Health Canada Module 1 Updates and Progess Towards ... - TOPRA

Health Canada Module 1 Updates and Progress towards Full Implementation of Electronic
Submissions of the CTD
Harmonization
The International Conference on Harmonization (ICH) was created in 1990, motivated by a growing
divergence in laws, regulations and guidelines between the ICH regions related to the reporting and
evaluation of the data on safety, quality and efficacy of new medicinal products. 1 For industry, this
divergence made it necessary to duplicate many time-consuming and expensive test procedures, in order
to market new products internationally and as a consequence had a negative impact on the timely access
to these medicines for patients. During the first decade, the ICH’s success in achieving agreement to
assemble all the Quality, Safety and Efficacy information in a common format (called CTD - Common
Technical Document) revolutionized the regulatory review processes. For industries the adoption of the
CTD has eliminated the need to reformat the information for submission to the different ICH regulatory
authorities. As of July 2003, use of the CTD was mandatory in the European Union (EU) and Japan and
was highly recommended for use in the United States (FDA). 2
Heath Canada
Health Canada (HC), as official observer to, and active participant in the International Conference on
Harmonization (ICH), is committed to the adoption and implementation of ICH guidance’s and
standards. 1 The throne speech delivered at the opening of the parliamentary session in September 2002
enunciated a new direction in Canadian regulatory activities that entailed speeding up the regulatory
process for drug approvals to ensure that Canadians have faster access to the safe drugs they need 3 .
Improving Canadians access to therapeutic products has is stated as a high priority for Health Canada.
Health Products and Food Branch (HPFB) is the Canadian regulatory organization responsible for the
delivery and implementation of e-Review for therapeutic products. The implementation of a phased
approach to e-review was adopted which consisted of three streams. Stream 1 was targeted for completion
by the second quarter of 2005 4 . The key deliverable was the acceptance of e-submissions for; new drug
submissions (NDS), supplemental new drug submissions (SNDSs) and supplemental abbreviated new
drug submissions (SANDs) 4. For stream 2, targeted for completing between 2006 and 2008, the key
deliverables were; the integration of viewing capabilities from stream 1and the Health Canada support
application from stream 2; full submission life-cycle tracking, analysis and reporting; evaluation of
security requirements and standards by the Government of Canada and ICH-ESTRU. 4 As part of stream
3, there was to be implementation of a 24-turn around time to address special access programs /
emergency drug release; implementation of a tracking system for process management and clinical trial
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adverse event monitoring and implementation of end-to-end solution that will incorporate ICH
guidelines 4 . Iimplementation of the structured approach to the eCTD was undertaken in three stages; cosubmission
filing format (no longer accepted as of 20 January 2010), hybrid filing format (full eCTD
format accompanied by Module 1 and 2 in paper format), and electronic only filing format. 5
The ICH - Multi-disciplinary Group 2 (M2) Expert Working Group (EWG) was established in 1994 to
facilitate international electronic communication by evaluating and recommending, open and nonproprietary
- to the extent possible - electronic standards for the transfer of regulatory information
(ESTRI) to meet the requirements of the pharmaceutical companies and regulatory authorities. 6 The
International Conference on Harmonization of Technical Requirements for the Registration of
Pharmaceuticals for Human Use (ICH) first developed a standardized message for the content of the
submissions, the Common Technical Document (CTD) 6 . Shortly after, the electronic, XML-version
version of this message was created (eCTD).
The HPFB and industry is committed to achieve the long-term goal of an automated standards-based
information technology environment for the exchange, review, and management of information
supporting the process for the regulatory activities throughout the product lifecycle 4 . The HPFB vision is
to implement a fully electronic submission and review environment of all regulatory documents and data;
and, where possible, the elimination of future paper-based submissions. 4 The HPFB and government as a
whole have identified information technology as a key element of a modern organization and recognize
its importance to the future of the government workplace. The HPFB has made progress in moving
toward electronic systems, particularly in the area of submission review. However, there are opportunities
to improve on current systems as well as the development of new systems to fill gaps, provide improved
service and interaction, as well as increase efficiency in current processes. A few years ago, there was a
significant shift in the drivers at the international level for the e-submission initiative 2 . The numbers of
non-ICH parties are increasing seeking inclusion in the harmonization process.
