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Myung Soo Ahn Drug and Device Development in Korea

DRUG AND DEVICE


DEVELOPMENT IN
SOUTH KOREA
FEB 26, 2017

Myung-soo Ahn

Ministry of USC
Food and Drug Safety Regulatory Science

Contents

1. Introduction of Korea
2. Introduction of MFDS
3. Korean Pharmaceutical Industry
4. Characteristics of Korean System
5. Regulatory pathways of pharmaceuticals
6. Regulatory pathways of medical devices

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Myung Soo Ahn Drug and Device Development in Korea

Where is Korea?

East Sea

Facts and Figures


Population (S.Korea)
- 51.3 Million (2014 estimate) (25 Mil.-N.Korea)
Life expectancy
- Life expectancy: 81.4(M: 77.9, F:84.6)(2012)
Geographic distribution
- More than 60% located in Seoul and the 5 largest cities

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Myung Soo Ahn Drug and Device Development in Korea

Size: about 20% of California

What is Korea? _ Dramatic Events


5,000 year History

1950 ~ 1953 Korea War

1962 ~ Industrialization
(Miracle on the Han River)

1987 ~ Democratization

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Myung Soo Ahn Drug and Device Development in Korea

Life in Korea_ easy comfortable interesting


Everything’s in Korea:
(Past_Present_Future / Orient_West / Nature_Art)

99% literacy (easy communication)


Public transportation: Very excellent (subway, taxi, bus, train)
Food delivery: Very fast (24/7 free)
Sauna: Very excellent Very pleasant (24/7)
Safety: Very good (night life 24/7 anywhere)
Internet Speed: Very Very fast (No 1)
Free Wifi: Available nationwide (hard to find location unavailable)
Nature: 70% mountain, 3 side sea, one-day distance life (nationwide)

Korea in your life

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Myung Soo Ahn Drug and Device Development in Korea

Food

Culture

K-pop; Kangnam Style (2014)


(2,722,372,241 views)

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Myung Soo Ahn Drug and Device Development in Korea

Korea has a market economy that ranks 11th in the world by


nominal GDP and 13th purchasing power parity(PPP)

Korea’s GDP per capita in 2015 was USD 27,222(28th, IMF)

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Myung Soo Ahn Drug and Device Development in Korea

1. Introduction of Korea
2. Introduction of MFDS
3. Korean Pharmaceutical Industry
4. Characteristics of Korean System
5. Regulatory pathways of pharmaceuticals
6. Regulatory pathways of medical devices

Ministry of Food and Drug Safety _ History


346 Foundation of the Korea Food and Drug Safety Headquarters and six Regional
Apr 1996 offices under the Ministry of Health and Welfare

776 Inauguration of the Korea Food and Drug Administration


Feb 1998

1,413 Reorganization
2009 National Center of Toxicological Research was expanded and reorganized to
National Institute of Food and Drug Safety Evaluation
(3 departments 18 divisions 3 departments 29 divisions)

1,449
Nov 2010 Relocation of Headquarters to Osong from Seoul

1,770 Elevation to Ministry under the Prime Minister


- 6 Regional Offices of FDS remained
Mar 2013 - Expansion of its capacity from 1 headquarters(5 bureaus) to 1 headquarters(7 bureaus)

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Myung Soo Ahn Drug and Device Development in Korea

MFDS _ Facts and Figures


Headquater: in O-song
O-Song

Scope in responsibilities
Food, Dietary Supplements, Drugs, Bio-pharmaceuticals
Korean traditional(herbal) medicine, Quasi-drugs,
Cosmetics, Cosmeceuticals, Medical devices

Organization
• Headquarters : 7 Bureaus, 46 Divisions
• National Institute of Food and Drug Safety (NIFDS)
• 6 Regional FDA

Staff (1,762)
• Headquarters : 577
• NIFDS: : 406
• Regional KFDA(6) : 774

Regional - FDA
6 Regional Food and Drug Administration

Seoul
-FDA
Gyungin
-FDA

Daejeon
-FDA

Daegu
-FDA

Gwanju Pusan
-FDA -FDA

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Myung Soo Ahn Drug and Device Development in Korea

