11

New TB Drugs Approval in Thailand

TharnkamolTharnkamol ChanprapaphChanprapaph, Ph.D., Ph.D.Drug Control Division, Drug Control Division,

Thai Food and Drug AdministrationThai Food and Drug Administration

Third Annual Open Forum on Key Issues in Third Annual Open Forum on Key Issues in Tuberculosis Drug Development, New Delhi, IndiaTuberculosis Drug Development, New Delhi, India

55--6 May 20086 May 2008

22

OutlinesOutlinesTB Drugs in National List of Essential TB Drugs in National List of Essential DrugsDrugsApproved TB DrugsApproved TB DrugsRegulation concerning New TB drug Regulation concerning New TB drug Registration in ThailandRegistration in Thailand

New DrugsNew Drugs

Process of New Drug RegistrationProcess of New Drug RegistrationRequirements for New Drug Registration Requirements for New Drug Registration

ASEAN Pharmaceutical HarmonizationASEAN Pharmaceutical HarmonizationImplementationImplementationACTR for NCEACTR for NCE

33

TB Drugs in National List of Essential Drugs

•• EthambutolEthambutol HClHCl TabTab

•• IsoniazidIsoniazid TabTab

•• PyrazinamidePyrazinamide TabTab

•• RifampicinRifampicin Cap,TabCap,Tab,,

Dry Dry syrsyr, , SyrSyr

•• Streptomycin sulfateStreptomycin sulfate Sterile powderSterile powder

Standard drug sublist

44

TB Drugs in National List of Essential Drugs

Specialist sublist where monitoring of prescribing is required.

•• AmikacinAmikacin sulfatesulfate Sterile solSterile sol

•• CycloserineCycloserine CapCap

•• EthionamideEthionamide TabTab

•• Isoniazid+RifampicinIsoniazid+Rifampicin Cap/TabCap/Tab

(100+150mg/150+300 mg)(100+150mg/150+300 mg)

55

TB Drugs in National List of Essential Drugs

•• Isoniazid+RifampicinIsoniazid+Rifampicin ++ TabTabPyrazinamidePyrazinamide + + EthambutolEthambutol HClHCl(75+150+400+275 mg)(75+150+400+275 mg)

•• KanamycinKanamycin sulfatesulfate Sterile powderSterile powder

•• OfloxacinOfloxacin TabTab

•• ParaPara--aminosalicylicaminosalicylic acid acid EC TabEC Tab(PAS)(PAS)

Specialist sublist where monitoring of prescribing is required.

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Approved TB Drugs

•• EthambutolEthambutol HClHCl TabTab•• IsoniazidIsoniazid Tab, sterile solTab, sterile sol•• PyrazinamidePyrazinamide TabTab•• RifampicinRifampicin Cap,Tab,DryCap,Tab,Dry syrsyr, ,

SuspSusp•• Streptomycin sulfateStreptomycin sulfate Sterile powderSterile powder•• CycloserineCycloserine CapCap•• EthionamideEthionamide TabTab•• Sodium Sodium aminosalicylateaminosalicylate EC tabEC tab

77

Approved TB Drugs

•• Isoniazid+RifampicinIsoniazid+Rifampicin Cap, TabCap, Tab

•• Isoniazid+RifampicinIsoniazid+Rifampicin ++ TabTab

PyrazinamidePyrazinamide + + EthambutolEthambutol HClHCl

•• Isoniazid+RifampicinIsoniazid+Rifampicin ++ TabTab

PyrazinamidePyrazinamide•• Isoniazid+EthambutolIsoniazid+Ethambutol HClHCl++ TabTab

Pyridoxine Pyridoxine HClHCl

•• IsoniazidIsoniazid+ Pyridoxine + Pyridoxine HClHCl TabTab

88

Approved TB Drugs

•• Number of Approved TB DrugsNumber of Approved TB Drugs 152 152

• Single drug productsSingle drug products 124124

•• Combination drug productsCombination drug products 2828

•• Local manufacturing drugsLocal manufacturing drugs 131 (86%)131 (86%)

•• Imported drugsImported drugs 2121 (14%)(14%)

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Regulation concerning Regulation concerning New TB drug Registration New TB drug Registration

in Thailandin Thailand

1010

New Drugs

• New Chemical Entities (NCE)

