COMMON TECHNICAL DOCUMENT
Dr. Sukanta Sen
MBBS, DNB, MD, MNAMS
Dept. of Clinical & Exp. Pharmacology
If you want to go fast go alone.
If you want to go far go together.
WILL DISCUSS ABOUT :What is CTD?
Evolution of CTD
Preparing and organizing the CTD
What is the current status of CTD?
ICH – eCTD
Advantages of CTD
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 Harmonisation
IND: Investigational New Drug application
NDA: New Drug Application
USFDA: US Food and Drug Administration
TGA: Therapeutic Goods Administration
EMA: European Medicines Agency
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 analyses.
Such omissions can result in unnecessary delays in approvals.
Thus, a common format of submission will help in overcoming
WHAT IS CTD?
The CTD is a set of specifications for a dossier for the
registration of medicines (TGA)
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).
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
ORIGIN OF CTD…
WAS OFFICIALLY SIGNED
OFF IN NOVEMBER 2000,
AT 10TH ANNIVERSERY of
CTD IS A JOINT EFFORT OF 3 REGULATORY AGENCIES:
2. Food and Drug Administration (FDA, USA) and
3. Ministry of Health, Labour and Welfare (MHLW,Japan).
CTD is maintained by ICH through EWG.
In July 2003, the CTD became the mandatory format for new drug
applications in the EU and Japan, and the strongly recommended format
of choice for NDAs submitted to the FDA.
It has been adopted by several other countries including Australia, Canada
and Switzerland (2004).
1.European Medicines Agency (EMEA, Europe),
Any guideline which is given by ICH passes through different
These different steps are called STATUS of that GUIDELINE.
Development of Consensus
Status of CTD
Text released for consultation
Consultation outside ICH
STEP 4 STATUS ACHIEVED IN
NOV.2000 IN 5TH ICH CONFERENCE
STEP 5 STATUS ACHIEVED IN
MAY.2001 IN ICH MEETING IN
ICH guideline finalized
GUIDANCE MADE AVAILABLE TO
INDUSTRY IN OCTOBER 16,2001 BY
In 2000, the 10th Anniversary of ICH, Dr. Caroline Nutley Loew
of the Pharmaceutical Research and Manufacturers of America
(PhRMA) wrote a report, The Value and Benefits of ICH to
Industry, which detailed ICH’s creation, procedures, and
guideline development in the areas of safety, efficacy, and quality.
Her report anticipated that the CTD would revolutionize the
submission procedures for industry’s regulatory staff.
Dr. Loew characterized the CTD as “offering potential benefits
to industry far greater than any other single ICH topic,” and
predicted the CTD would afford significant savings in time and
resources as complex multiple submissions were replaced by a
single technical dossier submitted in the three ICH regions—
facilitating simultaneous submission, approval, and launch of new
In calling the CTD “a topic whose value to industry
cannot be underestimated,”
Dr. Loew noted that with full incorporation of the CTD and
the electronic CTD (eCTD), ICH could turn its sights to
disseminating guideline information to non- ICH countries,
yielding additional benefits to both regulators and industry.
Ten years later and in anticipation of ICH’s 20th
Anniversary, the value and benefits of ICH to regulators have
Moreover, implementation of the CTD in 2003 promoted the
involvement of drug regulatory authorities (DRAs) not initially
part of ICH, thereby extending ICH’s harmonized approach.
The development of the Global Cooperation Group, which
includes representatives from five regional harmonization
initiatives and the newly established Regulators Forum, created
to promote participation by non-ICH countries interested in
implementing ICH’s strategies, have also helped incorporate
the CTD into regulatory processes, creating a common
regulatory language that promotes faster access to life-saving
treatments to patients beyond ICH regions.
In ICH Region
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
July 1, 2003: Mandatory Requirement in Three ICH Regions.
2009: CDSCO Adopt CTD format for Technical requirements
for registration of biological products.
October 28, 2010: CDSCO give guideline for feedback purpose
for Industry on Preparation of CTD for Import/Manufacture
and Marketing Approval of New Drug for Human Use (i.e. 18
NDA) & ask for comments and suggestion within 60 days.
This guidance is developed by CDSCO based on,
- The ICH Harmonised Tripartite Guideline on “Organisation of
the Common Technical Document for the Registration of
Pharmaceuticals for Human Use”. M4, Step 4 version dated
January 13, 2004, and
- Drugs & Cosmetics Act 1940 and Rules made thereunder.
