypes, predict compound-ligand interactions, performhigh-throughputscreeningofmoleculesagainstcelllinesandnetwork-based in silico drug efficacy screening, and datamining for potentialtherapeutic targets based on existing knowledge. At the point ofconvergence of several academic research fields (e.g., appliedmathematics, computer science, artificial intelligence, statistics andmachine learning), data mining takes advantage of the potential tocarry out novel multi-dimensional analytics to connect data ondiseases,mechanisms,proteins,anddrugs.

Relevance to rare diseasedrugdevelopment

Piecedtogether,dataminingmethodsenablethediscoveryofneworthe repurposing of previously known pharmaceutical compounds inthedevelopmentoftreatmentsfornewindications.

Category Developmentopportunity

Availability Data mining is a tool, accessible for use in both the public and


ITEM DESCRIPTION

privatedomain, for rare and commondiseases, or evenoutsideofthediseasecontext.

Geographicalscope Globally

Scopeofuse To combine different types and kinds of data, and extract mostavailableinformationfromthis.

Subject Researchers

Enablers/Requirements NA

Output Newknowledgebasedonalreadyavailabledatasets.

ActorsandStakeholders Researchers(publicandprivate);dataexperts

Use Todiscovernewconnectionsand ideas,basedonalreadyavailabledata.

PROs/advantages Allows you to systematically discover new correlations that youmighthavemissedotherwise.

CONs/risks Sufficient(freelyaccessible)dataisneededifyouwanttobeabletofindnewinformation

Besttimetoapply Especially in the early phases of drug development, to gather themaximumofinformation

Duration Severalweeks

Cost Nocosts

Practicaltips Ifyoudo intendtousedataminingstrategies,makesureyouhaveseveral robust data sets, including different data sources, such asbiological data, patient health record data, and other real-worlddata.



BuildingBlockI408


ITEM DESCRIPTION


BBMRI-ERIC-Europeanresearchinfrastructureforbiobanking.

References

http://www.bbmri-eric.eu/

Description

BBMRI-ERIC isaEuropeanresearch infrastructure forbiobanking.Webring togetherallthe main players from the biobanking field – researchers, biobankers, industry, andpatients – to boost biomedical research. To that end, we offer quality managementservices,supportwithethical,legalandsocietalissues,andanumberofonlinetoolsandsoftwaresolutions.Ultimately,ourgoalistomakenewtreatmentspossible.BBMRI-ERICExpert Centres are non-profit organisations that represent a novel public-privatepartnershipmodel. They are responsible for the analysis of samples in the country oforigin under internationally standardised conditions and for the generation of primarydata. BBMRI-ERIC Expert Centres integratepre-competitive public andprivate researchand development activities by providing access not only to biological samples andmedicaldatabutalsotothebroadspectrumofmedicalandscientificexpertiserelatedtothesamples,data,andtheiranalysis.

The directory is the central listing of Biobanks and their collections in the BBMRI-ERICmemberstates.Forresearchers,theDirectoryoffersameansoffindingrelevantsamplesand data for their research. Rare Disease Biobanks have a separate section in thedirectory.

Category DevelopmentResourcesBuildingBlock


Geographicalscope

EuropeanUnion

(http://www.bbmri-eric.eu/national-nodes/)

Availability


Scope ofuse

Test biomarkers analyze data. Pre-clinical development work. Biobanks providebiomaterials&dataderivedfromthosehttp://www.bbmri-eric.eu/faq/

Stakeholders

• Biobankholders

• Academia

• Industry

• Civilsociety

• Patientorganisations


Itisnotcompletelyclearfromthewebsitewhoisentitledaccess.

Output Biomaterials&Datathereof


ThetoolhasitsuseduringR&Dphase.

Experttips

Checkearlyifinformationonyourdiseaseisincludedinthisinfrastructure.


OrphanDrugDevelopmentGuidebookTaskForce

GalaxyGuidefordrugdevelopmentBuildingBlockFACTSHEETFORMcontent

This document defines the content of the FACT SHEET to be created for each identified tool,incentives, initiative or practice (the Building Block) introduced by public bodies or used bydeveloperstoexpeditedrugdevelopmentinRareDiseases(RDs).

ITEM DESCRIPTION

BuildingBlock (BB)Title

Orphanetdatabase

References www.orpha.net

www.orphadata.org

Activity report:https://www.orpha.net/orphacom/cahiers/docs/GB/ActivityReport2017.pdf

DescriptionEstablished in 1997, Orphanet is a unique public resource worldwide, gathering andimprovingknowledgeonallrarediseases(RD),affectinglessthan1in2’000peopleintheEuropeanpopulation.Orphanetderivesfromitsmulti-lingual,manuallycuratedandexpertvalidatedknowledgebaseanontologyofRD(OrphanetRareDiseaseOntology,ORDO),informationonRD(www.orpha.net)anddata(www.orphadata.org).Orphanetmaintains theOrphanetRDnomenclature (seeCodificationBB), improvingthe visibility of RD in health and research information systems, acting as aninteroperability vector between healthcare and research(https://drive.google.com/file/d/1dsfAAdxF4USmsKK9YQ4IpDW44OqNIZ--/view?usp=sharing).The nomenclature is semantically alignedwith:OMIM, ICD, SNOMED-CT,MedDRA,UMLS,MeSH,GARD.RDareannotatedwithmanuallycurateddataonageofonset,age of death, prevalence, incidence, gene-disease qualified relationship, cross-references with other databases (OMIM, UniProtKB, HGNC, ensembl, Reactome,IUPHAR, Genatlas), the frequency of phenotypic features (using HPO), andInternationalClassificationofFunctioning(ICF-CY)derivedterms.Orphanet knowledge base includes, besides the nomenclature, scientific annotations(phenotypes, disabilities, epidemiological data, genes, age of onset and of death),textual information (produced by Orphanet or from tother sources after qualityassessment),orphandesignationsanddrugdatafromEMAandFDA,andacatalogueof expert services/resources in Orphanet consortium countries described withmeta-


ITEM DESCRIPTION

data, including:expertcentres,diagnostictestsandlabs,patientorgnisations,patientregistries,biobanks,researchprojects,clinicaltrialsandresearchinfrastructures.Orphanet, and its nomenclature is now an internationally recognized standard:International Rare Disease Research Consortium (IRDiRC) awarded Orphanet andORDO IRDiRC Recognized Resource status in 2015. These two resources were alsonamedHumanVariomeProjectRecommendedSystemsin2017.

Relevance torare diseasedrugdevelopment

As far as the second IRDiRC goal is concerned, namely 1000 new therapies for rarediseasestobeapprovedby2027,themajorityofwhichwillfocusondiseaseswithoutapproved options, efficient translation from basic and pre-clinical research to clinicaltrials and therapies discovery is required: “this important goal can be achieved onlythroughadramaticallymoreefficientdevelopmentprocessdrivenbya radicallynewapproach utilising common standards across distinct research fields, sharing of bestpractices, creating sustainable business models, and redefining the regulatoryenvironment.”Orphanetanditsontologicalrepresentation,ORDO,providesacommonlanguage between the healthcare and research field, improving interoperabilitybetweenelectronichealthrecords,codificationsystems,registriesandcohorts,variantdatabases,andbiobanks. InEurope,EuropeanReferenceNetworkshaveadoptedtheORPHA nomenclature for sharing data through their eHealth platform and for theirregistries.

Inaddition,OrphanetdatabaseallowsforanalysisoftheresearchlandscapeinEurope(i.e.identificationoftrendsandgaps)andforidentificationofwheretheresourcesare(i.e.:patientregistries,datarepositories…).

Category RegulatoryBB

AvailabilityDataisRDspecificandavailableforalltypesofpublicsatthefollowingconditions:

• Productspromotingtheinteroperabityofrarediseasedataonwww.orphadata.org:free,openaccess,CCBY4.0

1. Orphanetnomenclatureanddefinitions,classificationsandcross-references

2. Disease-geneannotationsandcross-references3. Disease-phenotypeannotations4. Epidemiological/naturalhistoryannotations5. OrphanetRareDiseaseOntologyandHPO-ORDOOntological

Module(HOOM)• DatasetsrequiringDTAforacademia/feeforindustry:

1. Textualinformation2. Catalogueofexpertservices/ressources3. Orphandrugdata

Geographicalscope

OrphanetdatabaseisbasedattheInserm,inFrance.

Coverage of expert resources include 37 countries


ITEM DESCRIPTION

https://www.orpha.net/orphacom/cahiers/docs/GB/Orphanet_Network_MB_members.pdf

Scopeofuse Academic researchers and the pharmaceutical industry use Orphadata datasets forresearchanddevelopmentpurposes.Examplesofpharmaindustryusecasesincludetheincorporation of Orphadata datasets in pre-competitive tools in order to prioritisetherapiesdevelopment,aswellasepidemiologicaldatatoassessmarketsize.Otherusecases include datamining technology applications to generate hypotheses fromOrphanetdataandtextualinformation.

Subject Academicresearchers,SMEs,pharmaindustry,policydecisionmakers


Anyparticularrequirementforopenaccessdatasets(seeabove)thatareavailablein:• XML• JSON• SparqlEndPoint• Ontology:OWL,txt,obo(andforORDO:

http://bioportal.bioontology.org/ontologies/ORDO(OWL,CSV,RDF/XML)

DTA signature for restricted access datasets (academia, public not-for profitinstitutions);contract(forfee)forprivatefor-profitcompanies.

OutputA public website, www.orpha.net: around30millionpagesviewedin2017,>40,000dailyvisitorsfrom232countriesperday

A download platform (reusable datasets) www.orphadata.org. Orphadataproductsweredownloadedmorethan212,000times,withanaverageof17,690timespermonthin2017.

Ontologies:ORDO(downloaded7,137timesin2017)andHOOM,launchedin2017(availableatorphadata.org)

Actors andStakeholders

Funders:Public:Inserm,FrenchMinistryofHealth,EuropeanCommission,AgencedelaBiomédecine,Ministriesofhealth,universitiesandhospitalsinthecountriesoftheOrphanetnetwork;Private:AFM-Téléthon,FondationGroupamapourlaSanté

Pharmacompaniesandbio-techsusingfor-feedata

Academic researchers, public administrations and Patient organisations: using theopenaccessdatasets

Health professionals, patients, researchers, students, decision makers (Orphanetwebsiteusers)


ITEM DESCRIPTION

Use Epidemiologicaldata:determinationofthesizeofthemarketpergeographicalregion

Recruitment, collaborations: identification of experts, patient organisations,registries, biobanks, research groups developing i.e. animal models, biomarkers,targets,etc,bydisease/groupofdiseases.

Pre-competitive tools: integration with other sources of data, including privatepharmadata,togeneratehypothesis.

PROs/advantages

Computable structured data, manually curated, organized hierarchically (thusallowingforclusteringandaggregationofdata)anddescribedwithuniqueidentifiers.Numerouscross-referenceswithotherrelevantresources(genefunction,pathways,compoundsandtargets,…)

Versioninganddifferentialsforopenaccessdata.Documentationprovided.

Anumberchannelsareavailable tohelpuserswishing toaccessandre-useOrphanetdata. Firstly, there is a contact form on the Orphadata website(http://www.orphadata.org/cgi-bin/contact.php) as well as a dedicated [email protected],witha24hourfirstresponsetimeduringofficedays.AFAQanduser guide is alsoavailable. In addition, there is anORDOusermailing list (ordo-users.orphanet)todeliverupdatesconcerningtheontology.

CONs/risks Dataset formatsarestandardizedandon-demand,customizeddatasetsasaservicearenotyetdeveloped(butwillbe)

APIsindevelopment,notyetavailable.

Hands-on assistance can be necessary to make the best use of the resource (asprovenbytheOrphanetparticipationtothetrainingcoursesorganizedbyISSforRDregistries:BYOD (RD-Connect/Excelerate). Not already available as a service, but indiscussion.

Best time toapply

N/A(Comment:theanswerdependsonthepurposeforwhichthedatabasecontentisused;wecanprovidemoreexplanationsifneeded)

Duration DTAorfor-feecontractsareone-yearinduration,re-conductible.

