Guidance For Industry Management of Regulatory Submissions

Transcription

1 Health Santé Canada Canada Guidance For Industry Management of Regulatory Submissions Veterinary Drugs Directorate Health Products and Food Branch Health Canada

2 Table of Contents Foreword Introduction Purpose Scope An Overview of the Regulatory Requirements for Filing Drug Submissions with VDD Request for authorization to sell-marketing authorization Request for authorization to sell a drug that does not have a DIN Post-approval obligations: Scientific amendments to initial product registration Post-approval obligations: Administrative amendments to initial product registration for all drugs Procedure for Sending ALL Regulatory Submissions and Related Information to VDD Sending information by mail or fax Sending information by electronic mail ( ) Submission Holds During initial processing During screening During the NOC and/or DIN issuance stage Review and Approval Process for NDS, ABNDS, SNDS and SABNDS Pre-Submission meeting Initial processing of original NDS, ABNDS, SNDS, SABNDS submissions and responses to screening and review decision letters Screening of original NDS, ABNDS, SNDS, SABNDS submissions and responses to screening and review decision letters Reviewing original submissions (NDS, ABNDS, SNDS, SABNDS) and responses to review decision letters Update Notices Additional points to consider when responding to a SDN, MIR, NOD Review and Approval Process for Scientific Amendments to Product Registration - SNDS, SABNDS and NC Submissions Page 2 of 43

3 8.1 Consultation - Pre-submission Initial processing of original SNDS, SABNDS and NC submissions and responses to screening and review decision letters Screening of original submissions and responses to screening and review decision letters Reviewing of original SNDS, SABNDS and NC submissions Administrative Amendments to Submissions Under Review Final Label Review Post-Approval Obligations - Administrative Amendments to Initial Product Registration for All Drugs Notification of the commencement of sale of a drug product Annual drug notification - Products that are marketed Cancellation of the DIN Changes to the product s brand name or changes to DIN ownership Transfer of business product lines Changes to a company s address and contact name Withdrawing a Submission Prior to Approval Refiled Submission Data requirement Screening of Unsolicited Amendments to Submissions Under Review Appeal Process Access to Submission-Related Information Submission status Establishment License (E.L.) Requirement Drug Submission Evaluation Fees Appendix A: Performance Targets Appendix B: Mailing and Faxing of Regulatory Submissions and Related Documents Appendix C: Process Overview for NDS, ABNDS, SNDS and SABNDS Submissions Page 3 of 43

4 Appendix D: Request for Pre-Submission Meeting Appendix E: Process Overview for NC Submissions Appendix F: Request for Regulatory Guidance - Submission Classification Appendix G: Definitions Appendix H: Acronyms Page 4 of 43

5 Foreword This guidance document provides clarification to submission sponsors on how to comply with the Veterinary Drugs Directorate s policies, governing statutes and regulations. It also serves to provide review and compliance guidance to staff, thereby ensuring that mandates are implemented in a fair, consistent and effective manner. Guidance documents are administrative instruments that do not have force of law and, as such, allow for flexibility in approach. Alternative approaches to the practices described in this document may be acceptable, provided they are supported by adequate scientific and regulatory justifications. Alternate approaches should be discussed in advance with the Directorate to avoid the possible findings that applicable statutory or regulatory requirements have not been met. This document has been developed in accordance with the applicable sections of the Food and Drugs Act and Regulations; thus, should be used in conjunction with the Food and Drugs Act and Regulations. Page 5 of 43

6 1. Introduction Pursuant to the Food and Drugs Act and Part C of the Food and Drug Regulations, all drugs, unless specifically exempted, must be registered before being sold or imported for sale in Canada. The regulatory authority for the administration of the Food and Drugs Act and Regulations in connection with the sale of drugs intended for use in animals is the Veterinary Drugs Directorate of Health Canada (referred to as VDD or the Directorate hereafter). This guidance document provides clarification to submission sponsors on how to comply with VDD s policies, governing statutes and regulations. 2. Purpose This document defines the way that VDD manages regulatory submissions and related information filed by the submission applicants (referred to as sponsors hereafter) in accordance with the Food and Drugs Act and Regulations. This document also describes the process that both the staff of VDD and the submission sponsors should follow in order to facilitate and streamline all submission-related activities. It will also help minimize some of the delays that are related to the lack of written procedures. 3. Scope This guidance is applicable to the following submission types: New Drug Submission (NDS); Administrative NDS including submissions filed in support of corporate and brand name changes; Supplemental New Drug Submission (SNDS); Abbreviated New Drug Submission (ABNDS); Supplemental Abbreviated New Drug Submission (SABNDS); Notifiable Change (NC). For each of the submission types listed above, this guidance provides a procedural outline on the following stages of the submission review and approval process: Pre-submission phase; Initial processing of submissions; Screening of submissions; Review of submissions; Page 6 of 43

