05_Basic Understanding of Medicinal Product Registration

7/29/2019 05_Basic Understanding of Medicinal Product Registration

1/39


2/39

All Rights Reserved 2008 Health Sciences Authority | 2

Basic Understanding ofBasic Understanding of

Drug RegistrationDrug Registration

Dr Lou Huei-XinDeputy Director

Clinical Regulatory UnitPharmaceuticals & Biologics Branch

Therapeutic Products DivisionHealth Products Regulation Group

7 November 2008


3/39


OverviewOverview Drug Registration Development

Pre-market Risk Assessment Legislative Framework

New Licence Type

Evaluation Route Registration Proces

Post Approval Variation

Data Protection and Exclusivity Patent Declaration

Responsibilities of the Applicant


4/39


Our MissionOur Mission

To safeguard public health

To wisely regulate health products


5/39


Safeguard Public HealthSafeguard Public Health

Pre-marketing evaluation to ensurethat medicinal products marketed inSingapore meet appropriate standards

of quality, safety and efficacy

Post-marketing surveillance and

monitoring (Pharmacovigilance Unit)


6/39


Drug Registration System and Standards:Drug Registration System and Standards:

Development Over the YearsDevelopment Over the Years

1987 1991 2004

Implementation

of DR system

ImplementationPhase

StrengtheningPhase

HarmonisationPhase

Strengthening of DR requirements

Strengthening of drug evaluation

capabilities

Enhancing flexibility, clarity and

robustness of DR process

Increasing communication

between MOH/HSA and

stakeholders

Enhancing strategic alliances and

leveraging on work done by

mature and developed agencies

Implementation of

Quality Medicines

Harmonisation

Programme

Ongoing efforts to

strengthen

capabilities,communication with

stakeholders and

strategic alliances

HSA formed

in Apri l 2001


7/39


PrePre--Market Risk AssessmentMarket Risk Assessment

To determine the risk vs benefit profile ofmedicines in the local context

Risk Benefit


8/39


PrePre--Market Risk AssessmentMarket Risk Assessment

Risk-based Assessment

Application of current international scientific

standards and guidelines including ICHguidelines

Inherent risk of product (ingredient, route ofadministration, etc)

Confidence based on prior approval byreference agencies

Enhanced efficiency by leveraging onevaluations conducted by reference agencies

5 reference agencies: US FDA, EMEA, AustraliaTGA, Health Canada, UK MHRA


9/39


Legislative FrameworkLegislative Framework

Medicine Act (Chapter 176)Medicine Act (Chapter 176)

Medicine (Advertisement and SaleMedicine (Advertisement and SaleAct (Chapter 177)Act (Chapter 177)

Poisons Act (Chapter 234)Poisons Act (Chapter 234)

Sale of Drugs Act (Chapter 282)Sale of Drugs Act (Chapter 282)

Misuse of Drugs RegulationsMisuse of Drugs Regulations

subsidiary legislation under thesubsidiary legislation under the

Misuse of Drugs Act (Chapter 185)Misuse of Drugs Act (Chapter 185)

Health Product ActHealth Product Act


10/39


Legal requirements under theLegal requirements under the

Medicine Act were implemented sinceMedicine Act were implemented since

19871987

To ensure that medicinal productsTo ensure that medicinal products

marketed in Singapore meetmarketed in Singapore meet

appropriate standards of safety,appropriate standards of safety,efficacy and qualityefficacy and quality

Legislative FrameworkLegislative Framework


11/39


Medicinal ProductMedicinal Product

Under the Medicines Act, a medicinal product refers

to any substance or article (not being aninstrument, apparatus or appliance) which ismanufactured, sold, supplied, imported orexported for use wholly or mainly in the

following ways: use by being administered to one or more

human beings for a medicinal purpose;

and/or,

use as an ingredient in the preparation of asubstance or article which is to be administeredto one or more human beings for a medicinalpurpose.

P8


12/39


Medicinal PurposeMedicinal PurposeUnder Medicine Act, medicinal purpose means any one

or more of the following purposes:

treating or preventing disease;

diagnosing disease or ascertaining the existence,degree or extent of a physiological condition;

contraception;

inducing anaesthesia; and/or,

otherwise preventing or interfering with the normaloperation of a physiological function, whether

permanently or temporarily, and whether by way ofterminating,

reducing or postponing, or increasing oraccelerating, the operation of that function or in anyother way.

