The Common Technical Document

CTD
April 8, 2019
Rashid Mahmood
Plant Manager, Dyson Research Laboratories
(Pvt.) Limited
 Abbreviations

 HA: Health Agencies

 ICH: International Conference on
Harmonization
 CTD: Common Technical Document
 EFPIA: European Federation of Pharmaceutical
Industries and Associations
 MHLW: Ministry of Health, Labor and Welfare
Japan
 Abbreviations

 JPMA: Japan Pharmaceutical Manufacturers

Association
 FDA: Food and Drugs Administration
 PhRMA: Pharmaceutical Research and
Manufacturers of America
 EFTA: European Free Trade Area
 IFPMA: International Federation of
Pharmaceutical Manufacturers Associations
 Abbreviations
 ISS: Integrated summaries of safety
 ISE: Integrated summaries of effectiveness
 CPMP: Committee for Proprietary Medicinal
Products
 CMC: Chemistry, Manufacturing &
Control
 TSE: Transmissible Spongiform
Encephalopathy
 BSE: Bovine Spongiform Encephalopathy
 Topics
 What is ICH?
 Who is ICH?
 ICH Guidelines
 What is CTD?
 Applicability and Implementation of CTD
 CTD Structure
 What’s New with CTD?
 Benefits of CTD
 What is ICH?
(International Conference on Harmonization)
 An Agreement between EU, Japan, and US
 Joint Initiative between HA Regulators and
Industry
 System of Steering Committee and Expert
Working Groups
 Defined Process for Implementation of
agreements in ICH regions
 ICH Mission
 “A more economical use of
– human, animal and material resources,
– and the elimination of unnecessary delay in the
– global development and availability of new
medicines
– whilst maintaining safeguards on
– quality, safety and efficacy, and regulatory
obligations
– to protect public health.”
 ICH Mission

 “A more economical use of human, animal

and material resources, and the elimination
of unnecessary delay in the global
development and availability of new
medicines whilst maintaining safeguards on
quality, safety and efficacy, and regulatory
obligations to protect public health.”
 ICH Parties
 European Commission - European Union
 European Federation of Pharmaceutical Industries
and Associations (EFPIA)
 Ministry of Health, Labor and Welfare (MHLW) -
Japan
 Japan Pharmaceutical Manufacturers Association
(JPMA)
 US FDA
 Pharmaceutical Research and Manufacturers of
America (PhRMA)
 ICH Observers
 WHO
 European Free Trade Area (EFTA)
– represented at ICH by Switzerland
 Canada
– represented at ICH by Health Canada
 ICH Secretariat managed by International
Federation of Pharmaceutical Manufacturers
Associations (IFPMA) to ensure contact with
industry outside ICH region
 ICH Topics
(Q S E M)
 Q = QUALITY Topics
– those relating to chemical and pharmaceutical Quality
Assurance
 S = SAFETY Topics
– those relating to in vitro and in vivo preclinical studies
 E = EFFICACY Topics
– those relating to clinical studies in human subjects
 M = Multidisciplinary Topics
 ICH Guidelines

 E1: The Extent of Population Exposure to Assess

Clinical Safety
 E3: Structure and Content of Clinical Study
Reports
 E5: Ethnic Factors in the Acceptability of Foreign
Clinical Data
 E6: Good Clinical Practice (GCP)
 Q7: GMP for Active Pharmaceutical Ingredients
 Multidisciplinary ICH Topics

 M1 = Medical Terminology
 M2 = Electronic Standards for Transmission
of Regulatory Information
 M3 = Timing of Preclinical Studies in
Relation to Clinical Trials
 M4 = The Common Technical Document
 ICH Process
 Step 1 - Consensus Building
– Sign off by Expert Working Group members
 Step 2 - Start of Regulatory Action (and
testing)
 Step 3 - Regulatory Consultation (Draft
guidance)
 Step 4 - Adoption of a Tripartite (three
parties) Harmonized Text
 Step 5 - Implementation
 What is the Common Technical
Document?
CTD is
– an agreed format for common organization of
documents in regulatory applications.
CTD is not
– a common content for all markets.
As always, content is data and label
driven for a given market.
 What does CTD specify?

 The intention of the CTD format is to save

time and resources and to facilitate
regulatory review and communication
 CTD guidance gives NO information about
the content of a dossier and does not
indicate which studies and data are required
for a successful application.
 Content guidelines distinct from CTD
 Why a common format?

