Analysis Report - APACFSC Free Sale Certificate: FtoF or F2F or FTF Face to Face : GDA Generic Drug...

Asia Partnership Conference of Pharmaceutical Associations (APAC)

Analysis Report ver. 2014

Identification and Clarification of the Differences in Regulatory Requirements between Asian Economies

APAC Regulations and Approvals Expert Working Group

April 10, 2014 Tokyo, Japan

Member Associations

HKAP (Hong Kong) Hong Kong Association of the Pharmaceutical Industry

IPMG (Indonesia) International Pharmaceutical Manufacturers Group

IRPMA (Taiwan) International Research-Based Pharmaceutical Manufacturers Association

JPMA (Japan) Japan Pharmaceutical Manufacturers Association

KPMA (Korea) Korea Pharmaceutical Manufacturers Association

KRPIA (Korea) Korean Research-based Pharmaceutical Industry Association

OPPI (India) Organization of Pharmaceutical Producers of India

PhAMA (Malaysia) Pharmaceutical Association of Malaysia

PHAP (Philippines) Pharmaceutical and Healthcare Association of the Philippines

PreMA (Thailand) Pharmaceutical Research & Manufacturers Association

RDPAC (China) China Association of Enterprise with Foreign Investment R&D-based Pharmaceutical Association Committee

SAPI (Singapore) Singapore Association of Pharmaceutical Industries

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AbbreviationAbbreviation DescriptionACTD ASEAN Common Technical DocumentACTR ASEAN Common Technical RequirementsADR Adverse Drug ReactionAE Adverse EventAIDS Acquired Immune Deficiency SyndromeA.O. Administrative Order (in Philippines)API Active Pharmaceutical IngredientASEAN Association of South‐East Asian NationsBP British PharmacopoeiaPBRER Periodic Benefit Risk Evaluation Report (Philippines）BSE Bridging study evaluationCDCR Control of Drugs and Cosmetic Regulation (Malaysia）CDE Center for Drug EvaluationCDSCO Central Drugs Standard Control Organization (in India)CEP Certification of Suitability to the monographs of the European PharmacopoeiaCFDA China Food and Drug AdministrationCFS Certificate of Free SaleCIRB Centralised Institutional Review Board (Singapore）cGMP current Good Manufacturing PracticeCh.P. Chinese PharmacopoeiaCMC Chemistry, Manufacturing and ControlCoA/COA/CA Certificate Of AnalysisCPP Certificate of Pharmaceutical ProductCRC Clinical Research CentreCRF Case Report FormCRO Contract Research OrganizationCSR Clinical Study ReportCT Clinical TrialCTA Clinical Trial ApplicationCTA Clinical Trial AuthorizationCTC Clinical Trial Certificate CTD Common Technical DocumentCTIL Clinical Trial Import License（in Malaysia）CTM Clinical Trial MaterialCTN Clinical Trial NotificationCTRI Clinical Trials Registry- India CTT Clinical Trial TeamCTX Clinical Trial ExemptionCV Curriculum Vitae DB Double BlindDCGI Drugs Controller General（in India）DMF Drug Master FileDOH Department of HealthDP Drug ProductDS Drug SubstanceDSRB National Healthcare Group Domain-Specific Review Board (Singapore)EC Ethical/Ethics CommitteeEMA European Medicines AgencyEP European PharmacopoeiaEPAR European Public Assessment Report

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Abbreviation DescriptionEPW Empowered Procurement Wing (in India)EU European UnionFDA Food and Drug Administration (in U.S.)FDC Fixed Dose CombinationFSC Free Sale CertificateFtoF or F2F or FTF Face to Face GDA Generic Drug ApplicationGCP Good Clinical PracticeGLP Good Laboratory PracticeGMP Good Manufacturing PracticeGMP CERT GMP CertificationGpvP Good Pharmacovigilance Practice GS-1 Global Standard OneGSB Global Safety Board GTIN Global Trade Item NumberHA Health AuthoritiesHAS Health Sciences in SingaporeHIV Human Immunodeficiency VirusHKD Hong Kong dollarHSA Health Sciences Authority (in Singapore)IB Investigator's BrochureIC Informed ConsentICF Informed Consent Form

ICH The International Conference on Harmonization of Technical Requirements forRegistration of Pharmaceuticals for Human Use

ICH E5 ICH E (Efficacy) 5 Guideline (Ethnic Factors in the Acceptability of ForeignClinical Data)

ICH E6 ICH E (Efficacy) 6 Guideline (Good Clinical Practice)ICSR Individual Case Safety ReportIDL Import Drug Licence　（China)IEC(EC) Independent Ethics CommitteeIND Investigational New DrugIP Indian PharmacopoeiaIP International PharmacopoeiaIRB Institutional Review BoardJP Japanese PharmacopoeiaKP Korean PharmacopoeiaKRW South Korean wonLOA Letter of Authorization MAH Marketing Authorization HolderMAV Major Variation (in ASEAN)MF Master FileMFDS Ministry of Food and Drug SafetyMHLW Ministry of Health Labour and Welfare （in Japan）MIDR Million Indonesian rupiahMIV Minor Variation (in ASEAN)MOH Ministry of Health (in China)MOHFW Ministry of Health and Family Welfare (in India)MOHW Ministry of Health, Welfare (in Korea)MOPH Ministry of Public Health（in Thailand）MRCT Multi-Regional Clinical Trial

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Abbreviation DescriptionMREC Medical Research Ethics/Ethical CommitteeNADFC National Agency of Drug and Food Control（in Indonesia）NBE New Biological Entities NCE New Chemical EntityNDA New Drug Application NDAC New Drug Advisory Committee NF National FormularyNHG DSRB National Healthcare Group Domain-Specific Review Board (Singapore）NIBIO National Institute of Biomedical InnovationNiFDS National Institute of Food and Drug Safety EvaluationNLT Not less thanNME new molecular entity NPCB National Pharmaceutical Control Bureau (Malaysia）NT$ New Taiwan dollarOTC Over-The-Counter （drug）PD PharmacodynamicsPFDA Philippines　Food and Drug AdministrationPhP Philippine pesoPI Principal InvestigatorPI Package Insert

PIC/S The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme

PK PharmacokineticsPMDA Pharmaceuticals and Medical Devices Agency (JAPAN)PMS Post-Marketing Surveillance/StudyPP Philippine PharmacopoeiaPSUR Periodic Safety Update Reportr-DNA recombinant DNAREMS Risk Evaluation and Mitigation StrategyRM ringgitRMB renminbi = CNY (CHINESE YUAN)RMP Risk Management PlanRRC research review committeeRs RupeeSAE Serious Adverse EventSAR Serious Adverse ReactionSKU Stock Keeping UnitSMF Site Master FileSMP Safety Monitoring Program (in Thailand)SOP Standard operating procedureSMPC summary product characteristicsSQOS Singapore Quality Overall SummarySUSAR Suspected Unexpected Serious Adverse ReactionTB TuberculosisTFDA Taiwan Food and Drug AdministrationTGA Therapeutic Goods AdministrationTOX ToxicologyUS United StatesUSP United States PharmacopoeiaWHO World Health Organization

Survey Results Data sheets from Each Economy

on the areas of IND, NDA, Clinical Trials and GMP Evaluation System

China (RDPAC) Hong Kong (HKAPI) India (OPPI) Indonesia (IPMG) Japan (JPMA) Korea (KPMA) Korea (KRPIA) Malaysia (PhAMA) Philippines (PHAP) Singapore (SAPI) Taiwan (IRPMA) Thailand (PreMA)

Survey Results: Data sheets from each economy on the areas of IND, NDA, Clinical Trials and GMP Evaluation System 10 April, 2014

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China Hong Kong India Indonesia Japan Korea Malaysia Philippines Singapore* Taiwan ThailandRDPAC HKAPI OPPI IPMG JPMA KPMA/KRPIA PhAMA PHAP SAPI IRPMA PReMA

Requirementsof the applicant

CRO is possible? Companies or regulatoryagency (CRO)

Basically, CRO anddoctors who can followstandards of GCP.

Sponsor companies, CROs anddoctors who can follow standardsof GCP.

CRO , Companies anddoctors who can followstandards of GCP.

Basically, companies anddoctors who can followstandards of GCP.

Company, CRO or doctor, whocan follow standards of GCP,can be IND holder.

Investigator, or sponsor orCRO can make theapplication.

Sponsor companies, CROsand doctors who can followstandards of GCP.

Sponsor companyshould make theapplication.

CRO can be an applicant (INDholder), just the company registers inTaiwan with legal entity.

Drug manufacturing/import license holder orgovernment (applicant can be sponsor or CRO)

Clinical trialconsultationsystem

System, Timing,Procedure

There are formal andinformal consultations withCDE (Center for DrugEvaluation).1) CDE started formalconsultation system in 2011.2) pre-IND, IND, end of PhI,end of PhII or pre-NDA areapplicable if the productaccepted for special reviewprocedure.Flow: application withquestions anddocuments/data (-8Weeks),FtoF meeting, then, fixedminutes (4W)3) If initiated by CDE,consultation meeting usuallyis held during IND or NDAreview period.

No Non-formal consultation ispossible.Pre-screening of the application isdone at DCGI office beforeaccepting our application.1. IND- For phase 1 trials of NCEsapplication is referred to INDcommittee scheduled to meetevery quarter(for moleculediscovered outside India FIMstudies are not permitted.2. Other IND application -Theapplication is referred to NewDrug Advisory Committee (NDAC)for review. Post review, theSponsor/CRO is invited to a Faceto Face meeting with NDACwhere they need to present &defend the proposal

The consultation withHead of evaluator is veryTuesday and consultationwith Assistant Director ofregistration everyWednesday or byappointment .

There are many kinds ofcharged consultation withPMDA. Ex. Pre-PhI/Pre-PhIIa/Pre-PhIIb/End ofPhIIstudy, Pre-application,Quality, Safety, etc.Flow: Tentative application(-8Week), submit thequestions and documents (-5W), Inquiries and theanswers, PMDA' opinion(<-4day), FtoF meeting, Fixedminutes (30days)

Official pre IND consultation canbe held 40 days beforeexpected consultation meetingand it should be requested inwritten form. Meeting minuteswill be issued 10 days after themeeting by MFDS(Ministry ofFood and Drug Safety).Pre-review system covers INDpreparations. F2F meeting14~24 days after primary reviewresult.

No For company-initiated localtrial, the proposed clinical trialprotocol is prepared by themedical department inconsultation with a physician-specialist who becomes a co-author. The protocol is thensubmitted to the GSB andregional Safety Department &Regulatory Department forapproval. The final approvalcomes from the FDA. Forinvestigator-initiated trials, theproposed protocol is written bythe authors subject to theapproval of the medical dept ofHI-Eisai. The protocol is thensent to the variousdepartments similar tocompany-initiated trials.(see FDA Circular 2012-007)

No. But for first-in-human trials, HSAwould prefer if companyhas a pre-submissionconsultation about 2months beforesubmission.

Regulation consultation service isavailable for all phases of productdevelopment. It is free of chargewithout legal binding. The way forthe consultation can choice officialletter response, face to face meetingetc. The procedure should be on-line submission first. Then the projectmanager of CDE will contact with theapplicant for confirm the questionwhich applicant raised andrequesting more information. 2 to 4weeks after the submission will betaken for meeting arrangement. Alsothe project manager will arrange theappropriate time and attendee list forthe consultation meeting. In general,1 hour for FTF meeting, and meetingminutes may be available 2 weeksafter the meeting.

Can consult at FDA (Such as direct contact,telephone)

Flow of clinicaltrial notification,IND applicationand IRBpermission

Flowchart Clinical trial can be initiatedafter IND approval and IRBpermission.In China, clinical trialapplication is necessary.After getting Clinical TrialApproval (CTA), sponsorshould apply for IRBpermission with CTA,protocol, IB etc. Even ifIRB/IEC review isindependent of CTA, allIRB/IEC require CTA as partof the application document.

Approval by DOH isrequired.IRB approval is alsorequired.

Clinical trial on new drug shall beinitiated after authorization byCDSCO (NOC:No ObjectionCertificate from DCGI) andapproval of respective EC.In case of parallel applications,CDCSO will grant conditionalapproval and note that the trialshould start after Ethics approval.

Flow Chart of Clinical TrialNotification seeAttachment II a & II b , IIIa& IIIb , IV a & IV b , (SeeAnnex 1)

In Japan, a clinical trial isconducted based onnotification, not onapplication.Contracts with clinical sitesshould be signed after 30days from the clinical trialnotification (14 days fromthe second trial onwards).

There is no clinical trialnotification system, and onlyIND approval is available.Clinical trial should beconducted within 2 years afterIND approval.(See the flow chart at Annex 2)

Approval by NationalMedical Research Registeris required. IRB approval isalso required.

We now have a central ethicalreview board in the FDA. Thisboard reviews the protocol.Once approved, the CT mayproceed. Centers where theclinical trial is to be conductedis notified.Please see FDA Circular 2012-007 (p. 6 &8)

Approval by HSA andIRB approval arerequired respectivelybefore start of clinicaltrial.Parallel submissions ispossible to both theHSA and the respectiveIRB.

TFDA has clinical trial notification(CTN) process and general INDapplication procedure. CTN processonly reviews the administrationdocuments by CDE without scientificreview for protocol.IRB permission will depend on thesite requirement and approval timealso depends on IRB. Most contractswith clinical sites need to get IRBapproval first prior to sign thecontract, the time for contract maytake around 2 months.

Apply for IRB or IEC Review and Approval- There are 8 accredited IRB/IEC by Thai FDA- For other study sites that IRB has notaccredited, required to submit CT protocol toIRB of MOPH for approval.After IRB/IEC approval, submit the approvalletter for IND applicationFlow chart: Refer to Guideline on Application forDrug Import permit into Thailand for Clinical Trial(2009)

Time requiredfor clinical trialnotification, INDapplication andIRB permissionobtainment

Official timeline:**working days

Timeline based onactual experience

IND review usually takes12+/-2M months at leastafter application.After IND approval, sponsorshould conduct clinical trialwithin 3 years that CTA isinvalid.

3 months IND review: 6-8 monthsEC review: 2-4 months

Timeline for evaluation is14 working days forprotocol & amendment ofclinical trial after NADFCstated the protocol &amendment complete .

The rule of “after 30 daysfrom the first clinical trialnotification” for drugscontaining new activeingredients, new ethicalcombination drugs anddrugs with a newadministrative route.The clinical trial can bestarted after 14 days fromclinical trial notification forthe second trial onwards (forthe same product).

IND application official timelinebased on the results of theconsultation: 30 working daysTimeline based on actualexperience: Given 1 time queryby MFDS during their INDreview period, it takes 2-3months.According to sites, IRB reviewwill be held every 2 weeks toevery 2 months depending onthe sites.Totally, for initial 3 months, wecan get IND approval & IRBapproval in parallel.

Official Timeline forCTIL/CTX: forFirst in Man (FIM),AdvanceTherapy Product(ATP), biological productsand herbal products: 45working daysfor Others: 30 working daysEthics approval: completesubmission without queriescan be approved within 4 to8 weeks.

No specific timelines for trialnotification.(Basically not more than 60days from submission)

HSA review 4-6 weeks(30 days), CTT/IRBreview 30-60 days.

The time for CTN will be within 30days. General IND applicationprocedure will review protocol indetail by CDE and may request torevise protocol based on their reviewresult. the approved time may takearound 30 working days.IRB permission time depends. Theapprove time may takes around 3 to4 months average.

IND notification : (to Thai FDA ) - 20 daysIND : (to Thai FDA ) - 2 monthsIRB : (each study site or EC of MOPH) - 4-6months

Application form Requirements andlanguage

Yes application form (inChinese)

Application form forCertificate for ClinicalTrial

Yes (Form 44, in English) There is a checklistrequirement .

Yes: Clinical trial notificationform (in Japanese)

Yes: Clinical Plan ApprovalRequest form (in Korean)

Application form forCTIL/CTX (Clinical TrialImport Licence/ Clinical TrialExemption).In English or BahasaMalaysia

Yes, in English.Please see FDA Circular 2012-007

Application form forClinical Trial Certificate(CTC) to HSA. IRB hasno form.

Application form is needed and it canbe in English. But the format is inChinese.

Local form (in Thai)

A statementregarding thereason why thesponsoring ofthe proposedclinical trial is

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Requirements andlanguage

Yes (in Chinese) No Yes (in English) and vernacularlanguage

Yes Yes (in Japanese) Yes (in Korean) No Please see FDA Circular 2012-007 (p.4)

No Yes, the official letter to indicate thesponsoring of proposed clinical trialis needed.

Cover letter (have template in Thai)

Protocol Requirements andlanguage

Yes (in Chinese） Yes, in English Yes (in English) Yes Yes (in Japanese） Yes (in Korean) Yes, in English or BahasaMalaysia

Yes, in English Yes, in English Required. Chinese or English isacceptable. But for global clinicaltrial, English version protocol is bestchoice.

See detail in guideline, can be in Thai or English

Detail or Example

IND

INDappli-cationmaterials

Item Contents


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China Hong Kong India Indonesia Japan Korea Malaysia Philippines Singapore* Taiwan ThailandRDPAC HKAPI OPPI IPMG JPMA KPMA/KRPIA PhAMA PHAP SAPI IRPMA PReMADetail or ExampleItem Contents

IB Requirements andlanguage

Yes (in Chinese)Usually synopsis or abstractof each report in Chinese isrequired, attached withsource report.

