Health Canada Guidance Document: Management of Drug Submissions & Applications PDF

Guidance Document Management of Drug Submissions and Applications Date Adopted: 2020/11/26 Revised Posted: 2022/08/02 Effective Date: 2022/08/02 Health Canada is responsible for helping Canadians maintain and improve their health. It ensures that high-quality health services are accessible, and works to reduce health risks. Également disponible en français sous le titre : Ligne directrice : Gestion des présentations et des demandes de drogues To obtain additional information, please contact: Health Canada Address Locator 0900C2 Ottawa, ON K1A 0K9 Tel.: 613-957-2991 Toll free: 1-866-225-0709 Fax: 613-941-5366 TTY: 1-800-465-7735 E-mail: [email protected] © Her Majesty the Queen in Right of Canada, as represented by the Minister of Health, 2022 Publication date: August 2022 This publication may be reproduced for personal or internal use only without permission provided the source is fully acknowledged. Cat.: H164-277/2022E-PDF ISBN: 978-0-660-44261-7 Pub.: 220295 Guidance Document: Management of Drug Submissions & Applications |2 Document change log Version Guidance Document: Replaces Guidance Management of Drug Document: Submissions and Applications Management of Drug Submissions and Applications Date November 26, 2020 (posted Date November 8, 2019 May 21, 2021) Date Change Location Nature of and/or Reason for (Section, Change paragraph) August 2, 2022 Removal of the Submission Section 10.2.3.1 Policy Change Certification requirement for: Section 12.1.3.1  Response to SDN Section 13.6.1  Response to NOD  Response to NON Define the duration of a 10.2.2 Administrative Response to Clarification Request Administrative Updating email addresses Appendix 2 Removal of physical addresses Adding Pharmaceutical Drugs Directorate contact information (formerly Therapeutic Products Directorate) Section 9.3 Policy Change Increase in performance Section 13.3 standard for a Post-authorization Division 1 Change (PDC- Section 13.4 prescription) for prescription Section 15.5 pharmaceuticals and those Appendix 3 administered or obtained through a health professional in Appendix 4 the Pharmaceutical Drugs Appendix 6 Directorate Guidance Document: Management of Drug Submissions & Applications |3  Includes a screening and review component Separate Post-authorization Division 1 Change (PDCs) into:  PDC-prescription  PDC-non-prescription  PDC-disinfectant July 7, 2021 Change to include joint reviews Section 11.1.3 Policy Change with other regulatory authorities into Pause-the-Clock mechanism November 26, Changes were made to reflect Section 2 & Administrative 2020 the new names of the bureaus in Appendix 2 the Marketed Health Products Directorate (MHPD) Change to reflect the new Sections 1.1 &5.1 Administrative Medical Device Directorate Appendix 2 (MDD) Correct the email address for Sections 5 & 5.2 Administrative questions about the classification of products at the device-drug interface to drug.device.classification- [email protected] Guidance Document: Management of Drug Submissions & Applications |4 Date Change Location Nature of and/or (Section, Reason for Change paragraph) November 8, 2019 Deleted: Appendix 3 As of April 1, 2020, new fees along with  Notifiable Changes Section 11.1.3 a revised fee policy (NCs) Safety (90 days) will come into force and Safety (120 day). requiring significant New fee categories for: changes to the  Labelling Only guidance document. (Generic) and Safety Updates to Labelling (each with a 120 day performance standard), and  Labelling Only (Disinfectants) with a 90 day performance standard. Eliminate fee categories for:  Published Data and Rx to OTC Switch. Revised performance standard for:  Labelling Only for Div.1 (180 days to 120 days) and for Div.8 (60 days to 120 days),  DINA, DINF, DIND, Labelling Standard (45 days to 60 days), and  Addition of screening 1, 2 and review 2 timelines for existing and new fee categories where none previously existed. Added: Guidance Document: Management of Drug Submissions & Applications |5  Information regarding the Pause-the-Clock mechanism July 25, 2019 Information was Whole Administrative reorganized and document reformatted to reflect current procedures (with no change to existing practices). Added: Section 5, Addition of new  A section on the information to assist Appendices 6 Classification of a sponsors in the &7 Therapeutic Product, preparation and  An Appendix indicating filing of drug the individual submissions and responsible for signing applications Decision Documents, and  An Appendix listing relevant guidance and policy documents. Deleted: Sections: Deletion of sections  Update Notices, 5.5.1, 5.5.2, from the previous  Final Data, 5.4 version because no  Safety Information, longer used or  Advance Notice Letters, applicable and  Issuance of Sections: 9.1, Acknowledgement 9.1.1 Letters upon receipt of information by OSIP Other Changes: Section 12.1.2 Administrative  Amended the existing 15-day standard timeline for response to a Clarification Request during Scientific Review based on the type and performance standards of the submission/application. Guidance Document: Management of Drug Submissions & Applications |6 Reorganization of the Target Appendix 3 Performance Standards Table (Appendix 3) to delete replication of the classes/types of submissions/applications filed. December 19, 2013 Changes were made (posted December to the document to 19, 2013) reflect an amendment to the Food and Drug Regulations that replaced Schedule F with the Prescription Drug List. Guidance Document: Management of Drug Submissions & Applications |7 Foreword Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. Guidance documents also provide assistance to staff on how Health Canada mandates and objectives should be implemented in a manner that is fair, consistent and effective. Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met. Health Canada reserves the right to request information or material, or define conditions not specifically described in this document, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented. Guidance Document: Management of Drug Submissions & Applications |8 Table of Contents 1. Introduction.............................................................................................................................. 13 1.1 Purpose/overview............................................................................................................... 13 2. Scope and application............................................................................................................... 13 3. Policy objectives........................................................................................................................ 14 4. Background............................................................................................................................... 14 5. Classification of a therapeutic product..................................................................................... 15 5.1 Combination products......................................................................................................... 15 5.2 Other regulations that influence the classification of a drug............................................. 16 6. Specific submission/application pathways............................................................................... 16 6.1 Priority review..................................................................................................................... 17 6.2 Notice of Compliance with conditions (NOC/c).................................................................. 17 6.3 Extraordinary use new drug................................................................................................ 17 6.4 Biosimilar biologic drug....................................................................................................... 18 6.5 Administrative processing................................................................................................... 18 7. Guidance for implementation................................................................................................... 18 7.1 Pre-Submission or pre-application meetings...................................................................... 18 7.1.1 Meeting requests.......................................................................................................... 20 7.1.2 Meeting packages......................................................................................................... 21 7.1.3 Post-meeting requirements......................................................................................... 21 8. Filing of information to Health Canada..................................................................................... 22 8.1. Acceptable formats for filing submissions/applications.................................................... 22 8.2 Filing formats and where to file for CTAs and CTA-As........................................................ 23 8.3 Transmission of electronic data.......................................................................................... 23 9. Submission/application processing.......................................................................................... 23 9.1 Processing of an initial submission/application.................................................................. 23 9.2 Cancellation or withdrawal letter during the processing period........................................ 24 9.3 Submissions/applications for administrative processing.................................................... 25 10. Screening of submissions/applications................................................................................... 25 10.1 Screening of a submission/application during the Screening 1 period............................ 25 10.1.1 Cancellation letter during the Screening 1 period..................................................... 26 10.1.2 Screening Acceptance Letter (SAL)............................................................................. 