 CTD concept provides a common format to:

 allow each HA to find supporting
information they need for their assessment
(consistency of scientific content)
 show approach to scientific development
plan and assess quality of design, study
performance, and compliance
 Applicability of CTD

 The CTD was designed to apply to all categories

of medicinal products, including
– drugs
– biologics
– generics
– herbals
– radiopharmaceuticals
– vaccines
 Applies to all types of applications (stand alone
and abridged)
 CTD through the ICH Process
 Step 1: Consensus Building
– presented to ICH Steering Committee March 1996

 Step 2: Start of Regulatory Actions

– Dates not known
 Step 3: Regulatory Consultation
 Step 4: Adoption
– Endorsed by the ICH Steering Committee October 2000
 Step 5: Implementation
– Ongoing in ICH regions
 Implementation of CTD
(ICH Step 5)
 July, 2001 Optional EU
Japan
US
 July, 2003 Mandatory EU
Mandatory Japan
Highly Recommended US
 Oct, 2018 Mandatory Pakistan
 Implementation of CTD
(ICH Step 5)
 DRA Pakistan named it as Form 5-F
(Common Technical Document) vide
S.R.O. 713(I)/2018 dated 08.06.2018 and
proposed to be implemented by 08.12.2018
but extended twice to be effective from
Mar/2019
 Region-specific requirements
 Module 1 (all)
– regional administrative information (forms), labeling,
Environmental Risk Assessment, signature of experts...
 Module 3 (3.2R and 2.3R summary)
– US: Method validation package, comparability protocols
– US and Canada: Executed batch records
– EU: Process validation scheme for drug product, medical device
 Module 5 (no location specified)
– ISE, ISS and case report forms if required by FDA
– tabulated list of trial subjects if required by MHLW
 Making a CTD Submission

 Submission format as defined by M4 is

paper
 Electronic applications before July ‘03 must
be hybrid based on “old” electronic
guidelines with CTD pieces mapped in
 Electronic CTD guidance is separate and
lags behind CTD for definition and
implementation
 CTD Structure

Full dossier contains 5 “Modules”

– Only Modules 2 - 5 are “CTD”
 Module 1 - region-specific but always
included in complete CTD structure
 Module 2 - All summaries/overviews
 Module 3 - CMC (“Quality”)
 Module 4 - Preclinical
 Module 5 - Clinical
 Module 1
(Administrative)
 Cover Letter and Fee Deposit Slip
 Table of Contents from Module 1 -5
 Applicant Information:
– (Name, address and contact details of Applicant /
Marketing Authorization Holder)
 Type of Application:
1. Application for registration of
• New Drug Product (NDP)
• Generic Drug Product (GDP)
2. Type of Market
• Domestic
• Export
• Both
 Module 1
(Administrative)
3. For imported products, please
specify one of following:
Finished Pharmaceutical Product
Import Authorization
Bulk Import and local repacking
(specify status of bulk).
Bulk Import Local Repacking for
Export purpose only.
 Module 1
(Administrative)
4. Contract Manufacturing as per Rule 20-A of
Drugs (Licensing, Registering and
Advertising) Rules, 1976.
Domestic Manufacturing.
Export Purpose Only.
 Detailed Information of Drug, Dosage form
and Labeling Claim.
 Miscellaneous Information
 Module 2 (CTD Summaries)
 2.1 Overall CTD Table of contents (ToC)
 2.2 CTD Introduction
 2.3 Quality Overall Summary
 2.4 Non-Clinical Overview
 2.5 Clinical Overview
2.4-2.7 EXMPTED
 2.6 Non-Clinical WrittenFOR GDP
and Tabulated
Summaries
 2.7 Clinical Summary
 2.2 CTD Introduction

 General introduction to the pharmaceutical,

including
– pharmacologic class
– mode of action
– proposed clinical use

Typically would take 1 page only

 2. 3 Quality Overall Summary -
Content
 A summary that follows the scope and
outline of the Body of Data in Module 3
 Emphasize and discuss critical key
parameters of the product
 Discuss key issues to integrate information
from Module 3 and other modules
Typically would take 40 pages excluding
tables, figures
 2. 3 Quality Overall Summary -
Format
 2.3 Introduction S = Substance
 2.3.S Drug Substance P = Product
A = Appendices
 2.3.P Drug Product
R = Regional
 2.3.A Appendices
 2.3.R Regional Information
2. 4 Nonclinical Overview - Content
 An integrated and critical assessment of the
pharmacologic, pharmacokinetic, and toxicologic
evaluation
 Discuss relevant guidance, and any deviations
from guidance should be discussed and justified
 Nonclinical testing strategy should be justified,
including GLP status of submitted studies
 Discuss associations with quality characteristics,
clinical trial results, effects with related products

