2. If you want to go fast go alone
If you want to go far go together
-African Proverb
2
3. CONTENTS
What is CTD?
Evolution of CTD
Why CTD?
Preparing and organizing the CTD
What is the current status of CTD?
ICH – eCTD
Advantages of CTD
Limitations
Benefits
3
4. ABBREVATIONS
CDSCO: Central Drugs Standard Control
Organization
CTD: Common Technical Document
DCGI: Drug Controller General of India
eCTD: Electronic Common Technical Document
FDA: Food and Drug Administration
ICH: International Conference on
Harmonization
IND: Investigational New Drug application
NDA: New Drug Application
USFDA: US Food and Drug Administration
EMA: European Medicines Agency
4
5. INTRODUCTION
• Substantial documentation and data are
required in submissions for import/manufacture
and marketing approval of drugs for human use,
resulting in large, complex applications.
• Till date, applicants have used many different
approaches in organizing the information and
the differences in organization of data in each
application has made reviewing more difficult
and can also lead to omission of critical data or
analysis.
• Such omissions can result in unnecessary delays
in approvals. Thus, a common format of
submission will help in overcoming these
hurdles.
5
6. WHAT IS CTD ?
Application format
The CTD is a set of specifications for a dossier for
the registration of medicines .
CTD is an internationally agreed “well structured
common format” for the organization of the
technical requirements that is to be submitted to
the regulatory authority as an application for the
registration of pharmaceuticals for human use in all
three ICH regions (U.S.A., Europe and Japan).
6
7. HISTORY
Prior to the advent of the CTD, regulatory reviewers
received an application from one company and spent a
year or more engaged in its review.
When the review was completed, reviewers received the
next application—most likely in a different format—and
had to learn the structure of the new application.
1996- Industry proposed CTD but ICH regulators were
hesitant
disruptive to the review process
Regulators asked industry to do a feasibility study.
That study, conducted in May 1996, evaluated the time it
took to convert an FDA new drug application into an
European Medicines Agency (EMA) submission, and the
reverse.
Regulators quickly saw the potential value of harmonizing
submission formats.
7
8. ORIGIN OF CTD
10
ICH
EWG
CTD
Was officially signed off
In November 2000.
At 10th anniversary of ICH
In san Diego , California
8
9. 1995: Concept of CTD proposed by Industry.
November 2000: ICH CTD guideline finalized.
September 2002: Guideline re-edited with Numbering & Section
Header changes.
Prior to July 2003: Voluntary Submission Phase in 3 ICH Region.
July 1, 2003: Mandatory Requirement in Three ICH Regions.
9
10. 2009: CDSCO Adopted CTD format for Technical requirements for
registration of biological products.
October 28, 2010: CDSCO gave guideline for feedback purpose for
Industry on Preparation of CTD for Import/Manufacture and
Marketing Approval of New Drug for Human Use (i.e., NDA) & ask for
comments and suggestion within 60 days.
This guidance is developed by CDSCO based on,
I. The ICH Harmonized Tripartite Guideline on Organization of the
Common Technical Document for the Registration of
Pharmaceuticals for Human Use. 10
11. OBJECTIVE OF ICH TO PREPARE THE CTD
The primary objective of the ICH is to avoid duplicative animal and human
testing and to reach a common understanding of the technical requirements
to support the registration process in the three ICH regions.
These objectives are achieved through harmonized guidelines and result in a
more economical use of human, animal and material resources, as well as
the elimination of unnecessary delays in the global development and
availability of new medicines, whilst maintaining safeguards on quality, safety
and efficacy, and regulatory obligations to protect public health.
With the development of the Common Technical Document (CTD), the ICH
hopes to accomplish many of its objectives. 11
12. WHY CTD ?
I. To provide a harmonized common format/template for the submission of
technical requirement to the regulatory authorities that is acceptable in all 3
ICH regions.
