Drug and cosmetic act

(TobepublishedinPartI,Section3,Sub-section(i)oftheGazeteofIndia, Extraordinary,datedthe….)

GovernmentofIndia MinistryofHealthandFamilyWelfare

(DepartmentofHealthandFamilyWelfare) NewDelhi,the…………,2018

Notification.

G.S.R._(E).-WHEREASthedraftoftheNew DrugsandClinicaltrialsRules,

2018 was published,in supersession ofPartXA and Schedule Y ofthe Drugs and

CosmeticsRules,1945,andinexerciseofthepowersconferedbysection12andsection

33 of the Drugs and Cosm etics Act, 1940 (23 of 1940), in the Gazet te of India,

Extraordinary,PartI,section3,sub-section(i),videnotificationnumberG.S.R.104(E),

st
datedthe1 February,2018,bytheCentralGovernment,afterconsultationwiththeDrugs

TechnicalAdvisoryBoard,invitingobjectionsandsuggestionsfrom alpersonslikelytobe afectedthereby,beforetheexpiryofaperiodoffortyfivedaysfrom thedateonwhich copiesofthesaidGazetecontainingthesaidnotificationweremadeavailabletothe public;

ANDWHEREAS,copiesoftheGazetecontainingthesaidnotificationweremade availabletothepubliconthe1stFebruary,2018;

AND WHEREAS,alobjectionsandsuggestionsreceivedinresponsetothesaid draftnotificationhavebeendulyconsideredbytheCentralGovernment;

N O W , T H E R E F O R E ,in s u p e rs e s s io n o f P a rt X A a n d S c h e d u le Y o f th e D ru g s a n d CosmeticsRules,1945,andinexerciseofthepowersconferedbysection12andsection 33oftheDrugsandCosmeticsAct,1940(23of1940),theCentralGovernment,after consultationwiththeDrugsTechnicalAdvisoryBoard,herebymakesthefolowingrules, namely,-

CHAPTERI PRELIMINARY

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1.Shorttitle,commencementandapplicability.-(1)Theserulesmaybecaledthe NewDrugsandClinicaltrialsRules,2018.
(2)Itshalcomeintoforcefrom thedateofitsfinalpublicationintheOficial

st GazeteexceptChapterIVoftheseruleswhichshalcomeintoforcefrom 1

dayofJanuary2019.
(3)Itappliestoalnew drugs,investigationalnew drugsforhumanuse,clinical

trial,bioequivalencestudy,bioavailabilitystudyandEthicsCommitee. 2.Definitions.-(1)Intheserulesunlessthecontextotherwiserequires,-

(a)“academicclinicaltrial”meansaclinicaltrialofadrugalreadyapprovedfora certainclaim andinitiatedbyanyinvestigator,academicorresearchinstitution foranew indicationornew routeofadministrationornew doseornew dosage form,wheretheresultsofsuchatrialareintendedtobeusedonlyforacademic orresearch purposes and notforseeking approvalofthe CentralLicencing Authority or regulatory authority of any country for marketing or commercialpurpose;

(b)“Act”meanstheDrugsandCosmeticsAct,1940(23of1940); (c)“activepharmaceuticalingredient”meansanysubstancewhichcanbeused

inapharmaceuticalformulationwiththeintentiontoprovidepharmacological activityortootherwisehavedirectefectinthediagnosis,cure,mitigation, treatmentorprevention ofdisease,orto have directefectin restoring, corectingormodifyingphysiologicalfunctionsinhumanbeingsoranimals;

(d)“adverse event”means Any untoward medicaloccurence (including a symptom /diseaseoranabnormallaboratoryfinding)duringtreatmentwith aninvestigationaldrugorapharmaceuticalproductinapatientoratrial subjectthatdoesnotnecessarilyhavearelationshipwiththetreatmentbeing given.

(e)“bioavailabilitystudy”meansastudytoassesstherateandextenttowhich thedrugisabsorbedfrom apharmaceuticalformulationandbecomes available in the system ic circulation or availability of the drug at the site ofaction;

(f)“bioequivalence study”means a study to establish the absence ofa statisticalysignificantdiferenceintherateandextentofabsorptionofan activeingredientfrom apharmaceuticalformulationincomparisontothe referenceformulationhavingthesameactiveingredientwhenadministeredin thesamemolardoseundersimilarconditions;

(g)“bioavailabilityandbioequivalencestudycentre”meansacentrecreatedor establishedtoundertakebioavailabilitystudyorbioequivalencestudyofa drugforeitherclinicalpartorforbothclinicalandanalyticalpartofsuchstudy;

(h)“biomedicalandhealthresearch”meansresearchincludingstudiesonbasic, appliedandoperationalresearchorclinicalresearchdesignedprimarilyto increase scientific knowledge aboutdiseases and conditions (physicalor socio-behavioural);theirdetection and cause;and evolving strategies for healthpromotion,prevention,orameliorationofdiseaseandrehabilitationbut

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doesnotincludeclinicaltrialasdefinedinclause(j);

. (i)  â€œCentralLicencingAuthority”meanstheDrugsControlerGeneralofIndiaas
referedtoinRule3;

. (j)  â€œclinicaltrial”inrelationtoanew drugorinvestigationalnew drugmeansany
systematicstudyofsuchnew drugorinvestigationalnew druginhuman subjectstogeneratedatafordiscoveringorverifyingits,-
(i)Clinicalor; (i)pharmacologicalincludingpharmacodynamics,pharmacokinetic,or; (i)adverseefects,
withtheobjectiveofdeterminingthesafety,eficacyortoleranceofsuch
newdrugorinvestigationalnewdrug;

(k)“clinicaltrialprotocol”means a documentcontaining the background,

objective,rationale,design,methodology including maters concerning performance,management,conduct,analysis,adverse event,withdrawal, statisticalconsiderationandrecordkeepingpertainingtoclinicaltrial;

(l) “clinical trial site” m eans any hospital or institute or any other clinical establishmenthavingtherequiredfacilitiestoconductaclinicaltrial;

(m)“eficacy”inrelationtodrugsmeansitsabilitytoachievethedesiredefectin acontroledclinicalseting;

. (n)  â€œefectiveness”inrelationtoadrugmeansitsabilitytoachievethedesired efectinarealworldclinicalsituationafterapprovalofthedrug;

. (o)  â€œEthicsCommitee”meansforthepurposeof,- (i)clinicaltrial,EthicsCommitee,constitutedunderule7;
(i i) b io m e d ic a l a n d h e a lth re s e a rc h , E th ic s C o m m it te e ,c o n s titu te d u n d e r rule16.(p)“globalclinicaltrial”meansanyclinicaltrialwhichisconductedas partofaclinicaldevelopmentofadruginmorethanonecountry;

. (p)  â€œinvestigationalnewdrug”meansanewchemicalorbiologicalentityorsubstance thathasnotbeenapprovedformarketingasadruginanycountry.

. (q)  â€œinvestigationalproduct”meansthepharmaceuticalformulationofanactive ingredientorplacebobeingtestedorusedinaclinicaltrial;

. (r)  â€œinvestigator”meansapersonwhoisresponsibleforconductingclinicaltrial attheclinicaltrialsiteundertheseRules;

. (s)  â€œmedicalmanagement”meanstreatmentandothernecessaryactivitiesfor providingthemedicalcaretocomplementthetreatment.

. (t)  â€œnewchemicalentity”meansanysubstancethathasnotbeenapprovedfor marketingasadrugbyanydrugregulatoryauthorityandisproposedtobe developedasanewdrugforthefirsttimebyestablishingitssafetyand eficacy;

. (u)  â€œnew drug”m eans,-
(i)a drug, including active pharmaceutical ingredient or
phytopharmaceuticaldrug,whichhasnotbeenusedinthecountryto anysignificantextentunderconditionsspecifiedinthelabelingthereof

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andhasnotbeenapprovedassafeandeficaciousbytheCentral

LicencingAuthoritywithrespecttoitsclaims;or (i)adrugapprovedbytheCentralLicencingAuthorityforcertainclaims

and proposed to be m arketed w ith m odified or new claim s including

indication,routeofadministration,dosageanddosageform;or (i)afixeddosecombinationoftwoormoredrugs,approvedseparately forcertainclaimsandproposedtobecombinedforthefirsttimeina fixedratio,orwheretheratioofingredientsinanapprovedcombination

is proposed to be changed w ith certain claim s including indication,

routeofadministration,dosageanddosageform;or (iv)amodifiedorsustainedreleaseform ofadrugornoveldrugdelivery

systemofanydrugapprovedbytheCentralLicencingAuthority;or (v)avaccine,recombinantDeoxyribonucleicAcid(r-DNA)derivedproduct,

livingmodifiedorganism,monoclonalanti-body,stem cel,gene

therapeuticproductorxenografts,intendedtobeusedasdrug; Explanation.–Thedrugs,otherthandrugsreferedtoinsub-clauses(iv)and (v),shalcontinuetobenew drugsforaperiodoffouryears

from thedateoftheirpermissiongrantedbytheCentral LicencingAuthorityandthedrugsreferedtoinsub-clauses(iv) and(v)shalalwaysbedeemedtobenewdrugs;

(v) ‘orphandrugs’meansadrugintendedtotreataconditionwhichafectsfewerthan fivelacpersoninIndia.

(w)“pharmaceuticalformulation”meansanypreparationforhumanorveterinaryuse containing one ormore active pharmaceuticalingredients,with orwithout pharmaceuticalexcipients oradditives,thatis formulated to produce a specific physicalform (e.g.Tablet,capsule,solution)suitableforadministrationtohumanor animals;

. (x)  â€œpharmacovigilance” means the science and activities relating to detection, assessment,understandingandpreventionofadverseefectsoranyotherdrug- relatedproblem;

. (y)  â€œphytopharmaceuticaldrug”meansadrugofpurifiedandstandardisedfraction assessedqualitativelyandquantitativelywithdefinedminimum fourbio-activeor photochemicalcompoundsofanextractofamedicinalplantoritspart,forinternal orexternaluseonhumanbeingsoranimalsfordiagnosis,treatment,mitigationor preventionofanydiseaseordisorderbutdoesnotincludedrugadministeredthrough parenteralroute;

. (z)  â€œplacebo”meansaninactivesubstancevisualyidenticalinappearancetoa drugbeingtestedinaclinicaltrial;

(a)“post-trialaccess”meansmakinganewdrugorinvestigationalnewdrugavailableto atrialsubjectaftercompletionofclinicaltrialthroughwhichthesaiddrughasbeen foundbeneficialtoatrialsubjectduringclinicaltrialforsuchperiodasconsidered necessarybytheinvestigatorandtheEthicsCommitee;

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(ab)“registeredpharmacist”meansapersonwhohasbeenregisteredasapharmacist underthePharmacyAct,1948;

(ac)“Schedule”meanstheScheduleappendedtotheseRules;

(ad)“seriousadverseevent”meansanuntowardmedicaloccurenceduringclinicaltrial resultingindeathorpermanentdisabilityorhospitalisationofthetrialsubjectwhere the trialsubjectis an outdoorpatientora healthy person,prolongation of hospitalisationwherethetrialsubjectisanindoor-patient,persistentorsignificant disabilityorincapacity,congenitalanomaly,birthdefectorlifethreateningevent;

(ae)“similarbiologic”meansabiologicalproductwhichissimilarintermsofquality, safetyandeficacytoreferencebiologicalproductlicencedorapprovedinIndiaor any innovator product approved in International Council of Harmonisation (ICH)membercountries;

(af) “sponsor” includes a person, a com pany or an institution or an organisation responsibleforinitiationandmanagementofaclinicaltrial;

(ag)“StateLicencingAuthority”meanstheStateDrugsControler,bywhatevername caled,appointedbyaStateGovernment;

(ah)“trialsubject”meansapersonwhoiseitherapatientorahealthypersonto whom investigationalproductisadministeredforthepurposesofaclinical trial;

(2)The words and expressions used in these rules butnotdefined herein but d e fin e d in th e D ru g s a n d C o s m e tic s A c t, 1 9 4 0 (2 3 o f 1 9 4 0 ) s h a l l h a v e th e meaningassignedtothem intheAct.

3.

4.

CHAPTERI AUTHORITIESANDOFFICERS.

CentralLicencing Authority.-The Drugs ControlerGeneralofIndia appointedbytheCentralGovernmentintheMinistryofHealthandFamily W e lfa re s h a l l b e th e C e n tra l L ic e n c in g A u th o rity fo r th e p u rp o s e s o f theserules.

Delegation ofpowers ofCentralLicencing Authority.-(1)The Drugs ControlerGeneralofIndia,with the priorapprovalofthe Central Government,may,byanorderinwriting,delegatealoranyofpowersof theCentralLicencingAuthoritytoanyotherOficeroftheCentralDrugs Standard ControlOrganisation notbe below the rank ofAssistant DrugsControler.

(2)Theoficertowhom thepowershavebeendelegatedundersub-rule(1) shalexercisealoranyofthepowersoftheCentralLicencingAuthority underitsnameandseal.

5. ControlingOficer.-(1)TheDrugsControlerGeneralofIndiamaydesignate any oficer not below the rank of Assistant Drugs Controler as ControlingOficer.

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(2)TheDrugsControlerGeneralofIndiashal,byanorder,specifytheareas andpowersoftheControlingOficer.

(3).TheControlingOficer,designatedundersub-rule(1)shalsupervisethe w ork of sub-ordinate of ficers and shal l exercise pow ers and perform functionswhichmaybeassignedtothatOficer.

CHAPTERI ETHICSCOMMITTEEFORCLINICALTRIAL,BIOAVAILABILITYANDBIOEQUIVALENCESTUDY

6. RequirementoftheEthicsCommitee.(1)Anypersonintendstoconduct clinicaltrialorbioavailabilitystudyorbioequivalencestudyshalberequiredto haveapprovalofanEthicsCommitee. (2)TheEthicsCommiteeshalapplyforregistrationwiththeCentralLicencing

Authorityunderrule8.
7. ConstitutionofEthicsCommitee.-(1)TheEthicsCommiteeshalhave aminimum ofsevenmembersfrom medical,non-medical,scientificandnon- scientificareaswithatleast,-

(i) Onelayperson;

(i) Onewomanmember;

(i) Onelegalexpert;

(iv) Onesocialscientistorrepresentativeofnon-governmentalvoluntary agencyorphilosopherorethicistortheologianorasimilarperson.

(2)Thereshouldpreferablybe50% externalmembersinanEthicsCommitee andadequateageandgenderrepresentation.

(3)OnememberoftheEthicsCommiteeshalbetheChairperson,whoshalnot berelatedinanymannerwiththeinstituteororganisation.

(4)OneafiliatedmemberoftheEthicsCommiteeshalbeappointedasMember Secretary.

(5)Thecommiteeshalincludeatleastonememberwhoseprimaryareaof interestorspecializationisnon-scientificandatleastonememberwhois independentoftheinstitution.

(6)ThemembersoftheEthicsCommiteeshalfolow theprovisionsofthese rules,GoodClinicalPracticesGuidelinesandotherregulatoryrequirementsto safeguardtherights,safetyandwel-beingoftrialsubjects.

(7)EverymemberoftheEthicsCommiteeshalberequiredtoundergosuch traininganddevelopmentprogrammesasmaybespecifiedbytheCentral LicencingAuthorityfrom timetotime:

P ro v id e d th a t a n y m e m b e r, w h o h a s n o t s u c c e s s fu l ly c o m p le te d suchtraininganddevelopmentalprogrammes,shalbedisqualifiedtohold thepostofmemberoftheEthicsCommiteeandshalceasetobeamember ofsuchcommitee.

(8)Themembersrepresentingmedicalscientistsandcliniciansshalpossessat leastpostgraduatequalificationintheirrespectiveareaofspecializationand adequateexperienceintherespectivefieldsandhaverequisiteknowledge andclarityabouttheirroleandresponsibilityascommiteemembers.

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(9)Asfaraspossible,basedontherequirementofresearchareasuchasHIV, geneticdisorder,etc.,specificpatientgroupmayalsoberepresentedinthe EthicsCommitee.

(10)No memberan Ethics Commitee,having a conflictofinterestshalbe involvedintheoversightoftheclinicaltrialorbioavailabilityorbioequivalence studyprotocolbeingreviewedbythecommiteeandalmembersshalsigna declarationtotheefectthatthereisnoconflictofinterest.

(1 1 ) W h ile c o n s id e rin g a n a p p lic a tio n w h ic h in v o lv e s a c o n flic t o f in te re s t o f anymemberoftheEthicsCommitee,suchmembermayvoluntarilywithdraw from theEthicsCommiteereviewmeeting,inwriting,totheChairperson.

(12)Thedetailsinrespectoftheconflictofinterestofthemembershalbeduly recordedintheminutesofthemeetingsoftheEthicsCommitee.

8. RegistrationofEthicsCommiteerelatingtoclinicaltrial,bioavailability and bioequivalence study -(1)Every Ethics Commitee,constituted under rule7,shalmakeanapplicationforgrantofregistrationtotheCentralLicencing AuthorityinForm CT-01.

(2)The Ethics Commitee shalfurnish such information and documents as specifiedinTable1oftheThirdSchedulealongwiththeapplicationmadein FormCT-01.

(3)TheCentralLicencingAuthority,- (i)shalscrutinizetheinformationanddocumentsfurnishedwiththe

applicationundersub-rule(2);and (i)makesuchfurtherenquiry,ifany,considerednecessaryandafter

being satisfied,thatthe requirements ofthese rules have been compliedwith,maygrantregistrationtoEthicsCommiteeinForm CT-02andiftheCentralLicensingAuthorityisnotsatisfiedwiththe complianceoftheserulesbytheapplicantEthicsCommitee,may, rejecttheapplication,forreasonstoberecordedinwriting,

withinaperiodofforty-fiveworkingdays,from thedateofthereceiptofthe application,madeundersub-rule(1),bythesaidAuthority. (4)AnapplicantEthicsCommiteeaggrievedbythedecision,ofrejectionofthe

application,oftheCentralLicencingAuthorityunderclause(i)ofsub-rule(3), m a y p ro f fe r a n a p p e a l, b e fo re th e C e n tra l G o v e rn m e n t in th e M in is try o f HealthandFamilyWelfare,withinsixtyworkingdaysfrom thedateofthe receiptoforderofsuchrejection.

(5)TheGovernmentmay,aftersuchenquiry,asconsiderednecessary,andafter givinganopportunityofbeingheardtotheappelantreferedtoinsub-rule(4), shaldisposeoftheappealproferedundersub-rule(4)withinaperiodofsixty workingdaysfrom thedateonwhichtheappealhasbeenprof fered.

9 . V a lid ity p e rio d o f re g is tra tio n o f E th ic s C o m m it te e . -T h e re g is tra tio n grantedinForm CT-02shalremainvalidforaperiodoffiveyearsfrom thedate ofitsissue,unlesssuspendedorcanceledbytheCentralLicencingAuthority.

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10. RenewalofregistrationofEthicsCommitee,-(1)Onexpiryofthevalidity periodofregistrationgrantedunderrule8,anEthicsCommiteemaymakean applicationforrenewalofregistrationinForm CT-01alongwithdocumentsas specifiedinTable1oftheThirdSchedulethreemonthspriortothedateofthe expiryoftheregistration:

Providedthatiftheapplicationforrenewalofregistrationisreceivedbythe Central Licencing Authority three m onths prior to the date of expiry, the registrationshalcontinuetobeinforceuntilanorderispassedbythesaid authorityontheapplication:

P ro v id e d a ls o th a t fre s h s e t o f d o c u m e n ts s h a l l n o t b e re q u ire d to b e furnished,iftherearenochangesinsuchdocumentsfurnishedatthetimeof grant of registration. In such cases, a certificate shal l be rendered by the applicationindicatingthedocumentsthatthereisnochange.

(2)TheCentralLicencingAuthorityshal,afterscrutinyofinformationfurnished withtheapplicationandaftertakingintoaccounttheinspectionreport,ifany, andaftersuchfurtherenquiry,asconsiderednecessaryandonbeingsatisfied thattherequirementsoftheseruleshavebeen,-

(i)compliedwith,renewtheregistrationofEthicsCommiteeinForm CT-02,or (i)notcompliedwith,rejecttheapplication,forreasonstoberecordedin

writing,withinaperiodofforty-fiveworkingdays,from thedateof renewalapplicationmadeundersub-rule(1).

1 1 . F u n c tio n s o f E th ic s C o m m it te e . – T h e E th ic s C o m m it te e s h a l l p e rfo rm th e folowingfunctionsforaperson,institutionororganization:

(i) review and accord approval to a clinical trial,bioavailability or bioequivalencestudyprotocolandotherrelateddocuments,asthecase m a y b e , in th e fo rm a t s p e c ifie d in c la u s e (B ) o f T a b le 1 o f th e T h ird Scheduleandoverseetheconductofclinicaltrialtosafeguardtherights, safetyandwelbeingoftrialsubjectsaspertheserules,GoodClinical Practicesguidelinesandotherrelateddocuments;

(i)EthicsCommitee(s)shouldmake,atappropriateintervals,anongoing review oftheclinicaltrialsforwhichtheyhaveaccordedapproval.Sucha review maybebasedonperiodicstudyprogressreportsfurnishedbythe investigatorsand/ormonitoringandinternalauditreportsfurnishedbythe Sponsorand/orbyvisitingthestudysites.

(i)indicatethereasonsthatweighedwithitwhilerejectingoraskingfora changeornotificationintheprotocolinwritingandacopyofsuchreasons shalalsobemadeavailabletotheCentralLicencingAuthority;

(iv)whereanyseriousadverseeventoccurstoatrialsubjectoratostudy subjectduringclinicaltrialorbioavailabilityorbioequivalencestudy,shal analysetherelevantdocumentspertainingtosucheventandforwardits reporttotheCentralLicencingAuthorityandotheractionsinaccordance withCHAPTERVI;

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(v)whereatanystageofaclinicaltrial,itcomestoaconclusionthatthetrial islikelytocompromisetheright,safetyorwelbeingofthetrialsubject, thecommiteemayorderdiscontinuationorsuspensionoftheclinicaltrial andthesameshalbeintimatedtotheheadoftheinstitutionconducting clinicaltrialandalsototheCentralLicencingAuthority;

(vi)alow anyoficerauthorisedbytheCentralLicencingAuthoritytoenter, withorwithoutpriornotice,toinspectthepremises,anyrecord,orany documentsrelatedtoclinicaltrial,furnishinformationtoanyqueryraised bysuchauthorisedperson,inrelationtotheconductofclinicaltrialandto verify compliance withthe requirements ofthese rules,Good Clinical Practicesguidelinesandotherapplicableregulationsforsafeguardingthe rights,safetyandwel-beingoftrialsubjects.

(vi)comply with the requirements or conditions in addition to the requirementsspecifiedundertheActandtheserulesasmaybespecified by the CentralLicencing Authority,with the approvalofthe Central Government to safeguard the rights of clinical trial subject or bioavailabilityorbioequivalencestudysubject.

12. ProceedingsofEthicsCommitee.-(1)Noclinicaltrialorbioavailabilityor bioequivalenceprotocolandrelateddocumentsshalbereviewedbyanEthics Commiteeunlessatleastfiveofitsmembersasdetailedbelowarepresent,-

(i)medicalscientist(preferablyapharmacologist);
(i)clinician;
(i)legalexpert; (iv)socialscientistorrepresentativeofnon-governmentalvoluntaryagencyor

philosopherorethicistortheologianorasimilarperson; (v)laypersonfromcommunity.

(2)Thecommiteemayconstituteoneormoresub-commiteeofitsmembersto assistinthefunctionsassignedtoit.

(3)TheEthicsCommiteemayassociatesuchexpertswhoarenotmembersof the commitee,in its deliberations butsuch experts shalnothave any votingrights.

(4)AnychangeinthemembershiportheconstitutionoftheregisteredEthics CommiteeshalbeintimatedinwritingtotheCentralLicencingAuthority withinthirtyworkingdays;

13. MaintenanceofrecordsbyEthicsCommitee.-(1)TheEthicsCommitee shalmaintain data,record,registers and otherdocuments related to the functioningandreview

ofclinicaltrialorbioavailabilitystudyorbioequivalencestudy,asthecasemaybe, foraperiodoffiveyearsaftercompletionofsuchclinicaltrial. (2)Inparticularandwithoutprejudicetothegeneralityofthesub-rule(1),the

EthicsCommiteeshalmaintainfolowingrecordsforaperiodoffiveyears aftercompletionofeveryclinicaltrialorbioavailabilitystudyorbioequivalence study,namely,-

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(i) theconstitutionandcompositionoftheEthicsCommitee;
(i i) th e c u r ric u lu m v ita e o f a l l m e m b e rs o f th e E th ic s C o m m it te e ; (i)standardoperatingproceduresfolowedbythecommitee; (iv)nationalandinternationalguidelinesfolowedbythecommitee; (v) copiesoftheprotocol,datacolectionformats,casereportforms,

investigator’sbrochures,etc.,submitedforeview;
(vi) al l cor respondence w ith com m it tee m em bers and investigators

regardingapplication,decisionandfolowup; (vi)agendaofalEthicsCommiteemeetingsandminutesofalEthics

CommiteemeetingswithsignatureoftheChairperson; (vi)copiesofdecisionscommunicatedtoapplicants; (ix)recordsrelatingtoanyorderissuedforprematureterminationof

studywithasummaryofthereasonstherefore;
(x) finalreportofthestudyincludingmicrofilms,compactdisksor

videorecordings; (xi)recommendationgivenbyEthicsCommiteefordeterminationof

compensation.
(xi)records relating to the serious adverse event, medical

managementoftrialsubjectsandcompensationpaid. (3)TheEthicsCommiteeshalfurnishtheinformationmaintainedundersub-rule (1)andsub-rule(2),asandwhenrequiredbytheCentralLicencingAuthority

oranyotheroficerauthorisedonitsbehalf.

14. SuspensionorcancelationofregistrationofEthicsCommitee.-(1) WhereCentralLicensingAuthorityisoftheopinionthatanyEthicsCommitee failstocomplywithanyprovisionoftheActandtheserules,mayissueshow cause notice to such Ethics Commitee specifying therein the such non- compliances and period in which reply is to be furnished by such EthicsCommitee.

(2)Onreceiptofreplyoftheshow causenoticewithinaperiodspecifiedinthe showcausenotice,theCentralLicensingAuthoritymaygiveanopportunityof beingheard,inpersontosuchEthicsCommitee.

(3)After consideration of the facts and reply given by the Ethics Com m it tee undersub-rule(2),theCentralLicensingAuthority,maytakeoneormore actions,namely,- (i)maywithdrawshowcausenoticeissuedundersub-Rule(1); (i)issuewarningtotheEthicsCommiteedescribingthedeficiencyordefect

observedduringinspectionorotherwise,whichmayadverselyafectthe rightsorwel-beingofthetrialsubjectorthevalidityofclinicaltrialor bioavailabilityorbioequivalencestudybeingconducted;

(i)rejecttheresultsofclinicaltrialorbioavailabilityandbioequivalencestudy;

(iv)suspend forsuch period as considers appropriate orcancelthe registrationissuedunderRule8;

(v)debaritsmemberstooverseeanyclinicaltrialinfutureforsuchperiodas Page10of10

maybeconsideredappropriatebytheCentralLicencingAuthority.
(4)W here the Ethics Com m it tee or any m em ber of the Ethics Com m it tee,

aggrieved by an order of the Central Licencing Authority under sub-Rule (3),such aggrieved Ethics Commit tee ormember,may,within a period of sixtyworkingdaysofthereceiptoftheorder,proferanappealtotheCentral Government.

(5)Whereanappealhasproferedundersub-Rule(4),theCentralGovernment may,aftersuchenquiry,asitthinksnecessary,andaftergivinganopportunity ofbeingheard,passsuchorderinrelationtheretoasitthinksappropriatein thefactsandcircumstancesofthecasewithinaperiodofsixtyworking daysfrom thedatewhentheappealisprof fered.

CHAPTERIV ETHICSCOMMITTEEFORBIOMEDICAL ANDHEALTHRESEARCH

15. Requirementforthe Ethics Commitee forbiomedicaland health research.-Any institution or organisation intends to conduct biom edical and health research shal lbe required to have an Ethics Com m it tee to review andoverseetheconductofsuchresearchasdetailedinNational EthicalGuidelinesforBiomedicalandHealthResearchInvolvingHuman Participants.

16. ConstitutionofEthicsCommitee.-(1)TheEthicsCommiteereferedtoin Rule15,relatingtobiomedicalandhealthresearchshalbeconstitutedin accordancewiththeNationalEthicalGuidelinesforBiomedicalandHealth ResearchInvolvingHumanParticipantsasmaybespecifiedbytheIndian CouncilofMedicalResearchfrom timetotimeandshalfunctionin accordancewiththeseguidelines.

(2)TheEthicsCommiteereferedtoinsub-Rule(1),shalreview theworkof thebiomedicalandhealthresearchcentrebeforeinitiationandoversee throughout the duration of the biom edical and health research as per NationalEthicalGuidelinesforBiomedicalandHealthResearchInvolving HumanParticipants..

(3)Aninstitutionororganizationoranypersonshalconductanybiomedical andhealthresearchwiththeapprovaloftheEthicsCommiteeregistered underRule17.

(4)Anybiomedicalandhealthresearchshalbeconductedinaccordancewith the NationalEthicalGuidelines forBiomedicaland Health Research InvolvingHumanParticipantsasmaybespecifiedbytheIndianCouncilof MedicalResearchfrom timetotime.

(5)Institutionsdesirousofconductingbiomedicalandhealthresearchaswel as clinical trials or bioavailability or bioequivalence study shalrequireobtainingregistrationfrom specifiedauthoritiesasunderrule8

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andrule17.

17. RegistrationofEthicsCommiteerelatedtobiomedicalandhealthresearch.- (1)An EthicsCommiteeconstitutedunder Rule

16,shalberequiredtoregisterwiththeauthoritydesignatedbytheDepartmentof HealthResearch,intheMinistryofHealthandFamilyWelfare,Governmentof India,undertheseRulesforwhichanapplicationshalbemadeinForm CT-01 tothesaidauthority.

(2)The application refered to in sub-Rule (1)shalbe accompanied with theinformationanddocumentsasspecifiedinTable1oftheThirdSchedule.

(3)OnreceiptofapplicationinForm CT-01undersub-rule(1),theauthority designatedundersub-Rule(1)shalgrantprovisionalregistrationwhichshal remainvalidforaperiodoftwoyears.

(4)Afterthegrantofprovisionalregistrationundersub-rule(3),theauthority designatedundersub-rule(1)shalscrutinizethedocumentsandinformation furnishedwiththeapplication,andonbeingsatisfied,thatherequirementsof these rules have been complied with,grantfinalregistration to Ethics CommiteeinForm CT-03andifnot,rejecttheapplication,forreasonstobe recordedinwriting.ThefinalregistrationinForm CT-03shalsupersedethe provisionalregistrationgrantedundersub-rule(3).

(5)Anapplicantwhoisaggrievedbythedecisionoftheauthoritydesignated undersub-Rule(1),mayfileanappealwithinsixtyworkingdaysfrom thedate ofreceiptofsuchrejectionbeforetheCentralGovernmentintheMinistryof HealthandFamilyWelfare,andtheGovernment,may,aftersuchenquiryasis considerednecessaryinthefactsandcircumstancesofthecaseandafter givinganopportunityofbeingheardtotheappelant,disposeoftheappeal withinaperiodofsixtyworkingdays.

(6)TheEthicsCommiteeshalmakeanapplicationforrenewalofregistrationin Form CT-01alongwithdocumentsasspecifiedinsub-rule(2)atleastthree monthspriortothedateoftheexpiryofitsfinalregistration:

Providedthatiftheapplicationforrenewalofregistrationisreceived bytheauthoritydesignatedundersub-Rule(1),threemonthspriortothedate ofexpiry,theregistrationshalcontinuetobeinforceuntilanorderispassed bythesaidauthorityontheapplication:

Providedfurtherthatfreshsetofdocumentsshalnotberequiredto befurnished,iftherearenochangesinsuchdocumentsfurnishedearlier.In suchcases,acertificateshalberenderedbytheapplicationindicatingthe documentsthatthereisnochange.

(7)Theauthoritydesignatedundersub-Rule(1)shalafterscrutinyofinformation furnishedwiththeapplicationandaftersuchfurtherenquiry,asconsidered necessaryandonbeingsatisfiedthattherequirementsoftheseRuleshave b e e n c o m p lie d w ith , re n e w th e re g is tra tio n o f E th ic s C o m m it te e in F o rm C T – 03,orifnotrejecttheapplication,forreasonstoberecordedinwriting,

(8) Theauthorityshaltakeadecisionundersub-rule(7)withinaperiodofforty

fiveworkingdays,from thedateofapplicationmadeundersub-Rule(1). Page12of12

(9) TheregistrationgrantedinForm CT-03shalremainvalidforaperiodof fiveyearsfrom thedateofitsissue,unlesssuspendedorcanceledbythe authoritydesignatedundersub-Rule(1).

(10)Thefunction,proceedingsofethicscommiteeandmaintenanceofrecords aspernationalethicalguidelines.

(11)IncasethereisachangeincompositionofregisteredECinaninstitutionit shouldbereportedtoAuthority.

18. SuspensionorcancelationofregistrationofEthicsCommitee.-(1) SubjecttoprovisionofRule17,wheretheEthicsCommiteefailstocomplywith anyprovision oftheseRules,theauthoritydesignatedundersub-Rule(1),may, aftergivinganopportunitytoshow causeandafterafordinganopportunityof beingheard,byanorderinwriting,takeoneormoreofthefolowingactions, namely,-

(i) is s u e w a rn in g to th e E th ic s C o m m it te e d e s c rib in g th e d e fic ie n c y o r defectobserved,whichmayadverselyafecttherightsorwel-beingof thestudysubjects;

(i i) suspend for such period as considered appropriate or cancel the registrationissuedunderRule18;

(i)debaritsmemberstooverseeanybiomedicalhealthresearchinfuture forsuchperiodasmaybeconsideredappropriate.

(2)WheretheEthicsCommiteeoritsmember,asthecasemaybe,isaggrieved byanorderoftheauthoritydesignatedundersub-Rule(1),itmay,withina periodofforty-fiveworkingdaysofthereceiptoftheorder,makeanappeal to the CentralGovernmentin the MinistryofHealth and FamilyWelfare, GovernmentofIndia,andtheCentralGovernmentmay,aftersuchenquiry,as deemednecessary,andaftergivinganopportunityofbeingheard,passsuch orderinrelationtheretoasmaybeconsideredappropriateinthefactsand circumstancesofthecase.

CHAPTERV CLINICALTRIAL,BIOAVAILABILITYANDBIOEQUIVALENCESTUDYOFNEW

DRUGSANDINVESTIGATIONALNEW DRUGS

PARTA CLINICALTRIAL

19. Clinicaltrialofnew drugorinvestigationalnew drug.–(1)Nopersonor institution or organisation shal l conduct clinical trial of a new drug or investigationalnewdrug,-

(i)exceptinaccordancewiththepermissiongrantedbytheCentral LicencingAuthority;and

(i)withouttheprotocolthereofhavingbeenapprovedbytheEthics CommiteeregisteredinaccordancewiththeprovisionsofRule8.

Page13of13

(2) Everypersonassociatedwiththeconductofclinicaltrialofanew drugor investigationalnew drugshalfolow thegeneralprinciplesandpracticesas specifiedintheFirstSchedule.

(3)Nopersonorinstitutionororganisationshalconductclinicaltrialofanew drugorinvestigationalnew drugexceptaspertheprocedureprescribed undertheprovisionsoftheActandtheseRules.

20. Oversightofclinicaltrialsite.–Theworkofeveryclinicaltrialsiteshalbe overseen by an Ethics Com m it tee refer red to in Rule8,before initiation and throughoutthedurationoftheconductofsuchtrial.

21. Applicationforpermissiontoconductclinicaltrialofanew drugor investigationalnew drug.-(1)Anypersonorinstitutionororganisationintendsto conductclinicaltrialofanew drugoraninvestigationalnew drugshalmakean applicationtotheCentralLicensingAuthoritydulyfiledinFormCT-04.

(2)The application made undersub-rule (1)shalbe accompanied with the informationanddocumentsasspecifiedintheSecondScheduleandbyafee asspecifiedintheSixthSchedule:

Providedthatnofeeshalbepayabletoconductaclinicaltrialbya personofaninstitutionororganisationfundedorowned,wholyorpartialyby theCentralGovernmentorbyaStateGovernment.

22. Grantofpermissiontoconductclinicaltrial.-(1)TheCentralLicencing Authoritymay,afterscrutinyoftheinformationanddocumentsfurnishedwiththe applicationinForm CT-04andsuchfurtherenquiry,ifany,asmaybeconsidered necessary,-

(i)ifsatisfied,thattherequirementsoftheseruleshavebeencomplied with,grantthepermissiontoconductclinicaltrialforanew drugor investigationalnewdruginForm CT-06;

(i)incase,wheretheCentralLicencingAuthorityconsidersthatthereare somedeficienciesintheapplicationandthesamemayberectified, saidAuthorityshalinform theapplicantofthedeficiencies;

(i)ifnotsatisfiedthattherequirementsoftheseruleshavebeencomplied with,rejecttheapplication,forthereasonstoberecordedinwriting;

(2)Thedecisionundersub-rule(1)shalbetakenwithinninetyworkingdays.

(3)Theapplicant,afterbeinginformed,asreferedtoinclause(i)ofsub-rule(1), bytheCentralLicencingAuthority,may,-

(i)rectify the deficiencies within a period specified by the Central LicencingAuthority;

(i)wheretheapplicantrectifiesthedeficiency,asreferedinsub-rue (1),andprovidesrequiredinformationanddocuments,theCentral LicencingAuthorityshalscrutinizetheapplicationagainandif satisfied,grantpermissiontoconductclinicaltrialofthenewdrug orinvestigationalnewdrugorifnotsatisfied,rejecttheapplication:

Page14of14

Provided thatin case ofrejection,the applicantmay requesttheCentralLicencingAuthority,toreconsidertheapplication withinaperiodofsixtyworkingdaysfrom thedateofrejectionofthe applicationonpaymentoffeeasspecifiedintheSixthScheduleand submissionofrequiredinformationanddocuments.

(4 ) A n a p p lic a n t w h o is a g g rie v e d b y th e d e c is io n o f th e C e n tra l L ic e n c in g Authorityundersub-Rule(1)sub-Rule(2),mayfileanappealbeforetheCentral GovernmentintheMinistryofHealthandFamilyWelfarewithinfortyfivedays from thedateofreceiptofsuchdecisionandtheGovernment,may,aftersuch enquiry,and aftergiving an opportunityofbeing heard to the appelant, disposeoftheappealwithinaperiodofsixtyworkingdays.

23. Permissiontoconductclinicaltrialofanew drugorinvestigationalnew drug as part of discovery, research and manufacture in India.- (1) Notwithstanding anything contained in these Rules,where any person or institutionororganisationmakeanapplicationunderRule21toconductclinicaltrialof anew drugoraninvestigationalnew drugwhichiscompleteaspertheserulesand fulfilsthefolowingconditions,namely,-

(i) thedrugisdiscoveredinIndia;or (i)researchanddevelopmentofthedrugarebeingdoneinIndiaandalsothe

drugisproposedtobemanufacturedandmarketedinIndia, Suchapplicationshalbedisposedbywayofgrantofpermissionorrejectionor processedbywayofcommunicationtorectifyanydeficiencyoftheapplication, asthecasemaybe,asspecifiedinRule22,bytheCentralLicensingAuthority withinaperiodofthirtyworkingdaysfrom thedateofthereceiptofthe applicationbythesaidAuthority:

Providedthat,wherenocommunicationhasbeenreceivedfrom the CentralLicensingAuthoritytotheapplicantwithinthesaidperiod,thepermission toconductclinicaltrialshalbedeemedtohavebeengrantedbytheCentral LicensingAuthorityandsuchpermissionshalbedeemedlegalyvalidforal purposesandtheapplicantshalbeauthorisedtoinitiateclinicaltrialunderthese rules. (2)Theapplicantwhohastakendeemedapprovalundersub-rule(1)shalbefore

initiatingtheclinicaltrialinform theCentralLicensingAuthorityinForm CT- 4A.OnthebasisofthesaidinformationtheCentralLicensingAuthorityshal takeonrecordtheForm CT-4Awhichshalbecomepartoftheoficialrecord andshalbecaledautomaticapprovaloftheCentralLicensingAuthority.

24. Permissiontoconductclinicaltrialofanew drugalreadyapproved outsideIndia.-NotwithstandinganythingcontainedintheseRules,whereany person or institution or organisation m akes an application under Rule 21 to conductclinicaltrialofanew drugwhichisalreadyapprovedandmarketedina country,asspecifiedunderRule100,theapplication,shalbedisposedofbyway ofgrantofpermissionorrejectionorprocessedbywayofcommunicationto

rectifyanydeficiency,asthecasemaybe,asspecifiedinRule22,bytheCentral Page15of15

LicensingAuthoritywithinaperiodofninetyworkingdaysfrom thedateofthe receiptoftheapplicationbythesaidAuthority.

25. Conditionsofpermissionforconductofclinicaltrial.-Thepermission g ra n te d b y th e C e n tra l L ic e n c in g A u th o rity to c o n d u c t c lin ic a l tria l u n d e r th is chaptershalbesubjecttofolowingconditions,namely,-

. (i)  clinicaltrialateachsiteshalbeinitiatedafterapprovaloftheclinicaltrial protocolandotherrelateddocumentsbytheEthicsCommiteeofthatsite, registeredwiththeCentralLicencingAuthorityunderRule8;

. (i)  whereaclinicaltrialsitedoesnothaveitsownEthicsCommitee,clinical trialatthatsitemaybeinitiatedafterobtainingapprovaloftheprotocol fromtheEthics Commitee ofanothertrialsite;oran independentEthics CommiteeconstitutedinRule7:
P ro v id e d th a t th e a p p ro v in g E th ic s C o m m it te e s h a l l in s u c h caseberesponsibleforthestudyatthetrialsiteorthecentre,asthe casemaybe:
ProvidedfurtherthattheapprovingEthicsCommiteeandtheclinical trialsiteorthebioavailabilityandbioequivalencecentre,asthecasemaybe, s h a l l b e lo c a te d w ith in th e s a m e c ity o r w ith in a ra d iu s o f 5 0 k m o f th e c lin ic a l trialsite.

. (i)  theCentralLicencingAuthorityshalbeinformedabouttheapproval grantedbytheEthicsCommiteewithinaperiodof15workingdaysofthe grantofsuchapproval;

(iv)

(v)

(vi)

(vi)

(vi)

(ix)

ClinicaltrialshalberegisteredwiththeClinicaltrialRegistryofIndia maintainedbytheIndianCouncilofMedicalResearchbeforeenroling thefirstsubjectforthetrial; clinicaltrialshalbeconductedinaccordancewiththeapprovedclinical trialprotocolandotherrelateddocumentsandasperrequirementsof GoodClinicalPracticesguidelinesandprovisionsoftheserules; StatusofenrolmentofthetrialsubjectsshalbesubmitedtotheCentral LicencingAuthorityonquarterlybasisorasappropriateasperthe durationoftreatmentaspertheapprovedclinicaltrialprotocol, whicheverisearlier. sixmonthlystatusreportofeachclinicaltrial,astowhetheritisongoing, completedorterminated,shalbesubmitedtotheCentralLicencing Authorityelectronicaly; incaseofterminationofanyclinicaltrialthedetailedreasonsforsuch te rm in a tio n s h a l l b e c o m m u n ic a te d to th e C e n tra l L ic e n c in g A u th o rity withinthirtyworkingdaysofsuchtermination; anyreportofseriousadverseeventoccuringduringclinicaltrialtoa subject of clinical trial, shal l, after due analysis, be forw arded to the CentralLicencingAuthority,thechairpersonoftheEthicsCommiteeand theinstitutewherethetrialhasbeenconductedwithinfourteendaysof itsoccurenceasperTable5oftheThirdScheduleandincompliance

Page16of16

withtheproceduresasspecifiedinCHAPTERVI;
(x) in case ofan injuryduring clinicaltrialto the subjectofsuch trial,

completemedicalmanagementandcompensationshalbeprovidedin accordancewithCHAPTER VIanddetailsofcompensationprovidedin suchcasesshalbeintimatedtotheCentralLicencingAuthoritywithin thirtyworkingdaysofthereceiptofrecommendationsmadebyEthics CommiteeinaccordancewithCHAPTERVI;

(xi)incaseofclinicaltrialrelateddeathorpermanentdisabilityofanysubject ofsuch trialduring the trial,compensation shalbe provided in accordancewithCHAPTER VIanddetailsofcompensationprovidedin suchcasesshalbeintimatedtotheCentralLicencingAuthoritywithin thirtyworkingdaysofreceiptoftheorderissuedbytheCentralLicencing AuthorityinaccordancewithCHAPTERVI;

(xi i) the prem ises ofthe sponsorincluding his representatives and clinicaltrial sites,shalbeopenforinspectionbyoficersoftheCentralLicencing Authoritywhomaybeaccompaniedbyoficersofthestatelicencing authority oroutside experts as authorised by the CentralLicencing Authority,toverifycomplianceoftherequirementsoftheseRulesand GoodClinicalPractices,toinspect,searchandseizeanyrecord,result, document,investigationalproduct,related to clinicaltrialand furnish replytoqueryraisedbythesaidoficerinrelationtoclinicaltrial;

(x i i i) w h e re th e n e w d ru g o r in v e s tig a tio n a l n e w d ru g is fo u n d to b e u s e fu l in clinical developm ent, the sponsor shal l subm it an application to the CentralLicencingAuthorityforpermissiontoimportormanufacturefor saleorfordistributionofnewdruginIndia,inaccordancewithCHAPTER XoftheseRules,unlessotherwisejustified;

(xiv)thelaboratoryownedbyanypersonoracompanyoranyotherlegal entityandutilisedbythatpersontowhom permissionforclinicaltrialhas been granted used for research and developm ent shal l be deem ed registered with the Licensing Authorityand maybe used fortestor analysisofanydrugforandonbehalfofLicensingAuthority.

(xv) TheCentralLicencingAuthoritymay,ifconsiderednecessary,imposeany otherconditioninwritingwithjustification,inrespectofspecificclinical trials,regarding the objective,design,subjectpopulation,subject eligibility, assessment, conduct and treatment of such specific clinicaltrial.

(xvi)TheSponsorandtheInvestigatorshalmaintainthedataintegrityofthe datageneratedduringclinicaltrial.

26.Validityperiodofpermissiontoinitiateaclinicaltrial.-Thepermissionto initiateclinicaltrialgrantedunderRule22inForm CT-06shalremainvalidfor aperiodoftwoyearsfrom thedateofitsissueunlessextendedbytheCentral LicencingAuthority.

Page17of17

27. Post-trialaccessofinvestigationalnew drugornew drug.-Whereany investigatorofaclinicaltrialofinvestigationalnew drugornew drughas recommendedpost-trialaccessofthesaiddrugaftercompletionofclinicaltrial toanytrialsubjectandthesamehasbeenapprovedbytheEthicsCommitee, thepost-trialaccessshalbeprovidedbythesponsorofsuchclinicaltrialtothe trialsubjectfreeofcost,-

(i)ifthe clinicaltrialis being conducted foran indication forwhich no alternativetherapyisavailableandtheinvestigationalnewdrugornewdrug hasbeenfoundtobebeneficialtothetrialsubjectbytheinvestigator;and (i)thetrialsubjectorlegalheirofsuchsubject,asthecasemaybe,has consentedinwritingtousepost-trialinvestigationalnew drugornew drug; and

theinvestigatorhascertifiedandthetrialsubjectorhislegalheir,asthecase maybe,hasdeclaredinwritingthatthesponsorshalhavenoliabilityforpost- trialuseofinvestigationalnewdrugornewdrug.
28. Academicclinicaltrial.-(1)Nopermissionforconductinganacademic clinicaltrialshalberequiredforanydrugfrom theCentralLicencing Authoritywhere,-

. (i)  the clinical trial in respect of the perm it ted drug form ulation is intendedsolelyforacademicresearchpurposesforanewindicationor newrouteofadministrationornewdoseornewdosageform;and

. (i)  theclinicaltrialreferedtoinclause(i)hasbeeninitiatedafterprior approvalbytheEthicsCommitee;and

(i)theobservationsgeneratedfrom suchclinicaltrialarenotrequiredto besubmitedtotheCentralLicencingAuthority;and

(iv)theobservationsofsuchclinicaltrialarenotusedforpromotional purposes.

(2)Intheeventofapossibleoverlapbetweentheacademicclinicaltrialand clinicaltrialora doubton the nature ofstudy,the Ethics Commitee c o n c e rn e d s h a l l in fo rm th e C e n tra l L ic e n c in g A u th o rity in w ritin g in d ic a tin g its viewswithinthirtyworkingdaysfrom thereceiptofapplication.

(3)TheCentralLicencingAuthorityshal,afterreceivingthecommunicationfrom the Ethics Com m it tee refer red to in sub-rule (2), exam ine it and issue necessaryclarification,inwriting,withinthirtyworkingdaysfrom thedateof receiptofsuchcommunication:

ProvidedthatwheretheCentralLicencingAuthoritydoesnotsend therequiredcommunicationtotheEthicsCommiteewithinthirtyworking daysfrom thedateofreceiptofcommunicationfrom thesaidEthics Commitee,itshalbepresumedthatnopermissionfrom theCentral LicencingAuthorityisrequired.

