Organization and document placement for Canadian module 1

• Cover Letter

• Refer to the relevant sections of the eCTD and non-eCTD Guidance Documents for detailed information regarding the Cover Letter requirements.
  • The cover letter is not required when filing Post NOC changes: Level III form

Do not include in this section:

• Scientific information
• Summary response in a Question and Answer format
• Response to request for additional information

• Life Cycle Management (LCM) Table (eCTD only)

• The copy of the original request issued by Health Canada, such as (but is not limited to):
  • Request for Clarification (during processing, screening or review)
  • Notice of Deficiency (NOD)
  • Notice of Non-Compliance (NON)
  • Not Satisfactory Notice (NSN)
  • Post-Notice of Compliance Letters (Post-NOC)
  • No Objection Letter (NOL)
  • Screening Deficiency Notice (SDN)
  • Advisement Letter
  • Priority Review Decision Letter
  • Advanced Consideration NOC/c Decision Letter
  • Post-Market Request Letter
  • Master File Administrative Process Hold Letter

• Summary response in a Question and Answer format

• The summary response in a Question and Answer format:
  • should summarize the response and cross-reference the supporting data placed in the appropriate Module of the regulatory activity
  • is in response to questions posed by any division at Health Canada
  • should be a single document that answers all questions
  • may be incorporated as a separate document, when prepared by the master file holder and provided by the sponsor in support of a regular submission (such as ANDS)

Do not include in this section:

• Supporting data; examples: revised specifications, additional stability data, revised analytical methods, PSUR, Certificate of Analyses, GMP attestation, Letter of Authorization, payment document, clinical study data, etc.

• Any meeting related information and documentation such as:
  • Meeting request
  • Meeting information package¹
  • Brief slide presentation
  • Sign-In Sheet
  • Meeting minutes

• The items listed should be provided as separate documents.
• ¹Meeting Information package should be provided as one single file.

Do not include in this section:

• Pipeline and Reconsideration meetings

• Letter of Intent
• Request for Reconsideration
• Other Reconsideration related Information (such as presentations, background documents, draft questions)

• Note to Reviewer¹
• Post NOC/DIN Quality Changes Chart (summary document)
• Expert Statements
• Expert Opinions
• PAAB approved documents, promotional material
• Expression of Interest (EOI) Request Form / Summary of Differences (ACCESS Consortium)
• A side-by-side comparison table (summary of changes) listing all changes for Master File Updates² (MF only)
• A side-by-side comparison table (summary of changes) listing all changes for Master File conversions provided as a complete replacement for an existing MF in paper format. (for MF in non-eCTD format only)²
• A side-by-side comparison table (summary of changes) listing all differences between the CEP and the Canadian Master file² (MF only)
• Summary of Batch Analyses for Clinical Studies Chart
• Completed Template for Determination of medical necessity of a drug product (FRM-0378)³
• Proposed redaction control sheet (Public Release of Clinical Information (PRCI))
• Anonymization report (PRCI)
• Prescription Drug List (PDL) Principles and Factors Assessment⁴
• Application Plan – list of document to be provided for Covid19 submissions⁵
• Canadian Pediatric Development Plan (C-PDP)
• Canadian addendum to the approved foreign PDP
• Amended Canadian Pediatric Development Plan
• Annual report for foreign approved PDP
• Annual report for Canadian PDP
• Pediatric Pilot Survey

• ¹Notes to reviewers are not a requirement. However, if sponsors include them, the following guidelines are provided to promote a consistent approach to their naming and placement within the regulatory activity.
  • A Note to Reviewer that addresses the regulatory activity as a whole should be in this section.
  • A Note to Reviewer that is specific to a section should be filed as the first leaf element/document in that section. For example, a Note to Reviewer that addresses the product monograph should be filed as a leaf element under the m1-3-1-product-monograph heading. The title of the leaf should be "Note to Reviewer PM".
• ²Do not include supporting information in the side-by-side comparison table document. The document should only contain the table, and all other supporting information must be placed in the relevant sections of modules 2 and 3.
• ³Must be provided as part of the actual regulatory activity such as ANDS, and not as a standalone regulatory transaction.
• ⁴Appendix B: Completing the PDL principles and factors assessment of the Draft Guidance Document: Switching a medicinal ingredient from prescription to non-prescription status.
• ⁵As per the Guidance Documents; Guidance on amendments to the Food and Drug Regulations for drugs for use in relation to COVID-19, Guidance for market authorization requirements for COVID-19 drugs, Guidance for market authorization requirements for COVID-19 vaccines.