Free, open-access data can be accessed at any time and are monthly updated in


ITEM DESCRIPTION

Orphadata.

Cost Opendatasetsareforfree.

For fee datasets (for for-profit organisations) are here:http://www.orphadata.org/cgi-bin/img/PDF/Catalogue_Orphadata_2018.pdf

(Thecatalogwillbeupdatedin2019,inparticular:epidemiologicaldatawillbecomeopenaccess)

Practicaltips ThiscanincludeDOsandDON’Tsandstrategicconsiderations.

Ana Rath � 9-12-18 20:02Opmerking [1]: Needclarificationtoanswerthisitem.



BuildingBlockI410


ITEM DESCRIPTION


NCATSandNHGRIGeneticandRareDiseasesInformationCenter(GARD)

References

https://ncats.nih.gov/gard

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

Description

TheGeneticandRareDiseases InformationCenter (GARD) isaprogramoftheNationalCenter forAdvancingTranslational Sciences (NCATS) and is fundedby twopartsof theNational Institutes of Health (NIH): NCATS and the National HumanGenome ResearchInstitute(NHGRI).GARDprovidesthepublicwithaccesstocurrent,reliable,andeasy-to-understand information about rare or genetic diseases their families, health careproviders,researchers,andthepublicinEnglishorSpanish.

It provides accurate, up-to-date information about ongoing research, symptoms,treatment options, and other details. Sources for GARD and other hard-to-findinformation include the National Library of Medicine, scientific conferences, supportgroups,andclinicaltrialsandresearch.

Category DevelopmentResourceBuildingBlock

Geographicalscope

International


Availability


Scope ofuse

Foundationalinformationandlinkstodatasourcesorganizedbydisease.

Accesstothewebsiteandtofindappropriateinformationbydisease.

Stakeholders

• AnyDeveloper

• NIH

• National Center for Advancing Translational Sciences (NCATS) and NationalHumanGenomeResearchInstitute(NHGRI)


Internetaccesstoresourcesandinformation.

Output Disease-specificinformationandresources


The tool is best to access early on in development to get full view of research andactivitiesinthedisease-specificspace.

Experttips

Ifyoucan’tfindtheinformationyouneedontheGARDwebsite,callorwritetoGARD,andtheInformationSpecialistswillansweryourquestions.

E-mail form: https://rarediseases.info.nih.gov/about-gard/contact-gardWebsite: http://rarediseases.info.nih.gov/



BuildingBlockI411


ITEM DESCRIPTION


CodingofRareDiseases:Orphanetnomenclature

References

Downloadablenomenclatureandrelatedresourceshere:http://www.orphadata.org/cgi-bin/rare_free.htmlSOPsforproducingthenomenclaturehere:http://www.orpha.net/orphacom/cahiers/docs/GB/eproc_disease_inventory_PR_R1_Nom_04.pdfhttp://www.orpha.net/orphacom/cahiers/docs/GB/Orphanet_ICD10_coding_rules.pdfhttp://www.orpha.net/orphacom/cahiers/docs/GB/eproc_Disease_naming_rules_in_English_PR_R1_Nom_01.pdfhttp://www.orpha.net/orphacom/cahiers/docs/GB/eproc_Rare_disease_Nomenclature_Production__national-language.pdfStandardprocedureandguideforcodingwithOrphacodeshttp://www.rd-action.eu/wp-content/uploads/2017/05/D5.2_Standard-procedure-and-guide_final.pdfRecommendationforroutinemaintenancehttp://www.rd-action.eu/wp-content/uploads/2018/09/677024_DEL5.5_Recommendation-routine-maintenance-codification.pdf

State-of-Art of codification and Tool specifications here: http://www.rd-action.eu/leaflet-and-documents/

Description

TheOrphanetnomenclatureofRDcomprisesthelistofrareclinicalentities(<1/2000inprevalence;<5/10000accordingtoRegulation141/2000)definedbyanORPHAnumber(the Orphacode) unique and stable over time, a preferred term, exact synonyms, atypology (category, group of disorder, disorder (including: disease, malformationsyndrome, clinical syndrome, morphological anomaly, biological anomaly, particularclinicalsituation),sub-typeofdisorder(includingclinical,etiologicalandhistopathologicalsubtypes)), and a definition. Orphanet nomenclature is provided as a flat list and as amulti-hierarchical classification system. It is also providedwith semantic alignments to


OMIM,ICD10,MedDRA,MeSH,UMLS,GARD,andmappingfileswithICD11andSNOMEDCTareunderdevelopment.

The European Commission Expert Group on Rare Diseases has also promoted theinclusionofORPHAcodesinhealthinformationsystems(“RecommendationonWaystoImproveCodificationforRareDiseasesinHealthInformationSystems”2014).

TheOrphanetnomenclature is annotatedwithgenes (gene-disease relationships) (withgenesbeingalignedtoHGNC,OMIM,andotherresources),aswellaswithphenotypes(HPO terms), and disability-related terms (controlled vocabulary derived from WHO’sICF). These annotations are semantic (qualified) and computable as xml and JSONformatsandasOWLandoboformats:theOrphanetRareDiseasesOntology(ORDO)andtheHPO-ORDOontologicalmodule(HOOM)fromOrphadata.org

Orphanet nomenclature is released monthly as xml and JSON files in 9 languages,together with obsolete and deprecated entities and their corresponding active codes.DifferentialsbetweenmonthlyversionscanberetrievedandcomputedintheOrphanetGitHubhttps://github.com/Orphanet/Orphadata.org

Finally,documentation isprovided (User’sguides,procedures)both inOrphanetand inOrphadata.


Geographicalscope

International

Availability

Applicantsdevelopingmedicinesforrarediseases.

Scope ofuse

BeingabletoidentifyRDpatientsinhealthcaresystemsshouldspeedrecruitment,andaspecific RD codification is therefore a key step toward this aim. RD are poorlyrepresentedinanyothermedicalterminologyforuseinhospitals.Orphacodeshavebeenrecognized a best practice by the SGPP (Steering Group for Promotion of health andPrevention of non-communicable diseases) and EU funding is dedicated to fasten theimplementationinEUMS.OrphacodesareincreasinglyadoptedinEUcountries,aswellas in Australia, Japan andArgentina. Chinawill also adopt it and translationswill startsoon. Orphacodes are adopted in ERNs CPMS and in RD registries and biobanksprogressively. The use of Orphacodes is also recommended in the Common DataElementsdefinedbytheJointResearchCenter(JRC)whenbuildingaregistryforRD. Italso constitutes the core of RD representation in aggregated ontologies like MONDO(Monarchinitiative).InuseinhealthcareandinresearchtheadoptionofOrphacodesas


a standard codification system for RD increases semantic interoperability betweenresourcesandthereforeimprovesdatasharingandexchange.

CountriesthatuseORPHAcodestocoderarediseasepatients(asofMay2017)-Source:http://www.rd-action.eu/wp-content/uploads/2017/09/2017-09_RD-ACTION-implementation-coding-survey2.pdf

Stakeholders

• Funders:

o Public:Inserm,FrenchMinistryofHealth,EuropeanCommission,AgencedelaBiomédecine,Ministriesofhealth,universitiesandhospitalsinthecountriesoftheOrphanetnetwork;

o Private:AFM-Téléthon,FondationGroupamapourlaSanté

• Users:

o Health information systems (ex DIMDI in Germany, BNDMR in France)andregistries(ex:Venetoregistry)

o Pharmacompaniesandbio-techs

o Academicresearchers,publicadministrationsandPatientorganisations


o Health professionals, patients, researchers, students, decision makers(Orphanetwebsiteusers)

o EuropeanReferenceNetworks:bothusingandcontributingtoOrphanetdata.


Anyparticularrequirementforopenaccessdatasets(seeabove)thatareavailablein:• XML• JSON• SparqlEndPoint• Ontology:OWL,txt,obo(andforORDO:

http://bioportal.bioontology.org/ontologies/ORDO(OWL,CSV,RDF/XML)

Tutorials were developed to support the use of Orphanet nomenclature: OrphanetTutorialschannel–WhatistheOrphanomenclature

Output AnomenclatureandclassificationsofRDaccessibleattheOrphanetwebsite(www.orpha.net),asaflatlistinPDFformatupdatedtwice/year(https://www.orpha.net/consor/cgi-bin/Education_Home.php?lng=EN),andasdowloadableformats(XML,JSON)inOrphadata(www.orphadata.org),updatedthe1stdayofeachmonth.

AnontologyofRD:Orphanetrarediseasesontology(ORDO)updatedtwice/year(OWL,txt,obo)availableatorphadata.organdonhttp://bioportal.bioontology.org/ontologies/ORDO(OWL,CSV,RDF/XML)


N/A

Experttips

PROs:

− Computable structured data, manually curated, organized hierarchically (thusallowing for clustering and aggregation of data) and described with uniqueidentifiers. Numerous cross-references with other relevant resources (genefunction,pathways,compoundsandtargets,…).

− Versioninganddifferentialsforopenaccessdata.Documentationprovided.

− A number channels are available to help users wishing to access and re-useOrphanet data. Firstly, there is a contact form on the Orphadata website(http://www.orphadata.org/cgi-bin/contact.php) as well as a dedicated [email protected],witha24hourfirstresponsetimeduringofficedays.


AFAQanduserguideisalsoavailable.Inaddition,thereisanORDOusermailinglist(ordo-users.orphanet)todeliverupdatesconcerningtheontology.

CONs:

− APIsindevelopment,notyetavailable.− Hands-onassistancecanbenecessarytomakethebestuseof theresource (as

provenbytheOrphanetparticipationtothetrainingcoursesorganizedbyISSforRDregistries:BYOD(RD-Connect/Excelerate).Notalreadyavailableasaservice,butindiscussion.

ODDG–BuildingBlockI412–Version11


BuildingBlockI412


ITEM DESCRIPTION

BuildingBlock(BB)Title Decentralizedtrials

References https://www.fda.gov/NewsEvents/Speeches/ucm629942.htm

SommerC,ZuccolinD,ArneraV,SchmitzN,AdolfssonP,ColomboN,GilgR, McDowell B. Building clinical trials around patients: Evaluation andcomparison of decentralized and conventional site models in patientswith low back pain. Contemp Clin Trials Commun. 2018 Jun 28;11:120-126.

https://www.imi.europa.eu/sites/default/files/uploads/documents/apply-for-funding/future-topics/IndicativeTopic_RemoteTrials.pdf

https://www.ctti-clinicaltrials.org/sites/www.ctti-clinicaltrials.org/files/dct_recommendations_final.pdf

Description One of the identified key barriers to patients’ participation in trials isgeographyandthedistancetotheclinicalsite,aswellastheburdenthatparticipationrepresentstopatients,includingthedurationandnumberofclinical visits.Decentralized trials aim to improvepatient access to trialsbyenablingpatientfollow-upfromhomeorcommunitycare,increasetheparticipationofmorediversepopulations,andenhancingdatacollectionby combining the adoption of digital endpoints and telemedicine asapplied to trials. To that purpose, web-based platforms, tele-health,online patient diaries, e-informed consent programs, patient apps,wearablesandsystemsadaptedtocapturedata fromelectronicmedicalrecords are used to collect clinical information in the setting of clinicaltrials.

TheEuropeanMedicinesAgencyhasidentifiedamongstitsstrategicgoalsfor2025 todevelop the regulatory framework foremergingclinicaldata


ITEM DESCRIPTION

generation. The specific goals include to develop methodology toincorporate clinical care data sources in regulatory decision-making, tomodernize theGCP regulatoryoversight to enabledecentralizedmodelsof clinical trials coupled with direct digital data accrual, to develop thecapability to assess complex datasets captured by technology such aswearables, and to facilitate training and understanding of healthcareprofessionals and patients to access and participate effectively in suchtrials. However, the approval of all the clinical trials still under theresponsibilityoftheNationalCompetentAuthorities(NCA).