(4)Theapprovedacademicclinicaltrialshalbeconductedinaccordancewith the approved clinicaltrialprotocol,ethicalprinciples specified in ethical guidelinesforbiomedicalandhealthresearchonhumanparticipant,notified

Page18of18

bytheIndianCouncilofMedicalResearchwithaview toensuringprotection ofrights,safetyandwel-beingoftrialsubjectduringconductofclinicaltrial oflicencedandapproveddrugordrugformulationforanynew indicationor new routeofadministrationornew doseornew dosageform foracademic researchpurposes.

29. Inspection of prem ises relating to clinical trial.-The person or the institutionortheorganizationpermitedtoconductclinicaltrialunderRule22in Form CT-06includinghisrepresentativesandinvestigator,shalalowanyoficer authorisedbytheCentralLicencingAuthority,whomay,ifconsiderednecessary, beaccompaniedbyanoficerauthorisedbytheStateLicencingAuthority,to enterwithorwithoutpriornoticehispremisesandclinicaltrialsitetoinspect, searchorseize,anyrecord,statisticalresult,document,investigationaldrugand otherrelatedmaterialandreplytoqueriesraisedbytheinspectingauthorityin relationtoconductofsuchclinicaltrial.

30. Suspensionorcancelationofpermissiontoconductclinicaltrial.-(1) Whereanypersonorinstitutionororganisationtowhom permissionhasbeen grantedunderrule22inForm CT-06failstocomplywithanyprovisionoftheAct andtheserules,theCentralLicencingAuthoritymay,aftergivinganopportunity to s h o w c a u s e a n d a fte r a f fo rd in g a n o p p o rtu n ity o f b e in g h e a rd , b y a n o rd e r in writing,takeoneormoreofthefolowingactions,namely,-

(i) issuewarninginwritingdescribingthedeficiencyordefectobserved duringinspectionorotherwise,whichmayafectadverselytheright,or wel-beingofatrialsubjectorthevalidityofclinicaltrialconducted;

(i i) rejecttheresultsofclinicaltrial;
(i) suspend forsuch period as considered appropriate orcancelthe

permissiongrantedunderrule22inForm CT-06;

(iv)debartheinvestigatororthesponsorincludinghisrepresentativesto conductany clinicaltrialin future forsuch period as considered appropriatebytheCentralLicencingAuthority.

(2)Whereapersonoraninstitutionoranorganisationtowhom permissionhas beengrantedunderrule22inForm CT-06orthesponsorisaggrievedbythe orderoftheCentralLicencingAuthority,thepersonortheinstitutionorthe organizationmay,withinaperiodofsixtyworkingdaysofthereceiptofthe order,makeanappealtotheCentralGovernmentandthatGovernmentmay, aftersuchenquiry,asdeemednecessary,andafterafordinganopportunity ofbeingheard,passsuchorderinrelationtheretoasmaybeconsidered appropriateinthefactsandcircumstancesofthecase.

PARTB BIOAVAILABILITYANDBIOEQUIVALENCESTUDY

31. Bioavailabilityorbioequivalencestudyofnew drugorinvestigational Page19of19

new drug.– (1)Nobioavailabilityorbioequivalencestudyofanynew drugor investigationalnew drugshalbeconductedinhumansubjectsbyanypersonor institutionororganisationexceptinaccordancewiththeprovisionsoftheAct andtheserules.

(2) Nopersonorinstitutionororganisationshalconductbioavailabilityor bioequivalencestudyofanew drugorinvestigationalnew druginhuman subjectsexceptinaccordancewiththepermissiongrantedbytheCentral LicencingAuthorityandwithouttheprotocolthereofhavingbeenapproved bytheEthicsCommiteeconstitutedinaccordancewiththeprovisionsof rule7.

(3)Everypersonassociatedwiththeconductofbioavailabilityorbioequivalence studyofanew drugorinvestigationalnew drugshalfolow thegeneral principlesandpracticesasspecifiedintheFirstSchedule.

32. Oversightofbioavailabilityorbioequivalencestudycentre.–Theworkof everybioavailabilityorbioequivalencestudycentreshalbeoverseenbyanEthics Commiteereferedtoinrule7,beforeinitiationandthroughoutthedurationof theconductofsuchstudy.

33. Applicationforpermissiontoconductbioavailabilityorbioequivalence study.-(1)Any person orinstitution ororganisation intends to conduct bioavailabilityorbioequivalencestudyofanew drugoraninvestigationalnew druginhumansubjectsshalobtainpermissionforconductingbioavailabilityor bioequivalencestudyfrom theCentralLicencingAuthoritybymakingan applicationinFormCT-05.

(2)An application for grant of permission to conduct bioavailability or bioequivalencestudyofanynew drugorinvestigationalnew drugshalbe accompanied by a fee as specified in Sixth Schedule and such other informationanddocumentsasspecifiedintheTable2oftheFourthSchedule:

Providedthatnofeeshalbepayableforconductingabioavailabilityor bioequivalencestudybyaninstitutionororganisationownedorfundedwholy andpartialybytheCentralGovernmentorStateGovernment.

34. Grantofpermissiontoconductbioavailabilityorbioequivalencestudy.- (1)TheCentralLicencingAuthoritymay,afterscrutinyoftheinformationand documentsfurnishedwiththeapplicationinForm CT-05andsuchfurtherenquiry, ifany,asmaybeconsiderednecessary,-

(i) ifsatisfied,thattherequirementsoftheseruleshavebeencomplied with,grantthepermissiontoconductbioavailabilityorbioequivalence studyforanew drugorinvestigationalnew druginForm CT-07,ifnot satisfied reject the application, for that reasons to be recorded in writingwithinaperiodofninetyworkingdaysfrom thedateofreceipt ofitsapplicationinFormCT-05;

(i)incase,wheretheCentralLicencingAuthorityconsidersthatthereare somedeficienciesintheapplicationandthesamemayberectified,

Page20of20

saidAuthorityshalinform theapplicantofthedeficiencieswithinthe

stipulatedperiodreferedtoinclause(i); (2)Thedecisionundersub-rule(1)shalbetakenwithinninetyworkingdays. (3)Theapplicant,afterbeinginformed,asreferedtoinclause(i)ofsub-rule(1),

bytheCentralLicencingAuthority,may,
(i)rectify the deficiencies within a period specified by the Central

LicencingAuthority; (i)wheretheapplicantrectifiesthedeficiency,asreferedinsub-rue

(1)andprovidesrequiredinformationanddocuments,theCentral LicencingAuthorityshalscrutinizetheapplicationagainandif satisfied, grant permission to conduct bioavailability or bioequivalencestudyofthenew drugorinvestigationalnew drug orifnotsatisfied,rejecttheapplicationwithinaperiodofninety working days reckoned from the day when the required informationanddocumentswereprovided:

Provided thatin case ofrejection,the applicantmay requesttheCentralLicencingAuthority,toreconsidertheapplication withinaperiodofsixtyworkingdaysfrom thedateofrejectionofthe applicationonpaymentoffeeasspecifiedintheSixthScheduleand submissionofrequiredinformationanddocuments.

(4 ) A n a p p lic a n t w h o is a g g rie v e d b y th e d e c is io n o f th e C e n tra l L ic e n c in g Authorityundersub-rule(1)andsub-rule(3),mayfileanappealbeforetheCentral Governmentwithinforty-fiveworkingdaysfrom thedateofreceiptofsuch decision and thatGovernment,may,aftersuch enquiry,and aftergiving an opportunityofbeingheardtotheappelant,disposeoftheappealwithinaperiod ofsixtyworkingdays.

35. Conditionsofpermissionforconductofbioavailabilityorbioequivalence study.-ThepermissiongrantedbytheCentralLicencingAuthoritytoconduct bioavailabilityorbioequivalencestudyunderrule34shalbesubjecttofolowing conditions,namely,-

. (i)  bioavailabilityorbioequivalencestudyateachsiteshalbeinitiated afterapprovalofbioavailabilityorbioequivalencestudyprotocol,as the case may be,and other related documents by the ethics commiteeofthatsite,registeredwiththeCentralLicencingAuthority inaccordancewithRule8;

. (i)  whereabioavailabilityorbioequivalencestudycentredoesnothaveits ownethicscommitee,bioavailabilityorbioequivalencestudyatthat sitemaybeinitiatedafterobtainingapprovaloftheprotocolfrom the EthicsCommiteeregisteredunderrule7:
Providedthattheapprovingethicscommiteeshalinsuch caseberesponsibleforthestudyatthecentre:
Providedfurtherthatboththeapprovingethicscommitee andthecentre,shalbelocatedwithinthesamecityorwithina

Page21of21

radiusof50km ofthebioavailabilityorbioequivalencestudy

centre:

. (i)  theCentralLicencingAuthorityshalbeinformedabouttheapproval
grantedbytheethicscommiteewithinaperiodof15workingdays
ofthegrantofsuchapproval;

. (iv)  bioavailabilityorbioequivalencestudyofnewdrugorinvestigational
new drug shalbe conducted only in the bioavailability or bioequivalence studycentre registered with the CentralLicencing AuthorityunderRule47;

. (v)  bioavailabilityorbioequivalencestudyofinvestigationalnewdrug shalberegisteredwiththeClinicaltrialRegistryofIndiamaintained bytheIndianCouncilofMedicalResearchbeforeenrolingthefirst subjectforthestudy;

. (vi)  bioavailability or bioequivalence study shal be conducted in accordancewiththeapprovedbioavailabilityorbioequivalencestudy protocolandotherrelateddocumentsandasperrequirementsof GoodClinicalPracticesguidelinesandprovisionsoftheserules;

. (vi)  incaseofterminationofanybioavailabilityorbioequivalencestudy, thedetailedreasonsforsuchterminationshalbecommunicatedto theCentralLicencingAuthoritywithinthirtyworkingdaysofsuch termination;

. (vi)  anyreportofseriousadverseeventoccuringduringbioavailabilityor bioequivalence studyto a subjectofsuch study,shal,afterdue analysis,be forwarded to the CentralLicencing Authority,the chairpersonoftheethicscommiteeandtheinstituteorthecentre wherethebioavailabilityorbioequivalencestudy,asthecasemaybe, hasbeenconductedwithinfourteendaysofitsoccurenceasper Table5oftheThirdScheduleandincompliancewiththeprocedures asspecifiedinCHAPTERVI;

. (ix)  incaseofaninjuryduringbioavailabilityorbioequivalencestudyto the subjectofsuch study,complete medicalmanagementand compensationshalbeprovidedasperCHAPTER VIanddetailsof compensation provided in such cases shalbe intimated to the CentralLicencingAuthoritywithinthirtydaysofthereceiptoforder issuedbyethicscommitee;

. (x)  incaseofbioavailabilityorbioequivalencestudyrelateddeathor permanentdisabilityofanysubjectofsuchstudyduringthestudy, compensationshalbeprovidedinaccordancewithCHAPTERVIand detailsofcompensationprovidedinsuchcasesshalbeintimatedto theCentralLicencingAuthoritywithinthirtydaysofreceiptofthe orderissuedinaccordancewithCHAPTERVI;

. (xi)  thepremisesofthesponsorincludinghisrepresentativesand bioavailabilityand bioequivalence studycentre shalbe open for inspectionbyoficersoftheCentralLicencingAuthoritywhomaybe

Page22of22

accompaniedbyoficersoftheStateLicencingAuthorityoroutside expertsasauthorisedbytheCentralLicencingAuthority,toverify com pliance of the requirem ents of these rules and Good Clinical Practices,toinspect,searchandseizeanyrecord,result,document, investigational product, related to bioavailability or bioequivalence study,asthecasemaybe,andfurnishreplytoqueryraisedbythe saidoficerinrelationtobioavailabilityorbioequivalencestudy;

(xi) the bioavailability orbioequivalence study shalbe initiated by enrolingthefirstsubjectwithinaperiodofoneyearfrom thedateof grantofpermission,failingwhichpriorpermissionfrom theCentral LicencingAuthorityshalberequired;

36. Validityperiodofpermissiontoconductbioavailabilityorbioequivalence study. -(1) The perm ission to conduct bioavailability or bioequivalence study grantedunderrule34inForm CT-07shalremainvalidforaperiodofoneyear from thedateofitsissue,unlesssuspendedorcanceledbytheCentral LicencingAuthority.

(2 ) In e x c e p tio n a l c irc u m s ta n c e s , w h e re th e C e n tra l L ic e n c in g A u th o rity is satisfied about the necessity for an extension beyond one year, the said authoritymay,ontherequestoftheapplicantmadeinwriting,extendthe periodofpermissiongrantedforafurtherperiodofoneyear.

37. Inspectionofpremisesrelatingtobioavailabilityorbioequivalencestudy. – The person or the institution or the organization perm it ted to conduct bioavailabilityorbioequivalencestudyunderrule34inForm CT-07includinghis representativesandinvestigator,shalalowanyoficerauthorisedbytheCentral LicencingAuthority,whomay,ifconsiderednecessary,beaccompaniedbyan oficerauthorisedbytheStatelicencingauthority,toenterwithorwithoutprior noticehispremisesandbioavailabilityorbioequivalencestudycentretoinspect, searchorseize,anyrecord,statisticalresult,document,investigationaldrugand otherrelatedmaterialandreplytoqueriesraisedbytheinspectingauthorityin relationtoconductofsuchbioavailabilityorbioequivalencestudy.

38. Suspensionorcancelationofpermissiontoconductbioavailabilityor bioequivalencestudy.-(1)Whereanypersonorinstitutionororganisationto whom permissionhasbeengrantedunderrule34inForm CT-07failstocomply withanyprovisionoftheActandtheserules,theCentralLicencingAuthoritymay, aftergivinganopportunitytoshow causeandafterafordinganopportunityof being heard,by an orderin writing,take one ormore ofthe folowing actions,namely,-

(i) issuewarninginwritingdescribingthedeficiencyordefectobserved duringinspectionorotherwise,whichmayafectadverselytheright,or w el l- being of a subject enrol led in for the study or the validity of bioavailabilityorbioequivalencestudyconducted;

Page23of23

(i) rejecttheresultsofbioavailabilityorbioequivalencestudy,asthecase maybe;

(i i i) suspend for such period as considered appropriate or cancel the permissiongrantedunderrule34inForm CT-07;

(iv)debartheinvestigatororthesponsorincludinghisrepresentatives,to conductanybioavailabilityorbioequivalencestudyinfutureforsuch periodasconsideredappropriatebytheCentralLicencingAuthority.

(2)Whereapersonoraninstitutionoranorganisationtowhom permissionhas beengrantedunderrule34inForm CT-07orthesponsorisaggrievedbythe orderoftheCentralLicencingAuthority,thepersonortheinstitutionorthe organizationmay,withinaperiodofsixtydaysofthereceiptoftheorder, makeanappealtotheCentralGovernmentandtheCentralGovernmentmay, aftersuchenquiry,asdeemednecessary,andafterafordinganopportunity ofbeingheard,passsuchorderinrelationtheretoasmaybeconsidered appropriateinthefactsandcircumstancesofthecasewithinaperiodofsixty daysfrom thedateofreceiptoftheappeal

CHAPTERVI COMPENSATION

39.Compensation in case ofinjuryordeath in clinicaltrialorbioavailabilityor bioequivalencestudyofnewdrugorinvestigationalnewdrug.-(1)Whereanydeathof atrialsubjectoccursduringaclinicaltrialorbioavailabilityandbioequivalencestudy andthedeathisrelatedtotheclinicaltrialorbioavailabilityandbioequivalencestudyas rule42,thelegalheirofthetrialsubjectshalbeprovidedfinancialcompensationbythe sponsororitsrepresentative,whohasobtainedpermissiontoconductclinicaltrialor bioavailabilityorbioequivalencestudy,inaccordancewiththeprocedurespecifiedin rule42. (2)Wherepermanentdisabilityoranyotherinjuryoccurstoatrialsubjectduringa

clinicaltrialorbioavailabilityorbioequivalencestudy,andthepermanentdisabilityor anyotherinjuryisrelatedtotheclinicaltrialorbioavailabilityorbioequivalencestudy asperrule42,thetrialsubjectshalbeprovidedfinancialcompensationbythesponsor orits representative,who has obtained permission to conductclinicaltrialor bioavailabilityorbioequivalencestudy,inaccordancewiththeprocedurespecifiedin rule42. (3)Thefinancialcompensationasreferedtoinsub-rule(1)orsub-rule(2)shalbe overandaboveanyexpensesincuredonmedicalmanagementofthetrialsubject. (5)Intheeventofaninjury,notbeingpermanentinnature,thequantum of compensationshalbecommensuratewiththelossofwagesofthesubject.

 

Page24of24

(6)Wherethesponsororitsrepresentative,whohasobtainedpermissiontoconduct clinical trial or bioavailability or bioequivalence study, fails to provide financial compensation,as refered to in sub-rule (1)orsub-rule (2),the centrallicencing authorityshal,afterafordinganopportunityofbeingheard,byanorderinwriting, suspendorcanceltheclinicaltrialorbioavailabilityorbioequivalencestudyorrestrict the sponsorincluding its representative,who has obtained permission to conduct clinicaltrialorbioavailabilityorbioequivalencestudy,toconductanyfurtherclinical trialorbioavailabilityorbioequivalencestudyortakeanyotheractionforsuchperiod asconsideredappropriateinthelightofthefactsandcircumstancesofthecase.

40.MedicalManagementinclinicaltrialorbioavailabilityandbioequivalencestudyof n e w d ru g o r in v e s tig a tio n a l n e w d ru g . – (1 ) W h e re a n in ju ry o c c u rs to a n y s u b je c t duringclinicaltrialorbioavailabilityandbioequivalencestudyofanew drugoran investigationalnewdrug,thesponsor,shalprovidefreemedicalmanagementtosuch subjectaslongasrequiredaspertheopinionofinvestigatorortilsuchtimeitis established that the injury is not related to the clinical trial or bioavailability or bioequivalencestudy,asthecasemaybe,whicheverisearlier.

(2)Theresponsibilityformedicalmanagementasreferedtoinsub-rule(1),shal bedischargedbythesponsororthepersonwhohasobtainedpermissionfrom the CentralLicensingAuthority.

41.Considerationofinjuryordeathorpermanentdisabilitytoberelatedtoclinical trialorbioavailability and bioequivalence study,-Any injury ordeath or permanentdisability ofa trialsubjectoccuring during clinicaltrialor bioavailabilityorbioequivalencestudyduetoanyofthefolowingreasonsshal beconsideredasclinicaltrialorbioavailabilityorbioequivalencestudyrelated injuryordeathorpermanentdisability,namely,-

(2)adverseefectoftheinvestigationalproduct; (3)violationoftheapprovedprotocol,scientificmisconductornegligencebythe

sponsororhisrepresentativeortheinvestigatorleadingtoseriousadverse

event; (4)failureofinvestigationalproducttoprovideintendedtherapeuticefectwhere,

therequiredstandardcareorrescuemedication,thoughavailable,wasnot

providedtothesubjectasperclinicaltrialprotocol; (5)Notprovidingtherequiredstandardcare,thoughavailabletothesubjectas

perclinicaltrialprotocolintheplacebocontroledtrial;
(6)adverse ef fects due to concom itant m edication excluding standard care,

necessitatedaspartoftheapprovedprotocol; (7)adverseefectonachildin-uterobecauseoftheparticipationoftheparentin

theclinicaltrial; (8)anyclinicaltrialproceduresinvolvedinthestudyleadingtoseriousadverse

event.



Page25of25

42.Procedure forCompensation in case ofinjury ordeath during clinicaltrial, bioavailability and bioequivalence study.-(1)The investigatorshalreportal serious adverse events to the centrallicencing authority,the Sponsororits representative,w ho has obtained perm ission from the central licencing authority for conductofclinicaltrialorbioavailabilityorbioequivalencestudy,asthecasemay be,andtheethicscommiteethataccordedapprovaltothestudyprotocol,within twenty-fourhoursoftheiroccurence.Incase,theinvestigatorfailstoreportany seriousadverseeventwithinthestipulatedperiod,heshalhavetofurnishthe reasonsfordelaytothesatisfactionofthecentrallicencingauthorityalongwiththe reportoftheseriousadverseevent.

(2)Acaseofseriousadverseeventofdeathshalbeexaminedinthemannerdetailed below,-

(i)thecentrallicencingauthorityshalconstituteanindependentexpertcommitee toexaminethecasesandmakeitsrecommendationstothesaidauthorityfor arivingatthecauseofdeathandquantum ofcompensationincaseofclinical trialrelateddeath;

(i)thesponsororitsrepresentativeandtheinvestigatorshalforwardtheirreports onseriousadverseeventofdeathafterdueanalysistothecentrallicencing authorityandtheheadoftheInstitutionwheretheclinicaltrialorbioavailability orbioequivalence study has been conducted within fourteen days ofthe knowledgeofoccurenceofseriousadverseeventofdeath;

(i)theethicscommiteeshalforwarditsreportonseriousadverseeventofdeath afterdueanalysisalongwithitsopiniononthefinancialcompensation,ifany, determinedaspertheformulaspecifiedintheseventhschedule,tobepaidby thesaidsponsororitsrepresentative,whohasobtainedpermissionfrom the centrallicencing authority forconductofclinicaltrialorbioavailability or bioequivalence study,as the case m ay be, to the centrallicencing authority withinaperiodofthirtydaysofreceivingthereportoftheseriousadverseevent ofdeathfrom theinvestigator;

(iv ) th e c e n tra l lic e n c in g a u th o rity s h a l l fo rw a rd th e re p o rt o f th e in v e s tig a to r, sponsororitsrepresentativeandtheethicscommiteetotheChairpersonofthe expertcommitee;

(v)theexpertcommiteeshalexaminethereportofseriousadverseeventofdeath Page26of26

andmakeitsrecommendationsavailabletothecentrallicencingauthorityfor thepurposeofarivingatthecauseoftheseriousadverseeventofdeathwithin sixtydaysfrom thereceiptofthereportoftheseriousadverseevent,andthe expertcommiteewhileexaminingtheevent,maytakeintoconsideration,the reports ofthe investigator,sponsororits representative and the ethics commitee;

(vi)incaseofclinicaltrialorthebioavailabilityorbioequivalencestudyrelateddeath, theexpertcommiteeshalalsorecommendthequantum ofcompensation, determinedaspertheformulaspecifiedintheSeventhSchedule,tobepaidby thesponsororhisrepresentativewhohasobtainedthepermissiontoconduct theclinicaltrialorthebioavailabilityorbioequivalencestudy,asthecasemaybe;

(vi i)the central licencing authority shal l consider the recom m endations of the expertcommiteeandshaldeterminethecauseofdeathwithregardstothe relatedness of the death to the clinical trial or the bioavailability or bioequivalencestudy,asthecasemaybe;

(vi)incaseofclinicaltrialorthebioavailabilityorbioequivalencestudyrelated death, the central licencing authority shal, after considering the recommendationsoftheexpertcommitee,decidethequantum of compensation,determined as perthe formula specified in the Seventh Schedule,tobepaidbythesponsororitsrepresentativeandshalpassorders asdeemednecessarywithinninetydaysofthereceiptofthereportofthe seriousadverseevent;

(ix)Thesponsororitsrepresentativeshalpaythecompensationincasethe seriousadverseeventofdeathisrelatedtoclinicaltrialorthebioavailabilityor bioequivalencestudy,aspertheorderasreferedtoinclause(vi)ofthe centralicencingauthoritywithinthirtydaysofthereceiptofsuchorder.

(3) Casesofseriousadverseeventsofpermanentdisabilityoranyotherinjuryother thandeathsshalbeexaminedasunder:

(i)thesponsororitsrepresentative,andtheInvestigatorshalforwardtheirreports onseriousadverseevent,afterdueanalysis,tothecentrallicencingauthority, chairpersonoftheethicscommiteeandheadoftheinstitutionwherethetrialor bioavailabilityorbioequivalencestudyhasbeenconductedwithinfourteendays ofthereportingofseriousadverseevent;

(i i) th e e th ic s c o m m it te e s h a l l fo rw a rd its re p o rt o n s e rio u s a d v e rs e e v e n t o f Page27of27

 

permanentdisabilityoranyotherinjuryotherthandeaths,asthecasemaybe, afterdueanalysisalongwithitsopiniononthefinancialcompensation,ifany, determinedaspertheformulaspecifiedintheSeventhSchedule,tobepaidby the sponsor or its representative w ho has obtained perm ission to conduct clinicaltrialorthebioavailabilityorbioequivalencestudy,asthecasemaybe, withinthirtydaysofreceivingthereportoftheseriousadverseevent;

(i)thecentrallicensingauthorityshaldeterminethecauseoftheinjuryandpass orderasdeemednecessary.Thecentralicensingauthorityshalhavetheoption toconstituteanindependentexpertcommitee,whereverconsideritnecessary, toexaminesuchseriousadverseeventsofinjury,whichshalrecommendtothe centrallicensingauthorityforthepurposetoariveatthecauseoftheserious adverseeventandalsothequantum ofcompensation,asdeterminedasper formula as specified in the Seventh Schedule in case ofclinicaltrialor bioavailabilityorbioequivalencestudyrelatedinjury,withinaperiodofsixtydays ofreceiptofthereportoftheseriousadverseevent.

(iv)incaseofclinicaltrialorthebioavailabilityorbioequivalencestudyrelatedinjury, thecentrallicencingauthorityshaldecidethequantum ofcompensation, determinedaspertheformulaspecifiedintheSeventhSchedule,tobepaidby thesponsororhisrepresentativewhohasobtainedthepermissiontoconduct theclinicaltrialorthebioavailabilityorbioequivalencestudy,asthecasemaybe, withinaperiodofninetydaysofreceiptofthereportoftheseriousadverse event;

(v)Thesponsororitsrepresentative,whohasobtainedpermissiontoconductthe clinicaltrialorbioavailabilityorbioequivalencestudy,asthecasemaybe,shal paythecompensationincaseofclinicaltrialorbioavailabilityorbioequivalence studyrelatedinjury,asperordersofthecentrallicensingauthorityasreferedto inclause(iv)withinthirtydaysofreceiptofsuchorder.

43. Medicalmanagementand compensation forinjuryordeath relating to biom edical and health research overseen by an Ethics Com m it tee as referedtoinChapterIV.-Notwithstandinganythingcontainedinthese rules,medicalmanagementandcompensationforinjuryordeathrelatingto biom edical and health research, overseen by an Ethics Com m it tee as referedtoinChapterIV,shalbeinaccordancewiththeNationalEthical Guidelines for Biomedical and Health Research Involving Human ParticipantsspecifiedbytheIndianCouncilofMedicalResearchfrom time

Page28of28

44.

45.

46.

CHAPTERVI BIOAVAILABILITYANDBIOEQUIVALENCESTUDYCENTRE

Registration ofBioavailability and Bioequivalence Study Centre.-No bioavailability and bioequivalence study centre shal conduct any bioavailability study or bioequivalence study of a new drug or investigationalnew drug exceptin accordance with the registration grantedbytheCentralLicencingAuthorityundertheserules.

Applicationforregistrationofbioavailabilityandbioequivalencestudy centre. -(1) Application for registration of any bioavailability and bioequivalencestudycentrewiththeCentralLicencingAuthorityshalbe madetothesaidauthorityinForm CT-08. (2)Theapplicationundersub-rule(1)shalbeaccompaniedbyafeeas specified in the Sixth Schedule and such other information and documentsasspecifiedintheFourthSchedule.

Inspectionofbioavailabilityandbioequivalencestudycentre.-Onreceipt ofanapplicationundersub-rule(1)ofrule45,anyoficerauthorisedbythe C e n tra l L ic e n c in g A u th o rity w h o m a y b e a c c o m p a n ie d b y th e o f fic e rs authorisedbythestatelicencingauthority,maycauseaninspectionofthe bioavailabilityandbioequivalencestudycentretoverifythefacilityofthe centreandthecapacityoftheapplicanttocomplytherequirementsof theserules.

totime.

47. Grantforregistrationofbioavailabilityandbioequivalencestudycentre.-(1)The C e n tra l L ic e n c in g A u th o rity m a y , a fte r s c ru tin y o f th e in fo rm a tio n a n d documentsfurnishedwiththeapplicationinForm CT-08andsuchfurther enquiry, if any, as m ay be considered necessary if satisfied, that the requirementsoftheseruleshavebeencompliedwith,grantregistrationto theapplicantinForm CT-09withinaperiodofninetyworkingdaysfrom the dateofreceiptofitsapplicationinForm CT-08,ifnotsatisfied,rejectthe application,forthatreasonstoberecordedinwriting,from thedate,the applicationmadeundersub-rule(1)ofrule45;

(2)Incase,wheretheCentralLicencingAuthorityconsidersthattherearesome deficienciesintheapplicationandthesamemayberectified,saidAuthority shal linform theapplicantofthedeficiencieswithintheperiodasprovidedin sub-rule(1);

(3)The applicant,afterbeing informed,as persub-rule (1),by the Central LicencingAuthority,may,-

(i) rectifythedeficiencieswithinaperiodspecifiedbytheCentral LicencingAuthority;

(i) wheretheapplicantrectifiesthedeficiency,asreferedinsub-rue (1),withintheperiodreferedtoinclause(i)andprovidesrequired

Page29of29

informationanddocuments,theCentralLicencingAuthorityshal scrutinizetheapplicationagainandifsatisfied,grantregistration totheapplicantinForm CT-09orifnotsatisfied,rejectthe applicationwithinaperiodofninetydaysreckonedfrom theday whentherequiredinformationanddocumentswereprovided:

Provided thatin case ofrejection,the applicantmay requesttheCentralLicencingAuthority,toreconsidertheapplication withinaperiodofsixtydaysfrom thedateofrejectionofthe applicationonpaymentoffeeasspecifiedintheSixthScheduleand submissionofrequiredinformationanddocuments.

(4 ) A n a p p lic a n t w h o is a g g rie v e d b y th e d e c is io n o f th e C e n tra l L ic e n c in g Authorityundersub-rule(1)orsub-rule(2)orsub-rule(3),mayfileanappeal withinforty-fivedaysfrom thedateofreceiptofsuchrejectionbeforethe CentralGovernmentandthatGovernmentmay,aftersuchenquiryandafter givinganopportunityofbeingheardtotheappelant,disposeoftheappeal withinaperiodofsixtydays.

48. Validity Period and renewalof registration of bioavailability and bioequivalencecentre.-(1)Theregistrationgrantedunderrule47inForm CT-09 shalremainvalidforaperiodoffiveyearsfrom thedateofitsissue,unless suspendedorcanceledbytheCentralLicencingAuthority. (2)Thebioavailabilityorbioequivalencecentreshalmakeanapplicationfor

renewalofregistrationinForm CT-08alongwithdocumentsasspecifiedin the Fourth Schedule at least three m onths prior to date of expiry of its registration:

Providedthatiftheapplicationforrenewalofregistrationisreceivedby theCentralLicencingAuthoritywithinthreemonthspriortodateofexpiry,the registrationshalcontinuetobeinforceuntilordersarepassedbythesaid authorityontheapplication.

(3)TheCentralLicencingAuthorityshal,afterscrutinyofinformationenclosed withtheapplicationandaftertakingintoaccounttheinspectionreport,and suchfurtherenquiry,ifany,asconsiderednecessary,shal,ifsatisfied,that therequirementsoftheserules,havebeen,- (i)compliedwith,grantregistrationorrenewregistrationofethicscommitee

inForm CT-09;or (i)notcompliedwith,rejecttheapplication,forreasonstoberecordedin

writing,withinaperiodofforty-fivedays,from thedate,theapplication wasmadeundersub-rule(2).

49. Conditionsofregistration.–Theregistrationgrantedunderrule47in Form CT-09shalbesubjecttofolowingconditions,namely:-

(i) Thecentreshalmaintainthefacilitiesandadequatelyqualifiedand trainedpersonnelasspecifiedintheFourthScheduleforperforming itsfunctions;

Page30of30

. (i)  thecentreshalinitiateanybioavailabilitystudyorbioequivalence studyofanynew drugorinvestigationalnew drugafterapprovalof theprotocolandotherrelateddocumentsbytheethicscommitee and permission of such study granted by the Central LicencingAuthority;

. (i)  wherethebioavailabilityorbioequivalencestudycentredoesnot have its ow n ethics com m it tee, bioavailability or bioequivalence studyatthatsitemaybeinitiatedafterobtainingapprovalofthe protocolfrom the ethics com m it tee constituted underrule7:
Providedthattheapprovingethicscommiteeacceptsthe responsibilityforthestudyatthecentreand,boththeapproving ethicscommiteeandthecentre,arelocatedwithinthesamecity orwithinaradiusof50km ofthecentre.

. (iv)  theCentralLicencingAuthorityshalbeinformedabouttheapproval oftheethicscommitee;

. (v)  bioavailabilityorbioequivalencestudyofinvestigationalnew drug shalberegisteredwiththeClinicaltrialRegistryofIndiabefore enrolingthefirstsubjectforthestudy;

. (vi)  studyshalbeconductedinaccordancewiththeapprovedprotocol and otherrelated documents and as perrequirements ofGood Clinical Practices guidelines and provisions of the Act and theserules;

. (vi)  incaseofterminationofanysuchstudyprematurely,thedetailed reasonsforsuchterminationshalbecommunicatedtotheCentral LicencingAuthorityimmediately;

. (vi)  anyreportofseriousadverseeventoccuringduringstudytothe subject of such study shal l, after due analysis, be forw arded to CentralLicencingAuthoritywithinfourteendaysofitsoccurencein theformatasspecifiedinTable5oftheThirdScheduleandin compliancewiththeproceduresasspecifiedinrule42;

. (ix)  incaseofaninjurytothestudysubjectduringstudy,thecomplete medicalmanagementand compensation in the case ofstudy relatedinjuryshalbeprovidedinaccordancewithCHAPTERVIand detailsofcompensationprovidedinsuchcasesshalbeintimated totheCentralLicencingAuthoritywithinthirtydaysofthereceiptof theorder;

. (x)  incaseofdeath,permanentdisability,injuryotherthandeathsand permanentdisability,as the case may be,ofa study subject, compensationshalbeprovidedinaccordancewithCHAPTERVIand detailsofcompensationprovidedinsuchcasesshalbeintimated totheCentralLicencingAuthoritywithinthirtydaysofthereceiptof theorder;

. (xi)  if there is any change in constitution or ownership of the bioavailability and bioequivalence study centre,the centre shal

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in tim a te th e c h a n g e in w ritin g to th e C e n tra l L ic e n c in g A u th o rity

withinthirtydaysofsuchchange;
(xi) thestudycentreshalmaintaindata,records,andotherdocuments

relatedtotheconductofthebioavailabilityorbioequivalencestudy foraperiodoffiveyearsaftercompletionofsuchstudyorforat leasttwoyearsaftertheexpirationdateofthebatchofthenew drugorinvestigationalnewdrugstudiedwhicheverislater;

. (xi)  thebioavailabilityandbioequivalencestudycentreshalalow any oficerauthorisedbytheCentralLicencingAuthoritywhomaybe accompaniedbyanoficerauthorisedbystatelicencingauthorityto enterwithorwithoutpriornotice,thepremisestoinspectanyrecord, statisticalobservation orresults orany documents related to bioavailability study and bio-equivalence study and furnish inform ation to any query raised by such authorised person, in relationtotheconductofsaidstudy;

. (xiv)  the CentralLicencing Authority may,ifconsidered necessary, imposeadditionalcondition,inwritingwithjustification,inrespect ofspecificbioavailabilityandbioequivalencestudy,regardingthe objective, design, subject population, subject eligibility, assessments,conductandtreatmentofsuchspecificstudy.

50. Inspectionofbioequivalenceandbioavailabilitystudycentreregistered with CentralLicencing Authority.-The bioavailability and bioequivalence study centreregisteredbytheCentralLicencingAuthorityunderRule47inForm CT-09, including his representatives and investigator,shal lal low any of ficerauthorised by the CentralLicencing Authority,who may be accompanied by an of ficer authorisedbythestatelicencingauthority,toenterwithorwithoutpriornotice, anypremisesofthebioavailabilityandbioequivalencestudycentretoinspect, searchorseize,anyrecord,document,investigationalproductandotherrelated materialandreplytoqueriesraisedbytheinspectingauthorityinrelationto functioningofthecentre.

51. Suspension or cancelation of registration of bioavailability and bioequivalencestudycentre.-(1)Whereanybioavailabilityandbioequivalence studycentreincludinghisrepresentativesorinvestigator,failstocomplywithany provisionoftheActandtheserules,theCentralLicencingAuthoritymay,after givinganopportunitytoshow causeandafterafordinganopportunityofbeing heard,byanorderinwriting,takeoneormoreofthefolowingactions,namely,-

. (i)  issuewarninginwritingdescribingthedeficiencyordefectobserved duringinspectionorotherwise,whichmayafectadverselytheright orwel-beingoftrialsubjectorthevalidityofanystudyconducted;or

. (i)  rejecttheresultsofthestudy;or

. (i)  suspendtheconductofastudy;or

. (iv)  suspendforsuchperiodasconsideredappropriateorcancelthe

Page32of32

registrationgrantedunderRule47inForm CT-09;
(v) debar the centre including itsrepresentatives to conduct any

bioavailabilityandbioequivalencestudyinfutureforsuchperiodas

consideredappropriatebytheCentralLicencingAuthority. (2)WhereabioavailabilityandbioequivalencestudycentreregisteredunderForm

CT-09againstwhom anorderhasbeenmadeundersub-rule(1)isaggrieved by the orderofthe CentralLicencing Authority,the bioavailability and bioequivalencestudycentremaywithinaperiodofsixtydaysofthereceiptof the order,make an appealto the CentralGovernmentand the Central Governmentmay,aftersuchenquiry,asdeemednecessaryandafterafording anopportunityofbeingheard,passsuchordersinrelationtheretoasmaybe consideredappropriateinthefactsandcircumstancesofthecase.

CHAPTERVI
MANUFACTUREOFNEW DRUGSORINVESTIGATIONALNEW DRUGSFORCLINICALTRIAL,

BIOAVAILABILITYORBIOEQUIVALENCESTUDYORFOREXAMINATION,TESTAND ANALYSIS

52.Applicationforpermissiontomanufactureofnew drugorinvestigationalnew drug for clinical trial or bioavailability and bioequivalence studyor for examination,testandanalysis.–

(1)Nopersonshalmanufactureanew drugoraninvestigationalnew drugto conduct clinical trial or bioavailability or bioequivalencestudy or for examination,testandanalysisunlessobtainedapermissiontomanufacture such new drug orinvestigationalnew drug from the CentralLicencing Authority.

(2)Anypersonwhointendstomanufactureanewdrugoraninvestigationalnew drugtoconductclinicaltrialorbioavailabilityandbioequivalencestudyorfor examination,testandanalysisshalmakeanapplicationinForm CT-10tothe CentralLicencingAuthoritytoobtainthepermission.

(3)The application refered in sub-rule (2)shalbe accompanied with such documentsandinformationasspecifiedintheFourthSchedulealongwithfee asspecifiedintheSixthSchedule.

53. Grantofpermissiontomanufacturenew drugsorinvestigationalnew drugs for clinical trial or bioavailability or bioequivalence study, or for examination,testandanalysis.-

(1)The Central Licencing Authority m ay, after scrutiny of the inform ation and documentsfurnishedwiththeapplicationinForm CT-10andsuchfurtherenquiry, ifany,asmaybeconsiderednecessary,ifsatisfied,thattherequirementsof theseruleshavebeencompliedwith,grantthepermissiontomanufacturefor conductofclinicaltrialorbioavailabilityorbioequivalencestudyorforexamination, testandanalysis,asthecasemaybe,forthenewdrugorinvestigationalnewdrug, inForm CT-11withinaperiodofninetyworkingdaysfrom thedateofreceiptof itsapplicationinForm CT-10,ifnotsatisfiedthattherequirementsoftheserules havebeencompliedwith,rejecttheapplication,forthatreasonstoberecorded inwriting,withinaperiodofninetyworkingdays,from thedate,theapplicationmade

Page33of33

undersub-rule(2)ofrule52.

(2)Incase,wheretheCentralLicencingAuthorityconsidersthattherearesome deficienciesintheapplicationandthesamemayberectified,saidAuthority shalinform theapplicantofthedeficiencieswithintheperiodspecifiedin sub-rule(1);

(3) The applicant,after being inform ed,as refer red to in sub-rule (2),by the CentralLicencingAuthority,may,

(i) rectify the deficiencies within a period specified by the Central LicencingAuthority;

(i)wheretheapplicantrectifiesthedeficiency,asreferedinsub-rue(1), within the period refered to in clause (i)and provides required in fo rm a tio n a n d d o c u m e n ts , th e C e n tra l L ic e n c in g A u th o rity s h a l l scrutinizetheapplicationagainandifsatisfied,grantpermissionto manufacture for conduct of clinicaltrialor bioavailability or bioequivalencestudy,orforexamination,testandanalysis,asthecase maybe,forthenew drugorinvestigationalnew drugorifnot satisfied,rejecttheapplicationwithinaperiodofninetyworkingdays reckoned from the day when the required information and documentswereprovided:

Provided thatin case ofrejection,the applicantmay requesttheCentralLicencingAuthority,toreconsidertheapplication withinaperiodofsixtyworkingdaysfrom thedateofrejectionofthe applicationonpaymentofeeasspecifiedintheSixthScheduleand submissionofrequiredinformationanddocuments.

(4)An applicantwho is aggrieved by the decision ofthe CentralLicencing Authorityundersub-rule(1)orsub-rule(2),mayfileanappealbeforethe centralGovernmentwithinforty-fivedaysfrom thedateofreceiptofsuch decisionandthatGovernment,may,aftersuchenquiry,andaftergivingan opportunityofbeingheardtotheappelant,disposeoftheappealwithina periodofsixtydays.

54. Validity period of permission to manufacture of new drug or investigationalnew drugsforclinicaltrialorbioavailabilityandbioequivalence study,orforexamination,testandanalysis.-(1)Thepermissiongrantedunder rule53inForm CT-11shalremainvalidforaperiodofthreeyearsfrom thedate ofitsissue,unlesssuspendedorcanceledbytheCentralLicencingAuthority. (2)In exceptionalcircumstances,where the CentralLicencing Authority is

satisfied about the necessity and exigency,it m ay,on the request of the applicantmadeinwriting,extendtheperiodofthepermissiongrantedfora furtherperiodofoneyear.

55. Conditionofpermission.–Thegrantofpermissionunderrule53inForm CT-11issubjecttothefolowingconditions,namely,-

(i) thepermissionholdershalmakeuseofnew drugmanufactured Page34of34

underForm CT-11onlyforthepurposesofconductingclinicaltrialor bioavailabilityandbioequivalencestudyorforexamination,testand analysisandnopartofitshalbesoldinthemarketorsuppliedtoany otherpersonoragencyorinstitutionororganization;

. (i)  thepermissionholdershalmanufacturenewdrugsforthepurposes ofclinicaltrialorbioavailability and bioequivalence studyor for examination,testandanalysisinaccordancewiththeprovisionsofthese rulesandatplacesspecifiedinthepermissionandinaccordance withtheprinciplesofGoodManufacturingPractices;

. (i)  thepermissionholdershalkeeparecordofnewdrugsmanufactured andpersonstowhom thedrugshavebeensuppliedforclinicaltrialor bioavailabilityandbioequivalencestudyorforexamination,testand analysis;

. (iv)  wherenew drugmanufacturedforpurposesofclinicaltrialor bioavailabilityorbioequivalencestudyorforexamination,testand analysis is leftoverorremains unused orgets damaged orits specified shelf life has expired or has been found to be of sub- standardquality,thesameshalbedestroyedandactiontakenin respectthereofshalberecorded.

56.Licencetomanufacturenew drugsorinvestigationalnew drugsforclinical trialorbioavailabilityorbioequivalenceorforexamination,testandanalysis study underthe Drugs and Cosmetics Rules,1945.-(1)Afterobtaining permissionunderRule53,thepersonintendstomanufacturethenewdrugor investigationalnew drugsforclinicaltrialorbioavailabilityorbioequivalence orforexamination,testand analysisorforexamination,testand analysisnew drugs orinvestigationalnew drugs forclinicaltrialor bioavailabilityorbioequivalencestudyorforexamination,testandanalysisin accordancewiththeprovisionsoftheDrugsandCosmeticsAct,1940and theDrugsandCosmeticsRules,1945.

(2)The application refered in sub-rule (1)shalbe accompanied by the permissionunderRule53inForm CT-11obtainedbytheapplicantfrom the CentralLicencingAuthoritytomanufacturethenew drugsforclinicaltrialor bioavailabilityorbioequivalencestudyorforexamination,testandanalysis.

57.Inspectionofnew drugsorinvestigationalnew drugsmanufacturedfor clinicaltrialorbioavailabilityandbioequivalencestudyorforexamination, testandanalysis.-Thepermissionholderorthepersontowhom newdrugs have been supplied forconducting clinicaltrialorbioavailability and bioequivalencestudyshalalow anyoficerauthorisedbytheCentral LicencingAuthorityortheStatelicencingauthoritytoenter,withorwithout priornotice,thepremiseswherethenew drugisbeingmanufacturedor stored,to inspectsuch premises and records,investigate the mannerin w hich the drugs are being m anufactured or stored or used and to take

Page35of35

samplethereof.

58. Suspension orcancel lation ofm anufacturing perm ission fornew drug or investigationalnew drugs.–(1)Subjecttoprovisionofrule57,wherethe permissionholder,failstocomplywithanyprovisionoftheActandthese rules,the CentralLicencing Authority may,aftergiving the centre an opportunity to show cause and after af fording an opportunity of being heard,byanorderinwriting,takeoneormoreofthefolowingactions, namely,-

(i)suspendthepermissionforsuchperiodasconsideredappropriate;or (i)cancelthepermissiongrantedunderRule53inFormCT-11.

(2)Where the permission holderwhose permission has been suspended or canceledundersub-Rule(1)isaggrievedbyanorderoftheCentralLicencing Authority,hemay,withinsixtydaysofthereceiptoftheorder,makeanappeal to the CentralGovernmentand the CentralGovernmentmay,aftersuch enquiry,asdeemednecessaryandafterafordinganopportunityofbeing heard,passsuchorderinrelationtheretoasmaybeconsideredappropriatein thefactsandcircumstancesofthecase.

59.Applicationforpermissiontomanufactureunapprovedactivepharmaceutical ingredientfordevelopmentofpharmaceuticalformulationfortestoranalysis orclinicaltrialorbioavailabilityandbioequivalencestudy.- (1)Whereamanufacturerofapharmaceuticalformulationintendstoprocure

activepharmaceuticalingredient,whichisnotapprovedunderRule76or Rule81,fordevelopmentofformulationandtomanufacturebatchesfortest oranalysisorclinicaltrialorbioavailabilityandbioequivalencestudyofsuch formulation,theapplicationforpermissiontomanufacturesuchdrugshal be made to the CentralLicencing Authority by the manufacturerof pharmaceuticalformulationinForm CT-12andmanufactureroftheactive pharmaceuticalingredientinFormCT-13.

(2)The application undersub-Rule (1)shalbe accompanied bysuch other particularsanddocumentsasarespecifiedinForm CT-12orForm CT-13,as thecasemaybe.

60. Grantofpermission to manufacture unapproved active pharmaceutical ingredientfordevelopmentofpharmaceuticalformulation fortestor analysisorclinicaltrialorbioavailabilityandbioequivalencestudy,- (1)TheCentralLicencingAuthoritymay,afterscrutinyoftheinformationand documentsfurnishedwiththeapplicationunderrule59inForm CT-12orCT- 13,asthecasemaybe,andsuchfurtherenquiry,ifany,asmaybeconsidered necessary,-

(i) ifsatisfied,thattherequirementsoftheseruleshavebeencomplied Page36of36

with,grantthepermissiontothemanufacturerofactivepharmaceutical ingredientinForm CT-15tomanufacturetheunapprovedactive pharmaceuticalingredientandtothemanufacturerofpharmaceutical formulation in Form CT-14 for development of pharmaceutical form ulation for test or analysis or clinical trial or bioavailability and bioequivalencestudywithinninetyworkingdays;

(i)incase,wheretheCentralLicencingAuthorityconsidersthatthereare somedeficienciesintheapplicationandthesamemayberectified,said Authorityshalinform theapplicantofthedeficiencieswithinthe stipulatedperiodreferedtoinclause(i);

(i)ifnotsatisfiedthattherequirementsoftheseruleshavebeencomplied with,rejecttheapplication,forthatreasonstoberecordedinwriting, withinaperiodofninetyworkingdays,from thedate,theapplication madeundersub-rule(1)ofrule59;

(2)Theapplicant,afterbeinginformed,asreferedtoinclause(i)ofsub-rule (1),bytheCentralLicencingAuthority,may,

(i) rectifythedeficiencieswithinaperiodspecifiedbytheCentralLicencing Authority;

(i i)where the applicantrectifies the deficiency,as refer red in sub-rue (1), within the period refered to in clause (i)and provides required information and documents,the CentralLicencing Authority shal scrutinize the application again and ifsatisfied,grantpermission the manufacturerofactivepharmaceuticalingredientinForm CT-15to manufacturetheunapprovedactivepharmaceuticalingredientandtothe manufacturer of pharmaceutical formulation in Form CT-14 for developmentofpharmaceuticalformulationfortestoranalysisorclinical trialorbioavailabilityandbioequivalencestudyorifnotsatisfied,reject theapplicationwithinaperiodofninetyworkingdaysreckonedfrom the daywhentherequiredinformationanddocumentswereprovided:

Providedthatincaseofrejection,theapplicantmayrequest the CentralLicencing Authority,to reconsiderthe application within a periodofsixtydaysfrom thedateofrejectionoftheapplicationon paymentoffeeasspecifiedintheSixthScheduleandsubmissionof requiredinformationanddocuments.