P8


13/39


Under Medicine Act, ProductUnder Medicine Act, Product LicenceLicence isisrequired before a medicinal product can berequired before a medicinal product can be

sold or supplied in Singapore (Medicine Act,sold or supplied in Singapore (Medicine Act,section 5)section 5)

ProductProduct LicenceLicence is specific to productis specific to product Of a particular nameOf a particular name

With a particular formulationWith a particular formulation

In a particular dosage formIn a particular dosage form (i.e. physicalpresentation) and strength; a n d

With a particular set of approvedWith a particular set of approvedindications and directions for useindications and directions for use

Legislative FrameworkLegislative Framework P8


14/39


Legislative RestructuringLegislative Restructuring

H e a l t h P r o d u c t s A c t

To consolidate medicines control laws

Modular approach more responsive &flexible to deal with different degrees of risk

Covers regulation of health products,dealers obligations and more appropriatepenalties

Opportunity to review process and licensingrequirements


15/39


New ProductNew Product LicenceLicence

In applying for aIn applying for a n ewn ew Product LicenceProduct Licencefor a medicinal product in Singapore,for a medicinal product in Singapore,

there are two types of applications:there are two types of applications:

a new drug application (NDA)a new drug application (NDA)

a generic drug application (GDA)a generic drug application (GDA)


16/39


Types of NDAs

Su b s e q u e n t strength(s) of an innovator product that has beenregistered or has been submitted as an NDA-1 or NDA-2. Theproduct name and pharmaceutical dosage form shall be thes a m e as that for the NDA-1 or NDA-2.

NDA-3

F i r s t strength of an innovator product

containing a new* combination of registeredchemical/biological entities;

containing registered chemical/biological entity(ies) in anew dosage form;

containing registered chemical/biological entity(ies) for use

by a different route of administration a n dmarketed under adifferent product name; or,

containing registered chemical/biological entity(ies) for newindication(s), dosage recommendation(s) and/or patientpopulation(s) a n dmarketed under a different product name.

NDA-2

F i r s t strength of an innovator product containing a new *chemical entity or a biological entity.

NDA-1

has not been registered for medicinal use in Singapore

P8


17/39


Types ofTypes ofGDAsGDAs

Subsequent strength(s) of the genericproduct that has been registered or hasbeen submitted as a GDA-1. The productname and pharmaceutical dosage form shallbe the same as that for the GDA-1

GDA-2

Firststrength of a generic product.GDA-1

Generic Drug Application for a product that is

e ss e n t i a l l y s im i la r to a currently registeredproduct in Singapore (not applicable to biologics).

P9


18/39


Evaluation Route forEvaluation Route for

New Drug ApplicationsNew Drug Applications

Since 2003, HSA offers 3 evaluationSince 2003, HSA offers 3 evaluation

routes which allow companies toroutes which allow companies to

opt for the route that most meetopt for the route that most meettheir needs.their needs.


19/39


Evaluation Routes For NDAsEvaluation Routes ForEvaluation Routes For NDAsNDAs

Product

approved by onedrug regulatory

agency

Verification based on full

assessment report by

reference regulatory agency.

Full

Abridged

VerificationProduct approved

by two reference

agencies

No prior

approval by any

country

Target

Timeline: 60

working days

Pre-submission

consultation

Full quality, non-clinical, &

clinical data.

Target Timeline:

270

working days

Full quality data and

Phase II & III clinical data.

Target Timeline:

180

working days


20/39


Dossier Types For NDAsDossier Types ForDossier Types For NDAsNDAs

1. Full Dossier

applies to a medical product that has n o tbeenapproved by a n ycompetent drug regulatory agencyat the time of submission for registration to HSA

2. Abridged Dossier

applies to a medical product that has been evaluatedand approved by at least one competent drugregulatory agency

3. Verification Dossier applies to a medicinal product that has been

evaluated and approved by at least two of HSAsreference drug regulatory agencies

1. Full Dossier

applies to a medical product that has n o tbeenapproved by a n ycompetent drug regulatory agencyat the time of submission for registration to HSA

2. Abridged Dossier

applies to a medical product that has been evaluatedand approved by at least one competent drugregulatory agency

3. Verification Dossier applies to a medicinal product that has been

evaluated and approved by at least two of HSAsreference drug regulatory agencies

P9,10


21/39


Dossier FormatDossier FormatDossier Format

ICH CTD

Module 1: Administrative

Module 2: Overview & overall summariesModule 3: Quality

Module 4: Non-clinical

Module 5: Clinical

ASEAN CTD

Part I: Administrative

Part II: QualityPart III: Non-clinical

Part IV: Clinical

Optional format: ICH CTD or ACTD

Dossier must conform with chosen format and documentary requirements

Applicable to all evaluation routes

T h e CTD f o r m a t c a n n o t b e c h a n g e d o n c e t h e a p p l ic a t i o n i s a p p r o v e d . A n y s u b s e q u e n t v a r i a t i o n a p p l i ca t i o n s f o r t h e p r o d u c t w o u l d n e e d t o f o l l o w t h e s a m e f o r m a t . An

electronic copy of the complete CTD dossier is to be submitted with the application i.e. Modules 1 to 5 of the ICH CTD or Parts 1 to 4 of the ACTD. Applicants are

responsible to ensure that the e-copies e.g. scanned documents of the dossier arelegible.