Similarly, theFDAhas identified theusedofdecentralized,or virtual, orpatient-centric clinical trials as a key development step that wouldfacilitaterecruiting,enrollingandretainingparticipants inclinicalstudies(I.e.,amajorchallengeandcostforstudysponsors).FDAhasestablisheda formal working group on decentralized trials that is responsible fordevelopingtheguidancefurtheroutliningtheseapproaches.

Category DevelopmentPracticesBuildingBlock

Geographicalscope International.

(TheBBisbasedontheavailabilityofinternetandthepotentialofremotevirtualconnection,thusisavailableglobally).

Availability There are a number of previous experiences in development, and toolsandcompaniesspecializedindifferentaspectsofdecentralizedtrials,andprojects focused on the subject. https://www.ctti-clinicaltrials.org/projects/decentralized-clinical-trials

These initiatives are particularly important in assessing rare diseasetherapies affecting small patient populations. The extremely lowprevalenceofcertainrarediseasesconditionthatpatientsarescarceatagivensite,aregeographicallydisperse,andmayhavedifficultiestoreachthe reference sites for trial participation. Long traveling for frequentvisiting,requiredforclinicaltrials,representsaburdenforfamiliesandabarrier to participation. Also, international trials with many centersrequire a high investment for setting up, and are costly in terms ofmonitoring.Theuseofinformationtechnologiesmayenableinternationalcollaborations of sites regardless of their distance, ease access to trialparticipation of bigger number of patients, and remove barriers torecruitmentandvisitpatientslivingfarfromthereferencesites.


ITEM DESCRIPTION

Also,theuseofwearables,appsandtoolsforcollectingpatientreportedoutcomesmayenabletoenrichclinicalinformationbycollectingpatient’sinput on the benefits and risks of experimental treatments as a part ofclinicaltrialdata.

Scopeofuse TheBBcanbeusedatthetimeofstudyplanninganddesign,asatooltomanage practical issues related to the burden of visits, the duration ofvisits or those derived from the lack of access to geographically distantresources.

Stakeholders Sponsors of clinical trials, clinical researchers and networks of clinicalresearchers, patients and patient’s associations, members of Ethic’sCommittees,regulatoryauthorities.


The BB may be considered in any clinical situation characterized bygeographical dispersion of patients and/or clinical sites where thedecentralizationofthetrialmaybeofbenefittoensureitsfeasibility.

Output A clinical trial design andprotocol that involvesmany sites and settingsfortheconductionofthestudy,withvariabledegreesofimplementationof remotedata capture for theassessmentofefficacy, safety,qualityoflife or other relevant parameters, that may involve telemedicine andvirtual visiting, applications, electronic records, wearables, web-baseddatacaptureorothertools.

Best time to apply andtimewindow

Bythetimeofplanningaclinicaltrialinrarediseases.Theapproachmaystartbeforeoratthetimeofplanningaclinicaltrial.

Experttips Anumberofrecommendationscanbefoundinrelevantliterature:

https://www.ctti-clinicaltrials.org/sites/www.ctti-clinicaltrials.org/files/dct_recommendations_final.pdf

The process should begin early at the time of clinical trial planning, byconsidering thepotential settingof thestudy tobewidened froma fewsites to a broader setting including smaller sites / primary care / othersettings, and the number of visits that require physical attendance vsthosethatcanbesupportedbytheuseofremoteorvirtualsystems.

Theextentof applicationoruseof anywebbased tools, apps, orothersystems should be considered early in the development to allow for


ITEM DESCRIPTION

design and validation if required, and checking of acceptability forregulatorypurposes should includenotonlyethic’s committeesbutalsoregulatoryauthoritiesthroughscientificadviceprocedures.Issuessuchasaccuracy and sensibility, robustness and privacy secureness must beproperly addressed. Any tools used during the trials will requiredevelopment, validation, setting up and training, and also a strong usersupportduringthetrialconduction.

PROs:

DCTs using telemedicine and other emerging and novel informationtechnology(IT)servicesofferthepotentialforlocalHCPstoparticipateinclinical trials. This may provide several advantages compared totraditionalclinical trialsconductedatmorecentralizedclinical trial sites,includingthefollowing:

• The use of web-based systems for randomization may ease theconnection of several sites that are physically distant into a singletrial,andmaybeusefultoreducebarriersandcostsof internationalmultisiteclinicalresearchinsmallpopulations.

• Also,theuseofremotemonitoringtechnologiesmayalsoreducetheneed for traditional on-site monitoring of each clinical site, whileassuring the integrity of data needed to assess patient safety andproductefficacy.

• Apotentialbenefitwouldbetoreduceadministrativeandeconomicburdensonsponsorsandinvestigators,whilealsopermittingpatientsto receive treatments from community providers withoutcompromisingthequalityofthestudyortheintegrityofdata.

• Otherpotentialbenefitsmayinclude:

o Fastertrialparticipantrecruitment.

o Improved trial participant retention, which may reducemissingdata,shortenclinicaltrialtimelines,andimprovedatainterpretability.

o Greater control, convenience, and comfort for trialparticipantsbyofferingat-homeorlocalpatientcare.

o Increaseddiversityofthepopulationenrolledinclinicaltrials.

Anopportunity forhomeadministrationorhomeuseof the IMP,which


ITEM DESCRIPTION

may be more representative of real-world administration/use post-approval.

CONs:

• Decentralized trials may be challenging for coordination, sincedispersionofsitesandanincreasednumberofinvestigatorsopenthe room for heterogeneity in interpretation or application ofstudyprotocols.

• Simplerdesignsarerequiredthatensurecoherence.

• Smaller human contact across the team and lower physicalpresencemay require stronger systems to ensure robustness ofmethods.

• Special attention should be paid to the treatment supply chain,sincedecentralizedtrialsmayposechallengestothedistribution,control and traceability of investigational medicinal products –theissueislessworrisomeiftrialmedicationisalreadyapproved.

• Adeepunderstandingof thedata is needed; understandhow itmaybepresentedandhowitshouldbeanalyzedtoavoiderrorsor use of frail, biased or inaccurate information for decisionmaking.

• Guidelines on standards and validation of data and tools areneededtoensuretheyarerobustenoughforregulatorydecision-making.

• Securemechanismstoprotectpatientconfidentiality in linewithdata protection legislation will be critical for securing patienttrust.

• Apps and software can also pose potential risks. A flexible, risk-basedframeworkthatprotectspatientswithoutblockingadvanceof digital health will be required, that provides the necessaryguarantees.



BuildingBlockI413


ITEM DESCRIPTION


UseofBiomarkersinOrphanDrugDevelopment

References

FDAAcceleratedApproval(surrogateendpoint):

https://www.fda.gov/drugs/resourcesforyou/healthprofessionals/ucm313768.htm

FDABiomarkerQualificationProgram:

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/default.htm

FDA/NIHBEST(Biomarkers,EndpointS,andotherTools)Resource:

https://www.ncbi.nlm.nih.gov/books/NBK326791/

FDARareDiseaseGuidance:

https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM458485.pdf

Qualificationofnovelmethodologiesfordrugdevelopment:guidancetoapplicants

https://www.ema.europa.eu/documents/regulatory-procedural-guideline/qualification-novel-methodologies-drug-development-guidance-applicants_en.pdf

Description

Biomarkers can be utilized as primary surrogate endpoint as a basis for acceleratedapproval(US),andassecondaryorexploratoryendpointsfordrugmechanismofactionoraspectsofsafetymonitoring.


For Europe, see BB# 110 on “EMA Qualification of novel methodologies for medicinedevelopment”.


Geographicalscope

International

Availability


Scope ofuse

This BB provides specific guidance regarding the different ways (contexts of use) thatbiomarkers may be incorporated into clinical trial designs in regulatory programs fordrugsusedtotreatpatientswithrarediseases.

It helps drug developers consider the incorporation of biomarkers into their trials inmultiple contexts of use, including patient selection (diagnostic), demonstration that adrug ishitting the target (pharmacodynamic),asa reasonably likelysurrogateendpointfor acceleratedapproval (FDA, JP), as in indicatorof drug toxicity (reflectiveof safety),and as a validated and qualified surrogate endpoint used in place of a primary clinicaloutcome measure to support market approval (reflective of efficacy). DifferencesbetweenFDAandEMAwillbehighlightedwhentheyexist,andthepathtoavalidatedsurrogatebiomarkerwillbeoutlined.

Stakeholders

• Drugdevelopers

• Regulatoryagencies

• Patientsandcaregivers

• Foundation/not-for-profits


None

Output Atooltoincorporatebiomarkersintoclinicaltrialdesign.

Best Thetoolhasitsbestuseattrialplanningstages.


time toapplyand timewindow

Experttips

Presentearlyplantoregulatoryagency.Pre-specifybiomarkersasprimary,secondaryorexploratory outcomes, with specific context of use identified. Be prepared to defend,withdata,whyyourbiomarkerisfitforthestatedpurpose.

PROs:

− A biomarker can serve as a surrogate endpoint and thus expedite time toapprovalviaAcceleratedApprovalpathways(USA,JP)

− Aqualifiedbiomarkerbridgedtolaterclinicaloutcomesmayserveasasurrogateendpointinanyapprovalpathway,andthusexpeditedrugapproval(US)

− Anexploratorybiomarkerindicatingadrughittingitsdesignatedtargetmayaiddoseselectionindose-rangingstudies,andinearlyde-riskingofanorphandrugprogram.

− Implementation of biomarkers in clinical trials can provide objective endpointsnot subject toplaceboeffect,and thusbolsteringclinical findings inearlyopenlabelclinicaltrials.

− Biomarkers can augment clinical trial design, increasing efficiency of trials,enables performance of smaller, early-phase, proof-of-concept studies inpatients,improvesafetymonitoring.

CONs:

− Itisquitechallengingtoobtainqualificationfornewbiomarkers.− MaynothaveconcordancebetweenEMA/FDA/JPonbiomarkercontextofuse,

andfitforpurpose.− If thebiomarker isa surrogateprimaryendpoint, thenmethoddevelopment,a

method validation plan, and method validation data should be presented toregulatorsforacceptancepriortotestingclinicaltrialsamples.



BuildingBlockI414


ITEM DESCRIPTION


Patientsurveys/PatientPreferencesstudies/Ethnographicresearch

References

https://www.imi-prefer.eu

https://www.fda.gov/media/92593/download

Description

Qualitative or quantitative assessments of the relative desirability or acceptability topatients of specified alternatives or choices among outcomes or other attributes thatdifferamongalternativehealthinterventions.

Patientpreference studiesmaybeparticularlyuseful inevaluatingadrug’sbenefit-riskprofile when patient decisions are “preference sensitive.” Patient decisions regardingtreatmentoptionsarepreferencesensitivewhen:

1)multipletreatmentoptionsexistandthere isnooptionthat isclearlysuperiorforallpatients;

2) when the evidence supporting one option over others is considerably uncertain orvariable;and/or

3)patients’viewsaboutthemostimportantbenefitsandacceptablerisksofadrugvaryconsiderablywithinapopulation,ordifferfromthoseofhealthcareprofessionals.



Geographicalscope

International

Availability


Scope ofuse

Patientpreferencestudiescanbeusefulduringregulatorybenefit-riskassessmentforcertaindrugsinseveralmajorways,including:

1)tohelpidentifythemostimportantbenefitsandrisksofadrugfromapatient’sperspective(includingtoinformselectionofprimaryorsecondaryendpoints);

2)toassesstherelativeimportancetopatientsofdifferentattributesofbenefitandrisk,andclarifyhowpatientsthinkaboutthetrade-offsofthesebenefitsandrisksforagivendrugs(includingtoinformminimumclinicallyimportantbenefitandeffectsize);

3)tohelpunderstandtheheterogeneityordistributionofpatientpreferencesregardingbenefitsandrisksofvarioustreatmentoptions(includingtoinformpatientsubgroupconsiderationsaspartofbenefit-riskassessments).

Thespecificroleofquantitativepatientpreferencestudiesaretoprovideestimatesofhowmuchdifferentoutcomes,endpointsorotherattributesarevaluedbypatients,andthetradeoffsthatpatientsstateordemonstratetheyarewillingtomakeamongthem.

