ind

investigational new drug application

1. Investigational New Drug
Application(IND)

2. Investigational New Drug Application
(IND)
•AnInvestigationNewDrugApplication(IND)isa
submissiontoFood&DrugAdministration(FDA)
requestingpermissiontoinitiatethestudyofNew
drugproduct
•Inmanyways,theinvestigationalnewdrug(IND)
applicationistheresultofasuccessfulpreclinical
developmentprogram.
•TheINDisalsothevehiclethroughwhichasponsor
advancestothenextstageofdrugdevelopment
knownasclinicaltrials(humantrials).

3. •Duringanewdrug'searlypreclinicaldevelopment,the
sponsor'sprimarygoalistodetermineiftheproductis
reasonablysafeforinitialuseinhumans,andifthe
compoundexhibitspharmacologicalactivitythat
justifiescommercialdevelopment.
•Whenaproductisidentifiedasaviablecandidatefor
furtherdevelopment,thesponsorthenfocuseson
collectingthedataandinformationnecessaryto
establishthattheproductwillnotexposehumansto
unreasonableriskswhenusedinlimited,early-stage
clinicalstudies.

4. Drug-Discovery, Development
Production
&
Marketing
•IND-Investigational New Drug Application
•NDA-New Drug Application

5. Drug-Discovery, Development & Approval Process
It takes 12-15 years on an average for an experimental drug to travel from the lab to the patients.
Only 5 in 5000 compounds that enter the pre-clinical testing stage, make it to the human-testing stage.
One of these 5 tested on people is approved.
Discovery/
Pre-Clinical
Testing
Phase I Phase II Phase III FDA Phase IV
Years 5 -6.5
File
IND
at FDA
1.5 2 2.5
File
NDA
at FDA
1.5-2
Test
Population
Laboratory &
Animal Studies
20 to 100
healthy
volunteers
100 to 500
patient
volunteers
1000 to 5000
patient
volunteers
Review &
Proposal
Process
Additional
Post-
Marketing
testing
required by
FDA
Purpose
Assess safety,
biological
activity &
formulation
Determine
safety &
dosage
Evaluate
effectiveness,
look for side-
effects
Confirm
effectiveness
monitor
adverse
effects from
long-time use
Success
Rate
5000
compounds
evaluated
5 Enter Trials
1
Approve
d

6. Pharmaceuticals may move across state lines
during two stages of human use
•Researchpriorto“approval”
–Requiresresearchpermit:e.g.,Investigational
NewDrugExemption(IND)
•Marketingafter“approval”
–Requiresmarketingpermit:e.g.,NewDrug
Application(NDA)

7. Who can apply for IND????
•Applicant(DrugSponsor)
•Anapplicant,ordrugsponsor,isthepersonor
entitywhoassumesresponsibilityforthe
marketingofanewdrug,includingresponsibility
forcompliancewithapplicableprovisionsofthe
FederalFood,Drug,andCosmeticActand
relatedregulations.
•The"sponsor"isusuallyanindividual,
partnership,corporation,governmentagency,
manufacturerorscientificinstitution.

8. •TheINDapplicationprovidesFDAwithdata
necessarytodecidewhetherthenewdrug&
theproposedClinicaltrialposeareasonable
risktohumansubjectsparticipatinginthe
study.
•TheINDapplicationallowsthecompanyto
initiate&conducttheclinicalstudiesoftheir
newdrugProduct.

9. •ThesafetyoftheClinicaltrialSubjectsisalways
theprimaryconcernofFDA.
•WhenpreparingtheIND&throughouttheDrug
developmentprocesstheprimarygoalofthe
SponsorshouldbetodemonstratetotheFDAthat
the
-newdrug
-proposedtrial
-entireclinicaldevelopmentplandescribedin
theINDisdesignedtominimizetherisktothe
trialsubjects.

10. When do I need an IND?
•AnINDwouldberequiredtoconductaClinicaltrialif
thedrugis–
-anewchemicalentitynotapprovedfortheindication
underInvestigationinthenewdosageform.
-beingadministeredatthenewdosagelevel.
-Incombinationwithantherdrug&thecombinationis
notapproved.
•Allclinicalstudieswherethenewdrugisadministered
tohumansubjects,regardlessofwhetherthenewdrug
willbecommerciallydeveloped,requiredanIND

11. •Thecontent&formatofINDapplicationis
laidoutin21CFRpart312.

