drug approval system in malaysia

1

DRUG APPROVAL SYSTEM

IN MALAYSIA

Rosilawati Ahmad

Deputy Director, Centre for Product Registration

National Pharmaceutical Regulatory Agency (NPRA), Malaysia

2019 K-Pharma Academy (KPA) for ASEAN

Sharing content

Intro-Pharmaceutical

Services Program& NPRA

Categories of Products & Registration

requirements

Registration process & timelines

Issues Identified in Korean product dossier

assessed at NPRASummary

2

Sharing content


Services Program & NPRA

Regulatory activities

Registration requirements &

process

Challenges & Regulatory reform

Summary

3

Organisation Chart – Ministry of Health, MALAYSIA

Organisation Chart - Pharmaceutical Services Program

Senior Director of Pharmaceutical Services

Program

National Pharmaceutical Regulatory Agency (NPRA)

Pharmacy Enforcement Division

Pharmacy Practice & Development Division

Pharmacy Policy & Strategic Planning

Division

Pharmacy Board Malaysia

Pharmacy and pharmaceutical services, Clinical & Technical, MoH

Drug Formulary, Special Drug Request approved by DG, Technical

support in medicines tender, Price control, Patients education

Strategic plans and policies, Human resources, National Medicines

Policy, ICT related, intra-agency, inter-agency and

international communication

Enforcement and prevention activities, control of licensing,

monitoring activities and consumer awareness activities,

advertisement

Registration of Pharmacists

NRA for medicines and cosmetics in Malaysia. Ensuring the QSE of medicines through the registration and licensing scheme, post-market activities

Poisons Act 1952 (Revised 1989)

Sales of Drugs Act 1952 (Revised 1989)

Dangerous Drugs Act 1952 (Revised 1980)

Registration of Pharmacists Act 1952 (Revised 1989)

Medicine (Advertisement & Sale) Act 1956 (Revised 1983)

Legislation

Legislation

Control of Drugs and Cosmetics Regulations CDCR 1984, Regulation 7(1) states:

• No person shall manufacture, sell, supply, import, possess or administer any product unless:

• (a) the product is a registered product, and

• (b) the person holds the appropriate license required & issued under these Regulations.

VISIONTo be an internationally renowned regulatory authority for medicinal

products and cosmetics

MISSIONTo safeguard the nation’s health

through scientific excellence in the regulatory control of medicinal

products and cosmetics

OBJECTIVETo ensure that therapeutic

substances approved for the local market are safe, effective and of quality and also to ensure that

cosmetic products approved are safe and of quality

REGULATORY SYSTEM

Role of National Pharmaceutical

Regulatory Agency

ORGANISATION CHART

81

Pharmacy

Assistants

329

Pharmacists

Total staff : 490

Staff Strength

Centre for Quality Control

DEPUTY DIRECTOR

Centre for Post Product

Registration and

Cosmetic Control

DIRECTOR

DEPUTY DIRECTOR

Centre for

Investigational New

Product

DEPUTY DIRECTOR

Centre for Product

Registration

DEPUTY DIRECTOR

Centre for Compliance

and Licensing

DEPUTY DIRECTOR

Centre for Development

and Strategic Planning

80

Administrative

& Support Staff

1

3

2

4

5

6DEPUTY DIRECTOR

NPRA’s international presence

10

Member

Non-member

Ad-hoc

Inter-agency collaboration

• WHO Collaborating Centre for Regulatory Control of Pharmaceuticals

• WHO Programme for International Drug Monitoring

• PIC/S

• ACCSQ-PPWG

• Network of Official Medicines Control Laboratories (NOMCoL)

• OECD GLP Mutual Acceptance of Data (MAD)