II. Reduce the time and resources used to compile applications.
III. It will ease the preparation of electronic submissions.
IV. To facilitate simultaneous submission in three regions.
V. To facilitate exchange of regulatory information.
VI. Faster availability of new medicines.
12
13. PREPARING & ORGANIZATION OF CTD
• It is organized into:-
Module 1: General Information
Module 2: CTD summaries
Module 3: Quality
Module 4: Nonclinical study reports
Module 5: Clinical study reports
13
15. MODULE 1 (Administrative Information and
Prescribing Information )
1.0 Cover Letter
1.1 Comprehensive Table of Content
1.2 Application Form
1.3 Product Information
1.3.1 SPC’s, Labelling and Packaging
1.3.2 Mock-Up
1.3.3 Specimen
1.3.4 Consultation with target patient group
1.3.5 SPC’s already approved in the Member states
1.3.6 Braille
15
16. 1.4 Information about the Experts
1.5 Specific Requirements for different types of applications
1.6 Environmental Risk Assessment
1.7 Information relating to Orphan Market Exclusivity
1.8 Information relating to Pharmacovigilance
1.9 Information relating to Clinical Trials
1.10 Information relating to Pediatrics
1.11 Response to Queries
1.12 Additional Data 16
17. MODULE- 2: CTD Summary
2.1 Table of Content (Comprehensive)
2.2 Introduction (general introduction to the pharmaceutical, including its
pharmacology class, mode of action, and proposed clinical use)
2.3 Quality Overall Summary
2.4 Non-clinical Overview
2.5 Clinical Overview
2.6 Non-clinical Written and Tabulated Summaries
2.7 Clinical summary
17
18. 2.4 Non-clinical Overview
2.4.1 Content and Structural Format
2.5 Clinical Overview
2.5.1 Product Development of Content 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 Literature References
18
19. 2.6 Non-clinical Written and Tabulated Summaries
2.6.1 Pharmacology
2.6.2 Pharmacokinetics
2.6.3 Toxicology
19
21. MODULE 3 QUALITY
• 3.1 Table of Contents
• 3.2 Body of Data
* 3.2.S Drug Substance
* 3.2.S.1 General Information
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure
3.2.S.1.3 General Properties
21
22. • 3.2.S.2 Manufacture
3.2.S.2.1 Manufacturer Details
3.2.S.2.2 Description of Manufacturing Process and Process Controls
3.2.S.2.3 Control of Materials
3.2.S.2.4 Controls of Critical Steps and Intermediates
3.2.S.2.5 Process Validation and /or Evaluation
3.2.S.2.6 Manufacturing Process Development
• 3.2.S.3 Characterization
3.2.S.3.1 Elucidation of structure and other Characteristics
3.2.S.3.2 Impurities
22
23. • 3.2.S.4 Control of Drug Substance
3.2.S.4.1 Specification of Drug Substance
3.2.S.4.2 Analytical Procedures
3.2.S.4.3 Validation of Analytical Procedures
3.2.S.4.4 Batch Analyses
3.2.S.4.5 Justification of Specification
• 3.2.S.5 Reference Standards or Materials
• 3.2.S.6 Container Closure System
• 3.2.S.7 Stability
3.2.S.7.1 Stability Summary and Conclusions
3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment
3.2.S.7.3 Stability Data
23
24. • 3.2.PDrug Product
3.2.P.1 Description and Composition of the Drug Product
• 3.2.P.2 Pharmaceutical Development
3.2.P.2.1 Components of Drug Product
3.2.P.2.2 Drug Product
3.2.P.2.3 Manufacturing Process Development
3.2.P.2.4 Container Closure System
3.2.P.2.5 Microbiological Attributes
3.2.P.2.6 Compatibility
24
25. • 3.2.P.3 Manufacture
3.2.P.3.1 Manufacturer
3.2.P.3.2 Batch Formula
3.2.P.3.3 Description of Manufacturing Process and Process Controls
3.2.P.3.4 Controls of Critical Steps and Intermediates
3.2.P.3.5 Process Validation and /or Evaluation
25
26. • 3.2.P.4 Control of Excipients
3.2.P.4.1 Specifications
3.2.P.4.2 Analytical Procedures
3.2.P.4.3 Validation of Analytical Procedures
3.2.P.4.4 Justification of Specifications
3.2.P.4.5 Excipients of Human or Animal Origin
3.2.P.4.6 Novel Excipients
26
27. • 3.2.P.5 Control of Drug Product
3.2.P.5.1 Specification of Drug Product
3.2.P.5.2 Analytical Procedures
3.2.P.5.3 Validation of Analytical Procedures
3.2.P.5.4 Batch Analyses
3.2.P.5.5 Characterisation of Impurities
3.2.P.5.6 Justification of Specification
• 3.2.P.6 Reference Standards or Materials
• 3.2.P.7 Container Closure System
27
28. 3.2.P.8 Stability
3.2.P.8.1 Stability Summary and Conclusions
3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment
3.2.P.8.3 Stability Data
3.2.A Appendices
3.2.A.1 Facilities and Equipment
3.2.A.2 Adventitious Agents Safety Evaluation
3.2.A.3 Novel Excipients
3.2.R Regional Information/ Requirements
3.2.R.1 Process Validation and or Evaluation
3.2.R.2 Medical Device
3.2.R.3 Restricted part of DMF
3.2.R.4 Medicinal products containing or using in the manufacturing process
materials of animal and / or human origin.