Yes, in EnglishFor Ph IV trials, HKregistered pack insertcan be used.

Yes (in English) Yes, ( in Indonesian orEnglish )

Yes (in Japanese) Yes (English acceptable) Yes,in English or BahasaMalaysia

Yes, in English Yes, in English Required. Chinese or English isacceptable. But for global clinicaltrial, English version is best choice.

See detail in guideline (for unregistered drug inThailand)

CRF (sample) Requirements andlanguage

MRCT: Yes (in Chinese)Import product: No

Yes, in English Yes (in English) Yes, ( in Indonesian orEnglish )

No, if the description of CRFis to be read by PC.

Yes (English acceptable) Yes, in English or BahasaMalaysia

Yes, in English Yes, in English Required. Chinese or English isacceptable. But for global clinicaltrial, English version is best choice.

No requirement

Informedconsent


MRCT: Yes (in Chinese)Import product: No

Yes, in English orChinese

Yes- ENGLISH to be submitted toDCGI. ICF in local regionallanguages has to be submitted toEthics committee for EC approval.(in a language that is non-technical and understandable bythe study subject.)

Yes, ( in Indonesian orEnglish )

Yes (in Japanese) Yes (in Korean) Yes, in English or BahasaMalaysia

Yes, in English Yes, in English Required. Should be in traditionalChinese.

No requirement

Investigator'sCV


No CV of PI Yes (in English) Yes, ( in Indonesian orEnglish )

No No GCP certificate for eachinvestigator.

Yes, in English CV of PI, in English Required. Chinese or English isacceptable. But for global clinicaltrial, usually request PI to provideEnglish version CV.

No requirement

Non-clinicalsummary


Yes (in Chinese) No Yes (in English) Yes, ( in Indonesian orEnglish )

No Yes (in Korean) Investigator's brochure. Yes, in English No Not required. including in IB

Non-clinicalreport



No Yes (in English) Yes, ( in Indonesian orEnglish )

No Yes (English acceptable) Investigator's brochure. Yes, in English No Not required. including in IB

Clinicalsummary



No Yes (in Korean) No Yes, in English No Not required. including in IB

Clinical report Requirements andlanguage


No Yes (in English) Yes, ( in Indonesian orEnglish )

No Yes (English acceptable) Published clinical data. Yes, in English No (for HSA, every 6monthly, status report ofthe trial to be submitted;for IRB usuallyannually)

Not required. including in IB

CMC summary Requirements andlanguage


No Yes (in Korean) Yes Yes, in English No Required. English version isacceptable.

See detail in guideline (for NCE)

CMC report Requirements andlanguage


No Yes (English acceptable) Yes Yes, in English No Not required. See detail in guideline (for NCE)

GMP certificateof theinvestigationaldrug

Necessary orUnnecessary

GMP certificate is notrequired. But a statementthat investigational productsare formulated inaccordance with GMPshould be submitted.

Yes YES. Yes, ( in Indonesian orEnglish )

No Necessary(This is now underthe revision)

Yes Yes, in English No (HSA application, toprovide GMP certificateof the Drug Product siteof Investigation drug,during CTC application)

Yes, provide CoA unnecessary

Sample of theinvestigationaldrug (for INDreview)


Yes for import productregistration.

Yes, proposed labeland COA also.

Samples of reference standardsand finished product (equivalentof 50 clinical doses or more, ifrequested by the Authority), withtesting Protocol/s, full impurityprofile and release specifications.DCGI normaly asks the applicantto submit the samples of the drugproduct along with referencestandard to the governmentlaboratory (Central Drug TestingLaboratory or IndianPharmacopoeial commissionLaboratory). The Applicant needsto submit the samples in thequantity sufficient for three foldanalysis.

No No No No, COA only. Yes (Laboratory testing may berequested)

No Not required. No requirement

INDappli-cationmaterials

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China Hong Kong India Indonesia Japan Korea Malaysia Philippines Singapore Taiwan ThailandRDPAC HKAPI OPPI IPMG JPMA KPMA/KRPIA PhAMA PHAP SAPI IRPMA PReMA

Acceptance ofCTD format

CTD or ACTD orOthers ?

CTD of CMC for chemical drugwith registration category 3~6 canbe acceptable. CTD of non-clinical,clinical documents are notacceptable at this moment.CTD of biologicals are still notacceptable.

Not specified.CTD can be accepted.

ICH-CTD is acceptable. However,it is not indicated in documentissued by HA.

ACTD format . Application data for newdrugs have to be handled bythe CTD format.

CTD format is required for NCE All applications are made inASEAN CTD format.

Application data for new drugshave to be handled by theASEAN CTD format. There isflexibility on the use of ICHdossier as per FDA Adoption ofACTD.

ACTD or CTD Application for NCE have to besubmitted in CTD format.

ACTD

NDA

New Drug I :(1) New chemical entity(2) New indication(3) New combination(4) New administration route New Drug2(1) New dosage form(2) New usage dose(3) New unit dose

Item Contents Detail or Example

Category ofNDA

ex. NCE, Generic,Supplemental,

1) New chemical entity nevermarketed in any country.i. Drug substance and itspreparations made by synthesis orsemi-synthesis.ii. Chemical monomer (includingdrug substance and preparation)extracted from natural sources orby fermentation.iii. Optical isomer (including drugsubstance and preparation)obtained by chiral separation orsynthesis.iv. Drug with fewer componentsderived from marketed multi-component drug.v. New combination products.vi. A preparation already marketedin China but with a newly addedindication not yet approved in anycountry.2) Drug preparation with changedadministration route and notmarketed in any country3) Drug marketed ex-China,including:i. Drug substance and itspreparations, and / or withchanged dose form, but no changeof administration route.ii. Combination preparations, and /or with changed dose form, but nochange of administration route.iii. Preparations with changedadministration route and marketedex-China.iv. A preparation already marketedin China but with a newly addedindication approved ex-China.4) Drug substance and itspreparation with changed acid oralkaline radicals (or metallicelements), but without anypharmacological change, and theoriginal drug entity alreadyapproved in China.5) Drug preparation with changeddose form, but no change ofadministration route, and theoriginal preparation alreadyapproved in China,6) Drug substance or preparationfollowing national standard.(Supplemental application is alsodescribed by regulations.)

Two categories:1. New Chemical Entity (NCE);2. Generic (i.e. drug substance alreadyregistered at Department of Health(DOH))

New Drug:1) New Chemical Entity (NCE),2) New indications, dosage,dosage form and route ofadministration3) Fixed Dose Combination (FDC)(See 122E of the Drugs andCosmetics Rule)

Note: all vaccines andRecombinant DNA (r-DNA)derived drugs shall be new drugsunless certified otherwise by theLicensing Authority

1) New Drug Product (NewChemical Entity): anypharmaceutical products thathave not been previouslyregistered-New Chemical Entity (NCE)/RadiopharmaceuticalSubstance-New Combination Product-Supplemental Product

2) Biologics :- Any products that isproduced using biotechnology,this includes vaccines,monoclonal antibodies, bloodproducts, biosimilars,recombinant proteins, etc.

3) Generic product (a productthat is essentially similar to acurrently registered product inMalaysia. However, the termgeneric is not applicable toBiologics.)

(1) Drugs containing newactive ingredients(2) New ethical combinationdrugs(3) Druds with a newadministration route(4) Drugs with a newindication(5) New dosage form drugs(6) New dosage drugs(7) Follow-on biologics(8) Drugs supplied in anadditional dosage form(9) Similar ethicalcombination drugs(10) Other drugs

(Minor changes in approvedmatters are handled bysimply submitting notices.)

<Chemical>(1) Drug containing new activeingredient. 1) New chemical structure 2) Combination drug includingnovel ingredient(2) Data requering drug(Drug fordata-based re-evaluation) 1) Drug with new salt or isomer 2) Drug with a new indication 3) New dosage drug - Increase/Decrease amount ofAPI - New combination drug 4) Drug with a new adminstrationroute 5) Drug with a new dosage andadministration 6) Yeast, Fungi derivated drug :New origines 7) Drug with a newformulation(same route)<Biologics>(3) Drug containing new molecularentities 1) DNA recombinant durg andCell culture drug 2) Biologics -Vaccine, antitoxins -Bloodproducts -Biologics other than above(therapeutic antigens, botiliniumproducts, ect).(4) Data requiring drug(Drug fordata-based re-evaluation) 1) Biologics : strains andmanufacturing methods are differentfrom authorized biologics 2) Recombinant DNA products:hosts, vectors, or methods to obtainDNA is different from authorizedbiologics 3) Cell culture derived products:same cell line, but different cellculture or purification methods fromauthorized biologics 4) Cell culture derived product:cell line is different from authorizedbiologics 5) When final bulk is the same,but the site for manufacture isdifferent 6) New dosage forms with thesame route of administration 7) Biosimilar product(recombinatDNA) 8) Others not separatelyclassified

A. New Registration , consistof : a. Category 1: New Drug andBiological Product registrationincluding Similar BiologicalProduct / SimilarBiortherapeutic product .b. Category 2: copy drug /generic product.c. Category 3: Registration ofother preparationt containing.B. Registration of drugvariation, consist of :a. Category 4: Major variationregistration (VaMa)b. Category 5 : Minor variationregistration that needs anapproval (VaMi-B)c Category 6.: Minor variationregistration with notification(VaMa-A)C. Re-registration :a. Re-registration / renewal .

(1) Drugs containing new activeingredients(2) New ethical combinationdrugs(3) Drugs with a newadministration route(4) Drugs with a new indication(5) New dosage form drugs(6) New dosage drugs(7) Follow-on biologics(8) Drugs supplied in anadditional dosage form(9) Similar ethical combinationdrugs(10) Other drugs

Minor changes in approvedmatters are handled submittingnotices and sometimesrequires prior approval

NDA-1 for the firststrength of NCE.NDA-2 for newcombination, newdosage form, new routeof administration or newindication of registeredchemical entities.NDA-3 for subsequentstrengths of a new drugproduct.GDA-1 for the firststrength of a genericchemical product.GDA-2 for subsequentstrenths of the genericchemical product.

1) Chemical drugs1.1) New Drugs (NCE, NI, NCO, ND, NR,NDOS, NS)1.2) New Generic (NG)1.3) Generic (G)2) Biological Products

*NCE = New Chemical Entity,NI = New Indication,NCO = New Combination,ND = New Delivery system,NR = New Route of administration,NDOS = New Dosage form of Approved NewDrug,NS = New Strength of Approved New Drug


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China Hong Kong India Indonesia Japan Korea Malaysia Philippines Singapore Taiwan ThailandRDPAC HKAPI OPPI IPMG JPMA KPMA/KRPIA PhAMA PHAP SAPI IRPMA PReMAItem Contents Detail or Example

Not required Required for Import DrugsTiming : When CPP is not besubmitted at NDA, MFDS(Ministry ofFood and Drug Safety) requests it asone of supplementary queries. So itshould be submitted assupplementary data.Number : One original documentSource : Manufacturingcountry/Marketing country (It couldbe submitted separately.)

Category 1 & 2: CPP requiredat time of application;Category 3: CPP required attime of application but notrequired for locally producedgenerics;For imported products, thefollowing requirements shall befurnished, either a:i) CPP from the competentauthority in the country oforigin; OR (Note: In the eventa CPP is not available from thecountry manufacture, e.g.where a product is not licensedfor sale in said countrybecause its manufacturer ismanufacturing under contractonly for product owner fromanother country, the followingalternatives may beconsidered: GMP Certification/Manufacturing License for themanufacturer from the relevantcompetent authority, togetherwith CPP from the country ofthe product owner; or CPPfrom country of release, if CPPfrom the country of the productowner is not available)ii) CFS and GMP from therelevant competent authoritiesis deemed acceptable by theAuthority for healthsupplements and naturalproducts only.CPP shall be in the format ofthe WHO Certification Schemeon the Quality ofPharmaceutical ProductsMoving in InternationalCommerce & be issued by theHealth Authorities listed in theWHO Certification Scheme (listis available from WHOwebsite: http://www.who.int).

Timing of submission is atNDA.Number of required CPP is 1from Source country e.g. ex.Manufacturing/exportingcountry, Marketing country(CPP or FSC/GMP) or anyreference country

NDA

The overseas clinical trial data areaccepted in accordance with ICH E5.BSE is mandatory for NCE NDA.Complete clinical data package relevantto the Asian population is required toBSE. Bridging study is generallyrequired when there is ethnic difference.A bridging study is to provide clinicaldata of pharmacokinetic /pharmacodynamic or clinical data onefficacy, safety, dosage and doseregimen in Taiwan that will allowextrapolation of the foreign clinical datato different populations.Taiwanese PK may be waived throughBSE submission. Some time may needsTaiwan PK or PD or dose-responsedata, it depends on the product. Theproduct with ethical difference mayneeds Taiwan local PK or PD data tosupport NDA approval.

Only for New Drugs, bridging data isneeded additionally.(See figures at Annex 3)

Approval can beobtained byutilizing foreignclinical trialdata.

Requirement ofbridgingdata/report andglobal clinical trialdata/report.Necessity of PKstudy in localpopulation.

Global / MRCT clinical data forchemical drugs are acceptable, butChinese P3 and PK data isindispensable.For biologicals, global / MRCTclinical data is unacceptable at thismoment.

The overseas clinical trial data isacceptable.Bridging data are not required.

Clinical data in Indian populationis required except few life savingtherapeutic categories which is atthe discretion of the regulatoryagency. However now a days,DCGI has become very strict andinsists for local clinical trial datafor every new drug.

Overseas clinical trial data isacceptable, as long as it isaligned with ICH and/or WHOguideline.

Local regulatory trials isrequired for newpyschotropics and drug forfamily planning program /

The overseas clinical trialdata is accepted inaccordance with ICH E5.The drugs approved byusing a bridging strategy orglobal clinical trial data haveincreased.But Japanese PK data isindispensable.

Overseas clinical trial data isacceptable, as long as it isaligned with ICH and/or WHOguidance, and accepted by themajor reference countries.

Local regulatory trials are notrequired.

The overseas clinical trial datais accepted.

Overseas clinical trialdata is acceptable

Not required

Requirement ofCPP

Timing ofsubmission.ex. at NDA, beforeapprovalNumber ofrequired CPP.Source country.ex.Manufacturing/exporting country,Marketing country(FSC)

Import drug require CPP at NDA.Both CPP granted bymanufacturing country ormarketing country are acceptable.

To be submitted at the time ofapplicationNo. of CPP required:NCE: 2 ICH countriesGeneric: 1 (source country only)

CPP or Free sale certificate(FSC) issued by country of originis required at NDA. The CPP andFSC should be notarised andapostilled or legalised by Indianembassy of the country of origin.

Copy CPP is submitted duringpre-registration. The originalCPP should be present duringregistration. CPP onlyrequired for imported product.The product with one CPP willevaluated with 300 workingdays . The product with threeCPP ( one CPP frommanufacturing country , twoCPP from harmonized countryevaluation{ EU} or countrywhich well known goodevaluation system { US, TGA,UK } will evaluated with 150working days. The renewal ofimport product should attachwith latest/new CPP &latest/new GMP certificate.

Submission of CPP isnot compulsory anddepends on type ofsubmission.In case of NDA withCPP, basically requiredat NDA.

At the time of filing, NDA can besubmitted without CPP. Whenapproaching approval time, if Taiwanparticipated two global clinical trials(Ph1+Ph3 or Ph2+ Ph3), (Clinicaldevelopment in Taiwan in earlier) thenCPP can be waived.NDA can be approved with one CPP inone of 10 advanced countries but alsoneed one clinical trial in Taiwan (Ph1 orPh2 or Ph3) within limited Taiwansubjects enrolled into the study.Product have to be launched in sourcecountry or 10 advanced countries.

NDA:Application fees ( the charge fee is amended onMarch 06, 2013, ”Fee-Charging Standards forthe Registration of Western Medicines andMedical Devices”)1. Product registration of a new drug which is ofnew active pharmaceutical ingredient(s):NT600,000.2. Product registration of a new drug which is ofnew composition or new administration route:NT50,000.3. Product registration of a new drug which is ofa new dosage form, new strength with newindication, new dose unit, or controlled releasedosage form, new strength of the sametherapeutic compound(s) and the sameadministration route: NT35,000.GMP Inspections for Western Medicines:1. GMP Inspections for domestic pharmaceuticalmanufacturers which is new establishment,relocation, expansion, resumption of operations,or addition of a new active pharmaceuticalingredient, dosage form, process operation,medicinal product: NT60,000; Additional fee ofNT20,000 will be charged whenever there is anadditional dosage form, biological drug, or activepharmaceutical ingredient.2. GMP Inspections for foreign pharmaceuticalmanufacturers1. Review of a Plant Master File (PMF) of anforeign pharmaceutical manufacturer: NT60,000;Additional fee of NT20,000 will be chargedwhenever there is an additional dosage form,biological drug, or active pharmaceuticalingredient.


5


Otherrequirements

Application for Import License isrequired after marketing approvaland Registration Certificate

Specific country requirementon product labeling on productpackage, example: genericname, retail price, symbol ofprescription drug, imported by.

For the NDA of a new drug, i) Safet &Efficacy ii) Standard and TestMethod iii) GMPand iv) DMF reiviwsare mandatory

Reference Standard Sample(at least 300 mg)PFDA has adopted ACTDformat for NDA submission.