Stakeholders

• EMA,FDAand/orMHLW

• Drugdevelopers

• Patientorganisations

• Reimbursementagencies


Earlycontactwithpatientorganizations.

OutputA report on the outcomes of the preferences of patients regarding treatment options,thatcanbeusedfordifferentpurposes,suchasregulatoryorpayer’sassessment.

Besttime toapplyand time

The tool may be used at several stages during drug development, therefore an earlydevelopmentisrecommended.


window

Experttips

Patient preference studies may not be relevant or appropriate for all drug types.Submissionofpatientpreferencestudiestoregulatoryagenciesisvoluntary.



BuildingBlockI415


ITEM DESCRIPTION


DevelopmentanduseofPatient-CentredOutcomesMeasures(PCOMs)

References

OrphanetJRareDis.2017Nov2;12(1):171:https://ojrd.biomedcentral.com/articles/10.1186/s13023-017-0718-x

https://link.springer.com/chapter/10.1007/978-981-10-4068-9_9

USFDAGuidance(2009)onPatient-ReportedOutcomeMeasures:https://www.fda.gov/downloads/drugs/guidances/ucm193282.pdf

US FDA Draft Guidance (2018) ‘Select, Develop or Modify Fit-for-Purpose ClinicalOutcomes Assessments’:https://www.fda.gov/downloads/Drugs/NewsEvents/UCM620708.pdf

Description

Despitegrowingacceptancethatpatientshavetheclearestviewofthehealthoutcomesthatmatter, the success (or failure) of themajority of rare disease drug developmentprogrammesrestsonsurrogateoutcomes(e.g.laboratorymeasures,organsize)thatmaynotreflecttreatmentbenefitsthatpatientsvalue.

Patient-CentredOutcomesMeasures(PCOMs)arequestionnairesthat‘directly’quantifythe impactof adiseaseand treatmentonhealthoutcomes thatmatter topatients (asidentified or affirmed by patients themselves, or their caregivers). PCOMs embrace allforms of clinical outcome assessments, namely ‘patient-reported outcome’ (PRO),clinician-reported (ClinRO), observer-reported (ObsRO) and performance outcome(PerfO)measures.Ideally,PCOMsshouldbeco-createdwithpatients.

Atpresent,appropriateand fit-forpurposePCOMsdonotexist formost rarediseases,andtheirusehasbeenlargelyomittedacrossthemedicalandresearchcommunity.


PCOMs are tools to translate care or observed treatment effect into an ‘interpretable’measureofpatientbenefit,andtherebyhelpdemonstrateclinicaleffectiveness.


Geographicalscope

International

Availability


Scope ofuse

PCOMsare tools that seek tounderstand thepatient’sperspectiveanddaily impactoftheir disease to better adapt therapies, whenever available. PCOMs may be used forseveral purposes, such as: efficacy endpoints in clinical trials, outcomes measures inregistries, guides to treatment choices fordaily care,or tools tomonitor caredelivery.PCOMsbringvalueacrossallhealthcarestakeholdersinvolved,asillustratedbelow.

The use of PROMs in the development of RD products is to enhance the ability ofresearcherstounderstandtheeffectofnewmedicinesandtheirimpactonthepatient’sdailylife.

Stakeholders

• Networkofpatients/patient’sgroups

• Healthprofessionals


• Researchers

• Drugdevelopers


Generating an extensive amount of patient evidence and of psychometric data isrequiredtodevelop/establishtheuseofaPCOM.

Multi-stakeholdercollaborationandtheconductofscientificadvice(withregulatoryandhealthtechnologyassessmentbodies)arehighlyrecommendedtopromotethescientificrationaleanduseofaPCOM.

WhendevelopingaPCOMdenovo, it is recommendedtoseek regularscientificadvicefromregulatorybodies.QualificationofanewPCOMmayalsobesought(e.g.USFDA’sDrugDevelopmentToolQualificationPrograms).

Output A PCOM is a tool aimed to better capture the patient experience and tomeasure theoutcomesthatmattermosttopatients.


Thetoolhas itsbestuseatasearlyaspossibleduringclinicaldevelopment.Developingand testing a patient-centred outcomes measurement strategy takes time thereforeactivitiesshouldinitiateasyoustartplanningphase1clinicaltrial.

Experttips

ManyPCOMsaregenericandnottailoredtothespecificsofindividualrarediseases.Itisbest to identify whether a PCOM is available and usable in early phase clinical trials,becauseiftheyarenot,developinganewPCOMoradaptingaPCOMandthenvalidatingit,willrequiretimeandresources.

PROs:

− PCOMsgenerate interpretabledata for thedemonstrationof treatmentbenefitinpatients.

CONs:

− PCOMdevelopmentisatime-andresource-intensiveactivity.



BuildingBlockI416


ITEM DESCRIPTION


CompanionDiagnostics

References

https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf

Description

A companion diagnostic is a medical device, often an in vitro device, which providesinformation that is essential for the safe and effective use of a corresponding drug orbiological product. The test helps a health care professional determine whether aparticular therapeuticproduct’sbenefits topatientswilloutweighanypotentialserioussideeffectsorrisks.

Companiondiagnosticscan:

− identify patients who are most likely to benefit from a particular therapeuticproduct;

− identifypatientslikelytobeatincreasedriskforserioussideeffectsasaresultoftreatmentwithaparticulartherapeuticproduct;or

− monitor response to treatment with a particular therapeutic product for thepurposeofadjustingtreatmenttoachieveimprovedsafetyoreffectiveness.



Geographicalscope

International

Availability


Scope ofuse

Drug developers often develop drugs for a specific subtype of patients based onparticulargeneticormolecular features.Drugs indevelopment thatare intendedtobeused in a biomarker-defined subtype of patientsmay require a companion diagnostic.Companion diagnostics are tests that provide information essential for the safe andeffective use of a corresponding drug. Therefore, if the drug is likely to only have afavorable benefit-risk profile in a biomarker-defined subtype of patients, the drugdevelopershouldconsiderdevelopingacompaniondiagnosticearlyinthedevelopment.

Stakeholders

• Drugdevelopers

• FDA


Notapplicable

Output DiagnosticTool


Thetoolhasitsbestuseattheearlyphasesofdevelopment.

Experttips

Companion diagnostics enable personalised medicine by analysing a patient’s DNA todetermineiftheirgeneticsareamatchforagivendrug.

Inmostcircumstances, ifuseofan invitrocompaniondiagnosticdevice isessentialforthesafeandeffectiveuseofatherapeuticproduct,theIVDcompaniondiagnosticdeviceandtherapeuticproductshouldbeapprovedorclearedcontemporaneouslybyFDAfortheuseindicatedinthetherapeuticproductlabelling.



BuildingBlockI417


ITEM DESCRIPTION


Developmentofproductspecificbio-analyticalassays

References

https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf

https://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf

https://www.nihs.go.jp/drug/BMV/index.html

Description

Measurement of drug concentrations in biological matrices (such as serum, plasma,blood, urine, and saliva) is an important aspect of drug development. Thesemethodsprovidedatatosupportthesafetyandeffectivenessofdrugs,whichmaybeneededtosupport applications for new drugs in regulatory pathways. The results of animaltoxicokinetic studies and of clinical trials, including bioequivalence studies are used tomake critical decisions supporting the safety and efficacy of a drug. It is thereforenecessary that the applied bioanalytical methods used are well characterized, fullyvalidatedanddocumentedinordertoyieldreliableresults,andtobeusedinregulatoryprocesses.

Thebioanalyticalassayscouldbechromatographicassaysandligandbindingassaysthatquantitativelydeterminethelevelsofdrugs,theirmetabolites,therapeuticproteins,andbiomarkersinbiologicalmatrices.


Geograp International


hicalscope

Availability


Scope ofuse

Validatingtheanalyticalmethodensuresthatthedataarereliablebyaddressingcertainkeyquestions,including:

• Does the method measure the intended analyte? For example, does anythinginterferewiththemeasurement,and isthemethodspecificorselectivefortheanalyte?

• Whatisthevariabilityassociatedwiththesemeasurements?Forexample,whataretheaccuracyandprecisionofthemethod?

• What is the range in measurements that provide reliable data? For example,whatisthesensitivityofthemethod(e.g.,whatisthelowerlimitofquantitation(LLOQ)of themethod, andwhat is theupper limit of quantitation themethod(ULOQ)?)

• Howdosamplecollection,handling,andstorageaffectthereliabilityofthedatafrom the bioanalytical method? For example, what steps need to be followedwhile collecting samples? Do the samples need to be frozen during shipping?What temperatures are required to store the samples, and how long can thesamplesbestored?

Stakeholders

• EMA,FDAand/orMHLW

• Drugdevelopers


Pivotal studies submitted inanapplication that requires regulatorydecisionmaking forapproval, safetyor labeling, suchasbioequivalenceorpharmacokinetic studies, shouldincludebioanalyticalmethodsthatarefullyvalidated.Exploratorymethodsthatwouldnotbeusedtosupportregulatorydecisionmaking(e.g.,candidateselection)maynotrequiresuchstringentvalidation.

OutputAwell-documented, reliable, andoptimizedbioanalyticalmethod, that canbeused forvalidationandissuitedfortheanalysisofstudysamples.Adetailed,writtendescription(e.g.,protocol,studyplan,and/orstandardoperatingprocedure(SOP))shouldhavebeenestablished for the bioanalytical method before initiating validation. The descriptionshould identify procedures that control critical parameters in the method (e.g.,environmental,matrix,proceduralvariables) fromthetimeofcollectionof thesamplestothetimeofanalysistominimizetheireffectsonthemeasurementoftheanalyteinthematrix.

Besttime to

The tool may be used at several stages during drug development, therefore an early


applyand timewindow

developmentisrecommended.

Experttips

GeneralandspecificSOPsandgoodrecordkeepingareessentialtoaproperlyvalidatedanalytical method. The data generated for bioanalytical method development and/orvalidationshouldbedocumentedandavailablefordataauditandinspection.



BuildingBlockI418


ITEM DESCRIPTION


NaturalHistoryStudies

References

PAVINP.Exp.Opin.Orph.Drugsvol.32015

Description

Natural histories studies are a major issue in Rare Diseases research. RDs arecharacterizedbyavarietyofphenotypesandseverityinsidethesamegeneticcondition.

ANaturalHistory istheunderstandingofadiseaseprogressionthroughoutthe lifespanof a patient. The collection of data from a significant number of patients affected bydiverse phenotypes inside the same condition contribute to describe the history of adisease.

Natural histories studies may help to address the special needs of the Orphan DrugDevelopment Process and the approval of Orphan Drugs. The understanding of thedevelopmentandprogressionofdiseaseswillhelpinunderstandinghowtherapiesmayimpact the progression of the disease delaying it or stopping it. The knowledge of thenaturalhistoriesofdiseasehelpthepolicymakersandthepayerstobetterevaluatehowtosustainorphandrugs.

At present, natural histories are most of the time build with scarce data due to thereducednumberofpatientsdiagnosedatdifferentages,delay inthediagnosiswhichispreventingtogeneratedatafrombirthtothediagnosis,differentmanagementprotocolsand availability of therapies. In fact, the availability of therapies in EU countries ischangingthenaturalprogressionofthedisease,forthisreasonnaturalhistoriesstudies


cannot be performed in countries where Orphan Drugs are reimbursed. However, thelack of proper natural histories is the cause of controversy for the reimbursement oforphandrugs.


Geographicalscope

International

Availability


Scope ofuse

− Tofollowtheprogressionofthediseasefrombirthfortheentirelifespanofthepatient

− Todescribethedifferentphenotypesofadisease− Tounderstandtherealimpactoftherapiesatdifferentmomentsofthediseases− Togeneratebetterguidelinesregardingthemanagementofpatients− Toperformbettergeneticandclinicalcounsellingregardingtheprognosisofa

raredisease− Tohelpthepolicymakerandpayerstobetterdecidethereimbursementand

sustainabilityofOrphanDrugs− Tohelppolicymakersandpayerstobetterunderstandtheimpactofreimbursed

drugs

Stakeholders

• Healthcareprofessionals

• Pharmaceuticalindustries

• Patientorganizations

• Policymakersandpayers


Enablers: ERNs representatives, Patients Organization and Pharmaceutical Industries,PolicyMakersandPayers.