Do not include in this section:

• A Note to Reviewer that is specific to a section should be filed in that section.

• Table of Contents (non-eCTD format only)

• A table of contents should not be provided for transactions in eCTD format.

• Regulatory Transaction (RT) XML file¹
• Product Information (PI) XML file²
• Third Party Authorization letter (for regulatory activities using REP only)³
• Submission Application Form (HC-SC3011) with applicable appendices (for Clinical Trials only)⁴
• Template Authorisation for a Third Party to Import the New Drug Described in the Clinical Trial Application or Amendment - Appendix 1 of HC-SC3011 form (Clinical Trial Notifications only)
• Template Authorisation for a Third Party To Sign/File a Drug Submission Application on Behalf of the Manufacturer/Sponsor – Appendix 2 of the HC-SC3011 form (Clinical Trial Notifications only)
• Master File Application Form⁵ (MF only)
• Agent Appointment Letter (MF only)
• Application for Authorization of Positron-emitting Radiopharmaceuticals (PERs) for Use in a Basic Clinical Research Study – Appendix 1 (for Basic Research Applications (BRAP) only)

• ¹As per the Guidance document: The Regulatory Enrolment Process (REP), the RT file replaces the submission application form (HC-SC3011) and the drug submission fee form.
• ²As per the Guidance document: The Regulatory Enrolment Process (REP), the PI file replaces the submission application form (HC-SC3011).
• ³Authorization to be provided within a regulatory transaction only if the party signing the regulatory activity is a third party acting on behalf of the Manufacturer/Sponsor. A separate authorization is required for each regulatory activity. For non-REP regulatory activities, this attestation is included on the HC-SC3011 form.
• ⁴When provided as part of a regulatory activity, the HC-SC3011 form must be provided as one single file including the applicable appendices. The appendices must not be separated and placed in other sections of module 1.
• ⁵Web-based Master File Application Form (generates an XML file)

• As per the Guidance document: The Regulatory Enrolment Process (REP), the fee form is built into the Regulatory Transaction XML file.
• For master file transactions the fee form is merged with the Master File Application Form.

• Sponsor Attestation: SANDS for Generic Drugs - Product Monograph Updates to be in line with the CRP¹
• Submission Certification Form^2,3 for NDS, SNDS, ANDS, SANDS, NC
• Drug Identification Number (DIN)³ Submission Certification for Human Drugs and Disinfectants.
• Sponsor Attestation Checklist for an ANDS
• Check list for filing requested Development Safety Update Report (DSUR) in electronic format
• Annual Summary Report Checklist (including PSUR and PBRER)
• Labels and Packages Certification Form for Prescription Products
• Labels and Packages Certification Form for Non-Prescription Drugs
• Non-prescription drug monograph attestation form⁴
• Administrative changes Certification Form (For Human Drug and/or Disinfectant regulatory activities)
• Bovine Spongiform Encephalopathy (BSE)/Transmissible Spongiform Encephalopathy (TSE) Attestation Form
• Attestations from the Active Pharmaceutical Ingredients (APIs) Manufacturer authorizing Health Canada to refer to the CEP and EDQM assessment reports
• Certification of Suitability to the Monographs of the European Pharmacopoeia (CEP) issued by the European Directorate for the Quality of Medicines and Healthcare (EDQM)
• CEP – Attestations
• Statement of Commitment (MF only)
• Summary of Additional Drugs (SOAD) form – Appendix 4 of the CTA guidance (Clinical Trials only)
• Research Ethics Board (REB) attestation or Institutional Review Board) IRB approval (if requested) (Clinical Trials only)
• Qualified Investigator Undertaking (QIU) Form (if requested) (Clinical Trials only)
• Research Ethics Board Attestation, or Research Ethics Board Approval Letter - Appendix 2 (for Basic Research Applications (BRAP) only).
• Certification letter with table of previously redacted information (PRCI)