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.
To provide a harmonized common format/template for the
submission of technical requirement to the regulatory
authorities (FDA) that is acceptable in all 3 ICH regions
Reduce the time and resources used to compile applications
will ease the preparation of electronic submissions.
To facilitate simultaneous submission in three regions.
To facilitate exchange of regulatory information.
Faster availability of new medicines
Figure 1: The Drug Approval Process: Drug approval involves passing a number of steps,
including preclinical and clinical studies, and later, post-marketing research.
PREPARING & ORGANIZATION
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
Administrative information and prescribing
Document specific to each region.
E.g. Application form
Proposed label for use in the region
MODULE 1: GENERAL INFORMATION
1.1 Covering letter & comprehensive table of contents (modules 1
1.2 Administrative information
1.2.1 Brief introduction about the applicant company
1.2.2 Duly filled and signed application in Form 44 and Treasury
1.2.3 Legal and Critical Documents
188.8.131.52 Copy of Clinical Trial/BE. No Objection letters issued by
184.108.40.206 For import and marketing of finished products
a. Copy of drug sale license in Form 20B / 21B
b. Copy of Free Sale Certificate (FSC) and/or Certificate of
Pharmaceutical Products (CPP) issued by the Regulatory
Authority of the country of origin
c. Batch release certificate issued by National Regulatory
d. Copy of Form 11 for imported drug product for testing purpose
220.127.116.11 For manufacture and marketing of finished products
a. Copy of existing manufacturing license in Form 25 / 28 / 26
b. Copy of Form-29
18.104.22.168 Undertaking or Declaration as per Annexure II
22.214.171.124 Certificate of Analysis
1.2.4 Coordinates related to the application
126.96.36.199 Name, address, telephone, fax, e-mail of applicant of drug
188.8.131.52 Name, address, telephone, fax, e-mail of manufacturer of
184.108.40.206 Name, address, telephone, fax, e-mail of the responsible
220.127.116.11 Name, address, telephone, fax, e-mail of other manufacturer(s)
involved in the production process
18.104.22.168 Name, designation, address, telephone, fax, e-mail of the
official responsible for releasing batches of drug product
22.214.171.124 Name, address, telephone, fax, e-mail of the authorized agent in India:
(for imported drug products)
126.96.36.199 Name, address, telephone, fax, e-mail of the manufacturing premises
holding Market Authorization of the drug product (for imported drug 30
1.3 GENERAL INFORMATION ON DRUG PRODUCT
1.3.1 A brief description of the drug and the therapeutic
class to which it belongs
1.3.2 Non-proprietary name or generic name of drug
1.3.3 Composition (As per label claim)
1.3.4 Dosage form
1.3.5 Strength per dosage unit
1.3.6 Dispensing requirements
1.3.7 Route of administration
1.3.8 Commercial presentation
1.3.9 Conditions of storage or conservation
1.3.10 Full Prescribing Information (Package insert)
1.3.11 Product Labeling: Proposed draft labels and cartons have to be
1.3.12 Summary of the packaging procedures for Indian shipments
1.4 SUMMARY OF TESTING PROTOCOL(S) FOR
QUALITY CONTROL TESTING together with a complete
impurity profile and release specifications for the product should
1.5 Regulatory status in other countries
1.5.1 List of countries where proposed drug is Marketed
1.5.2 List of countries where proposed drug is Approved for
1.5.3 List of countries where proposed drug is Approved as IND
1.5.4 List of countries where proposed drug is Withdrawn (if any,
with reasons for withdrawal)
1.5.5 Details of any restrictions on use, in any country where it is
1.6 Domestic price of the drug followed in the countries of
1.7 A brief profile of the manufacturer’s research activity
1.8 A brief profile of the manufacturer’s business activity in
domestic as well as global market
1.9 Information regarding involvement of experts, if any
1.10 Samples of drug product
1.11 Promotional materials
Common technical document table of contents (Modules 2–5)
Quality overall summary
Nonclinical written and tabulated summaries
Biopharmaceutic studies and associated analytical methods
Clinical pharmacology studies
Synopses of individual studies
In general, the Quality Overall Summary (QOS) is an outline of
data presented in Module 3.
Please do not provide the entire information present in Module 3
corresponding sections, but, provide brief information picked
from relevant sections.
This QOS normally should not exceed 40 pages of text,
excluding tables and figures.