Requirements:

• Inform(e.g.howtoperformaclinicalhistorystudy);

• Consult(written–e.g.surveys);

• Consultandinvolve(direct interactions–e.g.stakeholdermeetings,workshops,stakeholderconferences);


• Cooperate/participate(directinteractions-e.g.technicalexpertgroups)

Output Report on the situation of natural history studies with case reports. Generation ofrecommendationregardingthemethodstogeneratenaturalhistorystudies,generationofcollaborativeagreementforthegenerationofnaturalhistory.


Thetoolhasitsbestuseasearlyaspossibleatthebeginningofthedevelopment.

Experttips

PROs:

− Earlydiagnosis,generationofdatarelevanttotheunderstandingoftheevolutionand different phenotypes of rare diseases, generation of useful data to betterunderstandtherealsafetyefficacyandefficiencyoftherapies,generationofdatausefeulforthesuteinabilityandreimbursementofRDstherapies.



BuildingBlockI419


ITEM DESCRIPTION


RegistriesforRareDiseases

References

www.orpha.net/orphacom/cahiers/docs/GB/registries.pdf

www.ncbi.nlm.nih.gov/books/NBK208609/

Description

Registries collect information on patients afflicted by a particular disease or group ofdiseases. By combiningdataonasmanypatients aspossible, at the regional, national,European or global level, the potency of the data increases exponentially. Registries,particularly when used by many different centers, enable researchers to accrue a so-called‘criticalmass’ofpatientswhichwouldoftenotherwisebeimpossible.

Dataonanyrarecondition isextremelyprecious.Nosinglecountrywillseeasufficientnumberofpatientswithanyveryrarediseasetofullyunderstandthecondition,intermsof its epidemiology (e.g. howmany cases exists in any given population), the range ofsymptomsobserved,thedevelopmentofthediseaseovertime,andthelikelyoutlookfornewly-diagnosedpatients,theeffectintermsofsafetyandefficacyoftherapiestestedinclinicaltrialsorinpost-marketingsurveillanceprograms.

The generation of validated data regarding natural histories of rare diseases helps todefine the target to address for the therapy of rare diseases, the endpoints to bematchedbyinnovativetherapiesandthelevelofsafetyandefficacyreachedbytherapiesbycomparingpreandposttreatmentdata.



Geographicalscope

International

Availability


Scope ofuse

− NaturalHistoriesofRD:Bycollectingdataoveralongperiodoftime− EpidemiologyofRD:howthediseaseiscausedandtheincidenceonacertain

population− Assessmentofdiseasethreatsandplanningofhealthservices:analysisofquality

oflife− Assessmentofefficacyandefficiencyofdiagnosis− Assessmentofthesafety,efficacyandefficiencyoftreatments− Choiceofendpointstobeusedinclinicaltrialsondifferentpopulationandat

differentdiseaseconditions.− PostMarketingsurveillance− Genotype-phenotypecorrelation

Stakeholders

• Healthcareprofessionals

• Pharmaceuticalindustries


• ECrepresentatives


Enablers:ERNsrepresentatives,PatientsOrganizationandPharmaceuticalIndustries,ECrepresentativesforInformationandconsultantships.

Requirements:

• Inform(e.g.announcementofguidanceonregistries);



• Cooperate/participate(directinteractions-e.g.technicalexpertgroups

Output ReportonthemappingofregistriesforRD,generationofrecommendationregardingtheneedofunifiedregistries.

Besttime to

Thetoolhasitsbestuseatthestartofdevelopment.


applyand timewindow

Experttips

No



BuildingBlockI420


ITEM DESCRIPTION

BuildingBlock(BB)Title Privatefunding

References https://www.sciencedirect.com/science/article/pii/S1359644613004030

Description Different kinds of private funding is available for orphan drugdevelopment,forexample:

• Crowdfunding

• Majorgifts(includingawards)

• Donation/Private-Charitygrants

• Angelinvestments

• Venturecapitalism

• Researchbackedobligations

• Equityinvestments

• Loans

Category DevelopmentOpportunityBuildingBlock

GeographicalscopeInternational

AvailabilityDifferent kind of funding is available for public or private drugdevelopers. Different private funders provide research and innovationfundingformulti-nationalcollaborationprojectsaswellasforindividual


ITEM DESCRIPTION

researchersandsupportsSMEs.

Scopeofuse Togetfundsfordifferentphasesofdrugdevelopment.Differentkindoffunding is accessible by different type of developer according to theirlegalstatus.

Stakeholders Funder,drugdeveloper(bothpublicorprivate).

Enablers/Requirements Notapplicable

Output Asuccessfulfundingapplicationbothresultsinaresearchproposalandthemeanstoconducttheresearch.

Best time to apply andtimewindow

Throughout different phases; requesting for funding throughout thedifferentphasesisacontinuousprocess.

Experttips Startapplyingforfundingwellinadvance,andalsoconsideralternativefundingoptions.

CONs:

• The initiatives are many, scattered and fragmented thereforeyouhavetodoanextensivehorizonscanning.



BuildingBlockI421


ITEM DESCRIPTION


AlternativedesignsforSmallPopulationClinicalTrials

References

1. https://www.ema.europa.eu/documents/scientific-guideline/guideline-clinical-trials-small-populations_en.pdf

2. https://www.ema.europa.eu/documents/scientific-guideline/draft-ich-e11r1-guideline-clinical-investigation-medicinal-products-pediatric-population-step-2b_en.pdf

3. www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM610802.pdf

4. https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm614641.pdf



7. https://www.nap.edu/catalog/10078/small-clinical-trials-issues-and-challenges

8. DayS,JonkerAH,LauLPL,etal.Recommendationsforthedesignofsmallpopulationclinicaltrials.OrphanetJRareDis.2018Nov6;13(1):195.

Descripti Recognizing the difficulties of clinical research in rare diseases, a number of generalrecommendationsareavailabletoselectthemostefficientstudydesignforeachmedical


on conditionortrial,andonpotentialadaptionsofconventionaldesignstothelowsamplesizescenario.

Withinthemultiplealternativetrialdesignsavailable,masterprotocolsallowtoevaluatemore thanoneor two treatments inmore thanonepatient typeordiseasewithin thesame overall trial structure. Particular cases include multi-arm trials, platform trials,umbrellatrials,andbaskettrials.Thesedesignsallowforacollaborativeapproachwheremore thanone sponsormay test theirproducts ina single trial;useofa single controlarmallowsminimizingsamplesizeandplaceboexposure.

Lowprevalenceinherenttorarediseasesresultsinlackoffeasibilityoflargerandomizedtrials as often required by conventional regulatory requirements. The use alternativedesignssuitedtosmallpopulationsmayhelpincertaincircumstancestogatherthemostrobustevidencefeasible fromsmalldatasets. Incertaintypesofconditions, theuseofmaster protocols for multiple-arms, umbrella, basket or platform trials, may beappropriate.


Geographicalscope

International

Availability


Scope ofuse

Sponsors and investigators may use the available guidance to plan the most efficientapproachatthetimeofselectionofthedesignofexploratoryandconfirmatorytrialsandtheoveralldevelopmentplan.Methodsespeciallysuitedto thestudyofsmallpopulationsshouldbeconsideredearlyduringtheplanningofclinicaldevelopment,andespeciallyforearlytrials.Masterprotocoltrialscouldbeconsideredbeforereachingtheclinicalphase,whenevercompetitive intelligence suggests that several products might be developedindependentlyforsimilar indications,and/orpotentiallypredictivebiomarkersmightbeappliedtorefinethetargetpopulationandproductindication.

Regulatorswillapplyknowledgeonalternativemethodstotheirassessmentatthetimeof scientific advice procedures and for assessment of marketing authorizationapplications.

Shouldbeappliedby:

• Sponsors should consider methods especially suited to the study of small


populations early during the planning of clinical development. If masterprotocols are applicable, these should be considered early during strategicdiscussionsonclinicaldevelopmentofdrugcandidates.

• Clinical researchers, statisticians, other persons involved at any of the initialstages of clinical research planning should consider alternative options toclassicaldesignsthataresuitedtosmallpopulations.

• Ethics Committees assess the acceptability of the proposed approaches asregardstoabilitytoconcludeonproposedobjectivesandprotectionofsubjects’rightsandwellbeing.

• Patientsprovideinputontheacceptabilityoftheproposedapproachandimpactontheirparticipationandinterests.

RegulatorsmaybeconsultedatanearlystageonacceptabilityoftheapproachesthroughScientific Advice or similar procedures. Regulators assess the robustness andacceptabilityofdataatthetimeofmarketingregulatoryapplications.

Stakeholders

• Sponsors,

• Investigators,

• Anypersoninvolvedinthestrategicplanningofclinicaldevelopment,

• Ethic’sCommittees,

• Regulators,

• Patients.


• Sponsors consider the applicability of alternative methods at the time ofplanning the clinical development of a drug candidate. Ifmaster protocols aresuited involvingproductsfromotherSponsors,theyapproachatanearlystageother companies potentially interested to coordinate and arrange any legal,economicandlogisticissues.

• Investigators, statisticians andotherpersons involved in the trial contribute tostudy design and implement designs into study protocols and provide inputduring study conduction as required for any planned interim analysis oradaptions.

• Ethics Committees and regulators review the proposed protocol and issueauthorizationsforexecution.

• Regulatorsprovideinputatearlyconsultationandassessresultsaspresentedatthetimeofmarketingauthorizationapplication.

Output Clinical protocols implementing methodologies especially suited to the study of smallpopulations.



Thetoolhas itsbestuseatthetimeofselectionofthedesignofexploratorytrialsandplanning of the overall development plan, ideally before first-into-human trials. Timelyconsiderationveryearlyduringtheprocessofdrugdevelopmentisnecessarywhenevercoordinationacrosscompaniesorresearchgroupsisneeded.

Experttips

PROs:

• The application of alternative designs suited to the study of small populationsmay reduce the requirements for sample size, improve the feasibilityof clinicaltrials,increasetherobustnessofthedata,andimprovetheethicalaspectsofthetrial, such as proportion of subjects exposed to placebo or potentially poortherapeuticoptions.

• Master protocols advantages may be expected once their set-up is complete.They may allow the use of a trial network with infrastructure in place tostreamlinetrial logistics, improvedataquality,andfacilitatedatacollectionandsharing, speeding-up the execution of clinical trials. Patients may be moreefficientlyscreened,onlyonceascomparedtomanytimesinindependenttrialsandmayhaveincreasedchancesofparticipationintoarelevantinvestigation.

CONs:

• The use of alternative designs or trial adaptions suited to the study of smallpopulationsmaybeachallengetosponsors,becauseofregulatoryperceptionoftechnicalcomplexityandsecondaryreluctancetodeviatefromthedouble-blindrandomizedgoldstandard.

• Setting-up of trials under amaster protocol approachmay be long and costly,and requires good coordination and formal agreements between severalsponsors for trial governance. Stakeholder coordination, infrastructurerequirements,andcomplextrialdesignelementscanextendthestart-uptimeforamasterprotocolconsiderably,ascomparedwiththatforasingle-purposetrial.

• Reluctancetosharesensitivecompetitiveinformationbetweensponsorsmaybeabarriertocollaboration.

• Whiletheexploratorysettinginearlydevelopmentislessstringentasregardstomultiplicityissues,multipleobjectivesmayrepresentanissuewhentheobjectiveofthetrialisconfirmatory,duetotheextentofmultiplicityadjustmentsrequiredinaconfirmativesetting.

• Changesinthestandardofcareduringthestudyconductmayrequiretemporaryinterruptionofrecruitmenttoallowforimplementationofchangesinarmsand


designtoincludethenewstandard,toadaptthestatisticalanalysisplanstonewcomparators, and may impact the potential for recruitment if an effectivestandardofcareimpactstheperceptionofmedicalneed.