• ¹This document includes the "Document Compare 1: Summary of differences between proposed Product Monograph (PM) and most recent Canadian Reference Product (CRP) PM" and "Document Compare 2: Summary of Differences between proposed PM and most recently approved PM".
• ²Required as per section C.08.005.1 of the Food and Drug Regulations. The use of company letterhead is preferred. Please see the Health Canada website for an example of appropriate wording.
• ³To be signed and dated by the senior executive officer of the manufacturer in Canada and the medical or scientific director of the manufacturer. If the submission certification or any significant part of the certification was prepared by an agent authorized by the manufacturer, the submission certification must also be signed by that agent.
• ⁴To be signed by the associate filing the submission, does not require to be signed by an executive/medical director. If the attestation or any significant part of the attestation was prepared by an agent authorized by the manufacturer, the attestation must also be signed by that agent.
• Each of the documents listed in the column beside must be filed as single pdf files.

• Written correspondence related to the Patented Medicines (Notice of Compliance) Regulations. This includes written representations and any attachments such as affidavit evidence
• Notice of Allegation and proof of service under the Patented Medicines (Notice of Compliance) Regulations
• Form IV, including updates, filed in accordance with the Patented Medicines (Notice of Compliance) Regulations
• Form V, including updates, filed in accordance with the Patented Medicines (Notice of Compliance) Regulations
• Consent letters under the Patented Medicines (Notice of Compliance) Regulations

• In accordance with the Patented Medicines (Notice of Compliance) Regulations (PM(NOC) Regulations), a first person who files or who has filed a new drug submission or a supplement to a new drug submission may submit a patent list in relation to the submission or supplement for addition to the Patent Register by filing a Form IV: Patent List within the time limits and according to the conditions set out in section 4 of the PM(NOC) Regulations. Documents related patent listing eligibility are to be placed in this section.
• A second person (i.e. subsequent entrant) who seeks approval on the basis of a comparison with or reference to a drug on the Patent Register must address all patents listed on the Patent Register against that drug by first filing a Form V: Declaration Re: Patent List in accordance with section 5 of the PM(NOC) Regulations. Form Vs, consent letters and a copy of the Notice of Allegation and proof of service are to be placed in this section.

Do not include in this section:

• Litigation documents listed under section 6.13 of the Patent Medicines (Notice of Compliance) Regulations or verification requests under section 6.05. Refer to the Guidance Document: Patented Medicines (Notice of Compliance) Regulations.

• Written correspondence related to data protection under section C.08.004.1 of the Food and Drug Regulations. This includes written representations and any attachments such as affidavit evidence.
• Consent letters (data protection)

• Section C.08.004.1 of the Food and Drug Regulations provides a term of data protection for innovative drugs during which the Minister shall not approve a subsequent entry submission submitted for a new drug on the basis of a comparison between the new drug and the innovative drug. The term of data protection is effective from the date of the issuance of the Notice of Compliance and extends to eight years (or eight and one-half years if relevant paediatric clinical trial data is submitted). Information that supports the eligibility of an innovative drug for data protection or consent letters from an innovative drug manufacturer are to be placed in this section.

• Clinical Trial Site Information Forms (CTSI)

• As per the instructions for completing the CTSI form, https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/forms/instructions-clinical-trial-information-form.html, the CTSI form should be provided using the on-line form available on Health Canada's website at: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/forms.html

• Documents related to Establishment Licensing
• Canadian EL information should be provided for each new site involved in the manufacture of the drug substance, bulk process intermediate and drug product. Alternatively, a commitment that an EL application has/will be filed to ROEB may be provided (Biologics and Radiopharmaceuticals only)
• Copy of the acknowledgement of Application Acceptance for the DEL application provided by ROEB, if applicable¹.