For GDA, the referenceproduct must be theregistered product withSingapore HSA

NA

CMC summary Requirements andlanguage

Yes (Chinese) for NCE only (document in English) Yes, in English Yes ( in Indonesian or Englishas in part II Quality )

Yes (in Japanese as M2 inCTD)

Yes (M2 in CTD, Korean) Yes (Part 2 in ACTD) - inEnglish or Bahasa Malaysia

Yes, in English Yes (in English)Singapore QualityOverallSummary(SQOS) is

Yes (In English as M2 in CTD) Requirement, see ACTD of new drugregistration part II / Eng

CMCreport/body ofdata


Yes (Chinese) for NCE only (document in English) Yes　(English is acceptable as M3in CTD)

Yes ( in Indonesian or Englishas in part II Quality )

Yes　(English is acceptableas M3 in CTD)

Yes (M3 in CTD, English isacceptable, but spec.and testmethods in Application packageshould be prepared in Korean)

Yes - in full (Part 2 in ACTD) -in English or Bahasa Malaysia

Yes, in English Yes (in English) Yes (In English as M3 in CTD) Requirement, see ACTD of new drugregistration part II / Eng

Non-clinicalsummary


Yes (Chinese) for NCE only (document in English) Yes, in English Yes ( in Indonesian or Englishas in part II Quality)

Yes　(in Japanese as M2 inCTD)


Yes, in English Only for full dossier, inEnglish

Yes (In English as M2 in CTD) Requirement, see ACTD of new drugregistration part III / Eng

Non-clinicalreport


Yes (Chinese)Usually synopsis or abstract ofeach report in Chinese is required,attached with source report.

for NCE only (document in English) Yes　(English is acceptable as M4in CTD)

Yes ( in Indonesian or Englishas in part III Non Clinical Data)


Yes (M4 in CTD, English isacceptable)

Yes (Part 3 in ACTD) - inEnglish or Bahasa Malaysia

Yes, in English Only for full dossier, inEnglish

Yes. (In English as M4 in CTD) Requirement, see ACTD of new drugregistration part III / Eng

Clinicalsummary


Yes (Chinese) for NCE only (document in English) Yes, in English Yes ( in Indonesian or Englishas in part IV Clinical Data))

Yes　(in Japanese as M2 inCTD)


Yes, in English Yes (in English) Yes. (In English as M2 in CTD) Requirement, see ACTD of new drugregistration part IV / Eng

Clinical report Requirements andlanguage

Yes (Chinese)Usually synopsis or abstract ofeach report in Chinese is required,attached with source report.

for NCE only (document in English) Yes　(English is acceptable as M5in CTD)

Yes ( in Indonesian or Englishas in part IV Clinical Data ).Indonesia required full clinicalstudy report


Yes (M5 in CTD, English isacceptable)

Yes (Part 4 in ACTD) - inEnglish or Bahasa Malaysia

Yes, in English Yes (in English) Yes. (In English as M5 in CTD) Requirement, see ACTD of new drugregistration part IV / Eng

NDA

NDAappl-icationmaterials（NME）

NDA:Application fees ( the charge fee isamended on March 06, 2013, ”Fee-Charging Standards for the Registrationof Western Medicines and MedicalDevices”)1. Product registration of a new drugwhich is of new active pharmaceuticalingredient(s): NT600,000.2. Product registration of a new drugwhich is of new composition or newadministration route: NT50,000.3. Product registration of a new drugwhich is of a new dosage form, newstrength with new indication, new doseunit, or controlled release dosage form,new strength of the same therapeuticcompound(s) and the sameadministration route: NT35,000.GMP Inspections for WesternMedicines:1. GMP Inspections for domesticpharmaceutical manufacturers which isnew establishment, relocation,expansion, resumption of operations, oraddition of a new active pharmaceuticalingredient, dosage form, processoperation, medicinal product: NT60,000;Additional fee of NT20,000 will becharged whenever there is an additionaldosage form, biological drug, or activepharmaceutical ingredient.2. GMP Inspections for foreignpharmaceutical manufacturers1. Review of a Plant Master File (PMF)of an foreign pharmaceuticalmanufacturer: NT60,000; Additional feeof NT20,000 will be charged wheneverthere is an additional dosage form,biological drug, or active pharmaceuticalingredient.

For NCE and NBEs:- Single ingredient: RM4000-2 or more active ingredients:RM5000

For Prescription products(generic/line extensions):- Single ingredient: RM2200- 2 or more active ingredients:RM3000

NCE: 450 USDInitial Registration: 340 USD(1USD= 45 PhP)* above rates are current;however these may changepending implementation ofproposed new revised fees.

Screening Fees: Abridged/verification$500 Full dossier: $2,750Evaluation Fees: NDA-1 & NDA-2(abridged): $11,000, NDA-3 (abridged):$5,500 NDA-1 & NDA-2(verification): $16,500 NDA-3 (verification):$5,500 NDA full dossier:$82,500 GDA-1 (abridged):$3,850 GDA-2 (abridged):$2,200 GDA-1 (verification):$10,000 GDA-2 (verification):$5,000

Application fees of drugscontaining new activeingredientsTo Government : 533,800yenTo PMDA for review : 23,788,100yen for paper-basedcompliance inspection :6,747,000yen for GCP inspection : domestic 2,801,000yen, overseas 3,098,000yen +Travel expense for GMP inspection : domestic 760,900 yen,overseas 960,200 yen+Travel expense

Application fee(1) Chemical : NCE for review : 3,726,000 KRW (STMreview + S&E review + GMP review)(2) Biologics : NME for review : 3,726,000 KRW (STMreview + S&E review + GMP review)(3) Biosimilar for review : 1,134,000 KRW (STMreview + S&E review + GMP review)

for GMP/GCP inspection(around7,500,000KRW/person(overseas)) :This one is the travel expense forinspectors, so if GMP inspectionwould be waived, no more fee isneeded.cf. Generics: KRW 720,000(BE,CMC, GMP review included)

Application fees Fees necessary forapplying forapproval as forNME drug with fulldata (Category (1))

Application fees of drugs includes:- registration fee: IND:3,500 RMB (local drug) NDA: 20,000 RMB (local drug) IDL: 45,300 RMB (import drug)- drug quality test: around 50,000RMB, based on test items- GCP inspection: free charge- GMP inspection: free charge

Application fee: HKD 1100License fee: HKD 1370Renewal fee (every 5 years): HKD 575

Application fees:NDA: INR 50000 ( include MAAfee)Import License: Rs 1000 and atthe rate of Rs.100/- for additionaldrug.Registration Certificate (for importdrug): 1500USD for onemanufacturing site or itsequivalent in Indian currency and1000USD for one drug or itsequivalent in Indian currency. Anadditional fee at the rate of onethousand US dollars for eachadditional drug.Duplicate Registration certificate:three hundred US dollars shall bepaid for a duplicate copy of theRegistration Certificate, if theoriginal is defaced, damaged orlost.Inspection Fee: The applicantshall be liable for the payment of afee of five thousand US dollars forexpenditure as may be requiredfor inspection or visit of themanufacturing premises or drugs,by the licensing authorityTest License:The fee of importlicences for test and analysis of adrug has been kept Rs. 100 for asingle drug and at the rate of Rs.50/- for each additional drug

Application fee :Pre-Registration : 1 MillionIDR (MIDL)Registration fee for :Category 1 : new product &Biological Product : 30 MIDR,new indication : 20 MIDRCategory 2: copy product 7.5MIDR, copy product withBA/BE data: 12.5 MIDRCategory 3 : other product:7.5 MIDRCategory 4: VaMa : 2 MIDRfor each dosageform/packagingCategory 5: VaMa-B : 2 MIDRfor each dosageform/packaging.Category 6: VaMi-A : 1 MIDRfor each dosageform/packaging.Category 7: renewal : 5 MIDRFor pre-inspection GMPdocument: 7.5 MIDR.For GMP site inspection:three inspector three day = 90MIDR

Not required2,000 baht (pay after approval)


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Requirement, see ACTD of new drugregistration part I / Eng

Module 11.1 Table of contents of Module 11.2 Application form or approvalapplication(Copy)1.3 Signature of the person in chargeof preparation of CTD, His/Herinformation(career)1.4 Certificate of translator1.5 Information on the use of theapplied drug in foreign countries1.6 Information on comparison withother similar products available inthe Korean market and properties ofthe applied drug1.7 Various documents related toEnforcement regulation ofPharmaceutical Affairs Act Article 24-1) 1.7.1 Bioequivalence test data/Dissolution test data 1.7.2 CPP 1.7.3 GMP data 1.7.4 DMF data1.8 A contract(In case any processduring manufacturing, QC test wouldbe outsourced)1.9 LTOC1.10 Package insert(draft)1.11 Other data

In English or BahasaMalaysia:ACTD Part I :AdministrativeData And Product InformationSection A: Product ParticularsSection B: Product FormulaSection C: Particulars OfPackingSection D: Label (Mockup) ForImmediate Container, OuterCarton And Proposed PackageInsertOther admin doc: CPP, LOA,CA, GMP CERT

Please refer to ACTD list ofrequirement

Module 1 (or ACTD PartⅠ) documents e.g,Letter of authorizationsDeclarizationArtwork of packagingmaterialGMP certificatePatent declarationReferencecountry/productapproval and approvedpackage insert, ifapplicable

CTD Module 1 (Taiwan Specific) CTDformate was announced in July 2012and became mendatory for NCEproducts since Nov. 01, 2012. NewDrugs other than NCE, as well asgeneric products also need to besubmitted in CTD format starting fromJuly 01, 2014.1 Administrative Information andPrescribing Information1.1 Table of Contents of the SubmissionIncluding Module 11.2 Application Fee Receipt1.3 Official Letter and Document1.4 Application Form (original copy andduplicate copy)1.5 Affidavit1.6 Form for Sticking Label andPackage Insert1.7 Certificate/License1.8 Letter of Authorization1.9 CPP of Source Country1.10 Formulation Basis1.11 Certificate of PIC/S GMP/cGMP1.12 CPP1.13 Bridging Study Evaluation1.14 Status of Clinical Study Taiwaninvolved1.15 Status of Bioavailability (BA)/Bioequivalence (BE) Study Taiwaninvolved1.16 Contract Manufacturing1.17 Applications of Contract Analysis1.18 Radiation Dosage Study Report1.19 Risk Evaluation and MitigationStrategy (REMS)1.20 Other Documents or Reports

CTD Part I (Module 1)1.1 Table of Contents1.2 Approval application(copy)1.3 Various certificates1.4 Information on patentmatters1.5 Data concerning theorigin or background ofdevelopment1.6 Information on the useof the drug in foreigncountries1.7 List of similar productsfrom the same therapeuticcategory with the sameefficacy1.8 Package insert1.9 Documents pertaining tothe non-proprietary name ofthe drug1.10 Summary of datapertaining to the designationas a poisonous drug, etc1.11 Master plan for post-marketing surveillance1.12 List of attached data1.13 Other data

NDAappl-

icationmateri

als（NME）

Needs to be in English.General requirement for productregistration:1. Authorization letter from manufacturer– to authorize HKOP register, import andmarket the product2. Manufacturer license – original3. CPP- original4. Information on the manufacturingfacilities and practices of themanufacturer & GMP Certificate -original5. Registration sample – colorphotos/scanned image to show theproduct and sales pack/containerappearance.6. Proposed sales pack – color prototype7. Proposed pack insert - prototype- The following document(s) to supportthe proposed indication(s), dosage, routeof administration and other contents ofthe package insert (if any):a. a copy of reputable referenceb. documentary evidence showing thatthe package insert has been approvedby one of the listed countries8. Master formula (Batch formula notaccepted) - Non-proprietary names ofingredients, colour Index number or E-number for all colourants used should beprovided9. Finished product specifications10. Method of analysis11. COA of a representative batch12. Stability data13. Bioequivalence data for anti-epilepticdrugsThe BE studies should be conducted inaccordance with World HealthOrganization guidance on the“Multisource (generic) pharmaceuticalproducts: guidelines on registrationrequirements to establishinterchangeability” or other internationalguideline.14. Safety documents for ingredientswith animal originsAdditional requirements for NCEregistration1. 2 ICH country approvals2. expert evaluation reports on thesafety, efficacy and quality of theproduct. CV of experts who draft thereport.3. EU-RMP and/or US-REMS, ifapplicable. Information on whether anyrisk management plan activities andmitigation strategies will be implementedin HK.4. clinical and scientific documentationsubstantiating the safety and efficacy ofthe product.

Other requireddocuments


application formsummary part of applicationdossiers:(1) Name of the drug(2) Certified Documents, includingCPP etc.(3) Objectives and basis fordevelopment(4) Summary of CMC, Non-clinicaland clinical(5) packaging insert and itsreasons, and latest references(6) artwork and labeling

AS described in Schedule Y of theDrugs and Cosmetics Rules 19451.1 Comprehensive table ofcontents (Modules 1 to 5)1.2 Administrative information1.2.1 Application in Form 44 andTreasury Challan (fee)1.2.2 Legal and statutorydocuments1.2.3 Coordinates related to theapplication1.2.4 General information on drugproduct1.2.5 Summary protocol of batchproduction and control1.2.6 List of countries where MAor import permission for the saiddrug product is pending and thedate of pendency.1.2.7 List of countries where thedrug product has been licensedand summary of approvalconditions.1.2.8 List of countries where thedrug product is patented1.2.9 Domestic price of the drugfollowed in the countries of originin INR1.2.10 A brief profile of themanufacturer’s research activity1.2.11 A brief profile of themanufacturer’s business activity indomestic as well as global market.1.2.12 Information about theexpert(s)/ Information regardinginvolvement of experts, if any1.2.13 Environmental riskassessment1.2.14 Samples of drug product

ACTDSection I : AdministrativeDoc.& Drug Information(SMPC & Patient InformationLeaflet)Sub Section A: All Table ofContentSub Section B: AdministrativeDocuments Registration Form Statement of Applicant Certificate and other

Administrative Documents Result of Pre-registration Invoice/ Receipt of payment

& other documentsSub Section C: ProductInformation and LabelingSection II: Quality DocumentsSub section A: Summary ofQuality DocumentSub section B: QualityDocuments S. Active Substance P. Finished DrugSection III : Non clinical StudySection A: Review ofNonclinical StudySection B: Summary andPreClinical Study MatrixSection C: Non Clinical StudyReport xSection D: ReferencesSectionIf the manufactured not yetregistered, it should provideSMF.

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Division of Medicinal Products underTFDA, which is responsible for all drugproducts, has around 100 active staffincluding administrative, drug safety andregulation build-up. Among themenpower, about 40-50 staff belong tonew drug, generic drug and clinical trialreviewing force.

All staffs : 400 FDA employeesMFDSChemical Administration(Drugpolicy): 44GMP: 21Clinical Trial Management: 18Narcotics: 15Bio Administration(Bio policy): 21Bio GMP: 15Traditional medicine: 11

NiFDSDrug Review Management: 28Pharmaceutical Standardization: 15Circulating System: 17Oncology: 13Digestive System: 17Bioequivalent: 22Biologics: 19Recombinant Protein: 16Cell & Gene Therapy: 13Herbal: 11

Regional KFDSs

Revieworganization,Decisionorganization,Advice committee

Review: Drug Office, DOHApproval: Pharmacy and Poisons Board

CDCSO/DCGI (Drug ControlGeneral of India)Twelve New Drug AdvisoryCommittees (NDAC) were newlyconstituted to examine theapplications for permissions forclinical trials and approvals fornew drugs.

1. Committee of Safety-Efficacy Evaluation with thetask of evaluating the safetyand efficacy aspect to bediscussed in the periodicmeeting of NationalCommittee/ KOMNAS.2. National Committee onDrug Evaluation with the taskof discussing , formulating,giving consideration anddecision of the results of drugevaluation through a periodicforum meeting.3. Committee of QualityEvaluation with the task ofevaluating the quality aspect.4. Committee of ProductInformation LabelingEvaluation with the task ofevaluating in the aspects ofProduct Information andLabeling.

ReviewPMDA (Pharmaceutical andMedical Device Agency)DecisionMHLW (Ministry of Health,Labour and Welfare)AdviceCDFS (Council on Drug andFood Sanitation)

MFDS and NiFDS(National Instituteof Food and Drug Safety Evaluation)Advice : Central PharmaceuticalAffairs Council

National PharmaceuticalControl Bureau (NPCB):Receive and review the newdrug applications, and proposeit to the Drug Control Authority(DCA) for approval/rejection.Drug Control Authority (DCA):A committee that meets once amonth to decide on newproduct registrations &licenses.

Philippines FDA HSA (Panel of internaland external reviewers.)

Thai FDA

See Attached sheet-Number of reviewers(Annex 8)

CFDA accepts the NDA applicationdocuments and transfer thesedocuments to CDE in 30 workdays, then CDE reviews andevaluates it in 150days ,finally,CFDA approves it in 30 work days.CDE review process for IND/NDAis attached for reference.

Undisclosed Pre-registration reviewdocument until completedocuments --> Payment ofpre-registration fees -->submit pre-registration -->Evaluation--> Approval Pre-RegistrationRegistration review document--> Payment of registrationfees --> Submit registrationdocuments --> Clock start ofregistration review Note : *Only NCE/Biological ProductNon-Clinical & Clinical wereevaluated through Committeeof Safety-Efficacy evaluationand National Committee thencontinue with Committee ofQuality Evaluation , andCommittee of ProductInformation.*Others ( Generic & variation)were evaluated withCommittee of QualityEvaluation , and Committee ofProduct Information..