2.3.S Summary of drug substance
2.3.S.1 General Information (name, manufacturer)
2.3.S.2 Manufacture (name, manufacturer)
2.3.S.3 Characterisation (name, manufacturer)
2.3.S.4 Control of Drug Substance (name, manufacturer)
2.3.S.5 Reference Standards or Materials (name, manufacturer)
2.3.S.6 Container Closure System (name, manufacturer)
2.3.S.7 Stability (name, manufacturer)
2.3.P SUMMARY OF DRUG PRODUCT
2.3.P.1 Description and Composition of the Drug Product (name, dosage form)
2.3.P.2 Pharmaceutical Development (name, dosage form)
2.3.P.3 Manufacture (name, dosage form)
2.3.P.4 Control of Excipients (name, dosage form)
2.3.P.5 Control of Drug Product (name, dosage form)
2.3.P.6 Reference Standards or Materials (name, dosage
2.3.P.7 Container Closure System (name, dosage form)
2.3.P.8 Stability (name, dosage form)
2.4 NON-CLINICAL OVERVIEW
Nonclinical overview should present an integrated and critical
assessment of the pharmacologic, pharmacokinetic, and
toxicological evaluation of the pharmaceutical.
In general, it should address the interpretation of data, the
clinical relevance of findings, cross-linking with quality aspects
of the pharmaceutical, and the implications of nonclinical
findings for the safe use of the pharmaceutical.
2.4.1 Introduction and GLP statement
A brief introduction about the contents of this section and a
comment on the GLP status of the studies submitted should be
2.4.2 Overview of the Non Clinical Testing Strategy
2.4.6 Integrated Overview and Conclusions
2.4.7 List of Literature References
2.5 CLINICAL OVERVIEW
Summary and analysis of the clinical data
Provide a brief overview of the clinical findings, including
important limitations (e.g., lack of comparisons with an
especially relevant active comparator, or absence of information on
some patient populations, on pertinent endpoints, or on use in
Analyse the benefits and risks of the medicinal product in its
intended use based upon the conclusions of the relevant clinical
Address particular efficacy or safety issues encountered in
development, and how they have been evaluated and resolved.
Explore unresolved issues, explain why they should not be
considered as barriers to approval, and describe plans to resolve
Explain the basis for important or unusual aspects of the
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 Literature References
2.6 NON-CLINICAL SUMMARIES
Summary of pharmacokinetic, pharmacological and
toxicology studies – in-vivo/in-vitro, species, route
Appropriate age and gender related effects
2.6.2 Written Summary of Pharmacology
188.8.131.52 Brief Summary
184.108.40.206 Primary Pharmacodynamics
220.127.116.11 Secondary Pharmacodynamics
18.104.22.168 Safety Pharmacology - defined as those studies that
investigate the potential undesirable pharmacodynamic effects
of a substance on physiological functions in relation to
exposure in the therapeutic range and above.
22.214.171.124 Pharmacodynamic Drug Interactions
126.96.36.199 Discussion and Conclusions
2.6.3 Tabulated Summary of Pharmacology
2.6.4 Written Summary of Pharmacokinetics
2.6.4 Written Summary of Pharmacokinetics
188.8.131.52 Brief Summary
184.108.40.206 Methods of Analysis
220.127.116.11 Pharmacokinetic Drug Interactions
18.104.22.168 Other Pharmacokinetic Studies
22.214.171.124 Discussion and Conclusions
126.96.36.199 Tables and Figures
2.6.5 Tabulated Summary of Pharmacokinetics
2.6.6 Written Summary of Toxicology
188.8.131.52 Brief Summary
Study type and
po and iv
Rat and mouse
po and iv
Rat and mouse
Rat and dog
9 months etc.
184.108.40.206 Single-Dose Toxicity
220.127.116.11 Repeat-Dose Toxicity (including supportive toxicokinetics
Studies should be briefly summarised in the following order:
in vitro non-mammalian cell system
in vitro mammalian cell system
in vivo mammalian system (including supportive
o 18.104.22.168 Carcinogenicity (including supportive toxicokinetics
Short- or medium-term studies
22.214.171.124 Reproductive and Developmental Toxicity
126.96.36.199 Local Tolerance
2.7 CLINICAL SUMMARIES
This section is intended to provide a detailed, factual
summarization of all of the clinical information in the CTD.