P9,10


22/39


Dossier RequirementsDossier RequirementsFull

1. Chemistry &

manufacturingcontrol data

2. Biopharmaceuticstudy reports

3. PK study reports

4. PD study reports

5. Toxicology reports

6. Clinical studyreports (Phase I,II, III)

7. Post-marketingreports (ifapplicable)

Abridged

1. Chemistry &

manufacturingcontrol data

2. Summaries(biopharmaceutics,PK, PD, toxicology,efficacy, safety)

3. Clinical studyreports(Phase II & III)

4. Post-marketingreports or study

report(Phase IV, ifapplicable)

Verification

1. Chemistry &

manufacturing controldata

2. Summaries(biopharmaceutics,PK, PD, toxicology,efficacy, safety)

3. Clinical study reports(Phase II & III)

4. Post-marketingreports or studyreport

(Phase IV, ifapplicable)

5. Assessment reportfrom reference agency


23/39


PRE-SUBMISSION

PREPARATIONS

APPLICATION

SUBMISSION

APPLICATION

SCREENING

APPLICATION

EVALUATION

REGULATORY

DECISION

NON-

ACCEPTANCE /WITHDRAWAL

ACCEPTANCE

Registration Process fora Medicinal Product


24/39


Post Approval VariationsPost Approval VariationsPost Approval Variations

Throughout the life cycle of a medicinal

product, changes to a products efficacy,quality and/or safety are likely to occur.

HSA must be notified of any changes to a

products safety, efficacy or quality through anapplication process i.e. the variationapplication.

There are two types of variation applications:major variation application (MAV) and minorvariation application (MIV).

Throughout the life cycle of a medicinal

product, changes to a products efficacy,quality and/or safety are likely to occur.

HSA must be notified of any changes to a

products safety, efficacy or quality through anapplication process i.e. the variationapplication.

There are two types of variation applications:major variation application (MAV) and minorvariation application (MIV).


25/39


A change in current approved forensicclassification, also known as reclassification.

MAV-2

Any variation to the approved indication(s),dosing regimen(s), patient group(s), and/orinclusion of clinical information extending the

usage of the product (e.g. clinical trial informationrelated to an unapproved indication, dosingregimen and/or patient population; additionalbacterial strains for antimicrobial products).

MAV-1

Major Variation application for an existing registered

product.

Types of MAVsTypes ofTypes ofMAVsMAVs P52


26/39


Types of MIVsTypes ofTypes ofMIVsMIVs

A minor variation or an administrative change,which does not require regulatory approval; i.e.notification.

MIV-2

A minor variation, which requires regulatoryapproval.

MIV-1

Minor Variation application for an existing registered

product

P52


27/39


Evaluation Routes For MAVsEvaluation Routes ForEvaluation Routes For MAVsMAVs

Product

approved by onedrug regulatory

agency

Verification based on full

assessment report by

reference regulatory

agency..

Full

Abridged

VerificationProduct approved

by two reference

agencies

No prior

approval by any

country

Pre-submission

consultation

Full non-clinical, & clinical

data.

Target Timeline:

270

working days

Full Phase II & III clinical

data.

Target Timeline:180

working days

Target Timeline:

60

working days


28/39


TARGET PROCESSING TIMELINESTARGET PROCESSING TIMELINES

P67


29/39


Data Protection & ExclusivityData Protection & Exclusivity

Legal provision

Medicine Act Section 19A and 19B

a Effected in 1998 to comply with TRIPS Articlea Protection of confidential supporting information

about innovative medicinal product againstdisclosure and unfair commercial use

a Protected period: 5 years from the date ofreceipt of an application

P62


30/39



Legal provision

Medicine Act Section 19D

Effected in 2004 to comply with US-S FTAArticle 16.8.1

No product licence to be granted on the basis ofprevious grant

Relate to safety and efficacy information provided byapplicant for earlier product licence

Data exclusivity period: 5 years from date of grant ofearlier product licence


31/39



Approval of application based on safetyand efficacy of an earlier approval can onlybe granted after expiration of the dataexclusivity period

Applications riding on safety and efficacydata of an earlier approval may be

submitted 18 months before the expirationof the 5-year data exclusivity period


32/39


Patent LinkagePatent Linkage

Legal ProvisionsLegal Provisions

Medicine Act Sections 12AMedicine Act Sections 12A Effected in 2004 to comply with USEffected in 2004 to comply with US--A FTA ArticleA FTA Article

16.8.4(n), (c)16.8.4(n), (c)

Patent declaration and notification of patent proprietorPatent declaration and notification of patent proprietor