12. As per 21CFR part 312
IND
SUBPART A
GENERAL PROVISIONS
SUBPART B INVESTIGATIONAL
NEW DRUG APPLICATION
SUBPART C ADMINISTRATIVE
ACTIONS
SUBPART D
RESPONSIBILITIES OF
SPONSORS & INVESTIGATORS
SUBPART E
DRUGS INTENDED TO
TREAT LIFE THREATENING
AND SEVERLY
DEBILITATING ILLNESS
SUBPART F
MISCELLANEOUS
PROVISIONS
SUBPART G
DRUGS INTENDED FOR
INVESTIGATIONAL USE IN
LABORATORY RESEARCH
ANIMALS OR INVITRO TESTS

13. SUBPART B INVESTIGATIONAL NEW
DRUG APPLICATION
•312.20REQUIREMENTSOFANIND
•AsponsorshallsubmitanINDtoFDAwhointendsto
conductaclinicalinvestigation.
•Investigationisnotsupposedtobeginwithoutprior
writtenauthorizationofFDA
•312.21PHASESOFINVESTIGATION
•Phase1-ADME(20-80)healthysubjects
•Phase2–effectivenessinparticularindication(several
hundredpatients)
•Phase3–safetyandeffectiveness(100-1000)subjects.

14. •312.22GENERALPRINCILPLEOFIND
•Toassuresafetyandrightsofthesubject.
•Toassurethe scientificqualityof
investigationwillyielddatacapableof
meetingstatutorystandardsformarketing
approval
•Thecentralfocusshouldbeongeneral
investigationalplan&protocolwhichshould
besupportedbyadditionalinformation
includinganimaltoxicologicalstudies

15. 312.23 IND CONTENT & FORMAT
1.Coversheet(FORMFDA1571)
2.Tableofcontents
3.Introductorystatementandageneralinvestigationalplan
4.Investigatorsbrochure
5.Protocols
6.Chemistry,manufacturingandcontrolinformation
7.PharmacologyandToxicologyinformation
8.Previoushumanexperiencewiththeinvestigationaldrug
9.OtherrelevantinformationlikenoofINDsubmissions,
Noofcopiestobesubmitted(1+2)
10.Protocolamendments,anychangesintheprotocol.

16. •AnimalPharmacologyandToxicologyStudies
•Preclinicaldatatopermitanassessmentastowhetherthe
productisreasonablysafeforinitialtestinginhumans.
•ManufacturingInformation(CMC)
•Informationpertainingtothecomposition,manufacture,
stability,andcontrolsusedformanufacturingthedrug
substanceandthedrugproduct.
•Thisinformationisassessedastoensurethecompanycan
adequatelyproduceandsupplyconsistentbatchesofthedrug.

17. •ClinicalProtocolsandInvestigatorInformation
•Detailedprotocolsforproposedclinicalstudiesto
assesswhethertheinitial-phasetrialswillexpose
subjectstounnecessaryrisks.Also,informationon
thequalificationsofclinicalinvestigators--
professionals(generallyphysicians)whooversee
theadministrationoftheexperimentalcompound--
toassesswhethertheyarequalifiedtofulfilltheir
clinicaltrialduties

18. 2.Table of contents
•TABLEOFCONTENTS–
-ComprehensivelistingofcontentsofIND
applicationbrokeninvolumes&pagenumber.
-TOCshouldincludedetailsof-
sections,appendices,attachments,reports&
otherreferencematerial
-AwelldraftedTOCwillfacilitatethetaskof
review&decreasethereviewtime.

19. 3. GENERAL INVESTIGATIONAL
PLAN –
abrief3to4pagesnoteon–
-theinvestigationalproduct
-Sponsors’Investigationalplan
-Goalofthesectionisto–
-toprovidebriefdescriptionofthedrug
-layoutdevelopmentplanofthedrug

20. 4.Investigators brochure
-key document provided to each Investigator &
IRB at each of the Clinical site.
-includes-
ALL ABOUT THE INVESTIGATIONAL
DRUG
-IB is a living document & must be updated
by the Sponsor.

