Market Authorization ofMarket Authorization ofTraditional Medicine:Traditional Medicine:A Global ScenarioA Global Scenario

Prof.K.R.KohliProf.K.R.KohliDirectorDirector

Dabur Research FoundationDabur Research Foundation

Why Traditional Medicines are Why Traditional Medicines are popular worldwide??popular worldwide??

Unbroken tradition of practiceUnbroken tradition of practice--Efficacy Efficacy establishedestablishedImmigration of population leads to cultural Immigration of population leads to cultural exchangeexchangeBoundaries disappearing due to excellent Boundaries disappearing due to excellent information and communicationsinformation and communicationsIncrease interest into other System of Increase interest into other System of Medicines due to failure of Modern System of Medicines due to failure of Modern System of Medicine in certain diseasesMedicine in certain diseases

Popularity vs.AccountabilityPopularity vs.Accountability

QualityQuality Regulations to Regulations to

allow trade allow trade

of of

Traditional Traditional Medicines Medicines

(TM)(TM)

SafetySafety

EfficacyEfficacy

How to trade the TM??How to trade the TM??

As Traditional Herbal MedicinesAs Traditional Herbal Medicines

As DrugAs Drug

As SupplementsAs Supplements

Market authorization:DefinitionsMarket authorization:Definitions

Market:Market:The business of buying and selling a specified The business of buying and selling a specified commoditycommodity

Authorization:Authorization:a document giving an official instruction or commanda document giving an official instruction or commandthe act of conferring legality the act of conferring legality

Registration of the product in a country and right Registration of the product in a country and right to market the product in that countryto market the product in that country

Market authorization:Market authorization:Requirement of documentsRequirement of documents

Dossier preparationDossier preparation

Format of dossier varies countries to countriesFormat of dossier varies countries to countries

CTD(Common Technical Document) to make things CTD(Common Technical Document) to make things

easier (Based on ICH Guidelines)easier (Based on ICH Guidelines)

CTDCTD--Herbal(Module 1Herbal(Module 1--5)5)

Module 1Module 1--Administrative dataAdministrative dataModule 2Module 2--CTD SummariesCTD SummariesModule 3 QualityModule 3 Quality*Module 4*Module 4--Bibliographic review of Bibliographic review of SafetySafety*Module 5*Module 5--Traditional use evidenceTraditional use evidence

**CTDCTD--ICH differs from CTDICH differs from CTD--HERBAL with respect to Module 4, HERBAL with respect to Module 4, where Prewhere Pre--clinical studies are required and Module 5, clinical studies are required and Module 5,

where they need Clinical Studies.where they need Clinical Studies.

Regulatory requirements Regulatory requirements WorldwideWorldwide

EU:Directive 2001/83/ECEU:Directive 2001/83/ECDirective 2001/83/EC requires that applications Directive 2001/83/EC requires that applications for authorization to place a medicinal product on for authorization to place a medicinal product on the market have to be accompanied by a the market have to be accompanied by a Dossier containing particulars and documents Dossier containing particulars and documents relating in particular to the results of Physicorelating in particular to the results of Physico--Chemical,Biological or microbiological tests as Chemical,Biological or microbiological tests as well as pharmacological and toxicological tests well as pharmacological and toxicological tests and clinical trials carried out on the products and and clinical trials carried out on the products and thus proving its quality ,Safety and efficacythus proving its quality ,Safety and efficacy

EU:THMPDEU:THMPDDirective 2004/24/ECDirective 2004/24/EC

The THMP’s definition : A herbal medicinal product The THMP’s definition : A herbal medicinal product that fulfills the conditions laid down in article 16a(1)that fulfills the conditions laid down in article 16a(1)

Herbal Medicinal product: Herbal Medicinal product: any medicinal product,exclusively any medicinal product,exclusively containing as active ingredients one or more herbal containing as active ingredients one or more herbal substances or one or more herbal preparations,or one or more substances or one or more herbal preparations,or one or more substances in combination with one or more such herbal substances in combination with one or more such herbal preparations;preparations;

Article 16c….1.(c) Traditional use is established at Article 16c….1.(c) Traditional use is established at least 30 years of preceding the date of application, least 30 years of preceding the date of application, including 15 year within the community (Data on including 15 year within the community (Data on safety and efficacy will not be required)safety and efficacy will not be required)

EU:THMPDEU:THMPD…...The quality aspect of the medicinal product …...The quality aspect of the medicinal product is independent of its traditional use so that no is independent of its traditional use so that no derogation should be made with regard to the derogation should be made with regard to the

necessary physicochemical,biological and necessary physicochemical,biological and microbiological tests. Products should comply microbiological tests. Products should comply

with quality standards in relevant European with quality standards in relevant European pharmacopoeia monographs or those in pharmacopoeia monographs or those in

pharmacopoeia of member state.pharmacopoeia of member state.