BuildingBlockI422


ITEM DESCRIPTION


Feasibility-Patientengagementintrialdesignandfeasibility

References

Eurordisasfirstpointofcontact;thepatientorganizationofthespecificdisease

https://www.eurordis.org

https://www.eupati.eu

Description

It is important to involve patients at an early stage of designing clinical trials. Thiswillensure the trial is better tailored to patient needs. Specifically, patient input can helpensure that the burden of the trial is acceptable to and feasible by patients (e.g.withregards to accessibility issues, fatigue, assessments) but also ensuring inclusion criteriado not exclude all patients). Patient input is also important to confirm that trials aremeasuringwhatmatterstopeoplelivingwiththecondition.Thisisespeciallythecasefordiseaseswithnoclinicaltrialhistoryornoregulatorypathway.


Geographicalscope

International

Availability


Scope of Involvingpatientsmaypotentiallyexpediterecruitment,supportretentionandenhance


use executionof clinical trials andpotentially avoid trial amendments. Involvingpatients intrialdesignwilllikelyincreasecomplianceandwillpreventdesignsthatareunrealisticorwithtoohighapatientorcaregiverburden,ortodesignatrialthatmakesitimpossibletorecruittherequiredcohort.

Patient inputcanalsobehelpful inoperationalizationaspectsof thetrial,eg input intoinformed consent process and the ICF, supportive documentation, material andcommunication.

Stakeholders

• Patientrepresentatives

• Drugdeveloperofrareandnon-raredisease


None

Output More patient-centric trial design and easier/potentially faster recruitment and studycompletion


ThetoolhasitsbestusebetweenFirst-in-humanreadyandbeforePivotaldata.

Experttips

− When doing this, the conflict / declaration of interest of patients needs to betaken into account (participating in this effort may preclude them fromparticipatingaspatientexpertsinscientificadvicetotheregulators)

− Ensuresufficienttimeisbuiltintotheprocesstoallowforqualityinput

− Providefeedbacktopatientsabouttheimpactoftheirinput

PROs:

− Thisavoidstheset-upoftrialwithahighburdenordesignsthatarenotfeasibleforpatients(accessibility,physicaltests,caregiverimpact,inclusioncriteriaetc)

− HealthAuthoritiesencouragegreaterpatientinvolvementindrugdevelopment

CONs:


− Onepatientcannotberepresentativeofthewholepatientcommunity– ideallymultiplepatients,orsourcesofpatientinput,areinvolved,e.g.:aCAB,orpatientrepresentativeswhocanreflecttheneedsoftheircommunity

− Adequatetimeshouldbefactored intotheclinical trialdevelopmentprocesstoallowforpatientinput.



BuildingBlockI423


ITEM DESCRIPTION


Feasibility-Patientengagementintrialendpointselection

References

Description

It is importantthatpivotalclinicaltrialsmeasuresomethingthat isrelevanttopatients.This is something that only patients can tell you. Academics can then assess whetherthere is an outcome measure available that can measure this – if not, outcomemeasure(s)mayneedtobedeveloped.

Regulatorswillapprovemedicinesbasedontheclinicalbenefit/riskprofile–assuchitisimportantthatthetrialendpointmeasuressomethingthatismeaningfultopatients.

HealthAuthoritiesencouragepatientinputintodevelopmentofmedicines.

Havingpatientinputaroundpotentialendpointswillbeimportant,particularlywherenoregulatoryprecedenceorpathwayexists.


Geographicalscope

International


Availability


Scope ofuse

Toselectprimaryendpointsforpivotaltrials.

Selectingatrialendpointthat isrelevanttopatientswillhelpensurethattheresultsofthetrial(ifpositive)areacceptabletotheregulators

Stakeholders

• PatientsandDrugdevelopers

• Regulatorstoconfirmifselectedendpointisregulatorycompliant


Thesponsorofthetrialshouldinitiatethisinitiative

Output Bettertrialdesign


ThetoolhasitsbestusebetweenFirst-in-humanreadyandbeforePivotaldata.

Experttips

Involvepatientrepresentativesthatareawareoftheregulatorysystem.

PROs:

− Anendpointthatisrelevanttothepatients

CONs:

− Thepatientsinvolvedneedtoeitherbeawareoftheneedsoftheircommunity,ormultiplepatientsneedtobeinvolved,toavoidtailoringtheendpointselectiontothewishesofonepatient

− Patients involved need to be aware of the regulatory issues (e.g. EURORDISsummerschoolorEUPATIalumni)



BuildingBlockI424


ITEM DESCRIPTION


Ethic'sCommitteesassessmentofprotocolsfortrialswithorphanmedications

References

https://www.coe.int/t/dg3/healthbioethic/activities/02_biomedical_research_en/Guide/Guide_EN.pdf

https://www.hra.nhs.uk/about-us/committees-and-services/res-and-recs/research-ethics-committee-members-area/guidance-and-policy-for-rec-members/

https://doi.org/10.1016/j.clinthera.2014.01.013

https://www.ema.europa.eu/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-30.pdf

Description

To improve the quality of data supporting regulatory evaluation and clinical use oforphanmedications,theethicalassessmentofclinicaltrialsinorphanpopulationsshouldbe done by experienced committees,which should ensure that all relevant aspects onpatientprotectionarepresent,butalsothatthetrialsapplyrobustmethodologyandthemostefficientclinicaldesignable toconcludeon theefficacyandsafetyor thestudiedtreatments.

Protocolsofclinicaltrialsstudyingorphanmedicationsraiseparticulardifficultiesatthetimeofethicalassessmentbyethic’scommitteesor InstitutionalReviewBoards.Ethicalassessment of clinical trials in orphan diseases should be done by experiencedcommittees,andshouldensurethatallrelevantaspectsofthisparticulartypeoftrialsisproperlyassessed.

Trials in RD are often conducted in vulnerable populations (children or disabled), use


uncommonmethodologiesduetothescarcityofeligiblepopulation,usebiomarkersduetolackofpowertoassessclinicalend-points,lackinformationonpopulationstosupportdose selection or applymodelling fromother populations or diseases to that purpose,andfaceconcernsonplacebouseinsevereconditionswithnoavailablealternatives.

Oftenmarketingauthorizationsaregrantedbasedonearlyevidenceofefficacywhentheseverityoftheconditionishighandtherearenoavailablealternatives.Becauseofthis,itisrequiredthatinvestigatorsapplythemostefficientclinicaldesignabletoconcludeoncausalityeveninveryearlyorpreliminaryclinicalstudies.

Therearegeneralguidancesandprocedures forEthical reviewof research,suchas theoneinUK,andsimilardocumentsinothercountries:https://www.hra.nhs.uk/documents/1065/Ethical_Review_Form_V2_2_2017.09.01.docxAlso,someICHguidanceforethicalassessmentofpaediatrictrialscanbefound:https://www.ema.europa.eu/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-30.pdfGuidanceonmethodsandgeneralapproachtostudydesinginsmallpopulationsisalsoavailable:https://www.ema.europa.eu/documents/scientific-guideline/guideline-clinical-trials-small-populations_en.pdfhttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm458485.pdf

However, guidance for ethical assessment of trials in rare diseases are currentlyunavailableandwouldbeneeded.Thesemayincluderecommendationsandcheck-lists.

Thedurationofthetasksrelatedtostudydraftingandprotocolsubmissionisdependentonthesponsorandinvestigators,anddoesnothaveapredeterminedduration.

Tasks related to ethical assessment by committees are of variable duration acrosscountries,andmaydependonthetypeofapplicationsandproducts,rangingbetween30and120days.


Geographicalscope

International

Availability



Scope ofuse

During protocol design and assessment, to ensure that ethical, safety and practicalaspectsareconsidered,andthatrelevantoutcomesareincludedinthetrial.

Shouldbeappliedby:

• Clinicalresearchersattheinitialstagesofclinicalresearchplanning

Ethic’scommitteemembersatthetimeofauthorizationofatrial,andduringthefollow-upofthestudy.

The BB may be used by investigators at the time of designing a trial and writing aprotocolandbyEthic’sCommitteesmemberstoguidetheassessmentofclinicalresearchinpatientswithorphandiseases.

Stakeholders

• Clinicalresearchers,

• MembersofEthic’sCommittees,

• Authoritiesresponsibletoqualify/recognize/auditEthic’sCommittees


-InvestigatorsshouldusetheBBatthetimeofdraftingthestudyprotocolinRD

-ThesponsorsubmitsthestudyprotocolinRDtoEthic’sCommitteeforreview

-Ethic’sCommittees implement theBB toensure that theirprocedures implement therequiredstepstoguaranteeappropriatereviewofstudiesinRD.

Output Report with the result of the ethical review of a clinical trial in RD by IRBs/Ethic’scommittee,includingspecificconsiderationsforRD.


Thetoolhasitsbestusebythetimeatrial isbeingconceivedanddesigned,andatthetimeofassessingatrialbeforestart.

Experttips

The process begins when investigators decide that a clinical trial is required to test aworkinghypothesis.

The investigatorsdraftaprotocolandwork in teamswithstatisticians,methodologists,othercliniciansandinvestigatorsandpatientstogathermultidisciplinaryinput.Anumberoftoolssuchasguidancesandcheck-listsmayhelptoimprovetheprotocolqualityand


consistency.

The sponsor of the trial is responsible to gather all the required documentation andsubmits thestudy for reviewandapprovalbyboth the regulatorybodyand theethic’scommittee; each has the responsibility to assess key aspects of the trial to ensurecompliancewith regulation and laws, aswell as ethical principles of research involvinghumanbeings.

The ethic’s committee liaises withmembers and, where required, external experts, topreparetheevaluationreport.Tothatpurpose,StandardOperatingProcedures,relevantguidancesandcheck-listsareapplied.Theprojectisdiscussedinameetingandalistofquestionsorcomments is sent to thesponsor foramendmentorclarification.Once (if)resolved, an authorization is issued when appropriate, within the pre-establishedtimelinesassetbyregional/localregulation.

PROs:

− Availability of ethical andmethodological standardswill improve the quality ofdatasupportingregulatoryevaluationandclinicaluseoforphanmedications.

− Applicationofstandardsduringdesignandreviewshouldensurethatallrelevantaspects on patient protection are present, but also that the trials apply robustmethodology and the most efficient clinical design able to conclude on theefficacyandsafetyorthestudiedtreatments.

CONs:

− Itisdifficulttoreflectallpossiblesituationsinasingleguidancegiventhevarietyofclinicalsituationsandmethodspotentiallyapplicabletostudythem,andthusthereisriskofincompleteness.



BuildingBlockI425


ITEM DESCRIPTION


FAIRPrincipleforDatause

References

https://www.nature.com/articles/sdata201618

https://www.go-fair.org/fair-principles/

Description

Lackofultimatedatauseinrarediseasecreatedmanysilosslowingdowndevelopment.TheFAIRiscomingtobridgethisgapbyprovingessentialguidelinesforoptimaldatause.


Geographicalscope

International

Availability


Scope ofuse

FAIRistryingtogapthescarcityandfragmentationofdatainraredisease.

Stakeholders



• Academia

• HCPs

• Industry

• Regulatorybodies


Patient organizations can be the enablers by supporting the FAIR principles in theiradvocacy

Output Itisasetofprinciplesthatneedtobefollowedwhendealingwithdata.


Thetoolhasitsbestusethroughoutthelifecycledevelopment.

Experttips

PROs:

− Findable: easy to identify and find for both humans and computers, withmetadatathatfacilitatesearchingforspecificdatasets,

− Accessible: stored for long term so that they can easily be accessed and/ordownloaded with well-defined access conditions, whether at the level ofmetadata,orattheleveloftheactualdata,

− Interoperable: ready to be combined with other datasets by humans orcomputers,withoutambiguitiesinthemeaningsoftermsandvalues,

− Reusable:readytobeusedforfutureresearchandtobefurtherprocessedusingcomputationalmethods.Thisrequiresadequateinformationabouthowthedatawereobtainedandprocessed(provenance)andanappropriatelicense



BuildingBlockI426


ITEM DESCRIPTION


Initiativesforundiagnoseddiseases

References

https://undiagnosed.hms.harvard.edu/

http://www.udninternational.org/

http://care4rare.ca/

http://solve-rd.eu/

AmJHumGenet.2014Jun5;94(6):809-17.doi:10.1016/j.ajhg.2014.05.003.