3.3 List of Literature References
28
29. MODULE 4 (Non-clinical Study Reports )
• 4.1 Table of contents
• 4.2 Study Reports
• 4.2.1 Pharmacology
4.2.1 Primary Pharmacodynamic
4.2.2 Secondary Pharmacodynamic
4.2.3 Safety pharmacology
4.2.4 Pharmacodynamic drug interactions
29
30. • 4.2.2 Pharmacokinetics
4.2.2.1 Analytical Methods and validation Reports
4.2.2.2 Absorption
4.2.2.3 Distribution
4.2.2.4 Metabolism
4.2.2.5 Excretion
4.2.2.6 Pharmacokinetic Drug Interactions
4.2.2.7 Other Pharmacokinetic studies
30
31. • 4.2.3 Toxicology
4.2.3.1 Single-dose toxicity
4.2.3.2 Repeat-dose toxicity
4.2.3.3 Genotoxicity
4.2.3.4 Carcinogenicity
4.2.3.5 Reproductive and developmental toxicity
4.2.3.6 Local tolerance
4.2.3.7 Other toxicity studies
• 4.3 Literature References
31
32. MODULE 5 (CLINICAL STUDY REPORTS)
• 5.1 Table of Contents
• 5.2 Tabular Listings of All Clinical Studies
• 5.3 Clinical Study Reports
5.3.1.1 Bioavailability (BA) study Reports
5.3.1.2 Comparative BA and Bioequivalence study reports
5.3.1.3 In-vitro In-vivo Correlation study reports
5.3.1.4 Reports of Bioanalytical and Analytical methods
5.3.2.1 Plasma Protein Binding Study Reports
5.3.2.2 Reports of Hepatic metabolism and Drug Interaction Studies
5.3.2.3 Reports of Studies Using human Biomaterials 32
33. • 5.3.3.1 Healthy Subject PK and Initial Tolerability study reports
• 5.3.3.2 Patient PK and Initial Tolerability study reports
• 5.3.3.3 Intrinsic Factor PK study reports
• 5.3.3.4 Extrinsic Factor PK study reports
• 5.3.3.5 Population PK study reports
• 5.3.4.1 Healthy subject PD and PK/PD study reports
• 5.3.4.2 Patient PD and PK/PD study reports
33
34. • 5.3.5.1 Study reports of controlled clinical studies
• 5.3.5.2 Study reports of Uncontrolled clinical studies
• 5.3.5.3 Reports of Analyses of data from more than one study
• 5.3.5.4 Other clinical study reports
• 5.3.6 Reports of Post-Marketing Experience
• 5.3.7 Case report forms and Individual patient listings
• 5.4 List of Key Literature References
34
36. CONTENTS
• WHAT IS eCTD ?
• eCTD BENEFITS
• HOW IT IS DIFFERENT TO PAPER/DOCUMENT CTD
• eCTD IMPLEMENTATION-EU
• eCTD IMPLEMENTATION-MHRA
• eCTD IMPLEMENTATION-FDA
• REGULATORY CONTACT INFORMATION
• eCTD IMPLEMENTATION
• eCTD MODULES
• eCTD MANAGEMENT SOFTWARE
36
37. WHAT IS eCTD ?
• The eCTD is defined as an interface for industry to agency transfer, of
regulatory information while at the same time taking into
consideration the facilitation of the creation, review, lifecycle
management and archival of the electronic submission.