• ICH Observer

• Joint assessments

• Parallel reviews

• Bilateral meetings

Sharing content




requirements




11

12#RegulatoryReform

Pre marketing Post marketing

Regulatory Functions

Product Life

cycle

Drug

DiscoveryPreclinical Clinical trials Regulatory Review

Approval & Launch

Post-Marketing

Surveillance

National Regulatory System Regulatory Inspection

Licensing premises Laboratory access and Testing

Clinical Trial’s Oversight Marketing authorization

Vigilance Market surveillance and Control

Lot Release

NPRA registers products that fulfil registration criteria

New Drug Products

Biologics

Health Supplements Generics

Natural/herbal

VeterinaryQUALITY

EFFICACY SAFETY

13

New Drug ProductAny pharmaceutical product that has not been previously registered in

accordance with the legal provisions in Malaysia

Types of New Drug Product

New Chemical Entities

Hybrid

15

Product containing an active moiety/ radiopharmaceutical

substance that has not been registered in any

pharmaceutical product [full product dossier required]

Other products, e.g. combination of registered NCEs, new

dosage form, new strength, new route of administration

[abbreviated product dossier allowed]

Biologics

Biologic product refers to a product whose active substance is made by or derived from a living organism (plant, human, animal or microorganism)

May be produced by biotechnology methods and other sophisticated cutting-edge technologies.

The product imitates natural biological substances in our bodies such as hormones, enzymes or antibodies.

Therapeutics made out of proteinsthat can differ in size (large) and structural complexity

E.g. Vaccines

Blood/Plasma derived medicinal products

Biotechnology products including biosimilarCell and Gene Therapy Products (CGTPs)

GenericsA generic product is a product that is essentially similar to a currently registered product in

Malaysia. Classified into two groups:

Scheduled Poison

(Known as Controlled Medicine/ Controlled Poison) Products containing poisons as listed in the First Schedule under Poisons Act 1952

Non-scheduled Poison

(Known as Non-Poison or “Over-the-Counter”, OTC) Products containing active ingredients which are not listed in the First Schedule under Poisons Act 1952; and is excluding active ingredient which is categorized under health supplements or natural products or cosmetics

PROCEDURES FOR REGISTRATION

QUEST MEMBERSHIP REGISTRATION

• Product registration application is via QUEST3+ online submission system which enables itsusers to conduct secured online activities (eg. Product registration, cosmetic notification etc.).

20

Submission of Quest3+ Membership Registration application via https://quest3plus.bpfk.gov.my/

Received USB Token that contains a User Digital Certificate from MSC Trustgate.com Sdn. Bhd.

Access to QUEST online system for product registration application

REQUIREMENTS FOR REGISTRATION

21

Registration requirements for pharmaceutical products

InternationalWHO

ICH

EMA

US FDA

Regional

ASEAN Guidelines for:

Stability

Process validation

Variation

Local

Drug Registration Guidance Document

NPRA Guidelines

DCA Directives

Circulars 22

GUIDELINES

Drug Registration Guidance Document(DRGD)

ASEAN Guidelines on Process Validation

ASEAN Guidelines for the Conduct of BA/BE Studies

ASEAN Guidelines for Drug Product Stability Study

ASEAN Guidance on ACTD

Other guidilines may be applicable ) as and when needed

NPCB

MOH

Registration Application Format

ASEAN Common Technical Dossier / ASEAN

Common Technical Requirements ( ACTD/ACTR)

- adopted and adapted from ICH requirements

Implemented since July 2003

Registration Application Format

ASEAN Common Technical Dossier / ASEAN Common Technical Requirements ( ACTD/ACTR)

- adopted and adapted from ICH requirements

Implemented since July 2003

GMP Requirements

CANADA

AUSTRALIA

Malaysia -Member since 2002ARGENTINA LATVIAAUSTRALIA LIECHTENSTEINAUSTRIA LITHUANIA

BELGIUM MALAYSIACANADA MALTACYPRUS NETHERLANDSCZECH REP. (SUKL) NEW ZEALANDCZECH REP. (ISCVBM) NORWAYDENMARK POLANDESTONIA PORTUGALFINLAND ROMANIAFRANCE (ANSM) SINGAPORE FRANCE (ANSES) SLOVAK REPUBLICGERMANY SLOVENJIAGREECE SOUTH AFRICAHUNGARY SPAINICELAND SWEDENINDONESIA SWITZERLAND ISRAEL TAIWANIRELAND UKRAINEITALY UNITED KINGDOMJAPAN UNITED STATESKOREA

Pharmaceutical Inspection Cooperation Scheme

•PIC/s standards (also known as the Pharmaceuticals Inspection Cooperation

Scheme ).

