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2007/SOM2/LSIF2/028

Regulations for Approval and Pharmacoeconomics of Innovative Therapeutic Products in Korea

Submitted by: Korea

Fifth Annual APEC Life Sciences Innovation Forum

Adelaide, Australia 19-20 April 2007

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Regulations for Approval & Pharmacoeconomicsof Innovative Therapeutic Products in Korea

Regulations for Approval & Pharmacoeconomicsof Innovative Therapeutic Products in Korea

KOREA FOOD & DRUG ADMINISTRATION (KFDA)KOREA FOOD & DRUG ADMINISTRATION (KFDA)

Dong-Sup Kim, Ph.D., Director of Drug Evaluation Dept.

Dong-Sup Kim, Ph.D., Director of Drug Evaluation Dept.

KFDA’s long-term goal is to improvethe health status of the people by minimizing the risks associated with the usage of medical products and consumption of food in Korea by :

KFDA’s long-term goal is to improvethe health status of the people by minimizing the risks associated with the usage of medical products and consumption of food in Korea by :

Assuring the food safety

Establishing standards and specifications of food, drugs, cosmetics and medical devices, and monitoring their safety

Approving manufacturing and importation of drugs, medical devices and cosmetics

Controlling safety of narcotics and radiopharmaceuticals

Conducting basic and applied research on the safety of food and drugs

Mission of KFDAMission of KFDA

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Discovery Development Market

Candidate NonClinical

PhaseI

PhaseII

PhaseIII

NDA PhaseIV

PMS

INDReviewGLP InspectionGCP InspectionDMFAbout : 1 year

PMSData ExclusivityMonitoring

Approval

NEW DRUG APPROVAL PROCESSNEW DRUG APPROVAL PROCESS

1. Development plan, 2. Introduction, 3. CMC, 4. Efficacy, 5. Pharmacology, 6. ADME,7. Single dose toxicity, 8. Repeated dose toxicity, 9. Genotoxicity, 10. Reproductive, 11. Carcinogenicity, 12. Other toxicity, 13. Clinical Data, 14. References, 15. Comparison with similar drugs and characteristics

DATA SCOPE FOR DRUG APPLICATIONDATA SCOPE FOR DRUG APPLICATION

O : required, Δ : depending on the nature of drug, × : waived

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New ProductCandidate

7 waiver categories

At least ONE Bridging Study On KOREAN

(Global or Local)

At least ONE Bridging Study On KOREAN

(Global or Local)

Bridging ExemptionBridging Exemption

Bridging StudyBridging Study

Bridging Concept (1)Bridging Concept (1)

“Bridging Data” = “Korean Data”“Bridging Study” = “A trial conducted on Koreans”

“Bridging Data” means data resulting from trials conducted on Koreans living in Korea and abroad. The data was excerpted or selected from the clinical data package or obtained from the bridging study.“Bridging Study” means a trial conducted on Koreans in Korea for the purpose of obtaining bridging data. In case it is difficult to apply foreign clinical data, because of the ethnic factor relating to the safety and efficacy of a drug.

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Bridging Concept (2)Bridging Concept (2)

“Ethnic Factor” are factors relating to races or large populations grouped according to common traits and customs

Intrinsic factor : characteristics associated with the drug recipient

• genetic, physiological and pathological condition• P 450 information, pharmacogenomics, surrogate markers for

efficacyExtrinsic factor : culture, environment

• Diet, tobacco and alcohol use, compliance with prescribed medications

Current status : Bridging in KoreaCurrent status : Bridging in Korea

Waiver of BD

44%

Bridging study

50 %6%

Additional study

* Except Orphan drug

Phase III

67%

Phase I 33%

Phase II

Bridging study

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Bridging Waiver CategoriesBridging Waiver Categories

Orphan drugs or drugs that used to be orphan drugsDrugs for AIDS or other life-threatening diseaseAnticancer therapy for the following

No standard therapyTherapy after failure of a standard therapy

New drugs for which clinical trials will be conducted on KoreansDiagnostic or Radioactive drugsTopical drugs having no systemic effectNo ethnic differences

Less Likely to be Sensitive to Ethnic Less Likely to be Sensitive to Ethnic Factors:Factors:

ICH E-5 Appendix D Linear PKA flat PD curve for both efficacy and safety in the range of therecommended dosage and dose regimenA wide therapeutic dose rangeMinimal metabolism or metabolism by multiple pathwaysHigh bioavailability, thus less susceptibility to dietary absorption effectsLow potential for protein bindingLittle potential for drug-drug interaction, drug-diet and drug-disease interactionsNon-systemic effectLittle potential for inappropriate use

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Cases: Bridging waiverCases: Bridging waiver

Topical drugs

26%

8%8%

8%4%

46%

Orphan drug (including used to be)

Life ThreateningDignostics

Anti-cancer with no or failure of standard

therapy

With evidence of no ethnic difference

Cases of Bridging Waivers (1)Cases of Bridging Waivers (1)

AntibioticsTamiflu (Roche)

AnticancerIresa (Astra Zeneca)

AnticancerTS1 (Cheil)

AntibioticsVfend (Pfizer)