Medicine Act Section 16(1B)Medicine Act Section 16(1B) Provision of revocation of productProvision of revocation of product licencelicence related torelated to

patent infringement and declarationpatent infringement and declaration

Medicine (Licensing, Standard Provisions & Fee)Medicine (Licensing, Standard Provisions & Fee)RegulationRegulation

Regulation 5BRegulation 5B Declaration, notice and prescribed periodDeclaration, notice and prescribed periodunder section 12A of the Actunder section 12A of the Act

66thth Schedule, Part ISchedule, Part I Form for Declaration on PatentForm for Declaration on PatentInformation for Application for productInformation for Application for product licencelicence

66thth Schedule, Part IISchedule, Part II Template for Notice to ProprietorTemplate for Notice to Proprietorof Patentof Patent

P62


33/39


Patent DeclarationPatent Declaration

Is required for each new drug application (NDA, GDA)

Hard copy of the completed form with originalsignature of person authorised to make thedeclaration on behalf of the applicant and thecompany stamp of the applicant must be submitted

Patent declaration form needs to be submitted twicein original: at the time of dossier submission and priorto issuance of the Product Licence

The authorised person is ordinarily an officer of thecompany such as a director or the company secretary


34/39


Evidence of AuthorisationEvidence of Authorisation For companies with a Board of Director,

authorisation in the form of Board Resolution orArticle of Association is needed

The validity period of the Board Resolution or

Article of Association depends on how thedocument is worded

For single director company, the company directorwould be considered the authorised person withproof from ACRA stating the name of the directorconcerned


35/39


Responsibilities Of The ApplicantResponsibilities Of The Applicant

a) Ensure that all particulars given in the application form and

supporting documents are true and valid, and that all currentdata, reports and information relevant to the benefit/riskassessment of the medicinal product have been supplied atthe time of the application submission;

b) Ensure that all information and material included in theapplication dossier on paper exactly matches the informationand material included in the electronic submission dossier.No information has been added, removed, or changed;

c) Declare at the time of submission to HSA that the application

as submitted to HAS or similar directions of use includingindications have not been rejected, withdrawn from,approved via appeal process or pending deferral by anycompetent regulatory agency, with reasons in each case ifapplicable;

P63-4


36/39


Responsibilities Of The ApplicantResponsibilities Of The Applicantd) Notify HSA if the application as submitted to HSA or if

similar directions of use including indications have beenrejected, withdrawn or deferred by any competentregulatory agency, with reasons in each case if applicable,throughout the products life cycle in the Singapore market;

e) Notify HSA of any change in the particulars submitted in theapplication and of any new significant safety information

during the course of evaluation and throughout theproducts life cycle in the Singapore market;

f) Respond to HSAs queries on data submitted or requests formore data for review, within timelines stipulated by HSA;

g) Ensure that the product will be sold, supplied andrecommended for use in accordance with the approvedPI/PIL and in compliance with all licence conditions,applicable legislation and guidelines;


37/39


Responsibilities Of The ApplicantResponsibilities Of The Applicanth) Notify HSA of any manufacturing change(s) to the products

quality, efficacy or safety throughout the products life cycle inthe Singapore market;

i) Notify HSA if the products marketing authorisation iswithdrawn in any country, with the reasons in each case,throughout the products life cycle in the Singapore market;

j) Notify HSA if the product is no longer registered by any othercountry, throughout the products life cycle in the Singaporemarket; and,

k) Ensure that all information provided to HSA is true and correct

to the best of his/her knowledge and that he/she has notwilfully suppressed any material fact. The applicant is awarethat if he/she makes any false statement, representation ordeclaration in connection with an application submitted toHSA, he/she shall be guilty of an offence under the MedicinesAct (Chapter 176).

Overview of Medicinal Product Registration ProcessOverview of Medicinal Product Registration Process


38/39

Overview of Medicinal Product Registration ProcessOverview of Medicinal Product Registration ProcessP r o d u c t R e g i s t r a t i o n

Is product

registered with any

competent agency?

IS PRODUCT

REGISTERED IN

SINGAPORE?

NO

Essentially similar to

a currently registered

product?

YES

YES

Firststrength of

product?

GDA 1

GDA 2NO

YES

NDA 1

Contains new

chemical/

biological entity?NO

NO

YES

Change in safety,

efficacy or quality

aspect?

MAJOR

VARIATION

MINOR

VARIATION

MAV-1

Approved by at least two of

HSAs reference agencies?

NO

FULL

DOSSIER

YES

ABRIDGED

DOSSIER

NO

YES

VERIFICATION

DOSSIER*MAV-2 MIV-1 MIV-2

Po s t

A p p r o v a l

C h a n g e s

NDA 2

NDA --3


39/39


Thank You

05_Basic Understanding of Medicinal Product Registration

Documents

Transcript of 05_Basic Understanding of Medicinal Product Registration