(3 ) A n a p p lic a n t w h o is a g g rie v e d b y th e d e c is io n o f th e C e n tra l L ic e n c in g Authorityundersub-Rule(1)orSub-Rule(2),mayfileanappealbeforethe CentralGovernmentwithinsixtydaysfrom thedateofreceiptofsuch rejectionandthatGovernment,may,aftersuchenquiry,andaftergivingan opportunityofbeingheardtotheappelant,disposeoftheappealwithina periodofsixtydays.

61.Validity period of the permission to manufacture unapproved active pharmaceuticalingredientanditsformulationfortestoranalysisorclinicaltrial orbioavailabilityandbioequivalencestudy.-(1)Thepermissiongrantedunder

Page37of37

rule60 in FormCT-14orFormCT- 15,asthecasemaybe,shalremainvalidforaperiodofthreeyearsfrom thedateofits issue,unlesssuspendedorcanceledbytheCentralLicencingAuthority.
(2)In exceptionalcircumstances,where the CentralLicencing Authority is satisfiedaboutthenecessityandexigency,itmay,ontherequestoftheapplicant madeinwriting,extendtheperiodofpermissiongrantedforafurtherperiodof oneyear.

62.Suspensionorcancelationofpermissiontomanufactureunapprovedactive pharmaceuticalingredientfordevelopmentofformulationfortestoranalysis or clinical trial or bioavailability and bioequivalence study.- (1) Subject to provision of rule64, w here the form ulation m anufacturer or an active pharmaceuticalingredientmanufacturerfailstocomplywithanyprovisionof theActandtheserules,theCentralLicencingAuthoritymay,aftergivingan opportunitytoshowcauseandafterafording anopportunityofbeingheard,by anorderinwriting,takeoneormoreofthefolowingactions,namely,-

(i)suspendthepermissionforsuchperiodasconsideredappropriate;or

(i i) c a n c e l th e p e rm is s io n g ra n te d u n d e r ru le 6 0 in F o rm C T -1 4 o r F o rm C T -1 5 . (2)Where the formulation manufactureroractive pharmaceuticalingredient manufacturerwhosepermissionhasbeensuspendedorcanceledundersub-

rule(1),isaggrievedbyanorderoftheCentralLicencingAuthority,such manufacturermay,withinfortyfivedaysofthereceiptoftheorder,makean appealtotheCentralGovernmentandtheCentralGovernmentmay,aftersuch enquiry,asdeemednecessaryandafterafordinganopportunityofbeing heard,passsuchordersinrelationtheretoasmaybeconsideredappropriate inthefactsandcircumstancesofthecase.

63.Conditionsofpermission.-Thepermissiongrantedunderrule60inForm CT- 14orForm CT-15shalbesubjecttofolowingconditions,namely,-

(i)The manufacturer of pharmaceutical formulation or the active pharmaceuticalingredientshalmake use ofthe unapproved active pharm aceutical ingredient m anufactured on the basis of perm ission issuedunderrule60,onlyforthepurposesspecifiedinthesaidpermission, andnopartofitshalbesoldinthemarket;

(i i) The perm ission holder shal l m anufacture such active pharm aceutical ingredientoritspharmaceuticalformulationforthepurposesasspecified inpermissioninaccordancewiththeprovisionsoftheserulesandat placesreferedtoinsuchpermissionand,incase,themanufactureof suchdrugsisforclinicaltrialorbioavailabilityandbioequivalencestudy,it should be manufactured in accordance with the principles ofGood ManufacturingPractices;

(i)The manufacturer of a pharmaceutical formulation and active pharmaceuticalingredientreferedtoinclause(i),shalkeepalnecessary re c o rd s to in d ic a te th e q u a n tity o f d ru g p ro c u re d , m a n u fa c tu re d , u s e d ,

Page38of38

disposedofinanyothermanner,etc; (iv)Whereunapprovedactivepharmaceuticalingredientandpharmaceutical

formulationmanufacturedinaccordancewiththepermissionissuedunder rule60 isleftoveroremains,unusedorgetsdamagedoritsshelflifehasexpiredorhasbe enfoundtobeofsub-standardquality,thesameshalbedestroyedandaction takeninrespectthereofshalberecorded.

64.
fordevelopmentofformulation fortestoranalysis orclinicaltrialor bioavailabilityandbioequivalencestudyundertheDrugsandCosmeticsRules, 1945.-(1) After obtaining perm ission under rule 60, the person, intends to manufactureunapprovedactivepharmaceuticalingredientofthenew drugor investigationalnew drugforclinicaltrialorbioavailabilityorbioequivalence studyorforexamination,testandanalysis,shalmakeanapplicationforgrantof licence to manufacture unapproved active pharmaceuticalingredientfor developmentofformulationfortestoranalysisorclinicaltrialorbioavailabilityin accordancewiththeprovisionsoftheDrugsandCosmeticsAct,1940andthe DrugsandCosmeticsRules,1945.

(2)The application refered in sub-rule (1)shalbe accompanied by the permissiongrantedunderrule60inForm CT-14orForm CT-15,asthecase maybe,obtainedbytheapplicantfrom theCentralLicencingAuthorityto manufactureunapprovedactivepharmaceuticalingredientfordevelopment offormulationfortestoranalysisorclinicaltrialorbioavailability.

65. Inspection of manufacturer of unapproved active pharmaceutical ingredientfordevelopmentofformulationfortestoranalysisorclinicaltrialor bioavailability and bioequivalence study.–The manufacturer of active pharmaceuticalingredientorformulation,referedtoinrule60,shalalow any oficerauthorisedbytheCentralLicencingAuthorityorthepersonauthorisedby thestatelicencingauthoritytoenter,withorwithoutpriornotice,thepremises wheretheunapprovedactivepharmaceuticalingredientisbeingmanufactured, storedandused,toinspectsuchpremisesandrecords,inspectthemannerin whichtheunapprovedactivepharmaceuticalingredientisbeingmanufactured andstoredorusedandtotakesamplethereof.

66. Manneroflabeling.-(1)Anynew drugsorinvestigationalnew drugs manufactured,forthepurposeofclinicaltrialorbioavailabilityorbioequivalence study,shalbekeptincontainersbearinglabels,indicatingthenameofthedrug orcodenumber,batchorlotnumber,whereverapplicable,dateofmanufacture, usebeforedate,storageconditions,nameoftheinstitutionororganizationorthe centre where the clinicaltrialorbioavailability orbioequivalence study is p ro p o s e d to b e c o n d u c te d , n a m e a n d a d d re s s o f th e m a n u fa c tu re r, a n d th e purposeforwhichithasbeenmanufacturedorimported.

(2)Whereanew drugoraninvestigationalnew drugismanufacturedbythe Page39of39

Licence to m anufacture unapproved active pharm aceutical ingredient

permissionholderonbehalfofanotherperson,thepermissionholdershal indicateonthelabelofthecontainerofsuchdrug,thenameandaddressof themanufacturerandthepersontowhom itisbeingsuppliedalongwiththe scientificnameofsuchdrug,ifknown,otherwisereferencewhichshalenable suchdrugtobeidentifiedandthepurposeforwhichitismanufacture

(3)Nopersonormanufacturershalalter,obliterateordefaceanyinscriptionor markmadeonthecontainer,labelorwrapperofanynew drugimportedor manufacturedwithoutpermissionoftheCentralLicencingAuthority.

CHAPTERIX
IMPORTOFNEW DRUGSANDINVESTIGATIONALNEW DRUGSFORCLINICALTRIALOR

BIOAVAILABILITYORBIOEQUIVALANCESTUDYORFOREXAMINATION, TESTANDANALYSIS

67. Application forim portofnew drug orinvestigationalnew drug forclinicaltrial orbioavailabilityorbioequivalencestudyorforexamination,testandanalysis.- (1)Nopersonshalimportanew drugoranysubstancerelatingtheretofor conducting clinicaltrialorbioavailabilityorbioequivalence studyexceptin accordancewiththelicencegrantedbyCentralLicencingAuthority.

(2)Anypersonorinstitutionororganisationintendstoimportanew drugorany substance relating thereto for conducting clinical trial or bioavailability or bioequivalence study or for exam ination, test and analysis shal l m ake an applicationinForm CT-16totheCentralLicencingAuthority.

(3)Theapplicationundersub-rule(2)shalbeaccompaniedbyafeesspecifiedin theSixthScheduleandsuchotherinformationanddocumentsasspecifiedin Form CT-16.

68. Grantoflicenceforimportofnew drugorinvestigationalnew drugfor clinicaltrialorbioavailabilityorbioequivalencestudyorforexamination,testand analysis.-(1)TheCentralLicencingAuthoritymay,afterscrutinyoftheinformation anddocumentsfurnishedwiththeapplicationinForm CT-16andsuchfurther enquiry,ifany,asmaybeconsiderednecessary,-

(i) ifsatisfied,thattherequirementsoftheseruleshavebeencomplied with,grantthelicencetoimportofnew drugorinvestigationalnew drug for clinical trial or bioavailability or bioequivalence studyor for examination,testandanalysisinForm CT-17withinaperiodofninety daysfrom thedateofreceiptofitsapplicationinFormCT-16;

(i)incase,wheretheCentralLicencingAuthorityconsidersthatthereare somedeficienciesintheapplicationandthesamemayberectified, saidAuthorityshalinform theapplicantofthedeficiencieswithinthe stipulatedperiodreferedtoinclause(i);

(i)ifnotsatisfiedthattherequirementsoftheseruleshavebeencomplied with,rejecttheapplication,forthatreasonstoberecordedinwriting, withinaperiodofninetydays,from thedate,theapplicationmade undersub-rule(2)ofrule67;

Page40of40

(2)Theapplicant,afterbeinginformed,asreferedtoinclause(i)ofsub- rule(1),bytheCentralLicencingAuthority,may,

(i) rectifythedeficiencieswithinaperiodspecifiedbytheCentral LicencingAuthority;

wheretheapplicantrectifiesthedeficiency,asreferedinsub-rue (1)andprovidesrequiredinformationanddocuments,theCentral LicencingAuthorityshalscrutinizetheapplicationagainandif satisfied, grant licencetoimportofnewdrugorinvestigationalnewdrugforclinicaltrial orbioavailabilityorbioequivalencestudyorforexamination,test and analysis orifnotsatisfied,rejectthe application within a periodofninetyworkingdaysreckonedfrom thedaywhenthe requiredinformationanddocumentswereprovided:

Providedthatincaseofrejection,theapplicantmay requestthe CentralLicencing Authority,to reconsiderthe applicationwithinaperiodofsixtydaysfrom thedateofrejection of the application on paym ent of fee as specified in the Sixth Scheduleandsubmissionofrequiredinformationanddocuments.

(3 ) A n a p p lic a n t w h o is a g g rie v e d b y th e d e c is io n o f th e C e n tra l L ic e n c in g Authorityundersub-rule(1)orsub-rule(2),mayproferanappealbeforethe CentralGovernmentwithinsixtydaysfrom thedateofreceiptofsuch rejectionandthatGovernment,may,aftersuchenquiry,andaftergivingan opportunityofbeingheardtotheappelant,disposeoftheappealwithina periodofsixtyworkingdays.

69. bioavailabilityorbioequivalencestudyorforexamination,testandanalysis.-(1) Thelicencegrantedunderrule68inForm CT-17shalremainvalidforaperiodof threeyearsfrom thedateofitsissue,unlesssuspendedorcanceledbythe CentralLicencingAuthority.

(2)In exceptionalcircumstances,where the CentralLicencing Authority is satisfied about the necessity and exigency,it m ay,on the request of the applicantmadeinwriting,extendtheperiodofthelicencegrantedunder rule68forafurtherperiodofoneyear.

70. Conditionoflicence.–Thelicencegrantedunderrule68inForm CT-17is subjecttothefolowingconditions,namely,-

(i) itshalbetheresponsibilityofthelicenceetoensurethatthenew drughasbeenmanufacturedinaccordancewiththeprovisionsoftheAct, theserulesandprinciplesofgoodmanufacturingpractices;

(i) thelicenceeshalmakeuseofanew drugorsubstancerelatingthereto importedonthebasisoflicencegrantedunderrule68inForm CT-17only forthepurposesofclinicaltrialorbioavailabilityorbioequivalencestudyor forexamination,testand analysisand no partofsuch new drug or

Validityperiodoflicenceforimportofnew drugsforclinicaltrialor

Page41of41

substancerelatingtheretoshalbesoldinthemarketorsuppliedtoany otherpersonoragencyorinstitutionororganization;
(i) the licencee shalmaintain records ofimported new drug or substancerelatingthereto;

(iv) wheretheimportednew drugorsubstancerelatingtheretoisleft overorremainsunusedorgetsdamagedoritsspecifiedshelflifehas expiredorhasbeenfoundtobeofsub-standardquality,thesameshalbe destroyedanddetailsofactiontakeninsuchcasesshalberecorded;

71.Inspectionofimportednew drugforclinicaltrialorthebioavailabilityor bioequivalence study or for exam ination, test and analysis.-The person licencedtoimportanewdrugforclinicaltrialorbioavailabilityorbioequivalence studyshalalow anyoficerauthorisedbytheCentralLicencingAuthorityto enter,withorwithoutpriornotice,thepremiseswhereanewdrugorsubstances re la tin g th e re to h a s b e e n m a n u fa c tu re d o r im p o rte d , is s to c k e d o r is b e in g used,toinspectsuchpremisesandrecords,investigatethemannerinwhichsuchdrugi sbeingstockedorusedortotakesamplethereofifsorequiredbytheCentral LicencingAuthorityorhisauthorisedperson

.
72. Suspensionorcancelationofimportlicenceofnewdrugforclinicaltrial

orbioavailabilityorbioequivalencestudyorforexamination,testandanalysis.- (1)Wherethepersontowhom alicencehasbeengrantedunderrule68,failsto complywith anyprovision ofthe Actand these rules,the CentralLicencing Authoritymay,aftergivinganopportunitytoshow causeandafterafordingan opportunityofbeingheard,byanorderinwriting,suspendorcancelthelicence forsuchperiodasconsideredappropriateeitherwholyorinrespectofsomeof thesubstancestowhichtheviolationrelatesanddirecttheimportednewdrugsto bedisposedofinthemannerspecifiedinthesaidorder.

(2)Wherethepersonwhoselicencehasbeensuspendedorcanceledundersub- rule(1),isaggrievedbyanorderoftheCentralLicencingAuthority,such personmay,withinaperiodofforty-fivedaysofthereceiptoftheorderof suspensionorcancelation,makeanappealtotheCentralGovernmentand thatGovernmentmay,aftersuchenquiry,asdeemednecessaryandafter afordinganopportunityofbeingheard,passsuchorderinrelationtheretoas consideredappropriatewithinaperiodofsixtyworkingdays.

7 3 . M a n n e r o f la b e l lin g .- (1 ) A n y n e w d ru g s o r in v e s tig a tio n a l n e w d ru g s im p o rte d forthepurposeofclinicaltrialorbioavailabilityorbioequivalencestudyorfor examination,testandanalysisshalbekeptincontainersbearinglabels,indicatingthe nameofthedrugorcodenumber,batchorlotnumber,whereverapplicable,date ofmanufacture,usebeforedate,storageconditions,nameoftheinstitutionor organization or the centre where the clinical trial or bioavailability or bioequivalence study or for exam ination, test and analysis is proposed to be conducted,nameandaddressofthemanufacturer,andthepurposeforwhichit

Page42of42

hasbeenmanufacturedorimported.
(2)Whereanew drugoraninvestigationalnew drugisimportedbythelicencee

onbehalfofanotherperson,thelicenceeshalindicateonthelabelofthe containerofthesuchdrug,thenameandaddressoftheimporterandthe persontowhom itisbeingsuppliedalongwiththescientificnameofsuch drug, if know n, otherw ise reference w hich shal l enable such drug to be identifiedandthepurposeforwhichitismanufactured.

(3)Nopersonorimportershalalter,obliterateordefaceanyinscriptionormark madeonthecontainer,labelorwrapperofanynew drugimportedor manufacturedwithoutpermissionoftheCentralLicencingAuthority.

CHAPTERX IMPORTORMANUFACTUREOFNEW DRUGFORSALEORFORDISTRIBUTION

74. Regulationofnew drug.-Nopersonshalimportormanufactureforsale orfordistributionanynew drugintheform ofactivepharmaceuticalingredientor pharmaceuticalformulation,asthecasemaybe,exceptinaccordancewiththe provisionsoftheActandtheserules.

75. Applicationforpermissiontoimportnewdrugforsaleordistribution.-(1) Anypersonintendstoimportnewdrugsintheformofactivepharmaceuticalingredient orpharmaceuticalformulation,asthecasemaybe,forsaleorfordistributioninIndia, shalmakeanapplicationtoobtainapermissionfrom theCentralLicencingAuthorityin Form CT-18alongwithafeeasspecifiedintheSixthSchedule:

Providedthatanapplicationforgrantofpermissiontoimportanewdrug, in the form ofactive pharm aceuticalingredientw hich is a new drug notapproved earlier,shalbe accompanied byan application forgrantofpermission to manufacturepharmaceuticalformulationofthatnewdrug.

(2)Whereanew drugproposedtobemarketedbyanypersonisanew drug havingunapprovednew molecule,theapplicationinForm CT-18shalbe accompaniedbydataandotherparticularsincludingresultoflocalclinical trialasspecifiedintheSecondSchedulealongwithdataspecifiedinTable1 ofthe Second Schedule and accompanied with fee as specified in the SixthSchedule.

(3)Whereanewdrugisproposedtobemarketedwhichhasbeenapprovedasa newdruginthecountry,theapplicationinForm CT-18shalbeaccompanied bydataandotherparticularsasspecifiedintheSecondSchedulealongwith dataspecifiedinTable2oftheSecondScheduleandaccompaniedwithfee asspecifiedintheSixthSchedule.

(4)Whereanew drugwhichisalreadypermitedforcertainclaims,isnow proposedtobemarketedbyanypersonfornewclaims,newindicationornew dosageform ornew routeofadministrationornew strength,applicationin Form CT-18shalbeaccompaniedbydataandotherparticularsincluding resultoflocalclinicaltrialasspecifiedintheSecondSchedulealongwithdata specifiedinTable3oftheSecondScheduleandaccompaniedwithfeeas

Page43of43

specifiedintheSixthSchedule.
(5)Incaseanew drugwhichisafixeddosecombination,theapplicationinCT-

18shalbeaccompaniedbydataandotherparticularsincludingresultoflocal clinicaltrialasthecasemaybe,asspecifiedintheSecondSchedulealong withdataspecifiedinTable1orTable2orTable3,asthecasemaybe,ofthe SecondScheduleandaccompaniedwithfeeasspecifiedintheSixthSchedule.

(6)A person intends to marketphyto-pharmaceuticaldrugs shalmake an application in CT-18to the CentralLicencing Authority along with data specifiedinTable4oftheSecondScheduleanditshalbeaccompaniedwith afeeasspecifiedintheSixthSchedule.

(7)Thelocalclinicaltrialmaynotberequiredtobesubmitedalongwiththe applicationreferedtoinsub-rule(1)if,-

(i) ifthenewdrugisapprovedandmarketedinacountriesspecifiedby theCentralLicensingAuthorityunderrule100andifnomajorunexpected seriousadverseeventshavebeenreported;or
(i) iftheapplicationisforimportofanew drugforwhichtheCentral LicensingAuthorityhadalreadygrantedpermissiontoconductaglobal clinicaltrialwhichisongoinginIndiaandinthemeantimesuchnew drug hasbeenapprovedformarketinginacountryspecifiedunderrule100;and

(i i i) there is no probability or evidence, on the basis of existing knowledge,ofdiference in Indian population ofthe enzymes/gene involvedinthemetabolism ofthenew drugoranyfactorafecting pharmacokineticsandpharmacodynamics,safetyandeficacyofthenew drug;and

(iv)theapplicanthasgivenanundertakinginwritingtoconductPhaseIV clinicaltrialtoestablishsafetyandefectivenessofsuchnewdrugasper designapprovedbytheCentralLicencingAuthority:

Provided thatthe CentralLicencing Authority may relax the conditions at clause (i) to (i i i), w here the drug is indicated in life threatening/seriousdiseasesordiseasesofspecialrelevancetoIndian healthscenarioorforaconditionwhichisunmetneedinIndiasuchas XDRtuberculosis,hepatitisC,H1N1,dengue,malaria,HIV,orfortherare diseasesforwhichdrugsarenotavailableoravailableatahighcostorif itisanorphandrug.

(8) In the application refer red to in sub-rule (1),the subm ission of requirem ents relating to animaltoxicology,reproduction studies,teratogenic studies, perinatalstudies,mutagenicity and carcinogenicity,may be modified or relaxedincaseofnewdrugsapprovedandmarketedformorethantwoyears inothercountries,iftheCentralLicencingAuthorityissatisfiedthatthereis adequatepublishedevidenceregardingthesafetyofthedrug,subjecttoother provisionsoftheserules.

76. Grantofpermissionforimportofnew drugsforsaleordistribution.-(1) The Central Licencing Authority m ay, after scrutiny of the inform ation and

Page44of44

documentsfurnishedwiththeapplicationinForm CT-18andsuchfurtherenquiry, ifany,asmaybeconsiderednecessary,-

(i) ifsatisfied,thattherequirementsoftheseruleshavebeencomplied with,grantthepermissiontoimportnew drug,intheform ofactive pharmaceuticalingredientforsaleorfordistributioninForm CT-19or pharmaceuticalformulationforsaleorfordistributioninForm CT-20, asthecasemaybe,withinaperiodofninetyworkingdaysfrom the dateofreceiptofitsapplicationinFormCT-18;

(i)incase,wheretheCentralLicencingAuthorityconsidersthatthereare somedeficienciesintheapplicationandthesamemayberectified, saidAuthorityshalinform theapplicantofthedeficiencieswithinthe stipulatedperiodreferedtoinclause(i);

(i)ifnotsatisfiedthattherequirementsoftheseruleshavebeencomplied with,rejecttheapplication,forthatreasonstoberecordedinwriting, withinaperiodofninetyworkingdays,from thedateoftheapplication madeunderrule75;

(2)Theapplicant,afterbeinginformed,asreferedtoinclause(i)ofsub-rule (1),bytheCentralLicencingAuthority,may,

. (i)  rectifythedeficiencieswithinaperiodspecifiedbytheCentral LicencingAuthority;

. (i)  wheretheapplicantrectifiesthedeficiency,asreferedinsub-rule (1),withintheperiodreferedtoinclause(i)andprovidesrequired informationanddocuments,theCentralLicencingAuthorityshal scrutinizetheapplicationagainandifsatisfied,grantpermission to importnew drug,in the form ofactive pharmaceutical ingredient for sale or for distribution in Form CT-19 or pharmaceuticalformulationforsaleorfordistributioninForm CT- 20,asthecasemaybe,orifnotsatisfied,rejecttheapplication withinaperiodofninetydaysreckonedfrom thedaywhentherequired informationanddocumentswereprovided:
Providedthatincaseofrejection,theapplicantmay requestthe CentralLicencing Authority,to reconsiderthe applicationwithinaperiodofsixtydaysfrom thedateofrejection oftheapplicationonpaymentoffeeasspecifiedintheSixth Scheduleandsubmissionofrequiredinformationanddocuments.

(3 ) A n a p p lic a n t w h o is a g g rie v e d b y th e d e c is io n o f th e C e n tra l L ic e n c in g Authorityundersub-rule(1)andSub-rule(2),mayfileanappealbeforethe CentralGovernmentwithinsixtydaysfrom thedateofreceiptofsuch rejectionandthatGovernment,may,aftersuchenquiry,andaftergivingan opportunityofbeingheardtotheappelant,disposeoftheappealwithina periodofsixtyworkingdays.

77. Conditionofpermissionforimportofnewdrugsforsaleordistribution.-

Thepermissionforimportofnew drugsforsaleorfordistributionunderrule76 Page45of45

shalbesubjecttothefolowingconditions,namely,-

. (i)  the new drugs shal lconform to the specifications approved by the
CentralLicencingAuthority;

. (i)  thepropernameofthedrugorfixeddosecombinationdrugother
than fixed dose combinations ofvitamin and otherfixed dose combinationscontainingthreeormoredrugs,shalbeprintedor writeninaconspicuousmannerwhichshalbeinthesamefontbut atleasttwofontsizelargerthanthebrandnameorthetradename, ifany,andinboldleters,andinothercasesthebrandnameorthe tradename,ifany,shalbewriteninbracketsbelow orafterthe propername;

. (i)  thelabeloftheinnermostcontainerofthedrugandeveryother coveringinwhichthecontainerispackedshalbearaconspicuous redverticallineontheleftsiderunningthroughoutthebodyofthe labelwhichshalnotbelessthan3mm inwidthandwithout disturbing other conditions printed on the label to depict it as prescriptiondrug;

. (iv)  thelabelontheimmediatecontainerofthedrugaswelasthe packing in which the containeris enclosed should contain the folowing warning:”WARNING:To be sold by retailon the prescriptionofa.Only”whichshalbeinredbox.

. (v)  aspostmarketingsurveilance,theapplicantshalsubmitPeriodic SafetyUpdateReportsasspecifiedintheFifthSchedule;

. (vi)  alreportedadversereactionsrelatedtodrugshalbeintimatedto theCentralLicencingAuthorityandregulatoryactionresultingfrom theirreviewshouldbecompliedwith;

. (vi)  noclaimsexceptthosementionedaboveshalbemadeforthedrug withoutpriorapprovaloftheCentralLicencingAuthority;

. (vi)  specimenofthecarton,labels,packageinsertthatwilbeadopted formarketingthedruginthecountryshalbegotapprovedfrom the CentralLicencingAuthoritybeforethedrugsismarketed;

. (ix)  incaseofimport,eachconsignmentshalbeaccompaniedbyatest oranalysisreport.

78. Suspensionorcancelationofimportpermissionfornewdrug.-(1)Where theimporterfailstocomplywithanyprovisionoftheActandtheserules,the CentralLicencing Authority may,after giving show cause notice and an opportunityofbeingheard,byanorderinwriting,maysuspendthepermission forsuchperiodasconsideredappropriateorcancelthepermission.

(2) W here the im porter w hose perm ission has been suspended or cancel led undersub-rule(1),isaggrievedbyanorderoftheCentralLicencingAuthority, suchimportermay,withinfortyfivedaysofthereceiptoftheorder,makean appealto the CentralGovernmentand the CentralGovernmentmay,after suchenquiry,asdeemednecessaryandaftergivinganopportunityofbeing heard,passsuchorderasmaybeconsideredappropriateinthefactsand

Page46of46

circumstancesofthecase.

79. Licence to im portnew drug forsale orfordistribution underthe Drugs andCosmeticsRules,1945.-(1) Afterobtainingpermissionunderrule76,the person intend to im port new drug for sale shal l m ake an application to the CentralLicencingAuthorityasperprovisionsoftheDrugsandCosmeticsRules, 1945toobtainalicenceforimportofnewdrugforsaleorfordistribution.

(2) The application refer red in sub-Rule (1) shal l be accom panied by the permissioninForm CT-19orForm CT-20,asthecasemaybe,obtainedbythe a p p lic a n t fro m th e C e n tra l L ic e n c in g A u th o rity to im p o rt th e n e w d ru g s .

80. Application for perm ission to m anufacture new drug for sale or distribution.-(1)A person intends to m anufacture new drugs in the form ofactive pharmaceuticalingredientorpharmaceuticalformulation,asthecasemaybe,for s a le o r d is trib u tio n , s h a l l m a k e a n a p p lic a tio n fo r g ra n t o f p e rm is s io n to th e CentralLicencingAuthorityinForm CT-21alongwithafeeasspecifiedinthe SixthSchedule:

Provided thatno fee shalbe required to be paid along with the applicationformanufactureofanew drugbasedonsuccessfulcompletionof clinicaltrialsfrom PhaseItoPhaseIundertheserulesinIndia,wherefeehas alreadybeenpaidbythesameapplicantforconductofsuchclinicaltrials:

Providedfurtherthatanapplicationforgrantofpermissionofanewdrug intheform ofactivepharmaceuticalingredienthavinganinvestigationalnew drugnotapprovedearliershalbeaccompaniedbyanapplicationforgrantof permission to manufacture pharmaceutical formulation of the said investigationalnewdrug.
(2)Whereanew drug,proposedtobemanufactured,isanew drughaving

unapproved new molecule, the application in Form CT-21shal be accompaniedbydataandotherparticularsincludingresultsoflocalclinical trialasspecifiedintheSecondSchedulealongwithdataspecifiedinTable1 ofthe Second Schedule and accompanied with fee as specified in the SixthSchedule.

(3)Whereanewdrug,proposedtobemanufacturedwhichhasbeenapprovedas anew drug,theapplicationinForm CT-21shalbeaccompaniedbydataand other particulars as specified in the Second Schedule along with data specifiedinTable2oftheSecondScheduleandaccompaniedwithfeeas specifiedinSixthSchedule.

Whereanew drugwhichisalreadypermitedforcertainclaims,isnow proposedtobemanufacturedfornew claims,namelynew indicationornew dosageform ornew routeofadministrationornew strength,applicationin Form CT-21shalbeaccompaniedbydataandotherparticularsincluding resultsoflocalclinicaltrialasspecifiedintheSecondSchedulealongwith dataspecifiedinTable3oftheSecondScheduleandaccompaniedwithfee

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asspecifiedintheSixthSchedule. (4)Incaseanewdrugwhichisafixeddosecombination,theapplicationinForm

CT-21shalbeaccompaniedbydataandotherparticularsincludingresultsof localclinicaltrialas specified in the Second Schedule along with data specifiedinTable1orTable2orTable3,asthecasemaybe,oftheSecond ScheduleandaccompaniedwithfeeasspecifiedintheSixthSchedule.

(5)A person intends to marketphyto pharmaceuticaldrugs shalmake an applicationinForm CT-21totheCentralLicencingAuthorityalongwithdata specifiedinTable4ofSecondScheduleanditshalbeaccompaniedwitha feeasspecifiedintheSixthSchedule.

(6)Thelocalclinicaltrialmaynotberequiredtobesubmitedalongwiththe applicationreferedtoinsub-rule(1)if,-

. (i)  ifthenewdrugisapprovedandmarketedinacountriesspecifiedby the CentralLicensing Authority underrule100 and ifno major unexpectedseriousadverseeventshavebeenreported;or

. (i)  thereisnoprobabilityorevidence,onthebasisofexistingknowledge, ofdiferenceinIndianpopulationoftheenzymes/geneinvolvedinthe metabolism ofthenewdrugoranyfactorafectingpharmacokinetics andpharmacodynamics,safetyandeficacyofthenewdrug;and

(i i i) the applicanthas given an undertaking in writing to conductPhase IV clinicaltrialtoestablishsafetyandefectivenessofsuchnewdrugasper designapprovedbytheCentralLicencingAuthority:

Provided that the Central Licencing Authority may relax the conditions at clause (i) to (i i i), w here the drug is indicated in life threatening/seriousdiseasesordiseasesofspecialrelevancetoIndian healthscenarioorforaconditionwhichisunmetneedinIndiasuchas XDRtuberculosis,hepatitisC,H1N1,dengue,malaria,HIV,orfortherare diseasesforwhichdrugsarenotavailableoravailableatahighcostorifit isanorphandrug.

(7)Intheapplicationreferedtoinsub-rule(1),thesubmissionofrequirements relating to animaltoxicology,reproduction studies,teratogenic studies, perinatalstudies,mutagenicity and carcinogenicity may be modified or relaxedincaseofnewdrugsapprovedandmarketedforseveralyearsinother countriesiftheCentralLicencingAuthorityissatisfiedthatthereisadequate published evidence regarding the safety ofthe drug,subjectto other provisionsoftheserules.

81. Grantofpermissiontomanufactureofnewdrugforsaleordistribution.- (1)TheCentralLicencingAuthoritymay,afterscrutinyoftheinformationand documentsfurnishedwiththeapplicationinForm CT-21andsuchfurtherenquiry, ifany,asmaybeconsiderednecessary,-

(i) ifsatisfied,thattherequirementsoftheseruleshavebeencomplied with,grantthepermissiontomanufacturenew drug,intheform of activepharmaceuticalingredientforsaleorfordistributioninForm CT-

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22 orpharmaceuticalformulationforsaleorfordistributioninFormCT- 23,asthecasemaybe,withinaperiodofninetyworkingdaysfrom thedateof receiptofitsapplicationinForm CT-21;

(i)incase,wheretheCentralLicencingAuthorityconsidersthatthereare somedeficienciesintheapplicationandthesamemayberectified, saidAuthorityshalinform theapplicantofthedeficiencieswithinthe stipulatedperiodreferedtoinclause(i);

(i)ifnotsatisfiedthattherequirementsoftheseruleshavebeencomplied with,rejecttheapplication,forthatreasonstoberecordedinwriting, withinaperiodofninetyworkingdays,from thedate,theapplication madeunderrule81;

(2)Theapplicant,afterbeinginformed,asreferedtoinclause(i)ofsub-rule (1),bytheCentralLicencingAuthority,may,-

(i) rectify the deficiencies within a period specified by the Central LicencingAuthority;

(i)wheretheapplicantrectifiesthedeficiency,asreferedinsub-rue(1), within the period refered to in clause (i)and provides required information and documents,the CentralLicencing Authority shal scrutinizetheapplicationagainandifsatisfied,grantpermissionto manufacturenew drug,intheform ofactivepharmaceuticalingredient forsaleorfordistributioninForm CT-22orpharmaceuticalformulation forsaleorfordistributioninForm CT-23,asthecasemaybe,orifnot satisfied,rejecttheapplicationwithinaperiodofninetyworkingdays reckonedfrom thedaywhentherequiredinformationanddocuments wereprovided:

Provided thatin case ofrejection,the applicantmay requesttheCentralLicencingAuthority,toreconsidertheapplication withinaperiodofsixtyworkingdaysfrom thedateofrejectionofthe applicationonpaymentoffeeasspecifiedintheSixthScheduleand submissionofrequiredinformationanddocuments.

(3 ) A n a p p lic a n t w h o is a g g rie v e d b y th e d e c is io n o f th e C e n tra l L ic e n c in g Authorityundersub-rule(1)orsub-rule(2),mayfileanappealbeforethe centralGovernmentwithinsixtydaysfrom thedateofreceiptofsuch rejectionandthatGovernment,may,aftersuchenquiry,andaftergivingan opportunityofbeingheardtotheappelant,disposeoftheappealwithina periodofsixtyworkingdays.

82. Conditionofpermissionformanufactureofnew drugsforsaleor distribution.–Thepermissiongrantedunderrule81inFormCT-22orinForm CT- 23shalbesubjectfolowingconditions,namely,-

(i) thenew drugsshalconform tothespecificationsapprovedbythe CentralLicencingAuthority;

(i) thepropernameofthedrugorfixeddosecombinationdrugotherthan fixeddosecombinationsofvitaminandotherfixeddosecombinations

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containing three ormore drugs,shalbe printed orwriten in a conspicuousmannerwhichshalbeinthesamefontbutatleasttwofont sizelargerthanthebrandnameorthetradename,ifany,andinbold leters,andinothercasesthebrandnameorthetradename,ifany,shal bewriteninbracketsbeloworafterthepropername;

(i i i) th e la b e l o f th e in n e rm o s t c o n ta in e r o f th e d ru g a n d e v e ry o th e r c o v e rin g in which thecontainerispackedshalbearaconspicuousredverticalineontheleftsider unningthroughoutthebodyofthelabelwhichshalnotbelessthan3 mm inwidthandwithoutdisturbingtheotherconditionsprintedonthe labeltodepictitasprescriptiondrug;

(iv)thelabelontheimmediatecontainerofthedrugaswelasthepackingin whichthecontainerisenclosedshouldcontainthefolowingwarning:

“WARNING:Tobesoldbyretailontheprescriptionofa_Only” anditshalbeinboxwithredbackground.

(v) asPostmarketingsurveilance,theapplicantshalsubmitPeriodicSafety UpdateReportsasspecifiedintheFifthSchedule;

(vi)alreportedseriousunexpectedadversereactionsrelatedtothedrug shalbeintimatedtotheCentralLicencingAuthorityandregulatoryaction resulting from theirreview should be com pliedw ith;

(vi i)no claims exceptthose mentioned above shal lbe made forthe drug withoutpriorapprovaloftheCentralLicencingAuthority;

(vi)specimenofthecarton,labels,packageinsertthatwilbeadoptedfor marketingthedruginthecountryshalbegotapprovedfrom theCentral LicencingAuthoritybeforethedrugsismarketed;

83.Licencetomanufactureanew drugforsaleorfordistributionunderthe DrugsandCosmeticsRules,1945.-(1)Afterobtainingpermissiongranted u n d e r ru le 8 1 , th e p e rs o n in te n d s to m a n u fa c tu re a n e w d ru g fo r s a le s h a l l m ake an application for grant of licence to m anufacture for sale or for distributioninaccordancewiththeprovisionsoftheDrugsandCosmetics Act,1940andtheDrugsandCosmeticsRules,1945.

(2)The application refered in sub-rule (1)shalbe accompanied by the permissioninForm CT-22orForm CT-23,asthecasemaybe,obtainedbythe a p p lic a n t fro m th e C e n tra l L ic e n c in g A u th o rity to m a n u fa c tu re th e n e w d ru g .

84.Suspensionorcancelationofthepermission.-(1)Wherethemanufacturer failstocomplywithanyprovisionoftheAct,theserulesandanyconditionof the permission,the CentralLicencing Authority may,afterafording an opportunityofbeingheard,suspendorcancelthepermissionforsuchperiod as considered appropriate either w hol ly or in respect of som e of the substancestowhichtheviolationrelates.

(2)Wherethemanufacturerwhosepermissionhasbeensuspendedorcanceled undersub-rule(1)isaggrievedbyanorderoftheCentralLicencingAuthority,

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suchmanufacturermay,withinthirtydaysofthereceiptoftheorder,makean appealtotheCentralGovernmentandtheCentralGovernmentmay,aftersuch enquiry,asdeemednecessaryandafterafordinganopportunityofbeing heard,passsuchordersinrelationtheretoasconsideredappropriate.

85. Responsibilityoftheimportersormanufacturersinmarketingofnew drugs.-Themanufacturerorimporterofnewdrugsshalberesponsiblefor marketinganew drugfortheapprovedindicationandinonlysuchdosage fo rm fo r w h ic h it h a s b e e n p e rm it te d :

Providedthatthemanufacturerorimporterofnew drugshalnotbe punishedfortheconsequencesresultingfrom useofthedrugforan indication other than for w hich thedrug has been approved w here the manufacturerprovesthathehasnotbeeninvolvedinanymannerinthe promotionofuseofthenewdrugforotherthanapprovedindication.

CHAPTERXI IMPORTORMANUFACTUREOFUNAPPROVEDNEW DRUGFORTREATMENTOFPATIENTSIN

GOVERNMENTHOSPITALANDGOVERNMENTMEDICALINSTITUTION

86.ApplicationforimportofunapprovednewdrugbyGovernmenthospitaland Governmentmedicalinstitution.-(1)Notwithstandinganythingcontainedin theseRules,amedicaloficerofaGovernmenthospitaloraGovernment medicalinstitution,mayimportnewdrug,whichhasnotbeenpermitedinthe countryunderCHAPTERXoftheseRules,butapprovedformarketinginthe countryoforiginfortreatmentofapatientsuferingfrom lifethreatening diseaseordiseasecausingseriouspermanentdisabilityordiseaserequiring therapiesforunmetmedicalneeds,bymakinganapplicationdulycertifiedby the MedicalSuperintendentofthe GovernmenthospitalorHead ofthe Governmentmedicalinstitution,asthecasemaybe,totheCentralLicencing AuthorityinFormCT-24.

(2)The application undersub-rule (1)shalbe accompanied bysuch other particularsanddocumentsasarespecifiedinForm CT-24alongwithfeeas specifiedintheSixthSchedule.

87.GrantoflicenceforimportofunapprovednewdrugbyGovernmenthospital andmedicalinstitution.-(1)TheCentralLicencingAuthority,afterscrutinyof informationanddocumentsenclosedwiththeapplicationandsuchfurther enquiry,ifany,asconsiderednecessary,may,-

(i) ifsatisfied,thattherequirementsoftheseruleshavebeencompliedwith, grantlicenceforimportofanunapprovednew drugbyGovernment hospitalandGovernmentmedicalinstitutioninFormCT-25;

(i)ifnotsatisfiedwiththerequirementsasreferedtoinsub-clause(i),reject theapplication,forreasonstoberecordedinwriting,withinaperiodof ninetydays,from thedateofapplicationmadeundersub-rule(1)ofrule87.

(2)An applicantwho is aggrieved by the decision ofthe CentralLicencing Authorityundersub-rule(1),mayfileanappealbeforetheCentralGovernment

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withinforty-fivedaysfrom thedateofreceiptofsuchrejectionandthat Government,may,aftersuchenquiry,andaftergivinganopportunityofbeing heardtotheappelant,disposeoftheappealwithinaperiodofsixtyworking days.

(3)Thequantityofanysingledrugimportedonthebasisoflicencegrantedunder sub-rule(1),shalnotexceedonehundredaveragedosagesperpatientbutin exceptionalcircumstancesandonbeingsatisfiedaboutthenecessityand exigencytheCentralLicencingAuthoritymayalowimportofunapprovednew drugsinlargerquantities.

88. Conditionsoflicence.-Theimportlicencegrantedunderrule87inForm CT- 25shalbesubjecttothefolowingconditions,namely,-

. (i)  thelicenceshalremainvalidforaperiodofthreeyearsfrom the dateithasbeenissued;

. (i)  the licence shal l be displayed in the prem ises of the m edical institution including where the unapproved new drug is being stockedandusedintheOficeoftheMedicalSuperintendentofthe GovernmenthospitalorHeadofGovernmentmedicalinstitution;

. (i)  the licencee shal lstock the unapproved new drug im ported under thislicenceunderproperstorageconditions;

. (iv)  theunapprovednew drugimportedunderthislicenceshalbe exclusivelyusedfortreatmentofthepatientandsuppliedunderthe supervision ofa registered pharmacistand no partofsuch unapprovednewdrugshalbesoldinthemarketorsuppliedtoany otherperson,agency,institutionorplace;

. (v)  theregisteredpharmacistshalmaintainarecordasspecifiedin annexure of Form CT-25, countersigned by the Medical Superintendent of the Government hospital or Head of the Governmentmedicalinstitution which shalbe produced,on demandbytheoficerauthorisedbytheCentralLicencingAuthority undertheserules;

. (vi)  the Government hospital and Government medical institution re fe r re d to in s u b -ru le (1 ) o f ru le 8 7 , s h a l l s u b m it to th e C e n tra l LicencingAuthorityahalfyearlyreportaboutthestatusandstock ofunapprovednewdrugsimported,utilizedanddestroyed;

. (vi)  wheretheunapprovednewdrugsimportedunderlicencegranted undersub-Rule(1)ofRule87,areleftoverorremainunusedorget damagedoritsspecifiedshelflifehasexpiredorhasbeenfoundto beofsub-standardquality,thesameshalbedestroyedandthe action taken in respect thereof be recorded as refer red to in clause(iv)bytheregisteredpharmacist.

89.Suspensionorcancelationofimportlicenceforunapprovednew drugof GovernmenthospitalorGovernmentmedicalinstitution.– (1)Where any

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licenceereferedtoRule87,failstocomplywithanyprovisionoftheActand these rules,the CentralLicencing Authority,may after afording an opportunityofbeingheard,byanorderinwriting,suspendorcancelthe perm ission for such period as considered appropriate either w hol ly or in respectofsomeofthesubstancestowhichtheviolationrelates.

(2)Wherethelicencee,whoselicencehasbeensuspendedorcanceledunder sub-rule(1)isaggrievedbyanorderoftheCentralLicencingAuthority,hemay, withinaperiodofforty-fivedaysfrom thereceiptoftheorder,makeanappeal to the CentralGovernmentand the CentralGovernmentmay,aftersuch enquiry,asdeemednecessaryandafterafordinganopportunityofbeing heard,passsuchordersinrelationtheretoasconsideredappropriate.

90.Inspectionofunapprovednew drugimportedbyGovernmenthospitalor Governmentmedicalinstitution.-Thelicenceereferedtorule87,shalalow any person authorised by the CentralLicencing Authority who may be accompaniedbyanoficerauthorisedbytheStatelicencingauthority,to enter,withorwithoutpriornotice,thepremiseswheretheunapprovednew d ru g s a re s to re d , u s e d a n d re c o rd s , to in s p e c t s u c h p re m is e s , s to re a n d record,investigatethemannerinwhichthedrugsarebeingusedandstocked andtotakesamplethereof.

91.Applicationforpermissiontomanufactureunapprovednew drugbutunder clinicaltrial,fortreatmentofpatientoflifethreateningdisease.-(1)Where any medicaloficerofa GovernmenthospitalorGovernmentmedical institutionprescribesinspecialcircumstancesanynew drugforapatient suferingfrom seriousorlifethreateningdiseaseforwhichthereisno satisfactorytherapyavailableinthecountryandwhichisnotyetapprovedby theCentralLicencingAuthoritybutthesameisunderclinicaltrialinthe country,then,suchnewdrugmaybeapprovedtobemanufacturedinlimited quantitysubjecttoprovisionsoftheserules.

(2 ) W h e re a n y m a n u fa c tu re r in te n d s to m a n u fa c tu re n e w d ru g re fe r re d to in s u b – rule(1),heshalobtaintheconsentinwritingfrom thepatienttowhom the unapprovednewdrughasbeenprescribedundersub-rule(1)orhislegalheirs andmakeanapplicationtotheEthicsCommiteeoftheGovernmenthospital ormedicalinstitution,as the case may be forobtaining its specific recommendationformanufactureofsuchunapprovednewdrug.

(3)AfterobtainingtherecommendationoftheEthicsCommiteeundersub-rule (2),themanufacturershalmakeanapplicationinForm CT-26toobtainthe permissiontotheCentralLicencingAuthorityformanufacturingspecificnew drug.

(4)Theapplicationundersub-rule(3)shalbeaccompaniedbyconsentinwriting from thepatientreferedtoinsub-rule(1)orhislegalheirsregardinguseof suchunapprovednew drugandsuchotherparticularsanddocumentsasare specifiedinForm CT-26alongwithfeeasspecifiedintheSixthSchedule.

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92.Grantofpermissiontomanufactureunapprovednewdrugbutunderclinical trial,fortreatmentofpatientoflifethreateningdisease.-(1)TheCentral Licencing Authority may,afterscrutiny ofinformation and documents enclosed with the application and such further enquiry, if any, as considerednecessary,-

(i) ifsatisfied,thattherequirementsoftheseruleshavebeencompliedwith, grantpermissiontomanufactureunapprovednew drugbutunderclinical trialfortreatmentofpatientoflifethreateningdiseaseinFormCT-27;

(i)ifnotsatisfiedwiththerequirementsasreferedtoinsub-clause(i),reject theapplication,forreasonstoberecordedinwriting,withinaperiodof ninetydays,from thedateofapplicationmadeunderrule91.

(2)Thequantityofanysinglenewdrugmanufacturedonthebasisofpermission grantedundersub-rule(1)shalnotexceedonehundredaveragedosagesper patientbutinexceptionalcircumstancesonthebasisoftheprescriptionof themedicaloficerreferedtoinsub-rule(1)andtherecommendationofthe EthicsCommitee,theCentralLicencingAuthoritymayalowthemanufacture ofsuchnewdruginlargerquantity.

93.

Condition of permission.- The permission granted under rule 92 inFormCT-27,issubjecttothefolowingconditions,namely,-

. (i)  thepermissionshalremainvalidforaperiodofoneyearfrom the dateithasbeenissued;

. (i)  thepatientowhomtheunapprovednewdrugisprescribedundersub- Rule(1)ofRule92shalusesuchunapprovednew drugunderthe supervision ofthe medicaloficeratthe place specified in the permission oratsuch otherplaces,as the CentralLicencing Authoritymayauthorise;

. (i)  themanufacturertowhom thepermissionisgrantedundersub-rule (1)ofrule93,shalmakeuseoftheunapprovednewdrugonlyforthe purposesspecifiedinthepermissionandnopartofitshalbesold inthemarketorsuppliedtoanyotherperson,agency,institution orplace;

. (iv)  themanufacturerreferedtoinclause(i)shalkeeprecordofthe unapproved new drugs m anufactured,stored and supplied by him to thepatientinaregisterintheformatasspecifiedinannexureof FormCT-27;

. (v)  the m anufacturer refer red to in clause (i i i), shal l subm it to the CentralLicencingAuthorityahalfyearlyreportaboutthestatusof the unapproved new drugs manufactured, supplied to the authorisedpatient;

(vi) themanufacturershalbekeptandstoredinaccordancewiththe storageconditionsspecifiedonitslabelandsuppliedtothepatient underthesupervisionofthemedicaloficerreferedtoinsub-rule(1) ofrule92oraregisteredpharmacistdulyauthorisedbyhim;

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. (vi)  theregisteredpharmacistshalmaintainarecordofthefulname and address of the patients, diagnosis, dosage schedule, total quantity of drugs imported and issued,countersigned by the MedicalSuperintendentoftheGovernmenthospitalorHeadofthe medicalinstitution which shalbe produced,on demand bythe oficerauthorisedbytheCentralLicencingAuthorityundertheAct;

. (vi)  wheretheunapprovednewdrugmanufacturedinaccordancewith thepermissionissuedundersub-rule(1)ofrule93,isleftoveror remainunusedorgetdamagedoritsspecifiedshelflifehasexpired or has found to be of sub-standard quality, the sam e shal l be destroyed bythe manufacturerand the action taken in respect thereofshalberecorded;

(ix) ThepermissionholdershalinformtheCentralLicencingAuthority oftheoccurenceofanyseriousadverseeventandactiontaken thereonincludinganyrecalwithinfifteendaysofoccurenceof suchevent.

