Ind enabling studies.

contains all about investigational new drug enabling studies.

1. IND Enabling Studies
Presented by: Shikha Choudhary
M.pharm (Pharmacology)
1904650002

2. CONTENTS
➢Definition of IND
➢Importance of IND
➢Industry perspective
➢Studies needed for IND submission
➢Safety pharmacology studies-origin, concepts and importance
➢Tier1-CVS, CNS and respiratory safety pharmacology, HERG Assay
➢Tier2-GI, renal and other studies
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3. DEFINITION OF IND:
•AnINDisasubmissiontothefoodanddrugadministration(FDA)requestingpermissionto
initiateaclinicalstudyofanewdrugproductonhumans.
•Thefederalfood,drugandcosmeticactrequiresthatdrugshaveanapprovedmarketing
applicationbeforetheycanbeshippedininterstatecommerce.
•TheINDapplicationallowsacompanytoinitiateandconductclinicalstudiesfortheirnewdrug
products.
•TheINDapplicationprovidestheFDAwiththedatanecessarytodecidewhetherthenewdrug
andtheproposedclinicaltrialposeareasonablerisktothehumansubjectsparticipatinginthe
study.
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4. WHEN DO WE NEED AN IND :
•AnINDisrequiredanytimewhenwe
wanttoconductaclinicaltrialofan
unapproveddrug.
•AnINDwouldberequiredtoconducta
clinicaltrailifthedrugis:
•Anewchemicalentity,notapprovedfor
theindicationunderinvestigationinanew
dosageform.
•Beingadministeredatanewdosagelevel.
•Incombinationwithanotherdrugandthe
combinationisnotapproved.
WHEN DO WE DON’T NEED AN IND :
•AnINDisnotrequiredtoconductastudyifthe
drug:
•Isnotintendedforhumansubjects,butis
intendedforinvivotestingorlabresearch
animals(nonclinicalstudies).
•Isanapproveddrugandthestudyiswithinits
approvedindicationforuse.
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5. TYPES OF IND STUDIES
•Allclinicalstudieswhereanewdrugisadministeredtohumansubjects,regardlessofwhether
thedrugwillbecommerciallydeveloped,requireanIND.
1.InvestigatorINDissubmittedbyaphysicianwhobothinitiatesandconductsaninvestigation,
andunderwhoseimmediatedirectiontheinvestigationaldrugisadministeredordispensed.
2.EmergencyINDalltheFDAtoauthorizeuseofanexperimentaldruginanemergency
situation.
3.TreatmentINDissubmittedforexperimentaldrugsshowingpromiseinclinicaltestingfor
seriousorimmediatelylife-threateningconditionswhilethefinalclinicalworkisconducted
andtheFDAreviewtakesplace.
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6. CLASSIFICATION OF IND
•Commercial : permits sponsor to collect data on clinical safety and effectiveness needed for
application for marketing in the form of NDA.
•Research (non-commercial) :permits the sponsor to use drug in research to obtain advanced
scientific knowledge of new drug o no plan to market the product.
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7. IMPORTANCE OF IND
➢Helpsintheresultofsuccessfulpreclinicaldevelopmentprogram.
➢Indisalsothevehiclethroughwhichasponsoradvicethenextstageofdrugdevelopmenti.e.Clinical
trial.
➢Thepreclinicalstudy,helpsthesponsor’sprimarygoaltodeterminethattheproductisreasonablysafe
forinitialuseinhuman.
➢Itisimportantinthecommercialdevelopmentofcompoundsifitexhibitpharmacologicalactivity.
➢Itisimportantinassuringthemarketingofanewdrugandresponsibilityforcomplianceofsponsor.
➢Itisimportantforthecompanytoinitiateandconducttheclinicalstudiesoftheirnewproduct.
➢Itsecurethesafetyandeffectivenessoftheclinicaltrialsubjects.