GMP on-site inspectionor PMF registration(paper review) isrequested and theapproval should be gotthen NDA can beapproved accordingly.Otherwise NDAApproval will be helduntil GMP sttusconfirmed (inspection orPMF approval). TheGMP compliance checkshould be done byTFDA for eachmanufacturing site,even toll manufacturesite or packaging site.

All staffs : 714(As of Oct 1, 2013)Pharmacology : 384Medical doctors andDentists : 42Engineering : 44Veterinarian and Toxicity :25Biostatistics : 13Science and agriculture, etc.: 63Clerical work : 101 (As of April 1,2012)

Total NPCB staff: ~ 380Reviewers in Centre forProduct Registration: 80

All staffs : 103Traditional Chinese drug : 16CMC : 25Biologics : 8Non-clinical : 13Clinical : 20Biostatistics : 3Clerical work : 18 (As of August, 2013)

Undisclosed CDSCO total manpower 327 (asof 2009).No detailed information.

Annex 9 - the timeframe for approvalSee Annex 6 See figures at Annex 7 Screening/evaluation/queries, inputrequests/regulatorydecision

See Annex 5Dossier Submission via online--> Screening & Acceptance ofdossier via online --> Paymentof registration fees--> clockstart of registration review-->Sending for external expertreview on clinical section forNCE/Biologics--> EvaluationCommittee's recommendation-> Decision by Drug ControlAuthority. (Annex 4)

Please see Flowchart_PSD_revised_Aug 2007

Approvalreview

Review process DCGI accept the application inForm 44 and then it is forwardedto NDAC for expert review.

Append the flow ofthe review ofapplications fornew drug with theattached paper.

ReviewCDE (Center for Drug Evaluation)DecisionCFDA (China Food & DrugAdministration)InspectionRegional Drug Administration

Revieworganization

Number ofreviewersex. Clinical, Non-clinical, CMC,Chemical/Biological

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Special review procedure exists,which is appropriate for followingapplications of new drugs:1) Active ingredients extractedfrom plants, animals or minerals,etc. and their preparations not yetmarketed in China, and newlydiscovered Chinese crude drugsand their preparations;2) Chemical drug substance andtheir preparations and biologicalproducts not yet approved formarketing in China or abroad;3) New drugs for the treatment ofdiseases such as AIDS, malignanttumors and rare diseases, etc. withsignificant clinical advantages; and4) New drugs for the treatment ofdiseases, for which effectivetherapeutic method is notavailable.For those drugs specified in items1) & 2), the applicant of drugregistration (hereinafter “theApplicant”) may apply for thespecial examination and approvalwhen submitting the application forclinical trials of the new drugs.For those drugs specified in items3) & 4), the Applicant may apply forthe special examination andapproval only when submitting theproduction applications.

Practically around 12 months areneeded for NDA.

Annex 9 - the timeframe for approvalReview timePriority review products: 12 monthsstandard review products: 18 months

Review time of FY 2012(Median)Priority review products : 9monthsStandard review products : 15months

New lead time: 18 months

The priority review system existsUnmet medical needs and drug forserious life threatening disease and ismajor medical advance can apply topriority review system.It should be apply for priority review first,after recognition by TFDA as priorityreview case then can be reviewed bypriority review process.TFDA release new regulation for NCE -2simple review regulation. For theproduct which launch in top 10 countriesfor over 10 yrs, the review process couldbe simpfy. For the product whichapproval by both USFDA and EMA, theyproduct could also apply the simplereivew system.

NCE: 12-15 monthsGeneric: 9-12 months

About 12-15 months for marketingapproval and registrationcertificate.About 3 months for ImportLicense.

Timeline of pre-registration 40 working days aftercompleted documents forcategory 1,2,3,4,5.Timeline ofregistration 100 working daysafter completed documents for: a. New Drug & BiologicalProduct that are indicated forthe treatment of serious life-threatening human disease ,or classify as Orphan drug, orclassify for public healthprogram, or new drug whichdevelopment byPharmaceutical industry /research institution inIndonesia b. New registrationof generic essential copydrug. c. New registration ofcopy drug with standardelectronically information (Stinel). d.Major variation .Timeline of registration 150working days after completeddocuments for a New Drug ,Biological Product , majorvariation with : 3 (three) CPPfrom countries with knowngood evaluation, system orapproved in the country thathas applied harmonizedevaluation system ( EU ,EPAR, EMEA). b. NewRegistration of Copy Productwithout Stinel. Time line ofregistration of 300 workingdays after completeddocuments:1 CPP fromoriginal country.

Presence ofpriority reviewsystem, Content ofsystem,Subject drug forpriority reviewex. unmet medicalneeds, for seriouslife-threateningdisease

Review time The standardperiod of time fromacceptance ofapplications to theapproval of newdrugs.

Official timeline of CTA / NDA ofimport drug from submission toapproval: 145 working daysBut, actual timeline is much longer.The recommendation timeline for2013 by RDPAC: CTA or NDA ofimport chemical drug is 22 or 23months; Initial MRCT of category 1drug is 12 months while MRCT ofcategory 3 drug is 13 months.(MRCT:Muti-Regional ClinicalTrial)

Priority reviewsystem

NCE/NBE: 245 Working daysPriority review : 6-9 monthsGenerics: 210 working days

Review time of FY2012(Median)Priority review products : 6.1monthsStandard review products :10.3 months

Screening: 25 workingdaysEvaluation:Full dossier: 270working daysAbridged: 180 workingdaysVerification: 60 workingdays

usually no; except official request fromHospital Authority upon urgent situation

There is no formal priorityreview system in place.Priority review status will beprovided on case to casebasis, based on the applicant'sjustification. Usually priorityreview status is granted for thefollowing group of products:- life-saving products, e.g. viralinfection/oncology drugs- fulfill unmet medical needs- treatment for rare diseaseswhere currently there isn't atreatment option available.

The priority review systemexists.For serious diseases and life-threatening conditions andwhich are apparently expectedto contribute to theimprovement of quality ofhealthcare based on overallevaluation of the seriousness ofthe target disease and medicalusefulness of the drugs.Consideration is made basedon the opinions of externalexperts if an application issubmitted with an applicationfor marketing approval.

No separate priorityreview system orpathway. Only if productis submitted viaAbridged Evaluation(with 1 referencecountry approval); andmeets the pre-definedcriteria in the guide(unmet medical need,etc). Grant of priorityreview is on case-by-case basis, at discretionof the Agency duringScreening. Applicant willbe notified at the pointof acceptance ofapplication, if request isgranted.

The priority review systemexists.Orphan drugs receivepriority review automatically.New drugs not designatedas orphan drugs whichtarget other seriousdiseases and which areapparently expected tocontribute to theimprovement of quality ofhealthcare may bedesignated as "non-orphanpriority review products"based on overall evaluationof the seriousness of thetarget disease and medicalusefulness of the drugs.Designation is made basedon the opinions of externalexperts if an application issubmitted with anapplication for marketingapproval.

The priority review system exists1) Drugs which target for life-threatening or serious diseases suchas AIDS, cancers etc.2) Drugs of which is deemednecessary because treatment is notpossible with existing therapies dueto resistance or other reasons3) Other drugs such as anti-canceragents, orphan drug, DNA chip etc :recognized by MFDS minister forpatients or industrial development4) Herbal medicines for cancer orAIDS

There is no formal priority reviewsystem.Depends on therapeutic area andunmet requirement.

There will be the fast track for life-threateningdesease e.g. HIV drug, anti-cancer drug.

Approvalreview

Approvalreview

There is no priority system.The review following thetimeline of registration ( 100 or150 or 300 working days )


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・Non-proprietary Name・Brand name・Ingredents and Contentsor Nature・Manufacturing Method・Dosage and Administration・Indications・Storage Methods andExpiration Date・Specifications and TestMethod・Name of theManufacturing Site used toManufacture the Product,Address,License/AccredetationCategory, etc.

A regulatory decision shall bemade based on the outcome ofthe evaluation of the submitteddocumentation. An applicationmay be approved or rejectedby the Authority, and theAuthority decision will be sentvia email/ official letter to theproduct registration holder.Upon registration of a productby the Authority, the productregistration holder shall benotified by the Authority and aproduct registration number(i.e. MAL number) shall beassigned to the registeredproduct. Registration status ofa product shall be valid for five(5) years or such period asspecified in the registrationnotification (unless theregistration is suspended orcancelled by the Authority).

・Generic Name・Brand name・Manufacturing Method・Dosage and Administration・Indications・Storage Methods and ExpirationDate・Specifications and Test Method・Name of the Manufacturing Siteused to Manufacture the Product

Besides MarketingAuthorization , it attached with:* Registration Form* Approved Labelling* Approved Package Insert* Approved PatientInformation Leaflet

・Non-proprietary Name・Brand name・Ingredents and Contents or Nature・Appearance・Manufacturing Method・Dosage and Administration・Indications , Precautions for use・Storage Conditions and ExpirationDate・Specifications and Test Method・Name of the Manufacturing Siteused to Manufacture the Product,Address,　License/AccredetationCategory, etc.・Approval condition, if necessary

approvalmatters

You may appendthe approvalmatters with theattached paper.

・Approval number・Marketing License Holder and itsaddress・Manufacturer and its address・Non-proprietary Name・Brand name in Chinese ifapplicable・Active ingredents and Contentsor Nature・Dosage form・Dosage strength・Packaging size・Shelf life・Specification & test methods・labeling and artwork・packaging insert

The orphan drug system doesnot exists but we have a DOHA.O. 4 s. 1992 forCompassionate Special Permitfor life-saving drugs. This is theclosest that we can get in as farguidelines for orphan drugs areconcerned.

Available in Regulationsbut implemented asNamed-Patient Basispathway.

The orphan drug system exists.Designation criteria:Number of patients: the standard forrare diseases is if it’s prevalent in lessthan 1/10,000. It is different with US(U.S. it is considered a rare disease if itaffects less than 200,000 people/prevalent in less than 7.5/10,000) andJapan (the number of patients total lessthan 50,000 /prevalent in less than5/10,000)Definition of Rare Disease:The rare diseases specified in this Actrefer to diseases with prevalence lowerthan that formulated and publiclyannounced by the central competentauthority, and recognized by theCommittee specified in Article 4 of thisAct; or diseases designated and publiclyannounced by the central competentauthority under special circumstances.Reward: To encourage the R&D andmanufacturing of orphan drugs, TFDAannounced and implemented the“Rewarding Standards for theManufacturing and R&D of OrphanDrugs. But it focus on Domesticmanufacturer.

The orphan drug systemexists.

Designation criteriaNumber of patients Less than 50,000 in JapanMedical need There are no appropriatealternative drugs ortreatment methods.The efficacy and safety areexpected to beoutstandingly greater thanthose of existing drugs.Possibility of development There is a theoreticalground for using the drug forthe target desease and thedevelopment plan isacceptable.Incentives(1) Subsidy payment(Thetotal budget for financialyear 2010 was 650 millionyen.)(2) Guidance andconsultation on researchand development activities(HMLW, PMDA, NIBIO).PMDA provides a priorityconsultation system.(3) Preferential taxtreatment(4) Priority review(5) Extension of re-examination periodThe re-examination periodfor the drugs will beextended up to 10 years.

The orphan drug system exists.Designation criteria-Prevalence is less than 20,000 inKorea-Drugs to treat diseases for whichappropriate therapy and drugs havenot been developedor have been significantly improvedin terms of safety and/or efficacy,compared to existing alternativedrugs- Pharmaceutical product whoseannual sum of importation does notexceed 1.5 million USD or annualsum of GDP does not exceed 1.5billion KRW(On condition that lessthan 500 pateints in Korea,pharmaceutical product whoseannual sum of importation does notexceed 5 million USD or annual sumof GDP does not exceed 5 billionKRW)- Products which do not meet thecriteria above can be designated asan orphan drug if it is acknowledgedthat the limited supply of productwould cause any serious harm to theconcerned population or the MFDSminister recognizes it.

Incentives2) Exemption of following data 1) CMC(specification and testmethod) : No review, but in-housespec. should be submitted 2) GMP 3) DMF 4) following data for S&Ereview - bridging data - Some Toxicity data : onlysingle dose toxicity and 1 to 3 monthsrepeat dose toxicity data are needed - Pharmacology data will bereplaced by pharmacodynamic dataor clinical trial data - Phase 2 study will beincluded in phase 3 study 5) Some regulations on Koreanlabeling3) Priority review

Approvalreview

Orphan drugsystem

Presence oforphan drugsystem,Criteria fordesignation,Incentive, etc.

No orphan drug designationsystem.

No The orphan drug system does notexists.

The orphan drug will evaluatewill evaluated within 100working days. No regulationestablishing for Orphan drug.

The MoH is in the process ofestablishing the orphan drugsystem; the industry has beenengaged for consultation on aproposed guideline.Meanwhile, the registration oforphan drugs follows thestandard/priority reviewregistration track.

Available, the requirement for orphan drugregistration is only Admin part and some ofQuality part.


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Pre-approvalinspection

GCP inspection GCP on-site inspection is executedby provincial FDA for lcoalmanufacturing drug at principalinvestigator's site. GCP on-siteinspection for import drug is notmandatory yet.

Not required DCGI may conduct GCP on-siteinspection. DCGI will issueinstructions to the CDSCOofficers/Inspectors to conduct theinspection identifying the clinicaltrial site/ facilities to be inspected.CDSCO issued 'GUIDANCE ONCLINICAL TRIAL INSPECTION'in Nov. 2010.

GCP inspection for localclinical study in Indonesia .GCP inspection for importproduct is not required.

The GCP on-site inspectionis executed by PMDA to 2 or4 medical institutions andapplicants.

GCP on-site inspection to sites,company and CROs according toMFDS's yearly plan.Self-inspection by sites was adoptedand is being implemented from 2012.

GCP Inspection extended toclinical trial sites andSponsors; also planned forContract ResearchOrganisations (CRO) by 2015.

The GCP on-site inspection isexecuted by FDA to medicalinstitutions and applicants.Frequency not clear.

CT in SIngaporePre-marketing approvalapplication inspectionsare usually doneannounced and apply tocompleted clinical trials.Criteria during GCPInspections:(i)Protocol(ii)Medicines (ClinicalTrials) Regulations(iii)SG-GCP, adaptedfrom ICH E6 on GCP(iv)SOPs for conductingclinical trials

The GCP on-site inspection is executedby TFDA around 4-6 weeks after CSRsubmitted to TFDA in selected medicalinstitutions (depends on the number ofinvolved site)

As stipulated under the CDCR1984, Regulation 11(1), theAuthority may, at any timereject, as well as cancel orsuspend the registration of anyproduct if there aredeficiencies in safety, quality orefficacy of the product orfailure to comply withconditions of registration. Anyperson aggrieved by thedecision of the Authority or theDirector of PharmaceuticalServices, a written appeal maybe made to the Minister ofHealth Malaysia. All notice ofappeals shall be made withinfourteen (14) days from thedate of notification from theAuthority. A period of 180 daysfrom the date of notice ofappeal is given for submissionof any additional information/supplementary data/documents for New DrugProducts and Biologics. Aperiod of 90 days is allowed forother categories of product.Re-submission for productregistration of a rejectedapplication due to reason ofsafety and efficacy shall not beaccepted within two (2) yearsafter the rejection. However, ifthe product is registered in thereference countries,submission of application canbe made earlier.

NCE should provide API DrugMaster File or InternalMonograph as required inPart II Quality . Approval ofSMF should also beconsidered to get approval ofregistration number.

Approvalreview

Otherinformationconcerningapproval review

N/A NA


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Otherinspections

ex. GLPrequirement andevaluation

For local drug, source data on-siteinspection including GLP and CMCis mandatory after IND or NDAsubmission.

Not required N/A In the GMP inspection site ,the Laboratory is inspected byNAFDC . The Laboratoryinspected following GLPrequirements.

"Paper-based complianceinspections" is executed byPMDA to confirm whetherdata attached to NDAapplications accuratelyreflect the results of clinicaltrials and other studies, andwhether those are made inaccordance with GCP, GLPand reliability standards.

n/a GLP Inspection of non-clinicaltest facilities is on-going.Subject to companies internalaudit & ethics committees ofthe research institutionsrequirements.

Paper-based complianceinspections is executed by FDAto confirm whether gooddistribution practice is beingimplemented.

Non-clinical studiesproviding toxicologyinformation to supportclinical trials should beconducted incompliance with GLP.

Current Taiwan had not perform GpvPinspection. But the regulation for GLPsite inspection already exists and somestudy will be performed GLP siteinspection. As to the regulation relatedto GpvP inspection is under discussion.

Document inspection only, CPP/GMPcertificate from source country accepted

GMP on-site inspection or PMFregistration (paper review) is requestedand the approval should be got thenNDA can be approved accordingly.Otherwise NDA Approval will be helduntil GMP sttus confirmed (inspection orPMF approval). The GMP compliancecheck should be done by TFDA for eachmanufacturing site, even tollmanufacture site or packaging site.

GMP certificate (PIC/S)New foreign manufacturer may be inspected onsite if needed.

GMP inspection of Indian mfg.units will be arranged beforegranting the manufacturing licenseand periodic review of the mfg.unitThe Licensing authority or by anyother persons to whom powershave been delegated in this behalfby the licensing authority of Indiamay inspect the manufacturingpremises of mfg. units outsideIndia on need basis

For imported product : Basedon evaluation of Site MasterFile , if necessary GMPinspection site will be requestby NAFDC .