Typically would take 30 pages

2. 4 Nonclinical Overview - Format

 2.4.1 Overview of Nonclinical Testing Strategy

 2.4.2 Pharmacology
 2.4.3 Pharmacokinetics
 2.4.4 Toxicology
 2.4.5 Integrated Overview and Conclusions
 2.4.6 List of Literature Citations
 2. 5 Clinical Overview - Content
 Highest level summary and analysis of clinical
data and overall clinical development plan
 Overview of the clinical part of the dossier with
succinct (Brief and Clear) discussion and
interpretation
 Critical analysis of clinical data for efficacy and
safety, as well as other relevant information (e.g.
pertinent animal data or quality issues

Typically would take 30 pages

 2.5 Clinical Overview - Format

 2.5.1 Product development rationale

 2.5.2 Overview of Biopharmaceutics
 2.5.3 Overview of Clinical Pharmacology
 2.5.4 Overview of Efficacy
 2.5.5 Overview of Safety
 2.5.6 Benefits and Risks Conclusions
 2.5.7 References
 2.6 Nonclinical Written and
Tabulated Summaries - Content
 Integrated information across studies and across
species
 Primarily text, with examples of tables and figures
 Exposure in test animals should be related to
exposure in humans given maximum intended
doses
 Age, gender, and metabolite-related effects
 In vitro studies first, then in vivo
 Ordered by species, route, duration
Typically would take 100-150 pages
 2.6 Written and Tabulated
Summaries - Format
 2.6.1 Introduction
 2.6.2 Written Summary of Pharmacology
 2.6.3 Tabulated Summary of Pharmacology
 2.6.4 Written Summary of Pharmacokinetics
 2.6.5 Tabulated Summary of Pharmacokinetics
 2.6.6 Written Summary of Toxicology
 2.6.7 Tabulated Summary of Toxicology
 2. 7 Clinical Summary - Content

 Provides factual summary and support for

conclusions and critical issues identified in
the Clinical Overview
 Comparison of results across studies with
integration of clinical information
 Analysis of all relevant information for
dosing recommendations