The Food and Drug Administration (FDA) now had a requirement to use Health Level 7 (HL7) in the
standard development process as the standard development organization. 2 RPS, an HL7 standard, is a
single message structure that can be used globally for all regulated products, including
biopharmaceuticals, medical devices, veterinary medicines, and food which offers two-way
communication between the submitter and the regulatory agency, whereas eCTD is a one-way
communication tool. 2 In addition, with RPS, previously submitted documents will not have to be
resubmitted in marketing applications, as it will be possible to apply previously submitted documents to
the marketing application. This will spare submitters from having to retest hyperlinks and bookmarks
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ecause the agency will already have those documents. Lifecycle management will also improve with
RPS as it will be possible to change granularity and move documents, steps that are not possible with
eCTD. This created the conditions to have multiple competing standards and loss of harmonization. The
solution was to join forces and propose an all inclusive solution to cover all interested parties, countries
and product lines. Agreements were put in place between Standard Development Organizations (SDO). 2
The end product will be the International Organization for Standardization (ISO) standards created in
collaboration with ICH, the European Committee on Standardization (CEN), and HL7. 2 Revisions to the
Module 1 structure in the CTD format were required in order for Health Canada to adopt the eCTD v4.0
Regulated Product Submissions (RPS).
Health Canada has completed the transition to the acceptance of stand-alone submissions in eCTD format
and now accepts all regulatory activities in eCTD electronic-only filling format that are filed in
compliance with the ICH eCTD specification. Sponsors filing a regulatory activity in eCTD format must
comply with the specifications included in; Draft Guidance Document: Preparation of Drug Regulatory
Activities in eCTD (version date March 30 th , 2012) 7 , Guidance for Industry: Creation of the Canadian
Module 1 Backbone 8 , as well as ICH M2 EWG Electronic Common Technical Document Specification
(Version 3.2.2, July 16, 2008) 6 and the corresponding Questions and Answers, developed by the ICH M2
Expert Working Group (EWG) .
The following drug submission information is eligible for filing in eCTD format; New Drug Submission
(NDS), Abbreviated New Drug Submission (ANDS), Supplement to a New Drug Submission (SNDS),
Supplement to an Abbreviated New Drug Submission (SANDS), Notifiable Change (NC) only when
related to previously filed submissions in eCTD format, Forms summarizing the Changes to Marketed
Human New Drug Products: Notices of Change (Level III), only when related to previously filed
submissions in eCTD format, and Periodic Safety Update Reports (PSURs) requested during the premarket
review process by Therapeutic Products Directorate (TPD) and Biologics and Genetic Therapies
Directorate (BGTD). 10
The regulatory activities currently not accepted in eCTD format by Health Canada include; Clinical Trial
Application or Amendment (CTA or CTA-A);Natural Health Product (NHP) application; Drug Master
File (DMF); Site Reference File (SRF); Medical Devices - License Application or Amendment (LAp or
LAm); Lot Release documentation; Adverse Reaction Reports for MHPD. 7
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Module 1Changes
Module 1 contains region specific administrative and local prescribing information. Table 1 contains the
current regional requirements for the eCTD submission in Canada. As displayed in Table 1, Module 1
identifies place holders, defined by numerical items listed in Module 1 table of contents (ToC), for all
administrative and product information documentation. The ToC listing all documents includes in
Modules 1-5 should be placed in section 1.1 1 . The ToC is consistent with the harmonized CTD; the eCTD
also provides a harmonized technical solution to implementing the CTD electronically.
Module 1 has undergone significant revision in the last draft. Notably, 1.0 -Administrative Information
now contains a lifecycle management table (1.0.2), which is a specific requirement for filing submissions
or applications in the eCTD format. Life Cycle Management is comprised of three layers; drug product
layer (Dossier), submission layer (regulatory activity) and the document layer. A life-cycle management
plan should address early drug development, submission filing, monitoring after market authorization,
and all issues that may arise during a drug’s lifetime. 7 The ICH Guidance “Granularity Document Annex
to M4: Organization of the CTD” outlines three levels of allowed granularity for Quality Overall
Summary (QOS). 11 According to ICH, the mid-range granularity consists of separate documents under
each of the following heading sections; Introduction, Drug Substance, Drug Product, Appendices and
Regional. 11 This approach is a compromise between the single file and maximum granularity options. It
would include the highest level headings of the QOS, allowing for fewer files to maintain under lifecycle
management principles. Health Canada does not currently use comprehensive planning for the entire lifecycle
of a drug. Although decisions by Health Canada take into account the history and the future of a
drug, authorization and monitoring take place in discrete steps that are not integrated to form a cohesive
drug life-cycle management plan however can require that drug sponsors file a life-cycle management
plan with their submission to identify the tools and activities that may be necessary during the drug’s
development, review, and entry onto the market. A significant amount of additional background material
has been added, including: a figure illustrating an eCTD Structure showing multiple sequences, an
example of the Life Cycle Management Table, a series of tables illustrating valid and invalid scenarios for
life cycle management scenarios for operation attributes. 7 Companies are using a variety of approaches
for the presentation of the QOS. Experience shows that health authorities have accepted each of these
approaches without expressing a consistent preference. 11 The QOS is a summary document that follows
the scope and outline of the Body of Data in Module 3 -Quality. Module 3.2.R Regional Information now
contains a yearly biological product report (YBPR) – for Biologics and Genetic Therapies Directorate
(BGTD) only 7 . There are currently is no clear regulatory guidance regarding eCTD-specific topics which
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facilitate the submission and subsequent lifecycle management of the QOS in electronically filed
registration applications. 11
Administrative information (1.2 – 1.2.9) now contains; intellectual property information, good
manufacturing processes (GMP) and establishment of licensing information have been broken down into
twelve separate modules (1.2.5 – 1.2.5.7). As of 2008, the regulatory experts from the European Union
and Canada are able to exchange confidential information about the authorization and safety of
medicines. 12 Module 1.2.6 authorization for sharing information has replaced Module 1.2.6 letter of
access in the revised guidance. DMF and Site Reference Files (SRF) should be provided in the section.