MFDS Headquarter Organization Chart


Headquarter
Minister

Spokesperson

Vice
Minister
Criminal Investigation General Services
Office Division

Director General for Audit and Inspection


Planning and Coordination Office

Agro- Pharma- Biopharma-


Customer Risk ceuticals
Food Safety Food Nutrition
Livestock and ceutical and Herbal
Medical
Device Safety
Prevention Policy Bureau and Dietary Fishery
Bureau Safety Bureau Products Safety Medicine Bureau
Safety Bureau Bureau Bureau

Pharmaceu- Pharmaceutical Narcotics Pharmaceuti cal Clinical Trials Pharamceutical Pharmaceutical


tical Policy Management Policy Quality Management Approval-Patent Safety
Division Division Division Division Division Management Evaluation
Division Division

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Organization Charts for NIFDS

National Institute of Food and Director General


Drug Safety Evaluation
General Services
Division
Research Planning &
Management Division
National Center for
Lot Release

Biopharmaceu- Pharmaceutical
Toxicological
Food Safety Drug Evaluation ticalsand Herbal Medical Device and Medical Evaluation and
Evaluation Department Medicine Evaluation Device
Department Research
Evaluation Department Research Department
Department Department

Drug Review Pharmaceutical Cardiovascular Oncology & Gastroenter Bioequivalence


Management Standardization and Neurology Antimicrobial ology & Evaluation
Division Division Products Products Metabolism Division
Division Division Products
Division

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Myung Soo Ahn Drug and Device Development in Korea

NIFDS - Drug Evaluation Department


Drug Evaluation Department

Drug Pharmaceutical Cardiovascular Oncology Gastroenterology Bioequivalence


Review Standardization and and and Evaluation
Management Division Neurological Antibiotics Metabolism Division
Division Products Products Products
Division Division Division

3 NDA Review Division


1 ANDA(Bioequivalence) Review Division
1 ANDA(Quality) and DMF Review Division
1 Drug Approval and Review Management Division

1. Introduction of Korea
2. Introduction of MFDS
3. Korean Pharmaceutical Industry
4. Characteristics of Korean System
5. Regulatory pathways of pharmaceuticals
6. Regulatory pathways of medical devices

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Myung Soo Ahn Drug and Device Development in Korea

Introduction of Korean Pharmaceutical Industry

https://youtu.be/TEW94qhSVPA

Key Changes in Drug Safety Management (1)

Global
Active
New Drugs
New Drug
Beginning of Development
New Drug
Formulation Development 2010s
Domestic Technology
Industry 2000s
Development 1990s

1960/70s GCP
Advancement Assessment of
PIC/S(2014)
(2000)

IND(2001)
Implement the
DMF(2002) regulation of
GCP(1995) Compaensation
on the damage
GLP(2003) caused by side
GMP(1994) effect of
GMP pharmaceuticals
Advancement (2014)
(2008)

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Myung Soo Ahn Drug and Device Development in Korea

Key Changes in Drug Safety Management (2)

PICS join ICH member


(2014) (2016)

PICS : Pharmaceutical Inspection Cooperation Scheme

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Current Status in Global Pharma Industry

Drug Clinical
Development Trials Market Scale
World’s 10th Country Market Share of City $16 Billion (2015) Export
getting Approval By Total Site Number
from FDA with LGLS $2.4 Billion (2015)
“factive”(2003) Seoul : 1st(2012-2014)
2nd (2015)
27 New Drugs (2016)

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Myung Soo Ahn Drug and Device Development in Korea

Now a leader in clinical trials

Domestic Pharmaceutical Market Scale

Domestic Pharmaceutical Market, 2000-2014


2015
US$ Millions $ 16,170 million %
(expected)
20,000 35.0

18,000
30.2 30.0
16,000 27.6
25.2 28.8 28.0
27.0 27.1
23.3 23.6 25.5 25.0
14,000
21.7
19.6 21.3
22.6
12,000
17.8 20.0

10,000

15.0
8,000

6,000 10.0

4,000
5.0
2,000

0 0.0
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Market Size Import Market Share

