21CFRPART 316ORPHAN DRUGS.docx

21CFRPART 316ORPHAN DRUGS.docx

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21CFRPART316ORPHANDRUGS

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Title21→ChapterI→SubchapterD→Part316

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Title21:

FoodandDrugs

PART316—ORPHANDRUGS

Contents

SubpartA—GeneralProvisions

§316.1Scopeofthispart.

§316.2Purpose.

§316.3Definitions.

§316.4Addressforsubmissions.

SubpartB—WrittenRecommendationsforInvestigationsofOrphanDrugs

§316.10Contentandformatofarequestforwrittenrecommendations.

§316.12Providingwrittenrecommendations.

§316.14Refusaltoprovidewrittenrecommendations.

SubpartC—DesignationofanOrphanDrug

§316.20Contentandformatofarequestfororphan-drugdesignation.

§316.21Verificationoforphan-drugstatus.

§316.22Permanent-residentagentforforeignsponsor.

§316.23Timingofrequestsfororphan-drugdesignation;designationofalreadyapproveddrugs.

§316.24Deficiencylettersandgrantingorphan-drugdesignation.

§316.25Refusaltograntorphan-drugdesignation.

§316.26Amendmenttoorphan-drugdesignation.

§316.27Changeinownershipoforphan-drugdesignation.

§316.28Publicationoforphan-drugdesignations.

§316.29Revocationoforphan-drugdesignation.

§316.30Annualreportsofholderoforphan-drugdesignation.

SubpartD—Orphan-drugExclusiveApproval

§316.31Scopeoforphan-drugexclusiveapproval.

§316.34FDArecognitionofexclusiveapproval.

§316.36Insufficientquantitiesoforphandrugs.

SubpartE—OpenProtocolsforInvestigations

§316.40Treatmentuseofadesignatedorphandrug.

SubpartF—AvailabilityofInformation

§316.50Guidancedocuments.

§316.52Availabilityforpublicdisclosureofdataandinformationinrequestsandapplications.

Authority:

21U.S.C.360aa,360bb,360cc,360dd,371.

Source:

57FR62085,Dec.29,1992,unlessotherwisenoted.

EditorialNote:

Nomenclaturechangestopart316appearat69FR13717,Mar.24,2004.

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SubpartA—GeneralProvisions

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§316.1Scopeofthispart.

（a）Thispartimplementssections525,526,527,and528oftheactandprovidesprocedurestoencourageandfacilitatethedevelopmentofdrugsforrarediseasesorconditions,includingbiologicalproductsandantibiotics.Thispartsetsforththeproceduresandrequirementsfor:

（1）SubmissionstoFDAof:

（i）Requestsforrecommendationsforinvestigationsofdrugsforrarediseasesorconditions;

（ii）Requestsfordesignationofadrugforararediseaseorcondition;and

（iii）Requestsforgainingexclusiveapprovalforadrugforararediseaseorcondition.

（2）Allowingasponsortoprovideaninvestigationaldrugunderatreatmentprotocoltopatientswhoneedthedrugfortreatmentofararediseaseorcondition.

（b）Thispartdoesnotapplytofood,medicaldevices,ordrugsforveterinaryuse.

（c）ReferencesinthisparttoregulatorysectionsoftheCodeofFederalRegulationsaretochapterIoftitle21,unlessotherwisenoted.

[57FR62085,Dec.29,1992,asamendedat78FR35132,June12,2013]

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§316.2Purpose.

Thepurposeofthispartistoestablishstandardsandproceduresfordeterminingeligibilityforthebenefitsprovidedforinsection2oftheOrphanDrugAct,includingwrittenrecommendationsforinvestigationsoforphandrugs,a7-yearperiodofexclusivemarketing,andtreatmentuseofinvestigationalorphandrugs.ThispartisalsointendedtosatisfyCongress'requirementsthatFDApromulgateproceduresfortheimplementationofsections525（a）and526（a）oftheact.

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§316.3Definitions.

（a）Thedefinitionsandinterpretationscontainedinsection201oftheactapplytothosetermswhenusedinthispart.

（b）Thefollowingdefinitionsoftermsapplytothispart:

（1）ActmeanstheFederalFood,Drug,andCosmeticActasamendedbysection2oftheOrphanDrugAct（sections525-528（21U.S.C.360aa-360dd））.

（2）Activemoietymeansthemoleculeorion,excludingthoseappendedportionsofthemoleculethatcausethedrugtobeanester,salt（includingasaltwithhydrogenorcoordinationbonds）,orothernoncovalentderivative（suchasacomplex,chelate,orclathrate）ofthemolecule,responsibleforthephysiologicalorpharmacologicalactionofthedrugsubstance.

（3）Clinicallysuperiormeansthatadrugisshowntoprovideasignificanttherapeuticadvantageoverandabovethatprovidedbyanapproveddrug（thatisotherwisethesamedrug）inoneormoreofthefollowingways:

（i）Greatereffectivenessthananapproveddrug（asassessedbyeffectonaclinicallymeaningfulendpointinadequateandwellcontrolledclinicaltrials）.Generally,thiswouldrepresentthesamekindofevidenceneededtosupportacomparativeeffectivenessclaimfortwodifferentdrugs;inmostcases,directcomparativeclinicaltrialswouldbenecessary;or

（ii）Greatersafetyinasubstantialportionofthetargetpopulations,forexample,bytheeliminationofaningredientorcontaminantthatisassociatedwithrelativelyfrequentadverseeffects.Insomecases,directcomparativeclinicaltrialswillbenecessary;or

（iii）Inunusualcases,whereneithergreatersafetynorgreatereffectivenesshasbeenshown,ademonstrationthatthedrugotherwisemakesamajorcontributiontopatientcare.