21. 5.Protocols
describeshowtheClinicaltrialwouldbe
conducted.
-Itdescribes–theobjectiveofthestudy
-thetrialdesign
-howsubjectswouldbeselected
-howthetrailistobeconducted.
-ALLABOUTTHEHOWTHESTUDY
WOULDBECONDUCTED??

22. 6.Chemistry , manufacturing and
control information
•CMCinformation-
-sufficientdetailonQUALITY,IDENITY,PURITY&
POTENCYofthedrugproduct.
-manufacturedinconformancewithcGMP.
-CMCsectionincludesthefollowing–
1.IntroductionCMC
2.Summary
3.informationofPlacebo,ifany
4.Proposedclinicallabel
5.categoricalexclusionofanyenvironmentalassessment

23. 7.Pharmacology and Toxicology
information
•PHARMACOLOGY &TOXICOLOGYDATA
–
-non-clinicalsafetydatathatsponsorgenerated
toprovethattheIPissafeforclinicalstudy.
-theamount&typeofdatadependson-
classofnewdrug
durationofproposedclinicaltrial
patientpopulationthatwillbeexposedduring
thetrial

24. 8.Previous human experience with
the investigational drug
integratedsummaryreportofanyhumanstudies
conductedontheinvestigationaldrug
Relevanttothesafetyoftheinvestigationstobe
done–Pkstudies,Pdstudies
observedadverseeventprofile

25. 9. Other relevant information like no of IND
submissions,
No of copies to be submitted (1 + 2)
•ADDITIONAL INFORMATION –special
topics
drugdependence&abusepotential
Radioactivedrugs
pediatricpopulation&otherinformation
OTHERRELEVANTINFORMATION–
InformationspecificallyrequestedbyFDA

26. •Financial disclosure information from each
Investigator & sub Investigator.
•Drug master File ( DMF)
•Reports or journal articles
•The IND application is always submitted in 1+ 2
format i.e. 1 original & 2 additional copies of
each application.

27. 312.34 Treatment use of an investigational new drug.
Thepurposeofthissectionistofacilitatetheavailabilityof
promisingnewdrugstodesperatelyillpatientsasearlyinthedrug
developmentprocessaspossible,beforegeneralmarketingbegins,
andtoobtainadditionaldataonthedrug'ssafetyandeffectiveness
Inthecaseofanimmediatelylife-threateningdisease,adrugmay
bemadeavailablefortreatmentuseunderthissectionearlierthan
Phase3,butordinarilynotearlierthanPhase2.
The“treatmentuse”ofadrugincludestheuseofadrugfor
diagnosticpurposes.
Ifaprotocolforaninvestigationaldrugmeetsthecriteriaofthis
section,theprotocolistobesubmittedasatreatmentprotocol

28. 312.35Submissions for treatment use.
•TreatmentprotocolsubmittedbyINDsponsor
Atreatmentprotocolisrequiredtocontainthefollowing:
•Theintendeduseofthedrug.
•Anexplanationoftherationaleforuseofthedrug,
•Abriefdescriptionofthecriteriaforpatientselection,The
methodofadministrationofthedrugandthedosages.
•Adescriptionofclinicalprocedures,laboratorytests,orother
measures.

29. 312.36Emergency use of an
investigational new drug (IND)
•Need for an investigational drug may arise in an emergency
situation that does not allow time for submission of an IND in
accordance with content & format .
•A request for such authorization may be transmitted to FDA by
telephone or other rapid communication means.

30. Forallotherinvestigationaldrugs,therequestfor
authorizationshouldbedirectedtotheDivisionofDrug
Information,CenterforDrugEvaluationandResearch.
Afternormalworkinghours,easternstandardtime,the
requestshouldbedirectedtotheFDAOfficeofEmergency
Operations.
Exceptinextraordinarycircumstances,suchauthorization
willbeconditionedonthesponsormakinganappropriateIND
submissionassoonaspracticableafterreceivingthe
authorization.