Confidentiality arrangements were agreed between the European Commission and the European
Medicines Agency (EMEA) on the one side and the Health Products and Food Branch of Health
Canada. 12 The partners will be able to exchange confidential information, for instance on safety issues
with marketed medicines and therapeutic products being developed or considered for authorization. The
potential benefits of this exercise are expected to include: accelerated access of patients to new and
innovative medicines; improved performance and safety as a result of the involvement of the best
available regulatory expertise from both the EU and Canada.
The status of outstanding Post-Marketing commitments, that are not subject to the Notice of Compliance
with conditions (NOC/c) policy, either because they do not meet the requirements or because they are
Level II changes, over the lifecycle of a product, in tabular form in the Post- Authorization Information
section (1.2.8). 7
Product information, formerly product labeling (1.3) has seen the addition of; the Investigator Brochure
(IB), Reference Product Labeling, Certified Product Information (CPID) and a Look-alike / Sound alike
Assessment (1.3.7) and Pharmacovigilance Information (1.3 – 1.3.7). LA/SA names with spelling
similarities and/or similar phonetics tend to create confusion for the Health Products and Food Branch
(HPFB) in its review and analysis of a health product name. 13 Furthermore, such names may constitute a
tangible risk to Canadians health by increasing the potential for errors in the prescription, dispensing or in
the administration of a drug. Health Canada Summaries (1.4) has been revised. The CPID formerly filed
in 1.4.1 has been moved to 1.3.6. In its place are Protocol Safety and Efficacy Assessment Templates –
Clinical Trial Application (PSEAT-CTA) is listed. In 2008, the PSEAT-CTA replaced the Preclinical and
Clinical Evaluation Report Template (PCERT) listed in Appendix 4 of the Guidance for Clinical Trial
Sponsors – Clinical Trial Applications posted in June 2003. 14
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A Multidisciplinary Tabular Summary section (1.4.3) has been added 1 . The title of Module 1.6 has been
changed from Electronic Review Documents to Regional Clinical Information and now contains
comparative bioavailability information for pivotal comparative bioavailability (bioequivalence) studies
(1.6.1). Module 1.7 Clinical Trial Application and Clinical Trial Application Amendment (CTA-A)
Specific Requirements has been added. 7 The section includes; submission rationale / brief (1.7.1), study
protocol (1.7.2), informed consent forms (1.7.3), Canadian research ethics board (REB) refusals (1.7.4)
and information on prior-related applications (1.7.5). A section for appendices has been added (1.A). The
electronic review package (1.A.1) is the only item listed in this section. All electronic media submitted to
support the drug submission or application should be placed in this section.
Health Canada also made major changes in its Module 1 metadata, including adding elements applicant,
product-name, dossier-identifier, dossier-type, regulatory-activity-type, regulatory-activity-lead and
removing elements submission-identifier, and submission-date. The eCTD Regulatory Transaction
Information section allows information about the submission and sequence to be included in a form which
is easily processed. 7 This information, broadly categorized as metadata, allows Health Canada to more
effectively manage incoming electronic submissions and lowers the possibility of errors introduced by
manually re-entering this key data. On the technical front, the revised eCTD guidance calls for a technical
change to the use of a Schema instead of DTD. 9 The current implementation timeline to accept regulatory
activities built with the revised Canadian Module 1 Schema is late September 2012 9 . As of March 21,
2013, Health Canada will no longer be accepting regulatory activities built with the old Canadian Module