（4）DirectormeanstheDirectorofFDA'sOfficeofOrphanProductsDevelopment.

（5）FDAmeanstheFoodandDrugAdministration.

（6）Holdermeansthesponsorinwhosenameanorphandrugisdesignatedandapproved.

（7）INDmeansaninvestigationalnewdrugapplicationunderpart312ofthischapter.

（8）ManufacturermeansanypersonoragencyengagedinthemanufactureofadrugthatissubjecttoinvestigationandapprovalundertheactorthebiologicsprovisionsofthePublicHealthServiceAct（42U.S.C.262-263）.

（9）Marketingapplicationmeansanapplicationforapprovalofanewdrugfiledundersection505（b）oftheactoranapplicationforabiologicslicensesubmittedundersection351ofthePublicHealthServiceAct（42U.S.C.262）.

（10）Orphandrugmeansadrugintendedforuseinararediseaseorconditionasdefinedinsection526oftheact.

（11）Orphan-drugdesignationmeansFDA'sactofgrantingarequestfordesignationundersection526oftheact.

（12）Orphan-drugexclusiveapprovalorexclusiveapprovalmeansthat,effectiveonthedateofFDAapprovalasstatedintheapprovalletterofamarketingapplicationforasponsorofadesignatedorphandrug,noapprovalwillbegiventoasubsequentsponsorofthesamedrugforthesameuseorindicationfor7years,exceptasotherwiseprovidedbylaworinthispart.Adesignateddrugwillreceiveorphan-drugexclusiveapprovalonlyifthesamedrughasnotalreadybeenapprovedforthesameuseorindication.

（13）Orphansubsetofanon-rarediseaseorcondition（“orphansubset”）meansthatuseofthedruginasubsetofpersonswithanon-rarediseaseorconditionmaybeappropriatebutuseofthedrugoutsideofthatsubset（intheremainingpersonswiththenon-rarediseaseorcondition）wouldbeinappropriateowingtosomeproperty（ies）ofthedrug,forexample,drugtoxicity,mechanismofaction,orpreviousclinicalexperiencewiththedrug.

（14）Samedrugmeans:

（i）Ifitisadrugcomposedofsmallmolecules,adrugthatcontainsthesameactivemoietyasapreviouslyapproveddrugandisintendedforthesameuseasthepreviouslyapproveddrug,eveniftheparticularesterorsalt（includingasaltwithhydrogenorcoordinationbonds）orothernoncovalentderivativesuchasacomplex,chelateorclathratehasnotbeenpreviouslyapproved,exceptthatifthesubsequentdrugcanbeshowntobeclinicallysuperiortothefirstdrug,itwillnotbeconsideredtobethesamedrug.

（ii）Ifitisadrugcomposedoflargemolecules（macromolecules）,adrugthatcontainsthesameprincipalmolecularstructuralfeatures（butnotnecessarilyallofthesamestructuralfeatures）andisintendedforthesameuseasapreviouslyapproveddrug,exceptthat,ifthesubsequentdrugcanbeshowntobeclinicallysuperior,itwillnotbeconsideredtobethesamedrug.Thiscriterionwillbeappliedasfollowstodifferentkindsofmacromolecules:

（A）Twoproteindrugswouldbeconsideredthesameiftheonlydifferencesinstructurebetweenthemwereduetopost-translationaleventsorinfidelityoftranslationortranscriptionorwereminordifferencesinaminoacidsequence;otherpotentiallyimportantdifferences,suchasdifferentglycosylationpatternsordifferenttertiarystructures,wouldnotcausethedrugstobeconsidereddifferentunlessthedifferenceswereshowntobeclinicallysuperior.

（B）Twopolysaccharidedrugswouldbeconsideredthesameiftheyhadidenticalsacchariderepeatingunits,evenifthenumberofunitsweretovaryandeveniftherewerepostpolymerizationmodifications,unlessthesubsequentdrugcouldbeshowntobeclinicallysuperior.

（C）Twopolynucleotidedrugsconsistingoftwoormoredistinctnucleotideswouldbeconsideredthesameiftheyhadanidenticalsequenceofpurineandpyrimidinebases（ortheirderivatives）boundtoanidenticalsugarbackbone（ribose,deoxyribose,ormodificationsofthesesugars）,unlessthesubsequentdrugwereshowntobeclinicallysuperior.

（D）Closelyrelated,complexpartlydefinabledrugswithsimilartherapeuticintent,suchastwoliveviralvaccinesforthesameindication,wouldbeconsideredthesameunlessthesubsequentdrugwasshowntobeclinicallysuperior.

（15）Sponsormeanstheentitythatassumesresponsibilityforaclinicalornonclinicalinvestigationofadrug,includingtheresponsibilityforcompliancewithapplicableprovisionsoftheactandregulations.Asponsormaybeanindividual,partner