BottlenecksBottlenecks in in EU:THMPD Directive 2004/24/ECEU:THMPD Directive 2004/24/EC

There is need to amend Article 16cThere is need to amend Article 16cThe traditional use data for the TM should The traditional use data for the TM should be based on authorized text books and be based on authorized text books and pharmacopoeias of the countries of its pharmacopoeias of the countries of its originoriginThe quality parameters to be uniform and The quality parameters to be uniform and rational rational

Natural Health Products RegulationsNatural Health Products RegulationsTraditional medicines, Herbal remedies, Traditional medicines, Herbal remedies, homeopathic medicines, vitamins, homeopathic medicines, vitamins, minerals, probiotics, amino acids and minerals, probiotics, amino acids and essential fatty acidsessential fatty acidsA product licensing system requires that A product licensing system requires that all licensed products display a Product all licensed products display a Product identification Number prefixed by identification Number prefixed by NPN/NPNNPN/NPN--HMHMThe number is issued once a product is The number is issued once a product is authorized for sale in Canada by Natural authorized for sale in Canada by Natural Health Product DirectorateHealth Product Directorate

Canada: Natural Health Products Canada: Natural Health Products RegulationsRegulations

The site licensing has been developed, requires that The site licensing has been developed, requires that all manufacturers,packagers,labelers and importers all manufacturers,packagers,labelers and importers be licensedbe licensedThe site to meet GMPs as per Natural products The site to meet GMPs as per Natural products RegulationsRegulationsGMPs are to be employed to ensure product safety GMPs are to be employed to ensure product safety and quality. and quality. For foreign sitesFor foreign sites--The certificate of the compliance by The certificate of the compliance by the regulatory authorities of any countries as in the regulatory authorities of any countries as in Appendix 3 (US/UK/ EU/ Malaysia/Singapore etc.)Appendix 3 (US/UK/ EU/ Malaysia/Singapore etc.)--inspection report no more than 3 yrsinspection report no more than 3 yrs

Canada: Natural Health Products RegulationsCanada: Natural Health Products RegulationsCommentsComments

Those countries not in Appendix 3, have real Those countries not in Appendix 3, have real

problems, inspections from Health Canadaproblems, inspections from Health Canada--

SAARC does not fall into it.SAARC does not fall into it.

Traditional use of data, sometimes not available in Traditional use of data, sometimes not available in

English and copies of translation need to be English and copies of translation need to be

certified and accepted.certified and accepted.

Regulations in USRegulations in US

Three categoriesThree categories--DrugDrugFoodFoodDietary supplementDietary supplement

Dietary supplements in USDietary supplements in US

DSHEA(Dietary Supplement Health and Education DSHEA(Dietary Supplement Health and Education act of 1994)act of 1994)Definition of Dietary Supplements.Section 291(21 Definition of Dietary Supplements.Section 291(21 U.S.C.321)U.S.C.321)--“ (1) means a product(other than tobacco) intended “ (1) means a product(other than tobacco) intended to supplement the diet that bears or contains one or to supplement the diet that bears or contains one or more of the following dietary ingredientsmore of the following dietary ingredients--

(A) a vitamin; (A) a vitamin; (B) a mineral;(B) a mineral;(C) an herb or other botanical;(C) an herb or other botanical;(D) an Amino acid…………….(D) an Amino acid…………….