➢INDcanbealternativeinalifethreateningsituationwhennostandardacceptabletherapyisavailable.
➢Itgivestheindicationofnewdrugs.
➢Pharmacologyandtoxicologyinformationofnewdrugs.
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8. Studies Needed For IND Submission
TheINDapplicationmustcontaininformationinthreebroadareas:animalpharmacologyand
toxicologystudies-preclinicaldatatopermitanassessmentastowhethertheproductisreasonably
safeforinitialtestinginhumans.Alsoincludedareanypreviousexperiencewiththedrugin
humans(oftenforeignuse).
Applicationcontent:TheINDapplicationmustcontaininformationinthreebroadareas:
•Animalpharmacologyandtoxicologystudies–preclinicaldatatopermitan
assessmentastowhethertheproductisreasonablysafeforinitialtestinginhumans.Also
includedareanypreviousexperiencewiththedruginhumans(oftenforeignuse).
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9. •Chemistryandmanufacturinginformationstudies–informationpertainingto
thechemicalcomposition,manufacturingmethods,stability,andcontrolsusedfor
manufacturingthedrugsubstanceandthedrugproduct.Thechemicalstabilityandactivityof
theproductmustalsohavebeentested.Thisinformationisassessedtoensurethatthecompany
canadequatelyproduceandsupplyconsistentandactivebatchesofthedrug.
•ClinicalProtocolsandInvestigatorInformationstudies–Detailedprotocolsfor
proposedclinicalstudiestoassesswhethertheinitial-phasetrialswillexposethesubjectsto
unnecessaryrisks.Informationonthequalificationsofclinicalinvestigators—professionals
(generallyphysicians).
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10. IND (Investigational New Drug Application)
•Aninvestigationnewdrugapplication(IND)isasubmissiontofood&drugadministration
(FDA)requestingpermissiontoinitiatethestudyofnewdrugproduct
•FDAsroleinthedevelopmentofanewdrugbeginswhenthedrug'ssponsorhasscreenedthe
newmoleculeforpharmacologicalactivityandacutetoxicitypotentialinanimals,wantstotest
itsdiagnosticortherapeuticpotentialinhumans.
•Themoleculechangesinlegalstatusunderthefederalfood,drug,andcosmeticactandbecomes
anewdrugsubjecttospecificrequirementsofthedrugregulatorysystem.
•Drugistobethesubjectedtoanapprovedmarketingapplicationbeforeitistransportedor
distributedacrossstatelines.
•IND-noticeofclaimedinvestigationalexemptionforanewdrugmustbefiledwithregulatory
body.
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11. REQUIREMENTS FORIND
•AsponsorshallsubmitanINDtoFDAwhointendstoconductaclinicalinvestigation.
•InvestigationisnotsupposedtobeginwithoutpriorwrittenauthorizationofFDA.
PhasesOfInvestigation
•Phase1-ADME(20-80)healthysubjects
•Phase2–effectivenessinparticularindication(severalhundredpatients)
•Phase3–safetyandeffectiveness(100-1000)subjects.
GeneralPrincipleOfIND
•Toassuresafetyandrightsofthesubject.
•Toassurethescientificqualityofinvestigationwillyielddatacapableofmeetingstatutory
standardsformarketingapproval
•Thecentralfocusshouldbeongeneralinvestigationalplan&protocolwhichshouldbesupported
byadditionalinformation
•Includinganimaltoxicologicalstudies
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12. IND CONTENT & FORMAT
1.Coversheet(FORMFDA1571)
2.Tableofcontents
3.Introductorystatementandageneralinvestigationalplan
4.Investigatorsbrochure
5.Protocols
6.Chemistry,manufacturingandcontrolinformation
7.Pharmacologyandtoxicologyinformation
8.Previoushumanexperiencewiththeinvestigationaldrug
9.Otherrelevantinformationlikeno.ofINDsubmissions,no.ofcopiestobesubmitted(1+2)
10.Protocolamendments,anychangesintheprotocol.