•If > 1 manufacturer involved, GMP certification should be available for all

manufacturers

26

Sharing content




requirements




27

Registration process

Step 6

Step 5

Step 4

Step 3

Step 2

Step 1

TECHNICAL ASSESSMENT

• Evaluator’s

review

• Expert opinion-

KOL (for NCE

and Biologics

only)

• Correspondence

with applicant

DCA MEETING

Final report

presented at

Drug Control

Authority (DCA)

ACCEPTANCE OFDOSSIER

Acceptance

of Dossier for

full evaluation

ASSESSMENT COMPLETEEvaluation report

presented at

NPRA Evaluation

Committee

FINAL DECISION

Approval

(MAL no.)

rejection

SCREENING

Screening of

application

received via

QUEST 3+

online system

Normal Timeline: Generics: 210wd

NCEs, Biologics: 245 wd

TIMELINE FOR REGISTRATION

Type of Application Timeline

Full Evaluation New Drug Products & Biologics

245 working days

Full Evaluation

Generic (Scheduled & Non-Scheduled Poison)

210 working days

Abridged Evaluation

Generic (Non-Scheduled Poison)• Single active ingredient• Two or more active ingredients

• 116 working days• 136 working days

FEES FOR REGISTRATION

Product Classification Processing Fees

(RM)

Analysis Fees (RM)

Total Fees (RM)

(USD)

a) New DrugProducts

b) Biologics

1000.00 Single active ingredient : 3000.00

4000.00

(950)

Two or more active ingredients : 4000.00

5000.00

(1200)

Generic (Scheduled Poison)

1000.00 Single active ingredient : 1200.00

2200.00

(525)

Two or more active ingredients : 2000.00

3000.00

(715)

Facilitating Approval to new/innovative medicines/generics/biosimilars– alternative registration pathway

PRIORITY REVIEW

(i) Unmet medical needs with no treatment options locally available

(ii)Life-saving with no treatment options locally available

(iii)first *generic/ biosimilar product, or first locally manufactured generic/biosimilar product.

CONDITIONAL REGISTRATION

• Products for unmet need supported by early clinical data such as phase II clinical data (based on fully validated surrogate endpoints)

• Conditionally registered for 2 years period with specific conditions

FACILITATED REGISTRATION

PATHWAY

• Leveraging on a Stringent Regulatory Authority decision and information -rely on assessment report issued by the reference agencies

• Abbreviated and Verification Review

To allow promising new medicines to reach patients with unmet need earlier based on early phase data such as phase II clinical data to support the efficacy and safety.

To provide guidance on the application necessary for implementation of conditional registration

To ensure that appropriate measures are in place to manage the risks inherent as additional data are still required.

32

Guidelines on Conditional Registration for NCEs and Biologics

NPRA National Pharmaceutical Regulatory Agency

1

2

3


Published May 2018


Full Registration (Normal Regulatory Approval) vs Conditional Registration (early access)

Clinical trial

(evaluating of efficacy and safety)Approval Marketing

33

Clinical Research

Clinical Research

Clinical trial (prediction of efficacy and assurance of

safety)

Conditional approval for

a limited time period

(2 years)

Marketing

Confirmation of efficacy and safety

in the post marketing stage

Full registration or Revocation of

the conditional registration

Continued marketing

(if approved)

Submission of renewal application within the

limited time period

Conditional Registration Pathway*Faster access of patients to new product is expected

• Based on the clinical data from limited number of patients, efficacy is predicted in a shorter time compared with the conventional process• Acute-phase adverse reactions etc. can be evaluated for safety in a short period of time

Normal Regulatory Approval Pathway

34

Guidelines on Facilitated Registration Pathway: Abbreviated and Verification Review

NPRA National Pharmaceutical Regulatory Agency NPRA National Pharmaceutical Regulatory Agency NPRA National Pharmaceutical Regulatory Agency

Published March 2019

ensure innovative medicines addressing

current unmet medical needs can be accessible to patients in need in a timely manner

reduce duplication, especially for products where safety and efficacy have already been confirmed by Stringent Regulatory Authorities

drive greater focus toward risk-based evaluations, focusing on what is locally critical versus what can be leveraged/relied upon from decisions made by SRAs

1

2

3

a) New Drug Products

b) Biologics including Biosimilar

.