(2) means a product that…….(c ) is labeled as dietary (2) means a product that…….(c ) is labeled as dietary supplementsupplement””

Dietary supplements Dietary supplements in USin USDietary supplements:Statement of Nutritional Dietary supplements:Statement of Nutritional support for the purpose of the paragraph(r)(1)(B)support for the purpose of the paragraph(r)(1)(B)

…(A) statement claims a benefit related to a classical nutrient …(A) statement claims a benefit related to a classical nutrient deficiency disease and discloses the prevalence of such deficiency disease and discloses the prevalence of such disease in the United States,describes the role of a nutrient ordisease in the United States,describes the role of a nutrient ordietary ingredient intended to affect the dietary ingredient intended to affect the structure and structure and function in humans…function in humans…( B)The manufacturer of the dietary supplement has ( B)The manufacturer of the dietary supplement has substantiation that such statement is substantiation that such statement is truthful and not truthful and not misleading,misleading, andand(c) display on label… “(c) display on label… “this statement is not evaluated by this statement is not evaluated by the Food and Drug Administration”the Food and Drug Administration”

A statement under this subparagraph may not A statement under this subparagraph may not claim to diagnose,mitigate,treat,cure or prevent a claim to diagnose,mitigate,treat,cure or prevent a certain disease or class of diseases.certain disease or class of diseases.

Dietary supplements Dietary supplements in USin USCommentsComments

There is no separate category for Traditional There is no separate category for Traditional medicinesmedicinesNo treatment claims are allowed under the No treatment claims are allowed under the DSHEADSHEAGMP is proposed and final notification is awaited. GMP is proposed and final notification is awaited.

Therapeutic Goods Administration (TGA)Therapeutic Goods Administration (TGA)The Ayurvedic medicines and Traditional Chinese The Ayurvedic medicines and Traditional Chinese Medicines are classified as Medicines are classified as complementary complementary medicinesmedicinesQuality standards are same as other medicinesQuality standards are same as other medicinesTGA maintains the Australian Register of TGA maintains the Australian Register of Therapeutic Goods(ARTG)Therapeutic Goods(ARTG)--Approx.16000 Approx.16000 Complementary medicines included)Complementary medicines included)TM may be included on ARTG as Listed(low risk) TM may be included on ARTG as Listed(low risk) or Registered Medicines(high risk)or Registered Medicines(high risk)

Therapeutic Goods Administration Therapeutic Goods Administration AustraliaAustralia--Complementary medicinesComplementary medicines

Listed complementary MedicinesListed complementary Medicines--Listed medicines may be supplied following application to the Listed medicines may be supplied following application to the TGA by the sponsorTGA by the sponsorSelf certification by sponsorSelf certification by sponsorValidation by TGA that certain Key requirements of the Validation by TGA that certain Key requirements of the legislations are being metlegislations are being met

Registered Complementary medicinesRegistered Complementary medicinesRegistration is similar to modern medicinesRegistration is similar to modern medicinesThe licensing and audit of manufacturersThe licensing and audit of manufacturersPrePre--market assessment of the productsmarket assessment of the productsPost market activitiesPost market activities

Food and Drug AdministrationFood and Drug AdministrationThe Drug Act of The Drug Act of B.E.2546(2003) is in the final stage B.E.2546(2003) is in the final stage

of promulgationof promulgation

Types of Medicines classified into Prescription Types of Medicines classified into Prescription

only,Pharmacy dispensing and House hold only,Pharmacy dispensing and House hold

remediesremedies

Market Authorization for 5 years;GMPs mandatoryMarket Authorization for 5 years;GMPs mandatory

Subcommittee on review and approval on TMSubcommittee on review and approval on TM

Thailand:Food and Drug AdministrationThailand:Food and Drug AdministrationDrug control divisionDrug control division

Pre market controlLicensing-license to sale/manufacture/Import TMDrug registration-for 5 yearsRegistration of General MedicinesRegistration of TM

Post market controlInspection of GMPReceiving and handling of complaintsSafety monitoringReevaluation of Products

Guidelines for Traditionally used Herbal ProductsGuidelines for Traditionally used Herbal ProductsDepartment of Health(Bureau of Food and Drugs BFADDepartment of Health(Bureau of Food and Drugs BFADTo ensure safety ,Good quality and claimed application To ensure safety ,Good quality and claimed application of Traditionally used Herbal Productsof Traditionally used Herbal ProductsTraditional usage more than 50 years as documented in Traditional usage more than 50 years as documented in medical,historical and ethnological literaturemedical,historical and ethnological literatureFor products originating from other countries For products originating from other countries authentication of the documents authentication of the documents ––Philippine consulatePhilippine consulateRegistration RequirementsRegistration Requirements