Sources : Korean Pharmaceutical Manufactuers Association, Korean Pharmaceutical Traders Association

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Myung Soo Ahn Drug and Device Development in Korea

Market Scale index

Sources : IMS Health, Global Medicines Use in 2020

1. Introduction of Korea
2. Introduction of MFDS
3. Korean Pharmaceutical Industry
4. Characteristics of Korean System
5. Regulatory pathways of pharmaceuticals
6. Regulatory pathways of medical devices

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Myung Soo Ahn Drug and Device Development in Korea

Regulatory Hierarchy

• Pharmaceutical Affairs Act

• enforcement of PAA
• drug safety regulation
(GMP, GCP, GSP etc)

• approval review guidelines


• clinical trial registration guidelines
• DMF notifications

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Regulatory Statutes
PAL (1953) : Drugs, Quasi-drugs, Medical devices, Cosmetics

Cosmetics/
Cosmeceuticals(2000)

Medical Devices (2004)

PAL MDA COA

PAL : Pharmaceutical Affairs Act


COA : Cosmetics Act
MDA : Medical Devices Act

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Myung Soo Ahn Drug and Device Development in Korea

Premarket Key Elements

Safety/Efficacy Quality Insurance


Cinical Study CMC / GMP Drug Pricing

Sciences : International Harmonization


(Proof - what) (reflected on National Regulations)

Policies : National Sovereignty


(Action - who, how) (Implemented through Regulations)

Same but Different !!

Regulatory Science of Korea


Same vs Different

Science (Fact) Regulations (Policy)

International Harmonization National regulations


(ex. Clinical trial, standards, etc) (ex. Importer license, CPP, etc)
National deviations
(ex. Bridging study, Orphan drugs, etc)

ICH guidelines (QSEM) Korean Laws and Regulations:


compliance rate 90% Domestic enforcement,
not on foreign territory

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Myung Soo Ahn Drug and Device Development in Korea

Characteristics of Regulatory Systems


Business
Manufacturer Permission Import business report
Contract manufacturing business (domestic legal entity)

Product
Manufacturing product license Import product license
(notification) (notification)
* Bridging Study
* CPP: new drug (2014)
Labelling is not premarket review
Local GMP audit for import product
It is illegal selling drugs online
Veterinarian drugs are regulated by the Ministry of
Agriculture, Food and Rural Affairs (MAFRA)

Regulatory Authorities

Ministry of Ministry of
Food and Drug Safety Health and Welfare
(MFDS) (MOHW)

Clinical(Pre-clinical), Distribution,
Premarket approval, Retailing(dispensing)
Postmarket audit Classification,
Insurance(HTA, coverage)

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Myung Soo Ahn Drug and Device Development in Korea

Korean Healthcare System


Compulsory National Health Insurance (NHI) System:
- National single payer system
- Has covered entire population from 1989
- Government administers funds, coverage, coding, payment
and pricing

Ministry of Health and Welfare

HIRA
NHIS
(Health Insurance Review &
(National Health Insurance Service)
Assessment )

Contribution Collection Review Claims


Provider Payment Quality Assessment
Negotiation for Fee schedule Benefit Management
with providers

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Myung Soo Ahn Drug and Device Development in Korea

MFDS
MOHW
Premarket Safety/Efficacy Premarket
Review Confirm Approval
Safety/Efficacy Notification
Standards (30 days)
GMP
Manufacturer

Price
Price Negotioation
Application (60 days)

Benefits
HIRA Assessment NHIS
(120-150 days)

Drug Pricing System

Negative Positive
• All medical services, drugs, • Grant benefits selectively to
medical are divided into two products offering excellent
categories: targeted healthcare treatment and high economic
benefits and targeted non- 2006
value
healthcare benefits.

Economic Evaluation
Introduction of positive listing (included in the benefit
package) based on cost effectiveness, starting in 2006.