• New combination

• New indication

• New delivery system

1111

Application Application

RegistrationNO

RM

AL

FAST

TR

AC

K

Process of New Drug RegistrationProcess of New Drug Registration

NCE 210-280 days

New Generic

110 days

NCE 110-130 days

New Generic 70 daysRegistration

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Process of New Drug Process of New Drug Registration in ThailandRegistration in Thailand

Track 1 : Standard Review

(Normal Track)

210 - 280 working days

Track 2 : Accelerated or Priority Review (Fast Track)

Drugs for public health problems/ for life-threatening diseases

100-130 working days

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Requirements for New Drug Requirements for New Drug RegistrationRegistration

• Chemical and Pharmaceutical data• Preclinical data• Clinical data• Current status of drug approval or registration in foreign countries• Patent status• Sample of the product, Label and Package insert• Certificate of Pharmaceutical Products /

Certificate of Free Sale etc.

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Requirements for New Drug Requirements for New Drug RegistrationRegistration

• Comparative data between new drugs and approved drugs in the same therapeutic group on the following scopes are required for antimicrobials.

• Antimicrobial spectrum• Pharmacokinetic properties• Pharmacodynamic properties• Efficacy• Safety• Resistance mechanism• Price

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Chemical and Pharmaceutical Data

• Complete formulation per unit dose • Master formulation• Manufacturing process• Route of synthesis of active ingredients• References of each raw material• Raw material specification and control method

1616

Chemical and Pharmaceutical Data

• In-process control and specification• Finished product specification and control method• Certificate of analysis of active ingredient raw material• Certificate of analysis of finished product• Packaging• Stability studies of finished products• Stability studies of active ingredients(NCE)

1717

Preclinical data Pharmacological data

• Comprehensive Summary of Pharmacological data

• Pharmacodynamics• Mode of action• Undesirable effects

• Pharmacokinetics• Absorption• Distribution• Biotransformation• Excretion

1818

Preclinical dataToxicological data• Comprehensive Summary of Toxicological data

• General Toxicological data• Acute

• Subacute

• Chronic

• Reproductive toxicology• Fertility and general reproductiveperformance• Teratogenicity•Pre-natal and Post-natal study

1919

Preclinical dataToxicological data

• Mutagenicity (if relevant)

• Carcinogenicity (if relevant)

• Antigenicity (if relevant)

• Dependence (if relevant)

• Local toxicity (if relevant)

2020

Clinical data

• Comprehensive Summary onClinical Data

• Phase I• Pharmacokinetics

• Absorption• Distribution• Biotransformation• Excretion• Bioavailability

2121

Clinical data

• Phase I

• Pharmacodynamics

• Therapeutic effects

• Mechanism of action

• Phase II

• Phase III

• Phase IV (if any)

2222

New Drug Registration SchemeNew Drug Registration Schemein Thailandin Thailand

New drug applications

Conditional approval

Unconditional approval

Voluntary Spontaneous ADR Reporting System

Safety Monitoring Program &Limited distribution (2 yrs)

Experts/Subcommittee ApprovalStep I

Step II

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Conditional ApprovalConditional Approval•• Safety Monitoring Program (SMP) Safety Monitoring Program (SMP) will be conducted for approx. 2 years.will be conducted for approx. 2 years.•• Drug packages must bear labeling Drug packages must bear labeling to show conditional approval status.to show conditional approval status.

– Triangle shows monitoring status.– Specially-control drug

– Registration No. (NC)

1C 10/51 (NC), 1A 10/51 (NC)

– Limited distribution only through medical institutes or hospitals

ใชเฉพาะสถานพยาบาล / ใชเฉพาะโรงพยาบาล

ตอง ติดตาม

2424

ASEAN Pharmaceutical HarmonizationASEAN Pharmaceutical Harmonization

ImplementatioImplementation:n:

•• ASEAN ASEAN deadlideadlinene::

End of 2008End of 2008

•• Trial period Trial period ((voluntarvoluntaryy)) : : StartedStarted inin JunJune 2004e 2004

•• Official announcement for full Official announcement for full implementation: implementation:

January 2008January 2008

2525

ASEAN Pharmaceutical HarmonizationASEAN Pharmaceutical Harmonization

ASEANASEAN Harmonized ProductsHarmonized Products

•• ASEAN Common Technical ASEAN Common Technical RequiremeRequirementsnts(ACTR)(ACTR)

•• ASEAN Common Technical ASEAN Common Technical DossierDossiers s (ACTD)(ACTD)

•• 4 4 TechnicalTechnical GuidelinesGuidelines•• Process ValidationProcess Validation