94.Inspectionofunapprovednewdrugbutunderclinicaltrialmanufacturedfor patientoflifethreateningdisease.-Themanufacturerreferedtoinrule92, shalalow personsauthorisedbytheCentralLicencingAuthorityincluding thepersonauthorisedbytheStatelicencingauthoritytoenter,withorwithout priornotice,the premises where the unapproved new drug is being manufactured,storedandsupplied,toinspectsuchpremisesandrecords, investigate the manner in which the unapproved new drug is being manufactured,suppliedandtotakesamplethereof.

95.Suspensionorcancelationofpermissiontomanufactureunapprovednew drugbutunderclinicaltrial.- (1)Wherethemanufacturertowhom permissionisgrantedunderrule92failstocomplywithanyprovisionofthe Actand these rules,the CentralLicencing Authority,may,aftergiving an opportunity of being heard, by anorder,in w riting, suspend or cancel the permissionforsuchperiodasconsideredappropriateeitherwholyorinrespectof someofthesubstancestowhichtheviolationrelates.

(2) W here the m anufacturer w hose perm ission is suspended or cancel led undersub-rule (1)is aggrieved by an orderofthe CentralLicencing Authority,hemay,withinaperiodoffortyfivedaysfrom thereceiptofthe order,makeanappealtotheCentralGovernmentinrespectofsuspension orcancelationofthepermissionandtheCentralGovernment,may,after suchenquiry,asdeemednecessaryandafterafordinganopportunityof beingheard,passsuchordersinrelationtheretoasconsideredappropriate.

96.Licencetomanufactureanunapprovednew drugbutunderclinicaltrial,for treatm ent of patient of life threatening disease under the Drugs and Cosmetics Rules,1945.-(1)Afterobtaining permission underrule 92,the personintendstomanufactureanunapprovednew drug,whichisunder

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clinicaltrial,fortreatmentofpatientoflifethreateningdisease,shalmakean applicationforgrantoflicencetomanufacturetheunapprovednewdrugunder the provisions ofthe Drugs and Cosmetics Act,1940 and the Drugs and CosmeticsRules,1945.

(2)Theapplicationreferedinsub-rule(1)shalbeaccompaniedbythepermission inForm CT-27obtainedbytheapplicantfrom theCentralLicencingAuthority toimportthenewdrugs.

CHAPTERXI MISCELLANEOUS

97.Pre-submissionmeeting.-(1)Anypersonintendstomakeanapplicationfor grantoflicenceorpermissionforimportormanufactureofnew drugsorto conductclinicaltrialmay,requestbymakinganapplicationinwriting,fora pre-submissionmeetingwiththeCentralLicencingAuthorityoranyother person authorised bythe CentralLicencing Authorityforseeking writen guidance about the requirem ents of law and procedure of such licence or permissionofmanufacturingprocess,clinicaltrialandotherrequirements.

(2) The application for pre-subm ission m eeting under sub-rule (1) m aybe accompaniedbyparticularsanddocumentsreferedtointheSecondSchedule, as available with the applicantto supporthis proposalalong with fee as specifiedintheSixthSchedule.

(3)Wheretheapplicantintendstoseekguidanceaboutthesaleprocessofnew drugsorimportlicence,inadditiontothepurposesreferedtoinrule(2),the fee as specified in the Sixth Schedule shalbe submited along with theapplication.

(4 ) W h e re th e C e n tra l L ic e n c in g A u th o rity is s a tis fie d th a t th e a p p lic a tio n is incom plete or the inform ation or the docum ents subm it ted along w ith the sameareinadequate,hemaywithinaperiodofthirtydaysfrom thereceiptof thesameintimatethefactstotheapplicantinwritinganddirecthim tofurnish suchfurtherinformationordocumentsasarenecessaryinaccordancewith theprovisionsoftheActandtheseRules.

(5)Inthepresubmissionmeeting,theCentralLicencingAuthorityoranyother person

authorisedbyitshalprovidetotheapplicant,extractsofthelawofprocedure,formso fapplication forpermission orlicence,necessary guidelines and other requirementsforthepurposesindicatedintheapplicationundersub-Rule(1).

98.Post-submissionmeeting.-(1)Iftheapplicantdesirestoseekclarificationin person in respectofpending application and queries related thereto, theapplicantmaymakeanapplicationforapost-submissionmeetingwiththe oficerdesignated bythe CentralLicencingAuthoritywithinaperiodofifteendaysfromthedatethequerywa s received for seeking guidance with regards to the queries concerningpendingapplication.

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(2)Theapplicantshalclearlystatethepointsonwhichclarificationisrequiredandafter receiptofsuchapplication,thedesignatedoficershalinformthetimeanddate scheduledforpostsubmissionmeeting.

(3)Thesummaryoftheclarificationprovidedbythedesignatedoficershalbemade availabletotheapplicant.

(4 ) T h e a p p lic a tio n fo r p o s t-s u b m is s io n m e e tin g u n d e r s u b -R u le (1 ) s h a l l b e accompaniedwiththefeeasspecifiedintheSixthSchedule.

(5) In the post subm ission m eeting, the of ficer designated by the Central LicencingAuthorityshalprovidesuitableclarificationtotheapplicant.

99.Constitution ofexpertcommitee orgroup by the CentralLicencing Authority.-TheCentralLicencingAuthoritymay,whensorequired,constitute oneormoreexpertcommiteeorgroupofexpertswithspecialisationin relevantfields,withtheapprovalofCentralGovernment,toevaluatescientific andtechnicalmatersrelatingtodrugsandsuchcommiteeorgroupmay, giveitsrecommendationstothatauthorityonmatersreferedtoitwithina periodofsixtydaysfrom thedateofreference.

100.Nameofthecountriesforthepurposeofnew drugapproval-TheCentral Licensing Authority,with the approvalofthe CentralGovernment,may specify,byanorder,thenameofthecountries,from timetotime,for consideringwaiveroflocalclinicaltrialforapprovalofnewdrugsCHAPTER XandforgrantofpermissionforconductofclinicaltrialunderCHAPTERV.

101.Modeofpaymentoffee.-Thefeesprescribedundertheserules,incaseof applicationmadetotheCentralLicencingAuthority,shalbepaidthrough chalanorbyelectronicmode,intheBankofBaroda,KasturbaGandhiMarg, NewDelhi-110001oranyotherbranchofBankofBaroda,oranyotherbank, n o tifie d b y th e M in is try o f H e a lth a n d F a m ily W e lfa re in th e C e n tra l Government,tobecreditedundertheHeadofAccount“0210-Medicaland PublicHealth,04-PublicHealth,104-FeesandFines.

102.Debarmentofapplicant.-(1)Whoeverhimselfor,anyotherpersononhis behalf,orapplicantisfoundtobeguiltyofsubmitingmisleading,orfake,or fabricateddocuments,may,aftergivinghim anopportunitytoshow cause astowhysuchanordershouldnotbemade,inwriting,statingthereasons thereof,bedebaredbytheCentralLicencingAuthorityforsuchperiodas deemedfit.

(2)WhereanapplicantisaggrievedbyanordermadebytheCentralLicencing Authority undersub- rule(1),suchapplicantmay,withinthirtydaysfromthereceiptofthe order,make anappealtotheCentralGovernmentandtheCentralGovernment,may, after such enquiry as it considers necessary, and after af fording an opportunity of being heard,pass such orders in relation thereto as

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consideredappropriate.

103.OrderofSuspensionorRevocationinpublicdomain.-Incase,theCentral LicencingAuthorityissueanyorderofsuspensionorrevocationorcancelation ofanypermissionorlicenceorregistrationgrantedundertheserules,such ordershalbemadeavailableinthepublicdomainimmediatelybyuploadingit inthewebsiteofCDSCO.

104.Digitalisation of form .-The form s prescribed under these rules m ay be suitablymodifiedforconversionintodigitalformsbytheCentralDrugs StandardControlOrganizationandsuchmodificationshalnotrequire anyamendmentintheserules.

105.Applicabilityincaseofinconsistency.-Ifthereisanyinconsistencybetween theseRulesandtheDrugsandCosmeticsRules,1945,theprovisionsofthese RulesshalprevailovertheDrugsandCosmeticsRules,1945.

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FIRSTSCHEDULE (SeeRule19,31)

GENERALPRINCIPLESANDPRACTICESFORCLINICALTRIAL

1. GeneralPrinciples.-(1)Theprinciplesandguidelinesforprotectionoftrial subjectsasdescribedinThirdScheduleaswelasGoodClinicalPractices guidelinesshalbefolowedinconductofanyclinicaltrial. (2)Thesponsorandinvestigatorsharetheresponsibilitiesfortheprotectionof
trialsubjecttogetherwithethicscommitee.Theresponsibilitiesofsponsor,
investigatorandethicscommiteearedescribedinthisThirdSchedule. (3)The results ofnon-clinicalstudies orprevious clinicaltrials should be suf ficientto ensure thatthe new drugs orinvestigationalnew drug is safe
fortheproposedclinicaltrial.
(4)Throughoutthe clinicaltrialand drug developmentprocess,the animal
toxicologicaldataandclinicaldatageneratedshouldbeevaluatedtoensure
theirimpactforthesafetyofthetrialsubject.

2. Approachindesignandanalysis.-(1)Clinicaltrialshouldbeplanned,designed,
conducted,analysedandreportedaccordingtosoundscientificandethical principles.Folowingimportantprinciplesshouldbefolowed.
(a)The primary objective ofany clinicaltrialshould be clearly and explicitly stated which may include exploratory or confirmatory characterisationofsafety,eficacy,assessmentofpharmacokinetic andpharmacodynamicparameters;
(b)Theclinicaltrialshouldbedesignedappropriatelysothatitprovides thedesiredinformation;
(c)Appropriatecomparatormaybeutilisedtoachievetheobjectivewith re s p e c t to p rim a ry a n d s e c o n d a ry e n d p o in ts . C o m p a ris o n m a y b e madewithplacebo,notreatment,activecontrolsorofdiferentdoses ofthenewdrugorinvestigationalnewdrug;
(d)Thenumberofsubjectstobeincludedintheclinicaltrialshouldbe adequatedependingonthenatureandobjectiveoftheclinicaltrial.

3. DevelopmentMethodology: (1)Nonclinicalstudies
(a)Thenatureofnon-clinicalstudiesandtheirtiminginrespectofconduct ofclinicaltrialshould be determined taking folowing aspects intoconsideration:
(i) characteristicsofthenew drugorinvestigationalnew drug;
(i i) disease of conditions for w hich the new drug or investigational
newdrugisintendedtobeindicated; (i)durationandexposureinclinicaltrialsubject; (iv)routeofadministration.
(b)Thedetailedrequirementsofnon-clinicalstudieshavebeenspecified intheSecondSchedule.
(c)For first in hum an studies the dose should be calculated careful ly Page59of59

based on the non-clinical pharmacological, toxicological datagenerated.

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(2)PhasesinClinicalTrial:Clinicaldrugdevelopmentgeneralyconsistsoffour phases(PhaseI-IV).Thedetailsofthesephasesaredescribedasunder.

(a)PhaseI.- Theobjectiveofstudiesinthisphaseistheestimationofsafetyand tolerabilitywiththeinitialadministrationofaninvestigationalnew drug into hum ans. Studies in this phase of developm ent usual ly have non- therapeuticobjectivesandmaybeconductedinhealthysubjectsorcertain typesofpatients.Drugswithsignificantpotentialtoxicitye.g.cytotoxic drugsareusualystudiedinpatients.PhaseItrialshouldpreferablybe cariedoutbyinvestigatorstrainedinclinicalpharmacologywithaccessto thenecessaryfacilitiestocloselyobserveandmonitorthesubjects.

StudiesconductedinPhaseI,usualyintendedtoinvolveoneora combinationofthefolowingobjectives:-

. (a)  Maximum tolerateddose:Todeterminethetolerabilityofthe doserangeexpectedtobeneededforlaterclinicalstudiesand to determine the nature ofadverse reactions thatcan be expected.These studies include both single and multiple doseadministration.

. (b)  Pharmacokinetics,i.e.,characterizationofadrug’sabsorption, distribution,metabolism andexcretion:Althoughthesestudies continue throughoutthe developmentplan,theyshould be performedtosupportformulationdevelopmentanddetermine pharm acokinetic param eters in dif ferent age groups to supportdosingrecommendations.

. (c)  Pharmacodynamics:Dependingonthedrugandtheendpoints studied,pharmacodynamicstudiesandstudiesrelatingtodrug bloodlevels(pharmacokineticorpharmacodynamicstudies) maybeconductedinhealthyvolunteersubjectsorinpatients with the targetdisease.Ifthere are appropriate validated indicatorsofactivityandpotentialeficacy,pharmacodynamic dataobtainedfrom patientsmayguidethedosageanddose regimentobeappliedinlaterstudies.

. (d)  Earlymeasurementofdrugactivity:Preliminarystudiesof activityorpotentialtherapeuticbenefitmaybeconductedin PhaseIasasecondaryobjective.Suchstudiesaregeneraly performedinlaterphasesbutmaybeappropriatewhendrug activityisreadilymeasurablewithashortdurationofdrug exposureinpatientsatthisearlystage.

(b)PhaseI.-
(i) The primary objective of Phase I trials is to evaluate the

efectivenessofadrugforaparticularindicationorindicationsin p a tie n ts w ith th e c o n d itio n u n d e r s tu d y a n d to d e te rm in e th e commonshort-term side-efectsandrisksassociatedwiththedrug. StudiesinPhaseIshouldbeconductedinagroupofpatientswho

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areselectedbyrelativelynarow criterialeadingtoarelatively homogeneous population. These studies should be closely monitored.Animportantgoalforthisphaseistodeterminethe doseandregimenforPhaseItrials.DosesusedinPhaseIare usualy(butnotalways)lessthanthehighestdosesusedinPhaseI.

(i)AdditionalobjectivesofPhaseIstudiescanincludeevaluationof potential study endpoints, therapeutic regimens (including concomitantmedications)andtargetpopulations(e.g.mildversus severe disease)forfurtherstudies in Phase IorI.These objectives may be served by exploratory analyses,examining subsetsofdataandbyincludingmultipleendpointsintrials.

(c)PhaseI.-
(i)Phase Istudies have primary objective ofdemonstration or

confirmation oftherapeutic benefits.Studies in Phase Iare designedtoconfirm thepreliminaryevidenceaccumulatedin PhaseIthatadrugissafeandefectiveforuseintheintended indication and recipient population. These studies should be intended to provide an adequate basis for m arketing approval. StudiesinPhaseImayalsofurtherexplorethedose-response relationships (relationships among dose,drug concentration in bloodandclinicalresponse),useofthedruginwiderpopulations, indiferentstagesofdisease,orthesafetyandeficacyofthe drugincombinationwithotherdrugs.

(i) Fordrugs intended to be administered forlong periods,trials involvingextendedexposuretothedrugareordinarilyconductedin PhaseI,althoughtheymaybeinitiatedinPhaseI.Thesestudies car ried out in Phase I I I com plete the inform ation needed to supportadequate instructions foruse ofthe drug (prescribing information).

(i i i) F o r n e w d ru g s a p p ro v e d o u ts id e In d ia , P h a s e I I I s tu d ie s m a y n e e d tobecariedoutifscientificalyandethicalyjustified,primarilyto generate evidence of ef ficacy and safety of the drug in Indian patients when used as recommended in the prescribing information.PriortoconductofPhaseIstudiesinIndiansubjects, CentralLicencingAuthoritymayrequirepharmacokineticstudies to be undertaken to verify thatthe data generated in Indian populationisinconformitywiththedataalreadygeneratedabroad. Incaseofanapplicationofanew drugalreadyapprovedand marketed in othercountry,where localclinicaltrialin India is waivedofornotfoundscientificalyjustifiedforitsapprovalfor manufacturingfirsttimeinthecountry,thebioequivalencestudies ofsuchdrug,asappropriate,isrequiredtobecariedoutandthe testbatches manufactured forthe purpose shalbe inspected beforeitsapproval.

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(d)PhaseIV.-
PhaseIVorpostmarketingtrialofnew drugsareperformedafterthe approvalofthedrugandrelatedtotheapprovedindication.Suchtrials gobeyondthepriordemonstrationofthedrug’ssafety,eficacyand dosedefinition.Suchtrialmightnothavebeenconsideredessentialat thetimeofnew drugapprovalduetovariousreasonssuchas limitationintermsofpatientexposure,durationoftreatmentduring clinicaldevelopmentofthedrug,needforearlyintroductionofthenew drugintheinterestofpatientsetc.PhaseIVtrialsincludeadditional drug-drug interaction,dose response orsafety studies and trials designtosupportuseundertheapprovedindicatione.g.mortalityor morbiditystudies,epidemiologicalstudies,etc.

(3)Studiesinspecialpopulations.-

Informationsupportingtheuseofthedruginchildren,pregnantwomen, nursing women,elderly patients,patients with renalorotherorgan systemsfailure,andthoseonspecificconcomitantmedicationisrequired to be submited ifrelevantto the clinicalprofile ofthe drug and its anticipatedusagepatern. (A)Geriatrics.-GeriatricpatientsshouldbeincludedinPhaseIclinical

trials(andinPhaseItrials,attheSponsor’soption)inmeaningful numbers,if-

(a)thediseaseintendedtobetreatedischaracteristicalyadisease ofaging;or

(b) the population to be treated is know n to include substantial numbersofgeriatricpatients;or

(c)whenthereisspecificreasontoexpectthatconditionscommon intheelderlyarelikelytobeencountered;or

(d)whenthenew drugislikelytoalterthegeriatricpatient’s response(withregardtosafetyoreficacy)comparedwiththat ofthenon-geriatricpatient.

(B)Paediatrics.-
(i)Thetimingofpaediatricstudiesinthenew drugdevelopment

program wildependonthemedicinalproduct,thetypeofdisease beingtreated,safetyconsiderations,andtheeficacyandsafetyof availabletreatments.Foradrugexpectedtobeusedinchildren, evaluationsshouldbemadeintheappropriateagegroup.When clinicaldevelopmentistoincludestudiesinchildren,itisusualy appropriatetobeginwitholderchildrenbeforeextendingthetrialto youngerchildrenandtheninfants.

(i)Ifthenew drugisfordiseasespredominantlyorexclusively afectingpaediatricpatients,clinicaltrialdatashouldbegenerated inthepaediatricpopulationexceptforinitialsafetyandtolerability data,which wil lusual ly be obtained in adults unless such initial

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safety studies in adults w ould yield lit tle useful inform ation or

exposethem toinappropriaterisk.
(i i i) If the new drug is intended to treat serious or life-threatening

diseases,occuringinbothadultsandpaediatricpatients,forwhich there are cur rently no or lim ited therapeutic options, paediatric populationshouldbeincludedintheclinicaltrialsearly,folowing assessmentofinitialsafety data and reasonable evidence of potentialbenefit.Incircumstanceswherethisisnotpossible,lack ofdatashouldbejustifiedindetail.

(iv)Ifthenew drughasapotentialforuseinpaediatricpatients– paediatric studies should be conducted. These studies m ay be initiated at various phases of clinical developm ent or after post marketingsurveilanceinadultsifasafetyconcernexists.Incases wherethereislimitedpaediatricdataatthetimeofsubmissionof application,more data in paediatric patients would be expected aftermarketingauthorisationforuseinchildrenisgranted.

(v)Thepaediatricstudiesshouldinclude–
(a) clinicaltrials,
(b) relative bioequivalence comparisons of the paediatric

formulationwiththeadultformulationperformedinadults,and

(c)definitivepharmacokineticstudiesfordoseselectionacrossthe agerangesofpaediatricpatientsinwhom thedrugislikelyto beused.Thesestudiesshouldbeconductedinthepaediatric patientpopulationwiththediseaseunderstudy.

(vi)Ifthenew drugisamajortherapeuticadvanceforthepaediatric populationthestudiesshouldbeginearlyinthedrugdevelopment, andthisdatashouldbesubmitedwiththenewdrugapplication.

(vi)Forclinicaltrials conducted in the paediatric population,the reviewing ethics commitee should include members who are knowledgeable about paediatric, ethical, clinical and psychosocialissues.

(C)Pregnantornursingwomen.-

. (i)  Pregnantornursingwomenshouldbeincludedinclinicaltrials
onlywhenthedrugisintendedforusebypregnantornursing women or foetuses or nursing infants and where the data generatedfrom womenwhoarenotpregnantornursing,is notsuitable.

. (i)  Fornewdrugsintendedforuseduringpregnancy,folow-updata (pertainingtoaperiodappropriateforthatdrug)onthepregnancy, foetusandchildwilberequired.Whereapplicable,excretionofthe drugoritsmetabolitesintohumanmilkshouldbeexaminedand the infant should be m onitored for predicted pharm acological efectsofthedrug.

4.ConductofClinicalTrial:Clinicaltrialshouldbeconductedinaccordancewith the principles as specified in Third Schedule.Adherence to the clinicaltrial

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protocolisessentialandifamendmentoftheprotocolbecomesnecessarythe rationalefortheamendmentshalbeprovidedintheform ofaprotocol am endm ent. Serious adverse events shal l be reported during clinical trial in accordancewiththeserules.

5.Analysis:Theresultsofaclinicaltrialshalbeanalysedaccordingtotheplan specifiedintheclinicaltrialprotocol.Safetydatashouldbeappropriately tabulated and aladverse events should be classified according to their seriousnessandcausalrelationshipwiththestudydrug.

6.Reporting:Reportofclinicaltrialshalbedocumentedinaccordancewiththe approachesspecifiedinTable6oftheThirdSchedule.Thereportshalbe certified by the principalinvestigatororifno principalinvestigatoris designatedthenbyeachoftheparticipatinginvestigatorsofthestudy.

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SECONDSCHEDULE (SeeRules21,75,80and97)

REQUIREMENTSANDGUIDELINESFORPERMISSIONTOIMPORTOR MANUFACTUREOFNEW DRUGFORSALEORTOUNDERTAKECLINICALTRIAL

1.Application forpermission.-(1)Application forpermission to importor manufacturenew drugforsaleortoundertakeclinicaltrialsundertheserules shalbemadetotheCentralLicencingAuthorityaccompaniedwithfolowing datainaccordancewiththeTable1orTable2orTable3,asthecasemaybe, namely:-

(i)chemicalandpharmaceuticalinformation; (i)animalpharmacologydata;

(a)specific pharmacologicalactions and demonstrating,therapeutic potentialforhumans shalbe described according to the animal models and species used. Wherever possible, dose-response relationshipsandED50sshalbesubmited.Specialstudiesconducted toelucidatemodeofactionshalalsobedescribed;

(b)generalpharmacologicalactions;
(c)pharmacokinetic data related to the absorption, distribution,

metabolism andexcretionofthetestsubstance.Whereverpossible,

thedrugefectsshalbeco-relatedtotheplasmadrugconcentrations; (i)animaltoxicologydata;

(iv)humanclinicalpharmacologydataasprescribedandasstatedbelow:- (a)fornew drugsubstancesdiscoveredordevelopedinIndia,clinical

trialsarerequiredtobecariedoutinIndiarightfrom PhaseIand

datashouldbesubmitedasprescribed; (b)fornewdrugsubstancesdiscoveredordevelopedincountriesother

than India,Phase Idata should be submited along with the a p p lic a tio n . A fte r s u b m is s io n o f P h a s e I d a ta g e n e ra te d o u ts id e IndiatotheCentralLicencingAuthority,permissionmaybegranted to repeat Phase I trials and/or to conduct Phase I I trials and subsequentlyPhaseItrialsconcurentlywithotherglobaltrialsfor th a t d ru g . P h a s e I I I tria ls a re re q u ire d to b e c o n d u c te d in In d ia beforepermissiontomarketthedruginIndiaisgrantedforthe drugswhichareintroducedforthefirsttimeintheworld.Forthe drugswhicharealreadyapprovedoutsideIndia.

(c)thedatarequiredwildependuponthepurposeofthenew drug application.Thenumberofstudysubjectsandsitestobeinvolved in the conductofclinicaltrialwildepend upon the nature and o b je c tiv e o f th e s tu d y . P e rm is s io n to c a r ry o u t th e s e tria ls s h a l l generalybegiveninstages,consideringthedataemergingfrom earlierphases;

(d)applicationforpermissiontoinitiatespecificphaseofclinicaltrial shouldalsoaccompanyinvestigator’sbrochureasperTable7of

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ThirdSchedule,proposedprotocolasperTable2ofThirdSchedule, caserecordform,trialsubject’sinformedconsentdocumentasper Table3ofThirdSchedule,investigator’sundertakingasperTable4 ofThirdScheduleandethicscommiteeclearance,ifavailableas perTable1ofThirdSchedule;

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() reportsofclinicalstudiessubmitedshouldbeinconsonancewith theformatspecifiedinTable6ofThirdSchedule.Thestudyreport shalbe certified bythe principalinvestigatoror,ifno principal investigatoris designated,then by each ofthe investigators participatinginthestudy.Thecertificationshouldacknowledgethe contentsofthereport,theaccuratepresentationofthestudywas undertaken,and express agreementwith the conclusions.Each pageshouldbenumbered;

(v)regulatorystatusinothercountriesasprescribedincludinginformationin respectofrestrictions imposed,ifany,on the use ofthe drug in other countries,e.g.dosagelimits,exclusionofcertainagegroups,warningabout adversedrugreactionsetc.Likewise,ifthedrughasbeenwithdrawninany countrybythemanufacturerorbyregulatoryauthorities,suchinformation shouldalsobefurnishedalongwiththereasonsandtheirrelevance,ifany,to India.Thisinformationmustcontinuetobesubmitedbythesponsortothe CentralLicencingAuthorityduringthecourseofmarketingofthedruginIndia;

(vi)thefulprescribinginformationshouldbesubmitedaspartofthenew drug application for m arketing. The form at of prescribing inform ation specifiedinTable8ofThirdSchedule.

(vi)Alpackageinserts,promotionalliteratureandpatienteducationmaterial subsequentlyproducedarerequiredtobeconsistentwiththecontents oftheapprovedfulprescribinginformation.Thedraftsoflabelandcarton textsshouldcomplywithprovisionsofrule96andrule97oftheDrugs andCosmeticsRules,1945.AftersubmissionandapprovalbytheCentral LicencingAuthority,nochangesinthepackageinsertshalbeefected withoutsuch changes being approved by the CentralLicencing Authority;and

(vi)Complete testing protocolforqualitycontroltesting togetherwith a completeimpurityprofileandreleasespecificationsfortheproductas prescribedshouldbesubmitedaspartofnew drugapplicationfor marketing.Samplesofthepuredrugsubstanceandfinishedproductare tobesubmitedwhendesiredbytheregulatoryauthority.

(ix)Iftheapplicationisfortheconductofclinicaltrialsasapartofmulti- nationalclinicaldevelopmentofthe drug,the numberofsites and patientsaswelasthejustificationforundertakingsuchtrialsinIndia should be provided to the CentralLicencing Authority along with theapplication.

(2) Specialsituationsforanewdrugwhererelaxation,abbreviations, omissionordefermentofdatamaybeconsidered.–

(i)Dependingoncategoriesandnatureofnew drugstobeimportedor manufacturedforsaleorclinicaltrialtobeundertaken,(viz.NewChemical Entity,biologicalproducts,similarbiologics,approvednew drug/new dosageform/new indication/new routeofadministration/new strengthof already approved drugs, etc.,) requirements of chemical and pharmaceuticalinformation,animalpharmacologyand toxicologydata,

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clinicaldatamaydifer.Therequirementsmayalsodiferdependingon thespecificphaseofclinicaltrialproposedtobeconductedaswelas clinicalparametersrelatedtothespecificstudydrugs.

(i)Fordrugs intended to be used in life threatening /serious disease conditions or rare diseases and for drugs intended to be used in the diseasesofspecialrelevance

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toIndiascenarioorunmetmedicalneedinIndia,disasterorspecialdefence use

e.g.haem ostatic and quick w ound healing, enhancing oxygen car rying capacity,radiation safety,drugs forcombating chemical,nuclear, biologicalinflictionetc.,folowingmechanism maybefolowedtoexpedite thedevelopmentofnewdrugandapprovalprocess:

(A)AcceleratedApprovalProcess:Acceleratedapprovalprocessmaybe a l lo w e d to a n e w d ru g fo r a d is e a s e o r c o n d itio n , ta k in g in to a c c o u n t its severity, rarity, or prevalence and the availability or lack of alternativetreatments,providedthatthereisaprimafaciecaseofthe product being of meaningful therapeutic benefit over the existingtreatment.

(a)Insuchcase,theapprovalofthenew drugmaybebasedondata generated in clinicaltrialwhere surogate endpointshalbe consideredratherthanusingstandardoutcomemeasuressuchas survivalordisease progression,which are reasonably likely to predictclinicalbenefit,ora clinicalendpoint.These should be measurableearlierthanireversiblemorbidityormortality(IMM) andreasonablylikelytopredictclinicalbenefit

(b)Aftergranting accelerated approvalforsuch drug,the post marketingtrialsshalberequiredtovalidatetheanticipatedclinical benefit.

(c)Acceleratedapprovalmayalsobegrantedtoanew drugifitis intendedforthetreatmentofaseriousorlife-threateningcondition ordisease ofspecialrelevance to the country,and addresses unmetmedicalneeds.Thisprovisionisintendedtofacilitateand expeditereviewofdrugssothatanapprovedproductcanreachthe therapeuticarmamentariumexpeditiously.

(d)Iftheremarkableeficacyisobservedwithadefineddoseinthe PhaseIclinicaltrialofinvestigationalnew drugfortheunmet medicalneeds ofserious and life threatening diseases in the country,itmaybeconsideredforgrantofmarketingapprovalbythe CentralLicencingAuthoritybasedonPhaseIclinicaltrialdata.In suchcases,additionalpostlicensurestudiesmayberequiredtobe conductedafterapprovaltogeneratethedataonlargerpopulation to furtherverify and describe the clinicalbenefits,as perthe protocolapprovedbytheCentralLicencingAuthority.

(e)Thetypeofinformationneededtodemonstratethepotentialofa drugtoaddressanunmetmedicalneedwildependonthestageof drugdevelopment.Earlyindevelopment,suchpotentialshouldbe suficiently demonstrated based on nonclinical models, a mechanistic rationale and pharmacologic data. Later in development,priortonew drugapprovalsuchpotentialshouldbe demonstrated through clinical data to address an unmet

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medicalneed. Explanation.-Forthepurposeofthisclause,anunmetmedicalneedis asituationwheretreatmentordiagnosisofdiseaseorconditionisnot addressedadequatelybyavailabletherapy.Anunmetmedicalneed includesanimmediateneedforadefinedpopulation(i.e.,totreata seriousconditionwithnoorlimitedtreatment)oralonger-term need forsociety (e.g.,to address the developmentofresistance to antibacterialdrugs).

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(B) Situationswherequick/expeditiousreview processcanbesoughtfor approvalofanewdrugafterclinicaldevelopment:- (i)Insituationwheretheevidenceforclinicalsafetyandeficacyhave

beenestablishedevenifthedrughasnotcompletedtheal/normal clinicaltrialphases,the sponsor/applicantmay apply to the licencing authority for expedited review process wherein the licencingauthoritywilexamineandsatisfythefolowingconditions: –

(a)itis fora drug thatis intended to treata serious /life threatening/rarediseaseorcondition;

(b)ifapproved,thedrugwouldprovideasignificantadvantagein termsofsafetyoreficacy;

(c)there is substantialreduction ofa treatment-limiting adverse reaction and enhancement of patient compliance that is expectedtoleadtoanimprovementinseriousoutcomes.

(i) thesponsor/applicantmayalsoapplytothelicencingauthority forexpeditedreviewprocessfornewdrugsdevelopedfordisaster ordefenceuseinextraordinarysituation,suchaswartime,the radiationexposurebyaccidentorintention,suddendeploymentof forcesatareaswithhigherhealthrisk,wherespecificpreventive andtreatmentstrategyisrequired,wherenew interventioninthe form of new drug,route of delivery/formulation has been developedandwherereallifeclinicaltrialmaynotbepossible,the permissionformanufactureofsuchnew drugmaybegrantedif folowingconditionsaresatisfied:-

(a)Thepreclinicaldatamakesacaseforclaimedeficacy;

(b)Thereisnopossibilityofobtaininginformedconsentfrom thepatientorhislegalyacceptablerepresentative,asthe casemaybe,adoptinginclusionandexclusioncriteriaand strictprotocoladherencebyeachsubject;

(c)There is no established management/therapeutic strategy available as on date and proposed intervention has clear possibleadvantage;

(d)Suchapprovalcanbeusedonlyforonetime.Thesubsequent approvalshalonlybegrantedoncedetailedeficacyreportof suchinterventionisgenerated.

(i)ifthenewdrugisanorphandrugasdefinedinclause(v)ofRule2 oftheserules.

(3)Requirementsofdataandinformationforpermissiontoimportormanufacture ofadrugalreadyapprovedwhichisnow proposedtobeclinicalytriedor marketedwithcertainnewclaims.–

(i)IncaseadrugalreadyapprovedbytheCentralLicencingAuthorityforcertain Page72of72

claims,whichisnowproposedtobeclinicalytriedormarketedwithmodifiedor new claims,namely,indications,dosage,dosageform (includingsustained releasedosageform)androuteofadministrationornoveldrugdeliverysystem (NDDS),therequirementsof

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dataandinformationforpermissiontoimportormanufactureofsuchnew drug forsale orto undertake clinicaltrialshaldepend on nature and regulatorystatusofthedrugforthenew claim inothercountry.Application forapprovalofmanufactureand/orimportofsuchnew drugortoundertake C lin ic a l tria l m a y d if fe r fro m a p p lic a tio n fo r a n e w d ru g m o le c u le in th a t th e y alow theapplicantandregulatoryauthoritytorelyatleastinpart,onthe safetyand/oreficacydataofdrugformulationalreadyapproved.However, additionalnon-clinicaland/orclinicaldatamaybenecessarytosubstantiate thenewclaimsconsideringthefolowing; (A)Chemicalandpharmaceuticalinformationwilbesameasprescribedin

thisSchedule.However,thedatarequirementsmaybeomiteddepending onwhetherthedrugformulationisalreadyapprovedandmarketedinthe countrybytheapplicantinthesamedosageform forcertainindication.If itisapprovedandmarketed,nofurtherchemicalandpharmaceuticaldata isrequiredtobesubmited.

(B)Theanimalpharmacologicalandtoxicologicaldata&clinicaldataneeded insuchcaseswilusualybedeterminedoncase-by-casebasisdepending onthetypeofnew claimsbeingmadebytheapplicantaswelasthe mechanism ofaction,patho-physiologyofthedisease/condition,safety andeficacyprofileintherespectiveconditions/populationandclinical data already generated with the drug in the approved claim.The requirem ents m ay be abbreviated / relaxed / om it ted as considered appropriatebytheCentralLicencingAuthorityunderfolowingconditions:

(a)Thedrugisalreadyapprovedandmarketedinothercountryforthe proposednewclaim.

(b)Clinicaldatasupportingthebenefit-riskratioinfavourofthedrugin theproposednewclaim isavailable.

(c)The clinicaltrialdoesn’tinvolve a route ofadministration,dose, patientpopulationthatsignificantlyincreasestheriskassociated withtheuseofthedrug.

(i)Incaseofanapplicationforpermissiontoundertakeclinicaltrialofanew drugformulation,whichisalreadyapprovedinthecountry,nochemicaland pharmaceuticaldata and non-clinical& clinicaldata is required to be submitedprovidedtheclinicaltrialisproposedtobeconductedwithanew drug manufactured/imported by a firm under necessary new drug permission/importregistrationandlicence,asthecasemaybegrantedbythe CentralLicencingAuthority.

Note.-ThedatarequirementsstatedinthisScheduleareexpectedtoprovide adequateinformationtoevaluatetheeficacy,safetyandtherapeuticrationaleof new drugspriortothepermissionforsale.Dependinguponthenatureofnew drugs and diseases,additionalinformation may be required by the Central

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LicencingAuthority.Theapplicantshalcertifytheauthenticityofthedataand documentssubmitedinsupportofanapplicationfornew drug.TheCentral LicencingAuthorityreservestherighttorejectanydataoranydocumentsifsuch dataorcontentsofsuchdocumentsarefoundtobeofdoubtfulintegrity.

2.Animaltoxicology(Non-clinicaltoxicitystudies).-
1. Generalprinciples.-ToxicitystudiesshouldcomplywiththenormsofGood

Laboratory Practice (GLP).Briefly,these studies should be performed by suitably trained and qualified staf employing properly calibrated and standardizedequipmentofadequatesizeandcapacity.Studiesshouldbe done as per writen protocols with modifications (if any) verifiable retrospectively.Standardoperatingprocedures(SOPs)shouldbefolowedfor almanagerialandlaboratorytasksrelatedtothesestudies.Testsubstances andtestsystems(in-vitroorin-vivo)shouldbeproperlycharacterizedand standardized.Aldocumentsbelongingtoeachstudy,includingitsapproved protocol,raw data,draftreport,finalreport,andhistologyslidesandparafin tissueblocksshouldbepreservedforaminimum offiveyearsaftermarketing ofthedrug.

Toxicokinetic studies (generation of pharm acokinetic data either as an integralcomponentofthe conductofnon-clinicaltoxicity studies orin special ly designed studies) should be conducted to assess the system ic exposureachievedinanimalsanditsrelationshiptodoselevelandthetime courseofthetoxicitystudy.Otherobjectivesoftoxicokineticstudiesinclude obtaining data to relate the exposure achieved in toxicity studies to toxicologicalfindingsandcontributetotheassessmentoftherelevanceof these findings to clinicalsafety,to supportthe choice ofspecies and treatmentregimeninnonclinicaltoxicitystudiesandtoprovideinformation which,inconjunctionwiththetoxicityfindings,contributestothedesignof subsequentnon-clinicaltoxicitystudies.

1.1 Systemictoxicitystudies
1.1.1 Single-dosetoxicitystudies.-Thesestudies(seeTable1)shouldbe

cariedoutin2rodentspecies(miceandrats)usingthesameroute asintendedforhumans.Inaddition,unlesstheintendedrouteof administrationinhumansisonlyintravenous,atleastonemore route should be used in one of the species to ensure system ic absorptionofthedrug.Thisrouteshoulddependonthenatureof the drug. A lim it of 2g/kg (or 10 tim es the norm al dose that is intendedinhumans,whicheverishigher)isrecommendedfororal dosing.Animals should be observed for14 days afterthe drug administration,andminimum lethaldose(MLD)andmaximum tolerateddose(MTD)shouldbeestablished.Ifpossible,thetarget organoftoxicityshouldalsobedetermined.Mortalityshouldbe observedforupto7daysafterparenteraladministrationandupto 14daysafteroraladministration.Symptoms,signsandmodeof death should be reported,with appropriate macroscopic and

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microscopicfindingswherenecessary.LD10 andLD50 shouldbe reported preferably with 95 percentconfidence limits.IfLD50s cannotbedetermined,reasonsforthesameshouldbestated. Thedosecausingseveretoxicmanifestationsordeathshouldbe definedinthecaseofcytotoxicanticanceragents,andthepost- dosingobservation

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period should be up to 14 days.Mice should firstbe used fordeterminationofMTD.Findingsshouldthenbeconfirmedinrat forestablishing linearrelationship between toxicity and body surfacearea.Incaseofnonlinearity,dataofthemoresensitive speciesshouldbeusedtodeterminethePhaseIstartingdose. Whererodentsareknowntobepoorpredictorsofhumantoxicity (e.g., antifolates), or w here the cytotoxic drug acts by a novel mechanism ofaction,MTDshouldbeestablishedinnon-rodent species.

1.1.2 Repeated-dosesystemictoxicitystudies.-Thesestudies(seeTable 1)shouldbecariedoutinatleasttwomammalianspecies,of whichoneshouldbeanon-rodent.Doserangingstudiesshould precedethe14-,28-,90-or180-daytoxicitystudies.Durationofthe finalsystematic toxicity study wildepend on the duration, therapeuticindicationandscaleoftheproposedclinicaltrial.Ifa species is know n to m etabolize the drug in the sam e w ay as humans,itshouldbepreferedfortoxicitystudies. Inrepeated-dosetoxicitystudiesthedrugshouldbeadministered7 daysaweekbytherouteintendedforclinicaluse.Thenumberof animalsrequiredforthesestudies,i.e.theminimum numberof animalsonwhichdatashouldbeavailable. Whereverapplicable,acontrolgroupofanimalsgiventhevehicle aloneshouldbeincluded,andthreeothergroupsshouldbegiven graded doses ofthe drug.The highestdose should produce observabletoxicity;thelowestdoseshouldnotcauseobservable toxicity,butshouldbecomparabletotheintendedtherapeuticdose inhumansoramultipleofit.Tomakealowanceforthesensitivity ofthespeciestheintermediatedoseshouldcausesomesymptoms, butnotgrosstoxicityordeath,andshouldbeplacedlogarithmicaly betweentheothertwodoses. Theparameterstobemonitoredandrecordedinlong-term toxicity studiesshouldincludebehavioural,physiological,biochemicaland microscopicobservations.Incaseofparenteraldrugadministration, thesitesofinjectionshouldbesubjectedtogrossandmicroscopic examination.Initialand finalelectrocardiogram and fund us examinationshouldbecariedoutinthenon-rodentspecies. Inthecaseofcytotoxicanticanceragentsdosingandstudydesign should be in accordance with the proposed clinicalschedule in terms ofdays ofexposure and numberofcycles.Two rodent speciesmaybetestedforinitiatingPhaseItrials.A non-rodent speciesshouldbeaddedifthedrughasanovelmechanism of action,orifpermissionforPhaseI,Iormarketingisbeingsought.

For m ost com pounds, it is expected that single dose tissue distribution studies w ith suf ficient sensitivity and specificity w il l

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provide an adequate assessmentoftissue distribution and the potentialforaccumulation.Thus,repeateddosetissuedistribution studiesshouldnotberequireduniformlyforalcompoundsand shouldonlybeconductedwhenappropriatedatacannotbederived from othersources.Repeateddosestudiesmaybe

appropriateundercertaincircumstancesbasedonthedatafrom single dose tissue distribution studies,toxicity and toxicokinetic studies.The studies may be mostappropriate forcompounds whichhaveanapparentlylonghalf-life,incompleteeliminationor unanticipatedorgantoxicity.

Notes:
(i) Singledosetoxicitystudy.-Eachgroupshouldcontainatleast5

animalsofeithersex.Atleastfourgradeddosesshouldbe given.Animalsshouldbeexposedtothetestsubstanceina singlebolusorbycontinuousinfusionorseveraldoseswithin 24hours.Animalsshouldbeobservedfor14days.Signsof intoxication,efectonbodyweight,grosspathologicalchanges shouldbereported.Itisdesirabletoincludehisto-pathologyof grosslyafectedorgans,ifany.

(i i) Dose-ranging study. – Objectives of this study include the identificationoftargetorganoftoxicityandestablishmentof MTDforsubsequentstudies.

. (a)  Rodents.-Studyshouldbeperformedinonerodentspecies (preferably rat) by the proposed clinical route of administration.Atleastfourgradeddosesincludingcontrol shouldbegiven,andeachdosegroupaswelasthevehicle controlshouldconsistofaminimum of5animalsofeach sex.Animalsshouldbeexposedtothetestsubstancedaily for10 consecutive days.Highestdose should be the maximum tolerateddoseofsingle-dosestudy.Animals shouldbeobserveddailyforsignsofintoxication(general appearance,activityandbehaviouretc),andperiodicalyfor the body weight and laboratory parameters. Gross examination ofviscera and microscopicexamination of afectedorgansshouldbedone.

. (b)  Non-rodents.-Onemaleandonefemalearetobetakenfor ascending Phase MTD study.Dosing should startafter initial recording of cage-side and laboratory param eters. Startingdosemaybe3to5timestheextrapolatedefective dose orMTD (whicheveris less),and dose escalation in suitablestepsshouldbedoneeverythirddayafterdrawing the sam ples for laboratory param eters. Dose should be loweredappropriatelywhenclinicalorlaboratoryevidence oftoxicityareobserved.Administrationoftestsubstance

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shouldthencontinuefor10daysatthewel-tolerateddose level fol low ing w hich, sam ples for laboratory param eters should be taken.Sacrifice,autopsy and microscopic examinationofafectedtissuesshouldbeperformedasin thecaseofrodents.

(i)14-28Day repeated-dose toxicity studies.- One rodent (6- 10/sex/group)andonenon-rodent(2-3/sex/group)speciesare needed.Dailydosingbyproposedclinicalrouteatthreedose levels should be done with highestdose having observable toxicity,middosebetweenhighandlow dose,andlow dose. Thedosesshouldpreferablybemultiplesoftheefectivedose andfreefrom toxicity.Observationparametersshouldinclude cageside observations,body weight changes,food/water intake,blood biochemistry, haematology, and gross and microscopicstudiesofalvisceraandtissues.

(iv)90-Day repeated-dose toxicity studies. – One rodent (15- 30/sex/group)andonenon-rodent(4-6/sex/group)speciesare needed.Dailydosingbyproposedclinicalrouteatthreegraded doselevelsshouldbedone.Inadditiontothecontrola“high- dose-reversal” group and its control group should be also included. Param eters should include signs of intoxication (generalappearance,activityandbehaviouretc),bodyweight, food intake,blood biochemicalparameters,haematological values,urine analysis,organ weights,gross and microscopic study of viscera and tissues. H alf the anim als in “reversal” groups(treatedandcontrol)shouldbesacrificedafter14days ofstoppingthetreatment.Theremaininganimalsshouldbe sacrificedafter28daysofstoppingthetreatmentorafterthe recovery ofsigns and/orclinicalpathologicalchanges – whichevercomeslater,andevaluatedfortheparametersused forthemainstudy.

(v) 180-Day repeated-dose toxicity studies. – One rodent (15- 30/sex/group)andonenon-rodent(4-6/sex/group)speciesare needed.Atleast4groups,includingcontrol,shouldbetaken. Dailydosingbyproposedclinicalrouteatthreegradeddose levels should be done.Parameters should include signs of intoxication,body weight,food intake,blood biochemistry, hematology, urine analysis, organ weights, gross and microscopicexaminationoforgansandtissues.

1.2 Malefertilitystudy
O n e ro d e n t s p e c ie s (p re fe ra b ly ra t) s h o u ld b e u s e d . D o s e s e le c tio n shouldbedonefrom theresultsoftheprevious14or28-daytoxicity studyinrat.Threedosegroups,thehighestoneshowingminimaltoxicity insystemicstudies,andacontrolgroupshouldbetaken.Eachgroup

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shouldconsistof6adultmaleanimals.Animalsshouldbetreatedwith thetestsubstancebytheintendedrouteofclinicaluseforminimum 28 daysandmaximum 70daysbeforetheyarepairedwithfemaleanimals ofprovenfertilityinaratioof1:2formating.

Drug treatmentofthe male animals should continue during pairing. Pairingshouldbecontinuedtilthedetectionofvaginalplugor10days, whicheverisearlier.Femalesgetingthuspregnantshouldbeexamined fortheirfertilityindexafterday13ofgestation.Althemaleanimals shouldbesacrificedattheendofthestudy.Weightsofeachtestisand epididymisshouldbeseparatelyrecorded.Spermsfrom oneepididymis should be examined fortheirmotility and morphology.The other epididymisandbothtestesshouldbeexaminedfortheirhistology.

1.3 Femalereproductionanddevelopmentaltoxicitystudies Thesestudiesneedtobecariedoutforaldrugsproposedtobestudied orusedinwomenofchildbearingage.SegmentI,IandIstudies(see below)aretobeperformedinalbinomiceorrats,andsegmentIstudy should include albino rabbits also as a second test species.On the occasion,whenthetestarticleisnotcompatiblewiththerabbit(e.g. antibiotics which are efective against gram positive,anaerobic organismsandprotozoas)theSegmentIdatainthemousemaybe substituted. 1.3.1Femalefertilitystudy(SegmentI).-Thestudyshouldbedoneinone

rodentspecies(ratprefered).Thedrugshouldbeadministeredto bothmalesandfemales,beginningasuficientnumberofdays(28 days in males and 14 days in females)before mating.Drug treatmentshouldcontinueduringmatingand,subsequently,during the gestation period.Three graded doses should be used,the highestdose(usualytheMTDobtainedfrom previoussystemic toxicitystudies)should notafectgeneralhealth ofthe parent animals.Atleast15malesand15femalesshouldbeusedperdose group.Controlandthetreatedgroupsshouldbeofsimilarsize.The route of adm inistration should be the sam e as intended for therapeuticuse. Damsshouldbealowedtoliterandtheirmedicationshouldbe continuedtiltheweaningofpups.Observationsonbodyweight, food intake,clinicalsigns of intoxication,mating behaviour, progress ofgestation/parturition periods,length ofgestation, parturition, post-partum health and gross pathology (and histopathologyofafectedorgans)ofdamsshouldberecorded. Thepupsfrom bothtreatedandcontrolgroupsshouldbeobserved forgeneralsignsofintoxication,sex-wisedistributionindiferent treatmentgroups,bodyweight,growthparameters,survival,gross examination,and autopsy.Histopathology of afected organs shouldbedone.