1 DTD 9 .
Periodic Safety Update Reports (PSURs) requested during the pre-market review process by Therapeutic
Products Directorate (TPD) and Biologics and Genetic Therapies Directorate (BGTD) may be filed in
eCTD format. 15 PSURs submitted to the Marketed Health Products Directorate (MHPD) may not be filed
in eCTD format. SNDS and SANDS are not longer limited to being filed when the original NDS or
ANDS was in eCTD format. 15 Health Canada will now allow a sponsor to switch to eCTD format for any
major submission (like the FDA and EMEA). 10
Next Steps
At this time, the plan and timeline for implementation includes; publication of the final version of this
guidance and the final Canadian Module 1 Schema by end of March 2012, regulatory activities built with
the revised Canadian Module 1 Schema to be accepted by end of September 2012, transition of eCTD
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submissions to the proposed Module 1 format by March 21, 2013 at which time Health Canada will no
longer be accepting regulatory activities built with the Canadian Module 1 format. 4
HC-FDA Regulatory Cooperation Council (RCC) Initiatives
The Health Canada -FDA Regulatory Cooperation Council (RCC) released the Joint Action Plan on
Regulatory Cooperation on December 7, 2011. 16 The Joint Action Plan is a practical first step to increased
regulatory cooperation between the United States and Canada. Implementation of a common electronic
submission gateway, common monographs for over-the-counter drug (OTC) and good manufacturing
processes are the first three RCC initiatives. Action plans for each initiative were released in May 2012
and are expected to be completed within two years. 16
Implementation of a Common Electronic Submission Gateway, using the current US gateway that allows
industry clients the ability to submit large size electronic documents seamlessly to Health Canada and US
FDA with a view toward further catalyzing increased review collaboration between the two regulatory
agencies, increased efficiency of sovereign decision making, and improved access to the introduction of
medicines for patients in both countries. Current plans include a pilot of this the e-submission gateway
process this summer with the intent of going live by the end of 2012. 16
The objectives of the RCC monograph alignment working group are to conduct a pilot program to
develop aligned monograph elements for a selected over-the-counter (OTC) drug category (e.g. aligned
directions, warnings, indications and conditions of use). Subsequently, the plan is to develop
recommendations to determine the feasibility of an ongoing mechanism for alignment in review and
adoption of these OTC drug monograph elements. 16 Finally, there is a plan to enhance collaboration on
enforcement and compliance by increasing mutual reliance on each other’s routine surveillance good
manufacturing practices (GMP) inspection reports of manufacturing facilities for drugs and personal
products, rather than having to conduct unnecessarily duplicative inspections in the other country. 16
Conclusion
Health Canada has made a great deal of progress towards the goal of moving to an eCTD only submission
process however there is still work to do. At this time, Health Canada is still accepting regulatory
submissions using the hybrid format. 17 Through the formation of the RCC, Health Canada and the FDA
will be able to align to common international data standard requirements (e.g. Regulated Product
Submissions) to support two-way communications and submission lifecycle management. The FDA is
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much further along in the implementation electronic submission process and has a wealth of experience to
share. In a time of budget cuts that have affected both countries regulatory bodies, modernizing the
regulatory and policy process in a way that fosters collaboration both now and in the future has the
potential to not only reduce costs but to increase quality and safety in the process. Careful attention must
be paid to ensure the standards adopted through harmonization do not result in a lowering of the current
guidelines.
Table 1: Regional Information for Canada – Required for the eCTD.
Regional Information for Canada
Administrative Information and Prescribing Information
1.1 Table of Contents (Modules 1-5)
1.2 Application Information
1.2.1 Drug Submission Application Form (HC/SC 3011)
1.2.2 Drug Submission Fee Application Form
1.2.3 Submission Certification Form
1.2.4 Patent Information
1.2.5 Good Manufacturing Practices (GMP) and Establishment Licensing (EL) Information
1.2.6 Letters of Access
1.2.7 International Registration Status
1.2.8 Other Application Information
1.3 Product Labeling
1.3.1 Product Monograph
1.3.2 Inner and Outer Labels
1.3.3 Non-Canadian Package Inserts
1.4 Health Canada Summaries
1.4.1 Certified Product Information Document
1.4.2 Comprehensive Summary: Bioequivalence
1.5 Environmental Assessment Statement 10
1.6 Electronic Review Documents
2 Common Technical Document Summaries
2.3 Quality Overall Summary - Chemical Entities
(QOS-CE) and Analytical Procedures and
Validation Information Summaries
3.2.R.1
Quality
Production Documentation
3.2.R.1.1 Executed Production Documents
3.2.R.1.2 Master Production Documents
3.2.R.2
3.2.R.3
Medical Devices
Executed Batch Records (not applicable
to Positron-Emitting
Radiopharmaceuticals (PERs))
(applicable to PERs only)
Lot Release Documentation
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References
1.ICH Secretariat, 2008, “The value and benefits of ICH to Drug Regulatory Authorities – Advancing
harmonization for Better Health”
2. Group on Electronic Regulatory Affairs (GERD) Activities Recommendations: White Paper; 31-Oct-
2012.