•• BA/BEBA/BE

•• Analytical ValidationAnalytical Validation

•• StabilityStability

2626

ACTR on ACTR on NonclinicalNonclinical Data for NCE Data for NCE

•• PharmacologyPharmacologyPrimary Primary PharmacodynamicsPharmacodynamicsSecondary Secondary PharmacodynamicsPharmacodynamicsSafety PharmacologySafety PharmacologyPharmacodynamicsPharmacodynamics Drug InteractionsDrug Interactions

•• PharmacokineticsPharmacokinetics•• AbsorptionAbsorption•• DistributionDistribution•• MetabolismMetabolism•• ExcretionExcretion•• Pharmacokinetics Drug Interaction (nonPharmacokinetics Drug Interaction (non--

clinical)clinical)•• Other Pharmacokinetics StudiesOther Pharmacokinetics Studies

2727

ACTR on ACTR on NonclinicalNonclinical Data for NCE Data for NCE

•• ToxicologyToxicology•• Single dose toxicitySingle dose toxicity

•• Repeat dose toxicityRepeat dose toxicity

•• GenotoxicityGenotoxicity

•• CarcinogenicityCarcinogenicity

•• Reproductive and developmental toxicityReproductive and developmental toxicity

•• Local tolerance when applicableLocal tolerance when applicable

•• Other toxicity studies when applicableOther toxicity studies when applicable

2828

ACTR on Clinical Data for NCE ACTR on Clinical Data for NCE

•• Bioavailability (BA) and Bioavailability (BA) and Bioequivalence (BE) Studies Bioequivalence (BE) Studies

BA Studies BA Studies

Comparative BA or BE StudiesComparative BA or BE Studies

•• Studies Pertinent to Studies Pertinent to Pharmacokinetics Using Human Pharmacokinetics Using Human BiomaterialsBiomaterials•• Plasma Protein Binding StudiesPlasma Protein Binding Studies

•• Hepatic Metabolism and Drug Interaction Hepatic Metabolism and Drug Interaction StudiesStudies

•• Studies Using Other Human BiomaterialsStudies Using Other Human Biomaterials

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ACTR on Clinical Data for NCE ACTR on Clinical Data for NCE •• Human Pharmacokinetic (PK) StudiesHuman Pharmacokinetic (PK) Studies

Healthy Subject PK and Initial Tolerability studiesHealthy Subject PK and Initial Tolerability studiesPatient PK and Initial Tolerability StudiesPatient PK and Initial Tolerability StudiesIntrinsic Factor PK StudiesIntrinsic Factor PK StudiesExtrinsic Factor PK StudiesExtrinsic Factor PK Studies

•• Human Human PharmacodynamicPharmacodynamic (PD) Studies(PD) StudiesHealthy Subject PD and PK/PD studiesHealthy Subject PD and PK/PD studiesPatient PD and PK/PD studiesPatient PD and PK/PD studies

•• Efficacy and SafetyEfficacy and Safety•• Controlled Clinical Studies Pertinent to the Controlled Clinical Studies Pertinent to the Claimed IndicationClaimed Indication

•• Uncontrolled Clinical StudiesUncontrolled Clinical Studies

•• Post Marketing Data Post Marketing Data (If available)(If available)

3030

ACTR on Quality ACTR on Quality

S DRUG SUBSTANCES DRUG SUBSTANCES1 General Information S1 General Information

S2 ManufactureS2 ManufactureS3 S3 CharacterisationCharacterisationS4 Control of Drug Substance S4 Control of Drug Substance S5 Reference Standards or Materials S5 Reference Standards or Materials S6 Container Closure System S6 Container Closure System S7 StabilityS7 Stability

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ACTR on Quality ACTR on Quality

P DRUG PRODUCTP DRUG PRODUCTP1 Description and Composition P1 Description and Composition P2 Pharmaceutical Development P2 Pharmaceutical Development P3 Manufacture P3 Manufacture P4 Control of P4 Control of excipientsexcipientsP5 Control of Finished Product P5 Control of Finished Product P6 Reference Standards or MaterialsP6 Reference Standards or MaterialsP7 Container Closure System P7 Container Closure System P8 Stability P8 Stability P9 Product Interchangeability Equivalence P9 Product Interchangeability Equivalence evidence (for generic)evidence (for generic)

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THANK YOU FOR YOUR THANK YOU FOR YOUR ATTENTIONATTENTION