IND Data Requirements and US FDA Submission.pdf

A clinical trial is a culmination of the several stages of a drug or medical
device development program that begins with the discovery of a
candidate molecule followed by preclinical toxicology studies in ex vivo, in
vitro, and animal models. Once the candidate molecule shows promising
results in these stages, the next step involves clinical studies on human
subjects. Drug testing in humans is often the most lengthy and expensive
phase of the drug development timeline, and therefore requires extensive
effort and careful execution to maximize the candidate’s chances of
success. In addition to scientific evaluation, clinical studies require
approval by the United States Food and Drug Administration (US FDA),
the regulatory authority in the United States to administer the
experimental drug in humans as well as ship it across state lines. This
approval comes in the form of an Investigational New Drug (IND FDA)
application that is required to be submitted by sponsors, investigators, or
research institutes to the FDA to commence studies on human
participants. The following figure shows the various stages of the drug
development program (Figure 1) marking IND submission on the timeline.
The US Food and Drug Administration (FDA) has established a comprehensive drug
development strategy for US FDA. This strategy is designed to ensure that the drugs
being developed meet the highest standards of safety and efficacy.The IND is a comprehensive document that contains all the information
gained from preclinical and other studies in an organized format. The
FDA reviews and makes the decision to support further clinical studies
from information in the IND that ultimately forms the basis of marketing
approval. INDs can be submitted at any phase during clinical
development to protect the safety and rights of subjects (Phase I) and to
assure adequate scientific evaluation of the drug’s effectiveness and
safety (Phase II and III). The Code of Federal Regulations CFR Title 21.
Part 312 Investigational New Drug Application contains information on
INDs as well as their content and format and should be reviewed
thoroughly by sponsors or investigators prior to submission of an IND
application.
The IND data requirements are important for the development of new drugs and
medical devices. They provide detailed information about the safety and efficacy of a
drug or device before it can be approved for use by the public

1. INDDataRequirementsandUSFDASubmission
TableofContents
​WhyisanINDrequired?
​TherearetwomaintypesofINDs:
​CommercialIND:
​ResearchIND:
​EmergencyuseIND:
​WhendoIneedtosubmitanIND?
​INDcontentandformat
​Module1-Regionalandadministrativeinformation
​Module2-Summaries
​Module3-Quality
​Module4-Nonclinicalstudyreports
​Module5-Clinicalstudyreport

2. INDSubmissionProcesstotheUSFDA
Aclinicaltrialisaculminationoftheseveralstagesofadrugormedical
devicedevelopmentprogramthatbeginswiththediscoveryofa
candidatemoleculefollowedbypreclinicaltoxicologystudiesinexvivo,in
vitro,andanimalmodels.Oncethecandidatemoleculeshowspromising
resultsinthesestages,thenextstepinvolvesclinicalstudiesonhuman
subjects.Drugtestinginhumansisoftenthemostlengthyandexpensive
phaseofthedrugdevelopmenttimeline,andthereforerequiresextensive
effortandcarefulexecutiontomaximizethecandidate’schancesof
success.Inadditiontoscientificevaluation,clinicalstudiesrequire
approvalbytheUnitedStatesFoodandDrugAdministration(USFDA),
theregulatoryauthorityintheUnitedStatestoadministerthe
experimentaldruginhumansaswellasshipitacrossstatelines.This
approvalcomesintheformofanInvestigationalNewDrug(INDFDA)
applicationthatisrequiredtobesubmittedbysponsors,investigators,or
researchinstitutestotheFDAtocommencestudiesonhuman
participants.Thefollowingfigureshowsthevariousstagesofthedrug
developmentprogram(Figure1)markingINDsubmissiononthetimeline.
TheUSFoodandDrugAdministration(FDA)hasestablishedacomprehensivedrug
developmentstrategyforUSFDA.Thisstrategyisdesignedtoensurethatthedrugs
beingdevelopedmeetthehigheststandardsofsafetyandefficacy.