26 Guidance Document: Management of Drug Submissions & Applications |9 10.2 Solicited Information......................................................................................................... 26 10.2.1 Clarification Requests during the Screening 1 period................................................ 26 10.2.2 Response to a Clarification Request during the Screening 1 period.......................... 27 10.2.3 Screening Deficiency Notice (SDN)............................................................................. 28 10.2.3.1 Response to Screening Deficiency Notice (SDN)................................................. 28 10.2.3.2 Acceptance letter following the response to a Screening Deficiency Notice (SDN)................................................................................................................................ 29 10.2.3.3 Screening Rejection Letter (SRL).......................................................................... 29 11. Scientific Review of submissions/applications....................................................................... 29 11.1 Scientific Review process.................................................................................................. 29 11.1.1 Screening solicited and unsolicited information submitted during the Scientific Review....................................................................................................................... 30 11.1.2 Cancellation letter during the Scientific Review........................................................ 30 11.1.3 Pause the Clock during the scientific review.............................................................. 30 12. Solicited information during the Scientific Review................................................................. 31 12.1 Solicited information......................................................................................................... 31 12.1.1 Clarification Request during the Scientific Review..................................................... 31 12.1.2 Response to a Clarification Request during the Scientific Review............................. 32 12.1.3 Notice of Deficiency (NOD) - NDS, SNDS, ANDS, SANDS or an Application for a DIN (DINA, DINB, DIND).................................................................................................... 33 12.1.3.1 Response to Notice of Deficiency (NOD) - NDS, SNDS, ANDS, SANDS or an Application for a DIN (DINA, DINB, DIND)............................................................. 33 12.1.3.2 Acceptance of a response to a Notice of Deficiency (NOD)................................ 34 12.1.3.3 Notice of Deficiency Withdrawal letter (NOD-W)............................................... 34 13. Completion of the Scientific Review of a submission/application......................................... 34 13.1 Processing of the submission/application following completion of the review............... 34 13.2 Notice of Compliance (NOC) - NDS, SNDS, ANDS, SANDS, EUNDS, EUSNDS, EUANDS, AEUSNDS, NDS-D, SNDS-D, SNDS-c, SANDS-c............................................................... 35 13.3 No Objection Letter (NOL) - Application for a DIN (DINA, DINB, DIND), NC, PDC- prescription, PDC-non-prescription, PDC-disinfectant, PDC-B, CTA, CTA-A................. 35 13.4 Not Satisfactory Notice (NSN) - NC, PDC-prescription, PDC-non-prescription, PDC- disinfectant, PDC-B, CTA, CTA-A.................................................................................... 35 13.5 Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN)............................ 36 13.6 Notice of Non-Compliance (NON) - NDS, SNDS, ANDS, SANDS, or an Application for a DIN (DINA, DINB, DIND)........................................................................................................ 36 13.6.1 Response to a Notice of Non-Compliance (NON)...................................................... 37 Guidance Document: Management of Drug Submissions & Applications | 10 13.6.2 Acceptance of a response to a Notice of Non-Compliance (NON)............................ 37 13.6.3 Notice of Non-Compliance Withdrawal letter (NON-W)............................................ 37 14. Unsolicited information.......................................................................................................... 38 14.1 Safety information............................................................................................................ 38 14.1.1 Information that may be submitted at any time during the submission process..... 38 14.1.2 Information that will not be accepted once the submission has been accepted for review........................................................................................................................ 39 14.2 Foreign regulatory information......................................................................................... 39 14.2.1 Assessment reports.................................................................................................... 39 14.2.2 Correspondence......................................................................................................... 39 14.3 Reports from an expert or from expert advisory committees.......................................... 39 14.4 Changes in the manufacturer’s/sponsor’s name and/or product name during the processing, screening or review of a submission/application...................................... 39 14.5 Efficacy data...................................................................................................................... 40 14.6 Stability data...................................................................................................................... 40 15. Refiled submissions or applications........................................................................................ 41 15.1 Refiling a submission/application following a screening rejection letter......................... 41 15.2 Refiling of a submission/application following a cancellation by the sponsor................. 41 15.3 Refiling of a CTA/CTA-A following the withdrawal by the sponsor.................................. 41 15.4 Refiling a submission/application following a Notice of Deficiency (NOD) withdrawal... 42 15.5 Refiling a submission/application in 5 years or less following a Not Satisfactory Notice (NSN)............................................................................................................................. 42 15.6 Refiling a submission/application in 5 years or less following a NON-W, a cancellation following the issuance of a NON (prior to the issuance of a NON-W).......................... 42 15.7 Refiling of a submission/application more than 5 years after receipt of a NON-W, cancellation following the issuance of a NON (prior to the issuance of a NON-W) or a NSN................................................................................................................................ 43 16. Reconsideration of decisions issued for human submissions and applications..................... 44 17. Accessing submission information.......................................................................................... 44 17.1 Scientific review reports.................................................................................................... 44 17.2 Drug Submission Tracking System (DSTS) - industry access............................................. 45 17.3 Status requests.................................................................................................................. 45 Appendix 1.................................................................................................................................... 46 Definitions................................................................................................................................. 46 Appendix 2.................................................................................................................................... 49 Review centre/bureau/office responsibilities and contact information.................................. 49 Guidance Document: Management of Drug Submissions & Applications | 11 Appendix 3.................................................................................................................................... 55 Performance standards for drug submission/application review............................................ 55 Appendix 4.................................................................................................................................... 60 Notes for the Performance standards for drug submission/application review table in Appendix 3..................................................................................................................... 60 Glossary of abbreviations.......................................................................................................... 60 Notes on terminology............................................................................................................... 61 Appendix 5.................................................................................................................................... 63 Types of administrative holds................................................................................................... 63 Appendix 6.................................................................................................................................... 65 Issuance of decision documents............................................................................................... 65 Appendix 7.................................................................................................................................... 68 Guidance and policy documents on drugs................................................................................ 68 Documents on clinical trials...................................................................................................... 71 Documents on medical devices and combination products..................................................... 71 Documents on biologics............................................................................................................ 