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13. 2.TABLEOFCONTENTS
TABLEOFCONTENTS–
•ComprehensivelistingofcontentsofINDapplicationbrokeninvolumes&pagenumber.
•Tocshouldincludedetailsofsections,appendices,attachments,reports&otherreferencematerial
•AwelldraftedTOCwillfacilitatethetaskofreview&decreasethereviewtime.
3.GENERALINVESTIGATIONAL PLAN–
Abrief3to4pagesnoteon–theinvestigationalproduct
•Sponsors'investigationalplan
•Goalofthesectionisto–
•Toprovidebriefdescriptionofthedrug
•Layoutdevelopmentplanofthedrug
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14. 4.INVESTIGATORS BROCHURE
•Keydocumentprovidedtoeachinvestigator&IRBateachoftheclinicalsite.
•Includes-
1.Allabouttheinvestigationaldrug
2.IBisalivingdocument&mustbeupdatedbythesponsor.
5.PROTOCOLS
•Describeshowtheclinicaltrialwouldbeconducted.
•Itdescribes–
•theobjectiveofthestudy
•Thetrialdesign
•Howsubjectswouldbeselected?
•Howthetrailistobeconducted?
•Allaboutthehowthestudywouldbeconducted?
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15. 6. CHEMISTRY , MANUFACTURING AND CONTROL INFORMATION
•CMCinformation-
•SufficientdetailonQUALITY,IDE
•NITY,PURITY&POTENCYofthedrugproduct.
•ManufacturedinconformancewithcGMP.
•CMCsectionincludesthefollowing–
1.IntroductionCMC
2.Summary
3.Informationofplacebo,ifany
4.Proposedclinicallabel
5.Categoricalexclusionofanyenvironmentalassessment
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16. 7. PHARMACOLOGY AND TOXICOLOGY INFORMATION
•Pharmacology&toxicologydata.
•Non-clinicalsafetydatathatsponsorgeneratedtoprovethattheIPissafeforclinicalstudy.
•Theamount&typeofdatadependsonclassofnewdrug.
•Durationofproposedclinicaltrialpatientpopulationthatwillbeexposedduringthetrial.
8.PREVIOUSHUMANEXPERIENCEWITHTHEINVESTIGATIONAL DRUG
•Integratedsummaryreportofanyhumanstudiesconductedontheinvestigationaldrug.
•Relevanttothesafetyoftheinvestigationstobedone–pkstudies,pdstudies.
•Observedadverseeventprofile.
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17. 9. OTHER RELEVANT INFORMATION LIKE NO. OF IND SUBMISSIONS -
•Noofcopiestobesubmitted(1+2)
•ADDITIONALINFORMATION–specialtopics
•Drugdependence&abusepotentialradioactivedrugspaediatricpopulation&otherinformation.
Otherrelevantinformation–
•InformationspecificallyrequestedbyFDA.
•Financialdisclosureinformationfromeachinvestigator&subinvestigator.
•Drugmasterfile(DMF)
•Reportsorjournalarticles.
•TheINDapplicationisalwayssubmittedin1+2formati.e.1original&2additionalcopiesofeach
application.
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18. IND APPLICATION PROCESS
EARLYCONSULTATION
•SponsorsmayrequesttomeetwithFDAreviewing
•Officialsearlyinthedrugdevelopmentprocesstoreviewandreachagreementonthedesignofnecessary
preclinicalandclinicalstudies.
Pre-investigationalnewdrug(IND)meetings:
•PriortothesubmissionoftheinitialIND,thesponsormayrequestameetingwithFDA-reviewing
officials.
•Theprimarypurposeofthismeetingistoreviewandreachagreementonthedesignofanimalstudies
neededtoinitiatehumantesting.