Since the amendment of thePharmaceutical Law (PAL)in April 2005, GMPcompliance inspectionshave become a requirementthat must be met formarketing approval.Application for GMPcompliance inspections forall manufacturing sites listedin the applicaitions formarketing approval must besubmitted to the GMPcompliance inspectionauthority (PMDA orprefectures) by eachmanufacturing site.

GMP inspection can be done formanufacturing sites of drug productand drug substance.Basically MFDS conduct on-siteinspection (from 2009). Beforeconducting site inspection, theyrequest "Minimum requirements"documents.

Document inspection; inspected sitewithin 1yr/aseptic product, 2yr/ sterileproduct, 3yr/ non-sterile product

Pre-approvalinspection

GMP inspection ex. On-siteinspection,Documentinspection,CPP/GMPcertificate fromsource countryaccepted

For local drug, GMP on-siteinspection should be done beforemanufacturing license approval.For import drug, CFDA startedGMP on-site inspection at the endof 2011. Only few import drugswere selected at that time.Moreover, GMP on-site inspectionwas done after IDL approval at thismoment, which is different from forlocal drug. It is sure that CFDAexpects GMP on-site inspectionprior to IDL approval onceexperience acuumulated.(IDL:Import Drug License)

For locally manufacturedproducts, there is siteinspection before issuance ofGMP by the Health Authority.Foreign manufacturers arealso subjected to GMPconformity assessmentsthrough acceptable GMPevidence or GMP inspection.For Imported products, on-siteinspection are exempted formanufacturers from orinspected by PIC/s orreference countries, or from anASEAN country included in theASEAN Sectoral MRA forGMP inspection ofmanufacturers of MedicinalProducts. All registration ofimported products need toprovide a GMP certissued/inspected by membercountries of PIC/S or referencecountries.

Since 1989, GMP complianceinspections have become arequirement that must be metfor marketing approval. Forforeign manufacturer, CPPand GMP certificate is beingrequired.

GMP conformityaccessment is requiredusually in documentreview. GMP certificatesmust be issued byPIC/S member, USFDA and/or JapanMHLW. If not, onsiteinspection by HSA AuditBranch required, beforeproduct approval isgranted.


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Necessaryprocedures tostart clinicaltrials

The actualprocedures to startclinical trials, forexample, IND/CTA=> import ofinvestigationaldrugs => IRB etc.,

IND/CTA => import ofinvestigational drugs andIRB => clinical trialclinical trial should bestarted within 3 years afterobtaining CTA.

a. IRB approvalb. if study medicationis required to beimported, thenApplication of clinicaltrial certificate (CTC)at Drug Office,Department of Healthis required

Clinical trial on new drug shall be initiated after authorization byCDSCO and approval of respective EC.In case of parallel applications, CDCSO will grant conditionalapproval and note that the trial should start after Ethics approval.Trials should also be registered with CTRI (Indian Registry) beforescreening patients

1. After having ClinicalTrial Approval Letter fromNAFDC, the ClinicalStudy can be start .Implementation of ClinicalTrial.

Notice of claimedinvestigational new drugexemption to MHLW.Clinical trial can be startedafter 30 days if there is anycomment from Authority

Get IND Approval and IRBapproval in apparel. After that, itwill be implemented CTA.Normally, it will take about 3months.

Application to The Research ReviewCommittee (RRC) & The MedicalResearch Ethics Committee (MREC)required. Also, application to theNational Pharmaceutical ControlBureau (NPCB) for clinical trial importlicense is (CTIL) necessary.Parallel submission is possible.

Clinical Trial Protocol approvalis required.Please see FDA Circular 2012-007 (flowchart).

Approval by both HSA (to obtain CTC) and IRBapproval are required respectively before start ofclinical trial.

IND approval by TFDA＋Import permit ofIMP → IND approval by IRB (IND inTFDA and IRB can be parellel) → CTAapproval by medical insitiuation →Payment pay to medical institutioncompletely →Site initiated visit.

IRB/EC approval -> Investigational drugs importapproval from Thai FDA -> initiation

Are there anynecessarydocuments/brochures outsideIND/CTA dossier

CRF & ICFContract with siteIRB approvalSome sites requireinsurance certificate for theclinical trial

Please refer to theguidelines (file name:CT-guid)

As per Schedule YRegistration of clinical trial is mandatory in the ICMR Clinical TrialRegistry prior to initiation of the trial.

Informed Consent to thepatient

Documents needed to getpatients' consent

CRF(Case Report Form), GMPwarranty letter or certificate,documents to get patients'consent

refer to CTIL guideline Documents needed to getpatients' consent.Please see FDA Circular 2012-007.

Original declaration document of the principalinvestigator and sponsor has to be submitted

No extra document requires outsideIND/CTA dossier. Only for biosampleneeds to send out to oversea, thestatement from central lab is needed.

Material Transfer Agreement

DocumentLanguage(acceptability ofEnglish document)

In Chinese. preferably English andpatients consent formin English andChinese/Chinese only

English Indonesian or English Usually Japanesedocuments are requested

Protocol, ICF should betranslated into Korean. HoweverEnglish IB is acceptable toMFDS.

English is acceptable.Note: Documents for patient - wouldneed Malay, Chinese and Tamil

English English Usually English version is acceptable. Thai and/or English

Requirement ofdomesticclinical data forNDAapplication, ifthere is foreigndata

Necessary or Not-necessary-Necessity in PK /healthy sbj.-Necessity inpatient data

Usually Chinese patient'sdata including DB study andPK study are needed, whichindicates similarity in drugresponse (i.e. efficacy andsafety) with foreign data.

Not necessary Necessary Generally, Indonesianpatient's data requestedwhich indicates similarityin drug response (i.e.Efficacy and safety) withforeign data for newpsychotropic drug, drugfor family planningprogramme and otherdrugs based on requestfrom Authorized body , forexample public healthprogramme for TB , etc.

Usually Japanese patient'sdata requested, whichindicates similarity in drugresponse (i.e. efficacy andsafety) with foreign data.

Foreign data is acceptable. Butbridging data in Korean shouldbe generated.

Not necessary Local clinical trial is optional;PSUR submission will berequired as part of Post-Marketing Surveillance.

Not necessary If there is foreign data available, it doesn'tneed domestic PK data for INDapplication. But some situation may needdomestic PK data for supporting NDAapproval even there is foreign dataapproval, that is the product with ethicaldifference between Asis population andCaucasians.

Not-necessary

Acceptance offoreign clinicaldata for NDA

Is there anyconditionalrequirements, forexample similarityin PK/PD?

No, just for reference.(Even if the similarity inPK/PD is indicated we can'trely only on foreign data toChina NDA)

Yes (for NCEproducts)Not required forgeneric products

Foreign Clinical data can be a supportive document, howeverIndian data (PhaseIII) is must.

Acceptable if the clinicaldata following GCP andthe result based onevaluation of safety andefficacy is good.

Acceptable if the similarityin PK/PD is indicated.

Acceptable; in case of similarityon S&E or PK/PD.

Yes Acceptable if the similarity inPK/PD is indicated.

Yes Acceptable if the similarity in PK/PD isproofed.

Yes

No definite requirement. Forboth local and multinationalclinical trials, statisticallymeaningful number of subject isneeded.

N/A There is no required number oflocal subjects in clinical trialsfor NDA approval.For PMS studies, it issuggested (but not required)that there should be 3,000subjects.*Correction: PMS was notreplaced but was expanded toinclude RMP /PSURsubmission

N/A. But in the HSA CTC application, applicanthas to declare expected number of subjects to beenrolled from each site.

it is request to show the consistency indrug response between Asia populationand Caucasians in multi-national clinicaltrials. For this purpose, at least 15-20% ofall subjects is hopefully to be Asianpopulation. As for NDA approval, it wasdivided to two situation.Non-CPP: Early clinical development inTaiwan, Ph 1+ Ph 3 or Ph 2+ Ph3.Taiwan patient No. for Ph1 study :≧10,for Ph 2 study: ≧20, for Ph3 study:≧80.One-CPP: One of Ph 1, Ph2 or Ph3 studyin Taiwan. Taiwan patient No. for Ph1study :≧10, for Ph 2 study: ≧20 or10%, for Ph3 study:≧80 or 10%, orMultinational Ph3 study: total sample size≧200 then Taiwan No.≧30 or 5%, totalsample size ＜200 thenTaiwan No.≧10.

Submission of Investigator Brochureis required.

Generally follow ASEANrequirement.Please see FDA Circular 2012-007

It depends on the product characteristicand study phase. Some time Tox datamay beneeded for initiation of clinicaltrials. General requirement also followsICH guidance.

Mostly according to ICHrequirements but regardingrepeat dose toxicity in rodents,administration period is longer(6months) than ICH guidelines(3months).Sometimes add reproductivetoxicity testings before clinicaltrials.

ICH E6

Requirednumber (or rate)of local subjectsin pivotalclinical studiesfor NDAapproval

Please explain forboth local andmultinationalclinical trials, ifnecessary.ex. totally around100ex. 1/5 of allsubjects in multi-national studies

At least 20-30 for Ph-1, 100for Ph-2, 300 for Ph-3 intreatment group for local trial(for category 1 of chemicaldrug).For registration purpose, 100pairs of Chinese patients inpivotal studies is requestedwhatever local studies orMRCT.Meanwhile, it is requested toshow similarity in drugresponse and safety profilebetween Chinese andforeign patients in MRCT.

Not specified Local clinical trial isneeded for newpsychotropic drugs .drugsfor family planningprogramme, certain drugbased on request fromAuthorized body.

It is requested to show theconsistency in drugresponse betweenJapanese and foreignpatients in multi-regionalclinical trials. For thispurpose, at least 15-20% ofall subjects is hopefully tobe Japanese.

1. Clinical trial protocol2. Patient information sheet and ICF form.3. Subject recruitment procedures andadvertisements (if applicable)4. Listing of overseas trial centres (if applicable)5. Principal investigator(s) CV, GCP cert6. GMP certificate or certificate of accreditation7. CoA (if appicable)8. Letter of approval issued by IRB9. Other relevant supporting documents, ifapplicable 10. IB

Clinical Trial Documentsconsist of : UK-1 Form,Protocol, Investigator'sBrochure, InformedConsent, Documents oftrial drugs, SummaryProtocol of BatchProduction (for Vaccineand biological products).

Generally we will follow ICHrequirement. Sometimesadd reproductive toxicitytestings before clinical trials.

Item Contents

Not-necessary

Detail or Example

Necessary data/documents/brochures tostart clinicaltrials

Necessary Toxdata for initiation ofclinical trials(specify localrequirement otherthan ICH-M3 orS6)

Protocol & IB.Usually TOX data aren'trequired for initiation ofclinical trial because all datahave been reviewed byauthorities. Because site/IRBalways follows CTA.

Please refer to theguidelines (file name:CT-guid)

List of necessary Tox data is shown in APPENDIX III of ScheduleY, the Drug and Cosmetics Rules 1945.

Clinicaltrials

P-I: 1-2 centers. At least 2 patients.P-II: 3-4 centers. At least 10-12 patients.P-III:a. The drug already approved/marketed in other countries: at least100 patients distributed over 3-4 centres.b. The drug is a new drug substance discovered in India and notmarketed in any other country: at least 500 patients distributedover 10-15 centres.(According to draft guideline) However Now a days DCGI asksfor 200 patients or more for Phase III studues for the drugapproved/marketed in other countries depending on the prevalanceof disaese and therapeutics area.

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Practicablenumber ofclinical centersor sites in thecountry

# of sites withfacility of clinicaltrialsIs there anylicense system forclinical study site?

Involved clinical center orsite should get a license ofCFDA.More than 300sites/hospitals are qualifiedby CFDA.

Practicable no. ofclinical study sites notspecified;No license system forclinical study sites;however, the clinicalstudy sites are usuallyuniversity orgovernment hospitals.

Not specified. It around 50 clinical centre.

Clinical trial can be initiatedin many study sites. Nolicense system for clinicalstudy sites.

Certified sites by MFDS: 156sites(Sep. 2012)

CRC(Clinical Research Centre)controls 17 clinical centers, 50hospitals and 100 clinics.

Clinical trial can be initiated inmany study sites. No licensesystem for clinical study sitesbut the protocol should beevaluated by IRB/EC.

There are 13 public hospitals and 16 privatehospitals which can conduct clinical trials.

More than 100 hospitals can conductclinical trials including 19 medicalcenenters. (Delete "38 clinical sites getconfirmation by TFDA for IRB certificationand allow these 38 IRBs can do reviewand approve without TFDA approval. "since this announcement has expired. 78Valid IRB name list is as "TFDA CertifiedIRB list" file 4.78 of them have valid IRBs per TFDAinspection result.There is no license system for evaluateclinical study sites.

8 officially recognized sites (IRB/EC site)No (Beware of USFDA blacklist)

IRB system forclinical trials

Installation ofIRB/EC in sitesIs there NationalIRB?

IEC at each site Yes.An IRB for eachcluster of hospitals

Independent Ethical Committee (IEC) & Institutional EthicsCommittee

There are National IRBsystem .

Institutional IRB. Institutional IRB institutional and national IRB (MREC)available depending on sites

Institutional IRB/EthicCommittee. The generalguidelines on CT may bereferenced from the "Nationalethical Guidelines for HealthResearch 2011 edition.Another reference is FDACircular 2012-007 thatrecognize ERB/ERC forpurposes of conducting CT ofInvestigational MedicinalProducts and it also validatesthe agreement between theFDA and PNHRS or PhilippineNational Health ResearchSystem which includes theestablishment of a clinical trialregistry.

Singapore has 2 clusters of public hospitals. 1cluster is under NHG DSRB (National HealthcareGroup Domain-Specific Review Board) and theother cluster is under SingHealth CIRB(Centralised Institutional Review Board). Forprivate hospitals, they have their own IRB/EC

c-IRB is composed of 18 hospital IRBs.Some other sites may also take fast trackfor c-IRB approved trials.JIRB covers 85 hospitals. ( thisinformation is collected from C-IRBwebsite)Every medical center has its own IRB.There is different requirement betweendifferent IRB.

available Yes, National IRB or Central IRB.

Prevalence ofGCP in clinicalcenters

GCP is observed in allclinical sites.

Yes Yes. GCP is observed in all clinical sites. GCP is observed in allclinical studies

GCP is observed in allclinical sites.

GCP is observed in all clinicalsites. Same as Japan.

GCP is observed in all clinical studies.(Local recognized GCP certificate iscompulsory for all investigators.)

Yes, GCP is observed in allclinical sites.ICH Guidelines, GCP E6

GCP is observed in all clinical studies GCP is observed in all medical centerand teaching hospital.

a must

Investigators ex. about 50physicians havebeen trained inUS/EC

uncountable number ofphysicians in China.

Yes Large pool of trained Investigators in diverse therapy areas Investigator must haveGCP training before thetrial and understand theprotocol comprehensivelyin order to conduct thetrial in accordance toGCP. No requirementinvestigator have beentrained in US/EC.

uncountable number ofphysicians in Japan

uncountable Information not available Uncountable number ofphysicians.In addition to CVs, IRBsrequire that investigatorsundergo GCP training and thisshould be renewed orrefreshed every 2 years.

No info TFDA regulated necessary training hoursneeded for GCP and ethical then qualifiedto conduct clinical trial. No actual numberof investigator to get GCP training.

no information (Beware of USFDA blacklist)

Condition ofcustoms procedure

Tax and custom clearance.If imported investigationaldrugs to be used, CTA isnecessary for Customsprocedures and clearance.

Application of ImportLicense based on theapproved CTC

Permission to import of investigational product shall be obtained byapplying for a test license. The application should be made inForm 12.

Sponsor request to importunregistered product wasto NAFDC. Approval letterfor Importation fromNAFDC is used forrelease product in thecustoms . .

After the IND approval.Import permit should be gottenfrom Korea PharmaceuticalTraders Association in advance.

clinical trial import license and properclearance required

yes Application for Import License of CTM required.Online application is possible. Can import lessthan the amount approved in the CTM, but notmore.The approved CTM form needs to be submitted tothe Trade Net office for custom clearance.

It needs to get import permit that issuefrom TFDA, then Customs will allowinvestigational product import into Taiwanwithin the quantity on the import permit.

Condition of customs procedure - importlicense, CoA, Airway bill, invoice

Investigationaldrug labeling(requirements andlanguage)

Chinese label is needed. IP name; Strength,dosage, storagecondition;manufacturer- English or Englishand Chinese

• "For Clinical Studies only”• Name or a code number of the study• Name and contact numbers of the investigator• Name of the institution• Subject’s identification code

In Indonesia language forclinical trial in Indonesia.

Japanese label is needed Korean label is neededRequirements :1) Investigational use onlystatement2) Code name or generic name3) Lot/batch number,expire/retest date4) Storage condition5) IND holder's name andaddress6) “It can not be used for otherpurposes except clinical trial”statement

refer to CTIL guideline.English acceptable

yes, in English 1. Designation or other identification mark on eachitem of such material.2. Name/address of manufacturer.3. Batch number.4. Name or other identification mark of the subject.5. Manufactured date and expiry date.6. Storage condition.7. 'The product should only be used under strictmedical surveillance' ; and/or "for Clinical TrialUse only"8. Must comply with GCP labeling requirements.

Traditional Chinese label is needed. Require local language with product name orrandom number, dosage, amount,manufacturer, expired date and the content of'this product is used for clinical trial only'.