31. 312.38Withdrawal of an IND.
•AtanytimeasponsormaywithdrawaneffectiveINDwithout
prejudice.
•IfanINDiswithdrawn,FDAshallbesonotified,allclinical
investigationsconductedundertheINDshallbeended,allcurrent
investigatorsnotified,andallstocksofthedrugreturnedtothe
sponsororotherwisedisposedofattherequestofthesponsor.
•IfanINDiswithdrawnbecauseofasafetyreason,thesponsorshall
promptlysoinformFDA,allparticipatinginvestigators,andall
reviewingInstitutionalReviewBoards,togetherwiththereasonsfor
suchwithdrawal.

32. The FDA Form “1572”
STATEMENT OF INVESTIGATOR
•INDsponsorsarerequiredtoobtainasignedFDA
Form“1572”fromeachclinicalinvestigator,
containing:
–NameandaddressofCI
–Nameandcodenumberofanyprotocol(s)
–Nameandaddressofresearchfacilityandany
clinicallabs
–NameandaddressofresponsibleIRB
–Namesofsubinvestigators
–Signedcommitmentbytheinvestigator

33. •Theform1571istherequiredpartoftheinitialINDand
everysubsequentsubmissionrelatedtotheIND
application.
•Form1571formsthecoversheetoftheapplication&
providesFDAinformationon–
-nameofthesponsor
-INDNumber
-nameoftheInvestigationaldrug
-typeofsubmission
-serialnumber
-contentsofapplication

34. •Form1571providesasectionforthesponsor
tostatewhetheraContractResearch
organization(CRO)willconductanypartsof
thestudy&ifanyoftheSponsors’obligation
wouldbetransferredtoCRO.
•Ifsponsorresponsibilitieswillbetransferred,
thenameoftheObligationwiththename&
theaddressoftheCROshouldbementionedin
theform1571

35. •WhensigningtheForm1571,Sponsormakes
•3importantcommitmentstotheFDA–
1.TheSponsoriscommittingnottoinitiatetheclinical
trialuntil30daysaftertheFDAreceivestheIND
unlessotherwisenotifiedbyFDA&nottobeginor
continueclinicalstudiescoveredbyINDiftheyare
placedonClinicalhold.
2.ThesponsoriscommittingtoensurethatIRBwouldbe
responsibleforinitial&continuingreview&approval
ofeachstudy.
3.TheSponsoriscommittingtoconducteachstudyis
accordancetootherRegulatoryRequirement

36. IND application process
•Early consultation
sponsorsmayrequesttomeetwithFDAreviewing
officialsearlyinthedrugdevelopmentprocessto
reviewandreachagreementonthedesignof
necessarypreclinicalandclinicalstudies.

37. •Pre-investigational new drug (IND) meetings
•PriortothesubmissionoftheinitialIND,thesponsor
mayrequestameetingwithFDA-reviewingofficials.
•Theprimarypurposeofthismeetingistoreview
andreachagreementonthedesignofanimal
studiesneededtoinitiatehumantesting.
•Themeetingmayalsoprovideanopportunityfor
discussingthescopeanddesignofphase1testing,
plansforstudyingthedrugproductinpediatric
populations,andthebestapproachforpresentation
andformattingofdataintheIND

38. •End-of-phase 1 meetings
•Whendatafromphase1clinicaltestingareavailable,the
sponsormayagainrequestameetingwithFDA-
reviewingofficials.
•Theprimarypurposeofthismeetingistoreviewand
reachagreementonthedesignofphase2controlled
clinicaltrials,withthegoalthatsuchtestingwillbe
adequatetoprovidesufficientdataonthedrug’s
safetyandeffectivenesstosupportadecisiononits
approvabilityformarketing,andtodiscussand
timingof,studiesofthedruginpediatrictheneedfor,
aswellasthedesignpatients.
•EndofPhase2meetingsistodeterminethesafetyof
proceedingstoPhase-III

39. FDA’s IND REVIEW PROCESS
•Once the IND is stamped as received , it is sent
to CDER for review.
•It is further categorically divided into different
sections –
Medical
Chemistry
Pharmacology / Toxicology
Statistics

40. FDA’s IND REVIEW PROCESS
•SafetyReview:
•FollowingreviewofaninitialINDsubmission,
CDERhas30calendardaysinwhichtodecideifa
clinicalholdisnecessary(i.e.,ifpatientswouldbeat
anunacceptableriskorifCDERdoesn'thavethedata
tomakesuchadetermination).
•Generally,drugreviewdivisionsdonotcontactthe
sponsorifnoconcernsarisewithdrugsafetyandthe
proposedclinicaltrials.
•IfthesponsorhearsnothingfromCDER,thenonday
31aftersubmissionoftheIND,thestudymay
proceedassubmitted.