• ¹Refer to the Notice: Submission Filing Requirements - Good Manufacturing Practices (GMP)/Drug Establishment Licences (DEL) dated February 10, 2017 for more information.

• Documents related to Good Clinical Licensing

• Documents related to Good Laboratory Practices

• A statement of GLP compliance consistent with the Organisation for Economic Co-operation and Development's (OECD) Principles of Good Laboratory Practice (GLP) should be placed in this section.

• Any other regulatory compliance and site-related information which is not currently covered under Module 1.2.5.1-1.2.5.6 should be placed in this section.

• Letters authorizing Health Canada to share information regarding the regulatory activity with other regulatory authorities (or vice versa), and/or to access other (third party) drug regulatory activities, Master Files and Site Reference Files (SRF). This may include, but not be limited to, the following:
  • Cross Reference Authorization Letter (Administrative Submissions¹)
  • Cross Reference Letter (Clinical Trials only)
  • Transfer of Ownership Letter (Clinical Trials only)
  • Letter authorizing sharing of information²
  • Letter of Access³
  • The up to date list of all applicants authorized to access the MF (MF only)⁴

• When providing a MF conversion, identical copies of all previously filed Letters of Access are recommended to be provided (one letter per pdf file with the name of the company, to whom access is granted, as the pdf file name).
• ¹Guidance Document: Administrative Processing of Submissions and Applications Involving Human or Disinfectant Drugs
• ²For sharing with health technology assessment organizations (HTAs).
• ³Each Letter of Access must be filed as single pdf file as per the Guidance document: Guidance Document: Master Files (MFs) - Procedures and Administrative Requirements.
• ³The Letter of Access (LoA) for Master files dossiers must be organized using node extensions for master file types 2 and 3s. The title of the node extension(s) must reflect the name of the company to which the access is granted. When subsequent LoAs are provided for the same company, the existing node extension must be used.
• ⁴Required with Master file Conversions and Administrative changes as per the Guidance Document: Master Files (MFs) - Procedures and Administrative Requirements sections 2.1.4.1 Converting MFs from the non-eCTD Format to the eCTD Format and 2.4.1 Administrative changes.

• Information on the product application, approved indications and marketing status in other countries/regions provide useful contextual information should be provided in this section when requested. Depending upon the status this may include, but not be limited to, the following:
  • International registration, review and/or marketing status, including date of filing, approval of product or supplemental changes in other jurisdictions, information regarding the withdrawal, stop of sale and/or market recall¹
  • Foreign Regulatory refusals
  • Foreign Research Ethics Board (REB) Refusals (Clinical Trials only)
  • Foreign clinical trial status
  • International Birth Date of the product and for all approved indications
  • Confirmation of filing or the date(s) of approval or withdrawal
  • Foreign review reports, including Question and Answer (Q and A) documents (upon request only)¹
  • Meeting minutes from other jurisdictions (upon request only) ¹.
  • Foreign Review Attestation
  • Assessment Aid (AAID) document²
  • Response documents for requests issued under Project Orbis¹
  • Foreign Pediatric Development Plan¹ (Food and Drug Administration (FDA) agreed, iPSP) and (European Medicines Agency (EMA) approved, PIP)
  • Foreign amended Pediatric Development Plan¹

• ¹A copy of the information received from or responses provided to other regulatory agencies. This information must be organized using node extensions (subsection) using a title relevant to the agency and/or organization (i.e., EMA, FDA, TGA, WHO). When subsequent information is provided for the same agency, the same title of the node extension must be used.
• ²For submissions filed under the Project Orbis initiative

• Market Notification Forms¹
• Post-Authorization Commitments²
• Notices of Change (Level III) forms³
• Notice of Decision and Summary Basis of Decision documents (all versions)
• Regulatory Decision Summary (RDS) - Summary of Cancellation

• ¹As per part C.01.014.3 of the Food and Drugs Regulations, companies are required to notify Health Canada of a drug being sold.

