E-CTD (ELECTRONIC COMMON PDF / PPT

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E-CTD
(ELECTRONIC COMMON

TECHNICAL DOCUMENT)

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 The ELECTRONIC version of ctd is known as E-Common Technical
Document.

 “The electronic common technical document (eCTD) is an
interface and international specification for the
pharmaceutical industry to agency transfer of regulatory
information.”

 The specification is based on the Common Technical Document (CTD)
format and was developed by the International Conference on
Harmonisation (ICH).

 The ICH M4 Expert Working Group (EWG) has defined the Common
Technical Document (CTD).

 The ICH M2 EWG has defined, in the current document, the
specification for the Electronic Common Technical Document (eCTD).

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HISTORY
Version 2.0 of eCTD – an upgrade over the original CTD –

was finalized on February 12, 2002, and version 3.0 was
finalized on October 8 of the same year.

As of August 2016, the most current version is 3.2.2,
released on July 16, 2008.

A Draft Implementation Guide for version 4.0 of eCTD
was released in August 2012. However, work stalled on the
project. An additional Draft Implementation Guide was
released in February 2015.

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E-CTD is composed of two types of specifications:

 Content specification (as defined by ICH)

 Technical specification (electronic software)

CTD TOC (PDF)

E-CTD XML backbone

E-ctd is highly recommended by USFDA for NDAs,
BLAs, DMFs and INDs filings.

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CHARACTERISTICS
OF E-CTD

Granularity: the level
of detail considered in

All Modules 1 to 5 have granularity options.
a model or decision

PDF documents linked via XML backbone. making process.

Increased document granularity.

Transparency of entire submission.

Ease of navigation and review.

Reducing the use of paper.
XML : Extensible Markup Language (that
defines a set of rules for encoding documents in
a format that is both human and machine
readable). 6

 

STRUCTURE OF E-CTD
Building blocks:
 PDF files for text*
 SAS transport files for data*
Connected through XML backbone
 Looks like a web page
 Viewing
 Links and bookmarks
 Search keywords, metadata
 Managing lifecycle (Append, Replace, Delete)

PDF: Portable Document SAS: Statistical Analysis System (a software suite
Format developed by SAS institute for advanced analytics7,

multivariate analysis, business intelligence, data
management and predictive analysis.

 

FILING PROCEDURE IN AN
e-CTD FORMAT

 In the first step, Sponsors filing a regulatory transaction in eCTD format
for the first time or for a major change in the eCTD environment are
recommended to hold a technical pre-submission consultation meeting with
Health Canada.

 This is followed by the Sponsor filing an eCTD sample to Health Canada.
The sample is reviewed by Health Canada, in the third step, to identify any
errors.

 If errors have been identified, the sample is returned to and corrected by
the Sponsor and the corrected sample re-filed to Health Canada for
verification (this process will continue until no errors have been identified).

 The filing of the sample eCTD should occur at least two months in advance
of the filing of the formal regulatory transaction.

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TECHNICAL REQUIREMENTS
FOR SUBMISSION

1) SUBMISSION MEDIA :
 Hard media (e.g. CD-ROMs, DVD-ROMs) must be used for the submission

of all e-CTDs.
 CD (CD-ROM) conforming to ISO 9660 or ISO 13346 can be accepted.
 Medical Control Council (MCC) will not accept any hardware (laptops,

desktops, zip drives, etc.) from applicants in connection with the submission
of information in electronic format.

 The submission media should be packed adequately to prevent damage to the
media.

2) COMPRESSION AND PASSWORD PROTECTION/ SECURITY SETTINGS :
 The applicant is required not to apply any compression to the submission or

the files inside the submission. Therefore the data on the media should not be
packed into a zip-file, rar-file or any other file format that has been

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compressed.

 

3) PDF FILES :
 Portable Document Format (PDF) is an electronic format that is open, de facto,

and published and created by Adobe Systems Incorporated
(http://www.adobe.com).

 Files should be PDF v1.4, 1.5, 1.6 or 1.7 and should be legible with the Acrobat
Reader search plug in or any other freeware viewer.

 PDF files produced from an electronic source document are preferred to PDF
files generated from scanned paper since such ‘electronic’ PDF files provide the
maximum functionality to the reviewers in terms of search capabilities and
copy & paste functionality.

 The maximum individual acceptable file size is approximately 200 MB. If a
file size exceeds 200 MB, the file should be split into two files.

4) FILE NAMING CONVENTIONS :
 It is recommended to use the eCTD file naming conventions described in the

ICH M2 eCTD Specification and the South African Specification for eCTD
Module 1.

 If an applicant wishes to submit multiple files in one section, where only one
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highly recommended name is available, this can be achieved using a variable
suffix to the filename (e.g. pharmaceuticaldevelopment-container.pdf).

 

5) HYPERLINKS AND BOOKMARKS :
 In general, hypertext links are encouraged within the eCTD to facilitate swift

navigation within the dossier, but should not be overused.
 Documents should be placed only once in the eCTD folder structure and

referred to via hyperlinks.
 Even though a submission is technically accepted, content validation /

evaluation may not be successful if hyperlinks or bookmarks are not functional
to a critical extent, and the submission may be returned due to formal reasons.