Investigationaldrug

Usability of anunapproved drugas a comparator

No (almost impossible). Yes No Unapproved drug shouldprovide data as below:Quality Data,Investigator's Brochure,and Summary Report ofNon -Clinical & Clinicaldata, Summary of BatchProduction Report (forVaccines and BiologicalProduct)

It is possible to use anunapproved drug as acomparator if theunapproved drug is theinternational standard drug.It is recommended to gatherrelevant safety informationof the unapproved drug inJapanese.

Possible if the unapproved drugis the international standarddrug. It is recommended todiscuss with MFDS in advance.

depend on protocol design andsupporting documents provided. E.g.drug approved in another country andnot MYS, should be acceptable aslong as required supportingdocuments (e.g. safety data) provided

It is possible to use anunapproved drug as acomparator if the unapproveddrug is the internationalstandard drug. It isrecommended to gatherrelevant safety information ofthe unapproved drug.

As long as protocol and CTC approved, can beused

It is possible to use an unapproved drugas a comparator if the unapproved drug isthe international standard drug. It isrecommended to gather relevant safetyand efficacy information of theunapproved drug in English.

Possible subject to IRB/EC approval

Investigationaldrug

Clinicaltrials

Clinicaltrials

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Export shipmentof bio-samplesfrom subjects

ex. possible, canbe measured atCentral Labs.

There is specific regulationfor export of humansamples. Samples can beexported after approval.

Possible Possible There are Regulation no657/MenKes/Per/VIII/2009for export shipment of bio-samples from subject.The request for export ofbio-samples to Ministry ofHealth.

Samples can be exported Samples can be exported samples can be exported. Exportpermit required

Possible, can be measured atcentral laboratory

Can, as long as meet the importing countriesnecessary requirements. It is the applicant'sresponsibility to comply with importing country'srequirements

Possible, can be measured at Centrallabs. But it needs statement from Centrallab, also the information for the Centrallab needs clarified in the statement indetail, ex address, contact window.If central lab is located in foreign,Sponsor/ central lab's warrent letter forexport of sample (which is not dislinkage)is needed to obtain IRB and TFDAapproval. according th TFDAannoucement regulation on Dec 28, 2011,(human research law).For Biogene sample, it needs to indicatethe test gene information in advance thencan allow to export.

Possible (MTA required by most IRB)

Availability ofmulti-nationalCRO

ex . ** has localbranch, many localCROs

Multi-national CRO isavailable in China, such asQuintiles, ICON, Covance,ICN, PPD, PRA, RPS etc

Yes (domestic andmulti-nationalcompanies)

Multi-national CROs like Quintiles, Parexel, PPD, ICON etc areavailable

Multi-national CRO isavailable in Indonesian.

multi-national CRO isavailable in Japan

There are many multi-nationalCROs branch.Many local CROs.

available Multi-national CRO is availablein Philippines

Available Multi-national CRO is available in Taiwan Approximately 10 CROs available

GCP siteinspection

Accreditated to thesites by separateparties

Yes. Yes Will be conducted by the HSA Clinical TrialBranch, on locally conducted clinical trials.

Yes

SUSAR: report to Authority within 7 daysfor death and life threatening case, within15 days for other cause. It is same asinternational rule.

To FDA: Only SAE related to product report toFDA, death or life-threatening related to studyproduct within 7 days, other SAEs within 15days, AE at the end of study. To site IRB/EC:Death or life-threatening within 24 hours, otherSAE within 7 days, AE at the end of study.

Investigator should reportall serious unexpectedadverse event to sponsor/CRO as soon as possibleafter known it, if there aresome next adverse event,report a.s.a.p. until end ofevent. Sponsor shouldreport all serious adverseevent in Clinical Trialinclude death to Head ofNAFDC and EthicsCommittee within 15 daysstart from known theevent , if there is nextevent, report it a.s.a.puntil end of event.

Report SUSAR to MFDSwithin 7 days : Death, life-threateningwithin 15days : other SUSARs

refer to CTIL guideline SAE: report to Authority within3-7 days.Please see FDA Circular 2012-007 (p.9-10)

Fatal or life-threatening unexpected ADRs: within7 calendar days.All other serious unexpected ADRs: within 15calendar days.(See Guidance for Industry: Safety ReportingRequirments for Clinical Drug Trials)

As per new Gazette GSR 53(E)passed by Govt. of India on 30January 2013, Any report of serious adverse event of deathoccurring in clinical trial, after due analysis shall be forwarded bythe Sponsor to Chairman of the Ethics Committee and Chairman ofthe Expert Committee constituted by the Licensing Authority asdefined under rule 21(b) under Appendix XII with a copy of thereport to the Licensing　Athority and the head of the lnstitutionwhere the trial has been conducted within ten calendar days ofoccurrence of the serious adverse event of death. The report of theserious adverse event other than death, after due analysis, shallbe forwarded by the Sponsor to the Licensing Authority, Chairmanofthe Ethics Committee and the head of the lnstitution where the trialhas been conducted within ten calendar days of occurrence of theserious adverse event.

Clinical

trials

Adversereactionreporting duringclinical trial

ex . SAE: report toAuthority within 7days etc.,

SAE: it is requested to reportto the relevant authority in24 hours after knowing theevent.

Serious andunexpected adverseevents- Fatal/life threatening:no later than 7calendar days; submitreport in 8 additionalcalendar days- Others: 15 calendardaysNSAE and seriousexpected adverseevents:- Brief summary at theend of trial


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Pharmacopeia What is standardpharmacopeia ?What is otheracceptedpharmacopeia?ex. USP/NF, JP, EP

Ch.P. BP, USP, EP and JP.In-house specification forNCE would be accepted byDOH.

If a DP/DS is official in the IndianPharmacopoeia(IP) than must conformto IP if not official in IP thanBP/USP/EU Pharmacopoeia standardsare to be followed

Standard Pharmacopoeia :Indonesian PharmacopeiaOther accepted Pharmacopoeia :USP/NF, BP, EP, JP.

JP (Japanese Pharmacopeia) Standard : KPAccepted : JP, Ph. Eur(EP),USP(NF), BP, DeutshcesArzneibuch, PharmaacipeeFrancaise

The main pharmacopieal references are BPand USP. Others are JP and EP.

JP, USP/NF, EP, BP, PP (PhilippinePharmacopoeia)

BP, EP, USP/NFJP (chemical drugs andexcipients)

Accepted pharmacopoeia are JP, EP,USP/NF.

USP 34, NF 29 and supplements, BP 2011volume 1-5 and Addenda, the fourth edition ofIP and supplements, Thai-pharmacopoeia IIvolume I part 1 and supplements, the seventhedition of EP and supplements

GMP system What is current GMPrequirements?ex. PIC/S

Chinese GMP 2010version(MOH order 79)

PIC/S has been adopted forlocal manufacturer licensingPIC/S would be adopted foroverseas manufacturerwithin a few years.

Indian GMP as outlined in Schedule Mof DRUGS AND COSMETICS RULES,1945Then, these regulations and guidelines( Schedule M ) were revised in order tobe based on WHO-GMP in 2003.

PIC/S GMP requirements Japan applied for membership in thePIC/S GMP (March 2012）

KGMPKorea applied for membership in thePIC/S GMP(May 2012)

The current PIC/S Guide to GMP forMedicinal Products and its Annexes havebeen adopted as the standard used by NPCBto assess the GMP conformity ofmanufacturers.

Philippine applied for membership inthe PICS (June 2010) --> PFDA hasadopted the PICs Guidelines forGMP of medicinal products as perAO 2012-0008

PIC/S GMPrequirements

Taiwan is PIC/S member since Jan 2013. Under application for PIC/S membership.

GMP compliance is pre-requisite forobtaining a Product Marketing Approvalin Japan (see Pre-approval inspection,GMP).GMP inspection to licensedmanufacturer is carried out every fiveyears either by on-site or documentinspection.

Pre-approval GMP review:1) documents (Minimumrequirements) -based2) Site inspection.In case MFDS visits the same sitewithin 3 years for another productswhich used the same manufacturingmethod, on-site inspection could bewaived. (In case of biologics,exemption period is maximum 2years.)Even though MFDS does not visitthe site, documents for GMP reviewshould be submitted.3) Supplementary request after siteinspection

For locally manufactured products:Site inspection is required before issuance ofGMP cert. For imported products:On-site GMP inspection is required to ensurethe conformance of foreign manufacturers toGMP requirements and standards forproducts that are registered or that areundergoing the registration/re-registration/change of manufacturing siteprocess and those products manufactured forclinical trial purposes (investigationalmedicinal products).However NPCB will accept documentaryevidence of GMP conformance of amanufacturer located outside Malaysia onthe following condition: The GMP evidence isissued by a PIC/S Participating Authority oran ICH member country Competent Authorityfollowing an on-site inspection conducted bythe authority; ORThe GMP evidence is issued by a ListedInspection Service under the ASEANSectoral Mutual Recognition Arrangement forGood Manufacturing Practice (GMP)Inspection of Manufacturers of MedicinalProducts.The acceptable GMP evidence shall be inthe format of a GMP certificate or GMPinspection report.Where acceptable GMP evidence of theforeign manufacturer is not available, orwhere the documentary evidence submittedis insufficient to demonstrate acceptableGMP standard, a GMP inspection has to beconducted on the manufacturer by NPCB.Nevertheless the availability of acceptableGMP evidence does not preclude NPCB fromcarrying out the GMP inspection on themanufacturer.

Manu-facturing

Please describe GMPevaluation process bythe authorities.

ex. GMP clearance/accreditation requiredbefore NDAex. On-site ordocument inspectionex. Acceptability ofGMP certificate fromoriginal country

Specifications and test methods are tobe set according to registeredspecifications.Official in pharmacopoeia or in-housespecifications with validation data areavailable.

Specification and test methods arefollowing Indonesian Pharmacopoeia,USP, BP, or other Pharmacopoeia.

Item Contents Detail or Example

Acceptance testfor Import drug

How thespecifications & testmethods foracceptance test ofimport drugs are set inyour country?

1)For local drug, GMPcompliance is pre-requisite forobtaining a Product MarketingApproval in China (see "NDA" -GMP inspection).GMP inspection to licensedmanufacturer is carried outevery five years by on-siteinspection. And the applicationfor GMP renewal should besubmitted 6 months before GMPexpiration.2)For import drug, GMP on-siteinspection has been startedrecently. So some import drugswere selected for GMPinspection to abroad site and itwere done after licenseapproval.

For overseas manufacturer,inspection is usually notrequired.For local manufacturer, aninspection by pharmacistinspector will be conductedat the company's premiseswithin 2 weeks from thesubmission of a newapplication. The applicationwill be considered by thecommittee. If approved, alicense valid for 1 year willbe granted.

To be tested accordingto approvedspecifications & testmethods

Specification and test methods are to beset according to internationalpharmacopoeia, like JP, EP, USP/NF. Forinnovative product, it is allow to useCompany Own specification and testmethods with validation data and scientificjustification.

Both compendial and non-compendial methodare acceptable

Manu-facturing

Specifications and test methods are tobe set according to JP.

Specification and test methods areusually set in accordance with officialcompendium or registered in-housespecifications.

The latest version of British Pharmacopoeia(BP) and United State Pharmacopeia (USP)shall be used as the main references.All tests and its specification listed in BPand/or USP shall be the minimumrequirement. However, a specific testingmethod for quantitative analysis shall beaccepted. All test specifications set by themanufacturer shall be in line or morestringent than official pharmacopoeias (BPand USP).The specifications can be set by company,as long as it is aligned with the internationalreference & approved by the referencecountries.Full validation for in-house methods isrequired. All the analytical validation done bythe industry should be in accordance toASEAN Guidelines for Analytical Procedures,ICH Technical Requirements for Registrationof Pharmaceuticals for Human Use underValidation of Analytical Procedures: Text andMethodology Q2 (R1), BritishPharmacopoeia (BP) or United StatePharmacopeia (USP).

Specifications and test methods areto be set according to registeredspecifications.PFDA has adopted theimplementation of the ACTD insubmission of registration ofpharmaceutical prooducts but thereis flexibility in the use of ICH dossiereven for generic drugs.

Specifications and test methodsare to be set according to qualityverification test done byauthority and Ch.P. (ChinesePharmacopoeia).

Based on the approvedparticulars.

GMP inspection will be arrangedbefore granting the manufacturinglicense and periodicallyThe Licensing authority or by anyother persons to whom powers havebeen delegated in this behalf by thelicensing authority of India may inspectthe manufacturing premises of mfgunits outside India on need basis.

The manufacturer which is first timeregister export product to Indonesiashould provide SITE MASTER FILE(SMF) for GMP evaluation. Afterevaluation of SMF, the NADFC willapprove to continue registrationprocess of NDA or request siteinspection. Before inspection, themanufacturer should provide Pre-inspection document for preparationof the site inspection . Afterinspection, the NADFC will issueapproved or reject to continueregistration NDA. The inspectionreport from other Authorized HealthAuthority is needed to supportevaluation of SMF.

GMP compliance is pre-requisite forthe site registration of themanufacturing site and source intothe License to Operate, which then isa requirement in obtaining a ProductMarketing Approval in Philippines.Current evaluation for foreign sites isbased on documentation review.GMP inspection of licensed localmanufacturer is conducted by localFDA every 2 years, either by on-siteor document inspection.Implementing guidelines for theForeign site GMP audit is still in-progress.

Domesticmanufacturers inSingapore aresubjected to licensingand periodic GMPaudits by HSA.All new overseasmanufacturers will besubjected to a GMPConformity Assessmentby HSA.

Refer to GuidanceNotes on GMPConformity Assessmentof an OverseasManufacturer (Dec,2008)

GMP compliance on-site inspection is pre-requisite for NDA approval for newmanufacturing site. The already registeredmanufacturing site should be get routineGMP renewal (follow up management)through onsite inspection or documentinspection every 2 to 4 years depends onthe first approved expiry date.

GMP accreditation is required for new site,which has never been registered in Thailand.GMP accreditation is allowed to be submittedon parallel with product registration, but GMPmust be accredited prior product licenseissuance. GMP license will last 2 years, but thesite may be inspected earlier than 2 yearsdepending on the judgment of the FDAinspector.

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DMF system Updating of DMF depends on post-approval applications as per theASEAN Variations Guideline

Applicants areresponsible to maintainand update the DMF.When a DMF has beenupdated, the DMFSubmission Form and asummary table ofchanges made in theDMFupdate mustaccompany the updatedsections of the DMF. Ifthere are changes totheDMF that will result in apost-approval variationto the drug product,applicants must file apost-approval variation

No annual updated system. Partialchange application or notification isrequired for changes.

Manu-facturing

DMF system Please describe DMFsystem (or plan forintroduction).Is DMF mandatory oroptional?

NCE and API for generics should besubmitted DMF since 2002.But all APIs should be registered by2015. (Every year, MFDS announcedthe list of APIs which should beregistered.)Only drug substance(API) is subjectof DMF.

A DMF is required for API registration,starting with Phase 1 for NCE registrations inJan 2012. This may be replaced by a CEPor full details of Part II S ACTD. Regulatorycontrol of active pharmaceutical ingredient(API) is applicable to all pharmaceuticalproducts either locally manufactured orimported, excluding biologics, healthsupplements and natural products.Phase 2 will also be implemented forGenerics (Scheduled Poison) as givenbelow:New Generics: Parenterals by 1 July 2014,Oral dosage forms by 1 July 2016, All otherdosage formsby: 1 July 2018Existing Products: At registration renewalsfor Parenterals by 1 July 2015, Oral dosageforms by 1 July 2017, All other dosage formsby 1 July 2019. (Submission of requireddocuments to be done 1 year before productlicence expiry.)

DMF system is recognized as peradoption of ASEAN VariationsGuideline.

DMF system is investigated butnot yet implement.

Not specified No DMF system exists.(Note: CMC part of application dossieris called DMF, but it does not meanDMF system as in other countries.)API DMF as per ICH CTD is alsoacceptable.

DMF is required for new activesubstance.

Yes. It is optional to useDMF in applicationsubmission.DMF SubmissionFORM in Appendix18(effective 1April2014. See UPDATEJan 2014: Guideline onMedical PtroductRegistration inSingapore)

Current only DMF regulation for drugsubstance available.But now it is no mandatory request for allAPI. TFDA will announce the product listfor DMF compliance in next year.It may effective since year 2016 for allAPI. The 1st stage DMFmanagement regualtion is announce onMay 21, 2013.

No DMF system

Please describefrequency/number ofon-site inspections todomestic/overseasmanufacturers by theauthorities.ex. number ofinspections conductedin last year

At the end of 2011, 7 GMP on-site inspections to overseasmanufacturers were conducted.The situation of 2012 and 2013is unclear, but GMP on-siteinspections to overseasmanufacturers is announced tobe conducted in 2014.GMP on-site inspection todomestic manufacturers were126 in 2011, and it were 141 asof 30th Nov. 2012.

Since the manufacturelicense valids for only 1 year,inspection will be made atleast on annual basis forlocal manufacturers

Annually.For overseas, CDSCO startedinspection of Pharmaceutical firms forimport registration of drugs. Six on-siteinspections in 2011 for DSmanufacturing site in China, and fourChina drug manufacturing sites in2012.

Every month there are on siteinspection to domestic and overseasmanufacturers by the Authorities.Almost Asia countries are inspected.

Number of on-site GMP inspection tooverseas manufacturer in FY 2012 was66. About 60% are in Asia.On-site inspection to Japanesedomestic manufacturer by PMDA in FY2012 was 132.

The submission of MF (Master File) isoptional.Drug substance, Intermediate, Newexcipients, Packaging materials etc.are subjects of MF.