information provided in clinical study reports;
information obtained from any meta-analyses or other cross-
study analyses for which full reports have been included in
Module 5; and
post-marketing data for products that have been marketed in
2.7.1 Summary of Biopharmaceutic Studies and Associated
188.8.131.52 Background and Overview
184.108.40.206 Summary of Results of Individual Studies
220.127.116.11 Comparison and Analyses of Results Across Studies
2.7.2 Summary of Clinical Pharmacology Studies
18.104.22.168 Background and Overview
22.214.171.124 Summary of Results of Individual Studies
126.96.36.199 Comparison and Analyses of Results Across Studies
188.8.131.52 Special Studies
2.7.3 Summary of Clinical Efficacy
184.108.40.206 Background and Overview of Clinical Efficacy
220.127.116.11 Summary of Results of Individual Studies
18.104.22.168 Comparison and Analyses of Results Across Studies
22.214.171.124.1 Study Populations
126.96.36.199.2 Comparison of Efficacy Results of all Studies
188.8.131.52.3 Comparison of Results in Sub-populations
184.108.40.206 Analysis of Clinical Information Relevant to Dosing
220.127.116.11 Persistence of Efficacy and/or Tolerance Effects
18.104.22.168.1.3 Other S2.7.4 Summary of Clinical Safety
22.214.171.124 Exposure to the Drug
126.96.36.199.1 Overall Safety Evaluation Plan and Narratives of Safety Studies
188.8.131.52.2 Overall Extent of Exposure
184.108.40.206 Adverse Events
220.127.116.11.1 Analysis of Adverse Events
18.104.22.168.1.1 Common Adverse Events
erious Adverse Events
22.214.171.124.1.4 Other Significant Adverse Events
126.96.36.199.1.5 Analysis of Adverse Events by Organ System or Syndrome
188.8.131.52 Clinical Laboratory Evaluations
184.108.40.206 Vital Signs, Physical Findings, and Other Observations
Related to Safety
220.127.116.11 Safety in Special Groups and Situations
18.104.22.168.3 Drug Interactions
22.214.171.124.4 Use in Pregnancy and Lactation
126.96.36.199.6 Drug Abuse
188.8.131.52.7 Withdrawal and Rebound
184.108.40.206.8 Effects on Ability to Drive or Operate Machinery or
Impairment of Mental Ability
220.127.116.11 Post-marketing Data
2.7.5 Literature References
2.7.6 Synopses of Individual Studies
MODULE 3 QUALITY
The Quality section of the Common Technical Document
(M4Q) provides a harmonised structure and format for
presenting CMC (Chemistry, Manufacturing and Controls)
information in a registration dossier.
Module 3 content
Module 3 table of contents
Body of data
3.2 BODY OF DATA
3.2.S DRUG SUBSTANCE(S)
3.2.S.1 General information (name, manufacturer)
3.2.S.1.1 Nomenclature (name, manufacturer)
3.2.S.1.2 Structure (name, manufacturer)
3.2.S.1.3 General Properties (name, manufacturer)
3.2.S.2 Manufacture of Drug Substance (name, manufacturer)
3.2.S.2.1 Manufacturer(s) (name, manufacturer)
3.2.S.2.2 Description of Manufacturing Process and Process Controls
3.2.S.2.3 Control of Materials (name, manufacturer)
3.2.S.2.4 Controls of Critical Steps and Intermediates
3.2.S.2.5 Process Validation and/or Evaluation (name, manufacturer)
3.2.S.2.6 Manufacturing Process Development (name,
3.2.S.3 Characterization of Drug Substance
3.2.S.4 Quality control of Drug Substance
3.2.S.5 Reference Standards or Materials
3.2.S.6 Container Closure System
3.2.S.7 Stability of Drug Substance
3.2.P DRUG PRODUCT (NAME, DOSAGE FORM)
3.2.P.1 Description and Composition of the Drug Product
3.2.P.2 Pharmaceutical Development
3.2.P.3 Manufacture of Drug Product
3.2.P.4 Control of Excipients
3.2.P.5 Control of Drug Product
3.2.P.6 Reference Standards or Materials
3.2.P.7 Container Closure System
3.2.P.8 Stability of drug product
MODULE 4: NON-CLINICAL STUDY REPORTS
Module 4 describes the format and organisation of the nonclinical
(pharmaco-toxicological) data relevant to the application.
4.2 STUDY REPORTS
4.3 literature references
MODULE 5: CLINICAL STUDY REPORTS
Module 5 describes the format and organisation of the clinical
data relevant to the application.