 Within Modules 2 to 5, bookmarks are needed for documents exceeding five
pages that contain multiple headings or sections, tables or figures, except for
literature references where bookmarks are not necessary.

6) ADDITIONAL FILES IN WORD DOCUMENT :
 MCC requires Word documents for the following documents, in addition to the

PDF for the purposes of review and document manipulation:
a. Module 1.2.1 -Application form
b. Module 1.3: – Package insert

– Patient Information Leaflet
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– Label

 

VALIDATION
 The validation criteria serve to aid the applicant to carefully set up the eCTD.
 A technically correct eCTD submission is pivotal for a timely and successful

review of the submission. Therefore it is the MCC’s intention to accept
technically correct e-CTDs only, to minimize any delay that might affect the
content validation and the review process.

 CATEGORIES OF VALIDATION RULES:
a) Pass/Fail Criteria : e-CTDs that fail to meet one or more of the “Pass/Fail”

criteria will not be processed and the applicant will be advised to rectify the
problems and resubmit with the same sequence number.

b) Best Practice Criteria : It is considered good practice to ensure that these
validation criteria are correct in the submitted eCTD. The applicant should
make every effort to address these areas before the eCTD is submitted.

 NOTE: Errors found during the content validation (evaluation)
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should be resolved through the submission of a new eCTD
sequence. These errors must never be resolved by resubmitting an
existing sequence.

 

 VALIDATION PROCESS :

 Applicants must use an eCTD validation tool that checks the submission for
technical interoperability before submission.

 The applicant must submit a validation report identifying validation results
including pass/fail and best practice.

 The MCC will carry out a three-step process on receipt of an eCTD:
(1) Screening: Administrative compliance check
(2) Technical validation: This will be performed in a single step
(3) Business validation: a. Content check

b. Content validation / evaluation
 In case of technical validation issues, the application will be returned to the

applicant with a report identifying issues to be corrected.
 If no technical validation issues are identified the applicant will be notified of

successful validation for the first sequence submitted (i.e. 0000) and the eCTD
will be imported into the review system for business validation.

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SUBMITTING THE e-CTD
 An eCTD Submission is an electronic-only submission in the eCTD format

that is supported by paper documents (e.g. some documents from Module 1).
 A statement that the submission is virus free with a description of the

software used to check the files for viruses.
 STEPS INVOLVED :
1) Copy eCTD to CD-ROM, DVD or DLT master
2) Reload eCTD from CD, DVD or DLT master and revalidate
3) Create eCTD copies from master
4) Number of copies determined by each EU MS

 The paper copies and the hard media should be submitted jointly.
 The eCTD on DVD/CD should be submitted to MCC at the following

address:
The Registrar of Medicines, Medicines Control Council, Room NG090,
Civitas Building, 42 Andries Street (Thabo Sehume Street), Pretoria, 15
South Africa .

 

BENEFITS OF E-CTD
Improved handling and archiving of submission (both

sponsor & FDA)

Improves reviewers efficacy

Search functionality and increased tracking ability

Allow for repurposing of docs for submission in other
regions

Accessibility to documents across modules

Submission via ESG allows immediate receipts by FDA

ESG: Electronic Submission Gateway (a
central transmission point for sending
information electronically to FDA. 16

 

INDUSTRY AND
FDA LIAISON

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INTRODUCTION

 Experienced Drug Regulatory Affairs (DRA) personnel are essential in the
process of new product development. They are largely responsible for
establishing a liaison with their counterparts at the U.S. Food and Drug
Administration (FDA) and other regulatory agencies globally.

 The FDA is one of our nation’s oldest consumer protection agencies
dating back to 1862.

 FDA is a public health agency, charged with protecting consumers by
enforcing the Federal Food, Drug, and Cosmetic Act and several related
public health laws.

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INSPECTIONS AND LEGAL
SANCTIONS

 The FDA investigators and inspectors ensure that products are made
correctly and labelled truthfully. As part of their inspections, they
collect about 80,000 domestic and imported product samples for
examination by FDA scientists or for label checks. If a company is
found violating any of the laws that FDA enforces, FDA can
encourage the firm to correct the problem voluntarily or to recall a
faulty product from the market.

 When a company cannot or will not voluntarily correct a public health
problem with one of its products, FDA has legal sanctions it can bring to
bear. The agency can go to court to force a company to stop selling a
product and to have items already produced seized and destroyed.

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.

 

FDA’s MAJOR PROGRAM CENTRES
 The FDA is divided into many centers; each center comprising a division

with specific regulatory responsibilities. The main centers are as follows:
CDER— Centre for Drug Evaluation and Research
CBER— Center for Biologics Evaluation Research
CDRH— Center for Devices and Radiologic Health
CFSAN— Center of Food Safety and Applied Nutrition
CVM— Center for Veterinary Medicine
NCTR—National Center for Toxicological Research

 The responsibility for reviewing new pharmaceutical products is the major
responsibility of CDER.

 CDER is responsible for all pharmaceutical products including Dental and most
Biologics.