•Themeetingmayalsoprovideanopportunityfordiscussingthescopeanddesignofphase1testing,plans
forstudyingthedrugproductinpaediatricpopulations,andthebestapproachforpresentationand
formattingofdataintheIND
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19. END-OF-PHASE 1 MEETINGS
•Whendatafromphase1clinicaltestingareavailable,thesponsormayagainrequestameetingwithFDA
reviewingofficials.
•Theprimarypurposeofthismeetingistoreviewandreachagreementonthedesignofphase2controlled
clinicaltrials,withthegoalthatsuchtestingwillbeadequatetoprovidesufficientdataonthedrug’ssafetyand
effectivenesstosupportadecisiononitsapprovabilityformarketing,andtodiscussandtimingofstudiesof
thedruginpaediatrictheneedfor,aswellasthedesignpatients.
ENDOFPHASE2MEETINGS:
Istodeterminethesafetyofproceedingstophase-3
•OncetheINDisstampedasreceived,itissenttoCDERforreview.
•Itisfurthercategoricallydividedintodifferentsections–
•Medical
•Chemistry
•Pharmacology/toxicology
•Statistics
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20. FDA’S IND REVIEW PROCESS
•SAFETY REVIEW:
•Following review of an initial IND submission, CDER has 30 calendar days in which to decide if
a clinical hold is necessary (i.e., If patients would be at an unacceptable risk or if CDER doesn't
have the data to make such a determination).
•Generally, drug review divisions do not contact the sponsor if no concerns arise with drug safety
and the proposed clinical trials.
•If the sponsor hears nothing from CDER, then on day 31 after submission of the IND, the study
may proceed as submitted.
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21. CLINICAL HOLD DECISION
•AclinicalholdisthemechanismthatCDERuseswhenitdoesnotbelieve,orcannotconfirm,
thatthestudycanbeconductedwithoutunreasonablerisktothesubjects/patients.
•Ifthisoccurs,thecentrewillcontactthesponsorwithinthe30-dayinitialreviewperiodtostop
theclinicaltrial.CDERmayeitherdelaythestartofanearly-phasetrialonthebasisof
informationsubmittedintheIND,orstopanongoingstudybasedonareviewofnewlysubmitted
clinicalprotocols,safetyreports,protocolamendments,orotherinformation.
•Whenaclinicalholdisissued,asponsormustaddresstheissuethatisthebasisoftheholdbefore
theorderisremoved
Clinicalhold
•Aclinicalholdcanbe–
•“completeclinicalhold”-adelayorsuspensionofallclinicalworkrequestedunderIND
submission
•“Partialclinicalhold”-adelayorsuspensionofonlypartofclinicalworke.g.Partofprotocol
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22. NOTIFY SPONSOR
•OnceaclinicalholdisplacedonacommercialIND,thesponsorwillbenotifiedimmediatelyby
telephonebythedivisiondirector.
•Thedivisionisrequiredtosendaletterwithinfiveworkingdaysfollowingthetelephonecall.
•Thelettershoulddescribethereasonsfortheclinicalhold,andmustbearthesignatureofthe
divisiondirector(oractingdivisiondirector).
•ThesponsormaythenrespondtoCDERbysendingan“INDclinicalholdresponse"lettertothe
division.Toexpediteprocessing,thelettermustbeclearlyidentifiedasan"INDCLINICAL
HOLDRESPONSE"letter.
•Thedivisionthenreviewsthesponsor'sresponseanddecideswithin30daysastowhetherthe
holdshouldbelifted.
•Ifthedivisiondoesnotreplytotheclinicalholdresponsewithin30calendardays,thedivision
directorwilltelephonethesponsoranddiscusswhatisbeingdonetofacilitatecompletionofthe
review.
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23. •Ifitisdecidedthattheholdwillnotbelifted,theholddecisionisautomaticallysenttotheoffice
directorforreview.
•Theofficedirectormustdecidewithin14calendardayswhetherornottosustainthedivision's
decisiontomaintaintheclinicalhold.