Initial RegistrationInitial Registration--11--5 years depends on fee5 years depends on feeReRe--registration registration ––valid for 5 yearsvalid for 5 years

Health Sciences AuthorityHealth Sciences AuthorityCentre for Drug AdministrationCentre for Drug Administration

Health supplements is currently not defined in legislationHealth supplements is currently not defined in legislationQuasiQuasi--medicinal productsmedicinal products((includes “medicated beverages”, includes “medicated beverages”, Vitamins and nutritional preparations from natural sources underVitamins and nutritional preparations from natural sources underlegislation Medicines(legislation Medicines(TM,Homeopathic medicinesTM,Homeopathic medicines and other and other substance)substance)Traditional Medicines Traditional Medicines (other than CPM, Jamu, Ayurvedics, (other than CPM, Jamu, Ayurvedics, Homeopathic) including herbal preparations under the legislationHomeopathic) including herbal preparations under the legislationmedicines(TM,Homeopathic medicines and other Substances)medicines(TM,Homeopathic medicines and other Substances)Health foods with vague and general medicinal claimsHealth foods with vague and general medicinal claims

Health supplements “ a product that is used Health supplements “ a product that is used to supplement to supplement a dieta diet, , with benefits beyond those of normal nutrientswith benefits beyond those of normal nutrients and and /or to /or to support or maintainsupport or maintain healthy functions of human bodyhealthy functions of human body

Singapore:Health Sciences AuthoritySingapore:Health Sciences AuthorityCentre for Drug AdministrationCentre for Drug Administration

Safety and quality requirementsSafety and quality requirements--not not subjected to subjected to pre market approvals and licensingpre market approvals and licensing for for their importation,sale or manufacture in Singaporetheir importation,sale or manufacture in SingaporeShall not contain any other substance except those stated on Shall not contain any other substance except those stated on the labelthe labelShall not contain any human part….Shall not contain any human part….Shall not contain substances listed in the Schedule of poisons Shall not contain substances listed in the Schedule of poisons actactShall not exceed the limits for microbial contamination and Shall not exceed the limits for microbial contamination and toxic heavy metalstoxic heavy metalsShall Shall not make claimnot make claim to directly or indirectly refer to the list of to directly or indirectly refer to the list of conditions diseases and disorders conditions diseases and disorders

Medical advertisement controlMedical advertisement controlSafety and quality specificationsSafety and quality specifications

Ministry of Indigenous MedicineMinistry of Indigenous MedicineBoard of indigenous medicines set up in 1928Board of indigenous medicines set up in 1928Ayurvedic Drug Formulary Committee under Ministry of Indigenous Medicines is regulatory body for the Ayurvedic Drug Registration. The particulars required to register a herbal product

The certificate of registration for the manufacturing institute or the drug importing agent with the govt. and the provincial councilReports on the experimental and clinical reports The certificate to ensure that the drug (product) is registered by the Government of original countryExperimental reports to ensure that the drug is free side effectsComposition of the proposed medicineProcedure of preparationDetails of preservatives in the preparationDetails of coloring agents in the preparationsDetails of the percentage of Alcohol (to be noted when relevant)

National Pharmaceutical Control BureauNational Pharmaceutical Control BureauMinistry of HealthMinistry of Health

Drug registration Guidance documentDrug registration Guidance documentApplication typeApplication type

Application for product registration via the Application for product registration via the abridgedabridgedprocedure(certain categories of OTC products and also for procedure(certain categories of OTC products and also for traditional Medicinestraditional Medicines))

Data requirementsData requirementsAdministrative data( Part I)Administrative data( Part I)

AA--Product particularProduct particular-- indication,dose/ use instructions, indication,dose/ use instructions, contraindications,warning and precautions,Drug contraindications,warning and precautions,Drug interactions,Side effects /adverse Reactions,Storage interactions,Side effects /adverse Reactions,Storage conditions,Shelf lifeconditions,Shelf lifeBB--Product FormulaProduct Formula--Manufacturing process,Attachment Manufacturing process,Attachment of in process quality control,Finished product quality of in process quality control,Finished product quality control,Stability datacontrol,Stability dataCC--PackagingPackaging

Ministry of HealthMinistry of HealthDefinition of pharmaceutical ProductsDefinition of pharmaceutical Products

“products intended for human consumption for the “products intended for human consumption for the purpose of prevention treatment relief or diagnosis of purpose of prevention treatment relief or diagnosis of diseases or for the modification of physiological diseases or for the modification of physiological functions”functions”