-> HIRA reviews the data submitted by manufacturers

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Myung Soo Ahn Drug and Device Development in Korea

Negotiating the price of Original


Instead of formula-based external reference pricing
(average price in 7 countries)
-> Introduce price negotiation between NHIS and
manufacturers with price-volume consideration

Benefits decision on listing Determining price

HIRA NHIS
New Drug (Pharmaceutical Benefit (Negotiation)
Assessment Committee)

HIRA
Generic
(Benefits Standard)

Generic Pricing (from March 2012)


- First year after patent expiration : 30% reduction in the
price of originator, 85% of which (59.5%) is set for the
price of generics
- Second year after patent expiration: 53.5% of originator
price (10% reduction from the year 1) for all generic
medicines, regardless of the order of entry
Before 2012 After 2012
First generic
First generic
Second year/
First 1 year
4 more products

Origina Original 6th 7th Original Original generic Original/


after first generic after first Generic
generic generic

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Myung Soo Ahn Drug and Device Development in Korea

Pharmaceuticals on Listing

Total Precriptions OTCs

Distributing (‘14) 24,624 16,238 8,386

Price Listing (’15) 20,401 18,458 1,943

Year ’08.1 ’09.1 ’10.1 ’11.1 ’12.1 ’13.1 ’14.1 ’15.1 ’16.1

Listing
15,223 14,900 14,883 14,410 13,814 14,576 15,734 17,115 20,401
Products

1. Introduction of Korea
2. Introduction of MFDS
3. Korean Pharmaceutical Industry
4. Characteristics of Korean System
5. Regulatory pathways of pharmaceuticals
6. Regulatory pathways of medical devices

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Myung Soo Ahn Drug and Device Development in Korea

Overview of Pharmaceutical Safety


Management System
Safety inform.
Re-evaluation

GLP GCP GMP GSP Re-examination

Non- Clinical
Approval/ Manufacture
Distribution Medication
clinical Review (Import)

• Summary • Consumer
Animal Subjects • Safety & Efficacy Protocol • Health
Evaluation Review for Professionals Safety
• Manufacturer
Set Manufacture/ • Quality & Biologics Issues
Quality Standards Reliability • Importer (Doctors,
• Hospitals Pharmacists
Verification • Pharmacies etc.)
Research &
Development • Wholesalers

Post- Approval Manufacture(Import) Recall / Provide


Change Hold Discard Information

(Safety Letters)
Quality
Inspection
Clinical Trials Approvals Manufacture(Import) Safety Inform.
Distribution Management

International Standards(ICH) are implemented in every process


of the management system

Major Changes in Regulatory Requirements

• 2000. KGCP revision (enactment in 1995)


- Harmonize with ICH guideline E6

• 2001. Adoption of the Bridging Concept (E5)

• 2004. Introduction of Good Review Practice(GRP)


- Guarantee quality, efficacy, clarity, transparency, consistency of review results

• 2008. Change GMP standards (enactment in 1994)


- International harmonization of GMP regulation
- International collaboration on GMP like PIC/S
• 2009.Common Technical document(CTD) - Adopted on New Drug
• 2015.7. Adoption of REMS (Risk Evaluation Mitigation Strategy)
• 2016.3. Common Technical document(CTD)
- including IMD and generics

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Myung Soo Ahn Drug and Device Development in Korea

Drug Classification
• Origin of Ingredients
Chemical, Biological, Herbal
• Public Accessibility
Prescription, OTC (pharmacy)
Safe-and-readily-available drugs (CVS)
• Data Requirements
Routes Classification Drugs Comparisons

Approval Drugs for Safety& New Drug ≒ FDCA 505(b)(1)


Efficacy Evaluation “Classic” NDA
IMD ≒ FDCA 505(b)(2)
“Hybrid” NDA
Generic Drugs Generic Drugs ≒ FDCA 505( j) ANDA
Notification Drugs on Pharmaco- ≒ Product Listing
poeia/Formulary

Classification on Regulatory pathways

Products that Requires Approval


New Drug(ND), New Molecular Entity(NME)
- An active ingredient never marketed in Korea

Incrementally Modified Drugs (IMD)


New derivative New combination
New efficacy New intended use
New formulation New route of Administration

Generic Drugs

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Myung Soo Ahn Drug and Device Development in Korea

Review and Approval Process of IND & NDA

IND Application NIFDS Review(30 days)