 CDER is organized into various divisions and offices—each one responsible for new
drug approval process according to the expertise of the personnel assigned to that
division. As of January 2001, there are 16 review divisions within CDER (including the
Division of Over the-Counter drug products) that are responsible for reviewing all INDs,
NDAs, SNDAs. 20

 

 The 16 divisions are grouped among one of five Offices of Drug
Evaluation(ODE).

 The Center for Drug Evaluation and Research is organized into three main
offices:

 the Office of the Center Director (OCD),

 the Office of Review Management (ORM), and

 the Office of Pharmaceutical Science (OPS).

All the three main offices works integrally for the new drug approval
process and regulates the chemistry, manufacture and controls of the drugs.

 For each IND or NDA, a “drug review team” is established to provide the
appropriate expertise to allow for a judgment regarding the drug’s overall
acceptance based on its safety, clinical efficacy, and manufacturing
information, provided to the FDA by the sponsor of the drug application.

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 The CDER drug review team members apply their individual, special
technical expertise to review INDs or NDAs.

All team members work together to assure that the label and the labeling
are accurate and provide clear instructions to health care practitioners
and consumers.

A key member of the review team is the project manager (PM), formerly
called the consumer safety officer or CSO. The PM evaluates regulatory
information to determine compliance with current policies and
regulations.

 In addition, project managers orchestrate and coordinate the drug review
team(s) interactions, efforts, and reviews, and they serve as the CDER
review team’s primary contact with the drug industry (FDA meetings
etc.). They may be considered as the liaison between the FDA and
industry.

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CONTACTS AND
COMMUNICATION WITH FDA

All the FDA divisions’ primary goal is to work collaboratively and
cooperatively with industry, academia, and others to improve new product
development and to expedite the review process. It also strives to provide
consumers and health care providers with drug information that is vital to
improve the public health.

 The topics listed below provide an overview of the various means of
communicating with the FDA divisions.

a. Consumer/Industry Inquiries
 The FDA is dedicated to ensure that all persons involved in new product

development, or who depend upon drug regulation excellence, have the
information needed to research, develop, review, market, dispense,
prescribe, or use products safely and effectively.

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b. Industry/FDA Meetings
 FDA meetings are extremely important and should be requested judiciously

by sponsors. Project managers (PMs) or, Consumer Safety Officers
(CSOs), a large percentage of who were former FDA field investigators,
are responsible for coordinating FDA/sponsor/industry meetings.

 Their other duties include acting as the contact point between the division
and the regulated industries, preparing minutes of FDA/industry meetings,
and assisting the division with the FDA advisory committee meetings.

c. FDA/Industry Meetings
 There are three categories of meetings that industry can request of the

agency. They are typically known as Type A, B, or C meetings:

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Type A meetings usually occur to dispute issues that arise during
new drug development, meeting to resolve clinical holds that FDA has
deemed necessary, or at times they may pertain to protocol assessments
after the FDA has critiqued the submitted protocols. These meetings are
usually scheduled 30 days from FDAs receipt of a written request for a
meeting.

Type B meetings are those that usually occur for a pre-IND, an
End-of-Phase 1 (EOP1), an End-of-Phase 2 (EOP2), a Pre-NDA, or
BLA Conference. All of these meetings will be honored by the FDA.
These meetings are usually scheduled 60 days from the time the agency
received the written request.

Type C meetings are any other meetings not falling into Type A
or B meetings. These are meetings that pertain to review of human drug
applications. These meetings are usually scheduled within 75 days of
the agencies receipt of the written request.

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FDA INITIATIVES TO SPEED UP
DRUG APPROVAL

 The FDA has instituted several programs designed to hasten the drug
approval process for effective drugs. Pharmaceutical regulatory
professionals should be aware of any and all ways that can be
recommended to their research and management staff for more rapid
drug approval.

 Subpart E in Section 312 of the Code of Federal Regulations
establishes procedures to expedite the development, evaluation, and
marketing of new therapies intended to treat people with life-
threatening and severely debilitating illnesses, especially where no
satisfactory alternatives exist.

a. Accelerated development and review program
b. Treatment IND
c. FDA guidance documents/ guidelines

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FREEDOM OF INFORMATION ACT
(FOIA)

Freedom of information is another important way in
which the public may readily obtain information from the
FDA. The FDA has a guidance handbook published
intended to facilitate requests for both public information
and records not originally prepared for distribution by the
FDA.

The Freedom of Information Act allows anyone to
request copies of records not normally prepared for
public distribution.

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SUMMARY
 FDA and Sponsor Liaison is an art that is developed over years of

experience gained from understanding Regulations , guidelines , and
recommendation from regulatory experts.

 It is vital that regulatory personnel attend meetings, conferences , and
courses of all aspects of regulatory issues on the process of new
product development.

A knowledge of how global regulatory agencies operate is essential
to the success of a DRA department.

All dealings with the regulatory agencies must be well conceived and
adequately planned.

Whether the regulatory goal is to speed the approval process for a
new product or to keep a product on the market, the firm must know
how best to work with all regulatory agencies involved.

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