Jalene_Poh_April26_Parallel_Track_Track3.pdf

Experience and Value of

CTD- Singapore’s Experience

Jalene Poh, Regulatory Consultant

Health Sciences Authority, Singapore

26 April 2011 | Korea

Overview of ACTD and ICH CTD

Implementation of CTD

• Background

• Implementation process

• Challenges

• Follow-ups

Benefits/Value of CTD

• Regulator’s perspective

• Industry’s perspective

• Public / Patients

AGENDA

Drug Information Association www.diahome.org 2

HSA Organisational Structure

HEALTH PRODUCT REGULATION GROUP

ORGANIZATION CHART

(wef 1 Jan 2011)

Pre-marketingVigilance, Compliance &

EnforcementAudit & Licensing

Scientific Advisory

Project Management

Office

Advisors

International Collaboration

Clinical Trials

Pharmaceuticals & Biologics

Generics & Biosimilars

Medical Device

Complementary Health Products

Vigilance

Compliance

Enforcement

Admin , Training & PEDU*

Group Director’s Office

Service Management

Quality Assurance

Office

Tobacco Regulation

Policy, Legislation &

Operations

Division Branch Function

Group Director

Dy. Group Director

Legend

* Pharmacoeconomics & Drug Utilization



• Background


• Challenges

• Follow-ups





AGENDA


The CTD provides a common format for the

preparation of a well-structured submission dossier

It provides a modular framework described in:

• ICH Topic M4 (ICH CTD)

• ASEAN guidelines on the Common Technical Document for

Registration of Pharmaceuticals for Human Use:

Organisation of the Dossier (ACTD)

According to the chosen format, the documents will

be group into:

• 4 parts (ACTD)

• 5 modules (ICH CTD)

Overview of ACTD & ICH CTD



ICH CTD Triangle


The main differences between these two formats are the

numbering and naming of the sections:


8www.diahome.orgDrug Information Association

Documents Location in

ICH CTD ACTD

Administrative Documents & Product Information

Module 1 Part I

Common Technical Document Overview & Summaries

Module 2 Incorporated in Parts II, III and IV

Quality documents Module 3 Part II

Non-clinical documents Module 4 Part III

Clinical documents Module 5 Part IV



• Background


• Challenges

• Follow-ups




• Public / Patient

AGENDA


Start of ASEAN harmonisation of pharmaceutical

product dossier

Revision of drug registration requirements

• Alignment with international requirements to guide and

facilitate review

Implemented use of CTD format in submission

dossier in 2004

• Several companies were already submitting their

registration dossiers in the CTD format prior to its official

implementation in Singapore


Background


CTD format applies to:

New drug applications

Post-approval variation application

• For products whose initial dossier was not in the ACTD or

ICH CTD format, the submission dossier would also need to

be organised in the ACTD or ICH CTD format



Background

Implementation process

• Seminar and dialogue sessions with industry groups were

held to brief industry on new registration requirements

• New initiatives were rolled out in phases

• Companies were given opportunities to clarify issues and

justify for waivers during pre-submission consultations

• Ongoing tracking of implementation issues, and maintained

dialogue sessions with industry

• Transition period prior to official implementation when

voluntary compliance with new data requirements (e.g. API,

BE data) was allowed

• Submission checklists which provide guidance on specific

documentary requirements


Process




Process

Perceived as increased regulatory and documentary

requirements for industry

• Early dialogue sessions (starting in 2003) to prepare

industry for upcoming changes

• Early communications allow companies (and global office)

more time to prepare updated filing dossier format

• Minimize impact on local resource by facilitating

submissions with use of checklists and by improving clarity

of the guidance


Challenges


Internal staff to familiarize and gain in depth

knowledge of the revised requirements

• Attended internal and external trainings including

attachments to other agencies using CTD format

• Experience sharing amongst peers



Challenges

Launch of new guide was followed up shortly with an

online e-filing system in-built with CTD filing format

(PRISM) in June 2004



Follow-Ups

Revised checklists for clarity (Apr 2011)


Follow-Ups




• Background


• Challenges

• Follow-ups





AGENDA


Required information are arranged in a specific

format and sequence which lead to ease of reference

and search of information

Facilitate review process as:

• Reviewers can quickly ascertain which information are

missing

• Required information can be efficiently located

• Communications (e.g. queries) with applicants are made

easier with a common point of reference

• Filing deficiencies can be easily and clearly laid out with

minimal ambiguity


Regulator’s Perspective


Guide evaluators in their review process by

highlighting the information required to support an

application

Allow easy sharing of information and discussions

amongst reviewers



Regulator’s Perspective

Global dossiers are commonly arranged in CTD

format

• Allow local applicants to submit global dossiers instead of

expending time and resources (at both global and local

offices) to prepare a local-specific dossier

• Facilitate earlier submissions with less time spent on

localization of the filing dossier


Industry’s Perspective


CTD format outlines drug registration requirements

and enables filings in a systematic manner

• CTD requirements which are applicable to most regions

help to streamline drug registration processes which in turn

aid in lowering cost of bringing a new product to market

Efficient use of limited resources with the use of a

harmonized dossier e.g. one office can prepare

submissions for several countries in the same

region



Industry’s Perspective

Reduced submission lead time and improved review

process will in turn facilitate early access to

medicinal products for patients

Harmonised technical requirements will help to

ensure standards (quality) of medicinal products

approved across regions are consistent

• Continued public access to safe, efficacious and good

quality essential drugs

Efficient use of resources for drug development and

filing dossier preparations can contribute towards

affordability of medicinal products


Public / Patients


ASEAN CTD:

• http://www.hsa.gov.sg/publish/hsaportal/en/health_products

_regulation/western_medicines/guidelines.html

ICH CTD:

• http://www.ich.org/products/ctd.html

Guidance on Medicinal Product Registration in

Singapore:

• http://www.hsa.gov.sg/publish/hsaportal/en/health_products

_regulation/western_medicines/guidelines.html

References


25

THANK YOU

Practical use of ICH CTD

in facilitating approval

of products by

prequalification

programme and beyond

Dr Lembit Rägo

Coordinator

Quality Assurance and Safety: Medicines

Essential Medicines and Pharmaceutical Policies

World Health Organization

Geneva, Switzerland

[email protected]

WHO has been supportive to CTD

since its beginning

• Promoted CTD but considered local views for

implementation

• CTD full implementation from 2001 when PQP started

was not considered feasible immediately

• Thus, implementation in WHO Prequalification of

Medicines Programme (PQP) has been in phases

– Close to CTD format first

– Since 2010 going to full CTD implementation

New guidelines in 2010

1. “Preparation” guideline: Guideline on submission of

documentation for a multisource (generic) finished

pharmaceutical product (FPP): Preparation of product

dossiers (PDs) in Common Technical Document

(CTD) Format;

2. “Quality” guideline: Guideline on submission of

documentation for a multisource (generic) finished

pharmaceutical product (FPP): Quality part

Background

• Previous generic guideline: “Guideline on Submission

of Documentation for Prequalification of Multi-source

(Generic) Finished Pharmaceutical Products (FPPs)

Used in the Treatment of HIV/AIDS, Malaria and

Tuberculosis” (2005)

• 2005-2011: policy/approaches to assessment change

continually over time due to harmonization efforts,

scientific advances, development of approaches

– e.g. process validation and pharmaceutical

development approaches have changed dramatically

over the past 10 years

New guideline development process

A guideline updated according to current

requirements, and adopting CTD format, was

needed.

• CTD formatting: (crafting of preparation document,

plus formatting of quality document) → initial

draft

• guideline populated with quality technical

guidance

- updated according to current practice

- including additional information on how to meet

the requirements

→ new draft

New guideline development process

• Consultation process with PQP senior assessors plus PQP

applicants (26) → new draft

• External consultation process (formal Expert Committee

circulation)

→ final draft

• Presentation to EC on Specifications for Pharmaceutical

Preparations in October 2010

Currently:

- Preparation of PD guideline adopted (will be presented to WHO

EB in May 2011 and printed after it)

- Quality guideline provisionally accepted for pilot use in PQP

45th Expert Committee on Specifications for

Pharmaceutical PreparationsGeneva, 18-22 October 2010

http://www.who.int/medicines/services/expertcommittees/pharmprep/en/index.html

1.2 Objectives

This guideline is intended to:

• assist applicants on the preparation of PDs for multisource products by providing clear general guidance on the format of these dossiers;

• fully adopt the modular format of the CTD as developed by ICH; and

• provide guidance on the location of regional information (Module 1) and other general data requirements.

1.2 Objectives

This guideline is intended to:

• assist applicants on the preparation of the Quality Module of PDs for multisource products by providing clear general guidance on the format of these dossiers;

• fully adopt the modular format of the Common Technical Document - Quality (M4Q) as developed by ICH; and

• provide guidance on the technical and other general data requirements.

These measures are intended to promote effective and efficient processes for the development of the PDs by applicants and the subsequent assessment procedures by WHO.

Introduction to the two documents

I: The preparation guideline

• Assists applicants with the preparation of product

dossiers (PDs) for multisource/generic products by

providing general guidance on the format of these

dossiers;

• Describes and adopts the modular format of the CTD

as developed by ICH;

• Provides guidance on the location of regional

information (Module 1) and other general data

requirements.

• Primarily addresses the organization of the information,

not the studies required.