AntibioticsInvanz (MSD)

AntibioticsZyvox (Pharmacia-Upjohn)

Antibiotics

Anticoagulant

IndicationProduct Name (Company)Waiver Category

Cancidas (MSD)AIDS or other life-threatening diseasesOncology drug products

Arixtra (Sanofi-Synthelabo)

No ethnic difference

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Cases of Bridging Waivers (2)Cases of Bridging Waivers (2)

Glioblastoma multiformeTemodal (Schering-Plough)

AnticancerMabthera (Roche)

Immune suppressantSimulect (Novartis)

AnticancerGlivec (Novartis)

HIVCrixivan (MSD)

Subfoveal choroidalneovascularization

Visudyne (Novartis)

ALS

Multiple sclerosis

IndicationProduct Name (Company)Category

Rilutek (Aventis)

Copaxone (Aventis)Orphan Drugs

Cases of Bridging Waivers (3)Cases of Bridging Waivers (3)

OphthalmicAlercon (Hanmi)

DermalFiblast (Hanmi)

InhalationRelenza Rotadisk (GSK)

OphthalmicTravatan (Alcon)

DermalElidel (Novartis)

PolymerNo absorption from intestine

AdministrationProduct Name (Company)Category

Renagel (Cheil-Kirin)No systemic effect

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Cases of Bridging Waiver (4)Cases of Bridging Waiver (4)

Teseos (Sangjung)

Product Name (Company)Category

Optimac (Iyeon)Diagnostic Reagents Radio-pharmaceuticals

Types of Bridging StudiesTypes of Bridging Studies

Bridging studyPharmacokineticsPharmacodynamics with pharmacological endpointsDose-response studyPhase III confirmatory studyPhase III with surrogate marker

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Approved Drugs by PKApproved Drugs by PK

DiabeticsRosiglitazoneAvandiaGSK

Irritable bowel syndromeAlosteronLotronexGSK

DiabeticsPioglitazoneActosLily

AntipsychoticsAripiprazoleAbilifyOtsuka

Allergic RhinitisBepotastineTalionDonga

Hepatitis-BAdefovirHepseraGSK

IndicationActive IngredientProductCompany

Approved Drugs by Phase IIIApproved Drugs by Phase III

Analgesics & AntipyreticsMorniflumateMornifluKolon

Irritable bowel syndromeTegaserodZelmacNovartis

AntibioticsTelithromycinKetekAventis

OsteoporosisRisedronateActonelAventis

AntipsychoticsZiprasidoneZeldoxPfizer

COPDTiotropiumSpirivaHandihaler

BoehringerIngelheim

Postoperative painParecoxibDynastatParmacia

Rheumatoid arthritisEtanerceptEnbrelWyeth

IndicationActiveProductCompany

DiabeticsInsulinLantusAventis

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Approved Drugs by Phase IIIApproved Drugs by Phase III

AntianxietyTandospironSediel TabYuhan

Fertility medicine (GnRH agonist)GanirelixOgalutran injOrganon

HypercholesterolemiaEzetemibEzetrolMSD

Erectile dysfuctionTadanafilCialis TabLiliy

Erectile dysfuctionVardenafilLevitra TabBayer

Postoperative painParecoxibDynasata injPfizer

HypercholesterolemiaRosuvastatinCrestor TabAstrazeneca

IndicationActiveProductCompany

Case of Dose Adjustment Case of Dose Adjustment

Actos Tablet(Pioglitazone hydrochloride)Gycemic control in patients with type 2 DMPharmacokinetics study with healthy Korean volunteers (n=24)Less likely to be sensitive to ethnic factors by ICH E5Dosage / administration in U.S.A

• Monotherapy : 15, 30, 45 mg once daily • Combination therapy : 15 or 30mg

Adjusted Dosage in Korea• Monotherapy : 15 mg, 30 mg• Combination therapy : 15mg

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AU

C (n

g hr

/mL)

0

5000

10000

15000

20000

25000

30000

35000

40000

Korean 15 mgWestern 30 mg

Korean 30 mgWestern 45 mg

Direct AUC comparisonDirect AUC comparisonKoreans vs. Western)Koreans vs. Western)

Case 2) BSCase 2) BS--Phase III, but PKPhase III, but PK

Rosuvastatin calciumPhase III study with primary hypercholesterolemia

• Comparative with placebo(54), for 10mg rosuvastatin(90)

Dosage referred at the time of starting BS• 10-40mg once daily (in Europe & USA)

Results from phase III study only• Similar results in Korean compared with European• 10-20 mg/day (in Korea, 2003)

Asian PK data different from Caucasian• US FDA changed the labeling (starting dose to 5mg/day, 2004)• Adjusted Dosage in Korea (5-20 mg once daily, 2005.1)• 2.5-20 mg once daily (in Japan, 2005)

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Bridging Issues in KoreaBridging Issues in Korea

Acceptability of Asian DataSame ethnicity?Mutual recognition of Asian data?

StatisticsStatistically meaningful sample size?Minimum requirement for inter-ethnic analysis

Study design

Thank you for your Thank you for your attention!attention!