71 Documents on pharmacovigilance monitoring......................................................................... 72 Guidance Document: Management of Drug Submissions & Applications | 12 1. Introduction 1.1 Purpose/overview The Guidance Document: Management of Drug Submissions and Applications (MDSA) gives sponsors and Health Canada staff from the Pharmaceutical Drugs Directorate (PDD), the Biologic and Radiopharmaceutical Drugs Directorate (BRDD), the Medical Device Directorate (MDD), the Non-Prescription Drug Evaluation Division (NDED) of the Natural and Non- prescription Health Products Directorate (NNHPD), the Office of Submissions and Intellectual Property (OSIP) within the Resource Management and Operations Directorate (RMOD), and the Marketed Health Products Directorate (MHPD) operational direction and guidance when managing information submitted in accordance with the Food and Drugs Act and its Regulations. 2. Scope and application This guidance document applies to all drug submission/application types1 including:  Clinical Trial Application (CTA), Clinical Trial Application - Amendment (CTA-A)2  New Drug Submission (NDS)  Supplement to a New Drug Submission (SNDS)  Abbreviated New Drug Submission (ANDS)  Supplement to an Abbreviated New Drug Submission (SANDS)  Extraordinary Use New Drug Submission (EUNDS)  Supplement to an Extraordinary Use New Drug Submission (EUSNDS)  Abbreviated Extraordinary Use New Drug Submission (EUANDS)  Supplement to an Abbreviated Extraordinary Use New Drug Submission (EUSANDS)  Supplement to a New Drug Submission - Confirmatory (SNDS-c)  Supplement to an Abbreviated New Drug Submission - Confirmatory (SANDS-c)  New Drug Submission for Disinfectant products (NDS-D)  Supplement to a New Drug Submission for Disinfectant products (SNDS-D)  Application for a Drug Identification Number for a pharmaceutical product, including non- prescription products attesting to a Labelling Standard (DINA)  Application for a Drug Identification Number for a Category IV Monograph Product (DINF)  Application for a Drug Identification Number for a biological product (DINB)  Application for a Drug Identification Number for a disinfectant product (DIND)  Notifiable Change (NC) (for human biologic or radiopharmaceutical drug quality changes)  Post-authorization Division 1 Change for a pharmaceutical product (PDC-prescription, PDC- non-prescription, PDC-disinfectant)3  Post-authorization Division 1 Change for a biologic drug product (PDC-B)4  Development Safety Update Reports (DSUR)5 Guidance Document: Management of Drug Submissions & Applications | 13 Post-Market pharmacovigilance monitoring documents The following documents are not within the scope of this guidance; however, they are part of the post market pharmacovigilance monitoring which is related to a submission. These documents should be sent to the Office of Submissions and Intellectual Property (OSIP) (https://www.canada.ca/en/health-canada/corporate/about-health-canada/branches- agencies/health-products-food-branch/resource-management-operations-directorate.html#a4) for processing. Refer to Appendix 2 for contact information. OSIP will notify the appropriate review bureau, or the MHPD of the document(s) submitted: Periodic Safety Update Report(PSUR-PV) Periodic Safety Update Report - Confirmatory (PSUR-C) Risk Management Plans (RMP-PV) Periodic Benefit-Risk Evaluation Report (PBRER-PV) Periodic Benefit-Risk Evaluation Report - Confirmatory (PBRER-C), and Other data Post-Market Vigilance (various types of Undefined Data Post-market Vigilance (UD-PV) Content-related questions specific to post market pharmacovigilance monitoring should be directed to the Marketed Pharmaceuticals Bureau or the Biologicals, Radiopharmaceutical and Self-Care Products Bureau in the MHPD. Refer to Appendix 2 for contact information. 3. Policy objectives The objective of this document is to ensure consistent application of the handling of submission/application information and procedures related to drug review by providing operational direction and guidance to sponsors and Health Canada staff on: the processes and procedures to be followed in the management of a drug submission/application or pharmacovigilance monitoring documents the tools available to share information (e.g., pre-submission meetings) related guidance documents, policies and other relevant information (e.g., related guidance and policies), and the performance standards that ensure predictability of the processes. 4. Background The first major revision to this guidance was in 1993. In 2013, changes were made to reflect an amendment to the Food and Drug Regulations that replaced Schedule F with the Prescription Drug List. In order to maintain consistency and enhance transparency, this guidance was updated in July 2019 to reflect the most current information, processes and procedures to be used by sponsors and Health Canada staff in the management of a drug submission/application or pharmacovigilance monitoring documents. The November 2019 version reflected new fee categories and performance standards due to the coming into force of the Fees in Respect of Drugs and Medical Devices Order on April 1, 2020. Guidance Document: Management of Drug Submissions & Applications | 14 5. Classification of a therapeutic product To proceed with the filing of information for a proposed product, sponsors should know how their product is classified (e.g., as a drug, a biologic, a medical device or a combination product). Classification of a therapeutic product determines whether a product is regulated as a device or a drug. In most cases, the distinction between drugs and devices is clearly identifiable and these products can be easily classified according to their definitions. As new technologies and products emerge, it can be increasingly difficult to identify the appropriate framework under which these products should be regulated. When the classification of a product is not clear, members of the Therapeutic Products Classification Committee (TPCC) may be consulted. The committee makes recommendations on the classification of a product as either a drug (pharmaceutical, biological, or natural health product), medical device, or combination product. If a product does not readily meet one of the definitions provided in the Food and Drugs Act, other regulatory areas of Health Canada are asked to participate in the committee's discussion. Refer to the Classification of Health Products at the Device-Drug Interface (https://www.canada.ca/en/health-canada/services/drugs-health-products/classification- health-products-device-drug-interface.html) and the Guidance Document: Factors Influencing the Classification of Products at the Device-Drug Interface (https://www.canada.ca/en/health- canada/services/drugs-health-products/classification-health-products-device-drug- interface/guidance-document-factors-influencing-classification-products-device-drug- interface.html) for more information. For questions about the classification of products at the device-drug interface, please email: [email protected] 5.1 Combination products For a combination product that has not been previously classified, sponsors or manufacturers may submit a written request for a classification decision to the relevant review Centre/Bureau/Office or make a presentation to the PDD, NNHPD, BRDD or the Medical Device Directorate (MDD) (as appropriate) for the purpose of classifying the product in advance of filing a submission/application. Alternatively, sponsors may file a submission/application to the review Centre/Bureau/Office based on their own classification. If the submission/application was filed incorrectly, the sponsor or manufacturer will be notified. If the receiving Centre/Bureau/Office cannot reach a consensus as to the classification of the combination product, the submission/application will be referred to the TPCC. The TPCC then makes a recommendation to the Review Centre/Bureau/Office. Submissions/applications for combination products will be handled in accordance with the Drug/Medical Device Combination Products Policy, (November 2005) (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/policies/drug-medical-device-combination-products.html) Guidance Document: Management of Drug Submissions & Applications | 15 and subject to either the Medical Devices Regulations or the Food and Drug Regulations based on the principal mechanism of action by which the claimed effect or purpose is achieved. Both principal and ancillary components must meet acceptable standards of safety, efficacy and quality. For a combination product classified as a drug, a submission or an application should be sent to the OSIP. The submission or application will be managed in accordance with this guidance. For a combination product classified as a medical device, manufacturers are to submit a device license application to the Medical Devices Directorate. Refer to the Guidance Document: Management of Applications for Medical Device Licenses (https://www.canada.ca/en/health- canada/services/drugs-health-products/medical-devices/application- information/policies/management-applications-medical-device-guidance-2019/document.html) for further information. 5.2 Other regulations that influence the classification of a drug Once a product has been classified as a drug and not a device at the level of the Food and Drugs Act (“the Act”), further classification is required to determine whether the product is a drug subject to the Food and Drug Regulations or a natural health product (NHP), a subset of drugs under the Act, subject to the Natural Health Products Regulations (NHPR). This further classification is guided by the definition of a NHP in section 1 of the NHPR, the exclusion of prescription drugs in section 2(2), and the inclusive and exclusive lists of substances set out in Schedules 1 and 2 to the NHPR. Personal care products may share characteristics of both “cosmetic” and “drug”, as currently defined under the Food and Drugs Act and could fall under one of three sets of regulations: the Cosmetic Regulations, the Food and Drug Regulations or the Natural Health Products Regulations. The Guidance Document: Classification of Products at the Cosmetic-Drug Interface (https://www.canada.ca/en/health-canada/services/consumer-product-safety/reports- publications/industry-professionals/guidance-document-classification-products-cosmetic-drug- interface.html) identifies criteria in the decision making process in determining the appropriate regulatory regime that applies to a given product at the cosmetic-drug interface. For questions about which regulatory framework may apply to a particular health product or about the classification of products at the device-drug interface please e-mail: [email protected]. 