7 Final review decision. As shown in the diagram below, all submissions and related information undergo a similar review and approval process. During each stage of the submission review and approval process (e.g., initial process, screening, review and final decision), the same submission management principles will be applied and the related decisions are to be made within VDD s Performance Targets (see Appendix A). Furthermore, additional sections have been provided regarding the following regulatory activities: Administrative amendments to submissions under review; Scientific amendments to submissions under review; Unsolicited amendments to submissions under review; Withdrawal of submissions under review; Refiled submission; Post approval activities; Access to submission-related information; Appeal procedures for veterinary drug submissions. Page 7 of 43

8 In summary, this is an administrative procedural document. Sponsors should consult with the Food and Drugs Act and Regulations as well as applicable Health Canada policies and scientific guidance documents to ensure that all required data components are present at the time of filing. Details on these applicable documents can be found at VDD s Web site: 4. An Overview of the Regulatory Requirements for Filing Drug Submissions with VDD 4.1 Request for authorization to sell-marketing authorization Pursuant to Section C of the Food and Drug Regulations, a drug must have a valid Drug Identification Number (DIN) in order for it to be sold or imported for sale (referred to as sold thereafter) in Canada. The sponsor can submit one of the following regulatory submissions to VDD for its request to obtain a DIN for selling a veterinary drug in Canada: A Drug Identification Number (DIN) submission pursuant to Section C (2) of the Food and Drug Regulations; A New Drug Submission (NDS) pursuant to Section C (3) and C and C of the Food and Drug Regulations; and An abbreviated NDS (ABNDS) pursuant to Section C (3) and C (1) and C of the Food and Drug Regulations. 4.2 Request for authorization to sell a drug that does not have a DIN Notwithstanding the above regulatory submission mechanisms for obtaining a DIN, a drug may be sold in Canada without a DIN when the following submissions are filed and a written authorization is obtained from VDD: An Experimental Studies Certificate (ESC) pursuant to C and C of the Food and Drug Regulations; A Pre-Clinical Submission [referred to as an Investigational New Drug (IND) submission] pursuant to Sections C and C of the Food and Drug Regulations; and A request made by a practitioner for the sale of a quantity of new drug for veterinary use in an emergency treatment of a patient under the care of that practitioner pursuant to Section C of the Food and Drug Regulations. 4.3 Post-approval obligations: Scientific amendments to initial product registration After a sponsor has received a marketing authorization for a new drug product pursuant to Section C of the Food and Drug Regulations (i.e., a Notice of Compliance), the sponsor is required to file updated information or changes to the new drug prior to implementation in accordance with Section C of the Food and Drug Regulations. Page 8 of 43

9 Depending on the nature of the changes made, the sponsor is required to file the following submission types: Supplement to a New Drug Submission (SNDS) or Supplement to an Abbreviated New Drug Submission (SABNDS), and Notifiable Change (NC) submission If a sponsor receives a marketing authorization for a drug product pursuant to Section C of the Food and Drug Regulations, the sponsor is required to file updated information about the drug in accordance with Section C of the Food and Drug Regulations. 4.4 Post-approval obligations: Administrative amendments to initial product registration for all drugs Notification of commencement of sale Pursuant to Section C of the Food and Drug Regulations, every DIN owner is required to notify the Directorate within 30 calendar days after commencing sale of a drug Annual drug notification for products that have been marketed Pursuant to Section C of Food and Drug Regulations, each year every DIN owner of a drug should provide VDD with a signed Annual Notification Form to confirm that all the information previously provided for that drug by the sponsor is still correct and current Cancellation of the DIN The DIN of a drug can be cancelled either by the Directorate or by the DIN owner in accordance with Section C of the Food and Drug Regulations Reactivation of DIN by the Directorate Once a DIN has been inactivated, the sponsor is required to submit a new submission in order to re-gain marketing approval for its product. Cross references to previously filed information may be permitted. However, additional information may be required by VDD to ensure that the submission complies with the current regulations and guidelines Changes to the product s brand name and DIN ownership Pursuant to Section C (a) and (f) of the Food and Drug Regulations, the DIN owner of a drug is required to file an administrative submission (DIN, NDS, or ABNDS) when changes are to be made to the product s brand name or the name of the DIN owner. Page 9 of 43