5.3.1 Reports of Biopharmaceutical Studies
5.3.2 Reports of Studies Pertinent to Pharmacokinetics Using
5.3.3 Reports of Human Pharmacokinetic (PK) Studies
5.3.4 Reports of Human Pharmacodynamic (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 Listings
5.4 literature references
GUIDANCE FOR THE INDUSTRY
Divided in 4 guidance document
6 months behind CTD
May, 2001, Tokyo, Step 2 of the eCTD ICH process was
agreed by Multidisciplinary Group 2 Expert Working Group
(ICH M2 EWG).
Specifications developed by ICH M2 EWG
Maintained by eCTD IWG
Electronic submission from applicant to regulator
M2 EWG – developed change control process to monitor
implementation process & provide solutions and added flexibility
found necessary during implementation
Addressed and resolved
- study report structure
- lifecycle management
- consistency with CTD
Developed by M2 EWG (Multidisciplinary 2 Expert
Working Group) of ICH.
Industry <-----> Message <------> Agency
Paper submission has
been replaced by electronic
CHARACTERISTICS OF ECTD:1. Files Referenced in the XML Backbone(s)
(Extensible Markup Language)
1.It manages the large data for the entire submission and for
each document within the submission.
2.This XML backbone allows the eCTD submission to be
viewed via a web browser and can be loaded on a Web
2.The file formats that can be included in
the eCTD are Portable Document
Format (PDF) and XML.
However other formats can be used for graphs and
-may be used for higher resolution.
3. All eCTD Submissions Include Module 1
Module 1 Identifies following important information:
NOMENCLATURE FOR FILES AND ECTD
EXAMPLE:- MODULE 2 FILE NOMENCLATURE AND eCTD
2.3 Quality overall summary
2.4 Non clinical Overview
2.5 Clinical Overview
2.6 Non clinical Written and
2.7 Clinical summary
ADVANTAGES OF CTD
To make the reviewing of each application more easy and
also to avoid omission of critical data or analyses. Omissions
of such data can result in unnecessary delays in approvals.
To save time and resources
To facilitate regulatory review and communications
Appropriate format for the data
Easy to understand and evaluation of data
Applicable to all types of products (NCE,
radiopharmaceuticals, vaccines, herbals, etc.)
SILENT BENEFITS OF THE CTD
More “reviewable” applications
Complete, well-organized submissions
More predictable format
More consistent reviews
Easier analysis across applications
Easier exchange of information
Facilitates electronic submissions
CTD is only a format, its not a single dossier with a single
Legal requirements differ in the different regions
ICH guidelines have not yet harmonized in all requirements
Pharmacopoeias are not harmonized
Applicant may have regional preferences.
•The eCTD has proved critical to improving application
submission efficiencies as well as reviewer efficiency.
•Besides delivering submission material to the reviewer in an
expedited manner, the eCTD format has made it easier to
develop standardized reviewer e-templates and review tools for
each of the review disciplines.
IS CTD MANDATORY FOR ALL TYPE OF
CTD is mandatory for all.
Import and/or manufacture and marketing approval of new
drugs (New chemical entity, new indication, new dosage
forms, new route of administration etc.), as a finished
pharmaceutical product, for first time submission and for
subsequent applications until 4 years.
Modified release formulations (even after 4 years of
approval by CDSCO)
Fixed Dose Combinations under item (a) of Appendix VI
of Schedule Y of Drugs and Cosmetics Rules 1945.
Whilst the realization of the CTD took many years, there is
now a common format for the submission of Marketing
Authorizations Applications across the three ICH regions Europe, Japan and the USA.
This should facilitate pharmaceutical companies to make
simultaneous filings in the ICH regions as it will eliminate the
extensive work previously required to convert, for example, a
US dossier to an EU dossier and vice versa.
1. Molzon J; “The Common Technical Document: the changing face of New Drug
Application”; Nature Reviews – Drug Discovery; Volume 2, January 2003;Page 7174.
2. “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
3. 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.
4. “The Common Technical Document- Quality (CTDQ)”. Available at
5. “Guideline M4: The Common Technical Document”. Available at
6. Smith C G, O’donnell J T; “The Process of New Drug Discovery & Development”;
2nd Edition; Informa Health Care USA, Inc.; Page 477.
7. “ICH Harmonised Tripartite Guideline: Organisation Of The Common Technical
Document For The Registration Of Pharmaceuticals For Human Use M4”.
Available at http://www.ich.org/fileadmin