Number of on-site inspection tooverseas manufacturers in 2011 was90.Domestic manufactures in 2011 :232 by MFDS (90 by otherauthorities, e.g. FDA, EMA)

Inspection is required for products that areundergoing the registration/re-registration/change of manufacturing siteprocess and those products manufactured forclinical trial purposes (investigationalmedicinal products). Domestic manufacturersare inspected at least once a year for annualmanufacturing license.In 2012, a total of 299 GMP inspectionswere conducted.The GMP inspections comprises of routineand nonroutine inspections of manufacturerpremises fromvarious categories such as pharmaceutical,traditional,cosmetics, veterinary, active pharmaceuticalingredient(API) and others. From the total 299inspections,the number of inspections conducted inpremises ofcosmetics, traditional, pharmaceutical andothers(veterinary, API, stem cells and etc.) are119, 102, 45 and33 respectively.

No details as of this moment. TFDA: domestic: about 180, overseas:about 30 (in 2012).

- Domestic:Non- sterile drug: every 3 yearsSterile drug: every 1.5 year- Overseas: if needed

FDA's plan on inspection:(Note: The FDA is working on the update of thisregulation, but not come out yet at time ofreport)• Routine Inspections ~ 60-70 plants/year• Special inspection in special case• And there will be Follow up Inspection whichthey are setting on criteria (may be from RiskAssessment).

Annual or periodicalupdate reportingrequired?

not yet implement. Not specified N/A N/A No annual updated system. Partialchange application or notification isrequired for changes.

Annual report should be submittedby Jan. 31 every year if the relevantchanges are applicable for thesubject of annual report

Manufacturers of finished products shouldestablish a mechanism by whichmanufacturers/suppliers of an API shallprovide information on any changes (i.e.variations) in manufacture and control thatmay have impact on the safety, purity andquality of the API. It is the MAH’sresponsibility to provide the Agency with theappropriate documentation (referring torelevant parts of the dossier) to prove thatany intended or implemented variation willnot have an impact on the safety, purity andquality of the API that has been previouslyapproved.The NPCB may conduct a re-evaluation ofthe APIs at a 5 year interval.

Not required

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Bar code onpackagingmaterials

Please describerequirements of BarCode on packagingmaterials andconcernedregulations.

Bar code on packaging materialfor national essential drugsshould be completed by Feb.2012, while the deadline forwhole drugs is by Dec. 2015.

For product registration, noconcern.For supply to governmenthospital: GTIN barcode asissued by GS-1

For product registration, no concern.For supply to government hospital:GTIN barcode is requiredBarcode requirements using GS1identification standards has beenimplemented.(reference: The Office MemorandumNo: Z-16025/02/08-EPW dated 6thMay 2011 by MoHFW). For localIndian market, it is still not mademandatory.

No regulatory requirement on barcode.It is an internal company logisticsrequirement.

The contents Should be written inJapanese.

Requirement : Article 75 of thePharmaceutical Affairs Act.Article 69 of the EnforcementRegulation on the Safety ofPharmaceuticals etc.& Notification on the Use andMamnagement of Drug Bar Codesand RFID tagsGS1-128 barcode system (GTIN-13Product code + expiry date + BatchNo. + Serial No(in the case of SerialNo., it should be applied as of Jan.2015.) should be used.

Bar code is an optional information. Barcode is required per SKU.It is not a regulatory requirement butmore of a marketing or traderequirement.

No regulatoryrequirement on barcode. It is a internalcompany logisticsrequirement.

Current barcode labeling of product codeis required to manufacturers/distributorsdepending on package unit (carton) orouter box.Barcode regulation on product unit (pertablet for blister, per bottle, per vial forinjection) is draft and under discussion.The requirement for the barcode will beGTIN(GS1) data matrix.

No regulatory requirement for Bar codeBut some hospitals require barcode.

Post marketingsurveillance orsafety monitoringprogram

PSUR submissionrequired?

Other post-approvalsafety requirements?ex. Safety monitoringprogram/monitoredrelease

PSUR submission is mandatoryannually until the first renewaldate and every 5 years after thefirst renewal date.Special monitoring over drugswithin the new drug observationperiod as well as drugs importedfor the first time within 5 years ismandatory performed. Themonitoring results shall besummarized, analyzed,evaluated and reported asrequired.

For NCE only.PSUR has to be submittedevery 6-monthly for the first 2years of product registrationapproval, and annually in thefollowing 3 years.

PSUR submission is mandatory for aperiod of four years.For new drug, every 6 months for thefirst 2 years, and annually for another2 years. May be extended by theauthority in the interest of publichealth.(Reference: Schedule Y of the Drugsand Cosmetics Rules amended in2005)PSURs due for a period must besubmitted within 30 calendar days ofthe last day of the reporting period.

PSUR submission is required only forNCE and certain product if it isrequired by HA.There is an obligation to report allAdverse Events(unexpected/expected , serious/ nonserious in Indonesia or foreigncountries) to NADFC .

PSUR submission is mandatory every6 month in first two years and annuallyafter two years.Use-result survey data should besubmitted together.

PSUR submission is mandatoryevery 6 month in first two years andannually after two years.Use-result survey data should besubmitted together.

PSUR is mandatory for NME: 6 months oncein the first 2 years, and 12 months once inthe subsequent 3 years.

As per PFDA Circular 2013-004,after the issuance of MA, the MAHshall submit a PSUR regularly to theFDA. When PBRER is part of theRMP, it shall also be submitted to theFDA. In general, a PSUR and/orPBRER shall be submitted at leastonce a year.Prompt and regular, or periodicsubmission of PSUR, PBRER,ICSRs,and spontaneous ADRreports shall constitute PMSactivities.

When requested byHSA, PSUR should besubmitted 6 months forthe first 2 years, and 12months for thesubsequent 3 years.Ad-hoc submissionrequests can be raisedif required.

PSUR submission is mandatory every 6months in first two years and annuallyafter two years.For NCE product, it necessary to submitPSUR in first 5 years.Other post approval safety requirementlike RMP/REMs will be initiated by TFDAor Pharmaceutical company, it depends.For non-CPP NDA submission case, it ismandatory requirement to submitRMP/REMs together with NDAsubmission. For one-CPP NDAsubmission case, it may request by TFDAafter their evaluation.

Yes, T-FDA requires PSUR for unconditionalapproval of New drug.SMP (Safety Monitoring Program) for NCE isrequired under conditional approval for 2 years.

Follow ASEAN labeling requirementsThai language required forcategory of drug- expiration date- special warning

The required contents are describedin Generic Labeling Law.The contents Should be written inEnglish.(see A.O. 55, series 1988)

Refer to:GUIDANCE ONMEDICINAL PRODUCTREGISTRATION INSINGAPOREAPPENDIX 6 POINTSTO CONSIDER FORSINGAPORELABELLING

The required contents are described inArticle 20 of "drug review and registrationguideline". The contents should be writtenin English and Chinese.

Renewal systemof approvedlicense

Please describerenewal system ofmarketingauthorization ormanufacturinglicense.

ex. renewal requiredevery 5 yearsex. re-evaluationsystem

Manu-facturing

Contents ofpackaging labeland language

Please describerequired contents ofpackaging label andlanguage to be used.ex. refer to guidancedocument

The required contents aredescribed in CFDA order 24.The contents should be writtenin Chinese.

English or English andChinese, requirementsdecribed in Guidelines on theLabelling of PharmaceuticalProducts

The required contents are described inrule 96 & Schedule D2 of the Drug andCosmetic Rules 1945.PI and packaging labels should bewritten in English.

New guideline 2011 for labelingprescription drug : request to providePackage insert ( English orIndonesia), Patient InformationLeaflet (Indonesian), outerbox shouldfollowing packaging requirement(name of the product, activesubstance, volume, indication,contraindication, dosage andadministration, storage condition,manufacturing name & address ,imported by, ) also retail price,Registration number, Harus denganresep dokter, Logo of prescriptiondrug.In the label, after product nameshould follow active substancenames, Label also followingregulation on registration.Guideline for OTC : inner box and allproduct information should be inIndonesian language.

The required contents are described inArticle 50 of the Pharmaceutical AffairsAct.The contents Should be written inJapanese.

Language : KoreanRequirement : Follow Article 56 ofthe Pharmaceutical Affairs Act and inAct Article 69 of the EnforcementRegulation on the Safety ofPharmaceutials etc..

The labeling content is stated in DrugRegulatory Guidance Document. Thelabeling for pharmaceutical products are inEnglish or Bahasa Malaysia. Some labellingstatements are mandatory in BahasaMalaysia, eg for “Keep medicine out of reachof children”.

There are 3 kinds of license in Thailand whichare Manufacturing license, Import license andSale license, all of which require annualrenewal.Based on current Thai Drug Act, the productlicense is life-long, no requirement of renewal,except for drug classified as narcotics andpsychotropics shall subject to renewal every 5years.

Not renewal but re-examination systemis adopted.Drug monitoring is required for 8 yearsfor NCE drug, 4-6 years for newindication/ administration route and 10years for orphan drug.

Renewal system of approvedlicenses will be implemented fromdrugs which would be approved in2013 (applicable for existing drugsas of Jan. 1, 2018).Documents should be submitted :1) Summary reports on Safety andEfficacy of the drug product includingthe last 5-year2) Usage in foreign countries, Anyaction related to safety in foreigncountries3) Data on Product Quality4) Safety update report5) In case anything would bechanged from approval, its evidentialdata6) Document on Drug Display (Labelin carton, PI and so on)7) Manufacturing or Importingrecords during the last five-year8) Product Permission letter issuedby MFDS

Renewal is required every 5 years of aproduct registration. Renewal needs to besubmitted 6 months prior to registrationexpiry.Additional Notes for renewal requirements:NPCB will also require Zone IVb stabilitydata to be updated during renewal review;however grace period for compliance hasbeen allowed until Jan 2016.For renewal of imported products from Jan2014, a GMP inspection is also requiredwhere acceptable GMP evidence of theforeign manufacturer is not available, orwhere the documentary evidence submittedis insufficient to demonstrate acceptableGMP standard.API registration for products containing"scheduled poisons" will be required beforerenewal, i.e. for Parenterals by 1 July 2015,Oral dosage forms by 1 July 2017, All otherdosage forms by 1 July 2019. (Submission ofrequired documents to be done 1 year beforeproduct licence expiry.)

Renewal system is beingimplemented.Renewal for products underMonitored Release status is after 3-5years. Products on regularregistration status, i.e. under Initial orRenewal status, renewal is doneevery 5 years. The PFDA is nowcontrolling the renewal of licenses ofnon-marketed products.

Postapproval

Product licenses shouldbe renewed every 12months.Auto renewal system isimplemented since2009.

Renewal system of approved license isexisted. The approved license needs to berenewed every 5 years.

Manufacturing license system isadopted for drug administration.So, renewal system is based onmanufacturing license.Renewal is required every 5years, and should be submittedwithin 6 months beforeexpiration date of license.

Renewal required every 5year.

Renewal system has beenimplemented for the followings.1) Import license (Every 3 years.Renewal application should be madethree months before the expiry of theexisting license.)2) Registration certificate (Every 3years. Renewal application should bemade nine months before the expiry ofthe existing license.)3) Manufacturing license (Every 5years. The license will be expired if therenewal applications not made withinsix months of its expiry)Marketing Authorization is one timeissue, no renewal required.

Marketing Authorization: Requiredevery 5 years.Renewal application needs to besubmitted 6 months prior toregistration expiry. If needed, theNADFC will do re-evaluation system.Manufacturing License: Requiredevery 5 years of every GMP facilityand dosage form.Sometimes the NADFC will inspectthe GMP facility before giving therenewal of Manufacturing license.

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Risk ManagementPlan (RMP)

Please describerequirements ofRMP/REMS.ex. Mandatory atNDA, submit up onrequest from theauthorities

Not yet officially implemented.For the product which isaccepted for special reviewprocedure, Risk Managementand Implementation Plan shouldbe submitted at NDA.

One of the mandatoryrequirements for NCEregistration

N/A at present Not required yet.RMP regulation will establish later on.

RMP document is mandated for NDAas M1.11.

MFDS has a plan to adopt REMSwithin several years.

Not a mandatory requirement. May berequired on request by the authorities, inparticular for biosimilar/biological products.

N/A at present.A RMP is a requirement for theissuance of appropriate authorization& shall be one of the requirementswhen applying for marketingauthorization application. It should beproportionate to the risks as shownby clinical evidences& the risk profileof the product. There is no specificformat for RMP issued by the PFDA.

When available,RMP/REMS submittedto EMA/US-FDA maybe requested at NDA,The need to implementa risk management planin Singapore would beassessed on a case-by-case basis during thereview process.

Mandatory at NDA for non-CPP product,submit up on request from TFDA.

Require for some specific group. Ex.Thalidomide.

Variationguideline

Is there any guidelinedocument for post-approval changes?If yes please show thetitle.

The variations to be approved orfiled are listed in DrugRegistration Regulation order28.Meanwhile, Guideline forVariations of Post-marketChemical Drug Products hasbeen implemented.

Please refer to the guidelinesfor Change of particulars (filename: copGuide).

Chemical products:In case major change, approval isneeded within 30 days by submissionof variation application. For minorchange, it should be notified to theauthorities within 30 days.(See Drugs and Cosmetics Rules,1945) Biological products:LEVEL I - Supplements (Major QualityChanges);LEVEL II - Notifiable Changes(Moderate Quality Changes)LEVEL III - Annual Notification (MinorQuality Changes)(See Guidance for Industry: Postapproval changes in Biologic Products– Quality, Safety and EfficacyDocuments)

There is regulation numberHk.o3.1.23.12.11.10690 .2011regarding Implementation ofPharmacovigilance forPharmaceutical Industry .Variation guideline are included in theCriteria and Procedure of DrugRegistration no HK03/23.10.11.08481. year 2011 /

Partial change application should besubmitted for approval of changes. Forminor changes, notification system canbe applied.Scope and handling of these changesare stipulated in the PharmaceuticalAffairs Law and several notices.

Changes in post-license should beapplyed to MFDS according to thelevel of the changes. PharmaceuticalAffairs Act, Several notices andGuidelines exist.

Malaysian Variation Guideline ForPharmaceutical Products (Date of firstedition: 12 April 2013)

Partial change application should besubmitted for approval of changes.For minor changes, notificationsystem can be applied. (Pendingimplementation)See attached files MaV and MiVPFDA has adopted the ASEANVariation Guidelines forPharmaceutical ProductsFinal Draft 7.2 2013

There are two sub-categories for eachMajor and Minorvariation.

Guidelines are found inChapter H andAppendix 15 for MIVand Chapter G forMAV.(Updatedguideline is effective 1April 2014). . TheGuideline is also guidedby the adoption of theASEAN VariationGuideline.

"drug review and registration guideline"was specify the document needed for postapproval change.

Yes, "Asean variation guideline" which will beimplemented in Jul 2013.ASEAN Variation Guideline

Adverse drugreaction reportingafter marketing

Reporting is mandated for ADRobserved in post-marketing products.1. AE Spontaneous seriousunexpected in Indonesia , as soon aspossible, not more than 15 calendardays.2. AE spontaneous non-seriousunexpected in Indonesia, report every6 months.3. AE Spontaneous serious expectedin Indonesia, as soon as possible, notmore than 15 calendar days.4. AE spontaneous seriousunexpected in froiegn countries, assoon as possible, not more than 15calendar days.

Please describereportingrequirements of ADRfor marketedproducts.

Reporting is mandated for ADRobserved in post-marketingproducts including PMS.Reporting period of Serious ADRand expected ADR are within 15days ( 30 days for non-SeriousADR for drugs within the newdrug observation period orimported drugs within 5 yearsfrom the date of initial importpermission).

For generic products,reporting is by means ofvoluntary basis.For NCE, SUSARs have tobe reported within 15calendar days from date offirst receipt.

Follow Guidance for Industry Post-marketingSafety Reporting Requirements for Human Drugand Biological Products Including Vaccines(Annex 10)

Fatal/life-threateningARs: NLT 7 calendardays.Serious ARs: NLT 15calendar days.

Productwithdrawal/productrecall/product defect:Within 24 hrsSignificant safetyissues: Within 7calendar days

See The Guidance forIndustry – SafetyReportingRequirements forRegistered MedicinalProducts, April 2011

Serious unexpected adversereactions: must be reported to thelicensing authority within 15 days ofinitial receipt of the information by theapplicant.Other: to be reported in PSUR.

Reporting is mandated for ADRobserved in post-marketing productsincluding PMS. Reporting period ofSerious ADR is within 15 days (or 30days for expected ADR).

Reporting is mandated for ADRobserved in post-marketing productsincluding PMS.SAE : within 15 days from reporteddayNSAE : within next year Feb fromreported day

Reporting is mandated for ADR observed inpost-marketing products including PMS.Non serious ADR / Serious but non-lifethreatening ADR: 15 days from date learned;Serious ADR(fatal and life threatening iswithin 7days.

Postapproval

Reporting is mandated for ADRobserved in post-marketing productsincluding PMS.Reporting period of Serious ADR iswithin 3-7 days (or on the 30th day ofthe 1st month of every quarter forexpected ADRs).

Reporting is mandated for ADR observedin post-marketing products including PMS.Reporting period of Serious ADR is within7 days for death and life threatening,within 15 days for other Serious ADR.