NDA Submission

Phase I Phase II Phase III NDA


Pre-clinical
Development Clinical Clinical Clinical Phase IV
Approval
Trial Trial Trial

Pre-IND Pre-NDA
Meeting Meeting

CPAC Review (90 days)


Consultation

*CPAC : Central Pharmaceutical Affairs Advisory Committee

Requirements for IND Approval

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Myung Soo Ahn Drug and Device Development in Korea

Essential Elements in Clinical Trials

• The protocol approval by MFDS


• Only at the MFDS designated clinical trial institutions
• Qualified investigators
• Protection of the rights and safety of subjects
• Informed consent before enrollment of subjects

New Drug Approval Process

Application Pre-review Review /


Approval
Inspection

NIFDS
(Drug Evaluation
Department )
Applicant NIFDS NIFDS
• Report Review
• Efficacy, Safety
• Quality Evaluation
• DMF

• Research and • Composition of • Issuing


development preliminary Regional FDA
certificate of
of drug report approval
• GMP Assessment
• Preparation of - Examination • GMP inspection
dossier for of submitted - Foreign Manufacturing
• Disclosure of
sites (MFDS) Review Result
drug approval application
- Domestic Manufacturing
sites (Regional FDA)

Sponsors have submitted application as electronic documents through online system for
Pharmaceutical application since Oct. 2nd, 2006

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Myung Soo Ahn Drug and Device Development in Korea

Data Requirements of NDA

Non Clinical
Clinical
CMC Pharmacology Phase I Bridging DMF CPP,
ADME Phase II etc
GMP ToxicologyPhase III

Safety and Efficacy Evaluation

* Documents should be submitted through CTD

Approval Time for NDA

• New chemical entity : 85 working days


• 60 days for scientific review
• 25 days for administrative review Major line
extension : 60 working days

• MFDS can request supplement data only


twice during one review cycle.
• Sponsor response time
- The First request : 60 calendar days
- The Second request : 10 working days
• Sponsor can extend their response time.

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Myung Soo Ahn Drug and Device Development in Korea

Bridging Concept

Bridging Data” = “Korean Data”


New
Bridging Study” = “A trial conducted for the Korean
Drug
People ”

Ethnic Factors Evaluation


(Ethnic differences)

Ethnic Sensitivity
Intrinsic factor
Approval (genetic) Foreign Clinical Data
in Korea Extrinsic factor Bridging Data
(culture, the
environment)

The Process of Generic Drugs Approval

1. Application of BE protocol

Pharmaceutical 2. Protocol Approval R-FDA


Company 4. ANDA NIFDS

5. Generic Drug Approval


(Inspection for some products)

3. Conduct of BE study
BE Study except for parenteral use

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Myung Soo Ahn Drug and Device Development in Korea

1. Introduction of Korea
2. Introduction of MFDS
3. Korean Pharmaceutical Industry
4. Characteristics of Korean System
5. Regulatory pathways of pharmaceuticals
6. Regulatory pathways of medical devices

1963 ~ 2002 2003 ~ Present

Medical Device Management Operation of independent Medical Device


System Provision Management system

Introduction of Classification Establishment of Medical device Act


Separation of permission/Notification (Apart from Pharmaceutical Affairs Laws)
Introduction of Clinical Trials
Introduction of GMP Instruction of Class 4 device, Repairer, Renter,
Post-management (Tracking system etc)
• Management operation under the
pharmaceutical affair laws

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Myung Soo Ahn Drug and Device Development in Korea

Characteristics of MD Regulatory Systems

Not as complex as pharmaceuticals


Similar pathways to Europe
4 Classes(I, II, III and IV)
Approval, 3rd party certification, Notification,
Almost operating NB except for Class IV Devices
- Technical file review(7 3rd parties)
- Type test(14 testing labs)
- GMP inspection(4 institutions)
ISO Standards
GMP based on ISO 13485

Before you start…

• Determine classification of your device based on the


device database, regulations provided by South Korea’s
Ministry of Food and Drug Safety (MFDS), as well as
predicate devices in the South Korean market.