Mol Genet Metab. 2016 Apr;117(4):393-400. doi: 10.1016/j.ymgme.2016.01.007. Epub2016Jan22.

IRDiRC vision: http://www.irdirc.org/future-of-rare-diseases-research-2017-2027-an-irdircs-perspective/

Description

ThepurposesofUndiagnosedDiseasesPrograms(UDPs)aretoprovidepatientswithanunknowngeneticconditionadiagnosisandtofindthecorrelationbetweengenotypeandphenotype; to share globally the information to facilitate the diagnosis through amatchmaking for finding possible second cases. Worldwide the UDPs are performedprimarily usingNextGeneration Sequencing (NGS) approaches (whole exomeorwholegenomesequencing)appliedtothefamilytrioorquartetUDPsshortenthetimetoreachadiagnosis,theso-called“diagnosticodyssey”,fromyearstoweeks.


The early diagnosis of an ultra-rare disease gives to the physician the possibility ofchoosingthemostadequatetreatment, ifavailableandtothepatientthepossibilitytobenefit from the treatment before the possible worsening of the clinical condition.Further insights on genetic diseases could trigger new therapeutic approaches. Thematchmaking allows the identification of other overlapping cases that can confirmdiagnosisandthereforeproviderelevantinformationregardingavailabletreatments.


Geographicalscope

International

Availability


Scope ofuse

− IdentificationofmoleculardiagnosisbyNGSandotherOMICSapproaches− Genotype-phenotypedatasharingtofindasecondcasethroughmatchmaking− Generationofnewdiagnostictechnologiesforgeneticdiseases− Generationofnewinformaticsapproaches(analysispipelineandartificial

intelligence)toshortenthe“diagnosticodyssey”.

Stakeholders

• Healthcareprofessionals,

• Pharmaceuticalindustries,

• Genomicsandbioinformaticscenters,

• Patientorganizations,

• Policymakers,

• NHS


Enablers:healthcareprofessionals’organizations,NationalHealthSystems-NHS,researchinstitutes,genomicscenters.Requirements:• Inform(e.g.announcementofguidanceonUDPs);• Consultandinvolve(directinteractions–e.g.stakeholdermeetings,workshops,

stakeholderconferences);• Cooperate/participate(directinteractions-e.g.technicalexpertgroupsand

networks)• Genotypeandphenotypedatasharing


Output ThenumberofenrolledpatientsanddiagnosisprovidedareUDPsoutputs.Reportonthemapping of the scenario of UDPs and networks worldwide, generation ofrecommendation regarding the need of applying NGS approaches to undiagnosedpatientsasfirst-tiertest.


Thetoolshouldbeappliedassoonaspossible.

Experttips

Strategicconsiderations:

- UDPs must be embedded in a multidisciplinary network, including clinicians,bioinformaticians,psychologistsetc

DOs:

- UDP adopted by NHS as of limited value if performed only in the researchenvironment

- Increasedawarenessonavailableprogramsamongany interested stakeholders(i.e.,patients)

- Datasharingiscrucial

- Awareness and empowerment of patients enrolled in theUDPs, extended alsoafter the positive/negative response received, through appropriate geneticand/orpsychologicalcounseling.

- Acost-effectiveanalysistobeconducted

DON’Ts:

- Donotlimittothe“pureresearch”environment

- Do not limit to genomics analysis only, but consider alternative diagnosticapproaches

PROs:

− Shortening the time to reach the diagnosis, early treatment if available,generation of data about ultra-rare disease, more adequate choice of thetreatmentifavailable,betterfollowupwithsupportivetherapies,preventionoflife-threateningeventsandcasualties.

− Data sharing to allow researchondiseasemechanisms and to findother ultra-


rarecasesworldwide.

CONs:

− UDPskeptasresearchprogramsvs.NHSadoption;increaseofdiagnosticcostfortheNHS;unmetpatients’expectations(unsolvedcases;possiblelackofavailabletreatmentsfordiagnosedpatients).



BuildingBlockI427


ITEM DESCRIPTION


New-bornscreeningprogramsforrarediseases

References

www.cdc.gov/newbornscreening/

www.nichd.nih.gov/health/topics/newborn/conditioninfo/purpose

Description

ThepurposeofNBS is todetectpotentially fatalordisablingconditions innewbornsasearlyaspossibleandpossiblybeforeonsetofsymptoms.Suchdetectionallowstheearlytreatment which may significantly modify the natural history of the disease andpotentiallypreventdevelopmentaldelays,physicaldisabilitiesandeventuallydeath.

Theidentificationofrarediseasesbeforetheonsetandtheclinicalevidencegivestothephysicianthepossibilityofchoosingthemostadequatetreatmentandtothepatientthepossibilitytobenefitofthetreatmentbeforetheonsetofirreversibledefects.

Regarding the development of new drugs, the possibility of studying pre-symptomaticpatientmight facilitatetheunderstandingof therealefficacyof innovativetherapies inmodifyingthenaturalhistoryofdiseases.

Category DevelopmentalResourcesBuildingBlock

Geographicalscope

International


Availability


Scope ofuse

− Identificationofrarediseasesatearlystage,potentiallyatthepre-symptomaticstage

− Epidemiology of RD: how the disease is caused and the incidence on a certainpopulation

− Preventionofdiseasethreatsandplanningofhealthservices:analysisofqualityoflife

− Assessmentofefficacyandefficiencyofdiagnosis− Assessmentofthesafety,efficacyandefficiencyoftreatments− Generation of awareness programs on RD for the early identification and

treatmentofRD− GenerationofnewtechnologiesforNBSmethods

Stakeholders

• Healthcareprofessionals,

• Pharmaceuticalindustries/drugdevelopers

• Patientorganizations,

• Policymakers


Enablers: ERNs representatives, Patients Organization and Pharmaceutical Industries,BoMS

Requirements:

• Inform(e.g.announcementofguidanceonNBS);



• Cooperate/participate(directinteractions-e.g.technicalexpertgroups

Output Report on themappingof the situationofNBS for RD, generationof recommendationregardingtheneedofapplyNBSinanextendedmanner.

Besttime toapply

Thetoolhasitsuseasearlyaspossibleatdiseaseknowledgephase.


and timewindow

Experttips

PROs:

− Earlydiagnosis,early treatment,generationofdataaboutefficacyof therapies,more adequate choice of the treatment is available, better follow up withsupportivetherapies,preventionoflife-threateningeventsandcasualties.

− GenerationofdataregardingepidemiologyandprevalenceofRDs.

CONs:

− Increaseofdiagnostic cost for theNHS, increaseof costdue to the treatmentsappliedtopre-symptomaticandearlyidentifiedpatients.



BuildingBlockI428


ITEM DESCRIPTION


IRDiRCRecognizedResources

References

http://www.irdirc.org/research/irdirc-recognized-resources/

ordoi:10.1038/ejhg.2016.137

Description

IRDiRCRecognizedResourcesisaqualityindicator,basedonaspecificsetofcriteriathatwascreatedtohighlightkeyresources,which,ifusedmorebroadly,wouldacceleratethepaceoftranslatingdiscoveriesintoclinicalapplications.Anyresourcecompliantwiththecriteriamayapplyforthelabel.Selectedplatforms,tools,standards,andguidelinesmustbe of fundamental importance to the international rare diseases research anddevelopmentcommunity.

IRDiRCRecognizedResourcesisaqualityindicator,whichisexpectedtohelpacceleratethepaceoftranslatingdiscoveriesintoclinicalapplications.ItthereforelistsanumberofresourcesimportantforOrphanDrugDevelopment.


Geographicalscope

International

Availabili Applicantsdevelopingmedicinesforrarediseases.


ty

Scope ofuse

Thistoolismostlyusedtoprovidevisibilitytothedifferentresourcesspecificallyrelevantfortherarediseasesfield.

Stakeholders

• Developers

• ReviewersfromtheIRDiRCScientificCommitteesandbeyond

• Theusersoftheseresources


AworkinginternetconnectionandaccessviaPubMed.

Output IRDiRC Recognized Resources criteria encourage long-term sustainability, peer review,andwidespreadrelevanceoftheplatforms,tools,standards,andguidelines.Applicationsforthelabelareacceptedonarollingbasisandevaluatedthroughapeer-reviewprocessby IRDiRCScientificCommitteemembersaswell asexperts in the relevant field. It is apubliclabelwhichcanbemadevisibleonandbytheresource,givingusersanassuranceofitsqualityandappropriateness.


Thetoolhasitsbestuseintheveryearlyphasesoftheorphandrugpipeline.

Experttips

LookregularlythroughthelistofIRDiRCRecognizedResourcesinordertobeinformedofnewresourcesthathavecomearound.

PROs:

− Freelyaccessible,easytoaccess.

CONs:

− Notacompletelist,keyresourcesmightbemissing,asresourceholdersneedtoapplythemselves.

ODDG–BuildingBlockE103–Version11


BuildingBlockI429


ITEM DESCRIPTION

Building Block (BB)Title

TREAT-NMDadvisorycommitteefortherapeutics(TACT)

References http://www.treat-nmd.eu/resources/tact/introduction/

https://doi.org/10.1038/d41573-019-00199-1

DescriptionEstablishedin2009,theTREAT-NMDAdvisoryCommitteeforTherapeutics(TACT)isauniquemulti-disciplinaryinternationalgroupofinternationallyrecognizedacademicandindustrydrugdevelopmentexpertsaswellasrepresentativesofpatientfoundationsandregulatoryexperts.Thegroupmeettwiceayeartoreviewandprovideguidanceonthetranslationanddevelopmentpathoftherapeuticsprogramsinrareneuromusculardiseaseswithlargeunmetneed,suchasmusculardystrophiesandamyotrophiclateralsclerosis(ALS).Theconfidentialandcomprehensivereviewprovidesrecommendationsincludinggo/no-gomilestones,andisindependentofanyfundingstream.

TACTwill:

• ConveneabespokepanelofexpertreviewerscoveredbyfullCDAandfreefromconflictsofinterest.

• Provideaonepointintimemulti-disciplinaryreview.• Meet2timesperyear(onceevery6months,1inEuropeand1inNorth

America).• Acceptapplicationsfortherapeuticstargetedtoanyformofrare

inheritedneuromusculardisease.• Applicationsareacceptedfromanywhereintheworld.• Carryoutreviewsunderaconfidentialdisclosureagreement.• Reviewtherapeuticsatanystageofdevelopment(oncealeadcompound

isidentified)thatarepresentedashavingaclearperspectivewithinthetranslationalprocesswiththelong-termgoalofanintendedclinicaltrialandpotentialregistration.


ITEM DESCRIPTION

• Considerreviewingpreviously-reviewedprogrammesiftheyhavesubstantiallyprogressedorchangedandifthecommitteefeltthatitcouldaddfurthervalue.

• Addressissuesofdrugformulation,bioavailabilityandtoxicologyaswellaspossibleregulatoryrequirementsandmarketingconsiderations.

• Provideapplicantswithacomprehensivewrittenreview,includingrecommendationsnolaterthan6weeksfollowingthemeeting.

• Publishanon-confidentialsummarytoensurethecommunityreceivesexpertfeedbackontheprogressoftheapplication.

• ProvideinformationabouttheprojectsreviewedandplannedtobereviewedatTACTmeetingsontheTREAT-NMDwebsiteandinTREAT-NMDnewsletters.

• Includepatientrepresentativesoneveryreviewpanel.

TACTwillnot:

• Provideon-goingfeedbacktoapplicantsonthedevelopmentprogramme.

• Respondtoqueriesfollowingtheissueofthefinalreport.• Amendorupdatethefinalreport.• Engagewithfundingorganisationsonbehalfofapplicants.• Providefunding;TACTisnotafundingorganizationbutprovides

evaluationandrecommendationswhichmayfacilitatedevelopmentofareviewintoanapplicationtoafundingorganization.