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タイプライターテキスト

Annex 1

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Annex 1

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Pre-Consultation

IND Submission

KFDA Review

IND Approval

IRB Submission

IRB Approval

Contract With Hospital

• Protocol, ICF (Translated), CRF • IB • CV

IRB Committee

• Protocol • CMC • Preclinical • IB

KFDA Approval Process

IRB Process; Parallel review with Regulatory process

30 working days

Study Initiation

Annex 2

6

Annex 3

Foreign Clinical data Bridging data on Koreans

1) Orphan drugs 2) Drugs for treating Aids, cancer or life- threatening disease 3) Diagnostic reagents 4) Drugs that do not effect systemically but locally 5) Drugs that have demonstrated no ethnic differences 6) Other drugs recognized by commissioner of KFDA

Exempt bridging data

1) When the confirmatory study data for safety & efficacy generated from Koreans living in Korea are available

2) Not show apparent differences between Koreans and other

ethnic groups: there should be no extrinsic factors between Korea and other regions

3) Given the characteristics of a drug developed from other

ethnic groups, when Koreans show similar reactions and when it has been substantiated that the drugs previously approved in Korea under its same drug group did not show differences between Korean and other regions in terms of safety and efficacy and dosage, dose regimen, and etc.

Exempt bridging study

When a bridging study is necessary to determine the application of foreign clinical data into Korea

Determine the type of a bridging study to be needed (next slide)

Bridging Data

Conduct bridging study

Exempt bridging data

Completed Assessment of Foreign Clinical Data and Etc.

When necessary, conduct a bridging study for safety

Annex 3

Annex 4

1

1

Review Process for NDA

1 1

Sponsor Application

Technical and administrative document, GMP/PMF

TFDA Review Team (TFDA Staff+ CDE)

Assessment report

Consult with AC experts for special concern Advisory

Committee

Sponsor

Decision

★ GMP: Good manufacturing practice PMF: Plant master file

Global New, Botanical product, Biosimilar product, etc.

GMP /PMF

Annex 5

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Annex 6

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( Source: Jiho. Drug Approval Licensing Procedures in Japan 2010. Tokyo. Jiho, Inc, 2011; P. 489. )

Annex ７

Annex 8

Number of reviewers New Generic (NG) Generic (G)NCE NI NCO ND NR NDOS NS NB BF B

CMC 2 - 2 2 2 2 2 2 2 2 2 2Clinical 2 2 2 2 2 2 2 2(BA/BE) - 2 1Non-clinical 2 2* 1* 1* 1* - 1* 1(labelling,efficacy&safety)1(labelling,efficacy&safety) 2 1 1(labelling,efficacy&safety)

* If applicable

NCE = New Chemical

Entity,

NI = New Indication,

NCO = New

Combination,

ND = New Delivery

system,

NR = New Route of

administration,

NDOS = New Dosage

form of Approved New

Drug,

NS = New Strength of

Approved New Drug

NB = New Biological

drug

BF = New Generic of

Biological drug

New Drugs Biologics

New Drug Registration Thailand

Annex 9

REGISTRATION PROCEDURE

Step I FDA Drug Bureau

Step II

Application for Importing of Drug Sample

Submit Application

Permit for Importing Drug Sample

Application for Registration

Submit Registration File

Document Checking and Preliminary Review

Experts and/or Subcommittee

Accept Revise or Request for Add. Document

Review

Accept

280 wd

Annex 9

Submit SMP Protocol

Registration Approval (Conditional)

Submit Comprehensive Summary Report

Registration Approval (Unconditional)

Application for Registration (cont.)

160 days

SMP& Limited distribution ( approx 2 yrs*)

Note: *Time can be extended from 2 years up to 4 years if justified

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Guidance for Industry

Post-marketing Safety Reporting Requirements for

Human Drug and Biological Products Including Vaccines

Food and Drug Administration

13 July 2011

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Table of Contents Page

1. Introduction 3

2. Purpose and Scope 3

3. Reporting Requirements for Individual Case Safety Reports 3

3.1 Essential Information in AE Reports 4

3.2 Follow-up Reports 4

3.3 Expedited Reporting 4

3.4 AE Reporting Channels 4

3.5 Time Frames for Reporting 5

4. Spontaneous or Unsolicited AE Reports 5

5. Scientific Literature Reports 6

6. Safety Reporting in Special Situations 6

6.1 Lack of Efficacy 6

6.2 Exposure During Pregnancy 6

6.3 Drug Overdose 6

7. Solicited Reports 6

8. Periodic Safety Update Reports (PSURs) 7

9. Other Safety Information 7

Annexes :

Annex I: Flowchart A: Post-Marketing Safety Reporting to HPVC 8

Flowchart B: Reporting of Drug Exposure During Pregnancy to HPVC 9

Annex II: Thai FDA AE reporting form 10

Annex III: CIOMS form 11

Annex IV: Glossary 12

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Guidance for Industry

Post-marketing Safety Reporting Requirements for

Human Drug and Biological Products Including Vaccines

1. Introduction

Although drugs approved by the Thai FDA have undergone extensive studies on efficacy and safety, from preclinical testing to clinical trials in phases I-III, there are still adverse reactions that are not detected during these studies, and are known only after marketing. This is the result of limitations in clinical studies, e.g. small number of patients, exclusion of children, the elderly and pregnant women as well as patients with liver or kidney abnormalities, and short duration of study. Therefore reporting and monitoring of adverse reactions following the marketing of a drug is crucial to pharmacovigilance. The Thai FDA has put in place a requirement upon registration of a new drug: that market authorization holders (MAHs) have to report adverse reactions/ events as a condition for a conditional approval. Subsequently, the Thai FDA also imposed a requirement for such reporting for all vaccines and has received good cooperation.

To improve effectiveness and standardize the pharmacovigilance requirements, the Thai FDA, representing by the Health Product Vigilance Center (HPVC), in cooperation with the Pharmaceutical Research and Manufacturers Association (PReMA) has issued the guidance document. This document serves as a guide for MAHs to implement pharmacovigilance activities after a drug is marketed. This guidance covers purpose and scope, individual case safety reports, reporting requirements in special situations, reporting flow charts, glossary, and reporting forms.

2. Purpose and Scope

The purpose of this document is to guide Marketing Authorization Holders (MAHs) on the submission of relevant safety information to Health Product Vigilance Center (HPVC) of the Food and Drug Administration, Ministry of Public Health. However, this guidance does not include medicinal products which are imported under the remit of the Bureau of Drug Control, the Thai FDA, for clinical studies.

This guidance consists of the following topics:

Reporting requirements for individual case safety report

Spontaneous or unsolicited AE report

Scientific literature report

Reporting requirements in special situations

Solicited report

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Periodic Safety Update Report (PSUR)

3. Reporting Requirements for Individual Case Safety Reports (ICSRs)

The MAH should report AEs of registered drugs and biological products Including vaccines that are spontaneously received to HPVC. Only serious suspected AEs should be reported to HPVC according to the process and time frame shown in Annex 1.

3.1 Essential Information in AE Reports

AE reports should be as complete as possible and contain essential information to facilitate assessment.

The minimum information required for submission of an initial AE report is:

1. An identifiable patient

2. An identifiable reporting source

3. At least one adverse event

4. At least one suspected product

3.2 Follow-up Reports

Additional information should be provided in the form of follow-up reports which should be clearly stated as such with reference to the initial report.

3.3 Expedited Reporting

Upon the first knowledge of a fatal adverse event associated with use of a vaccine or a new drug with conditional approval (NC), or death from unexpected/unlabelled ADRs, the MAH should notify the FDA by phone, fax within 24 hours and send a complete report within 7 calendar days of the first knowledge.

3.4 AE Reporting Channels

(1) the online reporting system which is available at: http://www.fda.moph.go.th/vigilance (passwords required)

(2) the Thai FDA AE reporting form with or without the CIOMS I form, and submit the reports via fax, email, mail to HPVC.

(3) The Thai FDA AE reporting form can be downloaded from:

http://www.fda.moph.go.th/vigilance/

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The CIOMS I form is available at: http://www.cioms.ch/

3.5 Time Frames for Reporting

The time frame depends on type of AE reports. Please see the table below:

Adverse Events Reporting Time Frame

Death As soon as possible but not later than 7 calendar days, except the following circumstances whereby the FDA should be notified by phone, fax, email within 24 hours, followed by a complete report within 7 days of the first knowledge:

(1). Death after use of

Vaccine

New drug with conditional approval (NC)

(2) Death from unexpected/unlabelled ADRs

Serious 15 calendar days*

Non-serious 2 months

*Calendar Day from the MAH’s receipt date of the report. 4. Spontaneous or Unsolicited AE Reports

4.1 Serious Adverse Events

Only serious adverse event reports that are suspected to be associated with drugs, biological products or vaccines should be submitted.

4.2 Non-Serious Adverse Events

(1) Non-serious AE reports, originated in Thailand, for all vaccines and for drugs and biological products under conditional approval should be submitted.

(2) Other such reports, originated in Thailand, should not be submitted, except upon request by the Thai FDA.

(3) AE reports originated in foreign countries should not be submitted except that the AE involves a product purchased from Thailand or occurs to a Thai citizen.

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5. Scientific Literature Reports

Cases of AEs reported in scientific and medical literature, including relevant published abstracts from meetings, may qualify for reporting if the source country is Thailand, the minimum information for reporting (see 3.1) is met, and the AEs are serious. The publication reference (s) should be given as the report source.

If multiple products are mentioned in the article, a report should be submitted only by the applicant whose product is suspected. The suspected product is identified as such by the article’s author.

6. Safety Reporting in Special Situations

6.1 Lack of Efficacy Synonyms: lack of effect, failure of expected pharmacological actions, etc.

Lack of efficacy is considered an adverse event. The underlying principle is that if a drug fails to produce the expected pharmacological, therapeutic or preventive benefit, there may be an adverse outcome for the patient, including a worsening of the condition for which the medication is being taken.

6.2 Exposure During Pregnancy

In the event that a MAH is aware that its product which is not recommended for use during pregnancy has been received by a pregnant patient, the MAH should follow up with the doctor on the pregnancy outcome. If a pregnancy results in a serious or an abnormal outcome which the reporting doctor considers might be due to the product, the MAH must submit the AE report to the HPVC within 15 calendar days.

6.3 Drug Overdoses

The MAH does not need to report cases of drug overdoses unless these lead to adverse events.

7. Solicited Reports

Solicited AE reports derived from organized data collection systems including studies e.g. phase IV clinical studies, may qualify for reporting to HPVC if the following is fulfilled:

(1) The medicinal product is used according to the approved label and prescribing information, and

(2) The medicinal product used in the study does not require an import permit from the Bureau of Drug Control

(3) Only serious adverse events from such studies need to be submitted.

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8. Periodic Safety Update Reports (PSURs)

MAHs are not required to submit PSURs except when requested by the Thai FDA.

9. Other Safety Information

When the MAH receives product safety information which may warrant changes in risk management measures, the MAH should send the information to HPVC as soon as possible.

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Annex I

Flow Chart A: Post-Marketing Adverse Event Reporting to HPVC

AE report received by MAH

Serious AE ?

Death ? Yes

Yes

No

No

Report within

15 calendar days

Report as soon as possible but not later than 7 calendar days, except the following circumstances whereby the FDA should be notified by phone, fax, email within 24 hours, followed by a complete report within 7 days of the first knowledge:

(1). Death after use of

Vaccine

New drug with conditional approval (NC)

(2) Death from unexpected/ unlabelled

vaccine ?

Report within

2 months

Yes

No

conditional approval ?

Reporting not required

No

Yes

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Annex I

Flow Chart B: Reporting of Drug Exposure During Pregnancy to HPVC

MAH notified of drug exposure in a pregnant woman

Abnormal pregnancy outcome ?

Reporting not required

No

Follow-up with the healthcare professional

Yes Report within 15 calendar days

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Annex II

The Thai FDA AE Reporting Form in Thai (See the HPVC website)

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Annex III CIOMS FORM

SUSPECT ADVERSE REACTION REPORT

I. REACTION INFORMATION

1. PATIENT INITIALS

1a. COUNTRY 2. DATE OF BIRTH 2a. AGE 3. SEX

4-6 REACTION ONSET 8-12 CHECK ALL

(first, last) Day Month Year Years Day Month Year APPROPRIATE TO ADVERSE REACTION

7 + 13 DESCRIBE REACTION(S) (including relevant tests/lab data) PATIENT DIED

INVOLVED OR PROLONGED INPATIENT HOSPITALISATION

INVOLVED PERSISTENT OR SIGNIFICANT DISABILITY OR INCAPACITY

LIFE THREATENING

CONGENITAL ANOMALY

OTHER MEDICALLY IMPORTANT CONDITION

II. SUSPECT DRUG(S) INFORMATION

14. SUSPECT DRUG(S) (include generic name) 20. DID REACTION ABATE AFTER STOPPING DRUG?

YES NO NA

15. DAILY DOSE(S) 16. ROUTE(S) OF ADMINISTRATION

21. DID REACTION REAPPEAR AFTER REINTRO-

17. INDICATION(S) FOR USE DUCTION?

YES NO NA

18. THERAPY DATES (from/to) 19. THERAPY DURATION

III. CONCOMITANT DRUG(S) AND HISTORY

22. CONCOMITANT DRUG(S) AND DATES OF ADMINISTRATION (exclude those used to treat reaction)

23. OTHER RELEVANT HISTORY (e.g. diagnoses, allergies, pregnancy with last menstrual period, etc.)

IV. MANUFACTURER INFORMATION

24a. NAME AND ADDRESS OF MANUFACTURER 26-26a. NAME AND ADRESS OF REPORTER (INCLUDE ZIP CODE)

RIGINAL REPORT NO. 24b. MFR CONTROL NO.

24c. DATE RECEIVED BY MANUFACTURER

24d. REPORT SOURCE STUDY LITERATURE HEALTH PROFESSIONAL REGULATORY AUTHORITY OTHER

DATE OF THIS REPORT 25a. REPORT TYPE INITIAL FOLLOW-UP

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Annex IV : Glossary

Adverse event or Adverse Experience (AE:

Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment.

Adverse Drug Reaction (ADR) :

A response to a medicine which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function.

An adverse drug reaction, contrary to an adverse event, is characterized by the suspicion of a causal relationship between the drug and the occurrence, i.e. judged as being at least possibly related to treatment by the reporting or a reviewing health professional.

For regulatory reporting purposes, if an event is spontaneously reported, even if the relationship is unknown or unstated, it meets the definition of an adverse drug reaction.

Causality assessment:

Causality assessment is the systemic review of data about an adverse reaction case to determine the likelihood of a causal association between the event and the medicinal product received.

CIOMS I form:

An adverse reaction reporting form developed by the Council for International Organisations of Medical Sciences (CIOMS), intended for notifying the regulatory authorities of countries other than the country where the report originated.

Labelled/ Unlabelled adverse reaction

An adverse reaction, the nature or severity of which is/is not consistent with domestic labeling or market authorization.

Periodic Safety Update Report (PSUR):

A systematic review of the global safety data which became available to the manufacturer of a marketed drug during a specific time period, produced in an internationally agreed format.

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Serious AE :

A serious adverse event is any untoward medical occurrence that at any dose:

results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in congenital anomaly/birth defect, is a medically important event or reaction.

To ensure no confusion or misunderstanding of the difference between the terms ‘serious’ and ‘severe’, the following note of clarification is provided:

The term ‘severe’ is not synonymous with serious. In the English language, ‘severe’ is used to describe the intensity (severity) of a specific event (as in mild, moderate or severe); the event itself, however, may be of relatively minor medical significance (such as severe headache). Seriousness (not severity) which is based on patient /event outcome or action criteria serves as guide for defining regulatory reporting obligations.

Marketing Authorization (MA) :

The approval granted by the Thai FDA for marketing in the Kingdom of Thailand.

Marketing Authorization Holder (MAH):

The company named on the Marketing Authorization for manufacturing in or importing into the Kingdom of Thailand

Solicited reports

Solicited reports are those derived from organized data collection systems, which include clinical trials, registries,

post-approval named patient use programs, other patient support and disease management programs, surveys of

patients or healthcare providers, or information gathering on efficacy or patient compliance. Adverse event

reports obtained from any of these should not be considered spontaneous.

Safety Monitoring Program (SMP):

A specific form of post-marketing adverse event reporting required for new drugs. For at least 2 years after a drug is marketed, it is marked on the label with a triangle within which is written ‘must monitor’ and the registration number is also labelled ‘NC’ (new drug with conditions), indicating that all suspected AEs associated with the drug should be reported to the Thai FDA according to specific reporting timelines. The distribution of such drugs is limited to hospitals and clinics. In certain circumstances, distribution is limited to only hospitals, and the words ”for hospital use only” must

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appear on the label. At the end of the SMP period, the MAH has to submit a summary of sales, distribution and AE information and comprehensive summary on the safety profile of the new drug which includes domestic adverse event reports in relation to usage, and safety information from foreign countries, i.e. PSUR, to the Thai FDA. If the safety information is sufficient to demonstrate safety profile of the drug, the Thai FDA may grant an unconditional approval. The drug registration number will be labeled ‘N’, and the triangle showing monitoring status will be removed. The drug can be available in drugstores if it is classified as a “Dangerous Drug” or “Non-Dangerous Drug” and not a “Special Controlled Drug”.

Spontaneous or unsolicited report:

Any unsolicited communication by healthcare professionals or consumers to a company, regulatory authority or other organization (e.g., WHO, Regional Center, Poison Control Center) that describes one or more adverse events in a patient who was given one or more medicinal products and that does not derive from a study or organized data collection scheme.

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