6. Specific submission/application pathways6 Information provided below is to inform sponsors of certain submission/application pathways that require the filing of a specific submission/application type or class. Sponsors are encouraged to consult existing guidance/policy documents on the Health Canada website to familiarize themselves with the requirements of each submission/application type or class.7 Guidance Document: Management of Drug Submissions & Applications | 16 6.1 Priority review A drug submission sponsor requesting priority review of a submission under the Guidance for Industry: Priority Review of Drug Submissions is to request Priority Review status in advance of filing a submission. Requests for Priority Review status of an NDS or SNDS (i.e., PRNDS, PRSNDS) should be sent to OSIP, to the attention of the Director of the appropriate Centre/Bureau/Office. Following the review of the request for Priority Review status, the submission (NDS or SNDS) should be filed. If the drug submission was granted Priority Review, the sponsor must clearly state this in their cover letter and the submission must be filed within 60 calendar days. For further information and management of Priority Review requests and submissions, including performance standards, refer to the Guidance for Industry: Priority Review of Drug Submissions (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/priority-review/drug- submissions.html). 6.2 Notice of Compliance with conditions (NOC/c) Sponsors requesting Advance Consideration to file a submission under the NOC/c Policy, as per the Guidance Document: Notice of Compliance with Conditions (NOC/c) should request a pre- submission meeting with the appropriate review Centre/Bureau/Office (refer to Section 7.1). Submissions should then be filed as a NDS, SNDS, ANDS or SANDS. If the drug submission is deemed eligible for Advance Consideration under the NOC/c Policy, the sponsor must clearly state this in their cover letter and the submission must be filed within 60 calendar days. Where a Notice of Compliance with Conditions (NOC/c) has been issued, results from confirmatory trials outlined in the Letter of Undertaking (LOU) should be filed as a SNDS-c or a SANDS-c. For further information on eligibility, procedural requirements and the performance standards, refer to the Guidance Document: Notice of Compliance with Conditions (NOC/c) (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/notice-compliance-conditions.html). 6.3 Extraordinary use new drug Submissions eligible under the criteria in C.08.002.01 (1) of the Food and Drug Regulations may be filed as an Extraordinary Use New Drug Submission (EUNDS), a Supplement to an Extraordinary Use New Drug Submission (EUSNDS), an Abbreviated Extraordinary Use New Drug Submission (EUANDS) or a Supplement to an Abbreviated Extraordinary Use New Drug Submission (EUSANDS). For submission requirements, refer to the Guidance Document: Submission and Information Requirements for Extraordinary Use New Drugs (EUNDS) (https://www.canada.ca/en/health- canada/services/drugs-health-products/biologics-radiopharmaceuticals-genetic- therapies/applications-submissions/guidance-documents/submission-information- requirements-extraordinary-drugs-eunds.html). These submissions have the same performance standards as the corresponding NDS, SNDS, ANDS or SANDS. Guidance Document: Management of Drug Submissions & Applications | 17 6.4 Biosimilar biologic drug Biosimilar biologic drugs, like all new drugs, are subject to Part C, Division 8 of the Food and Drug Regulations for authorization and oversight. Submissions for Biosimilar Biologic drug products should be filed as a NDS/SNDS and have the same performance standards as the corresponding NDS/ SNDS. For submission requirements, refer to the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs (https://www.canada.ca/en/health-canada/services/drugs-health-products/biologics- radiopharmaceuticals-genetic-therapies/applications-submissions/guidance- documents/information-submission-requirements-biosimilar-biologic-drugs-1.html). 6.5 Administrative processing Submissions/applications should be filed in accordance to the Guidance Document: Administrative Processing of Submissions and Applications Involving Human or Disinfectant Drugs (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/administrative-processing-human- disinfectant-drugs-2019/document.html). All information will be administratively processed to ensure it is complete and of suitable quality for the intended purpose. 7. Guidance for implementation 7.1 Pre-Submission or pre-application meetings Pre-submission or pre-application meetings may be requested by sponsors prior to filing a submission/application. Pre-submission or pre-application meetings may be conducted via a face to face meeting or by teleconference. Sponsors may request a pre-submission/application meeting with the appropriate Directorate within Health Canada if they have any questions or concerns prior to filing the following:  a drug submission/application (e.g., NDS, SNDS, ANDS, SANDS, DINA)  a clinical trial application  a request for a combination product classification (e.g., medical device-drug, drug-drug)  a request for a priority review  a request for advanced consideration of a submission under the Notice of Compliance with Conditions (NOC/c) Policy8  a submission for Extraordinary Use New Drugs (EUNDS)  a submission/application relying on third party data9, or  a response to a Notice of Deficiency (NOD) or Notice of Non-Compliance (NON) The purpose of pre-submission/application meetings is for Health Canada and the sponsor to discuss the data in support of the proposed submission/application. In addition, the purpose of such meetings could be to (if applicable):  familiarize Health Canada review staff with the submission/application prior to its filing, and provide a forum to discuss the data in the submission/application for the purpose of facilitating its review Guidance Document: Management of Drug Submissions & Applications | 18  identify potential problems or issues and manage disputes early in the submission/application process  identify studies the sponsor is relying on as adequate and well controlled in establishing the safety and efficacy of the drug  provide an opportunity for the sponsor to discuss details of the submission/application with Health Canada and obtain feedback regarding areas of concern based on current experience and regulatory requirements  provide an opportunity to discuss the potential eligibility of the submission for Priority Review or NOC/c consideration  increase the quality of information submitted, and  provide the appropriate Directorate the opportunity to re-align resources to accommodate the arrival of the submission/application Note: While the available data may be a point of discussion at the meeting, the acceptability of the data will only be considered during the scientific review of the proposed submission/application. For information on Pre-Clinical Trial Application (CTA) Consultation Meetings, refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications (Section 2.2) (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/clinical-trials/clinical-trial-sponsors- applications.html). Sponsors should ensure the requested feedback relates to clinical trial information and not market authorization requirements. For example, a meeting request to discuss pivotal clinical trials for market authorization may require a pre-NDS meeting rather than a pre-CTA meeting. For information related to pre-submission meetings for Priority Review requests or requests for advance consideration of a submission under the Notice of Compliance with Conditions (NOC/c) Policy, refer to the Guidance to Industry: Priority Review of Drug Submissions (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/priority-review/drug- submissions.html) and the Guidance Document: Notice of Compliance with Conditions (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/notice-compliance-conditions.html) respectively. For information related to pre-submission/application meetings relying on third party data, refer to the Guidance Document: Drug Submissions Relying on Third Party Data Literature and Market Experience (https://www.canada.ca/en/health-canada/services/drugs-health- products/drug-products/applications-submissions/guidance-documents/drug-submissions- relying-third-party-data-literature-market-experience.html). Guidance Document: Management of Drug Submissions & Applications | 19 7.1.1 Meeting requests For pre-CTA meeting requests, the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications (Section 2.2.1) provides meeting requirements and contact information. For all other pre-submission/application meeting requests, sponsors are encouraged to contact the appropriate review Centre/Bureau/Office prior to submitting a formal meeting request. Refer to the Appendix 2 for contact information. An administrative cover letter (refer to Section 2.1 of the Guidance Document: Preparation of Drug Regulatory Activities in the Electronic Common Technical Document Format (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/ectd/preparation-drug-submissions- electronic-common-technical-document.html) or Section 2.1 of the Guidance Document: Preparation of Drug Regulatory Activities in the Non-eCTD Electronic-Only Format for further details) (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/common-technical- document/updated-guidance-document-preparation-regulatory-activities-non-ectd-electronic- only-format.html) and