• Common structure for Modules 2 to 5
• Agency specific requirements for Modules 1
37
38. Technical Perspective
Structured set of common folders structure containing PDFs and SAS
files (Statistical Analysis Software) on a CD/DVD (Can also be
submitted through Agency web portals).
The eCTD backbone is an XML file (Extensible Markup Language)
representing the structure of the submission, it includes links to files
and other metadata such as check sum information , The scheme for
the XML is very rigid.
PDF hyperlinks
Granularity of files submitted is small (there are no longer issues of
creating large volumes of PDFs). 38
39. • Increased potential for reusing the same submission content across
agency submissions.
• The standard, and many of the modules have been agreed upon by
the main worldwide agencies.
• Once a submission is sent in eCTD format all future submissions for
the application should be in eCTD format.
• Opportunity to use Part 11 Compliant Electronic Signatures.
• Use only file formats specified in the guidance 39
40. eCTD BENEFITS
Easy to distribute and review
More efficient use of resources, less cost and stress to the organization
Highly organized electronic table of contents
Searchable
Self-validating
Integrated document and life-cycle management
Cross submission integration
Living document
New, replace, append & delete
40
41. How it is different to Paper/Document CTD
• Overall Table of contents provided in XML (Extensible Markup Language).
• Utility files to enable technical conformance and viewing.
• Submission Folders, XML and Utility Files are created automatically if an
eCTD builder is used.
• Generally high level of granularity in documents.
• Structure is more precise.
• Lifecycle Management of the submission is easier. 41
42. eCTD IMPLEMENTATION- EU
• Requirements on Electronic submissions and paper documentation
for New Application within MRP, DCP or National procedure –Refer
(CMDh/085/2008/Rev7 October 2010)
• From 1st July 2010, the EU M1 v 1.4 was used for all eCTD
submissions for all European procedures.
42
43. eCTD IMPLEMENTATION- MHRA
The preferred format for new marketing authorization (MA) applications is
the electronic Common Technical Dossier (eCTD).
eCTD applications must be created according to the current specifications,
eCTD specification v 3.2.2.
MHRA will accept applications in PDF-format only.
The Summary of Product Characteristics (SPMC’s) will need to be prepared
using the Word template.
Use the MHRA Adobe Application form which is available via MHRA Portal,
This will produce an XML file that MHRA can upload directly into their
database.
43
44. eCTD Implementation - FDA
• Jan 1, 2008, eCTD became CDER’s standard for electronic submission.
• FDA has made it mandatory for all ELECTRONIC submissions to be in
eCTD format since 2007-08.
• However, paper copies are still accepted , Suitable waivers will have
to be taken before hand.
• The number of ANDA submissions to FDA has increased from 72 in
the year 2006 to 1550 in 2009.
44
47. eCTD MODULES
• When making an electronic submission, each document should be
provided as a separate file.
• The documents, whether for a marketing application, an
investigational application, or a related submission, should be
organized based on the five modules in the CTD
• Module 1 includes administrative information and prescribing
information
• Module 2 includes CTD summary documents
• Module 3 includes information on quality
• Module 4 includes the nonclinical study reports
• Module 5 includes the clinical study reports.
47
49. REFERENCES
• Molzon J; “The Common Technical Document: the changing face of New Drug Application” Nature
Reviews – Drug Discovery; Volume 2, January 2003;Page 7174.
• “Guidance for Industry on Preparation of Common Technical Document for Import /Manufacture
And Marketing Approval Of New Drugs For Human Use (New Drug Application – NDA)”. Available
at http://cdsco.nic.in/CTD_Guidance%20-Final.pdf
• Roth I R; “Preparing the Common Technical Document for Registration of Pharmaceuticals for
Human Use (CTD) – Insight and Recommendations”; Drug Information Journal; Volume 42; 2008;
Page149-159.
• “The Common Technical Document- Quality (CTDQ)”. Available at http://www.ema.europa.eu/ .
• “Guideline M4: The Common Technical Document”. Available at
http://www.ich.org/products/ctd.html
• www.ich.org
• www.cdsco.nic.in
• http://www.fda.gov/cder/regulatory/ersr/ectd.htm
• http://esubmission.eudra.org/
• http://www.mhlw.go.jp/english/index.html
• http://www.tga.gov.au/docs/html/eugctd.htm
49