3. Figure1.Schematicrepresentationofdrugdevelopmentstages
WhyisanINDrequired?
TheINDisacomprehensivedocumentthatcontainsalltheinformation
gainedfrompreclinicalandotherstudiesinanorganizedformat.The
FDAreviewsandmakesthedecisiontosupportfurtherclinicalstudies
frominformationintheINDthatultimatelyformsthebasisofmarketing
approval.INDscanbesubmittedatanyphaseduringclinical
developmenttoprotectthesafetyandrightsofsubjects(PhaseI)andto
assureadequatescientificevaluationofthedrug’seffectivenessand
safety(PhaseIIandIII).TheCodeofFederalRegulationsCFRTitle21.
Part312InvestigationalNewDrugApplicationcontainsinformationon
INDsaswellastheircontentandformatandshouldbereviewed
thoroughlybysponsorsorinvestigatorspriortosubmissionofanIND
application.
TheINDdatarequirementsareimportantforthedevelopmentofnewdrugsand
medicaldevices.Theyprovidedetailedinformationaboutthesafetyandefficacyofa
drugordevicebeforeitcanbeapprovedforusebythepublic

4. TherearetwomaintypesofINDs:
●CommercialIND:
Thesearesubmittedbysponsorswiththeintenttocommercializethe
productatalaterstage
●ResearchIND:
Thesearesubmittedbyinvestigatorsorresearchinstitutionsthatdonot
intendtocommercializetheproduct
●EmergencyuseIND:
AllowsFDAtoauthorizetheuseofadruginanemergencyforwhich
thereisnocomparabletreatmentandthatdoesnotfollowtheexact
formatforthesubmissionofanINDaccordingto21CFRSection312
WhendoIneedtosubmitanIND?
AnINDshouldbesubmittedwhenplanningtotestanewdruginhumans,
whenplanningtouseanapproveddrugforanindicationthathasnot
beenintheapprovedlabeling,whenadministeredatadifferentdosage
orbyadifferentrouteofadministration,andwhenadministeredtoa
differentpopulation(unlesscertainexemptionsapply).
INDcontentandformat

5. Asof2018,commercialuseINDsmustbesubmittedusingtheelectronic
CommonTechnicalDocument(eCTD)formatforacceptabilitybythe
FDA.TheeCTDattemptstoharmonizemarketingapplicationstructure
andformatintheUS,EU,Japan,andothercountriesadheringto
InternationalCouncilforHarmonisation(ICH)guidelinesandhelpsto
saveonpaperandstorageresourcesfordocuments.
INDsmustcontaininformationfromthreemainareas:animal
pharmacologyandtoxicology,manufacturinginformation,andclinical
protocolsandinvestigatorinformation(Figure2).
Figure2.InformationrequiredforINDapplication

6. TheeCTDformatfortheINDapplicationcontains5moduleswithspecific
informationineach(Figure3).
Theinformationthatsponsors/investigatorsmustsubmitinanIND
applicationbasedon21CFR312.23canbearrangedintheCTDformat
asfollowsandshouldcontain:
Module1-Regionalandadministrativeinformation
●Coverletter(FDA1571)-sponsordetails,phaseofaclinicaltrial,
detailsaboutclinicaltrialinvestigatorsandmonitors,contract
researchorganization(CRO)details,IRBinformation
●Tableofcontents-introductorystatementandgeneral
investigationalplan,alongwithinformationonprevioushuman
experiencewiththedrug,investigationalmarketingexperience,
andwithdrawalinformation(ifapplicable)andplanforinvestigation
foroneyear
●FDA3674-certificationofcompliancewithrequirements
ClinicalTrials.govdatabank
●Labeling-acopyofalllabelsandlabelingtobeprovidedtoeach
investigator

7. ●GeneralInvestigationalPlan-containsinformationaboutthedrug
suchasstructuralformula,pharmacologicalclass,dosageform
anddose,routeofadministration,anddurationofthetrial
●Investigator’sbrochure-containsinformationonthedrugsubstance
andformula,asummaryofpharmacologicalandtoxicological
effectsinanimalsandhumans(ifknown),asummaryof
pharmacokineticsandbiologicaldispositioninanimalsand
humans(ifstudies),safetyandeffectivenessinhumansfromprior
clinicalstudies,possiblerisks,sideeffects,andprecautionsor
specialmonitoringasperexpectedadverseeventsbasedonprior
experiencewiththedrugorsimilardrugs
●Module2-Summaries
●Qualityoverallsummary-thisincludesinformationaboutthe
drugsubstancesuchasgeneralinformation(nomenclature,
structuralformula),manufacture,characterization,controlof
drugsubstance,referencestandardsormaterials,
container-closure,andstability.Drugproductdatamust
containdescription,pharmaceuticaldevelopment,
manufacture,controlofexcipientsanddrugproduct,
referencestandardormaterial,containerclosure,and
stability.
●Nonclinicaloverview-theaimofthissectionistopresent
datatoensurethesafeuseoftheexperimentaldrugin
humanstakingthepharmacological,pharmacokinetic,and
toxicologicalstudiesintoconsideration.
●Pharmacologyandpharmacokineticstudies:
includepharmacokinetic,toxicokinetic,and
metabolismstudieswiththemethodsusedand
analyticalmethods.Interspeciescomparisonsof
metabolismandpharmacokineticparameters(AUC,
Cmax),andlimitationsforextrapolationofanimaldata
tohumansshouldbediscussed.
●Toxicologystudies:onset,severity,anddurationof
toxiceffects,dose-dependency,reversibility(or
irreversibility),andspeciesandgenderdifferences.
Genotoxicity,carcinogenicity,toxicsigns,causesof
death,pathologicfindings,pre-andpostnataltoxicity,
thesafetyofthedrugduringpregnancyand
lactation,andlocaltolerance.InformationTypeof
animalspecies,numberofanimals,routeof
administrationanddosages,durationoftreatment,
andsystemicexposureshouldbeincluded.

