Regulation on Biopharmaceuticals and The Challenges

(Indonesian Perspective)

Ramjani Simalango

National Agency for Drug and Food Control, The Republic of Indonesia Presented in Global Bio Conference 2017

Seoul, June 30th, 2017

OUTLINES

INTRODUCTION

CONCEPTS OF PRE MARKET EVALUATION

EVALUATION SYSTEM

VACCINES AND BIOSIMILARS

CHALLENGES

THE WAY FORWARD

Pre-Market Control

Objective: Public protection unmedicines by providing assurance on the quality, safety and efficacy of medicinal product

Objective: Public protection from un-expected risk of medicines by providing assurance on the quality, safety and efficacy of medicinal products.

1. Health Law No 36/2009, 2.3.

1. Health Law No 36/2009, 2. MoH Decree No. 1010/2008 on Drug Registration 3. Head of NADFC Decree N0. HK.03.1.23.10.11.08481 of 2011 on

Criteria and Drug Registration Procedure

All medicines marketed in Indonesia should have Marketing Authorization.

- Registration of Medicines - cGMP Compliance - Clinical Trial Control

NADFC

Legal Provision

VISION

• Safe Food and Medicine to Improve Public Health and National Competitiveness.

MISSION

• Intensifying Risk-based Drug and Food Control System to protect public health

• Encouraging Self Reliance of Bussiness Actors in ensuring Drug and Food Safety and strengthening partnership with stakeholders

• Enhancing NADFC institutional capacity.

Vision and Mission of NADFC

NATIONAL AGENCY OF DRUG AND FOOD CONTROL

SECRETARY

1. Bureau of Planning and Financing 2. Bureau of International Cooperation 3. Bureau of Legal and Public Relation 4. Bureau of General Affairs

Control

Deputy II Traditional Medicines, Cosmetics and Complement Products Control

1. Directorate of Traditional 1. Directorate of Traditional Medicines, Food Supplement and Cosmetics Evaluation

2. Directorate of Traditional Medicines, Cosmetics and Compliment Product Standardization

3. Directorate of Traditional Medicines, Cosmetics and Compliment Product Control and Certification

4. Directorate of Indonesian Traditional Medicines

Deputy III Food Safety and Hazardous Substance Control

1. Directorate of Food Product

5. Directorate of Surveillance and Food

1. Directorate of Food Product Evaluation

2. Directorate of Food Standardization 3. Directorate of Food Control and

Certification 4. Directorate of Product and

Hazardous Substance Control 5. Directorate of Surveillance and Food

Safety

Deputy I Therapeutic Product, Narcotics, Psychotropic and Addictive Control

1. Directorate of Drug and Biological Product Evaluation

2. Directorate of Control of Production Therapeutic Product and Household Product

3. Directorate of Therapeutic Product Standardization

4. Directorate of Control of Distribution Therapeutic Product and Household Product

5. Directorate of Narcotics, Psychotropic and Addictive Control

Drug and Food Control

Regional Offices

INSPECTORATE INSPECTORATE

Centre of Drug and Food Investigation

National Laboratory of Drug and Food

Control

Centre of Drug and Food Research

Centre of Drug and Food

Information

Organization of NADFC

33 Technical Units in Indonesia

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Regulatory Framework On Ensuring Quality, Safety, and Efficacy of Medicine

Manufacturers PRE-IND AND IND STEPS or FORMULATION R & D

- Manufacturing process development

- Clinical development

Dossier submission

REGULATORY CONSULTATION

GMP

Phase 1

- Safety

- Efficacy/ Immuno genicity

Phase 2

- Efficacy/ Immuno genicity

- Safety

- Dose ranging

Phase 3

- Efficacy/immunogenicity

- Safety

- Monitoring safety, quality

- Inspection

- Phase 4 study

PRE-MARKET EVALUATION

PRODUCTION

GMP

III. POST-MARKET CONTROL

I. PRE SUBMISSION II. MA APPLICATION & PRODUCTION

Lab Testing

Lot Release

AEFI

Control & Enforcement

GMP

Product Information

QUALITY EFFICACY &

SAFETY

Based on Quality data: • Active substance • Finished product Comply with cGMP

Should be: • complete • Objective • Clear To ensure rational medicine use

Based on: • Nonclinical studies • Clinical studies

Evaluation Criteria

Criteria On Drug Evaluation (Risk Based Assessment)