a meeting request should be addressed to the Director of the appropriate review Centre/Bureau/Office and sent to OSIP as early as possible, but no less than three months prior to the proposed meeting date in one of the acceptable file formats (refer to Section 8.1). Meeting requests should be submitted in the form of a separate document (i.e., not included in the cover letter) and include the following information:  the purpose of the meeting (e.g., pre-NDS, pre-Phase III, pre-response to a NOD/NON, etc.)  the specific details regarding the product to be discussed (e.g., active ingredient, dosage form and therapeutic classification, etc., including whether the drug is first in class)  adequate information regarding the product to enable Health Canada to assess the utility of the meeting  a list of preliminary questions to be addressed during the meeting  submission/application information (control number, product name, etc.) and a copy of the NOD/NON if the meeting is regarding a response to a NOD/NON  three possible meeting dates, and whether an afternoon or morning meeting is being requested  suggestion regarding the review expertise necessary to discuss the proposed issues (e.g., clinical/chemistry/biopharmaceutics reviewers, biostatisticians, etc.), and  if the drug submission will rely solely on third-party data (as per Guidance Document: Drug Submissions Relying on Third-Party Data) (https://www.canada.ca/en/health- canada/services/drugs-health-products/drug-products/applications-submissions/guidance- documents/drug-submissions-relying-third-party-data-literature-market-experience.html) The Regulatory Project Manager (RPM) in PDD and NNHPD, or the Senior Regulatory Affairs Officer (SRAO) in BRDD will contact the sponsor to discuss the request. If Health Canada determines a meeting is warranted, this discussion will include possible meeting dates, the overall content of the pre-submission/application package and confirmation of the number of Guidance Document: Management of Drug Submissions & Applications | 20 meeting participants. The meeting request may be declined if the information listed above is not provided with the meeting request. If Health Canada considers that a formal meeting is not required, a response and rationale will be provided by the RPM/SRAO within a reasonable time period. 7.1.2 Meeting packages For information on the Pre-Clinical Trial Applications Consultation Information Package, refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications (Section 2.2.2) (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/clinical-trials/clinical-trial-sponsors- applications.html). Sponsors will be requested to submit a pre-submission/application meeting package in one of the acceptable file formats (refer to Section 8.1) at least one month in advance of the meeting. If the sponsor is making a presentation, the slide deck should be submitted one week prior to the meeting. Meeting packages should be as concise as possible and contain only the information listed below. Please note that hard copy meeting packages may be requested. Pre-submission/application meeting packages should include, where applicable:  a cover letter  a proposed meeting agenda  a brief slide presentation  a brief summary of the drug product  identification of the indication(s) for which approval is sought  proposed strengths and dosages  a summary of the clinical development plan for the drug, including identification of clinical trials completed in Canada (if any) and confirmation of which trials are still on-going (if any)  a summary of the development of the product, including any changes in production process, dosage form, testing methods etc., leading up to a description of the manufacturing process for the product to be marketed  brief summaries of the safety and efficacy data relating to the drug (e.g. draft of the Product Monograph (PM))  an overview of the market history of the product including the foreign regulatory status of the drug  a list of specific issues or questions (grouped by discipline) the sponsor would like to discuss or have addressed, and  the projected submission/application filing date 7.1.3 Post-meeting requirements For information on Pre-CTA consultation meeting records, refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications (Section 2.2.3). Guidance Document: Management of Drug Submissions & Applications | 21 After the pre-submission/application meeting, sponsors are to draft and submit meeting minutes to Health Canada no later than two weeks following the meeting. Final meeting minutes should be submitted in one of the acceptable file formats (refer to Section 8.1). When filing their submission/application, sponsors should reference the following information in the cover letter:  the control number of the pre-submission/pre-application meeting as well as a confirmation that the submission/application reflects what was committed to at the meeting, and  the meeting minutes and any other pre-submission/application correspondence with Health Canada It is in the sponsor’s best interest to file a submission/application within a reasonable time period following the pre-submission/application meeting. 8. Filing of information to Health Canada Sponsors should ensure that their submissions/applications contain the information needed to satisfy the regulatory requirements of Part C of the Food and Drug Regulations. All submitted information and any subsequent information filed (solicited and unsolicited) should accompany the cover letter that indicates the reason for filing the information and the date filed. 8.1. Acceptable formats for filing submissions/applications Currently, Health Canada accepts submissions/applications in the electronic common technical document (eCTD) electronic-only format and in the non-eCTD electronic-only format. Paper documents are no longer accepted by Health Canada for any type of submission/application. The eCTD Format is the mandatory format for filing a submission/application as per the Notice - Mandatory use of Electronic Common Technical Document (eCTD) Format (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/activities/announcements/notice-mandatory-use-electronic-common-technical- document-ectd-format.html). All submissions/applications filed in eCTD format, including subsequent information (e.g., SNDSs, NCs, PSURs, etc.), should be prepared using the requirements provided in the Guidance Document: Preparation of Drug Regulatory Activities in the Electronic Common Technical Document (eCTD) Format (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/ectd/preparation-drug-submissions- electronic-common-technical-document.html). The non-eCTD Electronic-Only Format: is the alternative format for filing a submission/application. All submissions/applications that are filed and any subsequent information submitted should be prepared using the requirements provided in the Guidance Document: Preparation of Regulatory Activities in the Non-eCTD Electronic-Only Format (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/common-technical- document/updated-guidance-document-preparation-regulatory-activities-non-ectd-electronic- only-format.html). Guidance Document: Management of Drug Submissions & Applications | 22 If the proposed submission/application will be filed in the eCTD format, the pre- submission/application meeting request and packages should be filed in the same format. 8.2 Filing formats and where to file for CTAs and CTA-As The CTA or CTA-A should be submitted on electronic media and organized in accordance with the Guidance Document: Preparation of Regulatory Activities in the Non-eCTD Electronic-Only Format (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/common-technical- document/updated-guidance-document-preparation-regulatory-activities-non-ectd-electronic- only-format.html). For additional information, refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications (Sections 2.3.2 and 2.4.4) (https://www.canada.ca/en/health- canada/services/drugs-health-products/drug-products/applications-submissions/guidance- documents/clinical-trials/clinical-trial-sponsors-applications.html). Sponsors should address the application to the Director of the appropriate review Centre/Bureau/Office and send information to the Office of Regulatory Affairs (ORA) in BRDD or to the Office of Clinical Trials (OCT) in PDD. Refer to Appendix 2 for contact information. 8.3 Transmission of electronic data Electronic data prepared in eCTD format should be provided as prescribed in the transmission section of the Guidance Document: Preparation of Regulatory Activities in the eCTD Format (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/ectd/preparation-drug-submissions- electronic-common-technical-document.html). Electronic data prepared in non-eCTD electronic-only format should be provided as prescribed in the transmission section of the Guidance Document: Preparation of Regulatory Activities in the Non-eCTD Electronic-Only Format (https://www.canada.ca/en/health- canada/services/drugs-health-products/drug-products/applications-submissions/guidance- documents/common-technical-document/updated-guidance-document-preparation- regulatory-activities-non-ectd-electronic-only-format.html). 