Scope

Abbreviated review - approved by atleast 1 reference drug regulatoryagency

Verification Review - Approved by 2reference drug regulatory agencies

Routes

US FDA & EMA

WHO Prequalified Medicinal Productscovered by the alternative listingprocedure (evaluated by US FDA andEMA)

Reference Agencies

Facilitated Registration Pathway

“RELIANCE….an act whereby a regulatory authority in one jurisdiction may take into account/give significant weight to work performed by another regulator or other trusted

institution in reaching its own decision….”

Documents required

-Complete Common Technical Document-stability study complies with ASEAN stability guideline-Protocol of Analysis & analytical method validation –checklist as Appendix

FULL DOSSIER

Complete assessment report including assessment on the Q&A documents between the PRH and reference DRA and all annexes. Note: may consider accepting public assessment reports accompanied by redacted information and Q&A provided that the applicant has shown proof and effort to obtain the unredacted assessment reports

PROOF OF

APPROVALProof of approval from the chosen reference DRA-

DECLARATION LETTERRelevant declaration letter(s) issued by the product owner/PRH- all aspects of the DS & DP quality and intended direction(s) for use, including but not limited to the formulation, manufacturing site(s), release and shelf life specifications, primary packaging and active pharmaceutical ingredient(s) source are identical to that currently approved by the chosen reference drug regulatory agency at the time of submission

ASSESSMENT REPORT

1

4

3

2

Full DossierApproved by any

regulatory agency

Full evaluation:

quality, non-clinical &

clinical

245 w.d.

Normal Registration Pathway

Facilitated / Abbreviated Registration Pathway

Facilitated / Verification Registration Pathway

Conditional Registration Pathway


regulatory agency

Evaluation: quality,

non-clinical & early

clinical data (phase II)245 w.d.

Full Dossier +

Reference agency

assessment report

Approved by EMA

/ US FDAAbridged evaluation:

quality & clinical120 w.d.

Full Dossier +

Reference agency

assessment report

Approved by both

EMA & US FDAReference agency

assessment report90 w.d.

37


regulatory agency

Full evaluation:

quality, non-clinical &

clinical120 w.d.

Priority Review

TIMELINES COMPARISON- NCEs & Biologics

Statistics

27%

7%3%

52%

11%

212,568Notified

CosmeticsAs of 10-09-19

444

ImportersAs of 31-08-19

1,386Wholesalers As of 31-08-19

23,254Registered Products

As of 03-09-19

545Manufacturersas of 31-08-19

77 Pharma 173 TMHS11 Veterinary 284 Cosmetics

12,208

Traditional

(T)

1,603

Non

Prescription

(X)

6,122

Prescription

(A)

2,554

Health

Supplement

(N)

767

Veterinary

(H)

1,158 Pharma 198 TMHS30 Veterinary

179 Pharma 229 TMHS36 Veterinary

7,725 Pharma 14,762 TMHS767 Veterinary

A comparison of new drug approval timelines, 2015-2017 (CIRS, London)

Trends in the Regulatory Landscapefor the Approval of New Medicinesin Asia

R&D BRIEFING 72

To address the complex challenges in the global regulatory environment and the growing demand for patient access to new medicines, regulatory agencies in Asia are actively engaging in regulatory-strengthening and capacity-building initiatives including the use of priority pathways, reliance in the prior reviews of trusted authorities and work sharing to facilitate better utilisation of resources.

This R&D Briefing focuses on the trends observed for 8 countries in the Asia region for 166 new active substances approved from 2009-2017*. The briefing explores converging review times, joint regional submissions and the positive effects of regulatory reform in China.*See page 6 for methodology

Briefing Highlights• From 2008-2017 average review times in India, Taiwan,

Singapore, South Korea and Malaysia converged to an average between 400-500 calendar days; this average increased slightly in 2017.