Adapting the CTD for new drugs

to CTD for generic drugs

Regional

Admin

Information

Module 1

Nonclinical

Overview

Nonclinical

Summary

Clinical

Overview

Clinical

Summary

Quality

Overall

Summary

QualityNonclinical

Study Reports

Clinical

Study Reports

Module 3 Module 4 Module 5

Module 2

Not Part of

the CTD

The CTD

Introduction to the two documents

II: The quality guideline

This guideline:

• assists applicants with the preparation of the Quality

Module of PDs for multisource/generic products by

providing general guidance on the format;

• adopts the modular format of the CTD

• provides guidance on the technical and other

general data requirements (including preparation of the

quality overall summary – product dossiers (QOS-PD)).

Key changes from the previous

guideline

• CTD format fully adopted

• Updating of requirements

• Elaboration of how to meet quality requirements,

including full elaboration on the three ways to submit

API data:

- CEP

- API Master File (APIMF)

- full API data provided in the dossier

Key changes from the previous

guideline

Reductions in requirements (as they were more stringent

than in ICH regions):

● fewer batches required to establish the FPP shelf-life

● process validation report for pilot batches no longer

required (replaced by uniformity demonstration for the biolot)

● reduced process validation/pharmaceutical development

requirements for “established” generics

FPP batches to support the shelf-life

Complicated FPPs:

● sterile products, metered dose inhaler products, dry

powder inhaler products and transdermal delivery

systems.

● ritonavir/lopinavir FDC tablets and FDCs containing

rifampicin or an artemisinin.

Two pilot batches required

Uncomplicated FPPs e.g. immediate-release solid FPPs

(with noted exceptions), non-sterile solutions

One pilot batch and a second batch which may be

smaller (e.g. for solid oral dosage forms, 25 000 or

50 000 tablets or capsules) are required

Navigating through the quality guideline

Section 1: introductory information

• Text includes bolded ICH M4Q text, and unbolded

additional WHO text

• ICH M4Q text revised to use WHO terminology:

► API/FPP, FDC, PD

► Generally refers to BE instead of clinical batches

• Presentation of the data is described for various

scenarios e.g. multiple APIs, multiple FPP strengths, co-

blistered FPPs, etc.

Quality document: quality summaries

QIS/QOS

Section 3: introduces the Quality information summary

(QIS)/Quality overall summary (QOS)

• The instructions for the QOS-PD (Module 2.3) run

throughout the quality guideline

• Instructions for the QIS (Module 1.4.2) are in Section

3.2 and preface the QIS template

Quality document: Section 4 – module 3

Quality Data Sections

Section 4: QUALITY data in CTD format

Section 4 is divided (according to CTD structure) into:

3.2.S Drug substance (or API), and

3.2.P Drug product (or FPP)

Quality document: Section 4 – module 3

Three options for API information:

1. CEP – PhEur certificate of suitability

2. APIMF – API master file

3. Full details in the PD

Quality Templates: QIS and QOS-PD

QOS-PD = Quality Overall Summary – Product Dossier

The QOS is part of the ICH CTD structure of a product

dossier (PD). Replaces the PQIF (previous quality

template for PQP)

The QOS-PD is based on the CTD QOS,

modified/expanded to be of the most use to WHO

Implementation dates

PDs in CTD format can be submitted now but are optional.

For all PDs submitted after 1 March 2011, the QOS-PD and QIS are mandatory.

CTD format dossiers are encouraged at this time. They are mandatory in PQP after 1 September 2011.

PQP experience in implementing CTD

• The requirements were pretty close to CTD already

before final implementation of CTD was undertaken

• Some applicants asked if they can submit CTD format

dossiers (which were accepted)

• No complaints since full CTD implementation started

• Transition period given - previous format still accepted

until October 2011

PQP experience in implementing CTD

– assessors views

• More difficult to "hide" missing data

• Pushes manufacturers for more mature submissions with

better quality of data

• Better structured format – easier to assess

• Easier to communicate with colleagues in the team, and

beyond

Benefits of the CTD experienced by

Less Resourced NMRAs

• More “reviewable” applications

• Complete, well-organized submissions

• More predictable format

• More consistent reviews

• Easier analysis across applications

• Easier exchange of information with other regulators

(harmonisation) and applicants (deficiency letters)

• Facilitates electronic submissions

Recent African NMRA Experience

Background

• The application forms and guidelines often old with no revisions

• The application forms not in line with current practice

• API information provided scanty, if at all

• No information on product development was provided

• There were many "briefcase" manufacturers that could afford to compile dossiers overnight and submit

• Many applicants based in SRA-regulated countries had to re-organize their applications to simplify the dossier and in some instances excluded key data

Challenges

• Legislation has to be changed and this is a huge task

• Loss of revenue due to reduced number of applications (applications number dropped!)

• Managing the change – stakeholders used to less documentation, less stringent review processes, evaluation capacity

• Involvement of stakeholders in the change process

ICH CTD – implementation workshop

WHO continues to organize and

support CTD implementation trainings

Jalene_Poh_April26_Parallel_Track_Track3.pdf

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