Drugs for national health program Based on decision by Health program

Newly innovated drugs Under patent protection Originator drugs

Drugs which are needed but not feasible to be produced locally Manufacturing technology & facility not available in Indonesia Manufacturing capacities is not sufficient for national need Economically not feasible to be produced in Indonesia due to low

need (i.e Orphan drugs) Produced through centralized system by foreign pharmaceutical

industry which has invesment in Indonesia, supported by balance of import and export activity

Criteria and Administrative Documents for

Imported Drugs (1)

Applicant Pharmaceutical Industries in Indonesia having written authorization

from the manufacturer abroad.

Site Inspection

A risk based inspection and also based on evaluation of pre-inspection documents, evidence of compliance to GMP may need to be verified by site inspection.

Manufacturer

Have manufacturing Licence and meet GMP requirement as proven by : - Valid GMP Certificate

- Data of last inspection within the last 2 years Submit latest Site Master File (SMF) document, if :

The manufacturer has not had any product with the same dosage form authorized to be marketed in Indonesia

The manufacturer has product with the same dosage form authorized to be marketed in Indonesia, but there is a change of production facilities.

Criteria and Administrative Documents for

Imported Drugs (2)

Flowchart of Drug Registration

Applicant Applicant

Registration Dossier Screening Registration Dossier Screening

Review Process: Efficacy, Safety, And Quality

Review Process: Efficacy, Safety, And Quality

Scientific and Evidence Based

Risk vs benefit assessment

Identify , measure and evaluate safety &

efficacy

Quality control of product and

production process

Inspection of Manufacturing Facility

Decision Making Decision Making

Finalization: Labelling and Licensing

Finalization: Labelling and Licensing

TIMELINESS

Additional data

required

evaluation approach Post-Approval Changes Post-Approval Changes

APPROVAL

DRUG REGISTRATION PROCEDURE Decree of the Head of the National Agency of Drug and Food Control No.HK.03.1.23.10.11.08481 of 2011 on Criteria and Procedure for Drug Registration

New Drug Application

2 Steps: Pre-Registration Step (40 WD): To determine the registration

category, evaluation path/timeline, registration fee Registration Step: Submission and evaluation of

dossier according to the registration category

• Drug(s) for life saving; • Orphan drug • Drug(s) for national

program;

100 WD

Drug(s) which has been approved by mature agencies

150 WD

Drugs which are not included in path 100WD and 150 WD category

300 WD

Same evaluation process (full review)

for all pathways Pharmaceutical Industries

located in Indonesia

DOSSIER Format-in line with ACTD

* Upon Request

Part I Administrative Data

& Product Information

Part II

Quality

Overall Summary

& Reports

Part III Non-clinical

Overview,

Summary

& Study Reports*

Part IV Clinical

Overview,

Summary,

Assessment Reports,

& Study Reports

Country-specific administrative data.

Not part of ACTD

ACTD

Pleno Meeting of National Committee for Drug Evaluation

Meeting of Team Evaluator

NADFC

Applicant

Evaluator

NADFC

Decision (Accept, Reject, Require additional data)

Head of NADFC

Evaluation result and recommendation

Appeal / Additional data

Flow of Evaluation and Decision Making Pathway

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• Consist of experts in the field of clinical pharmacology, pharmacy, biology and relevant clinicians

• Recruited from Universities and other relevant institutions

• Sign statement of independency (not to have a conflict of interest)

• Conducting meeting regularly to discuss the result of evaluation of drugs

National Committee on Drug Evaluation

Appeal and Hearing

Appeal • Opportunity provision for

applicant to appeal the decision of evaluation.