• From 2015-2017 median review time was longest in Indonesia (1057 days) and China (800 days).

• From 2009-2017 there was minimal variability in regulatory review times in Malaysia, Singapore, South Korea and Taiwan and review timing in South Korea was consistently under 1 year.

• Government-mandated 2015 regulatory review improvements in China have resulted in 133 new drugs being approved through a new priority review route and an application backlog decrease from 22,000 to 3,440.

• A number of countries and regions have developed facilitated regulatory review pathways. These reliance pathways are in place in Indonesia, Malaysia, Singapore and Thailand. China, Taiwan and Vietnam conduct priority review. Rolling submissions and conditional approval is possible in South Korea. These facilitated pathways contribute to a shortening of regulatory review times and increased regulatory efficiency.

Regulatory review processes and timelinesThe time to regulatory approval of new active substance (NAS) in Asia can be measured by three distinct time points: 1. time of approval in the first market, which generally is a first-wave market (USA or Europe); 2. the submission gap, (time between first-market approval and submission to a particular authority); 3. marketing authorisation (MA) time (time between submission and approval, which includes company and agency time). These time points are influenced by a number of factors, one of which is the regulatory landscape within different jurisdictions (Figure 1).

Figure 1: Overall median roll out time to Asian countries for NASs approved 2015-2017 and factors influencing their roll out.

(n1,n2) = number of NASs, number of companies

39EM: emerging market

Sharing content




requirements




40

New Drug Products: Issues Identified in Korean product dossier assessed at NPRA

Quality

Clinical

41

• Inconsistent information on product composition and specifications among

different sections of the dossier

• No data on degradation products of active pharmaceutical ingredient (API) and

drug product (e.g. stress stability testing)

• No justification on proposed drug product quality control test specifications

• Incomplete process validation report (e.g. no sampling plan)

• Incomplete stability data (e.g. no photostability study, only 3 months’ real time

stability data with a proposed shelf life of 36 months)

• Limited clinical data from Phase III studies to support efficacy and safety of all

proposed indications – this led to DCA approval of one out of all proposed

indications

• Clinical trial did not include active comparators with established use in treating

a particular disease

• Transdermal patch product did not include studies on adhesion (including the

influence of external factor such as heat and/or under other ‘in-use conditions’),

skin irritation and sensitisation

Biologics: Issues Identified in Korean product dossier assessed at NPRA (based on limited no. of products)

General

Clinical

42

• Translation issue from Korean to English- some may not be accurate

e.g. related clinical study protocol-impact on the different conduct of

the Clinical Trial

• Translation of NPRA queries from English to Korean and vice versa –

lost in translation-the true meaning of the questions raised were not

direct effectively to the applicant. Hence, unsatisfactory response

Generics: Issues Identified in Korean product dossier assessed at NPRA

Quality

Clinical

43

• Test for degradation products is not conducted• Test parameters are not included as per ASEAN Guideline on Stability study

of Drug Product. (e.g. Microbial limit test, drug release rate for transdermal patches)

• Process validation: Media Fill report with insufficient number of containers filled, incomplete media fill incubation information, filter validation report and information for tunnel sterilization

• In-use stability data /Compatibility Data upon dilution is not provided• Final concentration of diluted product is different from innovator product

Sharing content




requirements




44

Summary – NPRA regulatory strengthening

Structured training programs in collaboration with industry, academia and other DRA’s

important for capacity building

Organisational change, upgrading of systems and guidelines to support implementation of

regulatory frameworks

Collaboration with other NDRA’s to overcome regulatory oversights and improve application

time

Use of new approaches in regulatory practice towards efficient use of resources and avoid

duplication of work

Reliance and mutual trust with other NRA’s to ensure sustainability of collaboration, convergence, harmonisation efforts

1

2

3

4

5

Further reference

• Address : Lot 36, Jalan Universiti, 46200 Petaling Jaya, Selangor, Malaysia.

• Telephone : +603-78835510

• Fax : +603-79581312

• Email: [email protected]

• Website : www.npra.gov.my

http://www.npra.gov.my/