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1.3.2Teratogenicitystudy(SegmentI).-Onerodent(preferablyrat)and onenon-rodent(rabbit)speciesaretobeused.Thedrugshouldbe administeredthroughouttheperiodoforganogenesis,usingthree doselevelsasdescribedforsegmentI.Thehighestdoseshould causeminimum maternaltoxicityandthelowestoneshouldbe proportionaltotheproposeddoseforclinicaluseinhumansora multipleofit.Therouteofadministrationshouldbethesameas intendedforhumantherapeuticuse. Thecontrolandthetreatedgroupsshouldconsistofatleast20 p re g n a n t ra ts (o r m ic e ) a n d 1 2 ra b b its , o n e a c h d o s e le v e l. A l l foetuses should be subjected to gross exam ination, one of the foetuses should be exam ined for skeletal abnorm alities and the otherhalfforvisceralabnormalities.Observationparametersshould include:(Dams)signsofintoxication,efectonbodyweight,efect onfoodintake,examinationofuterus,ovariesanduterinecontents, numberofcorporalutea,implantationsites,resorptions(ifany);and forthefoetuses,thetotalnumber,gender,bodylength,weightand gross/visceral/skeletalabnormalities,ifany.

1.3.3 Perinatalstudy(SegmentI).-Thisstudyisspecialyrecommended ifthedrugistobegiventopregnantornursingmothersforlong periodsorwherethereareindicationsofpossibleadverseefects on foetal developm ent. One rodent species (preferably rat) is needed.Dosingatlevelscomparabletomultiplesofhumandose shouldbedonebytheintendedclinicalroute.Atleast4groups (includingcontrol),eachconsistingof15damsshouldbeused.The drug should be adm inistered throughout the last trim ester of pregnancy(fromday15ofgestation)andthenthedosethatcauses low foetal loss should be continued throughout lactation and weaning.Dams should then be sacrificed and examined as describedbelow.

1.3.4 Onemaleandonefemalefrom eachliterofF1generation(total15 m ales and 15 fem ales in each group) should be selected at weaningandtreatedwithvehicleortestsubstance(atthedose levels described above) throughout their periods of grow th to sexualmaturity,pairing,gestation,parturitionandlactation.Mating performance and fertility of F1 generation should thus be evaluatedtoobtaintheF2generationwhosegrowthparameters shouldbemonitoredtilweaning.Thecriteriaofevaluationshould bethesameasdescribedearlier.

Anim als should be sacrificed at the end of the study and the observationparametersshouldinclude(Dams)bodyweight,food intake,generalsigns ofintoxication,progress ofgestation/ parturitionperiodsandgrosspathology(ifany);andforpups,the clinicalsigns,sex-wisedistributionindosegroups,bodyweight,

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g ro w th p a ra m e te rs , g ro s s e x a m in a tio n , s u rv iv a l a n d a u to p s y (if

needed)andwherenecessary,histopathology. 1.4 Localtoxicity.-

Thesestudiesarerequiredwhenthenewdrugisproposedtobeusedby somespecialroute(otherthanoral)inhumans.Thedrugshouldbe appliedtoanappropriatesite(e.g.,skinorvaginalmucousmembrane) todeterminelocalefectsinasuitablespecies.Typicalstudydesignsfor thesestudiesshouldincludethreedoselevelsanduntreatedand/or vehiclecontrol,preferablyuseof2species,andincreasinggroupsize withincreaseindurationoftreatment.Wheredosingisrestricteddueto a n a to m ic a l o r h u m a n e re a s o n s , o r th e d ru g c o n c e n tra tio n c a n n o t b e increasedbeyondacertainlevelduetotheproblemsofsolubility,pHor tonicity,aclearstatementtothisefectshouldbegiven.Ifthedrugis absorbedfrom thesiteofapplication,appropriatesystemictoxicity studieswilalsoberequired. Notes:-(i)Dermaltoxicitystudy.-Thestudymaybedoneinrabbitand

rat.theinitialtoxicitystudyshalbecariedoutbynon-animal alternative tests as given in Organisation for Econom ic CooperationandDevelopmentGuidelines.Inrabbitandrat studies,dailytopical(dermal)applicationoftestsubstancein itsclinicaldosageform shouldbedone.;Testmaterialshould beappliedonshavedskincoveringnotlessthan10% ofthe totalbodysurfacearea.Porousgauzedressingshouldbe used to hold liquid materialin place.Formulations with diferentconcentrations (atleast3)oftestsubstance, severalfoldhigherthantheclinicaldosageform shouldbe used.Periodofapplicationmayvaryfrom 7to90days depending on the clinicalduration ofuse.Where skin iritationisgrosslyvisibleintheinitialstudies,arecovery groupshouldbeincludedinthesubsequentrepeated-dose study.Localsigns(erythema,oedemaandescharformation) aswelashistologicalexaminationofsitesofapplication shouldbeusedforevaluationofresults.

(i i) Photo-al lergy or derm al photo-toxicity. – It should be testedbyArmstrong/HarberTestinguineapig.Thistest should be done if the drug or a m etaboliteisrelated to an agent causing photosensitivity or the nature of action suggestssuchapotential(e.g.,drugstobeusedintreatment of leucoderm a). Pretest in 8 anim als should screen 4 concentrations(patchapplicationfor2hours±15min.)with andwithoutUVexposure(10J/cm2).Observationsrecorded at24and48hoursshouldbeusedtoascertainhighestnon- ir ritant dose. M ain test should be perform ed w ith 10 test animals and 5 controls.Induction with the dose selected

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from pretestshoulduse0.3ml/patchfor2hour±15min. fol lowed by 10 J/cm 2 of UV exposure. This should be repeatedonday0,2,4,7,9and11ofthetest.Animalsshould bechalengedwiththesameconcentrationoftestsubstance between day 20 to 24 ofthe testwith a similar2-hour application fol low ed by exposure to 10 J/cm 2 of UV light. Examinationandgradingoferythemaandoedemaformation atthechalengesitesshouldbedone24and48hoursafter the chalenge.A positive controllike musk ambretor psoralinshouldbeused. (i)Vaginaltoxicitytest.-Studyistobedoneinrabbitordog. Testsubstanceshouldbeappliedtopicaly(vaginalmucosa) intheform ofpessary,cream orointment.Sixtotenanimals perdosegroupshouldbetaken.Higherconcentrationsor severaldailyapplicationsoftestsubstanceshouldbedone to achieve m ultiples of daily hum an dose. The m inim um duration ofdrug treatmentis 7 days (more according to clinicaluse),subjecttoamaximum of30days.Observation parametersshouldincludesweling,closureofintroitusand histopathologyofvaginalwal.

(iv)Rectal tolerance test.- For al l preparations m eant for rectaladministrationthistestmaybeperformedinrabbitsor dogs.Sixtotenanimalsperdosegroupshouldbetaken. Formulationinvolumecomparabletohumandose(orthe maximum possible volume)should be applied once or severaltimesdaily,perrectaly,toachieveadministrationof multiplesofdailyhumandose.Theminimum durationof applicationis7days(moreaccordingtoclinicaluse),subject toamaximum of30days.Sizeofsuppositoriesmaybe smaler,butthedrugcontentshouldbeseveralfoldhigher than the proposed human dose.Observation parameters shouldincludeclinicalsigns(slidingonbackside),signsof pain,blood and/ormucus in faeces,condition ofanal region/sphincter, gross and (if required) histological examinationofrectalmucosa. (v)Parenteraldrugs.-Forproductsmeantforintravenousor intramuscularorsubcutaneousorintradermalinjectionthe sites of injection in system ic toxicity studies should be specialyexaminedgrosslyandmicroscopicaly.Ifneeded, reversibilityofadverseefectsmaybedeterminedonacase tocasebasis.

(vi)Oculartoxicitystudies(forproductsmeantforocular in s til la tio n ). -T h e s e s tu d ie s s h o u ld b e c a r rie d o u t in tw o species,oneofwhichshouldbethealbinorabbitwhichhasa

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suficientlylargeconjunctivalsac.Directdeliveryofdrugonto thecorneaincaseofanimalshavingsmalconjunctivalsacs shouldbeensured.Liquids,ointments,gelsorsoftcontact le n s e s (s a tu ra te d w ith d ru g ) s h o u ld b e u s e d . In itia l s in g le dose application should be done to decide the exposure concentrations for repeated-dose studies and the need to includearecoverygroup.Suchinitialtoxicitystudiesshalbe caried outby non-animalalternative tests as given in Organisation for Economic CooperationandDevelopment G u id e lin e s . D u ra tio n o f th e fin a l s tu d y w il l d e p e n d o n th e proposedlengthofhumanexposuresubjecttoamaximum of90days.Atleasttwodiferentconcentrationsexceeding the hum an dose should be used for dem onstrating the marginofsafety.Inacutestudies,oneeyeshouldbeusedfor drugadministrationandtheotherkeptascontrol.Aseparate controlgroupshouldbeincludedinrepeated-dosestudies. Slit-lampexaminationshouldbedonetodetectthechanges incornea,irisandaqueoushumor.Fluorescentdyes(sodium fluorescein,0.25to1.0%)shouldbeusedfordetectingthe defectsinsurfaceepithelium ofcorneaandconjunctiva. Changes in intra-ocular tension should be m onitored by a tonometer.Histologicalexaminationofeyesshouldbedone attheendofthestudyafterfixationinDavidson’sorZenker’s fluid.

(vi)Inhalation toxicity studies.-The studies are to be undertakeninonerodentandonenon-rodentspeciesusing the form ulation that is to be eventual ly proposed to be marketed.Acute,subacute and chronic toxicity studies shouldbeperformedaccordingtotheintendeddurationof humanexposure.Standardsystemictoxicitystudydesigns (describedabove)shouldbeused.Gasesandvapoursshould begiveninwholebodyexposurechambers;aerosolsareto be given by nose-only method. Exposure time and concentrationsoftestsubstance(limitdoseof5mg/l)should be adjusted to ensure exposure atlevels comparable to multiplesofintendedhumanexposure.Threedosegroups andacontrol(plusvehiclecontrol,ifneeded)arerequired. Durationofexposuremayvarysubjecttoamaximum of6 hoursperdayandfivedaysaweek.Foodandwatershould bewithdrawnduringtheperiodofexposuretotestsubstance. Temperature,humidityandflow rateofexposurechamber shouldberecordedandreported.Evidenceofexposurewith testsubstanceofparticlesizeof4micron(especialyfor a e ro s o ls ) w ith n o t le s s th a n 2 5 % b e in g 1 m ic ro n s h o u ld b e

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provided. Ef fects on respiratory rate, findings of bronchial lavage fluid examination, histological examination of respiratory passages and lung tissue should be included along with the regularparameters ofsystemic toxicity studiesorassessmentofmarginofsafety.

. 1.5  Alergenicity/Hypersensitivity Standardtestsincludeguineapigmaximizationtest(GPMT)andlocal lymphnodeassay(LLNA)inmouse.Anyoneofthetwomaybedone.
Notes:(i)Guineapigmaximizationtest.-Thetestistobeperformedin twosteps;first,determinationofmaximum non-iritantand minimum iritantdoses,andsecond,themaintest.Theinitial study wilalso have two components.To determine the intradermalinductiondose,4doselevelsshouldbetestedby thesamerouteinabatchof4maleand4femaleanimals(2of eachsexshouldbegivenFreund’sadjuvant).Theminimum iritantdoseshouldbeusedforinduction.Similarly,atopical minimum iritantdoseshouldbedeterminedforchalenge. This should be established in 2 males and 2 females.A minimum of6maleand6femaleanimalspergroupshouldbe usedinthemainstudy.Onetestandonecontrolgroupshould be used. It is preferable to have one m ore positive control group.Intradermalinduction (day 1)coupled with topical chalenge(day21)shouldbedone.Ifthereisnoresponse,re- chalenge should be done 7 to 30days afterthe primary chalenge.Erythemaandoedema(individualanimalscoresas welasmaximizationgrading)shouldbeusedasevaluation criteria.
(i)Locallymphnodeassay.-Miceusedinthistestshouldbeof the same sex,eitheronly males oronly females.Drug treatmentistobegivenonearskin.Threegradeddoses,the highestbeingmaximum non-iritantdoseplusvehiclecontrol shouldbeused.Aminimum of6micepergroupshouldbe used.Testmaterialshouldbeappliedonearskinonthree consecutivedaysandonday5,thedrainingauricularlymph nodesshouldbedissectedout5hoursafteri.v.H-thymidine orbromo-deoxy-uridine (BrdU).Increase in H-thymidine or BrdU incorporation should be used as the criterion for evaluationofresults.

. 1.6  Genotoxicity.- Genotoxiccompounds,intheabsenceofotherdata,shalbepresumed to be trans-species carcinogens,implying a hazard to humans.Such compoundsneednotbesubjectedtolong-term carcinogenicitystudies. However,ifsuch a drug is intended to be administered forchronic ilnessesorotherwiseoveralongperiodoftime-achronictoxicitystudy

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(uptooneyear)maybenecessarytodetectearlytumorigenicefects. Genotoxicity tests are in vitro and in vivo tests conducted to detect compoundswhichinducegeneticdamagedirectlyorindirectly.These testsshouldenableahazardidentificationwithrespecttodamageto DNAanditsfixation. Thefolowingstandardtestbateryisgeneralyexpectedtobeconducted: (i)Atestforgenemutationinbacteria. (i)Aninvitrotestwithcytogeneticevaluationofchromosomaldamage

withmammaliancelsoraninvitromouselymphomaticassay. (i)An in vivo test for chromosomal damage using rodent haematopoietic cels.Other genotoxicity tests e.g. tests for measurementofDNA adducts,DNA strandbreaks,DNA repairor recombinationserveasoptionsinadditiontothestandardbateryfor

furtherinvestigation ofgenotoxicity testresults obtained in the standardbatery.Onlyunderextremeconditionsinwhichoneormore tests com prising the standard bat tery cannot be em ployed for technicalreasons,alternativevalidatedtestscanserveassubstitutes provided suficientscientific justification should be provided to supportthe argumentthata given standard batery testis not appropriate.

(iv)Both in-vitro and in-vivo studies should be done.In-vitro studies should include Ames’ Salmonela assay and chromosomal aberations (CA)in cultured cels.In-vivo studies should include m ic ro n u c le u s a s s a y (M N A ) o r C A in ro d e n t b o n e m a r ro w . D a ta analysisofCAshouldincludeanalysisof‘gaps’.

(v)Cytotoxicanticanceragents.-Genotoxicity data are notrequired beforePhaseIandItrials.Butthesestudiesshouldbecompleted beforeapplyingforPhaseItrials.
Notes:Ames’Test(Reverse mutation assay in Salmonela):S.

typhimurium testerstrainssuchasTA98,TA100,TA102, TA1535,TA97orEscherichiacoliWP2uvrAorEscherichiacoli WP2uvrA(pKM101)shouldbeused.

(vi)In-vitro exposure (with and withoutmetabolic activation,S9 mix) shouldbedoneataminimum of5logdoselevels.“Solvent”and “p o s itiv e ” c o n tro l s h o u ld b e u s e d . P o s itiv e c o n tro l m a y in c lu d e 9 – amino-acridine,2-nitrofluorine,sodium azide and mitomycin C, respectively,inthetesterstrainsmentionedabove.Eachsetshould consistofatleastthreereplicates.A2.5fold(ormore)increasein numberofrevertantsincomparisontospontaneousrevertantswould beconsideredpositive.

(vi)In-vitrocytogeneticassay.-Thedesiredleveloftoxicityforinvitro cytogenetic tests using cellines should be greaterthan 50% reduction in celnumberorculture confluency.Forlymphocyte cultures,aninhibitionofmitoticindexbygreaterthan50% is

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consideredsuficient.ItshouldbeperformedinCHO celsoron humanlymphocyteinculture.In-vitroexposure(withandwithout metabolicactivation,S9mix)shouldbedoneusingaminimum of3 logdoses.“Solvent”and“positive”controlshouldbeincluded.A positivecontrollikeCyclophosphamidewithmetabolicactivation andMitomycinCforwithoutmetabolicactivationshouldbeusedto giveareproducibleanddetectableincreaseclastogenicefectover the background which demonstrates the sensitivity ofthe test system.Each setshould consistofatleastthree replicates. Increased numberofaberations in metaphase chromosomes shouldbeusedasthecriteriaforevaluation.

(vi)In-vivomicronucleusassay.-Onerodentspecies(preferablymouse) isneeded.Routeofadministrationoftestsubstanceshouldbethe sameasintendedforhumans.Fiveanimalspersexperdosegroups should be used.Atleastthree dose levels,plus “solvent”and “positive”controlshouldbetested.Apositivecontrollikemitomycin Corcyclophosphamideshouldbeused.Dosingshouldbedoneon day1and2ofstudyfolowedbysacrificeofanimals6hoursafter thelastinjection.Bonemarow from boththefemorashouldbe takenout,flushedwithfetalbovineserum (20min.),peletedand smearedonglassslides.Giemsa-MayGruenwaldstainingshouldbe done and increased numberofmicronucleiin polychromatic erythrocytes (minimum 1000) should be used as the evaluationcriteria.

(ix) In-vivocytogeneticassay.-Onerodentspecies(preferablyrat)isto beused.Routeofadministrationoftestsubstanceshouldbethe same as intended forhumans.Five animals/sex/dose groups should be used.Atleastthree dose levels,plus “solvent”and “p o s itiv e ” c o n tro l s h o u ld b e te s te d . P o s itiv e c o n tro l m a y in c lu d e cyclophosphamide.Dosingshouldbedoneonday1folowedby intra-peritoneal colchicine adm inistration at 22 hours. Anim als shouldbesacrificed2hoursaftercolchicineadministration.Bone marow from boththefemorashouldbetakenout,flushedwith hypotonicsaline(20min.),peletedandresuspendedinCarnoy’s fluid.Onceagainthecelsshouldbepeletedanddroppedonclean glassslideswithaPasteurpipete.Giemsastainingshouldbedone andincreasednumberofaberationsinmetaphasechromosomes (minimum 100)shouldbeusedastheevaluationcriteria.

1.7 Carcinogenicity.-
Carcinogenicity studies should be perform ed for al l drugs that are expectedtobeclinicalyusedformorethan6monthsaswelasfor drugs used frequently in an interm it tent m anner in the treatm ent of chronicorrecurentconditions.Carcinogenicitystudiesarealsotobe performedfordrugsifthereisconcernabouttheircarcinogenicpotential

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emanatingfrom previousdemonstrationofcarcinogenicpotentialinthe productclassthatisconsideredrelevanttohumansorwherestructure- activityrelationshipsuggestscarcinogenicriskorwhenthereisevidence ofpreneoplasticlesionsinrepeateddosetoxicitystudiesorwhenlong- term tissueretentionofparentcompoundormetabolite(s)resultsin localtissue reactions orotherpathophysiologicalresponses.For pharmaceuticals developed to treatcertain serious diseases,Central LicencingAuthoritymayalow carcinogenicitytestingtobeconducted aftermarketingpermissionhasbeengranted.

In instances where the life-expectancy in the indicated population is short(i.e.,lessthan2-3years)-nolong-term carcinogenicitystudiesmay berequired.Incaseswherethetherapeuticagentforcancerisgeneraly successfulandlifeissignificantlyprolongedtheremaybelaterconcerns regardingsecondarycancers.Whensuchdrugsareintendedforadjuvant therapy in tum our free patients or for prolonged use in non-cancer indications,carcinogenicitystudiesmaybe/areneeded.Completed rodentcarcinogenicitystudiesarenotneededinadvanceoftheconduct oflarge scale clinicaltrials,unless there is specialconcern forthe patientpopulation. Carcinogenicitystudiesshouldbedoneinarodentspecies(preferably rat).Mousemaybeemployedonlywithproperscientificjustification. Theselectedstrainofanimalsshouldnothaveaveryhighorverylow incidenceofspontaneoustumors. Atleastthreedoselevelsshouldbeused.Thehighestdoseshouldbe sub-lethal,anditshouldnotreducethelifespanofanimalsbymorethan 10% ofexpectednormal.Thelowestdoseshouldbecomparabletothe intendedhumantherapeuticdoseoramultipleofit,e.g.2.5x;tomake alowanceforthesensitivityofthespecies.Theintermediatedosetobe placed logarithmicaly between the othertwo doses.An untreated controland(ifindicated)avehiclecontrolgroupshouldbeincluded.The drugshouldbeadministered7daysaweekforafractionofthelifespan comparabletothefractionofhumanlifespanoverwhichthedrugis likelytobeusedtherapeuticaly.Generaly,theperiodofdosingshould be24monthsforratsand18monthsformice. Observationsshouldincludemacroscopicchangesobservedatautopsy anddetailedhistopathologyoforgansandtissues.Additionaltestsfor carcinogenicity(short-term bioassays,neonatalmouseassayortests em ploying transgenic anim als) m ay also be done depending on their applicabilityonacasetocasebasis.

Note:-Eachdosegroupandconcurentcontrolgroupnotintendedtobe sacrificedearlyshouldcontainatleast50animalsofeachsex. A high dose satel lite group for evaluation of pathology other thanneoplasiashouldcontain20animalsofeachsexwhilethe satel lite control group should contain10anim als of each sex.

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Observation param eters should include signs of intoxication, efect on body weight, food intake, clinical chemistry parameters,hematology parameters,urine analysis,organ weights, gross pathology and detailed histopathology. Comprehensivedescriptionsofbenignandmalignanttumour development, time of their detection, site, dimensions, histologicaltypingetc.shouldbegiven.

1.8 Animaltoxicityrequirementsforclinicaltrialsandmarketingofanewdrug.

SystemicToxicityStudies

Routeof administration

Durationof proposedhuman administration

HumanPhase(s)for whichstudyis

proposedtobe conducted

Longterm toxicity requireme nts

OralorParenteral orTransdermal

Singledoseorseveral dosesinoneday,up to1
wk

I,I,I

2sp;2wks

>1wkbutupto2wks

I,I,I

2sp;2wks

Upto2wks

Marketingpermission

2sp;4wks

>2wksbutupto4wks

I,I,I

2sp;equalto durationof

human exposure

Marketingpermission

2sp;12wks

>4wksbutupto12 wks

I,I,I

2sp;equalto durationof

human exposure

Marketingpermission

2sp;24wks

>12wksbutupto24 wks

I,I,I

2sp;equalto durationof

human exposure

Marketingpermission

2sp;Rodent 24wks,non- rodent

36wks

>24wks

I,I,I

2sp;Rodent 24 wks,non-

rodent36 wks

Marketingpermission

2sp;Rodent 24wks,non- rodent 36wks”;

Inhalation(general Anaesthetics, aerosols)

Upto2wk

I,I,I

2sp;Imo (Exposure time3h/d,

5d/wk)

Upto4wk

I,I,I

2sp;12wk (Exposuretim

6h/d,5d/wk)

e Page89of89

>14wk

I,I,I

2sp;24wk (Exposuretim

6h/d,5d/wk)

LocalToxicityStudies

Dermal

Upto2wk

I,I

1sp;4wk

I

2sp;4wk

>2wk

I,I,I

2sp;12wk

OcularorOpticor Nasal

Upto2wk

I,I

1sp;4wk

I

2sp;4wk

>2wk

I,I,I

2sp;12wk

VaginalorRectal

Upto2wk

I,I

1sp;4wk

I

2sp;4wk

>2wk

I,I,I

2sp;12wk

e

SpecialToxicityStudies

 MaleFertilityStudy: PhaseIinmalevolunteers/patients

FemaleReproductionandDevelopmentToxicityStudies:

  SegmentIstudiesin2species;PhaseI,Iinvolvingfemalepatientsof
childbearingage.

  SegmentIstudy;PhaseIinvolvingfemalepatientsofchild-bearingage.

  SegmentIstudy;PhaseIfordrugstobegiventopregnantornursing
mothers forlong periods orwhere there are indications ofpossible adverseefectsonfoetaldevelopment.

Alergenicity/Hypersensitivity:
 PhaseI,I,I-whenthereisacauseofconcernorfor parenteraldrugs(includingdermalapplication)

Photo-alergyordermalphoto-toxicity:
 PhaseI,I,I-ifthedrugorametaboliteisrelatedtoan

agentcausingphotosensitivityorthenatureofactionsuggestssuch apotential.

Genotoxicity:

  In-vitrostudies–PhaseI

  Bothin-vitroandin-vivo–PhaseI,I

Carcinogenicity:
 PhaseI–whenthereisacauseforconcern,orwhenthe drugistobeusedformorethan6months.

Abbreviations:sp-species;mo-month;wk-week;d-day;h-hour;I,I,I-Phaseof clinicaltrial;

Note:1.Animaltoxicitydatageneratedinothercountriesmaybeacceptedandmay not be asked to be repeated/duplicated in India on a case to case basis dependinguponthequalityofdataandthecredentialsofthelaboratorywhere suchdatahasbeengenerated.

2.Requirements forfixed dose combinations are given in clause 4 ofthis Schedule.

1.9 Numberofanimalsrequiredforrepeated-dosetoxicitystudies

14-28

84–182days

Page90of90

days

Group

Rodent(Rat

Non-rodent (DogorMonkey

Rodent(Rat)

Non-rodent (Dogor Monkey )

M

F

M

F

M

F

M

F

Control

6-10

6-10

2-3

2-3

15-30

15-30

4-6

4-6

Lowdose

6-10

6-10

2-3

2-3

15-30

15-30

4-6

4-6

Intermedia edose

6-10

6-10

2-3

2-3

15-30

15-30

4-6

4-6

Highdose

6-10

6-10

2-3

2-3

15-30

15-30

4-6

4-6

t

)

1.10 Laboratoryparameterstobeincludedintoxicitystudies:

prothrombintime,ActivatedpartialThromboplastin n Time
UrinalysisParameters

)

Haematologicalparameters

 H a e m o g lo b in

 TotalRBCcount

Haematocrit

Reticuloc yte

 TotalWBC count

 Dif ferentia lWBC Count

Plateletcount

Termina lBone Marow Examinatio

 ESR(Non- rodentsonly)

 GeneralBloodPicture:ASpecialmentionof abnormaland immaturecelsshouldbemade

n

Coagulationparameters(Non-rodentsonly):BleedingTime,coagulatio Time,

    

 Colour

 Reaction(p H)
 Bile pigments

 Appearance

 Albumin

 Urobilinogen

 SpecificGravity

 Sugar

 OccultBlood

 24- hour

urinary

output  Acetone

HDL

cholester

ol(Non-

rodentsonly)  SGOT

 Creatinine

 Microscopicexaminationofurinarysediment BloodBiochemicalparameters

 Glucose  Cholesterol

 LDL  Bilirubin Cholesterol(Non-rodentsonly)(AST)

 Triglycerides

 SGPT(ALT)  Blood

urea Nitrogen

 Alkaline Phosphata se(ALP)

 GGT(Non- rodentsonly)

Page91of91

Total proteins

 A lb u m in

Globulin(Calcula edvalues)

 Sodium

Potassium

 Phosphorus

Calcium

GrossandMicroscopicPathology

Bran*: Cerebrum, Cerebelu m, Midbrain

(Spinalcord)

Eye

(MiddleEar)

Thyroid

(Parathyroid)

Spleen

Thymus

Adrenal*

(Pancreas)

(Trachea)

Lung*

Heart*

Aorta

Oesophagus

Stomach

Duodenu m

Jejunum

Terminalileum

Colon

(Rectum)

Liver*

Kidney*

Urinarybladde

Epididymi s

Testis*

Ovary

Uterus*

Skin

Mammarygland

Mesentericlymp

Skeletalmuscl

node

r he

*Organsmarkedwithanasteriskshouldbeweighed. Organslistedinparenthesisshouldbeexaminedifindicatedbythenatureofthe drugorobservedefects.

Non-clinicaltoxicitytestingandsafetyevaluationdataofanINDneededfortheconduct ofdiferentphasesofclinicaltrials. Note:Referclause2ofSecondScheduleforessentialfeaturesofstudydesignsofthe

non-clinicaltoxicitystudieslistedbelow. ForPhaseIClinicalTrials SystemicToxicitystudies

(i) Singledosetoxicitystudies
(i) DoseRangingStudies
(i) Repeat-dose systemic toxicity studies ofappropriate duration to

supportthedurationofproposedhumanexposure. Malefertilitystudy

In-vitrogenotoxicitytests– Relevantlocaltoxicitystudieswithproposedrouteofclinicalapplication (durationdependingonproposedlengthofclinicalexposure). Alergenicity/Hypersensitivitytests(whenthereisacauseforconcernorfor parenteraldrugs,includingdermalapplication). Photo-alergyordermalphoto-toxicitytest(ifthedrugorametaboliteisrelatedto anagentcausingphotosensitivityorthenatureofactionsuggestssucha potential).

ForPhaseIClinicalTrials Provideasummaryofalthenon-clinicalsafetydata(listedabove)already

submitedwhileobtainingthepermissionsforPhaseItrial,withappropriate references.

t

Page92of92

IncaseofanapplicationfordirectlystartingaPhaseItrial-completedetails ofthenonclinicalsafetydataneededforobtainingthepermissionforPhaseItrial, asperthelistprovidedabovemustbesubmited.

Repeat-dosesystemictoxicitystudiesofappropriatedurationtosupportthe durationofproposedhumanexposure.

In-vivogenotoxicitytests-

SegmentIreproductive/developmentaltoxicitystudy(iffemalepatientsof childbearingagearegoingtobeinvolved).
ForPhaseIClinicalTrials

Provideasummaryofalthenon-clinicalsafetydata(listedabove)already submitedwhileobtainingthepermissionsforPhaseIandItrials,withappropriate references.IncaseofanapplicationfordirectlyinitiatingaPhaseItrial-complete details of the non-clinical safety data needed for obtaining the perm issions for PhaseIandItrials,asperthelistprovidedabovemustbeprovided.

Repeat-dosesystemictoxicitystudiesofappropriatedurationtosupportthe durationofproposedhumanexposure. Reproductive/developmentaltoxicitystudies

SegmentI(iffemalepatientsofchildbearingagearegoingtobeinvolved), andSegmentI(fordrugstobegiventopregnantornursingmothersorwherethere areindicationsofpossibleadverseefectsonfoetaldevelopment).

Carcinogenicitystudies(whenthereisacauseforconcernorwhenthedrug istobeusedformorethan6months).
ForPhaseIVClinicalTrials

Provideasummaryofalthenon-clinicalsafetydata(listedabove)already submited while obtaining the permissions forPhase I,Iand Itrials,with appropriatereferences.

IncaseanapplicationismadeforinitiatingthePhaseIV trial,complete details of the non-clinical safety data needed for obtaining the perm issions for PhaseI,IandItrials,asperthelistprovidedabovemustbesubmited. ApplicationofGoodLaboratoryPractices(GLP)–

The animalstudies be conducted in an accredited laboratory.Where the safetypharmacologystudiesarepartoftoxicologystudies,thesestudiesshould alsobeconductedinanaccreditedlaboratory.

2. Theanimaltoxicologyrequirementsasreferedinclause1aboveshouldbe viewedasgeneralguidancefordrugdevelopments.Animaltoxicologystudies maybeplanned,designedandconductedaspertheInternationalCouncilof Harmonization (ICH)guidelines to promote safe,ethicaldevelopmentand availabilityofnew drugswithreduceduseofanimalsinaccordancewiththe 3R(reduce/refine/replace)principles.

3.AnimalPharmacology.- 1.GeneralPrinciples

Specific and generalpharmacologicalstudies should be conducted to supportuse oftherapeutics in humans.In the early stages ofdrug developmentenoughinformationmaynotbeavailabletorationalyselect

Page93of93

studydesignforsafetyassessment.Insuchasituation,ageneralapproach to safety pharmacology studies can be applied.Safety pharmacology studiesarestudiesthatinvestigatepotentialundesirablepharmacodynamic efectsofasubstanceonphysiologicalfunctionsinrelationtoexposure withinthetherapeuticrangeorabove.

. 1.1  Specificpharmacologicalactions
Specific pharmacologicalactions are those which demonstrate the therapeuticpotentialforhumans. Thespecificstudiesthatshouldbeconductedandtheirdesignwilbe diferentbased on the individualproperties and intended uses of investigationaldrug.
Scientifical ly validated m ethods should be used. The use of new technologiesandmethodologiesinaccordancewithsoundscientific principlesshouldbeprefered.

. 1.2  Generalpharmacologicalactions

1.2.1 Essentialsafetypharmacology

Safety pharmacology studies need to be conducted to investigatethepotentialundesirablepharmacodynamicefects ofa substance on physiologicalfunctions in relation to exposure within the therapeutic range and above.These studies should be designed to identify undesirable pharmacodynamicpropertiesofasubstancethatmayhave relevance to its human safety; to evaluate adverse pharmacodynamicand/orpathophysiologicalefectsobserved in toxicologyand/orclinicalstudies;and to investigate the mechanism of the adverse pharmacodynamic efects observedand/orsuspected.

Theaim oftheessentialsafetypharmacologyistostudythe efectsofthetestdrugonvitalfunctions.Vitalorgansystems such as cardiovascular,respiratory and centralnervous system s should be studied. Essential safety pharm acology studiesmaybeexcludedorsupplementedbasedonscientific rationale.Also,theexclusionofcertaintestsorexploration(s) ofcertainorgans,systemsorfunctionsshouldbescientificaly justified.

. 1.2.1.1  Cardiovascularsystem Efectsoftheinvestigationaldrugshouldbestudiedonblood pressure,heartrate,andtheelectrocardiogram.Ifpossiblein vitro, in vivo and/or ex vivo methods including electrophysiologyshouldalsobeconsidered.

. 1.2.1.2  Centralnervoussystem Efectsoftheinvestigationaldrugshouldbestudiedonmotor activity,behaviouralchanges,coordination,sensoryandmotor

Page94of94

reflexresponsesandbodytemperature. 1.2.1.3 Respiratorysystem

Efectsoftheinvestigationaldrugonrespiratoryrateandother functions such as tidalvolume and haemoglobin oxygen saturationshouldbestudied.

1.3 Folow-upandsupplementalsafetypharmacologystudies Inadditiontotheessentialsafetypharmacologicalstudies,additional supplementalandfolow-upsafetypharmacologystudiesmayneedto beconductedasappropriate.Thesedependonthepharmacological properties orchemicalclass ofthe testsubstance,and the data generated from safety pharmacology studies, clinical trials, pharmacovigilance,experimentalin vitro orin vivo studies,orfrom literaturereports.

1.3.1 Folow-upstudiesforessentialsafetypharmacology
Fol low -up studies provide additional inform ation or a bet ter understanding than thatprovided by the essentialsafety pharmacology.

. 1.3.1.1  Cardiovascularsystem Theseincludeventricularcontractility,vascularresistanceand the efects ofchemicalmediators,theiragonists and antagonistsonthecardiovascularsystem.

. 1.3.1.2  Centralnervoussystem
These include behaviouralstudies,learning and memory, electrophysiologystudies,neurochemistryandligandbinding studies.

. 1.3.1.3  Respiratorysystem
These include airway resistance,compliance,pulmonary arterialpressure,bloodgasesandbloodpH.

1.3.2 Supplementalsafetypharmacologystudies Thesestudiesarerequiredtoinvestigatethepossibleadverse pharmacologicalefectsthatarenotassessedintheessential safetypharmacologicalstudiesandareacauseforconcern.

. 1.3.2.1  Urinarysystem Theseincludeurinevolume,specificgravity,osmolality,pH, proteins,cytology and blood urea nitrogen,creatinine and plasmaproteinsestimation.

. 1.3.2.2  Autonomicnervoussystem Theseincludebindingtoreceptorsrelevantfortheautonomic nervous system,and functionalresponse to agonistor antagonistresponsesinvivoorinvitro,andefectsofdirect stimulation of autonomic nerves and their efects on cardiovascularesponses.

. 1.3.2.3  Gastrointestinalsystem
These include studies on gastric secretion, gastric pH

Page95of95

measurement,gastric mucosalexamination,bile secretion,

gastricemptyingtimeinvivoandileocaecalcontractioninvitro. 1.3.2.4 Otherorgansystems

Efects ofthe investigationaldrug on organ systems not investigatedelsewhereshouldbeassessedwhenthereisa causeforconcern.Forexample,dependencypotential,skeletal muscle,immuneandendocrinefunctionsmaybeinvestigated.

. 1.4  Conditions under which safety pharmacology studies are not necessary.Safetypharmacologystudiesareusualynotrequiredfor lo c a l ly a p p lie d a g e n ts e .g . d e rm a l o r o c u la r, in c a s e s w h e n th e pharmacologyoftheinvestigationaldrugiswelknown,and/orwhen systemicabsorptionfrom thesiteofapplicationislow.Safety pharm acology testing is also not necessary, in the case of a new derivativehavingsimilarpharmacokineticsandpharmacodynamics.

. 1.5  Timingofsafetypharmacologystudiesinrelationtoclinicaldevelopment

. 1.5.1  Priortofirstadministrationinhumans
Theefectsofaninvestigationaldrugonthevitalfunctions listedintheessentialsafetypharmacologyshouldbestudied priorto firstadministration in humans.Any folow-up or supplementalstudies identified,should be conducted if necessary,basedonacauseforconcern.

. 1.5.2  Duringclinicaldevelopment Additionalinvestigationsmaybewarantedtoclarifyobserved orsuspectedadverseefectsinanimalsandhumansduring clinicaldevelopment.

. 1.5.3  Beforeapplyingformarketingapproval
Folow-up and supplementalsafety pharmacology studies shouldbeassessedpriortoapprovalunlessnotrequired,in whichcasethisshouldbejustified.Availableinformationfrom toxicologystudiesaddressingsafetypharmacologyendpoints orinformationfrom clinicalstudiescanreplacesuchstudies.

. 1.6  ApplicationofGoodLaboratoryPractices(GLP) Theanimalstudiesbeconductedinanaccreditedlaboratory.Where
thesafetypharmacologystudiesarepartoftoxicologystudies,these studiesshouldalsobeconductedinanaccreditedlaboratory.

4.FixedDoseCombinations(FDCs).-
Fixed dose combinations referto products containing one ormore active ingredients used fora particularindication.FDCs can be divided into the folowinggroupsanddatarequiredforapprovalformarketingisdescribed below:
(a) ThefirstgroupofFDCsincludesthoseinwhichoneormoreoftheactive

ingredientsisanew drug.ForsuchFDCstobeapprovedformarketing datatobesubmitedwilbesimilartodatarequiredforanynew drug (includingclinicaltrials).

Page96of96

. (b)  (i)ThesecondgroupFDCsincludesthoseinwhichactiveingredients alreadyapproved/marketed individualyare combined forthe first time,foraparticularclaim andwheretheingredientsarelikelyto have significant interaction of a pharmacodynamic or pharmacokineticnature.Ifclinicaltrialshavebeencariedoutwith theFDCinothercountries,reportsofsuchtrialsshouldbesubmited. IftheFDCismarketedabroad,theregulatorystatusinothercountries shouldbestated.
(i)Formarketingpermission,appropriatechemicalandpharmaceutical datawilbesubmited.Incasesuchacombinationisnotmarketed anywhere in the world but these drugs are already in use concom itantly (not as an FDC but individual ly) for the said claim , marketing permission may be granted based on chemicaland p h a rm a c e u tic a l d a ta . D a ta s h o w in g th e s ta b ility o f th e p ro p o s e d dosage form w il lalso have to besubm it ted.
(i)ForanyothersuchFDCs,clinicaltrialsmayberequired.Forobtaining permissiontocaryoutclinicaltrialswithsuchFDCsasummaryof available pharmacological,toxicologicaland clinicaldata on the individualingredientsshouldbesubmited,alongwiththerationale forcombiningthem intheproposedratio.Inaddition,acutetoxicity data(LD50)andpharmacologicaldatashouldbesubmitedonthe individualingredientsaswelastheircombinationintheproposed ratio.

. (c)  ThethirdgroupofFDCsincludesthosewhicharealreadymarketed,but inwhichitisproposedeithertochangetheratioofactiveingredientsor tomakeanew therapeuticclaim.ForsuchFDCs,theappropriate rationale including published reports (if any) should be subm it ted to obtainmarketingpermission.Permissionwilbegranteddependingupon the nature ofthe claim and data subm it ted.

. (d)  The fourth group ofFDC includes those whose individualactive ingredients(ordrugsfrom thesameclass)havebeenwidelyusedina particularindication(s)foryears,theirconcomitantuse is often necessaryandnoclaim isproposedtobemadeotherthanconvenience. Itwilhavetobedemonstratedthattheproposeddosageform isstable and the ingredients are unlikely to have significant interaction of a pharmacodynamicorpharmacokineticnature. NoadditionalanimalorhumandataaregeneralyrequiredfortheseFDCs, andmarketingpermissionmaybegrantediftheFDChasanacceptable rationale.

5.StabilityTestingofNewDrugs.- Stabilitytestingistobeperformedtoprovideevidenceonhow thequalityofa drugsubstanceorformulationvarieswithtimeundertheinfluenceofvarious environmentalfactorssuchastemperature,humidityandlight,andtoestablish shelflifefortheformulationandrecommendedstorageconditions.

Page97of97

Stability studies should include testing of those at tributes of the drug substance thatare susceptible to change during storage and are likelyto influencequality,safety,and/oreficacy.Incaseofformulationsthetesting should cover,as appropriate,the physical,chemical,biological,and microbiologicalatributes,preservativecontent(e.g.,antioxidant,antimicrobial preservative),andfunctionalitytests(e.g.,foradosedeliverysystem).

Validatedstability-indicatinganalyticalproceduresshouldbeapplied.For longterm studies,frequencyoftestingshouldbesuficienttoestablishthe stabilityprofileofthedrugsubstance.

Ingeneral,adrugsubstanceshouldbeevaluatedunderstorageconditions thattestitsthermalstabilityand,ifapplicable,itssensitivitytomoisture.The storageconditionsandthelengthofstudieschosenshouldbesuficientto coverstorage,shipmentandsubsequentuse.

Stresstestingofthedrugsubstanceshouldbeconductedtoidentifythe likelydegradationproducts,whichinturnestablishthedegradationpathways, evaluate the intrinsic stability ofthe molecule and validate the stability indicatingpoweroftheanalyticalproceduresused.Thenatureofthestress testingwildependontheindividualdrugsubstanceandthetypeofformulation involved.

Stresstestingmaygeneralybecariedoutonasinglebatchofthedrug substance.Itshould include the efectoftemperatures),humidity where appropriate,oxidation,andphotolysisonthedrugsubstance.

Datashouldbeprovidedfor(a)Photostabilityonatleastoneprimary batchofthedrugsubstanceaswelastheformulation,asthecasemaybeand (b)thesusceptibilityofthedrugsubstancetohydrolysisacrossawiderangeof pHvalueswheninsolutionorsuspension.

Long-term testingshouldcoveraminimum of12months’durationonat leastthreeprimarybatchesofthedrugsubstanceortheformulationatthetime ofsubmissionandshouldbecontinuedforaperiodoftimesuficienttocover theproposedshelflife.Acceleratedtestingshouldcoveraminimum of 6monthsdurationatthetimeofsubmission.

Incaseofdrugsubstances,thebatchesshouldbemanufacturedtoa minimum ofpilotscalebythesamesyntheticrouteandusingamethodof manufacturethatsimulatesthefinalprocesstobeusedforproductionbatches. Incaseofformulations,twoofthethreebatchesshouldbeatleastpilotscale andthethirdonemaybesmaler.

Themanufacturingprocessusedforprimarybatchesshouldsimulatethat tobeappliedtoproductionbatchesandshouldprovideproductsofthesame qualityandmeetingthesamespecificationsasthatintendedformarketing.

Thestabilitystudiesfordrugsubstancesshouldbeconductedeitherinthe samecontainer-closuresystem asproposedforstorageanddistributionorin acontainer-closuresystem thatsimulatestheproposedfinalpackaging.In caseofformulations,the

stabilitystudiesshouldbeconductedinthefinalcontainer-closuresystem Page98of98

proposedformarketing. Stabilitytestingofnewdrugsubstancesandformulations:
(i) Studyconditionsfordrugsubstancesandformulationsintendedtobe

storedundergeneralconditions

(i) Ifatanytimeduring6monthstestingundertheacceleratedstorage condition,suchchangesoccurthatcausetheproducttofailincomplying with theprescribed standards,additionaltesting underan intermediate storageconditionshouldbeconductedandevaluatedagainstsignificant changecriteria.

(i i i) Study conditions for drug substances and form ulations intended to be storedinarefrigerator.

(iv) Study conditions for drug substances and form ulations intended to be storedinafreezer

Long- -20 ̊C±5 ̊C 12months
(v) Drugsubstancesintendedforstoragebelow-20 ̊Cshalbetreatedona

case-by-casebasis.

(vi)Stability testing ofthe formulations afterconstitution ordilution,if applicable,shouldbeconductedtoprovideinformationforthelabelingon thepreparation,storagecondition,andin-useperiodoftheconstitutedor dilutedproduct.Thistestingshouldbeperformedontheconstitutedor dilutedproductthroughtheproposedin-useperiod.

TABLE1

DATATOBESUBMITTEDALONGWITHTHEAPPLICATIONTO CONDUCTCLINICALTRIALSORIMPORTORMANUFACTUREOFNEW DRUGSFORSALEINTHECOUNTRY

1.Introduction Abriefdescriptionofthedrugandthetherapeuticclasstowhichitbelongs. 2.Chemicalandpharmaceuticalinformation
2.1. Informationonactiveingredients

Druginformation(GenericName,ChemicalNameorINN) 2.2. Physicochemicaldata

Study

Studyconditions

Durationofstudy

Long-term

30 ̊C±2 ̊C/75%RH±5%RH

12months

Accelerated

40 ̊C±2 ̊C/75%RH±5%RH

6months

Study

Studyconditions

Durationofstudy

Long-term

5 ̊C±3 ̊C

12months

Accelerated

25 ̊C±2 ̊C/60%RH±5%RH

6months

Study

Studyconditions

Durationofstudy

Study

Studyconditions

Durationsof study

Page99of99

(a) Chemical name andStructure

Empiricalformula

Molecularweight (b) Physicalproperti es Description

Solubility Rotation Partition coeficient Dissociation constant

. 2.3.  Analyticaldata Elemental
analysisMass spectrum NMR spectra IRspectra
UV
spectra Polymorphicidentification

. 2.4.  Complete specificationincludingIdentification Identity/quantificationofimpurities Enantiomericpurity
Assay

. 2.5.  Validations Assaymethod
Impurityestimationmethod
Residualsolvent/othervolatileimpurities(OVI)estimationmethod

. 2.6.  Stability studies (for details refer clause 5 of
thisSchedule)Finalreleasespecification Referencestandardcharacterization Materialsafetydatasheet

. 2.7.  Dataonformulation i.Dosageform
i.Composition i.Mastermanufacturingformula

monograph

Page100of100

iv.Detailsoftheformulation(includinginactive ingredients)Inprocessqualitycontrolcheck

v.Finishedproductspecification vi.Excipientcompatibilitystudy

vi.Validationoftheanalyticalmethod

vi.Comparative evaluation with internationalbrand orapproved Indianbrands,ifapplicable.

ix.Packresentation

x. Dissolutionssay xi.Impurities

xi.ContentuniformitypH

xi.Forcedegradationstudy xiv.Stabilityevaluationinmarketintendedpackatproposedstorage

conditionsPackingspecifications xv.Processvalidation

When the application is forclinicaltrials only,the internationalnon- proprietaryname(INN)orgenericname,drugcategory,dosageform and datasupportingstabilityintheintendedcontainer-closuresystem forthe durationoftheclinicaltrial(informationcoveredinitem nos.2.1,2.3,2.6,2.7) arerequired.

3.Animalpharmacology(fordetailsreferclause3ofthisSchedule)

3.1. Summary

3.2. Specificpharmacologicalactions
3.3. Generalpharmacologicalactions
3.4. Folow-upandsupplementalsafetypharmacologystudies
3.5. Pharmacokinetics:absorption,distribution;metabolism;excretion

4.Animaltoxicology(fordetailsreferclause2ofthisSchedule) 4.1. Generalaspects
4.2. Systemictoxicitystudies
4.3. Malefertilitystudy

4.4. Femalereproductionanddevelopmentaltoxicitystudies 4.5. Localtoxicity
4.6. Alergenicity/Hypersensitivity
4.7. Genotoxicity

4.8. Carcinogenicity

Note.-Wherethedataonanimaltoxicityasperthespecificationsofclause 2has been subm it ted and the sam e has been considered by the regulatoryauthorityofthecountrywhichhadearlierapprovedthe drug,theanimaltoxicitystudiesshalnotberequiredtobeconducted inIndiaexceptincaseswheretherearespecificconcernsrecordedin

Page101of101

writing. 5.Human/Clinicalpharmacology(PhaseI)

5.1. Summary
5.2. SpecificPharmacologicalefects
5.3. GeneralPharmacologicalefects
5.4. Pharmacokinetics,absorption,distribution,metabolism,excretion 5.5. Pharmacodynamics/earlymeasurementofdrugactivity

6.Therapeuticexploratorytrials(PhaseI)

6.1. Summary
6.2. StudyreportasgiveninTable5ofthisSchedule

7.Therapeuticconfirmatorytrials(PhaseI)

7.1. Summary
7.2. Individualstudyreportswithlistingofsitesandinvestigators.

8.Specialstudies

8.1. Summary
8.2. Bio-availability/Bio-equivalence.
8.3 Otherstudiese.g.geriatrics,paediatrics,pregnantornursingwomen

9.Regulatorystatusinothercountries

. 9.1.  Countrieswherethedrugis (a)Marketed
(b)Approved
(c)ApprovedasIND (d)Withdrawn,ifany,withreasons

. 9.2.  Restrictionsonuse,ifany,incountrieswheremarketed/approved

. 9.3.  Freesalecertificateorcertificateofanalysis,asappropriate.

10.Prescribinginformation

10.1. Proposedfulprescribinginformation 10.2. Draftsoflabelsandcartons

11.SamplesandTestingprotocol/s

11.1.Samplesofpuredrugsubstanceandfinishedproduct(anequivalent of50clinicaldoses,ormorenumberofclinicaldosesifprescribedby theCentralLicencingAuthority),withtestingprotocol/s,fulimpurity profileandreleasespecifications.