3. Government of Canada, 2005, “Regulations and Beyond: Progress on Canada Therapeutic Access
Strategy”.
4. Health Products and Food Branch (HPFB) strategic frameworks: the 2007-2012 Strategic Plan:
http://www.hc-sc.gc.ca/ahc-asc/pubs/hpfb-dgpsa/map-feuille-2007-2012-eng.php
5. Release of Health Canada's Revisions to"1.6 Electronic Review Documents" in Draft Guidance for
Industry: Preparation of New Drug Submissions in the CTD Format.25-Feb-2008: http://www.hcsc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ctd/notice_avis_ctd-eng.php
6. ICH-M2 Expert Working Group; Electronic Common Technical Document Specifications V 3.2.2; 16-
Jul-2008.
7. Draft Guidance Document: Preparation of Drug Regulatory Activities in Electronic Common Technical
Document (eCTD) 30-Mar-12: http://www.hc-sc.gc.ca/dhp-mps/consultation/drugmedic/ctd_prep_draft_rev_ebauche_nds_2011-eng.php
8. Draft Guidance for Industry: Creation of the Canadian Module 1 Backbone 30-Mar-12: http://www.hcsc.gc.ca/dhp-mps/consultation/drug-medic/draft_ebauche_ectd_mod1_guide-ld-eng.php
9. Draft Canadian Module 1 Schema Version 2.1: http://www.hc-sc.gc.ca/dhp-mps/consultation/drugmedic/notice_draft_ectd_schema_ebauche_avis-eng.php
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10. Notice - Increased Scope of Submissions being accepted in Electronic Common Technical Document
(eCTD) electronic-only filing format: 30-Sep-11: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applicdemande/guide-ld/ctd/ectd/notice_scope_ectd_avis_augm-eng.php
11. Boehringer Ingelheim, Glaxo-Smith Kline, Image Solutions Inc, Lundbeck, Inc, Merck, Pfizer, sanofiaventis,
Takeda, and ePharmaCMC; March, 2010, Industry Book of Knowledge Practical Considerations
for eCTD Submissions: Quality Overall Summary (QOS) for Marketing Applications, QOS eCTD/CMC
v1.2.
12. Health Canada, EMEA; Closer ties on medicines safety between European and Canadian regulatory
authorities, 2008: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/announce_hcec-emea-sc_annonce-eng.pdf
13. Release of Revised Guidance Document: Drug Name Review: Look-alike Sound-alike
(LA/SA) Health Product Names: 31-Oct-2005: http://www.hc-sc.gc.ca/dhp-mps/brgtherap/proj/alikesemblable/lasa-pspcs_post_market-comm_guidance-directive_2-eng.php
14. Therapeutic Products Directorate (TPD) and Biologic and Genetic Therapies Directorate (BGTD)
Protocol Safety and Efficacy Assessment Template-Clinical Trial Application (PSEAT-CTA), 2008:
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/templatesmodeles/notice_pseat_cta_avis_meiep_dec-eng.php
15. Notice Regarding the Implementation of a Risk-Prioritized Periodic Safety Update Report Regulatory
Review Pilot at Health Canada, including the adoption of International Conference on Harmonization
(ICH) Guidance Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs -
ICH Topic E2C, as of April 1, 2010: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guideld/vigilance/notice_avis_psur-rrp_pecr-rppv-eng.php
16. Health Canada and FDA; Common Electronic Submissions Gateway (ESG) Work Plan - Proposal to
explore and develop joint proposals to identify on-going systemic alignment mechanisms between the
U.S. Food and Drug Administration (FDA) and Health Canada (HC):
http://actionplan.gc.ca/eng/feature.aspmode=preview&pageId=456
17. Non-electronic Common Technical Document (eCTD) Hybrid Pilot 27-Apr-12: http://www.hcsc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ctd/ectd/notice_non_ectd_hybrid_pilot_aviseng.php
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