• If no predicate exists, the device will follow the Clinical


Data Review route.

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Myung Soo Ahn Drug and Device Development in Korea

MD Regulations

The Medical Device Act Framework

The Medical Device Act : Definition of Medical Device, etc.

The Enforcement Decree : Medical Device Committee, Delegation of Authorities

The Enforcement Regulations : Document and format of technical regulations

MFDS Notice: Classification, Approval process, standard for GMP, etc.


(specified and published by the MFDS)

Regulatory pathways

Notification

Certification

Approval

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Myung Soo Ahn Drug and Device Development in Korea

Competent Authorities
MDITAC* NIFDS

GMP conformity GMP conformity


Application for assessment (30days) assessment (30days)
* Regional Branches & 3rd Parties * Regional Branches & 3rd Parties
Product Notification
Technical file Technical file
Review (25 days) Review (55, 70 days)
*Third-Parties

* GMP requirements
Certification Issue Approval Issue
(5 days) (10 days)

* MDITAC(Medical Devices Information and Technical Assistance Center


- Authorized for the above affairs from MFDS on July, 2015

3rd Parties for MD

MD Notifi. & Certifi.MDTAC(1)


Issuance (Medical Device Information & Technology Assistance Center,
MFDS affiliated org.)

3rd Parties : KTL(Korea Testing Lab), KTC(Korea Testing


MD Technical File Certification), KTR(Korea Testing & Research Institute),
Review KCL(Korea Conformity Laboratories), TUV Sud Korea, SGS
Korea, MDTAC (7 institutions)

MD Testing Lab. KTL, KTC, KTR, ..(14 institutions)

MD GMP Inspection KTL, KTC, KTR, KCL(4 institutions)

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Myung Soo Ahn Drug and Device Development in Korea

Technical documents and files


Technical documents

Documents related to quality of medical devices, such as, functions, safety. etc.
- Including information on raw materials, structure, purpose of use, instruction for use,
principles of functions, precautions for use, test standards, etc.
Data on raw materials,
Characteristics, purpose of use,
operation method, mechanism,
precautions, test specification,
etc

Technical files

Technical file is consist of application form and


supportive documents and is divided into two different
types of technical file reviews: (1)’General Review’(GR);
Clinical report review and (2) ‘Safety and Effectiveness Review’ (SER)

Types of Technical files

General Review (GR)


Devices substantially equivalent to previously approved products
Does not require clinical trial reports

Safety and Effectiveness Review (SER)


Significant concerns for safety and effectiveness compared to
previously approved products(New technology, design, performance,
purpose for use, etc..)
Clinical trial reports are essential

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Myung Soo Ahn Drug and Device Development in Korea

Regulatory Pathways (Notification, Certification & Approval)

Submission Review Approval


Class I
Docu. Notification
register
MDTAC
Class II

Technical
Documents Tech. file Review Documents Review
GMP Certi. issue
(25days) (5days)
Certi.
Tech. files
3rd Parties MDTAC

Class III, IV

Technical
Tech. file Review Documents Review
Documents
(55days) (10days)
GMP Tech. files
Certi. Tech. file & documents Review (GR, 65days)
Approval issue
Clinical Trial Report
NIFDS
STED (class IV)
Clinical Trial Reports Review(SER, +15days)

Technical Files for Class IV MD(STED)

STED are required for Class 4 (except IVD reagent)


- enforced as of 2014.Jan.1
- optional for other Classes

Application Application
STED : Summary Technical Documentation
for demonstrating conformity to the
safety and performance of medical
STED devices
: proposed by GHTF(IMDRF)
including design verification, risk
analysis & manufacturing process
Accompanying Accompanying regarding safety and performance
documents documents

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Myung Soo Ahn Drug and Device Development in Korea

Approval process

Application Review & Approval Clinical trial

▪ Plan (protocol)
▪ Technical
Document
Review submission (30 days) Approval
▪ Site description

Who Must Apply


- A person who intends to conduct clinical studies with medical devices
Exemption
To research clinical effectiveness and adverse effect on approved items
To collect data about safety & effectiveness on approved intended use &
performance

Hope your work takes you there soon!

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