12.NewchemicalentityandGlobalclinicaltrial:

12.1 Assessmentofriskversusbenefittothepatients 12.2 Innovationvis-à-visexistingtherapeuticoption 12.3 Unmetmedicalneedinthecountry.

13.Copyoflicensetomanufactureanydrugforsalegrantedbystatelicencing authority(incasetheapplicationisformanufactureforsaleofnewdrug)

NOTES:(1)Alitemsmaynotbeapplicabletoaldrugs.Forexplanation,refer Page102of102

textofthisFirstSchedule,SecondScheduleandThirdSchedule. (2)Forrequirementsofdatatobesubmitedwithapplicationfor clinicaltrialsrefertextofthisFirstSchedule,SecondScheduleand ThirdSchedule.

TABLE2 DATAREQUIREDTOBESUBMITTEDBYANAPPLICANTFORGRANTOF

PERMISSIONTOIMPORTORMANUFACTUREANEW DRUGALREADY APPROVEDINTHECOUNTRY

1. Introduction Abriefdescriptionofthedrugandthetherapeuticclass

2. Chemicalandpharmaceuticalinformation
2.1Chemicalname,code name ornumber,ifany;non-proprietary or

genericname,ifany,structure;physico-chemicalproperties 2.2Dosageform anditscomposition
2.3Testspecifications

(a)activeingredients

(b)inactiveingredients 2.4Testsforidentificationoftheactiveingredientsandmethodofitsassay 2.5Specificationsoffinishedproduct
2.6Outline of the method of manufacture of active ingredient and

finishedproduct 2.7Stabilitydata

3. Marketinginformation
3.1 Proposedpackageinsert/promotionaliterature
3.2 Draftspecimenofthelabelandcarton
4. SpecialstudiesconductedwithapprovalofCentralLicencingAuthority 4.1 BioavailabilityorBioequivalenceandcomparativedissolutionstudies

fororaldosageforms
4.2 Sub-acuteanimaltoxicitystudiesforintravenousinfusionsandinjectables.

TABLE3

DATAREQUIREDTOBESUBMITTEDBYANAPPLICANTFORCONDUCT OFCLINICALTRIALOFANAPPROVEDNEW DRUGWITHNEW CLAIMS, NAMELY,NEW INDICATIONORNEW DOSAGEFORM ORNEW ROUTEOF

ADMINISTRATIONORNEW STRENGTHORTOIMPORTOR MANUFACTURESUCHNEW DRUGFORSALEORDISTRIBUTION

1. Num ber and date of perm ission or license already granted for the approvednewdrug.

Page103of103

2.Therapeuticjustificationfornewclaim-newindication/modifieddosage form/newrouteofadministration 3.ChemicalandPharmaceuticalinformation 3.1Chemicalname,codenameornumber,ifany;non-proprietaryorgeneric name,ifany,structure;physico-chemicalproperties

3.2Dosageform anditscomposition 3.3Testspecifications

(a)activeingredients

(b)inactiveingredients 3.4Testsforidentificationoftheactiveingredientsandmethodofitsassay 3.5Specificationsoffinishedproduct 3.6Outlineofthemethodofmanufactureofactiveingredientandfinishedproduct 3.7Stabilitydata
4.Therapeuticjustificationfornewclaim /modifieddosageform 5.Animalpharmacologicalandtoxicologicaldataasreferedinsub-clause (3)ofclause1andclause2ofthisSchedule. 6.Clinicaltrialdataasreferedinsub-clause(3)ofclause1ofthisSchedule. 7.Regulatorystatusinothercountries
8.Marketinginformation:
8.1Proposedpackageinsert/promotionaliterature 8.2Draftspecimenofthelabelandcarton

TABLE4

DATATOBESUBMITTEDALONGWITHAPPLICATIONTOCONDUCTCLINICAL TRIALORIMPORTORMANUFACTUREOFAPHYTOPHARMACEUTICALDRUG INTHECOUNTRY

PART–A
1. Datatobesubmitedbytheapplicant:

1.1.A briefdescriptionorsummaryofthephytopharmaceuticaldrug giving the botanicalname ofthe plant(including vernacularor scripturalname,whereverapplicable),formulation and route of administration,dosages,therapeuticclassforwhichitisindicated andtheclaimstobemadeforthephytopharmaceuticalproduct.

1.2. Published literature including inform ation on plant or product or phytopharmaceuticaldrug,asatraditionalmedicineorasanethno medicine and provide reference to books and otherdocuments, regardingcomposition,processprescribed,doseormethodofusage, proportionoftheactiveingredientsinsuchtraditionalpreparations perdoseorperday’sconsumptionanduses.

1.3.Information on any contraindications,side efects mentioned in traditionalmedicineorethnomedicineliteratureorreportsoncurent usageoftheformulation.

1.4.Publishedscientificreportsinrespectofsafetyandpharmacological Page104of104

studies relevant for the phytopharm aceutical drug intended to be marketed,- (a)wheretheprocessandusagesaresimilarorsametotheproduct

knownintraditionalmedicineorethnomedicine;and (b)whereprocessorusageisdiferentfrom thatknownintraditional

medicineorethnomedicine.
1.5.Information on any contraindications,side efects mentioned or

reported in any of the studies, inform ation on side ef fects and adverse reactions reported during curent usage of the phytopharmaceuticalinthelastthreeyears,

whereverapplicable.
1.6.Presentusage ofthe phytopharmaceuticaldrug,– to establish

history of usages, provide details of the product, m anufacturer, quantum sold,extentofexposureonhumanpopulationandnumber ofyearsforwhichtheproductisbeingsold.

2. Humanorclinicalpharmacologyinformation: 2.1.Publishedscientificreportsinrespectofpharmacologicalstudies

includinghumanstudiesorclinicalstudiesorepidemiologicalstudies, relevantforthephytopharmaceuticaldrugintendedtobemarketed,- (a)wheretheprocessandusagesaresimilarorsametotheproduct

knownintraditionalmedicineorethnomedicine;and (b)whereprocessorusageisdiferentfrom thatknownintraditional

medicineorethnomedicine. 2.2.Pharmacodynamicinformation(ifavailable). 2.3.Monographs,ifany,publishedontheplantorproductorextractor

phytopharmaceutical.(Copiesofalpublications,alongwithenglish translationtobeatached.)

PART–B

DATAGENERATEDBYAPPLICANT 3.Identification,authenticationandsourceofplantusedforextraction

andfractionation:
3.1 Taxonom ical identity of the plant used as a source of the

phytopharmaceuticaldruggivingbotanicalnameofgenus,species andfamily,folowedbytheauthoritycitation(taxonomist’snamewho nam ed the species), the variety or the cultivar (if any) needs to bementioned.

3.2Morphologicalandanatomicaldescriptiongivingdiagnosticfeatures andaphotographoftheplantorplantpartforfurtherconfirmationof identity and authenticity. (Furnish certificate of confirm ation of botanicalidentitybyaqualifiedtaxonomist).

3.3Naturalhabitatandgeographicaldistributionoftheplantandalso mention whetherthe partofthe plantused is renewable or

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destructiveandthesourcewhethercultivatedorwild. 3.4Seasonortimeofcolection. 3.5Sourceoftheplantincludingitsgeographicallocationandseasonor

timeofcolection. 3.6Astatementindicatingwhetherthespeciesisanyofthefolowing,namely:-

(a)determined to be endangered or threatened under the Endangered Species Actorthe Convention on International TradeinEndangeredspecies(CITES)ofwildFaunaandFlora;

(b)entitledtospecialprotectionundertheBiologicalDiversityAct, 2002(18of2003);

(c)anyknowngenotypic,chemotypicandecotypicvariabilityofspecies. 3.7. Alistofgrowerorsupplier(includingnamesandaddresses)and

informationonthefolowingitemsforeachgrowerorsupplier,if availableoridentifiedalready,includinginformationofprimary processing,namely:-
(a)harvestlocation;

(b)growthconditions;
(c)stageofplantgrowthatharvest;
(d)harvestingtime; (e)colection,washing,dryingandstorageconditions; (f)handling,garblingandtransportation; (g)grinding,pulverisingoftheplantmaterial;and
(h)sieving forget ting uniform particle size ofpow dered plantm aterial.

3.8.Qualityspecifications,namely:-
(a)foreignmater;
(b)totalash;
(c)acidinsolubleash;
(d)pesticideresidue;
(e)heavymetalcontamination;
(f)microbiaload; (g)chromatographicfingerprintprofilewithphytochemicalreference marker;

(h)assayforbio-activeorphytochemicalcompounds;and (i)chromatographicfingerprintofasampleaspertestmethodgiven under quality control of the phytopharmaceutical drug (photodocumentation).

3.9Anundertakingtosupplyspecimensampleofplantdulylabeledand photocopyofthe certificate ofidentityconfirmation issued bya qualified taxonom ist along w ith draw ings or photographs of the diagnosticmorphologicalandhistologicalfeaturesofthebotanical rawmaterialusedfortheconfirmationofauthenticity.

4. Processforextractionandsubsequentfractionationandpurification: 4.1.Qualityspecificationsandtestmethodsforstartingmaterial. 4.2.Stepsinvolvedinprocessing.

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(a)detailsofsolventused,extractivevalues,solventresiduetests orlimits,physico-chemicaltests,microbialloads,heavymetal contaminants, chromatographic finger print profile with phytochemicalreferencemarkers,assayforactiveconstituents orcharacteristicmarkers,ifactiveconstituentsarenotknown;

(b)characterisationoffinalpurifiedfraction; (c)dataonbio-activeconstituentoffinalpurifiedfraction; (d)information on any excipients ordiluents orstabiliseror

preservativeused,ifany. 4.3.Detailsofpackagingofthepurifiedandcharacterisedfinalproduct,

storageconditionsandlabeling.

5.Formulationofphytopharmaceuticaldrugappliedfor: 5.1.Detailsofthecomposition,proportionofthefinalpurifiedfractionwith

defined markers ofphytopharmaceuticaldrug perunitdose,name andproportionsofalexcipients,stabilisersandanyotheragentusedand packagingmaterials.

5.2.Testforidentificationforthephytopharmaceuticaldrug. 5.3.Qualityspecificationsforactiveandinactivephytopharmaceutical

chromatographic fingerprintprofile with phytochemicalreference marker and assay of active constituent or characteristic chemicalmarker.

6.Manufacturingprocessoformulation: 6.1.Theoutlineofthemethodofmanufactureofthedosageform,along

with environmentalcontrols,in-process quality controltests and

limitsforacceptance.
6.2.Details of alpackaging materials used,packing steps and

descriptionofthefinalpacks. 6.3.Finishedproduct’squalityspecifications,includingtestsspecificfor

thedosageform,qualityandchromatographicfingerprintprofilewith phytochemicalreferencemarkerandassayforactiveconstituentor characteristicmarker,ifactiveconstituentsarenotknown.

7.Stabilitydata: 7.1.Stabilitydataofthephytopharmaceuticaldrugdescribedat4above,

storedatroom temperatureat40+/-2deg.Candhumidityat75%RH

+/-5%RHfor0,1,2,3and6months. 7.2Stabilitydataofthephytopharmaceuticaldrugindosageform or

formulationstoredatroom temperatureat40+/-2deg.Cand humidityat75%RH+/-5%RHfor0,1,2,3and6months,inthepack intendedformarketing.

8.Safetyandpharmacologicalinformation: 8.1.Dataonsafetyandpharmacologicalstudiestobeprovided. 8.2.Animaltoxicityandsafetydata:

(a) 28to90daysrepeatdoseoraltoxicityontwospeciesofanimals;

(b) In-vitro genotoxicity data (Ame’s test and Chromosomal aberationtest);

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(c) dermaltoxicitytestsfortopicaluseproducts; (d)teratogenicity study (only ifphytopharmaceuticaldrug is

intendedforuseduringpregnancy). 9.Humanstudies:

9.1.Clinicaltrialsforphytopharmaceuticaldrugstobeconductedasper applicableRulesandguidelinesfornewdrugs.

9.2.Foralphytopharmaceuticaldrugsdatafrom phaseI(todetermine maximum tolerateddoseandassociatedtoxicities)andtheprotocols shalbesubmitedpriortoperformingthestudies.

9.3.Dataofresultsofdosefindingstudiesperformedandtheprotocols shalbesubmitedpriortoperformingthestudies:

Providedthatinthecaseofphytopharmaceuticaldrugalready marketed formore than five years orwhere there is adequate publishedevidenceregardingthesafetyofthephytopharmaceutical drug,thestudiesmaybeabbreviated,modifiedorrelaxed.

10.Confirmatoryclinicaltrials: 10.1.Submitprotocolsforapprovalforanyspecificorspecialsafety

andeficacystudyproposedspecifictothephytopharmaceuticaldrug.

10.2.Submitproposedprotocolforapprovalforhumanclinicalstudies appropriatetogenerateorvalidatesafetyandeficacydataforthe phytopharmaceuticaldosageform orproductasperapplicableRules andguidelines.

10.3.Submitinformationonhowthequalityoftheformulationwouldbe maintainedduringtheabovestudies.

11.Regulatorystatus: 11.1.Statusofthephytopharmaceuticaldrugmarketedinanycountry

underanycategorylikefunctionalfoodordietarysupplementoras

traditionalmedicineorasanapproveddrug. 12.Marketinginformation:

12.1. Details of package insert or patient inform ation sheet of the phytopharmaceuticaldrugtobemarketed.

12.2.Draftofthetextforlabelandcarton. 13.Postmarketingsurveilance(PMS):

13.1.Theapplicantshalfurnishperiodicsafetyupdatereportseverysix monthsforthefirsttwoyearsafterapprovalthedrugisgranted.

13.2.Forsubsequenttwoyearstheperiodicsafetyupdatereportsneed tobesubmitedannualy.

14.Anyotherrelevantinformation: Anyotherrelevantinformationwhichtheapplicantconsidersthatitwilhelp inscientificevaluationoftheapplication.

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THIRDSCHEDULE (SeeRules8,10,11,17,25,35,42and49)

CONDUCTOFCLINICALTRIAL 1.Conductofclinicaltrial.-

(i) C lin ic a l tria l s h a l l b e c o n d u c te d in a c c o rd a n c e w ith th e p ro v is io n s o f th e A c t andtheseRulesandprinciplesofGoodClinicalPracticeGuidelines.

(i)Clinicaltrialonanew drugshalbeinitiatedonlyafterthepermissionhas beengrantedbytheCentralLicencingAuthorityandtheapprovalobtained from the respective ethicscom m it tee.

(i i i) T h e C e n tra l L ic e n c in g A u th o rity s h a l l b e in fo rm e d o f th e a p p ro v a l o f th e respectiveinstitutionalethicscommiteeinaccordancewiththeseRules.

(iv)Altrialinvestigatorshouldpossessappropriatequalifications,trainingand experience and should have access to such investigational and treatm ent facilitiesasarerelevanttotheproposedtrialprotocol.Aqualifiedphysician (ordentist,whenappropriate)whoisaninvestigatororasub-investigatorfor the trial, should be responsible for al l trial-related m edical (or dental) decisions.Laboratoriesusedforgeneratingdataforclinicaltrialsshouldbe compliantwithGoodLaboratoryPractices.

(v)Protocolamendments,ifbecomenecessarybeforeinitiationorduringthe courseofaclinicaltrial,alsuchamendmentsshouldbesubmitedtothe CentralLicencingAuthorityinwritingalongwiththeapprovalbytheethics commitee,ifavailable,whichhasgrantedtheapprovalforthestudy.

(vi)Nodeviationsfrom orchangestotheprotocolshouldbeimplemented withoutpriorwritenapprovaloftheethicscommiteeandCentralLicencing Authorityexceptwhenitisnecessarytoeliminateimmediatehazardstothe trialsubjectorwhenchangeinvolvesonlylogisticoradministrativeorminor aspectsofthetrial.Alsuchexceptionsmustbeimmediatelynotifiedtothe ethicscommiteeaswelastotheCentralLicencingAuthority.Administrative and/or logistic changes or m inor am endm ents in the protocol should be notifiedtotheCentralLicencingAuthoritywithinthirtydays.

2.InformedConsent.–

(a)Inaltrials,afreelygiven,informed,writenconsentisrequiredtobeobtained from eachstudysubject.TheInvestigatormustprovideinformationaboutthe studyverbalyaswelasusingapatientinformationsheet,inalanguagethat isnon-technicalandunderstandablebythestudysubject.

(b)Thesubject’sconsentmustbeobtainedinwritingusingan‘InformedConsent Form’.Boththepatientinformationsheetaswelastheinformedconsent form should have been approved by the ethics com m it tee and furnished to the Central Licencing

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Authority.Anychangesintheinformedconsentdocumentsshouldbeapprovedby

Page110of110

theethicscommiteeandsubmitedtotheCentralLicencingAuthoritybefore

suchchangesareimplemented. (c)Whereasubjectisnotabletogiveinformedconsent(e.g.anunconscious

personoraminororthosesuferingfrom severementalilnessordisability), thesamemaybeobtainedfrom alegalyacceptablerepresentative(alegaly acceptable representative is a person who is able to give consentforor authorizeandinterventioninthepatientasprovidedbythelawofIndia).

(d)Ifthetrialsubjectorhis/herlegalyacceptablerepresentativeisunableto read/writeanimpartialwitnessshouldbepresentduringtheentireinformed consentprocesswhomustappendhis/hersignaturetotheconsentform.

(e)Incaseofclinicaltrialsonpaediatrics,thesubjectsarelegalyunableto providewriteninformedconsent,andaredependentontheirparentorlegal guardiantoassumeresponsibilityfortheirparticipationinclinicalstudies.In suchcase-

(i)Writeninformedconsentshouldbeobtainedfrom theparentor legalguardian.However,alpaediatric participants should be informedtothefulestextentpossibleaboutthestudyinalanguage andintermsthattheyareabletounderstand.

(i)Where appropriate,paediatric participants should additionaly assenttoenrolinthestudy.Matureminorsandadolescentsshould personalysignanddateaseparatelydesignedwritenassentform.

(i)Althoughaparticipant’swishtowithdraw from astudymustbe respected,theremaybecircumstancesintherapeuticstudiesfor seriousorlife-threateningdiseasesinwhich,intheopinionofthe Investigatorandparentorlegalguardian,thewelfareofapaediatric patientwouldbejeopardizedbyhisorherfailingtoparticipateinthe study.Inthissituation,continuedparentalorlegalguardianconsent shouldbesuficienttoalowparticipationinthestudy.

(f) A checklistofessentialelements to be included in the study subject’s informedconsentdocumentaswelasaformatfortheinformedconsent form fortrialsubjectisgiveninTable2ofthisSchedule.

(g)An audio-video recording of the informed consent process in case ofvulnerablesubjectsinclinicaltrialsofNew ChemicalEntityorNew MolecularEntityincludingprocedureofprovidinginformationtothesubject and his understanding on such consent,shalbe maintained by the investigatorforecord: Providedthatincaseofclinicaltrialofanti-HIVandanti-leprosydrugs,only audio recording ofthe informed consentprocess ofindividualsubject including the procedure ofproviding information to the subjectand his understandingonsuchconsentshalbemaintainedbytheinvestigatorfor record.

2.Responsibilities.- (1)Sponsor.-

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. (i)  Theclinicaltrialsponsorisresponsibleforimplementingandmaintaining qualityassurancesystemstoensurethattheclinicaltrialisconductedand datagenerated,documentedandreportedincompliancewiththeprotocol and Good ClinicalPractices Guidelines as welas with alapplicable statutoryprovisions.Standardoperatingproceduresshouldbedocumented toensurecompliancewithGoodClinicalPracticesGuidelinesandapplicable regulations.

. (i)  Sponsorsarerequiredtosubmitastatusreportontheclinicaltrialtothe CentralLicencingAuthorityattheprescribedperiodicity.

. (i)  Incaseofstudiesprematurelydiscontinuedforanyreasonincludinglack ofcommercialinterestinpursuingthenew drugapplication,asummary reportshouldbesubmitedwithin3months.Thesummaryreportshould provideabriefdescriptionofthestudy,thenumberofpatientsexposedto thedrug,doseanddurationofexposure,detailsofadversedrugreactions, ifany,andthereasonfordiscontinuationofthestudyornon-pursuitofthe newdrugapplication;

. (iv)  Anyreportoftheseriousadverseevent,afterdueanalysisshalbe forwarded by the sponsor to the CentralLicencing Authority,the Chairpersonoftheethicscommiteeandtheheadoftheinstitutionwhere the trialhas been conducted,within fourteen days ofknowledge of occurenceoftheseriousadverseeventasspecifiedinTable5ofthis Schedule;

. (v)  Incaseofinjuryordeathoccuringtothetrialsubject,thesponsor (whetherapharmaceuticalcompanyoraninstitution)orhisrepresentative orthe investigatororthe institution orcentre where the study was conducted, as the case m ay be, shal l m ake paym ent for m edical managementofthesubjectandalsoprovidefinancialcompensationfor theclinicaltrialrelatedinjuryordeathinaccordancewiththeprocedureas prescribedinCHAPTERVIoftheseRules

. (vi)  Thesponsor(whetherapharmaceuticalcompanyoranInstitution)orhis representative,whosoeverhadobtainedpermissionfrom theCentral LicencingAuthorityforconductoftheclinicaltrial,shalsubmitdetailsof compensationprovidedorpaidforclinicaltrialrelatedinjuryordeath,tothe CentralLicencingAuthoritythirtydaysofthereceiptoftheorderofthe CentralLicencingAuthority.

. (vi)  Thesponsorshalprovidepost-trialaccessoftheinvestigationaldrugby givingthedrugfreeofcosttothetrialsubjectasperdirectionsofthe Central Licencing Authority in special circumstances on the recommendationsoftheinvestigatorandtheethicscommiteeandwriten consentofthepatientinaccordancewithRule29.

(2)Investigator.-

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(i) Theinvestigatorshalberesponsiblefortheconductofthetrialaccording totheprotocolandtheGoodClinicalPracticesGuidelinesandalsofor complianceaspertheundertakinggiveninTable4.Standardoperating proceduresarerequiredtobedocumentedbytheinvestigatorsforthe tasksperformedbythem.

. (i)  Duringandfolowingasubject’sparticipationintrial,theinvestigator shouldensurethatadequatemedicalcareisprovidedtotheparticipant foranyadverseevents.

. (i)  Investigatorshalreportalserious adverse events to the Central LicencingAuthority,the sponsororhis representative,whosoeverhad obtainedpermissionfromtheCentralLicencingAuthorityforconductof theclinicaltrial,andtheethicscommiteethataccordedapprovaltothe studyprotocol,withintwenty-fourhoursoftheiroccurence.

. (iv)  Incase,theinvestigatorfailstoreportanyseriousadverseeventwithin thestipulatedperiod,heshalhavetofurnishthereasonforthedelayto thesatisfactionoftheCentralLicencingAuthorityalongwiththereportof theseriousadverseevent.Thereportoftheseriousadverseevent,after due analysis,shalbe forwarded by the investigatorto the Central LicencingAuthority,theChairpersonoftheethicscommiteeandthe Headoftheinstitutionwherethetrialhasbeenconductedwithinfourteen daysoftheoccurenceoftheseriousadverseevent.

(v) The investigator shal l provide inform ation to the trial subject through inform ed consent process as provided in Table 3about the essential elements of the clinical trial and the subject’s right to claim compensationincaseoftrialrelatedinjuryordeath.Heshalalsoinform thesubjectorhis/hernomineeoftheirrightstocontactthesponsoror hisrepresentativewhosoeverhadobtainedpermissionfrom theCentral LicencingAuthorityforconductoftheclinicaltrialforthepurposeof makingclaimsinthecaseoftrialrelatedinjuryordeath.

(3)Ethicscommitee.-
(i) Itistheresponsibilityoftheethicscommiteethatreviewsandaccords

itsapprovaltoatrialprotocoltosafeguardtherights,safetyandwel- beingofaltrialsubjects.

(i) Theethicscommiteeshouldexerciseparticularcaretoprotecttherights, safetyandwel-beingofalvulnerablesubjectsparticipatinginthestudy, e.g.,membersofagroupwithhierarchicalstructure(e.g.prisonersarmed forcespersonnel,stafandstudentsofmedical,nursingandpharmacy academicinstitutions),patientswithincurablediseases,unemployedor impoverishedpersons,patientsinemergencysituation,ethnicminority groups,homelesspersons,nomads,refugees,minorsorotherincapable ofpersonalygivingconsent.

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(i)Ethics commitee should get documented ‘standard operating procedures’andshouldmaintainarecordofitsproceedings.

(iv) Ethics com m it tee should m ake, at appropriate intervals, an ongoing review ofthetrialsforwhichtheyhavereviewedtheprotocol.Sucha reviewmaybebasedontheperiodicstudyprogressreportsfurnishedby theinvestigatorsand/ormonitoringandinternalauditreportsfurnished bythesponsorand/orvisitingthestudysites.

(v) In case an ethics com m it tee revokes its approval accorded to a trial protocol,itmustrecord the reasons fordoing so and atonce communicatesuchadecisiontotheInvestigatoraswelastotheCentral LicencingAuthority.

Incaseofseriousadverseeventoccuringtothetrialsubject,theethics commitee shalforward its reportororderon the event,afterdue analysis, along with itsopiniononthefinancialcompensation,ifany,tobepaidbythesponsororhisr epresentativeorinstitutionorcentre,asthecasemaybe,inaccordance withCHAPTERVIoftheseRules.

TABLE1

INFORMATIONTOBESUBMITTEDBYANAPPLICANTFORGRANTOF REGISTRATIONOFETHICSCOMMITTEEANDFORMATFOR ACCORDINGAPPROVAL

(A)Informationrequiredtobesubmitedbytheapplicantforregistrationofethics commitee:

(a)Nameoftheethicscommitee.
(b ) A u th o rity u n d e r w h ic h th e e th ic s c o m m it te e h a s b e e n c o n s titu te d ,

membership requirements, the term of reference, conditions of

appointmentandthequorum required. (c)Theprocedureforresignation,replacementorremovalofmembers. (d)Addressoftheoficeoftheethicscommitee. (e)Name,address,qualification,organisationaltitle,telephonenumber,fax

number,e-mail,mailingaddressandbriefprofileoftheChairperson. (f)Names,qualifications,organisationaltitle,telephonenumber,faxnumber,

e-mailandmailingaddressofthemembersoftheethicscommitee.The informationshalalsoincludemember’sspecialty(primary,scientificor non-scientific),member’s afiliation with institutions and patientgroup representation,ifany.

(g)Detailsofthesupportingstaf. (h)Thestandardoperatingprocedurestobefolowedbythecommiteeingeneral. (i)Standard operating procedures to be folowed by the commitee for

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vulnerablepopulation
(j) P o lic y re g a rd in g tra in in g fo r n e w a n d e x is tin g c o m m it te e m e m b e rs a lo n g

withstandardoperatingprocedures. (k)Policytomonitororpreventtheconflictofinterestalongwithstandard

operatingprocedures. (l)Ifthecommiteehasbeenauditedorinspectedbefore,givedetails.

(B)Formatforaccording approvalto clinicaltrialprotocolby the ethicscommiteeTo

Dr. DearDr.

TheInstitutionalethicscommitee/independentethicscommitee(state name ofthe commitee,as appropriate)reviewed and discussed your applicationtoconducttheclinicaltrialentitled“………………”on……………(date). Thefolowingdocumentswerereviewed:

. (a)  Trialprotocol(includingprotocolamendments),dated…………………… versionNo.(s)…………………………….

. (b)  Patientinformation sheetand informed consentform (including updates,ifany)inEnglishand/orvernacularlanguage.

. (c)  Investigator’s brochure, dated……………………., Version no. ………………………

. (d)  Proposed methods forpatientaccrualincluding advertisement(s) etc.proposedtobeusedforthepurpose.

. (e)  Principalinvestigator’scurentCV.

. (f)  Insurancepolicy/compensationforparticipationandforserious adverseeventsoccuringduringthestudyparticipation.

. (g)  Investigator’sagreementwiththesponsor.

. (h)  Investigator’sundertaking(Table4).

Thefolowingmembersoftheethicscommiteewerepresentatthemeeting heldon(date,time,place).

……………………Chairpersonoftheethicscommitee ……………………Member-Secretaryoftheethicscommitee ……………………Nameofeachmemberwithdesignation

Weapprovethetrialtobeconductedinitspresentedform.

Theethicscommiteetobeinformedabouttheprogressofthestudy,any

SAEoccuringinthecourseofthestudy,anychangesintheprotocoland Page115of115



patientinformation/informedconsentandtobeprovidedwithacopyofthe finalreport.

TitlePage

Yourssincerely, MemberSecretary,EthicsCommitee

TABLE2 CONTENTSOFTHEPROPOSEDPROTOCOLFORCONDUCTING CLINICALTRIALS

a.Fultitleoftheclinicalstudy,

b.Protocol/Studynumber,andprotocolversionnumberwithdate.

c.TheINDname/numberoftheinvestigationaldrug.

d.CompletenameandaddressoftheSponsorandcontractresearchorganization ifany

e.Listofthe investigators who are conducting the study,theirrespective institutionalafiliationsandsitelocations

f.Name of clinical laboratories and other departments and/or facilities participatinginthestudy.

TableofContents 1.Backgroundandintroduction

a.Preclinicalexperience b.Clinicalexperience

Previousclinicalworkwiththenew drugshouldbereviewedhereanda descriptionofhow thecurentprotocolextendsexistingdatashouldbe provided.Ifthisisanentirelynew indication,how thisdrugwasconsidered for this should be discussed. Relevant information regarding pharm acological, toxicological and other biological properties of the drug/biologic/medicaldevice,andpreviouseficacyandsafetyexperience shouldbedescribed.

2.Studyrationale Thissectionshoulddescribeabriefsummaryofthebackgroundinformation relevant to the study design and protocol m ethodology. The reasons for perform ing this study in the particular population included by the protocol shouldbeprovided.

3.Studyobjective(primaryaswelassecondary)andtheirlogicalrelationtothe studydesign.

4.Studydesign–
(a)Overview ofthestudydesign:Includingadescriptionofthetypeofstudy

(i.e.,double-blind,multicentre,placebocontroled,etc.),adetailofthespecific treatment groups and number of study Subjects in each group and investigativesite,Subjectnumberassignment,andthetype,sequenceand

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durationofstudyperiods.
(b).Flowchartofthestudy (c).Abriefdescriptionofthemethodsandprocedurestobeusedduringthestudy. (d).Discussionofstudydesign:Thisdiscussiondetailstherationaleforthe

designchosenforthisstudy. 5.Studypopulation:thenumberofsubjectsrequiredtobeenroledinthestudyat

theinvestigativesiteandbyalsitesalongwithabriefdescriptionofthenature

ofthesubjectpopulationrequiredisalsomentioned. 6.Subjecteligibility

a.Inclusioncriteria

b.Exclusioncriteria 7.Studyassessments–plan,proceduresandmethodstobedescribedindetail. 8.Studyconductstatingthetypesofstudyactivitiesthatwouldbeincludedin

thissectionwouldbe:medicalhistory,typeofphysicalexamination,bloodor urinetesting,electrocardiogram (ECG),diagnostictestingsuchaspulmonary function tests, symptom measurement, dispensation and retrieval of medication,Subjectcohortassignment,adverseeventreview,etc. EachvisitshouldbedescribedseparatelyasVisit1,Visit2,etc. Discontinuedsubjects:DescribesthecircumstancesforSubjectwithdrawal, dropouts,orotherreasonsfordiscontinuationofSubjects.Statehowdropouts w ould be m anaged and if they w ould be replaced describe the m ethod of handlingofprotocolwaivers,ifany.Thepersonwhoapprovesalsuchwaivers should be identified and the criteria used for specific waivers should be provided.

Describes how protocolviolations wil lbe treated,including conditions where

thestudywilbeterminatedfornoncompliancewiththeprotocol. 9.Studytreatment-

(a)Dosing schedule (dose,frequency,and duration ofthe experimental treatm ent) Describe the adm inistration of placebos and/or dum m y m edications if they are part of the treatm ent plan. If applicable, concomitantdrug(s),theirdoses,frequency,anddurationofconcomitant treatmentshouldbestated.

(b)Studydrugsuppliesandadministration:Astatementaboutwhoisgoing to provide the study medication and thatthe investigationaldrug formulationhasbeenmanufacturedfolowingalregulationsDetailsof theproductstability,storagerequirementsanddispensingrequirements shouldbeprovided.

(c)Dosemodificationforstudydrugtoxicity:Rulesforchangingthedoseor stoppingthestudydrugshouldbeprovided.

(d)Possibledruginteractions (e)Concomitanttherapy:Thedrugsthatarepermitedduringthestudyand

theconditionsunderwhichtheymaybeusedaredetailedhere.Describe thedrugsthataSubjectisnotalowedtouseduringpartsofortheentire study.Ifanywashoutperiodsforprohibitedmedicationsareneededprior

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toenrolment,theseshouldbedescribedhere. (f)Blindingprocedures:Adetaileddescriptionoftheblindingprocedureifthe

studyemploysablindontheInvestigatorand/ortheSubject
(g ) U n -b lin d in g p ro c e d u re s : If th e s tu d y is b lin d e d , th e c irc u m s ta n c e s in

whichun-blindingmaybedoneandthemechanism tobeusedforun-

blindingshouldbegiven 10.AdverseEvents:

Descriptionofexpectedadverseeventsshouldbegiven. Proceduresusedtoevaluateanadverseeventshouldbe described.

11.Ethicalconsiderations:Givethesummaryof: a.Risk/benefitassessment: b.Ethicscommiteereviewandcommunications c.Informedconsentprocess

d.Statementofsubjectconfidentialityincludingownershipofdataand codingprocedures.

12.Studymonitoringandsupervision:
A description ofstudy monitoring policies and procedures should be providedalongwiththeproposedfrequencyofsitemonitoringvisits,and whoisexpectedtoperform monitoring.
CaseRecordForm (CRF)completionrequirements,includingwhogets whichcopiesoftheformsandanyspecificrequiredinfilingouttheforms CRF corection requirements,including who is authorized to make c o r re c tio n s o n th e C R F a n d h o w q u e rie s a b o u t s tu d y d a ta a re h a n d le d a n d howerors,ifany,aretobecorectedshouldbestated. Investigatorstudyfiles,includingwhatneedstobestoredfolowingstudy completionshouldbedescribed.

13.InvestigationalProductManagement:
(a)Give investigationalproductdescription and packaging (stating al

ingredientsandtheformulationoftheinvestigationaldrugandanyplacebos

usedinthestudy)

. (b)  Theprecisedosingrequiredduringthestudy

. (c)  Methodofpackaging,labeling,andblindingofstudysubstances

. (d)  Methodofassigningtreatmentstosubjectsandthesubjectidentification
codenumberingsystem

. (e)  Storageconditionsforstudysubstances

. (f)  Investigationalproductaccountability:Describeinstructionsforthereceipt,
storage,dispensation,andreturnoftheinvestigationalproductstoensurea completeaccountingofalinvestigationalproductsreceived,dispensed,and returned/destroyed.

. (g)  Describepolicyandprocedureforhandlingunusedinvestigationalproducts.

14.DataAnalysis:

Providedetailsofthestatisticalapproachtobefolowedincludingsamplesize, how thesamplesizewasdetermined,includingassumptionsmadeinmaking

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thisdetermination,eficacyendpoints(primaryaswelassecondary)andsafety endpoints. Statisticalanalysis:Givecompletedetailsofhowtheresultswilbeanalysedand reportedalongwiththedescriptionofstatisticalteststobeusedtoanalysethe primary and secondary endpoints defined above.Describe the levelof significance,statisticalteststobeused,andthemethodsusedformissingdata; methodofevaluationofthedatafortreatmentfailures,non-compliance,and Subjectwithdrawals;rationaleandconditionsforanyinterim analysisifplanned. DescribestatisticalconsiderationsforPharmacokinetic(PK)analysis,ifapplicable.

15.UndertakingbytheInvestigator(seeTable4)
16.Appendices: Provide a study synopsis, copies of the inform ed consent

documents(patientinformationsheet,informedconsentform etc.);CRFand other data colection forms;a summary of relevant pre-clinicalsafety informationandanyotherdocumentsreferencedintheclinicalprotocol.

TABLE3INFORMED CONSENT

1.Checklistofinformedconsentdocumentsforclinicaltrialsubject– 1.1Essentialelements:

(i) Statementthatthestudyinvolvesresearchandexplanationofthe purposeoftheresearch.

(i) Expecteddurationoftheparticipationofsubject.

(i)Description of the procedures to be folowed, including al invasiveprocedures.

(iv)DescriptionofanyreasonablyforeseeablerisksordiscomfortstotheSubject. (v) DescriptionofanybenefitstotheSubjectorothersreasonablyexpected from research.IfnobenefitisexpectedSubjectshouldbemadeaware

ofthis.
(vi) Disclosure of specific appropriate alternative procedures or therapies

availabletotheSubject.
(vi)Statementdescribing the extentto which confidentiality ofrecords

identifyingtheSubjectwilbemaintainedandwhowilhaveaccessto

Subject’smedicalrecords. (vi)Trialtreatmentscheduleandtheprobabilityforrandom assignmentto

eachtreatment(forrandomizedtrials).
(ix)Statementdescribing the financialcompensation and the medical

managementasunder:

a. In case ofan injury occur ring to the subjectduring the clinicaltrial,
freemedicalmanagementshalbegivenaslongasrequiredortil suchtimeitisestablishedthattheinjuryisnotrelatedtotheclinical trial,whicheverisearlier.

b. In the event of a trial related injury or death, the sponsor or his representativeortheinvestigatororcentre,asthecasemaybe,in

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accordancewiththerule39andrule40,asthecasemaybe,shal

providefinancialcompensationfortheinjuryordeath.
(x) Anexplanationaboutwhom tocontactfortrialrelatedqueries,rightsof

Subjectsandintheeventofanyinjury. (xi)Theanticipatedproratedpayment,ifany,tothesubjectforparticipating

inthetrial.
(xi)Responsibilitiesofsubjectonparticipationinthetrial. (xi)Statementthatparticipationisvoluntary,thatthesubjectcanwithdraw

from thestudyatanytimeandthatrefusaltoparticipatewilnotinvolve

anypenaltyorlossofbenefitstowhichthesubjectisotherwiseentitled. (xiv)Statementthatthereisapossibilityoffailureofinvestigationalproductto

provideintendedtherapeuticefect.
(xv)Statementthatin the case ofplacebo controled trial,the placebo

administeredtothesubjectsshalnothaveanytherapeuticefect. (xvi)Anyotherpertinentinformation.

1.2Additionalelements,whichmayberequired: (a)Statementofforeseeablecircumstancesunderwhichtheparticipationofthe

subjectmaybeterminatedbytheInvestigatorwithouthis/herconsent. (b)Additionalcoststothesubjectthatmayresultfrom participationinthestudy. (c ) T h e c o n s e q u e n c e s o f a S u b je c t’s d e c is io n to w ith d ra w fro m th e re s e a rc h a n d

proceduresfororderlyterminationofparticipationbySubject.

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(d)StatementthattheSubjectorSubject’srepresentativewilbenotifiedina timelymannerifsignificantnew findingsdevelopduringthecourseofthe researchwhichmayafecttheSubject’swilingnesstocontinueparticipation wilbeprovided.

(e).Astatementthattheparticulartreatmentorproceduremayinvolverisksto theSubject(ortotheembryoorfoetus,iftheSubjectisormaybecome pregnant),whicharecurentlyunforeseeable.

(f)ApproximatenumberofSubjectsenroledinthestudy. 2.Formatofinformedconsentform forSubjectsparticipatingina

clinicaltrial–InformedConsentform toparticipateinaclinicaltrial StudyTitle:
Study
Number:

Subject’sInitials: DateofBirth/Age: AddressoftheSubject
Qualification
Occupation (Pleaseclickasappropriate) Others

AnnualIncomeofthe subject

Subject’sName:

    

Student/Self-Employed/Service/Housewife/



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Nameandaddressofthenominee(s)andhisrelationtothesubject(for the purpose of compensationincaseoftrialrelateddeath).

Place Initial

box(Subject) (i) Iconfirm thatIhavereadandunderstoodtheinformation []

sheetdated fortheabovestudyandhavehadthe

opportunitytoaskquestions.

(i) Iunderstand thatmy participation in the study is [ ] voluntaryand

thatIam freetowithdraw atanytime,withoutgivingany reason,withoutmymedicalcareorlegalrightsbeingafected. [ ] (i) IunderstandthattheSponsoroftheclinicaltrial,others workingontheSponsor’sbehalf,theEthicsCommiteeand theregulatoryauthoritieswilnotneedmypermissiontolook atmyhealthrecordsbothinrespectofthecurentstudyand anyfurtherresearchthatmaybeconductedinrelationtoit, evenifIwithdraw from thetrial.Iagreetothisaccess. However,Iunderstandthatmyidentitywilnotberevealedin anyinformationreleasedtothirdpartiesorpublished.
(iv) Iagreenotorestrictheuseofanydataoresultsthatarise
from thisstudyprovidedsuchauseisonlyforscientific purpose(s)

(v) Iagreetotakepartintheabovestudy. [ ]

Signature(orThumbimpression)ofthe Subject/LegalyAcceptableRepresentative: Date: / / Signatory’sName:

[]

    

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SignatureoftheInvestigator: Date: / / StudyInvestigator’sName:

SignatureoftheWitness Date: / / NameoftheWitness:

c o p y o f th e P a tie n t In fo rm a tio n S h e e t a n d d u ly fil le d In fo rm e d C o n s e n t F o rm s h a l l b e handedovertothesubjectorhis/heratendant

TABLE4 UNDERTAKINGBYTHEINVESTIGATOR

1.Fulname,addressandtitleofthePrincipalInvestigator(orInvestigator(s)when thereisnoPrincipalInvestigator).

2.Nameandaddressofthemedicalcolege,hospitalorotherfacilitywherethe clinicaltrialwilbeconducted:Education,training&experiencethatqualifythe Investigatorforthe clinicaltrial(Atach details including MedicalCouncil registrationnumber,and/oranyotherstatement(s)ofqualification(s)

3.Nameandaddressofalclinicalaboratoryfacilitiestobeusedinthestudy. 4.NameandaddressoftheEthicsCommiteethatisresponsibleforapprovaland

continuingreviewofthestudy. 5.Namesoftheothermembersoftheresearchteam (Co-orsub-Investigators)who

wilbeassistingtheInvestigatorintheconductoftheinvestigation(s). 6.ProtocolTitleandStudynumber(ifany)oftheclinicaltrialtobeconductedbythe

Investigator. 7.Commitments:

(i)Ihavereviewedtheclinicalprotocolandagreethatitcontainsalthenecessary informationtoconductthestudy.Iwilnotbeginthestudyuntilalnecessary ethicscommiteeandregulatoryapprovalshavebeenobtained.

(i)Iagreetoconductthestudyinaccordancewiththecurentprotocol.Iwilnot implementanydeviationfrom orchangesoftheprotocolwithoutagreement bytheSponsorandpriorreviewanddocumentedapproval/favourableopinion from theethicscommiteeoftheamendment,exceptwherenecessaryto eliminate an immediate hazard to the trialsubjectorwhen the changes involvedareonlylogisticaloradministrativeinnature.

(i)Iagreetopersonalyconductand/orsupervisetheclinicaltrialatmysite. (iv)Iagreetoinform altrialsubject,thatthedrugsarebeingusedfor

investigationalpurposesandIwilensurethattherequirementsrelatingto obtaining informed consentand ethics commitee review and approval specified in the New Drugs and Clinicaltrials Rules,2018 and Good Clinical Practicesguidelinesaremet.

(v)Iagree to reportto the Sponsoral ladverse experiences thatoccurin the courseoftheinvestigation(s)inaccordancewiththeregulatoryrequirements andGoodClinicalPracticesguidelines.

    

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(vi)I have read and understood the inform ation in the Investigator’s brochure, includingthepotentialrisksandsideefectsofthedrug.

(vi)Iagreetoensurethatalassociates,coleaguesandemployeesassistingin theconductofthestudyaresuitablyqualifiedandexperiencedandtheyhave beeninformedabouttheirobligationsinmeetingtheircommitmentsinthetrial.

(vi) Iagreetomaintainadequateandaccuraterecordsandtomakethose records available for audit / inspection by the Sponsor,ethics com m it tee, CentralLicencingAuthorityortheirauthorizedrepresentatives,inaccordance withregulatoryprovisionsandtheGoodClinicalPracticesguidelines.Iwilfuly cooperatewithanystudyrelatedauditconductedbyregulatoryoficialsor authorizedrepresentativesoftheSponsor.

(ix)Iagreetopromptlyreporttotheethicscommiteealchangesintheclinical trialactivitiesandalunanticipatedproblemsinvolvingriskstohumansubjects orothers.

(x)Iagreetoinform alseriousadverseeventstotheCentralLicencingAuthority, sponsoraswelastheethicscommiteewithintwenty-fourhoursoftheir occurence.Incase,offailuretodoso,Ishalfurnishthereasonforthedelay tothesatisfactionoftheCentralLicencingAuthorityalongwiththereportof theseriousadverseevent.

(xi)The report of the serious adverse event, after due analysis, shal l also be forwardedbymetotheCentralLicencingAuthority,theChairpersonofthe ethicscommiteeandtheHeadoftheinstitutionwherethetrialhasbeen conductedwithinfourteendaysinaccordancewiththeregulatoryrequirements.

(xi)Iwilmaintainconfidentialityoftheidentificationofalparticipatingsubjects andassuresecurityandconfidentialityofstudydata.

(xi i i) I agree to com ply w ith al l other requirem ents, guidelines and statutory obligationsasapplicabletoclinicalInvestigatorsparticipatinginclinicaltrials.

8.SignatureofInvestigatorwithdate
TABLE5

DATAELEMENTSFORREPORTINGSERIOUSADVERSEEVENTSOCCURRING INACLINICALTRIALORBIOAVAILABILITYORBIOEQUIVALENCESTUDY

1.PatientDetails:- Initials&otherrelevantidentifier(hospital/OPDrecordnumber etc)*Gender
Ageand/ordateof
birthWeight
Height

2.SuspectedDrug(s)-
Genericnameofthedrug* Indication(s)forwhichsuspectdrugwasprescribedor testedDosageform andstrength Dailydoseandregimen(specifyunits-e.g.,mg,ml,mg/kg)

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Routeofadministration Startingdateandtimeofday Stoppingdateandtime,ordurationoftreatment

3.OtherTreatment(s)-

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Provide the same information for concomitant drugs (including non- prescription/OTCdrugs)andnon-drugtherapies,asforthesuspecteddrug(s). 4.DetailsofSeriousAdverseEvent–

Fuldescriptionoftheeventincludingbodysiteandseverity,aswelasthe criterion(orcriteria)forconsideringthereportasserious.Inadditiontoadescription ofthe reported signs and symptoms,wheneverpossible,describe a specific diagnosisfortheevent*

Startdate(andtime)ofonsetof eventStopdate(andtime)or durationofeventDechalengeand
rechalengeinformation Seting(e.g.,hospital,out-patientclinic,home,nursinghome)

5.Outcome Informationonrecoveryandanysequelae;resultsofspecifictestsand/or

treatmentthatmayhavebeenconducted.
For a fatal outcom e, cause of death and a com m ent on its possible

relationshiptothesuspectedevent;Anypost-mortem findings. Otherinformation:anythingrelevanttofacilitateassessmentofthecase,suchas medicalhistoryincludingalergy,drugoralcoholabuse;familyhistory;findingsfrom specialinvestigationsetc.

6.DetailsabouttheInvestigator* Name
Addres
s

Telephonenumber
Profession(specialty) DateofreportingtheeventtoCentralLicencingAuthority: Dateofreportingtheeventtoethicscommiteeoverseeing thesite:SignatureoftheInvestigator/Sponsor Note:Informationmarked*mustbeprovided.

TABLE6

STRUCTURE,CONTENTANDFORMATFORCLINICALTRIALREPORT

1. TitlePage:Thispageshouldcontaininformationaboutthetitleofthestudy, theprotocolcode,nameoftheinvestigationalproducttested,development Phase,indicationstudied,abriefdescriptionofthetrialdesign,thestartand end date ofpatientaccrualand the names ofthe Sponsorand the participatingInstitutes(Investigators).

2. StudySynopsis(1to2pages):Abriefoverviewofthestudyfrom theprotocol developmenttothetrialclosureshouldbegivenhere.Thissectionwilonly summarizetheimportantconclusionsderivedfrom thestudy.

3. Statementofcompliancewiththe‘GoodClinicalPracticesGuidelines.

4. Listofabbreviationsanddefinitions

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5. Tableofcontents
6. Ethics Commitee:This section should documentthatthe study was

conducted in accordancewiththeethicalprinciplesofDeclarationofHelsinki.Adetailed

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descriptionoftheEthicsCommiteeconstitutionanddate(s)ofapprovalsof trial docum ents for each of the participating sites should be provided. A declaration should state thatEC notifications as perGood ClinicalPractice Guidelines and EthicalGuidelines forBiomedicalResearch on Human Subjects,issuedbyIndianCouncilofMedicalResearchhavebeenfolowed.

7. Study Team : Briefly describe the adm inistrative structure of the study (Investigators,sitestaf,Sponsor/designates,Centralaboratoryetc.).

8. Introduction:Abriefdescriptionoftheproductdevelopmentrationaleshould begivenhere.

9. StudyObjective:Astatementdescribingtheoveralpurposeofthestudyand the primary and secondary objectives to be achieved should be mentionedhere.