9. Submission/application processing 9.1 Processing of an initial submission/application All information received by OSIP will be processed and sent to the appropriate review Centre/Bureau/Office within 10 calendar days of receipt with the exception of CTAs and CTA- As, which are sent directly to ORA in BRDD or OCT in PDD. Refer to Appendix 2 for contact information. For details on CTA and CTA-A processing, refer to Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications (Section 2.5) (https://www.canada.ca/en/health- canada/services/drugs-health-products/drug-products/applications-submissions/guidance- documents/clinical-trials/clinical-trial-sponsors-applications.html). Guidance Document: Management of Drug Submissions & Applications | 23 During the 10-day processing period, OSIP performs the following activities, depending on the submission/application type:  assigns a control number and Dossier ID (only when applicable) to the submission/application  enters the initial information into the Drug Submission Tracking System (DSTS) (e.g., medicinal ingredient, dosage form, brand name, date received, etc.  verifies that the information submitted is administratively complete (e.g., all necessary forms, including those related to cost-recovery have been submitted)  verifies that the format, structure and attributes of electronic data submitted comply with the CTD format and specifications  for submissions subject to the provisions of the Patented Medicines (Notice of Compliance) Regulations, verifies that a Patent Form V has been included in the submission/application and ensures that all relevant patents have been addressed through the filing of the Form V, and  verifies the submission is not subject to data protection under the data protection provisions of section C.08.004.1 of the Food and Drug Regulations10 At this stage in processing, the information package may be placed on the following administrative holds:  Process Hold - Initial  Cost Recovery Hold  Patent Form V Hold, or  Data Protection Refused Hold Refer to Appendix 5 for a description of the different types of “Administrative Holds.” When the hold is resolved or the initial information package is considered administratively complete, the following occurs:  the information package becomes a submission/application  the filing date is entered into the DSTS (i.e., the date when the submission/application is considered administratively complete)  the remainder of the submission/application information is entered into the DSTS, if applicable, and  the appropriate review Centre/Bureau/Office is notified that the submission/application has been processed and can be assigned to a RPM/SRAO for screening. 9.2 Cancellation or withdrawal letter during the processing period If a sponsor wishes to cancel their submission/application during the processing period, a signed letter requesting the cancellation should be sent to OSIP in the same format as the original submission/application. The status of the submission/application would be changed to “Cancelled Admin” in the DSTS, as the scientific review has not started. For CTAs/CTA-As, a signed letter requesting the withdrawal of an application/amendment should be sent directly to ORA (BRDD) or OCT (PDD). The status of the application/amendment would be changed to “Withdrawn” in the DSTS. Guidance Document: Management of Drug Submissions & Applications | 24 Submissions/applications that are cancelled/withdrawn by the sponsor may be done so without prejudice to a refiling (refer to Section 15.2 of this Guidance for pharmaceuticals/biologics or Section 15.3 for CTAs/CTA-As for refilling information). 9.3 Submissions/applications for administrative processing Submission/Applications for administrative processing are to be submitted to Health Canada when there is a change in manufacturer's name and/or product name such as following a merger, buy-out, other corporate restructuring, or through a licensing agreement. Submissions/Applications may be processed administratively only if the original manufacturer’s cross referenced drug product has received market authorization from Health Canada and has an active Drug Identification Number (DIN). These types of submissions/applications may be filed for: NDSs/ANDSs including their applicable Supplements, NCs (quality changes for biologics and radiopharmaceuticals) and Applications for a DIN and Post-Authorization Division 1 Changes (PDC-prescription, PDC-non- prescription, PDC-disinfectant, PDC-Bs). To be eligible for administrative processing, these submissions/applications should not contain scientific data, or require regulatory review. All aspects of the product, except for the manufacturer name and/or product name, must be identical to those previously authorized for that product. Any deviations from the previously authorized product is not accepted under the administrative pathway. For additional information on administrative processing, refer to the Guidance Document: Administrative Processing of Submissions and Applications: Human or Disinfectant Drugs (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/administrative-processing-human- disinfectant-drugs-2019/document.html). Solicited information in a Clarification Request should be submitted within five (5) business days from the date of the request. If the response to a Clarification Request is not satisfactory or not submitted within the specified time to respond, the following may be sent to the sponsor:  a Deficiency Notice (response should be submitted within 45 days from the date of the request), or  a Rejection Letter 10. Screening of submissions/applications 10.1 Screening of a submission/application during the Screening 1 period For information on the screening process of CTAs and CTA-As, refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications (Section 2.5.1) (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/clinical-trials/clinical-trial-sponsors- applications.html). Guidance Document: Management of Drug Submissions & Applications | 25 When the submission/application is received in the Centre/Bureau/Office, the Screening 1 period begins. The RPM/SRAO11 will screen all submissions/applications12 to:  verify that the type and class of the submission/application has been filed correctly given the intended purpose  ensure requisite information for the type and class of the submission/application has been provided, and  verify the fee is appropriate for the submission/application. Health Canada will screen the original submission/application within the performance standards in Appendix 3 for Screening 1 period. 10.1.1 Cancellation letter during the Screening 1 period If a sponsor wishes to cancel their submission/application during the screening period before it has been accepted into scientific review, a signed letter requesting the cancellation should be sent to OSIP in the same format of the original submission/application. The status of the submission/application would be changed to “Cancelled Admin” in the DSTS, as the scientific review has not started. The SRPM/SRAO13 will issue a cancellation acknowledgement letter. Submissions/applications that are cancelled by the sponsor may be done so without prejudice to a refiling (refer to Section 15.2 for refiling of pharmaceuticals/biologics or Section 15.3 for refiling of CTAs/CTA-As). 10.1.2 Screening Acceptance Letter (SAL) If the information submitted by the sponsor is acceptable at screening and requests for information/clarification are not required (refer to Section 10.2.1 for more information):  the submission/application or response to solicited information is accepted for scientific review and a Screening Acceptance Letter (SAL) is sent to the sponsor  the appropriate databases are updated, and  the relevant review division will be notified that the submission/application has been accepted for review. Once the submission/application is accepted for scientific review, the RPM/SRAO will continue to be the point of contact for communication with the sponsor, unless otherwise indicated. 10.2 Solicited Information Solicited information is considered any information that is requested by Health Canada during the screening of a submission/application. Examples include but are not limited to: Clarification Requests or Screening Deficiency Notices. 10.2.1 Clarification Requests during the Screening 1 period For information on the screening requests of CTAs and CTA-As, refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications (Section 2.5.1). Guidance Document: Management of Drug Submissions & Applications | 26 The purpose of a Clarification Request is to expand on, seek clarification on specific information or re-analyze existing information in the submission/application during the screening period. For example, Clarification Request may be used to locate misplaced documents, etc. Clarification Requests should not be used to request missing documents or new data such as, new clinical and/or pre-clinical information, including bioavailability studies or chemistry and manufacturing data not previously submitted. Requests will be solicited by fax or email and must be responded to in writing (for more information, refer to Section 10.2.2). The screening is not interrupted if a complete response is submitted within the requested timeframe. 10.2.2 Response to a Clarification Request during the Screening 1 period When responding to a Clarification Request, sponsors should clearly identify the name of the drug, the Dossier ID, the control number of the relevant submission/application and the purpose of the correspondence (i.e. “Response to a Screening Clarification Request”). Responses to Clarification Requests should be submitted in a Question and Answer format that is referenced to the applicable section(s) in the submission/application. Sponsors are requested to send their responses to Clarification Requests in accordance with the Guidance Document: Preparation of Drug Regulatory Activities in the Electronic Common Technical Document (eCTD) Format (https://www.canada.ca/en/health-canada/services/drugs- health-products/drug-products/applications-submissions/guidance- documents/ectd/preparation-drug-submissions-electronic-common-technical-document.html) or the Guidance Document: Preparation of Regulatory Activities in the Non-eCTD Electronic- Only Format (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/common-technical- document/updated-guidance-document-preparation-regulatory-activities-non-ectd-electronic- only-format.html), as applicable. For sponsors who filed in the non-eCTD electronic-only format, the response should be submitted to OSIP via electronic media (i.e., USB or CD) via courier mail. For the shorter response times to a Clarification Request, sponsors are reminded to take into account the delivery and processing time. For questions regarding filing submissions/applications electronically, sponsors can contact OSIP. Refer to Appendix 2 for contact information. The solicited information should be submitted