8. ●Nonclinicalsummary-thisincludeswrittenandtabulated
summariesforpharmacology,pharmacokinetic,and
toxicologystudies
●Pharmacologywrittensummaryandtabulated
summary-primarypharmacodynamicsstudieswithother
drugsintheclass,secondarypharmacodynamicstudies
summarizedbyorgansystems,safetypharmacology
studies,andpharmacodynamicdruginteractions.The
tabulatedsummaryshouldcontaininformationorganized
intosectionssuchastestsystem,methodofadministration,
dose,species/strain,gender,organsystemsevaluated,etc.
●Pharmacokineticswrittensummaryandtabulated
summary-methodandvalidationparametersforthe
analyticalprocedureusedforbiologicalsamplesinthe
study,absorptionstudies(invitroextentsandrate,BA/BE
studies),distributionstudies(tissuedistribution,protein
binding,andplacentaltransferstudies),metabolismstudies
(metabolicpathways,pre-systemicmetabolism,P450in
vitrostudies,enzymeinductionandinhibition),excretion
studies(routeandextent,excretioninmilk),
pharmacokineticdruginteractions.Thetabulatedsummary
shouldincludedataunderthefollowingheadingsspecies,
vehicle/formulation,gender,dose,methodofadministration,
sample,analyte,assay,feedingcondition,andsampling
time(s).
●Toxicologywrittensummaryandtabulated
summary-single-dosetoxicity(species,route),
repeated-dosetoxicity(species,route,duration),
genotoxicity(invitromammalianandnon-mammalian
system,invivomammaliansystem),carcinogenicitystudies
(long-termandshort-term),reproductiveanddevelopmental
toxicity,localtolerance,andotherstudies(immunogenicity,
antigenicity,dependence,studieson
impurities/metabolites).Tabulatedsummariesshould
includethespecies/strain,dose,routeofadministration,
duration,observedmaximumnon-lethaldose,andany
noteworthyfindings.
●Clinicaloverviewincludestheproductdevelopment
rationale(pharmacologicalclass,targetindication,current
majortherapies,summaryofongoingandplannedclinical
studies),biopharmaceutics(bioavailabilityissuesrelatedto
formulations),clinicalpharmacology(pharmacokinetics:
comparativePKrelatedtointrinsicandextrinsicfactors,
absorption,proteinbinding,metabolicpathways,

9. pharmacodynamics:mechanismofactionandreceptor
binding,PK/PDrelationships,geneticdifferences,
immunogenicity,andclinicalmicrobiology),efficacydata
(relevantpatientpopulation,studydesign,endpoint(s),
controls,statisticalmethods),safety(adverseeffectsand
monitoring,animaltoxicology,overdosereactions),benefits
andrisks.
●Theclinicalsummary-Thissectiongenerallyincludesa
tabulatedsummaryandcomparisonofindividualstudies
relatedtobiopharmaceuticsandanalyticalmethods,clinical
pharmacology,clinicalefficacy,andclinicalsafety.
●
●Module3-Quality
Thismodulecontainschemistry,manufacturing,andcontroldataforthe
drugsubstanceanddrugproduct.
●Drugsubstance-generalinformation(name,manufacturer),
nomenclature(CASno.,chemicalname),structure(formulaand
stereochemistry),generalproperties(pH/pKa,solubility,melting
point,hygroscopicity,polymorphicform),manufacturer’snameand
address,descriptionofthemanufacturingprocessandcontrols
(schematicflowdiagramofprocess,rawmaterials,catalysts,
solvents,pH,criticalsteps,equipment,andoperatingconditions),
controlofrawmaterialsandsolvents,controlofcriticalstepsand
intermediateswithacceptancecriteriaprocessvalidationand
evaluations,andmanufacturingprocessequipment.Specification
criteriafordrugsubstance,analyticalproceduresandvalidation
criteria,batchesandbatchanalyses,andspecification,reference
standardsandmaterials,container-closuresystemdescription,
andtabularlistingofstabilityprotocolandstudies
●Drugproductdescriptionofdrugproduct,dosage,composition,
typeofcontainersystem,drugsubstance,excipients,formulation
development,resultsfrominvitro/invivocomparativestudies,
physicochemicalandbiologicalpropertiesrelevanttoperformance
(pH,dissolution,particlesize,flowproperties,rheology,potency,
polymorphism,biologicalactivity,etc.),manufacturingprocess
development(keyvalidationparameters),containerclosure
systemsmicrobiologicattributes,compatibility,batchformula,
descriptionofthemanufacturingprocessandcontrols,process