IfyouwishtofindoutmoreaboutTACTyoumaywanttoviewavideoofapresentationgivenattheFasterCuresConferenceinNewYorkCity,November2012.

ForacademicapplicantsTACTrequestsnocontribution–theyhavehowevertocoverthetravelcoststotheTACTmeeting.


Geographicalscope

International.

Availability Companiesandacademicresearchersplanningtoperformclinicaltrials intheneuromusculardisorderscaninitiateaTACTreview.

CurrentlyTACTfocusesonneuromusculardisorders.Howeverthe“ACT”modelcouldeasilybeimplementedalsoforotherdiseasegroups.

TACTisavailabletobothIndustry(foracontributiontowardsmeetingcosts)oracademic researchers (no contribution requested). TACT is a not for profit


ITEM DESCRIPTION

organizationandreviewersreceiveonlyasmallhonorariumfortheirtime.

Scopeofuse TACTwill provide an assessment and advice that involves all aspects of drugdevelopment.Itwillencourageearlyphasedeveloperstoalreadystartthinkingabout requirements for later phases (e.g. upscaling manufacturing). It willprovidealldeveloperswithinformationtosetcleargo/no-gocriteriaandwithinformationtodesigntheirtrialsbetter.Itreducestheriskofsub-optimaltrialsand/ortakingdrugsintoclinicaltrialswithoutsufficientpreclinicaldata.

So far17TACTmeetingshavebeenheldreviewing50applications.30%havebeen from academics and 70% from industry. 34 applications have been fortherapiesforDuchennemusculardystrophy,5forspinalmuscularatrophyand11forotherNMDsincludingmyotubularmyopathy,FSHDandPompedisease.

TACThasreceivedapplicationsinbothearly(firstinman)andlater(phase2/3)clinicaltrials.TheaimofTACTistoprovideamulti-disciplinaryassessmentofatherapeuticapproach,tohelpdefinecleargo/nogodecisionpointsandtohelpoptimizeclinicaltrials.

Stakeholders TACT consists of a core group (around 10) with expertise in preclinicalexperiments, clinical trials, toxicology, outcome measures and regulatoryissues.Inadditionthereareanumberofextendedmembers(around60)whocan provide additional expertise for specific neuromuscular disorders or fordifferentaspectsoftherapydevelopment includingthepatientperspective.Atypical review panel is made up of 12-18 experts depending on therequirementsofeachapplication.

The core and extended committee can be seen here: http://www.treat-nmd.eu/resources/tact/committee-members/

The TACT Secretariat is based at Newcastle University and supports therunning,logisticsandadministrationofTACT.

TACT is and has been supported by generous funding from patientorganisationsincluding:CNMC(viaDoDgrant),PPMD,CureDuchenne,MDUK,MDA, Joining Jack, Duchenne UK, Duchenne Ireland, Myotubular Trust,DuchenneNow,DuchenneChildren’sTrust,SMAEurope


Interestedcompanies/researcherscontacttheTACTcoordinatorlocatedattheTREAT-NMD Secretariat (currently Cathy Turner, [email protected]) todiscuss the eligibility and timing of the TACT review. When eligible, theapplicant needs to fill out the ‘TACT review form”, thus providing the TACT


ITEM DESCRIPTION

reviewcommitteewiththerequestedinformationforassessment. Inadditionthey can provide additional information (publications, posters, manuscriptsetc).

Theinformationisthenreviewedbycommitteemembers(selectedasneededfor each application’s panel). They provide feedback (both strengths andlimitations) and address specific questions from the applicant based on theirindividual expertise and collected by the TACT coordinator. One experiencedTACT expert is assigned the role of ‘Lead reviewer’ and he/she collates thecommentstobesharedwiththepanel.DuringtheTACTface-to-facemeeting,theLeadbrieflyintroducestheapplication,andchairsfurtherdiscussionbythecommittee. The applicant then joins the committee meeting to facilitateclarification and further discussion about the application. Finally, the TACTcommitteediscussesfurtherinlightoftheface-to-facemeeting.Subsequently,the Lead writes the TACT report, which is then distributed amongst thecommitteemembersforinput.Thefinalreportissharedwiththeapplicantasaconfidentialdocumentwhichisfortheirownuse.TheapplicantmaychoosetosharethiswithothersbutTACTwillnotdoso.

Output TACT helps to provide independent, expert advice and go/no-go decisionswhichmaybeusedtoprioritizewhichdrugsshouldbetakenintoclinicaltrials.TACThelpstoensurethattrialsarewellplannedanddataisrobust–ithelpstoensuremoreoptimalclinicaltrials.

TheapplicantswillbeprovidedwithaconfidentialcomprehensiveTACTreportthat includes a multidisciplinary assessment from the TACT reviewers (withinput on preclinical data, clinical data (if available), clinical trial design,manufacturing, safety, regulatory and patient perspective). Furthermore, abriefnon-confidential summarywillbeprovidedon theTREAT-NMDwebsite(this isdone incollaborationwiththeapplicanttoavoidthatanyconfidentialinformationbecomespublic).

Best time to applyandtimewindow

In order to submit a TACT application, applicants need to have at leastidentifiedaleadcompound.However,applicationscanalsobereviewedduringlater clinical phases of a development program, before the initiation of aclinicaltrial.

Pre-application at least 3 months in advance of a TACT meeting (datespublishedontheTACTwebsite).Fullapplicationsubmittedatleast8weeksinadvanceofaTACTmeeting.

Applicantrequestedtoattendtheface-to-facemeetingforuptohalfaday.


ITEM DESCRIPTION

TACTconfidential reportprovided toapplicantwithin6weeksof the face-to-facemeeting.

Non-confidentialreportfortheTACTwebsiteagreedwithin2weeksofthefullreportbeingissued.

Experttips ContacttheTACTcoordinatorearlywhenconsideringtoapplyforareviewsothebesttimingcanbediscussed

PROs:

• Multidisciplinaryapproach

• Constructiveapproach(theaimistomakethingsbetterthroughadvicefromworldexpertsandoptimizetherapydevelopment)

• Onestopshopforcompaniesneedingscientificadvise

CONs:

• Atthemomentonlyapplicablefortheneuromusculardisorderfield



BuildingBlockI430


ITEM DESCRIPTION

BuildingBlock(BB)Title TechnologyTransferOffices(TTOs)

References Associatedwiththerelatedresearchinstitute/university

DescriptionMostuniversities/researchinstituteshaveatechnologytransferofficeresponsible for technology transferor collaborationofR&Dprojects.TheTTOsare responsible for theprotectionandmanagementof theintellectual property rights. TTOs increase researchinstitute/university’s visibility among for-profit players in the field(including pharma and biotech companies as well as venture capitalfirms) andactiveadvertiseof themostadvancedprojects. TTOsalsonegotiateagreementswithfor-profitplayersinthefield.


Geographicalscope International

AvailabilityMany rare disease programs originate from research at orcollaboration with academic institutions. The TTOs support theresearchersworkingbothinrareandnon-rarediseaseareas.

Scopeofuse Related to the protection and management of the intellectualpropertyrights,R&Dcollaborationandprogramlicensing.

Stakeholders PartyA:university/researchinstitute

PartyB:biotech/pharmacompany

Typically,partyAwillaskfor licensingupfrontpaymentandroyalty


ITEM DESCRIPTION

paymentontechnology/programitlicensestopartyB.

Enablers/Requirements R&Dlicensingownership

Output R&Dlicensingagreement

Best time to apply and timewindow

TTOs should be involved since early in the research/programdevelopment so that they can protect and manage properly theintellectualpropertyrights.

Experttips PROs:

TTOsfacilitateandmaximizetheinteractionsbetweenaresearcherandapharmacompanyonapotentiallicenseinterest.

CONs:

Technology transfer offices sometimes may consider only thecommercial terms when choosing a party to collaborate with orlicenseto.



BuildingBlockI431


ITEM DESCRIPTION

BuildingBlock(BB)Title TargetPatientValueProfile

References https://www.eurordis.org/content/eurordis-community-advisory-board-cab-programme

https://www.fda.gov/drugs/development-approval-process-drugs/external-resources-or-information-related-patients-experience

https://www.ctti-clinicaltrials.org/projects/patient-groups-clinical-trials

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

https://patientfocusedmedicine.org/

DescriptionA document outlining the goals, profile and potential benefit of aspecificproduct,addressingrelevantcurrentandfuturepatientneedsinadifferentiatedway.It provides accurate, up-to-date information describing the expectedbenefitforpatientsanddescribethedrug.



AvailabilityThistoolisdevelopedforthebenefitofdrugdevelopers.


ITEM DESCRIPTION

Scopeofuse Guidesproductdiscoveryanddevelopmenttowardsthemeaningfulbenefitandneedsexpressedbypatients,andcanalsobeusedasacommunication tool to patients and investigators and regulatoryauthorities to frame the potential value of the product indevelopment from the patient perspective. As guide and startingpointtodefinetheproductdevelopmentplan.

Stakeholders Drugdevelopers,patients

Enablers/Requirements Accesstopatients,likelythroughadvocacygroups

Output Patient-centricinformationandresources


Best toaccessearlyon indevelopment toget fullviewof researchandactivitiesinthedisease-specificspace.

Prepared first at the beginning of development, and periodicallyreviewed.

Experttips Bestdevelopedattheverystartofdrugdevelopment.

PROs:

Comprehensiveinformationaboutpatientgroupforwhichthedrugwillbedeveloped.

CONs:

None

ODDGTF–GalaxyGuide_BuildingBlockFactSheet1


BuildingBlockI432


ITEM DESCRIPTION

BuildingBlock(BB)Title Horizon Scanning: Landscape analysis/ Stakeholder identificationandengagement

References https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234281/

DescriptionAnalysisperformedbythedrugdeveloperandbyHealthTechnologyAssessment(HTA)bodiestoassess:1.thefuturerealneedforthetherapyfortheproductatthetimeofmarketentry;2.thepotentialfutureplaceintherapyfortheproduct;3.thecurrentandfuturecompetitivelandscapeofanearly-stagedrugtodeterminethepossibilitiesofmarketentryandtheviabilityofpossibledifferentiationstrategiestocompeteinthemarket;4.thebesttechnologysuitabletofulfilpatient’sneedatthebeginningofdevelopment.



AvailabilityThis tool is developed for drug developers and for HTA bodies. Ahorizon scanning canbedone foranydrug thatwill bedeveloped,notlimitedtoanorphanmedicinalproduct.

Scopeofuse To project the clinical andmarket situation at the timeof productlaunch.

Torefinethetargetproductprofileanddevelopmentplan,usingthisBBasadecisionsupporttoolforgo-no-godecisionmakingindrugdevelopment.


ITEM DESCRIPTION

To allow Health Technology Assessment bodies prioritize newtechnologies and pharmaceuticals, based on the expected healthbenefit or financial impact, inappropriate use, and variationof useacrossthecountryandeffectonotherhealth-relatedpolicies,suchasreductioninhealthinequalities.

Stakeholders Drugdevelopers,HTAbodies

Enablers/Requirements There are different tools available that could assist in horizonscanning,eachwithadifferentfocus.

Output Document


Best toaccessearlyon indevelopment toget fullviewofresearchandactivitiesinthedisease-specificspace.

To be produced at the start, periodically repeated throughout thedevelopmentprocess.

Experttips Bestdevelopedattheverystartofdrugdevelopment.

PROs:

Benefitscouldbe:

• Understandingthetherapeuticsolutionlandscape,nowandatthetimeofapproval

• Alignthedevelopmentoftheproductwiththefuturepotentialplaceintherapyandexistingtherapeutictrends

• Toavoidinvestingresourcesinpotentiallyuselessoroutofdatetargets/drugs

• Tounderstandexistingpotentialcompetitorsorcollaborators

• Targetingtherightgroupofpatientsconsideringthetherapeutictoolkitatthetimeofapproval

CONs:

Giventhecomplexityofthetherapeuticlandscapeincertaindiseases,anddrugdevelopmentattritionrate,resultsoflandscape


ITEM DESCRIPTION

analysisshouldalwaysbehandledwithcareininformingdrugdevelopmentdecisionstoavoiderrorsinexecution.