•Ifthedecisionismadetoliftthehold,thedivisiontelephonesthesponsor,informsthemofthe
decision,andsendsaletterconfirmingthattheholdhasbeenlifted.
•Theletterwillbesentwithin5workingdaysofthetelephonecall.However,thetrialmaybegin
oncethedecisionhasbeenrelayedtothesponsorbytelephone.
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24. SPONSOR NOTIFIED OF DEFICIENCIES
•IfotherdeficienciesarefoundinanINDthatthereviewdivisiondeterminesarenotserious
enoughtojustifydelayingclinicalstudies,thedivisionmayeithertelephoneorforwarda
deficiencylettertothesponsor.
•Ineithercase,thedivisioninformsthesponsorthatitmayproceedwiththeplannedclinicaltrials,
butthatadditionalinformationisnecessarytocompleteorcorrecttheINDfile,orthatthereare
issuesthatneedtobeaddressedpriortoamarketingapplication(NDA)submission.
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25. SAFETY PHARMOCOLOGY STUDIES
•Safetypharmacology(SP)isanessentialpartofthedrugdevelopmentprocessthataimstoidentifyand
predictadverseeffectspriortoclinicaltrials.SPstudiesaredescribedintheinternationalconferenceon
harmonisation(ich)s7aands7bguidelines.
•ThesupplementalSPstudiesevaluateeffectsofanewchemicalentity(NCE)atbothanticipated
therapeuticandsupra-therapeuticexposuresonmajororgansystems.Thisoutlinesthecurrentpractices
anduseofnon-standardspecies,biomarkers,andcombiningtoxicology.ThecorebatterySPstudies,
performedaccordingtogoodlaboratorypractice(GLP)standardsaspertheichguidelines,involvesthe
investigationofthemajorvitalorgansystemsincluding:-
•Cardiovascularsystem(CVS)
•Centralnervoussystem(CNS)
•Respiratorysystem
•Renalsystem
•Gastrointestinalsystem
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26. OBJECTIVE OF SAFETY PHARMACOLOGY
•According to ICH S7A:-
•To identify undesirable pharmacodynamic properties of a substances.
•To evaluate adverse pharmacodynamic and pathophysiological effect of a substance .
•To investigate the mechanism of action of a adverse pharmacodynamic effect .
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27. GENERAL CONSIDERATIONS IN SELECTION/DESIGN
❖Itwilldependeduponthespecificpropertiesofeachtestsubstance,thestudiesshouldbeselected
anddesignedaccordingly.Thefollowingfactorsshouldbeconsidered:
1)effectsrelatedtothetherapeuticclassofthetestsubstance,sincethemechanismofactionmay
suggestspecificadverseeffects.
2)adverseeffectsassociatedwithmembersofthechemicalortherapeuticclass,butindependentof
theprimarypharmacodynamiceffects.
3)ligandbindingorenzymeassaydatasuggestingapotentialforadverseeffects;
4)resultsfromprevioussafetypharmacologystudies,fromsecondarypharmacodynamicstudies,
fromtoxicologystudies,orfromhumanusethatwarrantfurtherinvestigationtoestablishand
characterizetherelevanceofthesefindingstopotentialadverseeffectsinhumans.
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28. USE OF IN VIVO AND IN VITRO STUDIES:
•Animalmodelsaswellasexvivoandinvitropreparationscanbeusedastestsystems.Exvivo
andinvitrosystemscaninclude,butarenotlimitedto:isolatedorgansandtissues,cellcultures,
cellularfragments,subcellularorganelles,receptors,ionchannels,transportersandenzymes.In
vitrosystemscanbeusedinsupportivestudies(e.g.,Toobtainaprofileoftheactivityofthe
substanceortoinvestigatethemechanismofeffectsobservedinvivo).
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29. SAMPLE SIZE AND USE OF CONTROLS
•Thesizeofthegroupsshouldbesufficienttoallowmeaningfulscientificinterpretationofthe
datagenerated.