within 15 calendar days from the date of the request or as indicated in the Clarification Request. A response is complete if:  all clarifications or questions identified in the Clarification Request have been addressed, or  the sponsor provided a sound scientific rationale as to why the requested information is not necessary. Note: The duration that a sponsor has to respond to a clarification request does not include the day that the clarification request is issued. The duration does include all other days, including weekends and statutory holidays. (For example, if a clarification request is issued on April 1 and is given 15 calendar days to respond, the deadline to submit the request would be April 16.) Guidance Document: Management of Drug Submissions & Applications | 27 For submissions/applications that are administratively processed, solicited information in a Clarification Request should be submitted within five (5) business days from the date of the request. If a Clarification Request is inquiring about the location of data in the submission/application, the response should only include the location of the data or an explanation as to why the data is missing. To clarify points of the Clarification Request, or the rationale for its issuance, sponsors should contact the RPM/SRAO. There is no limit on the number of Clarification Requests that may be solicited for one submission. However, no particular issue will be addressed more than once. Acknowledgement letters are not sent upon receipt of information received in response to Clarification Requests. During the screening of a submission/application, if a response to a Clarification Request is not satisfactory or is not submitted within the specified time to respond, a Deficiency Notice or Rejection letter will be sent for submissions/applications with administrative processing. For all other submission/application types, a Screening Deficiency Notice is sent. 10.2.3 Screening Deficiency Notice (SDN) If deficiencies are identified during the screening of material relating to a submission or application, the sponsor will be sent a Screening Deficiency Notice identifying the deficiencies. This may also include submissions where the drug is filed as a DIN Application but is considered a new drug or where the monograph attestation is found not to reflect the submission content. The status of the submission/application will change to “inactive 45” in the DSTS. A SDN can be sent to the sponsor without prior issuance of a Clarification Request. The solicited information is to be submitted within 45 calendar days from the date the SDN was sent. To clarify points of the SDN or the rationale for its issuance, sponsors should contact the RPM/SRAO. 10.2.3.1 Response to Screening Deficiency Notice (SDN) When responding to a SDN, sponsors should clearly identify the name of the drug, the Dossier ID, the control number of the relevant submission/application and the purpose of the correspondence (i.e. “Response to SDN”) in the cover letter. The response is to be submitted in a question and answer format, referenced to the applicable section(s) of the submission/application as appropriate. The response to a SDN should not contain unsolicited information (refer to Section 14.0) unless otherwise specified in the SDN. The sponsor should send all requested information along with the up-to-date documents including an updated cover letter in a single package to OSIP for processing. All information received by OSIP will be processed and sent to the appropriate review Centre/Bureau/Office within 10 calendar days. When OSIP begins to process the Response to SDN, the status of the submission would be changed to “Process” in the DSTS. Should OSIP determine that the Guidance Document: Management of Drug Submissions & Applications | 28 Response to SDN is administratively incomplete; the submission status will be changed to “Process Hold”. Once OSIP verifies that the “Response to SDN” is administratively complete, the RPM/SRAO will be notified that the response has been processed. Acknowledgement letters are not sent upon receipt of responses to SDNs. Upon receipt of the information requested in the Screening Deficiency Notice, a new Screening 1 period will begin (with the associated performance standards), and the requested material and information will be screened for completeness. 10.2.3.2 Acceptance letter following the response to a Screening Deficiency Notice (SDN) If the response to the SDN is acceptable, a SAL will be sent to the sponsor and the Review 1 Period will begin immediately (refer to Section 10.1.2 - SAL). 10.2.3.3 Screening Rejection Letter (SRL) A SRL will be sent for by the SRPM/SRAO14 for all drug submissions/applications if the sponsor fails to provide a response to the SDN within 45 calendar days or if the information submitted is incomplete, deficient or contains unsolicited information. A SRL (instead of a SDN) will be sent for a Notifiable Change (NC) or SNDS/SANDS if the proposed changes are Level III changes only15. To clarify points of the SRL or the rationale for its issuance, sponsors should contact the RPM or SRAO. If a SRL has been issued, the sponsor may refile the submission/application (refer to Section 15.1). A sponsor may file a Request for Reconsideration following the issuance of a SRL (Refer to Section 16 - Reconsideration of Decisions issued for Human Submissions and Applications). 11. Scientific Review of submissions/applications 11.1 Scientific Review process For information on the scientific review process of CTAs and CTA-As, refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications (Section 2.5.2) (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/clinical-trials/clinical-trial-sponsors- applications.html). The Review 1 period begins immediately after the SAL is issued. Health Canada will evaluate the submission/application within the performance standards in Appendix 3. The reviewer will examine and analyse the information submitted to ensure the product meets the requirements set out in the applicable sections of the Food and Drug Regulations. The RPM/SRAO is responsible for coordinating review timelines and is the initial point of contact for communication with the sponsor. Refer to Appendix 2 for contact information. Guidance Document: Management of Drug Submissions & Applications | 29 11.1.1 Screening solicited and unsolicited information submitted during the Scientific Review For information on what is considered solicited and unsolicited information, refer to Sections 12.0 and 14.0 respectively. Solicited and unsolicited information submitted by the sponsor during the scientific review may be screened, where appropriate, to ensure that:  a cover letter is provided with the information that includes the control number of the relevant submission/application  the purpose of the correspondence is clearly stated as solicited or unsolicited, and  the information submitted in an acceptable format (e.g. question and answer, side-by-side comparison), referenced to the applicable section in the electronic submission/application, as appropriate, and the information is complete for the intended purpose 11.1.2 Cancellation letter during the Scientific Review If a sponsor wishes to cancel their submission/application during the scientific review, but before a decision is made to issue an NOC, NOD, NON, Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN), NOD-Withdrawal (NOD-W) or NON-Withdrawal (NON-W), a signed letter requesting the cancellation should be sent to OSIP in the same format as the original submission/application. The status of the submission/application would be changed to “Cancelled Science” as the scientific review has started. The SRPM/SRAO will issue a cancellation acknowledgement letter. Submissions/applications may be cancelled by the sponsor without prejudice to a refiling (refer to Section 15.2 for information on refiling). 11.1.3 Pause the Clock during the scientific review Pause the clock is a tool that allows the review clock to be paused under specified circumstances. When there is a pause, the target date is shifted to account for the amount of time the clock has been paused. The review clock can pause only during the review period (e.g., Review 1 and Review 2) for cost-recovered submissions/applications. Administrative submissions/applications are excluded from this mechanism. Pauses can occur with these submissions/applications in the following instances: a) Sponsor request for an extension to respond to a Clarification Request A sponsor may request an extension to respond to a Clarification Request. The extension request should be submitted as soon as possible in the form of a letter and written rationale. The clock would pause if the following criteria are met:  the extension request is beyond the number of days allocated to respond to a Clarification Request as indicated in Section 12.1.2 of this guidance document, (i.e., 15 days for submissions with a 180 -300 day performance standard; 10 days for submission/application with a 91-179 day performance standard; 5 days for submissions/applications with a 0 -90 day performance standard), Guidance Document: Management of Drug Submissions & Applications | 30  the extension request is a minimum of 5 days but not beyond 90 days per Clarification Request, and  Health Canada approves the extension in writing to the sponsor. Following Health Canada’s approval of the extension and after the standard clarification response time has elapsed, the review clock pauses. The sponsor has the additional time approved by Health Canada to respond to the request, and the target date is changed. Note that there may be situations where Health Canada would not approve an extension or grant an extension to an existing pause. The review clock would resume at the end of the approved extension period. If the response to a Clarification Request is not satisfactory or not submitted within the specified time to respond, a NOD or NON will be issued (refer to Section 12.1.2). For example, if Health Canada issues a Clarification Request with a 10 day response time for a submission with a 91-179 day performance standard:  if an 8 day extension is requested beyond the standard 10 day response time and the extension request is approved, the review clock would pause for 8 days beginning on day 11, and the response would be due on day 18,  if a 2 day extension is requested beyond the standard 10 day response time, and the extension request is approved, the review clock would not pause. b) Seeking Advice from an External Advisory Committee16 Health Canada will inform the sponsor if an External Advisory Committee is required during the review period. Health Canada will strive to identify the need for an External Advisory Committee as early as possible in the review. If a pause is required, the sponsor will be notified of this by Health Canada. The nature of the questions for the External Advisory Committee will be included in the notification. Health Canada’s review clock would resume upon receipt of the final recommendation(s) from the committee, at which point the revised performance standard date will be confirmed. 