• ²Commitments are periodically made by the sponsors to provide additional information to Health Canada in order to further support the approved regulatory activity.

  Regulatory activities with Post-Authorization commitments should be tracked. These are the Post-Authorization commitments not subject to the NOC/c policy. For Post-Authorization commitments subject to the NOC/c policy, provide the information in Module 1.6.4.

  Some examples include (but are not limited to) the following:

  • additional stability data
  • periodic updates of ongoing trials or surveillance programs
  • risk management studies (e.g., phase IV, pharmacoepidemiologic, drug utilization studies)I

  To track the status of outstanding commitments over the Lifecycle of the product, the following table should be included in section 1.2.8 Post-Authorization Information.

  • Summary of Commitment
  • Date of No Objection Letter/ Notice of Compliance
  • Control #
  • Date Outstanding Information Provided
  • Date of commitment closure by Health Canada

  Once the commitment has been closed off by Health Canada, it should remain in the table for at least one subsequent regulatory activity, after which it can be removed.

  If there are no open commitments, a statement confirming there are no outstanding commitments should be provided.

• ³These forms should not be confused with the Annual Drug Notification Form, which is not included in the scope of this document.

• This section is for any administrative information that does not have a designated location for example:
  • Certificate of amalgamation
  • Proof of Company name change
  • Proof of Company address change
  • Certificate of Continuance

• Scientific information

• Product Monograph (annotated and clean) ¹
• Second Language Product Monograph¹
• Prescribing Information (annotated/clean)
• Second Language Prescribing Information

• The text of the annotated copy at the time of filing should be cross-referenced to supporting information and study findings reported in Module 2 documents and, when submitted, the Bioequivalence Summary (Module 1.4.2). Applicants may also choose to include references to related information in Modules 3 to 5, as appropriate.
• Articles from publications listed in the References section should be cited in accordance with the current edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journals Editors (ICMJE).
• When reference is made to a publication not provided in Modules 2 - 5, copies of the reference material should be provided in this section.
• When revisions are requested during the course of the review, an annotated version of the revised Product Monograph is required. The annotations should reflect all changes made, either in relation to the last approved PM or in response to a request made from Health Canada.
• ¹Including Product Monographs in Extensible Markup Language (XML) Format and related images as per the Guidance Document: Draft Guidance Document
• Preparation of the Product Monograph in Extensible Markup Language (XML) Format.

Do not include in this section:

• Literature references related to the Product Monograph (for proper, placement refer to section 2.4.2 of the Guidance Document: Preparation of Regulatory Activity in eCTD format)

• Inner and outer labels
• Package Inserts (English and French)
• Images, Audio, Video files of the electronic platform¹
• Electronic Canadian Drug Facts Table (eCDFT)²

• Include the mock-up labelling materials for all applicable strengths, dosage forms and reconstitution diluents. Typewritten or other draft label copy is acceptable for review purposes where waivers to submit mock-up labelling materials are permitted.
• When additional revisions are requested during the course of the review, an annotated version of the revised label maybe requested, and should be placed in this section.
• ¹As per the Guidance Document: Electronic Media in Prescription Drug Labeling these files must be provided as separate stand-alone files in an acceptable format as per the validation rules document.
• ²For non-prescription drugs as per Labelling requirements for non-prescription drugs guidance document.

• Copy of approved labelling from other regulatory jurisdictions

• If the drug product has been marketed outside Canada, the applicant is encouraged to supply the monograph or package inserts approved in other jurisdictions, clearly identifying them by country or region.

• Investigator's Brochure

• Product Monograph for Canadian Reference Products
• Product Monograph for Canadian Reference Biologic Drug
• Canadian Reference Product Labels
• Other Reference Product Labels

• Certified Product Information Document (annotated/clean)

• The text of the annotated copy at the time of filing should be cross-referenced to the corresponding sections of Module 3, while any further revisions should reflect all changes that have been made, including Level III changes. The clean version should not contain any cross-referencing.

• Look alike/Sound alike Assessment
• Audio files¹

• ¹Audio files, when included in the transaction, must be provided, as standalone files, in an acceptable format as per the validation rules document.