Typically would take 50-400 pages excluding tables

 2.7 Clinical Summary - Format

 2.7.1 Summary of bio-pharmaceutic studies

and associated analytical methods
 2.7.2 Summary of clinical pharmacology
(including clin micro characterization studies)
 2.7.3 Summary of clinical efficacy
 2.7.4 Summary of clinical safety
 2.7.5 References
 2.7.6 Synopses of individual studies
 Clinical Overview vs
Clinical Summary
 Clinical Overview (2.5):
– critical analyses of efficacy, safety, and benefit/risk
– links the dossier with the label
– links all aspects of the development program
 Clinical Summary (2.7):
– comprehensive factual summary of all relevant data,
including cross study analyses and post-marketing
experience
– includes references and synopses of clinical studies
 Module 3
(Quality)
 3.2 S Drug Substance
 3.2.S.1 General Information
 3.2.S.2 Manufacture
 3.2.S.3 Characterization
 3.2.S.4 Control of Drug Substance
 3.2.S.5 Reference Standard
 3.2.S.6 Container Closure System
 3.2.S.7 Stability
3.2.S 2.3, 3.4, 3.5 & 3.6 EXEMPTED for GDP
 Module 3
(Quality)
 3.2. P Drug Product
 3.2. P.1 Description and composition of Drug
Product
 3.2. P.2 Pharmaceutical Development
 3.2. P.3 Manufacture
 3.2. P.4 Control of excipients
 3.2. P.5 Control of Drug Product
 3.2. P.6 Reference Standard
 3.2. P.7 Container Closure System
 3.2. P.8 Stability
 Module 3
(Quality)
 3.2. A Appendices
 3.2. A.1 Facilities and Equipment
 3.2. A.2 Adventitious Agents Safety
Evaluation
 3.2. A.3 Excipients
 3.2. R Regional Information
 3.2.R.1 Production Documentation
 3.2.R.2 TSE Checklist with required
supporting documents
 3.2.R.3 Product Interchangeability
(Bioequivalence Study Reports)
3.2 P.2 Pharmaceutical Development
 Pharmaceutical Development
The aim of pharmaceutical development is to design a
quality product and its manufacturing process to
consistently deliver the intended performance of the
product.
 Objective of the Guideline:
 This guideline describes the suggested contents for the
3.2.P.2 (Pharmaceutical Development) section.
 This section provides an opportunity to present the
knowledge gained through the application of scientific
approaches and quality risk management.
3.2 P.2 Pharmaceutical Development
 Scope:
 Designed quality product and its manufacturing process
during pharmaceutical development.
 Does not apply on drug product during clinical research
stages.
 Scientific understanding to establish design space,
specification and manufacturing control.
 Quality can not be tested, it should be built in by design.
 Control strategies and critical aspects of product quality
should be justified.
 Choose to conduct Pharmaceutical Development studies
that can lead enhance knowledge of product performance.
3.2 P.2 Pharmaceutical Development
Components of the Drug Product
Drug Substance
 The physicochemical and biological
properties of the drug substance that can
influence the performance of the drug product
and its manufacturability, were specifically
designed into the drug substance.
 Excipients
The excipients chosen, their concentration,
and the characteristics that can influence the
drug product performance
3.2 P.2 Pharmaceutical Development
Drug Product:
Formulation design and development.
Overages should be justified.
Physicochemical and biological properties.
Manufacturing process development.
Container-closure system.
Microbiological attributes.
Compatibility
 Elements of Pharmaceutical
Development
 Quality Target Product Profile
(Intended use in clinical setting, route of administration,
dosage form, delivery systems; Dosage strength(s);
Container closure system;)
 Critical Quality Attributes
(e.g. those effect product quality generally associated with
the drug substance, excipients, intermediates (in-process
materials) and drug product.)
 Risk assessment
(e.g. linking material attributes and process parameters to
drug product)
 Elements of Pharmaceutical
Development
 Design Space
(The relationship between the process inputs (material
attributes and process parameters) and the critical quality
attributes can be described in the design space)
 Control Strategy
(e.g. controlling the source of variability and is designed to
ensure that a product of required quality will be produced
consistently.
 Product Lifecycle Management and Continual
Improvement
 Module 4
(Pre Clinical)
 4.1 Table of Contents
 4.2 Study Reports
 4.2.1 Pharmacological Study Report
 4.2.2 Pharmacokinetics Study Reports
 4.2.3 Toxicology
 4.3 List of Reference Literature

(Note. 4.2.3.3 to 4.2.3.7 are exempted for GDP)

 Module 5
(Clinical)
 5.1 Table of contents
 5.2 Tabular listing of all clinical studies
 5.3 Clinical Study Reports
 5.3.1 Reports of Bio pharmaceutics Studies
 5.3.2 Reports of Studies pertinent to PK using
human Biomaterials
 Module 5
(Clinical)
 5.3.3 Reports of Human PK Studies
 5.3.4 Reports of Human PD Studies
 5.3.5 Reports of Efficacy and Safety Studies
 5.3.6 Reports of Post Marketing Experience
 5.3.7 Case Report Forms and Individual
Patient Listing
 5.4 Literature Reference
 What’s New with CTD?

 Granularity and pagination of documents

within modules and study reports
 Definition of discrete header information
for documents within modules
 Cross referencing between modules
 Confusion about ISS requirement for US
Cross references between modules

 Quality and Nonclinical/Clinical:

– Quality module should include appropriate
reference to modules 4 and 5 for drug substance
and drug product batch information and
formulation development issues
– Process change information should cross
reference reports in modules 4 or 5 that
demonstrate comparability after the process
changes
Cross references between modules

 Nonclinical and Quality:

– Nonclinical overview should address:
• relevance of analytical methods used
• quality characteristics of human drug as relates to
nonclinical findings
• impurities and degradants present in drug substance
and product and what is known of their potential
pharmacologic and toxicologic effects
Cross references between modules

 Nonclinical and Clinical

– Nonclinical overview should include:
• Assessment of limitations and utility of nonclinical
studies for prediction of potential AEs in humans
• associations between nonclinical data and results of
clinical trials
• relevance of pharmacokinetic and nonclinical
models, including derived parameters
• effects seen with related products, metabolites,
excipients
 THANK YOU

QUESTIONS/DISCUSSION?