41. Clinical Hold Decision
•AclinicalholdisthemechanismthatCDERuseswhenit
doesnotbelieve,orcannotconfirm,thatthestudycanbe
conductedwithoutunreasonablerisktothe
subjects/patients.
•Ifthisoccurs,theCenterwillcontactthesponsorwithin
the30-dayinitialreviewperiodtostoptheclinicaltrial.
CDERmayeitherdelaythestartofanearly-phasetrialon
thebasisofinformationsubmittedintheIND,orstopan
ongoingstudybasedonareviewofnewlysubmitted
clinicalprotocols,safetyreports,protocolamendments,or
otherinformation.
•Whenaclinicalholdisissued,asponsormustaddressthe
issuethatisthebasisoftheholdbeforetheorderis
removed

42. FDA’s IND REVIEW PROCESS
•CLINICALHOLD
aclinicalholdcanbe–
-“completeclinicalhold”-adelayor
suspensionofallclinicalworkrequested
underINDsubmission
-“partialclinicalhold”-adelayor
suspensionofonlypartofclinicalworke.g.
partofprotocol.

43. Notify Sponsor
•OnceaclinicalholdisplacedonacommercialIND,the
sponsorwillbenotifiedimmediatelybytelephonebythe
divisiondirector.
•thedivisionisrequiredtosendaletterwithinfive
workingdaysfollowingthetelephonecall.
•Thelettershoulddescribethereasonsfortheclinical
hold,andmustbearthesignatureofthedivisiondirector
(oractingdivisiondirector).
•ThesponsormaythenrespondtoCDERbysendingan
"INDCLINICALHOLDRESPONSE"lettertothe
division.Toexpediteprocessing,thelettermustbe
clearlyidentifiedasan"INDCLINICALHOLD
RESPONSE"letter.

44. •Thedivisionthenreviewsthesponsor'sresponseand
decideswithin30daysastowhethertheholdshouldbe
lifted.
•Ifthedivisiondoesnotreplytotheclinicalhold
responsewithin30calendardays,thedivisiondirector
willtelephonethesponsoranddiscusswhatisbeing
donetofacilitatecompletionofthereview.
•Ifitisdecidedthattheholdwillnotbelifted,thehold
decisionisautomaticallysenttotheofficedirectorfor
review.

45. •Theofficedirectormustdecidewithin14
calendardayswhetherornottosustainthe
division'sdecisiontomaintaintheclinicalhold.
•Ifthedecisionismadetoliftthehold,the
divisiontelephonesthesponsor,informsthemof
thedecision,andsendsaletterconfirmingthat
theholdhasbeenlifted.
•Theletterwillbesentwithin5workingdaysof
thetelephonecall.However,thetrialmaybegin
oncethedecisionhasbeenrelayedtothesponsor
bytelephone.

46. Sponsor Notified of Deficiencies
•IfotherdeficienciesarefoundinanINDthatthereview
divisiondeterminesarenotseriousenoughtojustify
delayingclinicalstudies,thedivisionmayeither
telephoneorforwardaDEFICIENCYLETTERtothe
sponsor.
•Ineithercase,thedivisioninformsthesponsorthatit
mayproceedwiththeplannedclinicaltrials,butthat
additionalinformationisnecessarytocompleteorcorrect
theINDfile,orthatthereareissuesthatneedtobe
addressedpriortoamarketingapplication(NDA)
submission.

47. Study Ongoing
•OnceCDER's30-dayinitialreviewperiodexpires,clinical
studiescanbeinitiated,unlessaclinicalholdhasbeen
placed.