10.InvestigationalPlan:Thissectionshoulddescribetheoveraltrialdesign,the Subjectselectioncriteria,thetreatmentprocedures,blinding/randomization techniquesifany,alowed/disalowedconcomitanttreatment,theeficacy andsafetycriteriaassessed,thedataqualityassuranceproceduresandthe statisticalmethodsplannedfortheanalysisofthedataobtained.

1.TrialSubjects:AclearaccountingofaltrialSubjectswhoenteredthestudy w il l be given here. M ention should also be m ade of al l cases that w ere dropouts or protocol deviations. Enumerate the patients screened, randomised,and prematurely discontinued.State reasons forpremature discontinuationoftherapyineachapplicablecase.

12.Eficacyevaluation:Theresultsofevaluationofaltheeficacyvariableswil be described in this section with appropriate tabular and graphical representation.Abriefdescriptionofthedemographiccharacteristicsofthe trialpatientsshouldalsobeprovidedalongwithalistingofpatientsand observationsexcludedfrom ef ficacyanalysis.

13.SafetyEvaluation:Thissectionshouldincludethecompletelist 13.1alseriousadverseevents,whetherexpectedorunexpectedand 13.2unexpectedadverseeventswhetherseriousornot(compiledfrom data receivedasperTable5ofthisSchedule).Thecomparisonofadverseevents acrossstudygroupsmaybepresentedinatabularorgraphicalform.This sectionshouldalsogiveabriefnarativeofalimportanteventsconsidered relatedtotheinvestigationalproduct.

14DiscussionandoveralConclusion:Discussionoftheimportantconclusions derivedfrom thetrialandscopeforfurtherdevelopment.

15.ListofReferences: 16.Appendices:ListofAppendicestotheClinicalStudyReport

(a)Protocolandamendments
(b)SpecimenofCaseRecordForm (c)Investigators’name(s)withcontactaddresses,phone,e-mailetc. (d)Patientdatalistings (e)Listoftrialparticipantstreatedwithinvestigationalproduct (f)Discontinuedparticipants

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(g)Protocoldeviations
(h) CRFsofcasesinvolvingdeathandlifethreateningadverseeventcases

(i)Publicationsfrom thetrial (j)Importantpublicationsreferencedinthestudy (k)Auditcertificate,ifavailable
(l) Investigator’s certificate that he/she has read the report and that the reportaccuratelydescribestheconductandtheresultsofthestudy.

TABLE7INVESTIGATOR’S BROCHURE

TheInvestigator’sBrochureshouldcontaintheversionnumber,releasedatealongwith thefolowingsections,eachwithliteraturereferenceswhereappropriate:

1 TableofContents 2 Summary

A briefsummary(preferablynotexceeding two pages)should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological,toxicological,pharmacokinetic,metabolic,and clinical informationavailablethatisrelevanttothestageofclinicaldevelopmentof theinvestigationalproduct.

3 Introduction Abriefintroductorystatementshouldbeprovidedthatcontainsthechemical name(andgenericandtradenamewhenapproved)oftheinvestigational product,alactiveingredients,theinvestigationalproductpharmacological class and its expected position within this class (e.g.advantages),the rationaleforperformingresearchwiththeinvestigationalproduct,andthe anticipated prophylactic,therapeutic,ordiagnostic indication.Finaly,the introductorystatementshouldprovidethegeneralapproachtobefolowedin evaluatingtheinvestigationalproduct.

4 Physical,Chemical,andPharmaceuticalPropertiesandFormulation
A descriptionshouldbeprovidedoftheinvestigationalproductsubstance (including the chemicaland/orstructuralformula),and a briefsummary should be given ofthe relevantphysical,chemical,and pharmaceutical properties.Topermitappropriatesafetymeasurestobetakeninthecourse ofthetrial,adescriptionoftheformulationtobeused,includingexcipients, should be provided and justified if clinical ly relevant. Instructions for the storageandhandlingofthedosageform shouldalsobegiven.Anystructural similaritiestootherknowncompoundsshouldbementioned.

5 NonclinicalStudies 5.1Introduction:

The results of al relevant nonclinical pharmacology, toxicology, pharmacokinetic,andinvestigationalproductmetabolism studiesshouldbe providedinsummaryform.Thissummaryshouldaddressthemethodology used,theresults,andadiscussionoftherelevanceofthefindingstothe

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investigated therapeutic and the possible unfavourable and unintended efectsinhuman.Theinformationprovidedmayincludethefolowing,as appropriate,ifknown/available:

•Speciestested •Numberandsexofanimalsineachgroup •Unitdose (e.g.,m il ligram /kilogram (m g/kg) ) •Doseinterval
•Routeofadministration •Durationofdosing •Informationonsystemicdistribution •Durationofpost-exposurefolow-up •Results,includingthefolowingaspects:

−Natureandfrequencyofpharmacologicalortoxicefects −Severityorintensityofpharmacologicalortoxicefects −Timetoonsetofefects
−Reversibilityofefects

−Durationofefects

−Doseresponse Tabularformat/listingsshouldbeusedwheneverpossibletoenhancethe clarityofthepresentation.Thefolowingsectionsshoulddiscussthemost importantfindingsfrom thestudies,includingthedoseresponseofobserved efects,therelevancetohumans,andanyaspectstobestudiedinhumans.If applicable, the ef fective and nontoxic dose findings in the sam e anim al speciesshouldbecompared(i.e.,thetherapeuticindexshouldbediscussed). Therelevanceofthisinformationtotheproposedhumandosingshouldbe addressed.Wheneverpossible,comparisons should be made in terms of blood/tissuelevelsratherthanonamg/kgbasis. (a)NonclinicalPharmacology Asummaryofthepharmacologicalaspectsoftheinvestigationalproductand, whereappropriate,itssignificantmetabolitesstudiedinanimals,shouldbe included.Suchasummaryshouldincorporatestudiesthatassesspotential therapeuticactivity(e.g.eficacymodels,receptorbinding,andspecificity)as welas those thatassess safety (e.g.,specialstudies to assess pharmacologicalactionsotherthantheintendedtherapeuticefect(s). (b)PharmacokineticsandProductMetabolism inAnimals
A summary ofthe pharmacokinetics and biologicaltransformation and dispositionoftheinvestigationalproductinalspeciesstudiedshouldbe given.Thediscussionofthefindingsshouldaddresstheabsorptionandthe localand systemic bioavailability ofthe investigationalproductand its metabolites,andtheirrelationshiptothepharmacologicalandtoxicological findingsinanimalspecies.
(c)Toxicology Asummaryofthetoxicologicalefectsfoundinrelevantstudiesconductedin diferentanimalspeciesshouldbedescribedunderthefolowingheadings

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whereappropriate:
−Singledose
−Repeateddose
−Carcinogenicity −Specialstudies(e.g.iritancyandsensitization) −Reproductivetoxicity −Genotoxicity(mutagenicity)

6 EfectsinHumans (a)Athoroughdiscussionoftheknownefectsoftheinvestigationalproduct(s)

inhumansshouldbeprovided,includinginformationonpharmacokinetics, metabolism,pharmacodynamics,doseresponse,safety,eficacy,andother pharmacologicalactivities.Wherepossible,asummaryofeachcompleted clinicaltrialshould be provided.Information should also be provided regardingresultsofanyuseoftheinvestigationalproduct(s)otherthanfrom inclinicaltrials,suchasfrom experienceduringmarketing.

(b)PharmacokineticsandProductMetabolism inHumans
− Asummaryofinformationonthepharmacokineticsofthe

investigationalproduct(s)shouldbepresented,includingthefolowing,

ifavailable:
− Pharmacokinetics(includingmetabolism,asappropriate,and

absorption,plasmaproteinbinding,distribution,andelimination). −Bioavailabilityoftheinvestigationalproduct(absolute,wherepossible,

and/orrelative)usingareferencedosageform. −Populationsubgroups(e.g.,gender,age,andimpairedorganfunction). −Interactions(e.g.,product-productinteractionsandefectsofood). − Otherpharmacokineticdata(e.g.,resultsofpopulationstudies

performedwithinclinicaltrial(s). (c)SafetyandEficacy:Asummaryofinformationshouldbeprovidedabout

the investigationalproduct’s/products'(including metabolites,where appropriate)safety,pharmacodynamics,eficacy,anddoseresponsethat wereobtainedfrom precedingtrialsinhumans(healthyvolunteersand/or p a tie n ts ). T h e im p lic a tio n s o f th is in fo rm a tio n s h o u ld b e d is c u s s e d . In caseswhereanumberofclinicaltrialshavebeencompleted,theuseof summariesofsafetyandeficacyacrossmultipletrialsbyindicationsin subgroups may provide a clear presentation of the data.Tabular summariesofadversedrugreactionsforaltheclinicaltrials(including those for althe studied indications) would be useful.Important diferences in adverse drug reaction paterns/incidences across indicationsorsubgroupsshouldbediscussed.TheIB shouldprovidea description ofthe possible risks and adverse drug reactions to be anticipated on the basis of prior experiences w ith the product under investigation and with related products.A description should also be providedoftheprecautionsorspecialmonitoringtobedoneaspartofthe investigationaluseoftheproduct(s).

(d)Marketing Experience: The Investigator’s Brochure should identify Page132of132

countries where the investigationalproducthas been marketed or approved.Anysignificantinformationarisingfrom themarketeduse should be summarized (e.g., formulations, dosages, routes of administration,andadverseproductreactions).TheIBshouldalsoidentify althe countries where the investigationalproductdid notreceive approval/registration for marketing or was withdrawn frommarketing/registration.

7 SummaryofDataandGuidancefortheInvestigator

Thissectionshouldprovideanoveraldiscussionofthenonclinicaland clinicaldata,andshouldsummarizetheinformationfrom varioussources ondiferentaspectsoftheinvestigationalproduct(s),whereverpossible. Inthisway,theinvestigatorcanbeprovidedwiththemostinformative interpretation ofthe available data and with an assessmentofthe implicationsoftheinformationforfutureclinicaltrials.Whereappropriate, the published reports on related products should be discussed.This couldhelptheinvestigatortoanticipateadversedrugreactionsorother problemsinclinicaltrials.Theoveralaim ofthissectionistoprovidethe investigatorwithaclearunderstandingofthepossiblerisksandadverse reactions,andofthespecifictests,observations,andprecautionsthat maybeneededforaclinicaltrial.Thisunderstandingshouldbebasedon the available physical, chemical, pharmaceutical, pharmacological, toxicological,and clinicalinform ation on the investigationalproduct(s). Guidance should also be provided to the clinicalinvestigatoron the recognition and treatmentofpossible overdose and adverse drug reactions thatis based on previous human experience and on the pharmacologyoftheinvestigationalproduct.

TABLE8 PRESCRIBINGINFORMATION

1.GenericName 2.Qualitativeandquantitativecomposition 3.Dosageform andstrength 4.Clinicalparticulars

4.1Therapeuticindication
4.2Posologyandmethodofadministration
4.3Contraindications
4.4Specialwarningsandprecautionsforuse
4.5Drugsinteractions 4.6Useinspecialpopulations(suchaspregnantwomen,lactatingwomen,

paediatricpatients,geriatricpatientsetc.) 4.7Efectsonabilitytodriveandusemachines 4.8Undesirableefects
4.9Overdose

5.Pharmacologicalproperties 5.1Mechanism of Action

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5.2Pharmacodynamicproper ties 5.3Pharmacokineticproperties

6.Nonclinicalproperties 6.1AnimalToxicologyand/orPharmacology

7.Description 8.Pharmaceuticalparticulars

8.1Incompatibilities
8.2Shelf-life 8.3Packaginginformation 8.4Storageandhandinginstructions

9.PatientCounselingInformation 10.Detailsofmanufacturer 11.Detailsofpermissionand/orlicencenumberwithdate 12.Dateofrevision

FOURTHSCHEDULE (seerules33,45,48,49and52)

REQUIREMENTSANDGUIDELINESFORCONDUCTOFBIOAVAILABILITYAND BIOEQUIVALENCESTUDYOFNEW DRUGSORINVESTIGATIONAL

NEW DRUGS

1.GeneralPrinciples:(1)BioavailabilityorBioequivalencefocusonthereleaseofan active drug from its dosage form and subsequent absorption into the systemiccirculation.

BioavailabilityorBioequivalencestudyofapharmaceuticalformulationisoneofthe componentstoensureeficacyandsafetyofpharmaceuticalproduct. (2)Bioavailability can be general ly docum ented by a system ic exposure profile

obtained by m easuring drug and/or m etabolite concentration in the system ic

circulationovertime. (3)Bioequivalencestudyisconductedtoensuretherapeuticequivalencebetween

twopharmaceuticalyequivalenttestproductandareferenceproduct. (4)Bioavailability orBioequivalence study is conducted to ensure therapeutic

equivalencebetweenanapprovednew drugformulationandreferenceproduct

forsubsequentapplicant. (5)BioavailabilityorBioequivalencestudyisalsoconductedtoensuretherapeutic

equivalenceatanyphaseofClinicaltrialofanewchemicalentityforestablishing bioequivalencebetweentwoproductsofthechemicalentity,whichisimportant forcertain pharmaceuticalformulation ormanufacturing changes occuring duringthedrugdevelopmentstages.

(6)Fordrugs approved elsewhere in the world and absorbed systemicaly, bioequivalencewiththereferenceformulationshouldbecariedoutwherever

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applicable.Thesestudiesshouldbeconductedunderthelabeledconditionsof administration.Dataontheextentofsystemicabsorptionmayberequiredfor formulationsotherthanthosedesignedforsystemicabsorption.

(7)Evaluation ofthe efectoffood on absorption folowing oraladministration s h o u ld b e c a r rie d o u t. D a ta fro m d is s o lu tio n s tu d ie s s h o u ld a ls o b e s u b m it te d fo r alsolidoraldosageforms.

(8)Dissolutionandbioavailabilitydatasubmitedwiththenewdrugapplicationmust provideinformationthatassuresbioequivalenceorestablishesbioavailabilityand dosagecorelationsbetweentheformulationssoughttobemarketedandthose usedforclinicaltrialsduringclinicaldevelopmentoftheproduct.

(9)Albioavailabilityandbioequivalencestudiesshouldbeconductedaccordingto theGuidelinesforBioavailabilityandBioequivalencestudiesissuedbyCentral DrugsStandardControlOrganization,MinistryofHealthandFamilyWelfare.

(10)Bioavailabilityandbioequivalencestudiesofanew drugorinvestigationalnew drug shalbe conducted in a bioavailabilityand bioequivalence studycentre registeredunderRule39afterobtainingpermissionfrom theCentralLicensing Authority.

2.Bioavailabilityandbioequivalencestudycentre:

2.1TheBioavailabilityandbioequivalencestudycentreshalhavefolowingfacilities forconductingbioavailabilityandbioequivalencestudyofanynew drugor investigationalnewdrug:

2.1.1LegalIdentity:Theorganization,conductingthebioavailabilityorbioequivalence studies,

ortheparentorganizationtowhichitbelongs,mustbealegalyconstitutedbodywithapprop riatestatutoryregistrations.

2.1.2Impartiality,confidentiality,independenceandintegrity: Theorganizationshal:

a)havemanagerialstafwiththeauthorityandtheresourcesneededtodischarge theirduties.

b)havearangementstoensurethatitspersonnelarefreefrom anycommercial, financialand otherpressures which mightadversely afectthe quality of theirwork.

c)beorganizedinsuchawaythatconfidenceinitsindependenceofjudgmentand integrityismaintainedataltimes.

d)have documented policies and procedures,where relevant,to ensure the protectionofitssponsors’confidentialinformationandproprietaryrights.

e)notengageinanyactivitythatmayjeopardizethetrustinitsindependenceof judgmentandintegrity

f) havedocumentedpoliciesandproceduresforprotectionofrights,safetyand Page135of135

wel-beingofstudysubjectinconsistentwiththeProvisionsoftheDrugsand CosmeticsActandtheseRulesandGoodClinicalPracticesGuidelines

g)have documented policies and procedures forscientific integrity including proceduresdealingwithandreportingpossiblescientificmisconduct.

2.1.3)Organizationandmanagement: Thestudycentremustincludethefolowing:

) AnInvestigatorwhohastheoveralresponsibilitytoprovideprotectionfor safetyofthestudysubject.TheInvestigator(s)shouldpossessappropriate medical qualifications and relevant experience for conducting pharmacokineticstudies.

b)Thesiteshouldhavefacilitiesandidentifiedadequatelyqualifiedandtrained personneltoperform thefolowingfunctions:

i. ClinicalPharmacologicalUnit(CPU)management i. Analyticalaboratorymanagement

i. Datahandlingandinterpretation
iv. Documentationandreportpreparation

v. Qualityassuranceofaloperationsinthecentre 2.1.4)DocumentedStandardOperatingProcedures

(1)Thecentershalestablishandmaintainaqualitysystem appropriatetothetype, rangeandvolumeofitsactivities.Aloperationsatthesitemustbeconductedasper theauthorizedanddocumentedstandardoperatingprocedures.

(2)Thesedocumentedproceduresshouldbeavailabletotherespectivepersonnelfor readyreference.Theprocedurescoveredmustincludethosethatensurecompliance w ith a l l a s p e c ts o f p ro v is io n o f th e A c t a n d th e s e R u le s , G o o d C lin ic a l P ra c tic e s GuidelinesandGoodlaboratorypracticeguidelines.

(3 ) A p a rtia l lis t o f p ro c e d u re s fo r w h ic h d o c u m e n te d s ta n d a rd o p e ra tin g p ro c e d u re s shouldbeavailableincludes:

. a)  maintenance of working standards (pure substances) and respectivedocumentation;

. b)  withdrawal,storageandhandlingofbiologicalsamples;

. c)  maintenance,calibrationandvalidationofinstruments;

. d)  managingmedicalaswelasnon-medicalemergencysituations;

. e)  handlingofbiologicalfluids;

. f)  managinglaboratoryhazards;

. g)  disposalproceduresforclinicalsamplesandlaboratorywastes;

. h)  documentationofclinicalpharmacologyunitobservations,volunteerdataand
analyticaldata;

. i)  obtaininginformedconsentfromvolunteers;

. j)  volunteerscreeningandrecruitmentandmanagementofineligiblevolunteers;

. k)  volunteerrecycling(usingthesamevolunteerformorethanonestudy;

. l)  randomizationcodemanagement;

. m)  study subject management at the site (including check-in and check-

outprocedures);

Page136of136

n) recordingandreportingprotocoldeviations;
o) recording,reportingandmanagingscientificmisconduct; p) monitoringandqualityassurance.

(4)Whereverpossible,disposable(sterile,whereverapplicable)medicaldevicesmustbeused formakingsubjectinterventions.

(5)Ifservicesofalaboratoryorafacilityotherthanthoseavailableatthesite(whether withinIndiaoroutsidethecountry)aretobeavailed-its/theirname(s),address(s)and specificservicestobeusedshouldbedocumented.

2.1.5) ClinicalPharmacologicalUnit

(1)Itmusthaveadequatespaceandfacilitiestohouseatleast16volunteers.Adequate areamustbeprovidedfordiningandrecreationofvolunteers,separatefrom their sleepingarea.

(2)Additionalspaceandfacilitiesshouldalsobeprovidedforthefolowing:

a) Oficeandadministrativefunctions b) Samplecolectionandstorage
c) Controlsamplestorage
d) Wetchemicalaboratory

e) InstrumentalLaboratory
f) Library
g) Documentationarchivalroom
h) Facilityforwashing,cleaningandToilets i) Microbiologicalaboratory(Optional)
j) RadioImmuno-Assayroom(optional)

3. MAINTENANCEOFRECORDS

A l l re c o rd s o f in v iv o o r in v itro te s ts c o n d u c te d o n a n y b a tc h o f a n e w d ru g p ro d u c t to assurethattheproductmeetsabioequivalencerequirementshalbemaintainedbythe Sponsorforatleastfiveyearsafterthecompletionofanystudyorforatleasttwoyears aftertheexpirationdateofthebatchofthenewdrugproductwhicheverislater.

4. RETENTIONOFSAMPLES

(1)Al l sam ples of test and reference drug products used in bioavailability / bioequivalence study should be retained by the organization carying outthe bioavailability/bioequivalencestudyforaperiodoffiveyearsaftertheconductof thestudyoroneyearaftertheexpiryofthedrug,whicheverislater.

(2)Thestudysponsorand/ordrugmanufacturershouldprovidetothetestingfacility batchesofthetestandreferencedrugproductsinsuchamannerthatthereserve samplescanbeselectedrandomly.

(3)Thisistoensurethatthesamplesareinfactrepresentativeofthebatchesprovided bythestudysponsorand/ordrugmanufacturerandthattheyareretainedintheir original containers. Eachreservesampleshouldconsistofaquantitysuficient tocaryoutwicealtheinvitroandin- vivo tests required during bioavailability / bioequivalencestudy.

Page137of137

(4)The reserve sample should be stored underconditions consistentwith product labelingandinanareasegregatedfrom theareawheretestingisconductedand withaccesslimitedtoauthorizedpersonnel.

TABLE1

DOCUMENTREQUIREDFORREGISTRATIONOFBIOAVAILABILITYAND BIOEQUIVALENCECENTRE

1)Nameandaddressoftheorganizationtoberegisteredalongwithitstelephone no.,faxno.andemailaddress.

2)Documentregardinglegalidentityofthecentre 3)Nameandaddressoftheproprietors/partners/directors.

4)Anorganogram ofthecentreincludingbriefCVofKeypersonnel(Referpara2.1.3 ofthisSchedule)

6)Documents to ensure Impartiality,confidentiality,independence and integrity of thecentre.

Referpara2.1.2ofthisSchedule.
7)Listofequipmentinthefirm.
8)Listofstafinfirm. 9)ListofSOP’sforvariousactivities(refer2.1.4ofthisSchedule). 10)Layoutofacility. 11)DetailsofEthicsCommiteeincludingitsregistrationnumber. 12)Facilitiesformaintenanceofrecords. 13)DetailsofRetentionofsamples. 14)Almajortieupsforancilaryserviceslikeambulance,hospitaletc.

TABLE2 DATAANDINFORMATIONREQUIREDFORGRANTOFPERMISSIONTO

CONDUCTBIOAVAILABILITYANDBIOEQUIVALENCESTUDYOFANEW DRUG ORINVESTIGATIONALNEWDRUG

1.Introduction Abriefdescriptionofthedrugandthetherapeuticclasstowhichitbelongs.

2.Chemicaland pharmaceuticalinformation,Animalpharmacological andtoxicologicaldata,ClinicalTrialData-AsperSecondSchedule

3.PublishedreportsofPharmacokineticandPharmacodynamicsstudiescariedout inhealthysubjects/patientsdemonstratingsafetyandtolerabilityofthemolecule.

Page138of138

4.Regulatorystatusinothercountries Countrieswherethedrugis

(a)Marketed
(b)Approved
(c)ApprovedasIND (d)Withdrawn,ifany,withreasons

Restrictionsonuse,ifany,incountrieswheremarketed /approvedFreesalecertificateorcertificateofanalysis,as
appropriate.
5.Prescribinginformationofthenew drugincasethedrugisapprovedfor

marketinginthecountryorothercountry. 6.UndertakingbytheInvestigatorinoriginaldulysignedonacompanyleterhead

asperTable4oftheThirdSchedule.

7.CopyofregistrationcertificateissuedbyCentralLicencingAuthority. 8.Sponsor’s Authorization leterduly signed by the Authorized Signatory on

companyleterhead.

9.Thestudyprotocols,InformedConsentForm orPatientInformationSheetalong withaudio-visualrecordingsystem asperrequirementsofSecondSchedule

10.copyofapprovalofprotocolfrom theEthicscommitee,ifavailable.Copyof registrationoftheEthicsCommiteeunderRule8from theCentralLicencing Authority.

11.Thestudysynopsis.

1 2 . U n d e rta k in g le t te r fro m th e s p o n s o r s ta tin g th a t c o m p le te m e d ic a l m a n a g e m e n t inaccordancewithrule41andanundertakingleterfrom thesponsorstating thatcompensationincaseofstudyrelateinjuryordeathshalbeprovidedin accordancewithrule39.

13.CertificateofAnalysis(COA)ofrepresentativebatches(bothTest&Reference formulations)tobeusedintheBEstudyalongwithdissolutionprofileincase OralSoliddosageforms.

14.FormultipledoseBEstudyadequatesupportingsafetydataandPK/PDshould be subm it ted covering the duration of period for w hich the study has to beconducted.ForalInjectable,thesub-acutetoxicityshouldbesubmitedon theTestproductofthesponsor,studiedinatleasttwospeciesforminimum 14 days.IfRegulatoryGuidanceisavailableprovideacopyofthesame.

15.Forconducting BE studies with reference to Cytotoxic drugs,Hormonal preparations, Narcotic and Psychotropic substances and radioactive substancesinHealthyHumansubjectsaScientificjustificationwithspecial emphasisonSafetyofsubjectswithaproperRiskMitigationStrategyshouldbe submited.Ifregulatoryguidanceisavailableprovideacopyofthesame.

Page139of139

16.Forconducting BE studies with reference to cytotoxic drugs,Hormonal preparations, Narcotic and Psychotropic substances and radioactive substancesinPatientsascientificjustificationwithspecialemphasisonSafety withaproperRiskMitigationStrategyshouldbesubmited.

NOTES:(1)Alitemsmaynotbeapplicabletoaldrugs.Forexplanation,refertextof thisFirstSchedule,SecondScheduleandThirdSchedule.

TABLE3

DATAANDINFORMATIONREQUIREDFORGRANTOFPERMISSIONTO CONDUCTBIOAVAILABILITYANDBIOEQUIVALENCESTUDYOFANEW DRUG ALREADYAPPROVEDINTHECOUNTRY

1.Introduction:Abriefdescriptionofthedrugandthetherapeuticclasstowhichitbelongs. 2.Chemicalandpharmaceuticalinformation-AsperTable2ofSecondSchedule

3.PublishedreportsofPharmacokineticandPharmacodynamicsstudiescariedout inhealthysubjects/patientsdemonstratingsafetyandtolerabilityofthemolecule.

4.Prescribinginformation 5.UndertakingbytheInvestigatorinoriginaldulysignedonacompanyleterheadas perTable4ofThirdSchedule.

6.CopyofregistrationcertificateissuedbyCentralLicencingAuthority.

7.Sponsor’s Authorization leterduly signed by the Authorized Signatory on companyleterhead.

8.Thestudyprotocols,InformedConsentForm orPatientInformationSheetalong withaudio-visualrecordingsystem asperrequirementsofSecondSchedule.

9.copyofapprovalofprotocolfrom theEthicscommitee,ifavailable.Copyof registrationoftheEthicsCommiteeunderRule8from theCentralLicencing Authority.

11.Thestudysynopsis.

12.Undertakingleterfrom thesponsorstatingthatcompletemedicalmanagementin accordancewithrule41andanundertakingleterfrom thesponsorstatingthat compensationincaseofstudyrelateinjuryordeathshalbeprovidedinaccordance withrule39.

13.CertificateofAnalysis(COA)ofrepresentativebatches(bothTest&Reference formulations)tobeusedintheBEstudyalongwithdissolutionprofileincase OralSoliddosageforms.

14.FormultipledoseBEstudyadequatesupportingsafetydataandPK/PDshould be subm it ted covering the duration of period for w hich the study has to beconducted.

Page140of140

15.ForalInjectable,thesub-acutetoxicityshouldbesubmitedontheTestproduct ofthesponsor,studiedinatleasttwospeciesforminimum 14days.IfRegulatory Guidanceisavailableprovideacopyofthesame.

16.Forconducting BE studies with reference to Cytotoxic drugs,Hormonal preparations,NarcoticandPsychotropicsubstancesandradioactivesubstances inHealthyHumansubjectsaScientificjustificationwithspecialemphasison SafetyofsubjectswithaproperRiskMitigationStrategyshouldbesubmited.If regulatoryguidanceisavailableprovideacopyofthesame.

17.Forconducting BE studies with reference to cytotoxic drugs,Hormonal preparations,NarcoticandPsychotropicsubstancesandradioactivesubstances inPatientsascientificjustificationwithspecialemphasisonSafetywithaproper RiskMitigationStrategyshouldbesubmited.

Page141of141

FIFTHSCHEDULE POSTMARKETASSESSMENT (seerules77and82)

1.Postmarketingassessmentofnew drug.-(1)Whenanew drugisapprovedfor marketing,assessmentofsafetyandeficacyofthedrugaregeneralybasedon datafrom alimitednumberofpatients,manystudiedunderthecontroled conditions ofrandomized trials.Often,high risk patients and patients with concomitantilnessesthatrequireuseofotherdrugsareexcludedfrom clinical trials,andlong-term treatmentdataarelimited.Moreover,patientsintrialsare closelymonitoredforevidenceofadverseevents.

. (2)  In actualclinicalpractice,monitoring is less intensive,a broaderrange of patients are treated (age,co-morbidities,drugs,genetic abnormalities),and eventstooraretooccurinclinicaltrialsmaybeobserved.Therefore,subsequent toapprovalofanew drug,thedrugshalbecloselymonitoredandpost marketingassessmentofitsbenefit-riskprofileshalbecariedoutonceitis marketed.

. (3)  A person intending to importormanufacture any new drug forsale or distributionshalhaveapharmacovigilancesystem inplaceforcolecting, processing and forwarding the adverse drug reaction reportto the Central Licencing Authority emerging from the use of the drug imported or manufacturedormarketedbytheapplicantinthecountry.

(4)Thepharmacovigilancesystem shalbemanagedbyqualifiedandtrained personnelandtheoficerin-chargeofcolectionandprocessingofdatashalbe amedicaloficerorapharmacisttrainedincolectionandanalysisofadverse drugreactionreports.

(5)Postmarketingassessmentofnew drugmaybecariedout,indiferentwaysas under:-

A.PhaseIV(Postmarketing)trial:- PhaseIV(Postmarketing)trialincludeadditionaldrug-druginteractions,dose -responseorsafetystudiesandtrialsdesignedtosupportuseunderthe approvedindications,e.g.mortality/morbiditystudiesetc.Suchtrialwilbe conducted underan approved protocolwith defined scientific objectives, inclusionandexclusioncriteria,safetyeficacyassessmentcriteriaetc.with the new drug underapproved conditions foruse in approved patient population. Insuchtrialtheethicalaspectsforprotectionofrights,safetyandwel-being ofthe trialsubjects shalbe folowed as perthe regulatory provisions includingthatforcompensationincaseofclinicaltrialrelatedinjuryordeath andgoodclinicalpracticesguidelines. Insuchstudy,thestudydrugmaybeprovidedtothetrialsubjectfreeofcost unlessotherwisethereisspecificconcern/justificationfornotprovidingthe

Page142of142

drugfreeofcost,tothesatisfactionoftheCentralLicencingAuthorityand

theethicscommitee.
B.Postmarketing surveilance studyorobservationalornon-interventional

studyforactivesurveilance:-Suchstudiesareconductedwithanew drug underapprovedconditionsofitsuseunderaprotocolapprovedbyCentral LicencingAuthoritywithscientificobjective.Inclusionorexclusionofsubject are decided as per the recommended use as per prescribing information/approvedpackageinsert. Insuchstudiesthestudydrugsarethepartoftreatmentofpatientinthe wisdom oftheprescriberincludedintheprotocol.Theregulatoryprovisions andguidelines

applicableforclinicaltrialofanew drugarenotapplicableinsuchcasesas

drugsarealreadyapprovedformarketing. C.Postmarketingsurveilancethroughperiodicsafetyupdatereports:-Aspart

ofpostmarketingsurveilanceofnewdrugtheapplicantshalfurnishperiodic safetyupdatereports(PSURs)inaccordancewiththeproceduresasfolows;

(i)Theapplicantshalfurnishperiodicsafetyupdatereports(PSURs)inorderto- (a)reportal lrelevantnew inform ation from appropriatesources; (b)relatethedatatopatientexposure; (c)summarisethemarketauthorisationstatusindiferentcountriesand

anysignificantvariationsrelatedtosafety;and (d)indicatewhetherchangesshalbemadetoproductinformationin

ordertooptimisetheuseofproduct.

(i)Ordinarilyaldosageformsandformulationsaswelasindicationsfornew drugsshouldbecoveredinonePSUR.WithinthesinglePSUR separate presentationsofdatafordiferentdosageforms,indicationsorseparate populationneedtobegiven.

(i)Alrelevantclinicalandnon-clinicalsafetydatashouldcoveronlythe periodofthereport(intervaldata).ThePSURsshalbesubmitedevery sixmonthsforthefirsttwoyearsafterapprovalofthedrugisgrantedto the applicant.Forsubsequenttwo years – the PSURs need to be submited annualy.CentralLicencing Authoritymayextend the total durationofsubmissionofPSURsifitisconsiderednecessaryinthe in te re s t o f p u b lic h e a lth . P S U R s d u e fo r a p e rio d m u s t b e s u b m it te d within thirty calendardays ofthe lastday ofthe reporting period. However,alcasesinvolvingseriousunexpectedadversereactionsmust bereportedtothelicencingauthoritywithinfifteendaysofinitialreceipt of the inform ation by the applicant. If m arketing of the new drug is delayedbytheapplicantafterobtainingapprovaltomarket,suchdatawil havetobeprovidedonthedeferedbasisbeginningfrom thetimethe newdrugismarketed.

(iv)Newstudiesspecificalyplannedorconductedtoexamineasafetyissue shouldbedescribedinthePSURs.

(v)APSURshouldbestructuredasfolows: (a)TitlePage:

Page143of143

The title page ofPSUR should capture the name ofthe drug; reporting interval;permited indication ofsuch drug;date of permissionofthedrug;dateofmarketingofdrug;licenceename andaddress.

(b)Introduction:
ThissectionofPSUR shouldcapturethereportinginterval;drugs intended use,mode ofaction,therapeutic class,dose,route of administration,formulationandabriefdescriptionoftheapproved indicationandpopulation.

(c)Curentworldwidemarketingauthorizationstatus: ThissectionofPSUR shouldcapturethebriefnarativeoverview includingdetailsofcountrieswherethedrugiscurentlyapproved alongwithdateoffirstapproval,dateofmarketingandifproduct waswithdrawninanyofthecountrieswithreasonsthereof.

(d)Actionstakeninreportingintervalforsafetyreasons: ThissectionofPSUR shouldincludeadescriptionofsignificant actionsrelatedtosafetythathavebeentakenduringthereporting interval, related to either investigational uses or marketing experiencebythelicenceholder,sponsorofaclinicaltrial,regulatory authorities,datamonitoringcommitees,orethicscommitees.

(e)Changestoreferencesafetyinformation: ThissectionofPSURshouldcaptureanysignificantchangestothe reference safety information within the reporting interval.Such changes m ight include inform ation relating to contraindications, warnings,precautions,adverseevents,andimportantfindingsfrom ongoing and com pleted clinical trials and significant non-clinical findings.

(f)Estimatedpatientexposure: ThissectionofPSURshouldprovidetheestimatesofthesizeand natureofthepopulationexposedtothedrug.Briefdescriptionsof themethod(s)usedtoestimatethesubject/patientexposureshould beprovided.

(i)Cumulativeandintervalsubjectexposureinclinicaltrial. (i)Cumulativeandintervalpatientexposurefrom

MarketingExperiencefrom India. (i)Cumulativeandintervalpatientexposurefrom

MarketingExperiencefrom restoftheworld. (g)Presentationofindividualcasehistories:

ThissectionofPSURshouldincludetheindividualcaseinformation availabletoalicenceholderandprovidebriefcasenarative,medical historyindicationtreatedwithsuspectdrug,causalityassessment. Providefolowinginformation:

(i)Referenceprescribinginformation (i) IndividualcasesreceivedfromIndia

Page144of144

(i i i)Individualcasesreceivedfrom restoftheworld (iv)Cumulativeandintervalsummarytabulationsofserious

adverseeventsfrom clinicalinvestigations. (v)Cumulativeandintervalsummarytabulationsfrom post-

marketingdatasources (h) Studies:

ThissectionofPSURshouldcapturethebriefsummaryofclinicaly im portant em erging ef ficacy/ef fectiveness and safety findings obtainedfrom thelicenceholder,sponsoredclinicaltrialsand publishedsafetystudiesthatbecameavailableduringthereporting intervalofthereportwhichhaspotentialimpactonproductsafety information.

(i) Summariesofsignificantsafetyfindingsfrom clinicaltrials duringthereportingperiod

(i i) Findingsfrom non-interventionalStudies (i)Findingsfrom non-ClinicalStudies (iv)Findingsfrom literature

(i)Otherinformation:ThissectionofPSURshouldincludethedetailsabout signalsandRiskManagementPlaninplacebylicenceholder(ifany).
(a) Signalandriskevaluation:Inthissectionlicenceholderwilprovide thedetailsofsignalandriskidentifiedduringthereportingperiodand evaluationofsignalsidentifiedduringthereportingperiod.

(b) RiskManagementPlan:Inthissectionlicenceholderwilprovidethe briefdetailsofsafetyconcernandnecessaryactiontakenbyhim to mitigatethesesafetyconcerns.

(vi)OveralSafetyEvaluation: ThissectionofPSURshouldcapturetheoveralsafetyevaluationofthe drugbaseduponitsriskbenefitevaluationforapprovedindication.
(i) Summaryofsafetyconcerns
(i i) Benefitevaluation
(i)Benefitriskanalysisevaluation

(k)Conclusion: ThissectionofPSURshouldprovidethedetailsonthesafetyprofileof drugandnecessaryactiontakenbythelicenceholderinthisregards.

(l)Appendix: TheappendixincludesthecopyofmarketingauthorizationinIndia,copy ofprescribinginformation,linelistingswithnarativeofIndividualCase SafetyReports(ICSR).

Page145of145

SIXTHSCHEDULE (seerules21,22,33,34,45,47,52,53,60,67,68,75,76,80,81,86,91,97and98)

FEEPAYABLEFORLICENCE,PERMISSIONANDREGISTRATIONCERTIFICATE

t

r t

Sl.No

Rule

Subject

Inrupees (INR)except where

specifiedin dolars ($)

01

21

Application for permissionto conduc clinicaltrial

(i)PhaseI

3,00,000

(i)PhaseI

2,00,000

(i)PhaseI

2,00,000

(iv)PhaseIV

2,00,000

02

22

Reconsideration of application fo permissiontoconductclinicaltrial

50,000

03

33

Application for Permissionto conduc bioavailabilityorbioequivalencestudy

2,00,000

04

34

Reconsiderationofapplicationof permissiontoconductbioavailabilityor bioequivalence
study

50,000

05

46

Application for Registration ofbioavailability and bioequivalencestudy
centre

5,00,000

07

48

Reconsideration of application forregistration of bioavailability and bio- equivalencestudycentre

1,00,000

08

53

Application for permission to manufacture of new drugs o investigationalnewdrugsforclinicaltria orbioavailabilityor bioequivalencestudy

5000 per produc t

09

54

Reconsideration of application to manufacture of new drugs o investigationalnewdrugsforclinicaltria orbioavailability orbioequivalencestudy

2000 per produc t

r l

r l

Page146of146

10

60

Application for permission to manufacture unapproved active pharmaceutical ingredient fo developmentofformulationfortesto analysisorclinicaltrialorbioavailability or

bioequivalencestudy

5000 per produc t

11

61

Reconsideration of permission tomanufacture unapproved active

pharmaceuticalingredientfor development

2000

r r

Page147of147

offormulationfortestoranalysisor clinical trialorbioavailabilityorbioequivalence study

12

68

Applicationforimportofnewdrugsor investigationalnewdrugsforclinicaltria orbioavailabilityorbioequivalencestudy

5000 per produc t

13

69

Reconsideration of application fo Importofnew drugsorinvestigationa new drugs for clinical trial o bioavailabilityor

bioequivalencestudy

1000

14

76

ApplicationforPermissiontoimportnew

drug(FinishedFormulation)for marketing

5,00,00 0

15

ApplicationforPermissiontoimportnew drug (Finished Formulation) alreadyapprovedinthecountry formarketing

2,00,00 0

16

ApplicationforPermissiontoimportnew drug(ActivePharmaceuticalIngredient) formarketing

5,00,00 0

17

Application forPermission to impor new drug (Active Pharmaceutica Ingredient) already approved in the countryfor

marketing

2,00,00 0

18

Application forPermission to impor approvednew drugfornew claims,new indicationornew dosageform ornew routeofadministrationornew strength for

marketing

3,00,00 0

19

Application forPermission to impor fixed dose combination having one o moreoftheingredientsasunapproved newmolecules

formarketing

5,00,00 0

20

ApplicationforPermissiontoimport fixed
dose combination having approvedingredientsformarketing

4,00,00 0

21

ApplicationforPermissiontoimport fixed dosecombinationalreadyapproved

2,00,00 0

l

r l r

t l

t

t r

Page148of148

formarketing

22

Application forPermission to impor fixeddosecombinationfornew claims new indicationornew dosageform o new route ofadministration ornew strengthfor

marketing

3,00,00 0

23

77

Reconsideration of application fo

permissiontoimportnewdrugfor marketing

50,000

24

81

Applicationforpermission tomanufacture

new drug (Finished Form ulation or Active

5,00,00 0

t , r

r

Page149of149

PharmaceuticalIngredient)for sale o distribution

25

Application for permission to manufacture new drug (Active Pharmaceutical Ingredient) already approvedinthecountry forsaleordistribution

2,00,00 0

26

Applicationforpermission tomanufacture newdrug(FinishedFormulation)forsale ordistribution

5,00,00 0

27

Application for permission to manufacture new drug (Finished Formulation)already approved in the countryforsaleor

distribution

2,00,00 0

28

Applicationforpermissionto manufacturenew drug (Active Pharmaceutical Ingredient)forsaleordistribution

5,00,00 0

29

Application for permission to manufacture new drug (Active Pharmaceutical Ingredient) already approvedinthecountry forsaleordistribution

2,00,00 0

30

Application for permission to manufactureapprovednewdrugfornew claims,new indication ornew dosage form ornew routeofadministrationo newstrengthforsaleor

distribution

3,00,00 0

31

Application for permission to manufacture fixed dose combination havingoneormoreoftheingredientsas unapprovednew moleculesforsaleordistribution

5,00,00 0

32

Applicationforpermissionto manufacturefixeddosecombination havingapproved ingredientsforsaleordistribution

3,00,00 0

33

Applicationforpermissionto manufacturefixeddosecombination alreadyapprovedfor saleordistribution

2,00,00 0

r

r

Page150of150

34

81

Application for permission to manufacturefixeddosecombinationfo new claims,new indication or new dosage form or new route o administrationornew strengthforsale or

distribution

3,00,00 0

35

Application for permission to manufacture new drug (Active Pharmaceutical Ingredient) or to manufacturefinished

formulation

5,00,00 0

36

81

Applicationforpermissiontoimportort manufacturephyto-pharmaceuticaldrug

2,00,00 0

r f

o s

Page151of151

37

82

Reconsideration of application fo permissiontomanufacturenewdrugfor saleordistribution

50,000

38

87

ApplicationforImportofunapprovednew drugbyGovernmenthospitalandmedica institution

10,000

39

92

Application for permission to manufactureofunapprovednew drug butunderclinicaltrial,fortreatmento patientoflife

threateningdisease

5,000

40

98

Pre-submissionmeeting

5,00,00 0

41

99

Post-submissionmeeting

50000

42

Anyotherapplicationwhichisnot specified
above

50000

Note:(1)Nofeeshalbechargeableinrespectofapplicationforconductofclinical trialfororphandrugsasdefinedinclause(v)ofrule2.

(2)Incaseofapplicationreceivedfrom MicroSmalMedium Enterprises(MSME) firmsforconductofclinicaltrial,approvalofnew drugandpreandpost submissionmeeting,thefeepayableshalbehalfofthefeespecifiedabove.

r

l

f

Page152of152

SEVENTHSCHEDULE (seerules39,40,and42)

FORMULAETODETERMINETHEQUANTUM OFCOMPENSATIONINTHECASESOF CLINICALTRIALRELATEDINJURYORDEATH

1. Formulaincaseofclinicaltrialrelateddeath:

Compensation=(BxFxR)/99.37

Where, B=Baseamount(i.e.8lacs)

F=FactordependingontheageofthetrialsubjectasperAnnexure1(basedon WorkmenCompensationAct)

R=RiskFactordependingontheseriousnessandseverityofthedisease,presence ofco-morbidityanddurationofdiseaseofthetrialsubjectatthetimeof enrolmentintheclinicaltrialbetweenascaleof0.5to4asunder:

(1) 0.5terminalyilpatient(expectedsurvivalnotmorethan(NMT)6months) (2) 1.0Patientwithhighrisk(expectedsurvivalbetween6to24months) (3) 2.0Patientwithmoderaterisk
(4) 3.0Patientwithmildrisk

(5) 4.0HealthyVolunteersortrialsubjectofnorisk.

However,incaseofpatientswhoseexpectedmortalityis90%ormorewithin30days,afixedamountofRs.2 lacsshouldbegiven.

2.Formulaincaseofclinicaltrialrelatedinjury(otherthandeath):

Forcalculationofquantum ofcompensationrelatedtoinjury(otherthandeath),the compensationshalbelinkedtothecriteriaconsideredforcalculationofcompensationin casesofdeathofthetrialsubjectasreferedtoinsectionofthisSchedule.Thequantum of compensationincaseofClinicalTrialrelatedSAEshouldnotexceedthequantum of compensationwhichwouldhavebeendueforpaymentinCaseofdeathofthetrialsubject sincethelossoflifeisthemaximum injurypossible.AsperthedefinitionofSAE,the folowingsequelaeotherthandeatharepossibleinaclinicaltrialsubject,inwhichthetrial subjectshalbeentitledforcompensationincasetheSAEisrelatedtoclinicaltrial.

(i)Apermanentdisability. IncaseofSAEcausingpermanentdisabilitytothetrialsubject,thequantum ofcompensation

incaseof100%disabilityshalbe90%ofthecompensationwhichwouldhavebeenduefor payment10thenominee(s)incaseofdeathofthetrialsubject.

Thequantum forlessthan100% disabilitywil lbeproportionaltotheactualpercentage disabilitythetrialsubjecthassufered.

Accordingly,folowingformulashalbeapplicablefordeterminationofcompensation: Page153of153

Compensation=(CxDx90)/(100×100)

Where:

D=Percentagedisabilitythetrialsubjecthassufered.

C=Quantum ofCompensationwhichwouldhavebeendueforpaymenttothetrial subject’snominees)incaseofdeathofthetrialsubject.

(i i) Congenitalanom alyorbirthdefect. Thecongenitalanomalyorbirthdefectinababymayoccurduetoparticipationofanyoneor

boththeparentinclinicaltrial.Folowingsituationsmayariseduetocongenitalanomalyorbirth defect.

(a)Stilbirth;
(b)Earlydeathduetoanomaly; (c)Nodeathbutdeformitywhichcanbefulycorectedthroughappropriate; (d)Intervention;
(e)Permanentdisability(mentalorphysical).

Thecompensationinsuchcaseswouldbealumpsumamountsuchthatifthatamountiskeptbyway offixed depositoralike,itshalbringamonthlyinterestamountwhichisapproximatelyequivalenttohalfof m in im u m w a g e o f th e u n s k il le d w o rk e r (in D e lh i). T h e q u a n tu m o f c o m p e n s a tio n in s u c h c a s e s o f S A E shalbehalfofthebaseamountasperformulafordeterminingthecompensationforSAEresulting intodeath.

In c a s e o f b irth d e fe c t le a d in g to s u b -c la u s e (c ) & (d ) o f th is c la u s e to a n y c h ild , th e m e d ic a l managementaslongasrequiredshalbeprovidedbytheSponsororhisrepresentativewhichwilbe overandabovethefinancialcompensation.

(i i i) Chroniclife-threateningdisease;and (iv)ReversibleSAEincaseitisresolved.

IncaseofclinicaltrialrelatedSAEcausinglife-threateningdiseaseandreversibleSAEincaseitis resolved,thequantumofcompensationwouldbelinkedtothenumberofdaysofhospitalizationofthe trial subject.Thecompensationperdayofhospitalizationshalbeequaltothewageloss.Thewageloss p e r d a y s h a l l b e c a lc u la te d b a s e d u p o n th e m in im u m w a g e o f th e u n s k il le d w o rk e r (in D e lh i).

Since,incaseofhospitalizationofanypatientnotonlythepatientloseshis/herwage,therewilbe directorindirectlossesofvariouskindincludinginconvenience,wagelossofatendant,etc.The c o m p e n s a tio n p e r d a y o f h o s p ita liz a tio n in s u c h c a s e s h a l l b e d o u b le th e m in im u m w a g e .

Accordingly,folowingformulashalbeapplicablefordeterminationofcompensation:

Page154of154

Where,

W = M in im u m w a g e p e r d a y o f th e u n s k il le d w o rk e r (in D e lh i) N=Numberofdaysofhospitalization

Compensation=2XW XN.

Page155of155

Annexure1 Factor(F)forcalculatingtheamountofcompensation

Age Factor

Notmorethan…

16 228.54

17 227.49

18 226.38

19 225.22

20 224.00

21 222.71

22 221.37

23 219.95

24 218.47

25 216.91

26 215.28

27 213.57

28 211.79

29 209.92

30 207.98

31 205.95

32 203.85

33 201.66

34 199.40

35 197.06

36 194.64

37 192.14

38 189.56

39 186.90

40 184.17

41 181.37

42 178.49

43 175.54



. 44  172.52

. 45  169.44

. 46  166.29

. 47  163.07

. 48  159.80

. 49  156.47

. 50  153.09

. 51  149.67

. 52  146.20

. 53  142.68

. 54  139.13

. 55  135.56

. 56  131.95

. 57  128.33

. 58  124.70

. 59  121.05

. 60  117.41

. 61  113.77

. 62  110.14

. 63  106.52

. 64  102.93

65or 99.37 more

Page156of156

EIGHTSSCHEDULE FORM CT-01

(SeeRules8,10and17)

APPLICATIONFORREGISTRATIONOFETHICSCOMMITTEERELATINGTO CLINICALTRIALORBIOAVAILABILITYANDBIOEQUIVALNENCESTUDYOR BIOMEDICALHEALTHRESEARCH

I/We,. (name, designation and ful postal address of the applicant) of

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (nam e and ful l address w ith contact details of the ethicscommitee)herebyapplyforgrantofregistrationofethicscommitee.