10. validation,excipientcontrols,stabilitydata(stresstesting,
photostabilitytests)
●Module4-Nonclinicalstudyreports
Thissectioninvolvestheorganizationofnonclinicalstudyreportswhich
includepharmacology(primaryandsecondarypharmacodynamics,
safetypharmacology,andpharmacodynamicdruginteractions),
pharmacokinetics(analyticalmethodsandvalidationreports,absorption,
distribution,metabolism,excretion,pharmacokineticdruginteractions),
toxicology(single-dose,repeatdose,genotoxicity,carcinogenicity,
reproductiveanddevelopmentaltoxicity,localtolerance,andother
toxicitystudiessuchasantigenicity,immunogenicity,tolerance,
immunotoxicity,etc.),andliteraturereferences.
●Module5-Clinicalstudyreports
Thissectioninvolvestheorganizationofclinicalstudyreportswhich
includebiopharmaceuticstudyreports(bioavailabilitystudy,comparative
BA/BEstudies,Invitro-invivocorrelations,bioanalyticalandanalytical
methods),PKstudyreports(plasmaproteinbinding,hepaticmetabolism
anddruginteractions,humanbiomaterialstudies),humanPKstudies
(healthysubjectandpatientPKandtolerabilityreports,intrinsicand
extrinsicfactorPKreports,populationPKreport),humanPDreports
(healthysubjectandpatientPK/PDreports),efficacyandsafetyreports
(controlledanduncontrolledclinicalstudyreports,),reportsof
post-marketingexperience,casereportformsandindividualpatient
listings,andliteraturereferences.

11. INDSubmissionProcesstotheUSFDA
AnINDcanbesubmittedbythesponsor/investigatoratanyphaseofthe
clinicaltrialstagebutmustbesubmittedpriortotestingtheexperimental
druginhumanparticipants.Figure4showsthestepsforsubmissionof
theINDapplicationtotheFDAusingtheeCTDformatforelectronic
submissions.
Figure4.SubmissionprocesstoFDAusingtheelectronicsystemfor
INDs
FollowingreceiptoftheeCTDsubmissiontotheFDA,theFDAhasa
30-dayperiodtorespond.TheFDAcanbeinconstantcommunication
duringthisperiodtoclarifyanyconcernsordoubtsaboutthestudy.If
thereisnoresponsefromtheFDAduringthiswindow,thestudycan
proceed.Otherwise,theFDAcanplacethestudyonpartialholdor
clinicalholdwhichcanbeduetoinadequatedatainthesubmittedINDor
safetyconcerns.Itistheresponsibilityofthesponsor/investigatorto
addressquestionsthattheFDAhasposedandrespondtotheseina
separatesubmissiontotheFDA.TheFDAcaneitherlifttheclinicalhold

12. allowingtheclinicalinvestigationtoproceed,placethestudyonpartial
hold(withcertainrestrictions),orcontinuethehold.
InadditiontosubmittingtheinitialIND,thesponsor/investigatormust
keeptheINDcurrentandsubmitanyamendmenttotheINDsuchas
protocolamendments,safetyreports,andINDannualreports.
Thus,athoroughandclearunderstandingoftherequirementsforanIND
especiallyintheeCTDformatthatisrecommendedbytheFDAis
necessarytomaximizechancesforasmoothtransitionofexperimental
drugstotheclinicaltrialphase.Furthermore,reviewingtheFDA
submissionprocessandmaintainingcontactwiththeFDAisessentialin
updatingtheINDandprotectingpatientsafetyincaseofanyadverse
eventsorprotocoldeviations.
References
●UnderstandingFDARegulatoryRequirementsforInvestigational
NewDrugApplicationsforSponsor-Investigators–PMC(nih.gov)
●M4E(R2):TheCTD—EfficacyGuidanceforIndustry(fda.gov)
●QualityOverallSummary(QOS)ineCTDformat
(triphasepharmasolutions.com)
●InvestigationalNewDrug(IND)Application|FDA
●SubmitUsingeCTD|FDA