•Thus,thenumberofanimalsorisolatedpreparationsshouldbeadequatetodemonstrateorrule
outthepresenceofabiologicallysignificanteffectofthetestsubstance.
•Thesizeofthebiologicaleffectthatisofconcernforhumans.Appropriatenegativeandpositive
controlgroupsshouldbeincludedintheexperimentaldesign.
ROUTEOFADMINISTRATION
•Exposure achieved similar to or greater than in humans
•If clinical use involves multiple routes, consider more than one route
•The expected clinical route of administration should be used when feasible.
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30. DOSE LEVELS OR CONCENTRATIONS OF TEST SUBSTANCE
Invivostudies
•Safetypharmacologystudiesshouldbedesignedtodefinethedose-responserelationshipofthe
adverseeffectobserved.
•Thetimecourse(e.g.,Onsetanddurationofresponse)oftheadverseeffectshouldbeinvestigated.
•Generally,thedoseselicitingtheadverseeffectshouldbecomparedtothedoseselicitingtheprimary
pharmacodynamiceffectinthetestspeciesortheproposedtherapeuticeffectinhumans.
Invitrostudies:
•Invitrostudiesshouldbedesignedtoestablishaconcentration-effectrelationship.
•Therangeofconcentrationsusedshouldbeselectedtoincreasethelikelihoodofdetectingan
effectonthetestsystem.
•Theupperlimitofthisrangemaybeinfluencedbyphysicochemicalpropertiesofthetest
substanceandotherassayspecificfactors.
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31. 31
Central
Nervous System
Effects of the test substance
on the central nervous
system should be assessed
appropriately.
Motor activity, behavioural
changes, coordination,
sensory/motor reflex
responses and body
temperature should be
evaluated. For example, a
functional observation
battery (FOB) modified
Irwin’s or other appropriate
test can be used
.
Respiratory
System
Effects of the test substance
on the respiratory system
should be assessed
appropriately.
Respiratory rate and other
measures of respiratory
function (e.g., tidal volume
or haemoglobin oxygen
saturation) should be
evaluated.
Cardiovascular
System
Effects of the test substance
on the cardiovascular system
should be assessed
appropriately.
Blood pressure, heart rate,
and the electrocardiogram
should be evaluated.

32. CENTRAL NERVOUS SYSTEM:
•Behavioural pharmacology
•Learning and memory
•Ligand-specific binding
•Neurochemistry
•Electrophysiology examinations, etc.
CARDIOVASCULAR SYSTEM
•Cardiac output
•Ventricular contractility
•Vascular resistance
•The effects of endogenous and/or exogenous substances
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Respiratory system:
•Airway resistance
•Compliance
•Pulmonary arterial pressure
•Blood gases
•Blood pH, etc

33. 33
Renal/Urinary
System
Effects of the test substance on renal
parameters should be assessed.
For example, urinary volume,
specific gravity, osmolality,
pH, fluid/electrolyte balance,
proteins, cytology, and blood
chemistry determinations such
as blood urea nitrogen,
creatinine and plasma proteins
can be used.
Gastrointestinal
System
Effects of the test substance on the
gastrointestinal system should be
assessed.
For example, gastric secretion,
gastrointestinal injury
potential, bile secretion, transit
time in vivo, gastric pH
measurement and pooling can
be used.

34. HERG ASSAY (HUMAN ETHER -A-GO-GO RELATED GENE)
•The alpha subunit of a potassium ion channels in the heart that codes for a protein known as
k
v11.1
•Ion channel proteins (the 'rapid' delayed rectifier current (i
kr)) that conducts potassium (K
+
)
ions out of the muscle cells of the heart
•Inhibition of the herg current causes QT interval prolongation resulting in potentially fatal
ventricular tachyarrhythmia called torsade de pointes.
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36. THANK YOU
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