Thedetailsoftheapplicationareasunder:

1.Nameofapplicant:

2.Natureandconstitutionofapplicant:

(proprietorship,company,society,trust, independent,institutional,othertobe specified)

3.(i)Applicantaddressincludingtelephone number,mobilenumber,faxnumberande- mailid:

(i)Addressforcorespondence:

[corporate/registeredofice/clinicaltrial site/bioavailabilityandbioequivalencestudy centre/biomedicalhealthresearch]

4.Detailsofaccreditation,ifany(self-atested copyofcertificatetobeatached):

5.IhaveenclosedthedocumentsasspecifiedintheTable1oftheThirdSchedule oftheNewDrugsandClinicaltrialsRules,2018.

6.Iherebystateandundertakethat:

(i)IshalcomplywithaltheprovisionsoftheDrugsandCosmeticsAct,1940and theNewDrugsandClinicaltrialsRules,2018.

Place: Date:

DigitalSignature (Nameand designation)

 

Page157of157

FORM CT-02 (SeeRules8,9and10)

GRANTOFREGISTRATIONOFETHICSCOMMITTEERELATINGTOCLINICAL TRIALORBIOAVAILABILITYANDBIOEQUIVALNENCESTUDY

RegistrationNo.

The Central Licencing Authority is hereby register and permit (N a m e a n d fu l l a d d re s s w ith c o n ta c t d e ta ils o f th e

ethicscommitee)toperform dutiesofethicscommiteeasspecifiedintheNew DrugsandClinicaltrialsRules,2018.

2.Theethicscommiteeshalobservetheconditionsofregistrationspecifiedin CHAPTERIoftheNew DrugsandClinicaltrialsRules,2018andtheDrugsand CosmeticsAct,1940.

 

Place:…………. Date:.

CentralLicencing Authority

Stamp

Page158of158

FORM CT-03 (SeeRules17)

GRANTOFREGISTRATIONOFETHICSCOMMITTEERELATINGTOBIOMEDICAL HEALTHRESEARCH

RegistrationNo.

Thedesignatedauthorityisherebyregisterandpermit (Nameandfuladdresswithcontactdetailsoftheethicscommitee)toperform dutiesofethicscommiteeasspecifiedintheRegulationofNew DrugsandClinical TrialsRules,2017.

2.Theethicscommiteeshalobservetheconditionsofregistrationspecifiedin C H A P T E R IV o f th e N e w D ru g s a n d C lin ic a l tria ls R u le s ,2 0 1 8 a n d th e D ru g s a n d CosmeticsAct,1940.

 

Place:…………. Date:.

DesignatedAuthority Stamp

Page159of159

FORM CT-04 (SeeRules21and22)

APPLICATIONFORGRANTOFPERMISSIONTOCONDUCTCLINICALTRIALOF NEW DRUGORINVESTIGATIONALNEW DRUG

I/We,.(name and fulpostaladdress ofthe applicant)of. herebyapplyforgrantofpermission to conductclinicaltrialon new drug or investigationalnewdrug.

Thedetailsoftheapplicationareasunder:

1.NameofApplicant:

2.Natureandconstitution:

(proprietorship, partnership includinglimited liability partnership, company, society, trust, other to bespecified)

3.(i)Sponsoraddress,telephone number,mobilenumber,faxnumber ande-mailid:

(i)Clinicaltrialssiteaddress, telephonenumber,mobilenumber,fax numberande-mailid:

(i)Nameandaddressofperson responsibleforpaymentof compensation,ifany:

(iv)Addressforcorespondence:

[corporate/registeredofice/clinicaltrial site]

4.Detailsofnewdrugsorinvestigationalnewdrugsandclinicalinvestigationsite [AsperAnnexure].

5.PhaseoftheClinicalTrial

6.Clinicaltrialprotocolnumberwithdate:

7. Fee paid on Rs. receipt/chalan/transactionid .

 

8.IhaveenclosedthedocumentsasspecifiedintheSecondScheduleoftheNew DrugsandClinicaltrialsRules,2018.

Page160of160

9.Iherebystateandundertakethat:

(i)IshalcomplywithaltheprovisionsoftheDrugsandCosmeticsAct,1940and theNewDrugsandClinicaltrialsRules,2018.

Page161of161

Place: Date:

DigitalSignature (Nameand designation)

 

Page162of162

Annexure: Detailsofnewdrugsorinvestigationalnewdrugs:

Namesofthenewdrugor investigationalnewdrug:

Therapeuticclass:

Dosageform:

Composition:

Indications:

Detailsofclinicaltrialsite:

Namesandaddressofclinicaltrialsite

Ethicscommiteedetails:

Nameofinvestigator:

Page163of163

FORM CT-4A (SeeRule23)

INFORMATIONTOINITIATECLINICALTRIALOFNEW DRUGORINVESTIGATIONAL NEW DRUG

I/We,.(name and fulpostaladdressofthe applicant)of

.herebyinformtoinitiatetheconduct clinicaltrialonnewdrugorinvestigationalnewdrug.

Thedetailsoftheapplicationareasunder:

1.NameofApplicant:

2.Natureandconstitution:

(proprietorship, partnership includinglimited liability partnership, company, society, trust, other to bespecified)

3.(i)Sponsoraddress,telephone number,mobilenumber,faxnumber ande-mailid:

(i)Clinicaltrialssiteaddress, telephonenumber,mobilenumber,fax numberande-mailid:

(i)Nameandaddressofperson responsibleforpaymentof compensation,ifany:

(iv)Addressforcorespondence:

[corporate/registeredofice/clinicaltrial site]

4.Detailsofnewdrugsorinvestigationalnewdrugsandclinicalinvestigationsite [AsperAnnexure].

5.PhaseoftheClinicalTrial

6.Clinicaltrialprotocolnumberwithdate:

8.IherebydeclaredthatIhavealreadysubmitedtheapplicationunderRule21o theseRulesandgrantedautomaticapprovalunderRule23(2)andenclosed thedocumentsasspecifiedintheSecondScheduleoftheNew Drugsand ClinicaltrialsRules,2018.

Page164of164

f

9.Iherebystateandundertakethat:

(i)IshalcomplywithaltheprovisionsoftheDrugsandCosmeticsAct,1940and

theNewDrugsandClinicaltrialsRules,2018.

Page165of165

Place: Date:

DigitalSignature (Nameand designation)

 

Page166of166

Annexure: Detailsofnewdrugsorinvestigationalnewdrugs:

Namesofthenewdrugor investigationalnewdrug:

Therapeuticclass:

Dosageform:

Composition:

Indications:

Detailsofclinicaltrialsite:

Namesandaddressofclinicaltrialsite

Ethicscommiteedetails:

Nameofinvestigator:

Page167of167

FORM CT-05 (SeeRule33and34)

APPLICATIONFORGRANTOFPERMISSIONTOCONDUCT BIOAVAILABILITYORBIOEQUIVALENCESTUDY

I/We,. (name and ful postal address of the applicant) of

.hereby apply for grant of permission to conductbioavailabilityorbioequivalencestudy(strikeofwhicheverisnotapplicable) ofnewdrugorinvestigationalnewdrug,thedetailsofwhichareasunder:

1.Nameofapplicant:

2.Natureandconstitution:

(proprietorship, partnership including limited liability partnership,company, society,trust,othertobespecified)

3.(i)Sponsoraddress,telephone number,mobilenumber,faxnumber ande-mailid:

(i)Studyaddress,telephone number,mobilenumber,faxnumber ande-mailid:

(i)Addressforcorespondence:

[corporate/registeredofice/ bioavailabilityorbioequivalencestudycentre]

4.Detailsofnewdrugorinvestigationalnewdrugandstudycentre[AsperAnnexure

5.Studyprotocolnumberwithdate:

6. Fee paid on Rs. receipt/chalan/transactionid .

 

7.IhaveenclosedthedocumentsasspecifiedintheFourthScheduleoftheNew DrugsandClinicaltrialsRules,2018.

8.Iherebystateandundertakethat:

(i)IshalcomplywithaltheprovisionsoftheDrugsandCosmeticsAct,1940andth NewDrugsandClinicaltrialsRules,2018.

Place: Date:

e

DigitalSignature

].

 

Page168of168

Annexure:

Detailsofnewdrugorinvestigationalnewdrugs:

(Nameanddesignation)

Namesofthenewdrugor investigationalnewdrug:

Therapeuticclass:

Dosageform:

Composition:

Indications:

Detailsofstudycentre:

Namesandaddressofstudycentre

Ethicscommiteedetails:

Page169of169

FORM CT-06 (SeeRules22,26,29and,30)

PERMISSIONTOCONDUCTCLINICALTRIALOFNEW DRUGORINVESTIGATIONAL NEW DRUG

TheCentralLicencingAuthorityherebypermits

(Nameandfuladdresswithcontactdetailsoftheapplicant)toconductclinicaltrial ofthe



newdrugorinvestigationalnewdrugasperprotocolnumber inthebelowmentionedclinicaltrialsites.

dated

 

.Detailsofnewdrugorinvestigationalnewdrugandclinicaltrialsite[AsperAnnexure].

3. ThispermissionissubjecttotheconditionsprescribedinPARTAofCHAPTER VoftheNewDrugsandClinicaltrialsRules,2018undertheDrugsandCosmeticsAct, 1940.

Place:…………. Date:.

CentralLicencing AuthorityStamp

Page170of170

Annexure: Detailsofnewdrugorinvestigationalnewdrug:

Namesofthenewdrugorinvestigational newdrug:

Therapeuticclass:

Dosageform:

Composition:

Indications:

Detailsofclinicaltrialsite:

FORM CT-07 (SeeRules34,36,37and38)

PERMISSIONTOCONDUCTBIOAVAILABILITYORBIOEQUIVALENCESTUDYOF NEW DRUGORINVESTIGATIONALNEW DRUG

TheCentralLicencingAuthorityherebypermits
(Name and fuladdress with contactdetails ofthe applicant)to conduct bioavailability/bioequivalencestudy(strikeofwhicheverisnotapplicable)ofthenew drugorinvestigationalnewdrugasperprotocolnumber dated in the belowmentionedstudycentre.

2.Detailsofnewdrugorinvestigationalnewdrugandstudycentre[AsperAnnexure].

3.ThispermissionissubjecttotheconditionsprescribedinPARTBofCHAPTERV oftheNew DrugsandClinicaltrialsRules,2018undertheDrugsandCosmeticsAct, 1940.

Namesandaddressofclinicaltrialsite

Ethicscommiteedetails:

Nameofprincipalinvestigator:



Place:…………. Date:.

CentralLicencing AuthorityStamp

Page171of171

Annexure: Detailsofnewdrugorinvestigationalnewdrug:

Namesofthenewdrugor investigationalnewdrug:

Therapeuticclass:

Dosageform:

Composition:

Indications:

Detailsofstudycentre:

Namesandaddressofstudycentre:

Ethicscommiteedetails:

Nameofprincipalinvestigator:

Page172of172

FORM CT-08 (SeeRules45,47and48)

APPLICATIONFORREGISTRATIONOFBIOAVAILABILITYORBIOEQUIVALENCE STUDYCENTRE

I/We,.(name, designationandfulpostaladdressoftheapplicant)of. herebyapplyforgrantofregistrationofbioavailabilityorbioequivalencestudycentre. Thedetailsoftheapplicationareasunder:

1.Nameofapplicant:

2.Natureandconstitutionofapplicant:

(proprietorship,company,society,trust, independent,institutional,othertobe specified)

3.(i)Applicantaddressincludingtelephone number,mobilenumber,faxnumberande- mailid:

(i)Addressforcorespondence:

[corporate/registeredofice/ bioavailabilityorbioequivalencestudycentre]

4.Detailsofaccreditation,ifany(self-atested copyofcertificatetobeatached):

5. Fee paid on Rs. receipt/chalan/transactionid .

 

6.IhaveenclosedthedocumentsasspecifiedintheTable1ofFourthScheduleo theNewDrugsandClinicaltrialsRules,2018.

7.Iherebystateandundertakethat:

(i)IshalcomplywithaltheprovisionsoftheDrugsandCosmeticsAct,1940the NewDrugsandClinicaltrialsRules,2018.

Place: Date:

DigitalSignature (Nameand designation)

f

 

Page173of173

FORM CT-09 (SeeRules47,48,50and51)

GRANTOFREGISTRATIONOFBIOAVAILABILITYORBIOEQUIVALENCESTUDY CENTRE

RegistrationNo.

TheCentralLicencingAuthorityherebyregister
(N a m e a n d fu l l a d d re s s w ith c o n ta c t d e ta ils o f th e a p p lic a n t) fo r c o n d u c t o f bioavailability andbioequivalencestudiesofnewdrugsandinvestigationalnew drugsasspecifiedintheNewDrugsandClinicaltrialsRules,2018.

2.ThisregistrationissubjecttotheconditionsprescribedinCHAPTERVIoftheNew DrugsandClinicaltrialsRules,2018undertheDrugsandCosmeticsAct,1940.

 

Place:…………. Date:.

CentralLicencing Authority

Stamp

Page174of174

FORM CT-10 (SeeRule52and53)

APPLICATIONFORGRANTOFPERMISSION TOMANUFACTURENEW DRUGORINVESTIGATIONALNEW DRUGFORCLINICAL

TRIALORBIOAVAILABILITYORBIOEQUIVALENCESTUDYORFOR EXAMINATION,TESTANDANALYSIS

I/We,. (name and ful postal address of the applicant) of

.hereby apply for grant of permission to manufacturenew drugorinvestigationalnew drug forclinicaltrialorbioavailability orbioequivalencestudyorforexamination,testandanalysis.

Thedetailsoftheapplicationareasunder:

, ,

,

1.Nameofapplicant:

2.Natureandconstitutionofapplicant:

(proprietorship, partnership including limited lability partnership, company society,trust,othertobespecified)

3.(i)Corporate/Registered ofice address telephone number,mobile number,fax numberande-mailid:

(i) Applicant’saddress,telephonenumber mobilenumber,faxnumberande-mailid:

(i)Addressforcorespondence:

4.Detailsofnewdrugsandinvestigationalnewdrugstobemanufactured[Asper Annexure].

5.ParticularsofManufacturer,Manufacturingsite(s)[AsperAnnexure].

6. Fee paid on Rs receipt/chalan/transactionid .

 

7.Iherebystateandundertakethat: (i)IshalcomplywithaltheprovisionsoftheDrugsandCosmeticsAct,1940

andtheCHAPTERVIofNewDrugsandClinicaltrialsRules,2018.

(i i)The new drug to be m anufactured from M /s. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .shal lbe used exclusivelyforthepurposeofclinicaltrialandnopartofitshalbedivertedto thedomesticmarket.

Page175of175

      

Page176of176

Place: Date:

 

Digital Signature(Nameand

designation)

Annexure: Detailsofnewdrugorinvestigationalnewdrug:

Namesofthenewdrugorinvestigational newdrug:

Therapeuticclass:

Dosageform:

Composition:

Indications:

Detailsofmanufacturerandmanufacturingsite:

f

f

Name and address of API and form ulation m anufacturer (ful l address withtelephone,faxande-mailaddresso themanufacturer)

Name and address of manufacturing sitesofAPIandformulation(fuladdress withtelephone,faxande-mailaddresso themanufacturingsite)

Page177of177

FORM CT-11 (SeeRules53,54,55,56,and58)

PERMISSIONTOMANUFACTURENEW DRUGORINVESTIGATIONALNEW DRUGFOR CLINICALTRIAL,BIOAVAILABILITYORBIOEQUIVALENCESTUDYORFOR

EXAMINATION,TESTANDANALYSIS

LicenceNumber

TheCentralLicencingAuthorityherebygrantpermission (Nameandfulpostaladdresswithcontactdetailsoftheapplicant)tomanufacture thenewdrugorinvestigationalnewdrugforconductofclinicaltrialorbioavailability orbioequivalencestudyasperprotocolnumber dated inthebelow mentionedclinicaltrialsitesorbioavailabilityandbioequivalencestudycentre[Asper Annexure]orforexamination,testandanalysis.

. T h is lic e n c e is s u b je c t to th e c o n d itio n s s p e c ifie d in th e C H A P T E R V I I I o f N e w DrugsandClinicaltrialsRules,2018undertheDrugsandCosmeticsAct,1940.

. Thislicenceshal l,unlesspreviouslysuspendedorrevoked,beinforceforaperiod ofthreeyearsfrom thedateofitsissuance.

 

S.N.

Nameofthenewdrug orinvestigationalnew drugtobe

manufactured

Classofnewdrugor investigationalnew drug

Quantityto be manufacture d

4.Detailsofmanufacturerandmanufacturingsiteunderthislicence.

S.N.

Nameandaddressofmanufacturer (fuladdresswithtelephone,faxand e-mailaddressofthemanufacturer)

Name and address ofmanufacturing site (ful l address w ith telephone, fax and e-mail address of the manufacturingsite)

Place:…………. CentralLicencing Authority

Date:.

Stamp

Page178of178

Annexure: Detailsofclinicaltrialsite:

Namesandaddressofclinicaltrialsite

Ethicscommiteedetails:

Nameofinvestigator:

Page179of179

FORM CT-12 (SeeRule59and60)

APPLICATIONFORGRANTOFPERMISSIONTOMANUFACTUREFORMULATIONOF UNAPPROVEDACTIVEPHARMACEUTICALINGREDIENTFORTESTORANALYSIS ORCLINICALTRIALORBIOAVAILABILITYORBIOEQUIVALENCESTUDY

I/We,.(nameand fulpostaladdressoftheapplicant)of.hereby applyforgrantofpermissiontomanufactureformulationsofunapprovedactive pharmaceuticalingredientfortestoranalysisorclinicaltrialorbioavailabilityor bioequivalencestudy.

Thedetailsoftheapplicationareasunder:

,

1.Nameofformulationmanufacturer:

2.Natureandconstitutionofapplicant:

(proprietorship, partnership including limited liability partnership, company society,trust,othertobespecified)

3.(i) Corporate/ registered ofice address telephone number,mobile number,fax numberande-mailid:

(i i) Form ulation m anufacturer’s address including telephone number, mobile number,faxnumberande-mailid:

(i) Addressforcorespondence:

4.DetailsofunapprovedActivepharmaceuticalingredientanditsformulation[As perAnnexure].

5.DetailsofManufacturer,Manufacturingsite(s)offormulation[AsperAnnexure].

6. Fee paid on Rs receipt/chalan/transactionid.



7.Iherebystateandundertakethat: (i)IshalcomplywithaltheprovisionsoftheDrugsandCosmeticsAct,1940

andCHAPTERVIoftheNewDrugsandClinicaltrialsRules,2018.

(i)Theformulationoftheunapprovedactivepharmaceuticalingredienttobe manufacturedshalbeusedforthementionedpurposeonlyandnopartofit shalbesoldinthemarket.

Page180of180

Place: DigitalSignature



Date:

(Nameand designation)



Page181of181

Annexure: DetailsofActivepharmaceuticalingredientanditsformulation:

Name of theunapprovedAPI

Quantity

Name oftheformulation/test batches to be developed fortest/analysisor clinicaltrial

Quantity

Nameoftheformulationtobemanufactured

Quantity

Composition

Indication

Detailsofmanufacturerandmanufacturingsiteofformulation:

l, –

DetailsofmanufacturerandmanufacturingsiteofActivepharmaceuticalingredient:

f

l ll

S.N.

Name and address of m anufacturer of form ulation (ful addresswithtelephone,faxande mailaddressofthemanufacturer)

Nameandaddressofmanufacturingsite offormulation(fuladdresswithtelephone fax and e-mail address of the manufacturingsite)

S.N.

Name and address o manufacturer of Active pharmaceuticalingredient(ful addresswithtelephone,faxande mailaddressofthemanufacturer)

Nameandaddressofmanufacturingsite ofActivepharmaceuticalingredient(ful address with telephone,fax and e-mai addressofthemanufacturingsite)

Page182of182

FORM CT-13 (SeeRule59and60)

APPLICATIONFORGRANTOFPERMISSIONTOMANUFACTUREUNAPPROVED ACTIVEPHARMACEUTICALINGREDIENTFORDEVELOPMENTOF FORMULATIONFORTESTORANALYSISORCLINICALTRIALOR BIOAVAILABILITYORBIOEQUIVALENCESTUDY

I/We,.(nameand fulpostaladdressoftheapplicant)of.hereby apply for grant of perm ission to m anufacture unapproved active pharm aceutical ingredientfordevelopmentofformulationfortestoranalysisorclinicaltrialor bioavailabilityorbioequivalencestudy.

Thedetailsoftheapplicationareasunder:

,

1.Nameofmanufacture:

2.Natureandconstitutionofapplicant:

(proprietorship, partnership including limited liability partnership, company society,trust,othertobespecified)

3.(i)Corporate/registered ofice address telephone number,mobile number,fax numberande-mailid:

(i) Formulationmanufacturer’saddress including telephone number, mobile number,faxnumberande-mailid:

(i)Addressforcorespondence:

4.DetailsofunapprovedActivepharmaceuticalingredienttobemanufactured[Aspe Annexure].

5.Detailsofformulationtobemanufactured[AsperAnnexure].

6. Fee paid on Rs receipt/chalan/transactionid .

 

7.Iherebystateandundertakethat: (i)IshalcomplywithaltheprovisionsoftheDrugsandCosmeticsAct,1940and

CHAPTERVIoftheNewDrugsandClinicaltrialsRules,2018.

(i)Theunapprovedactivepharmaceuticalingredienttobemanufacturedshalbe suppliedtoM/s…………………………………………………onlyandnopartofitshalbesoldin

Page183of183

r

themarket.

Place: Date:

 

Digital Signature(Nameand

designation)

Page184of184

Annexure: DetailsofActivepharmaceuticalingredientanditsformulation:

Detailsofmanufacturerandmanufacturingsiteofformulation:

l, –

DetailsofmanufacturerandmanufacturingsiteofActivepharmaceuticalingredient:

l ll

Name of the unapprovedAPItobe obtained

Quantity

Name oftheformulation/test batches to be developed fortest/analysisor clinicaltrial

Quantity

S.N.

Name and address of m anufacturer of form ulation (ful addresswithtelephone,faxande mailaddressofthemanufacturer)

Nameandaddressofmanufacturingsite offormulation(fuladdresswithtelephone fax and e-mail address of the manufacturingsite)

S.N.

Name and address of manufacturer of Active pharmaceuticalingredient(ful addresswithtelephone,faxande mailaddressofthemanufacturer)

Nameandaddressofmanufacturingsite ofActivepharmaceuticalingredient(ful address with telephone,fax and e-mai addressofthemanufacturingsite)

Page185of185

FORM CT-14 (SeeRules60,61,62,63and64)

PERMISSIONTOMANUFACTUREFORMULATIONOFUNAPPROVEDACTIVE PHARMACEUTICALINGREDIENTFORTESTORANALYSISORCLINICALTRIALOR BIOAVAILABILITYORBIOEQUIVALENCESTUDY

LicenceNumber:

TheCentralLicencingAuthorityherebygrantpermissionto (Nameandfulpostaladdresswithcontactdetailsoftheformulationmanufacturer) tomanufacturetheformulationoftheunapprovedactivepharmaceuticalingredient specifiedbelow fortestoranalysisorforconductofclinicaltrialsbioavailabilityor bioequivalencestudy.

r

2.DetailsofManufacturer,Manufacturingsiteofformulation[AsperAnnexure].

l

3.ThislicenceissubjecttotheconditionsprescribedunderPartVIoftheNew DrugsandClinicaltrialsRules,2018undertheDrugsandCosmeticsAct,1940.

4.Details ofmanufacturerand manufacturing site ofactive pharmaceutical ingredienttobesupplied.

l

l

5.Thislicenceshal,unless previouslysuspended orrevoked,be in force fora period of.from thedateofitsissuance.

Place:…………. CentralLicencingAuthority Page186of186

 

Nameoftheformulation/testbatchestobedevelopedfo test/analysisorclinicaltrial

Quantity

S.N.

Name and address of manufacturer(fuladdress with telephone,faxande-mailaddress ofthemanufacturer)

Nameandaddressofmanufacturingsite (fuladdresswithtelephone,faxande-mai addressofthemanufacturingsite)

S.N.

Name and address of manufacturer(fuladdresswith telephone, fax and e-mai addressofthemanufacturer)

Nameandaddressofmanufacturingsite (fuladdresswithtelephone,faxande-mai addressofthemanufacturingsite)

Date:.

Stamp

FORM CT-15 (SeeRules60,61,62,63and64)

PERMISSIONTOMANUFACTUREUNAPPROVEDACTIVEPHARMACEUTICAL INGREDIENTFORTHEDEVELOPEMNTOFFORMULATIONFORTESTOR ANALYSISORCLINICALTRIALORCLINICALTRIALORBIOAVAILABILITYOR BIOEQUIVALENCESTUDY

LicenceNumber:

TheCentralLicencingAuthorityherebygrantpermissionto (Nameandfuladdressoftheactiveingredientmanufacturer)tomanufacturethe unapprovedactivepharmaceuticalingredientspecifiedbelow tomanufactureits formulationfortestoranalysisorforconductofclinicaltrialsorbioavailabilityor bioequivalencestudy.

2.DetailsofManufacturer,Manufacturingsiteofactivepharmaceuticalingredient.

3. Details ofManufacturer,Manufacturing site offormulation manufacturerto besupplied.

l l

4. ThispermissionissubjecttotheconditionsspecifiedinCHAPTERVIofthe NewDrugsandClinicaltrialsRules,2018undertheDrugsandCosmeticsAct,1940.

 

NameoftheunapprovedAPItobemanufactured

Quantity

S.N.

Name and address of m anufacturer (ful l address w ith telephone,faxande-mailaddress ofthemanufacturer)

Nameandaddressofmanufacturingsite (fuladdresswithtelephone,faxande mailaddressofthemanufacturingsite)

S. N.

N a m e a n d a d d re s s o f fo rm u la to r (fu l addresswithtelephone,faxande-mai addressofthemanufacturer)

Nameandaddressofsitewherethe manufactured unapproved active p h a rm a c e u tic a l in g re d ie n t to b e u s e d (fuladdresswithtelephone,faxande mailaddress ofthe manufacturing site)

Page187of187

5 . T h is p e rm is s io n s h a l l, u n le s s p re v io u s ly s u s p e n d e d o r re v o k e d , b e in fo rc e fo r a periodof.from thedateofitsissuance.

Page188of188

Place:…………. Date:.

CentralLicencing AuthorityStamp

Annexure Detailsofrecordofunapprovedactivepharmaceuticalingredientmanufactured:

r

Detailsofreconciliationofunapprovedactivepharmaceuticalingredientmanufactured:

*WriteNAwherenotapplicable.

S.No .

Dateof manufactu e

LicenceNo.

Nameofthe unapproved active pharmaceutic alingredient

Quantity manufactur ed

Manufacture dfor

Date

Nameofthe unapprovedactive pharmaceutical ingredient

Licenc eNo.

Quantity manufacture d

Quantit y supplie d

Quantity remaine d

Supplie dto

Quantity–left over/remain unused/got damaged/expi red/foundof sub-standard quality

Action taken

Page189of189

FORM CT-16 (SeeRule67and68)

APPLICATIONFORGRANTOFLICENCETOIMPORTNEW DRUGOR INVESTIGATIONALNEW DRUGFORCLINICALTRIALORBIOAVAILABILITYOR BIOEQUIVALENCESTUDYORFOREXAMINATION,TESTANDANALYSIS

I/We,. (nameandaddressoftheapplicant)ofM/s. herebyapplyforgrantoflicencetoimportnew drugorinvestigationalnew drugfor clinicaltrialbioavailabilityorbioequivalence studyorforexamination,testand analysis.

Thedetailsoftheapplicationareasunder:

,

1.Nameofapplicant:

2.Natureandconstitutionofapplicant:

(proprietorship, partnership including limited liability partnership, company society,trust,othertobespecified)

3.(i)Corporate/registered ofice address including telephone number, mobile number,faxnumberande-mailid:

(i) Applicant’s address including telephone number,mobile number,fax numberande-mailid:

(i)Addressforcorespondence:

4.Detailsofnewdrugstobeimported[AsperAnnexure].

5.ParticularsofoverseasManufacturer,Manufacturingsite(s)[AsperAnnexure].

6. Fee paid on Rs receipt/chalan/transactionid .

 

7.Iherebystateandundertakethat: (i)IshalcomplywithaltheprovisionsoftheDrugsandCosmeticsAct,1940and

CHAPTERIXoftheNewDrugsandClinicaltrialsRules,2018.

(i i) The new drug to be im ported from M /s. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .shal lbe used exclusivelyforthepurposeofclinicaltrialandnopartofitshalbedivertedto thedomesticmarket.

Page190of190

Place: Date:

DigitalSignature (Nameand designation)

 

Page191of191

Annexure:

Detailsofnewdrugorinvestigationalnewdrug:

Namesofthenewdrugor investigationalnewdrug:

Therapeuticclass:

Dosageform:

Composition:

Indications:

Detailsofmanufacturerandmanufacturingsite: r

Name and address ofmanufacture (fuladdresswithtelephone,faxande mailaddressofthemanufacturer)

Name and address ofmanufacturing site (fuladdress with telephone,fax and e-mail address of the manufacturingsite)

Page192of192

FORM CT-17 (SeeRules68,69,and70)

LICENCETOIMPORTNEW DRUGORINVESTIGATIONALNEW DRUGFORTHE PURPOSEOFCLINICALTRIALORBIOAVAILABILITYORBIOEQUIVALENCESTUDY ORFOREXAMINATION,TESTANDANALYSIS

LicenceNumber:

The Central Licencing Authority hereby grants licence to (Nameandfuladdresswithcontactdetailsof

theapplicant)toimportnewdrugorinvestigationalnewdrugforconductofclinical trialor
bioavailability orbioequivalence study as perprotocolnumber dated

orforexamination,testandanalysisinthebelowmentionedclinicaltrial sitesorbioavailabilityorbioequivalencestudycentre.[AsperAnnexure].

.

2 . T h is lic e n c e is s u b je c t to th e c o n d itio n s p re s c rib e d in C H A P T E R IX o f th e N e w DrugsandClinicaltrialsRules,2018.

3.Thislicenceshal,unlesspreviouslysuspendedorrevoked,beinforceforaperiod ofthreeyearsfrom thedateofitsissuance.

4.Detailsofoverseasmanufacturerandmanufacturingsiteunderthislicence.

5.Thelicenceeshalmaintaintherecordofimportednew drugorinvestigational newdrugs[AsperAnnexure].

Place:…………. Date:.

  

S.N

Nameofthenewdrug orinvestigationalnew drugtobeimported

Therapeuticclassofnew drugorinvestigational

newdrug

Quantitytobe imported

S.N.

Name and address ofmanufacturer (fuladdresswithtelephone,faxande mailaddressofthemanufacturer)

Name and address ofmanufacturing site(fuladdresswithtelephone,faxand e-mail address of the manufacturingsite)

Page193of193

Central Licencing Authority

Stamp

Page194of194

Annexure: Detailsofclinicaltrialsiteorbioavailabilityorbioequivalencestudycentre:

Namesandaddress

Ethicscommiteedetails:

Nameofinvestigator:

Page195of195

FORM CT-18 (SeeRules75and76)

APPLICATIONFORGRANTOFPERMISSIONTOIMPORTNEW DRUGFORSALEORFORDISTRIBUTION

I/We,. (nameandaddressoftheapplicant)ofM/s. herebyapplyforgrantofpermissiontoimportnewdrugforsale.

1.Nameofapplicant:

2.Natureandconstitutionofapplicant:

(proprietorship, partnership including limited liability partnership, company society,trust,othertobespecified)

3.(i)Corporate/registered ofice address including telephone number, mobile number,faxnumberande-mailid:

(i) Manufacturer’s address including telephone number,mobile number,fax numberande-mailid:

(i)Addressforcorespondence:

4.Detailsofnewdrugtobeimported(ActivepharmaceuticalIngredientor FinishedFormulation)[AsperAnnexure].

5.Detailsofthemanufacturerandmanufacturingsite[AsperAnnexure].

6. Fee paid on Rs receipt/chalan/transactionid .

 

7.Iherebystateandundertakethat:

(i)IshalcomplywithaltheprovisionsoftheDrugsandCosmeticsAct,1940 andCHAPTERXoftheNewDrugsandClinicaltrialsRules,2018.

Place: Date:

DigitalSignature (Nameand designation)

,

 

Page196of196

Annexure: Detailsofnewdrug:

Nameofthenewdrug

Dosageform

Compositionoftheformulation

Therapeuticclassofthenewdrug

Indicationsforwhichproposedtobe used

Manufactureroftherawmaterial(activ pharmaceuticalingredient)

Detailsofmanufacturerandmanufacturingsiteofnewdrug:

f

e

Name and address o m anufacturer (ful l address w ith telephone,faxande-mailaddress ofthemanufacturer)

Nameandaddressofmanufacturingsite (fuladdress with telephone,fax and e mailaddressofthemanufacturingsite)

Page197of197

FORM CT-19 (SeeRules76and79)

PERMISSIONTOIMPORTNEW ACTIVEPHARMCEUTICAL INGREDIENTFORSALEORFORDISTRIBUTION

TheCentralLicencingAuthorityherebygrantspermissionto
(N a m e a n d fu l l p o s ta l a d d re s s o f a u th o ris e d a g e n t w ith c o n ta c t d e ta ils o f th e organization)toimportnew activepharmaceuticalingredientmanufacturedbyan overseasmanufacturerspecifiedbelowforsale.

2.Detailsofoverseasmanufactureranditsmanufacturingsiteunderthislicence. .

lf

3.ThispermissionissubjecttotheconditionsprescribedinCHAPTERXoftheNew DrugsandClinicaltrialsRules,2018undertheDrugsandCosmeticsAct,1940.



S.N

Nam e and address of overseas manufacturer (ful name and addresswithtelephoneande-mai addressofmanufacturer)

Nameandaddressofmanufacturing site (fulname and address with telephone and e-mail address o manufacturingsite)

4.Detailsofactivepharmaceuticalingredienttobeimported.

Nameoftheactivepharmaceuticalingredienttobeobtained

Quantity

Place:…………. Date:.

Central LicencingAuthority

Stamp

Page198of198

FORM CT-20 (SeeRules76and79)

PERMISSIONTOIMPORTPHARMACEUTICALFORMULATIONSOFNEW DRUGFOR SALEORFORDISTRIBUTION

TheCentralLicencingAuthorityherebygrantpermissionto
(N a m e a n d fu l l p o s ta l a d d re s s o f a u th o ris e d a g e n t w ith c o n ta c t d e ta ils o f th e organization)toimportpharmaceuticalformulationmanufacturedbyanoverseas manufacturerspecifiedbelowforsale.

2.Detailsofoverseasmanufactureranditsmanufacturingsiteunderthislicence.

lf

3.Detailsofpharmaceuticalformulation:

4.ThispermissionissubjecttotheconditionsprescribedinCHAPTERXoftheNew DrugsandClinicaltrialsRules,2018undertheDrugsandCosmeticsAct,1940.



S. No

Nam e and address of overseas manufacturer (ful name and addresswithtelephoneande-mai addressofmanufacturer)

Nameandaddressofmanufacturing site (fulname and address with telephone and e-mail address o manufacturingsite)

Nameofthenewdrugtobeimported:

Dosageform:

Composition:

Indication:

Place:…………. Date:.

CentralLicencing AuthorityStamp

Page199of199

FORM CT-21 (SeeRules80and81)

APPLICATIONFORGRANTOFPERMISSIONTOMANUFACTURENEW DRUG FORMULATIONFORSALEORFORDISTRIBUTION

I/We,. (nameandfulpostaladdressoftheapplicant)ofM/s

.herebyapplyforgrantofpermissionto manufacturenewdrugforsaleordistribution.

Thedetailsoftheapplicationareasunder:

1.Nameofapplicant:

2.Natureandconstitutionofapplicant:

(i.e.proprietorship,partnership including limited liability partnership, company society,trust,othertobespecified)

3.(i)Corporate/registered ofice address including telephone number, mobile number,faxnumberande-mailid:

(i) Manufacturer’s address including telephone number,mobile number,fax numberande-mailid:

(i)Addressforcorespondence:

4.Detailsofnewdrugtobemanufactured(ActivepharmaceuticalIngredientor FinishedFormulationorboth)[AsperAnnexure].

5.Detailsofthemanufacturerandmanufacturingsite[AsperAnnexure].

6. Fee paid on Rs receipt/chalan/transactionid.



7.Iherebystateandundertakethat:

(i)IshalcomplywithaltheprovisionsoftheDrugsandCosmeticsAct,1940 andCHAPTERXoftheNewDrugsandClinicaltrialsRules,2018.

Place: Date:

DigitalSignature (Nameanddesignation)

,

 

Page200of200

Annexure: Detailsofnewdrug:

Nameofthenewdrug

Dosageform

Compositionoftheformulation

Therapeuticclassofthenewdrug

Indicationsforwhichproposedtobe used

Detailsofmanufacturerandmanufacturingsiteofnewdrug:

f

Name and address o m anufacturer (ful l address w ith telephone,faxande-mailaddress ofthemanufacturer)

Name and address ofmanufacturing site (fuladdresswithtelephone,faxande-mai addressofthemanufacturingsite)

Page201of201

l

FORM CT-22 (SeeRules81,82and83)

PERMISSIONTOMANUFACTURENEW ACTIVEPHARMACEUTICAL INGREDIENTFORSALEORFORDISTRIBUTION

The Central Licencing Authority hereby grant permission to …………………………………… (Name and fuladdress with contactdetails ofthe manufacturer)tomanufactureforsalethenew activepharmaceuticalingredient manufacturedbymanufacturerspecifiedbelow.

2.Detailsofmanufactureranditsmanufacturingsiteunderthispermission. f

lf

3.ThisissubjecttotheconditionsspecifiedinCHAPTERXoftheNew Drugsand ClinicaltrialsRules,2018undertheDrugsandCosmeticsAct,1940.

4.Detailsofthenewactivepharmaceuticalingredienttobemanufactured-.

S. No

Name and address o manufacturer (ful name and addresswithtelephoneande-mai addressofmanufacturer)

Nameandaddressofmanufacturing site (fulname and address with telephone and e-mail address o manufacturingsite)

Place:…………. Date:.

CentralLicencing AuthorityStamp

Page202of202

FORM CT-23 (SeeRules81,82and83)

PERMISSIONTOMANUFACTUREPHARMACEUTICALFORMULATIONOFNEW DRUGFORSALEORFORDISTRIBUTION

The Central Licencing Authority hereby grant permission to … … … … … … … … … … … … … … (N a m e a n d fu l l a d d re s s o f a u th o ris e d a g e n t w ith c o n ta c t detailsofthemanufacturer)tomanufactureforsaleofpharmaceuticalformulation manufacturedbyanmanufacturerspecifiedbelow.

2.Detailsofmanufactureranditsmanufacturingsiteunderthislicence. f

lf

3.Detailsofpharmaceuticalformulation:

S.No

Name and address o manufacturer (ful name and addresswithtelephoneande-mai addressofmanufacturer)

Nameandaddressofmanufacturing site (fulname and address with telephone and e-mail address o manufacturingsite)

Nameofthenewdrugtobeimported:

Dosageform:

Composition:

Indication:

Shelflifewithstoragecondition:

4.ThisissubjecttotheconditionsprescribedinCHAPTERXoftheNew Drugsand ClinicaltrialsRules,2018undertheDrugsandCosmeticsAct,1940.

Place:…………. CentralLicencing

Date:.

AuthorityStamp

Page203of203

FORM CT-24 (SeeRule86)

APPLICATIONFORLICENCETOIMPORTOFUNAPPROVEDNEW DRUGFOR TREATMENTOFPATIENTSOFLIFETHREATENINGDISEASEINAGOVERNMENT HOSPITALORGOVERNMENTMEDICALINSTITUTION

I/We,. (name and ful postal address of the applicant) of M/s

.herebyapplyforgrantoflicence to import unapprovednew drugbutunderclinicaltrialfortreatmentofpatientsoflife threateningdiseaseinagovernmenthospitalormedicalinstitution. Thedetailsoftheapplicationareasunder:

1.NameofMedicaloficer:

2.Natureandconstitutionofapplicant:

(GovernmentHospitalorMedical Institution)

3.(i)Aaddressincludingtelephonenumber mobilenumber,faxnumberande-mailid ofthe GovernmentHospitalorMedica Institution:

(i)Addressforcorespondence:

4.Detailsofunapprovednewdrugpharmaceuticalformulationtobeimported[As perAnnexure].

5.Detailsofthemanufacturerandmanufacturingsite[AsperAnnexure].

6.Detailsofthepatientanddisease[AsperAnnexure].

7. Fee paid on Rs receipt/chalan/transactionid.



8.Alegalundertakingstatingthattheunapprovednewdrugtobeimportedshalbe usedforthetreatmentofthepatientforthediseasementionedbelowonlyandno partofitshalbe
soldinthemarketisenclosedherewith.

Place: Date:

DigitalSignature (Nameand designation)

, l

 

Page204of204

Annexure: Detailsofunapprovednewdrugtobeimported:

Detailsofmanufacturerandmanufacturingsite:

f

Detailsofpatient:

Certificate Certifiedthattheunapprovednew drugspecifiedaboveforimportisurgently requiredforthetreatmentofpatientssuferingfrom…………………………….andthatthe

Nameofthenewdrug

Dosageform

Quantity

Indicationsforwhichproposedtobe used

Name and address o m anufacturer (ful l address w ith telephone,faxande-mailaddress ofthemanufacturer)

Name and address ofmanufacturing site (fuladdresswithtelephone,faxande-mai addressofthemanufacturingsite)

saiddrugisnotavailableinIndia.

Place. Date.

Signature

MedicalSuperintendentofthe GovernmentHospital/HeadofMedical Institution[Stamp]

Page205of205

l

Nameofthepatient

Diseasename

FORM CT-25 (SeeRules87and88)

LICENCETOIMPORTUNAPPROVEDNEW DRUGFORTREATMENTOFPATIENTS OFLIFETHREATENINGDISEASEINAGOVERNMENTHOSPITALOR MEDICALINSTITUTION

LicenceNumber:
TheCentralLicencingAuthorityherebygrantlicenseto (Name

and fulpostaladdress with contactdetails ofthe GovernmentHospitalor GovernmentMedicalInstitution)toimporttheunapprovednewdrugspecifiedbelow for the purpose of treatm ent of the patient for the disease ………………………………… (Nameofthedisease).

2.ThispermissionissubjecttotheconditionsprescribedinCHAPTERXIoftheNew DrugsandClinicaltrialsRules,2018undertheDrugsandCosmeticsAct,1940.

3.Thislicenceshal,unless previouslysuspended orrevoked,be in force fora period of.from thedateofitsissuance.



4.Detailsofthenewdrugtobeimported

Place:…………. Date:.

CentralLicencing AuthorityStamp

Nameofnewdrug:

Quantitytobeimported:

Page206of206

Annexure Detailsofnewdrugimported:

.n

Detailsofrecordofpatienthistory: .

Detailsofreconciliationofnewdrugtobeimported:

Sl.No

Date of import

Licenc eNo.

Nameof thenew drug imported

Imported through (Portofice name)

Consignme tNo.

Quantity imported

LicenceNo

Name ofthe new drug

Patien t name

Diagnosis detailwith date

Diseas e name

Dosage schedul e

Date

Na me of the new drug

Licenc eNo.

Initial quanti ty

Quantit yused

Quantity remaine d

Quantity–

leftover/remain unused/got damaged/expired/fo undofsub-standard quality

Actio n taken

*WriteNAwherenotapplicable.

Page207of207

FORM CT-26 (SeeRule91)

APPLICATIONFORGRANTOFPERMISSIONTOMANUFACTUREUNAPPROVED NEW DRUGBUTUNDERCLINICALTRIALFORTREATMENTOFPATIENTSOFLIFE THREATENINGDISEASEINAGOVERNMENTHOSPITALOR MEDICALINSTITUTION

I/We,. (name and ful postal address of the applicant) of M/s .hereby apply for grant of permission to

manufactureunapprovednewdrugbutunderclinicaltrialfortreatmentofpatientsof lifethreateningdiseaseinagovernmenthospitalormedicalinstitution. Thedetailsoftheapplicationareasunder:

,

1.Nameofapplicant:

2.Natureandconstitutionofapplicant:

(proprietorship, partnership including limited liability partnership, company society,trust,othertobespecified)

3.(i)Corporate/registered ofice address including telephone number, mobile number,faxnumberand

e-mailid:

(i) Manufacturer’s address including telephone number,mobile number,fax numberande-mailid:

(i)Addressforcorespondence:

4.Detailsofunapprovednewdrugtobemanufactured[AsperAnnexure].

5.Detailsofthemanufacturerandmanufacturingsite[AsperAnnexure].

6.DetailsoftheMedicaloficerandGovernmentHospitalandMedicalInstitution

7 . C o p y o f re c o m m e n d a tio n o f th e e th ic s c o m m it te e a n d c o n s e n t fro m th e p a tie n t inaccordancewithRule81oftheRegulationofNewDrugsandClinicalTrials Rules2017areherebyenclosed.

8. Fee paid on Rs receipt/chalan/transactionid .

 

9.Alegalundertakingstatingthattheunapprovednewdrugtobemanufactured shalbeusedforthetreatmentofthepatientforthediseasementionedbelowonly andnopartofit

Page208of208

shalbesoldinthemarketisenclosedherewith.

Page209of209

Place: Date:

DigitalSignature(Name anddesignation)

 

Annexure: Detailsofunapprovednewdrugtobemanufactured:

Detailsofmanufacturerandmanufacturingsite:

f

Nameofthenewdrug

Quantity

Indications

Name and address o m anufacturer (ful l address w ith telephone,faxande-mailaddress ofthemanufacturer)

Name and address ofmanufacturing site (fuladdresswithtelephone,faxande-mai addressofthemanufacturingsite)

Detailsofthegovernmenthospitalorgovernmentmedicalinstitutionandpatient:

Certificate
Certifiedthattheunapprovednew drugbutunderclinicaltrialspecifiedabovefor

manufactureisurgentlyrequiredforthetreatmentofpatientssuferingfrom and thatthesaiddrug(s)is/arenotavailableinIndia.

l

Nameofthegovernmenthospital orgovernmentmedicalinstitution

Addressofthegovernment hospitalorgovernmentmedical institution

Nameandaddressofthepatient

Diseasename



Place.

Date.

Page210of210

SignatureMedicalSuperintendentof theGovernment

Page211of211

Hospital/HeadofMedicalInstitution [Stamp]

FORM CT-27 (SeeRules92,93and96)

PERMISSIONTOMANUFACTUREUNAPPROVEDNEW DRUGBUTUNDER CLINICALTRIALFORTREATMENTOFPATIENTSOFLIFETHREATENING DISEASEINAGOVERNMENTHOSPITALORMEDICALINSTITUTION

LicenceNumber……………………

The Central Licencing Authority hereby grant permission to ……………………………………….(Nameandfulpostaladdresswithcontactdetailsofthe organization)tomanufacturetheunapprovednew drugspecifiedbelow onthe premisessituatedat…………………………………………..(fulpostaladdresswithcontact detailsofthemanufacturingsite)forsupplyto……………………………………(nameofthe medicaloficerandaddressoftheGovernmenthospitalormedicalinstitution)for thetreatmentofthepatientforthedisease………………………(Nameofthedisease).

2.ThislicenceissubjecttotheconditionsprescribedinCHAPTERXIoftheNew DrugsandClinicaltrialsRules,2018undertheDrugsandCosmeticsAct,1940.

3.Thislicenceshal,unlesspreviouslysuspendedorrevoked,beinforceforaperiod ofoneyearfrom thedatespecifiedbelow:–

4.Detailsofthenewdrugtobemanufactured

Name:

Quantity:

Place:…………. Date:.

CentralLicencing AuthorityStamp

Page212of212

Annexure: Detailsofunapprovednewdrugmanufactured:

.

Detailsofrecordofpatienthistory: .

Detailsofreconciliationofunapprovedactivepharmaceuticalingredientmanufactured:

Sl. No .

Dateof manufact ure

LicenceNo

Nameofthe unapprovednew drug

Quantity manufactur ed

Manufactur edfor

LicenceNo

Name ofthe new drug

Patien t name

Diagnosis detailwith date

Diseas e name

Dosage schedul e

Da te

Name of the unapprove dnewdrug

Licenc eNo.

Quantity manufacture d

Quantit y supplie d

Quantity remaine d

Supplie dto

Quantity–

leftover/remain unused/got damaged/expired/fo undofsub-standard quality

Action taken

*WriteNAwherenotapplicable.

Note:TheprincipalRuleswerepublishedintheGazeteofIndiavidenotificationNo.F.28-10/45-

st
H(1)dated21 December,1945andlastamendedvidenotificationnumberG.S.R…..(E)dated

……….

[FileNo.X.11014/10/2017-DRS-Part(1)]

(SudhirKumar) JointSecretarytotheGovernmentofIndia

Page213of213

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