12. Solicited information during the Scientific Review 12.1 Solicited information Solicited information is any information requested by Health Canada during the scientific review. Examples include but are not limited to: Clarification Requests, a Notice of Deficiency (NOD) or a Notice of Non-Compliance (NON). 12.1.1 Clarification Request during the Scientific Review Refer to Section 10.2.1 for information regarding Clarification Requests as the information in this section is also applicable to Clarification Requests solicited during the scientific review. Examples of solicited information during the scientific review may include clarification on a statistical analyses package, the rationale for interim pivotal trials, or changes to proposed labelling material. Guidance Document: Management of Drug Submissions & Applications | 31 12.1.2 Response to a Clarification Request during the Scientific Review Refer to Section 10.2.2 for information regarding the response to a Clarification Request during the screening period. This information is also applicable to a response to a Clarification Request submitted during the scientific review. Sponsors are to send their responses to Clarification Requests in accordance with the Guidance Document: Preparation of Drug Regulatory Activities in the Electronic Common Technical Document Format (https://www.canada.ca/en/health-canada/services/drugs-health- products/drug-products/applications-submissions/guidance-documents/ectd/preparation- drug-submissions-electronic-common-technical-document.html ) or the Guidance Document: Preparation of Regulatory Activities in the Non-eCTD Electronic-Only Format (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/common-technical- document/updated-guidance-document-preparation-regulatory-activities-non-ectd-electronic- only-format.html). The timeline to respond should be between 2 and 15 calendar days and will be based on the type and the performance standard of the submission/application (see Table 1 below). While the type of submission/application should guide response times, these are guidelines and can be adjusted. Where warranted, Health Canada can adjust the timelines to be longer or shorter based on the complexity of the request, dialogue with the sponsor and/or circumstances of the review. Table 1: Time to Respond to a Clarification Request during Scientific Review 180-300 day performance standard 15 days 91-179 day performance standard 10 days 0-90 day performance standard 5 days CTAs and CTA-As 2 days Note: During the review of a Clinical Assessment Package to request Priority Review status, the solicited information in a Clarification Request should be submitted within two (2) business days from the date of the request. Refer to the Guidance for Industry: Priority Review of Drug Submissions (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug- products/applications-submissions/guidance-documents/priority-review/drug- submissions.html). The review of the submission/application will not be interrupted if a complete response is submitted within the given time period. If the response to a Clarification Request submitted during the scientific review is not satisfactory, or not submitted within the specified time to respond, the following may be sent to the sponsor:  a Notice of Deficiency (NOD) (refer to Section 12.1.3)  a Not Satisfactory Notice (NSN) (refer to Section 13.4) , or Guidance Document: Management of Drug Submissions & Applications | 32  a Notice of Non-Compliance (NON) (refer to Section 13.6) 12.1.3 Notice of Deficiency (NOD) - NDS, SNDS, ANDS, SANDS or an Application for a DIN (DINA, DINB, DIND) A NOD will be sent to the sponsor when:  during the scientific review of a submission/application17, deficiencies and/or significant omissions that preclude continuing the review are identified, or  during the scientific review of an Application for a DIN (DINA, DINB, DIND), the product is identified as a New Drug and the sponsor is requested to file a NDS, or an ANDS. At the time of the NOD issuance, all scientific review streams will stop and the submission/application status will change to “Inactive 45” or “Inactive 90” in the DSTS (depending on the submission/application type) even if the review in the other streams has not been completed. Deficiencies identified to date from all review streams will be included in the NOD. Only one NOD is sent per submission/application. The difference between a NOD and a Notice of Non-Compliance (NON) is that the review of the submission/application is not complete when a NOD is issued. To clarify points of the NOD or the rationale for its issuance, sponsors should contact the RPM/SRAO. For NDSs, SNDSs, ANDSs and SANDSs, the Response to a Notice of Deficiency is to be submitted within 90 calendar days (or such time as the Centre/Bureau/Office and sponsor may agree upon) from the date the NOD was sent. For Applications for a DIN, the Response to a Notice of Deficiency is to be sent within 45 calendar days (or such time as the Centre/Bureau/Office and sponsor may agree upon) from the date the NOD was sent. If a NOD was issued during an early review, and after a subsequent review, the sponsor may be sent a:  Notice of Deficiency Withdrawal (NOD-W) (refer to Section 12.1.3.3)  Notice of Compliance (NOC) (refer to Section 13.2), or  Notice of Non-Compliance (NON) (refer to Section 13.6). 12.1.3.1 Response to Notice of Deficiency (NOD) - NDS, SNDS, ANDS, SANDS or an Application for a DIN (DINA, DINB, DIND) A Response to NOD is to be submitted in the same format as the original submission/application. The solicited information is to include a copy of the NOD and should be submitted in a question and answer format and referenced to the applicable section(s) of the submission/application. Should a sponsor decide it is not necessary to file the solicited information; a sound scientific rationale for this position must be presented in order for the response to be considered complete. Guidance Document: Management of Drug Submissions & Applications | 33 The sponsor should send all of the requested information along with up-to-date documents including an updated cover letter in a single package to OSIP for processing. All information received by OSIP will be processed and sent to the appropriate review Centre/Bureau/ Office within 10 calendar days. When OSIP begins to process the Response to NOD, the status of the submission would be changed to “Process”. Should OSIP determine that the Response to NOD is administratively incomplete; the submission status will be changed to “Process Hold”. Once OSIP verifies that the Response to a NOD is administratively complete, the appropriate Centre/Bureau/Office is notified that the response has been processed. When the response to the NOD is received, a new Screening 1 period begins (refer to Section 11.1.1 - Screening of Solicited and Unsolicited Information Submitted during the Scientific Review). Acknowledgement letters are not sent upon receipt of Responses to NODs. 12.1.3.2 Acceptance of a response to a Notice of Deficiency (NOD) When the Response to a NOD is screened and found acceptable for scientific review, a SAL will be sent to the sponsor (refer to Section 10.1.2 - SAL). A new Review 1 period begins immediately after the issuance of the SAL. The RPM/SRAO will serve as the initial point of contact for communication with the sponsor. 12.1.3.3 Notice of Deficiency Withdrawal letter (NOD-W18) A NOD-W will be sent to the sponsor if:  during the screening process the Response to a NOD is found to contain unsolicited information, is incomplete, or is deficient  the sponsor fails to submit the solicited information (i.e. the Response to the NOD) within the assigned time period. Health Canada will interpret this as a request to withdraw the submission/application, or  during the scientific review of the Response to a NOD, it is determined that the submission/application remains deficient. Submissions/applications may be withdrawn without prejudice to a refiling (refer to Section 15.4 for information on refiling). A sponsor may file a Request for Reconsideration following the issuance of a NOD-Withdrawal Letter (refer to Section 16 - Reconsideration of Decisions Issued for Human Submissions and Applications). 13. Completion of the Scientific Review of a submission/application 13.1 Processing of the submission/application following completion of the review Upon completion of a review where a decision has been recommended (either negative or positive), one of the following decision documents is prepared. Guidance Document: Management of Drug Submissions & Applications | 34 13.2 Notice of Compliance (NOC) - NDS, SNDS, ANDS, SANDS, EUNDS, EUSNDS, EUANDS, AEUSNDS, NDS-D, SNDS-D, SNDS-c, SANDS-c When the scientific review of a submission for a Division 8 product is completed and the submission complies with the Food and Drug Regulations, the sponsor may receive the following:  a Drug Identification Number, in the form of a Drug Notification Form (DNF), in accordance to sub-section C.01.014.2(1) of the Food and Drug Regulations, and  either a NOC once the req

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