• One appeal opportunity.

• Can be supported by additional data or justification of the previous submitted data.

• Can use hearing mechanism.

Hearing • If detailed clarification and

/ or technical explanation of the submitted documents is needed by National Commitee

• Request by applicant to provide convinced explanation, mostly if the application has been rejected.

5 Years

Validity of Marketing Validity of Marketing Validity of Marketing Validity of Marketing AuthorizationAuthorization

Exception for

Manufacturing product

Exception for License & Contract

Manufacturing product Renewal registration mechanism Can be extended trough

Renewal registration mechanism

Head of NADFC Regulation No. HK.03.1.23.12.11.10690 of 2011 on Pharmacovigilance Implementation for Pharmaceutical Industry and its Technical

Guidelines

Pharmaceutical Industry (MAH) must report: - ADEs/ADRs/AEFI as Spontaneous Reports of their marketed

drug/vaccines

- PSUR for the products that meet the criteria and as required

by NADFC

- Post Market Study for certain products as required by NADFC

- Scientific Journal and or publication relating with safety issue

of their respective product

- Regulatory Action by other DRAs relating with their respective

product

- Action by Global Company in other country

- Risk Management Plan (RMP) as required by NADFC

Pharmacovigillance Program

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• Implementation of GRevP

(Good Review Practices):

– Transparancy and profesionalism

– Standardize general review process

– Avoid inconsistent decision making

– Strengthen review management

– Accelerate review time

– Communication with stakeholder

Good Regulatory Practices (GRP)

VACCINES

Guideline for Evaluation of Vaccines

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CRITERIA DAN PROCEDURE FOR DRUG REGISTRATION

GUIDELINE ON EVALUATION SAFETY AND EFFICACY OF VACCINE

WHO GUIDELINE ON STABILITY EVALUATION OF VACCINE

WHO GUIDELINES ON SPECIFIC VACCINES

WHO TECHNICAL REPORT SERIES

• Domestic vaccines (for local use and export)

Samples for all batches will be taken by Provincial Office after filling and will be sent to NQCLDF

Laboratory testing (random, at least 10% of total vaccines)

Summary protocol production, CoA and raw data evaluation

Appearance test for all batches:

- VVM , label, leaflet, packaging review,

- Re-suspension test (vaccines containing whole cell pertussis)

Second reading slide of neurovirulence test for monovalent bulk of poliomyelitis (type 1, 2, and 3 )

National Lot Release System

Imported vaccines with Release Certificate from Country of origin and PQ WHO

Imported vaccines without Release Certificate from Country of origin and or non PQ WHO

* Appearance test: o VVM, label, leaflet, packaging review o Re-suspension test (vaccines containing whole cell pertussis) * Summary protocol production, CoA, and raw data evaluation

* Appearance test: o VVM, label, leaflet, packaging review o Re-suspension test

(vaccines containing whole cell pertussis)

* Summary protocol production, CoA, and raw data evaluation * Laboratory testing

National Lot Release System for Imported Vaccines

Link Between NRA– CDC– AEFI Committee On AEFI Surveillance Of Vaccines Used In EPI Program

NRA: PV, NCL,

LICENSING, INSPECTION

CDC EPI

PROGRAM: AEFI DATABASE

NATIONAL COMMITTEE ON

AEFI: CAUSALITY ASESSMENT and Expertise

support

REGIONAL NADFC

OFFICES

PROVINCIAL AEFI COMMITTEE:

INVESTIGATION and Causality assessment*

PROVINCE/DISTRICT HEALTH OFFICES

AEFI REPORT FROM HEALTH CENTRES

REPORTING

SAMPLING

COORDINATION for Serious AEFI Cases

CONSULTATION

INVES- TIGATION

REPORTING

REPORTING AND CONSULTATION

RECOMMENDATION

AND FEEDBACK

SUPERVISION AND FEED BACK SEND

SAMPLES

INSTRUCTION FOR

COORDINATION AND SAMPLING

CONSULTATION

RECOMMENDATION

LAB TESTING RESULTS,INFORMATION ON REGULATORY ACTION (IF LAB TESTING RESULTS,INFORMATION ON REGULATORY ACTION (IF RECOMMENDED AND REQUIRED)RECOMMENDED AND REQUIRED)

COORDINATION, EXCHANGE INFORMATION, SHARE DATA

RECOMMENDATION

INTERACTION ON CENTRAL LEVEL**

INTERACTION ON PROVINCIAL/DISTRICT

LEVEL**

1

3

4

4

5 5

6

7

8

9

10

11

7

7

12

2

10

11

13

Feedback

Industry

BIOSIMILARS

Regulation on Biosimilars

Principle:

• Biosimilars products should demonstrate similarity on quality, safety and efficacy to Reference Biotherapeutics Product (RBP).

Indonesia guidelines on biosimilars:

• Mostly refers to WHO guidelines and also considered other established biosimilar guidelines.

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Biosimilar Product Reference Product Comparability

Requirements in Q, S, E

Evaluation

Quality Characterizations

Nonclinical

Clinical

Policy for Biosimilar Product Evaluation

1. Quality comparability study

Characterisation: Physicochemical attribute, biological activity, immunochemical attributes, and impurities.

2. Nonclinical comparability study

Minimum repeated dose toxicity study and/or pharmacodynamics study

3. Clinical comparability study

PK/PD study, efficacy and safety, immunogenicity.

Comparative PK/PD studies may be appropriate to demonstrate similar efficacy of the Biosimilars and the RBP in cases:

- PK and PD properties of the RBP are well characterized;

- at least one PD marker is a marker linked to efficacy;

- the relationship between dose/exposure, the relevant PD marker(s) and response/efficacy of the RBP is established.

Comparability Exercises for Biosimilar Products

Reference product

Originator product approved in Indonesia

If no approved originator products

Originator product that has been approved in country/ies with established evaluation system & Never rejected in

Indonesia

If the originator product no longer produced

The most established biotherapeutic product which has been approved based on full Q, S, E evaluation & has

been marketed without any Q, S, E issues

Originator product Biotherapeutic product that was firstly developed by the manufacturer and having MA based on full quality, safety,

and efficacy data and having patent

Indonesia General Guideline on Evaluation of Biosimilar Products

Imported biosimilar products

Development process was under supervision of the NRA of country

of origin

Required final development

dossier

Quality

Non-clinical

Clinical

Co

mp

ara

bil

ity D

ata

Registration of a Biosimilar Products (1)

Locally manufactured biosimilar products

Development process will be under supervision of BPOM / NADFC

Evaluation data through IND like system: step wise approach with expert consultation on each stage of

development

Comparability Clinical study can only be conducted if comparability on quality and non clinical data are

considered appropriate and adequate.

Protocol of clinical study should be approved by ethical committee and BPOM / NADFC

Registration of a Biosimilar Products (2)

Challenges

• High Quality Decision: Predictability, Transparency, Timeliness, Scientific basis, Consistency, Clarity

• New technology achievement

• Handling and resolve Counterfeiting Drugs

• Encourage local pharmaceutical manufacturer to produce locally, rather than import drug.

• Various interpretation on the regulation

• Different registration requirements in importing countries

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The Way Forward

- Increase competency of evaluators - Compliance with Current international guideline as a

reference for evaluation - Maintain implementation of QMS - Improve communication with stakeholders - Facilitate local biologicals development - Continuous improvement of existing regulation - E-registration for new drug application Transparency of the evaluation process Tracking system of the review process Paperless Expedited application process by online dossier

submission and multiplatform (using multi device)

Kamsahamnida Thank You

Terima kasih

Questions are welcome...!