• Pharmacovigilance Plan

• Risk Management Plans (RMP)

• Specify on the Risk Management Plan title page and the submission cover page if submitted under the Terms and Conditions commitment for the new opioid regulations.

• Dear Health Care Professional Letter
• Dissemination lists
• Proposed dissemination strategy
• Dear Investigator/Doctor Letter (Clinical Trials only)

• Response to MHPD request for additional information
• Development Safety Update Report (DSUR)
• Line listings
• Registry reports or clinical study reports
• Patient exposure data
• Benefit-risk assessment
• Notification of change in benefit-risk profile
• Issue-related summary report
• Post-authorization commitments for Post market Vigilance (reports, updates, plans for risk mitigation activities in other jurisdictions, proposals for change of continued monitoring strategies, etc.)
• Educational materials (such as Patient Kit, Brochure, Health Care Professional Guide)
• Response to Terms and Conditions commitment, Test and Studies order, or Reassessment order
• Foreign Safety Action Notification/Information
• Endpoint Adjudication Committee (EAC) Charter document
• Enrollment Suspension (Clinical Trials only)
• Regulatory Hold (Clinical Trials only)
• Safety Update such as quarterly or ad hoc reports (Clinical Trials only)
• Study Suspension (Clinical Trials only)
• Response to OCT-ADR requests for information
• Data Safety Monitoring Committee Charter (Clinical Trials only)
• Data Safety Monitoring Committee Reports and Decisions (Clinical Trials only)

• Protocol Safety and Efficacy Assessment Template - Clinical Trial Application (PSEAT-CTA)
• Protocol Summary (BRAPs only)
• Investigational Status Assessment (ISA)

• Comprehensive Summary: Bioequivalence (CS:BE)
• Biopharmaceutics Modelling Evaluation
• Biopharmaceutics Classification System (BCS) based biowaiver

• Summary tables

• Data for the microbial claims (Disinfectants only)

• ¹This section is available only for regulatory transactions in Non-eCTD format.

• In September 2001, the New Substances Notification Regulations (NSNR) of the Canadian Environmental Protection Act, 1999 (CEPA) came into effect for substances in products regulated by the Food & Drugs Act. Substances affected include those used in pharmaceuticals, medical devices, cosmetics and personal care products, veterinary drugs, food additives, novel foods, biologics (including genetic therapies) and natural health products. Under the NSNR, a New Substances Notification (NSN) may be required before a new substance can be imported into or manufactured in Canada, whether on its own or as part of a product. A substance is considered new if it is not listed on the Domestic Substances List (DSL).
• For information regarding the NSNR, including who is responsible for notification, please visit the New Substances program website: www.canada.ca/new-substances.
• For questions regarding the NSNR, please contact the Environmental Assessment Unit at 613-948-3591; 1-866-996-9913; or eau-uee@hc-sc.gc.ca.

• Canadian Reference Product (CRP) Confirmation (e.g., proof of purchase)
• Requests for waivers and justification statements
• Verification of potency of the Test and Reference products (Certificates of Analysis)
• Pharmacokinetic data files

• Pharmacokinetic data files from pivotal BA/BE studies (.inf and.dat in ASCII format)

• Company Core Data Sheets

• Clinical Assessment Package

• The Copy of the Priority Review Decision Letter issued by Health Canada must be placed under 1.0.3 Copy of Health Canada Issued Correspondence section.

• Letter of Undertaking
• Qualifying Notice
• NOC/c Post-Authorization Commitments

• Documentation relating to an NOC/c is to be placed in this section only.
• The Copy of Notice of Compliance Decision Letter issued by Health Canada must be placed under 1.0.3 Copy of Health Canada Issued Correspondence section.

• Study Protocol
• Study Recruitment Timeline Extension
• Other Protocol related documents e.g. Protocol clarification letter, Pharmacy manual (if requested), Operational Manual (if requested)

• Informed Consent Forms

• Canadian Research Ethics Board (REB) Refusals

• Information on Prior-related Applications