Registration must with MOHRegistration must with MOHRegistration requirementsRegistration requirements

FSC from country of originFSC from country of originGMP certificateGMP certificateProduct informationProduct informationManufacturing processManufacturing processReal time stabilityReal time stabilityQuality specifications for Finished products and Raw MaterialsQuality specifications for Finished products and Raw MaterialsSamples with Certificate of analysisSamples with Certificate of analysisPackaging materialPackaging material

Ministry of Health Ministry of Health Pharmacy and Supply Sector: Pharmacy and Supply Sector:

Drug Control DepartmentDrug Control DepartmentRegistration of products derived from natural sourceRegistration of products derived from natural source : 2002: 2002

Registration of the manufacturer of products derived from Registration of the manufacturer of products derived from natural sourcesnatural sourcesRegistration of products derived from plant originRegistration of products derived from plant origin

Traditional Herbal medicines (THMTraditional Herbal medicines (THM):):-- Finished products intended Finished products intended for self for self ––medication that contain, as the active principles, herbal medication that contain, as the active principles, herbal ingredients that have received relatively little attention in thingredients that have received relatively little attention in the world e world scientific literature, but for which traditional of folkloric usscientific literature, but for which traditional of folkloric use is welle is well--documented in herbal references. THM may contain chemically documented in herbal references. THM may contain chemically defined or herbaldefined or herbal--based excipients in addition to the active based excipients in addition to the active principles.principles.

Registration of products derived from animal sourceRegistration of products derived from animal source

Observations and suggestionsObservations and suggestions

The spirit of Traditional Medicines need to carried in The spirit of Traditional Medicines need to carried in regulationsregulations..Quality:Quality:

Need for Uniform GMPs regulations for export of TMNeed for Uniform GMPs regulations for export of TMNeed for Uniform limits for heavy metals,pesticides etc.Need for Uniform limits for heavy metals,pesticides etc.

EfficacyEfficacyTraditional usage to be certified by Traditional usage to be certified by regulatory authoritiesregulatory authorities of of exporting countriesexporting countries--which will ensure the evidence from which will ensure the evidence from authoritative text books /Pharmacoepias or other data for authoritative text books /Pharmacoepias or other data for traditional usagetraditional usageClaims of efficacy be allowedClaims of efficacy be allowed

Registration processes to be made uniform & easyRegistration processes to be made uniform & easy

Useful Links:

We should find new ways to move forward by reducing the scope for conflict between our regulatory approaches and by forging closer cooperation.Peter Mandelson

Canada: Natural Health Products Canada: Natural Health Products RegulationsRegulations

The regulations are in force since Jan.1,2004The regulations are in force since Jan.1,2004Transition periodTransition period--2 years for Site Licensing2 years for Site LicensingTransition periodTransition period--6 years for Products with Drug 6 years for Products with Drug identification Numbers(DIN)identification Numbers(DIN)Product Authorization requires eitherProduct Authorization requires either--

Reference to a Reference to a Natural product monograph Natural product monograph (Published by NHPD)(Published by NHPD)Or Or Submission of other evidence of safety and health Submission of other evidence of safety and health claims(NHPD is working on standards of evidence claims(NHPD is working on standards of evidence framework)framework)

Philippines:Philippines:Guidelines for Traditionally used Herbal Guidelines for Traditionally used Herbal

ProductsProductsRegistration Documents requiredRegistration Documents required

Notarized application form 8Notarized application form 8Certificate of brand name clearance(if applicable)Certificate of brand name clearance(if applicable)Certificate of agreement between Certificate of agreement between manufacturer,trader,importer and/or distributormanufacturer,trader,importer and/or distributorRaw material authenticationRaw material authenticationFPSFPS--finished product specification COAfinished product specification COA--certificate of Analysiscertificate of AnalysisFree sale certificateFree sale certificateQuality control proceduresQuality control proceduresStability studiesStability studiesLabels Claims.. “traditional/folklorically used to relieve…”Labels Claims.. “traditional/folklorically used to relieve…”Display on label in box.. ‘The traditional application/use of thDisplay on label in box.. ‘The traditional application/use of this is product has not been evaluated by the Bureau of Food and product has not been evaluated by the Bureau of Food and Drug”Drug”