10 5. Procedure for Sending ALL Regulatory Submissions and Related Information to VDD 5.1 Sending information by mail or fax All submissions should be sent to VDD by mail, where possible. However, sponsors may send the information by fax provided that the following conditions are met: the related submission does not contain documents that require the presence of original signatures (e.g., Drug Submission Application Form, Submission Certification Forms) [If documents with original signature are sent in by fax, original versions should be sent by mail for VDD s record]; the submission contains less than (<) 10 pages; the fax copy of the submission documents is of the same quality as that of the mailed copy. This is particularly important for submissions that contain product labels. In order to facilitate submission processing and subsequent routing, it is requested that the sponsors do not fax and mail the submission unless necessary (e.g., items that require original signatures). The mailing address and fax information are detailed in Appendix B. Furthermore, consideration must be given to the following points when submitting information to VDD by mail, courier or fax: inclusion of a cover letter that describes the purpose of the submission; the physical content of the submission should be described in the cover letter especially when a Table of Contents is not provided in the submission; appropriate references to the related submission and file numbers, if available; and use of 3-ring binders in order to minimize the potential loss during submission processing; the use of paper clips should be avoided wherever possible, especially if the submission is greater than 10 pages in length. 5.2 Sending information by electronic mail ( ) Over the past several years, the use of has increasingly become a way for sponsors to submit information and to communicate with VDD instead of the traditional uses of fax, mail and telephone calls. At this time, the documents sent by cannot be considered as a substitute for the official hard copy submission that is necessary for VDD s records. Similarly, the documents sent by VDD staff cannot be considered an official record of decisions made by the Directorate. In addition, the system that VDD uses does not have the security features that are required for VDD to exchange proprietary or encrypted documents with the submission sponsors. Thus, care should be taken when using s to correspond with VDD about regulatory issues. Page 10 of 43

11 6. Submission Holds As outlined below, VDD may place administrative holds on a submission at various stages of the submission review and final decision process. Upon the decision to place a HOLD on a submission, the Directorate will issue a letter to the submission sponsors to inform them of the reason for the hold and the possible options for resolution (if available). 6.1 During initial processing If the information received in a submission does not correspond to what was specified in a sponsor s submission cover letter (e.g., missing volumes), the submission will be placed on hold. The Directorate will send a letter to the sponsor to explain the reasons for the administrative hold and ask the sponsor to provide a response within 15 calendar days. The submission may be rejected if a response is not provided within the time specified. 6.2 During screening A submission may be placed on hold during screening when any of the following situations arise: the sponsor of the submission did not provide the required patent-related information; or there are outstanding regulatory issues with the product for which the submission was filed. 6.3 During the NOC and/or DIN issuance stage Administrative holds may apply as a result of the following: patent concerns; scheduling switches (e.g., from Prescription to Over-the-Counter); regulatory hold needed due to issues identified with the product arising from review of other submissions or information provided by other regulatory agencies. 7. Review and Approval Process for NDS, ABNDS, SNDS and SABNDS A flow diagram for the review and approval process of NDS, ABNDS, SNDS and SABNDS can be found in Appendix C. 7.1 Pre-Submission meeting In addition to the Doing Business with VDD link on VDD s website, and this guidance (Guidance for Industry: Management of Regulatory Submissions), VDD has also published the Guidance for Industry Preparation of Veterinary New Drug Submissions, and the supporting documents Manufacturing and Quality Control Requirements, Human Safety Requirements, and Clinical Safety and Efficacy Data Requirements. These documents are intended to be the Page 11 of 43

12 sponsor s starting point when preparing a new submission. In cases where available VDD guidance does not cover all aspects of an intended submission, a pre-submission meeting may be useful to the sponsor. Before filing a submission, the sponsor may request a pre-submission meeting with VDD to seek regulatory guidance on specific items. The purpose of the meeting would be to: familiarize VDD review staff with the information to be submitted; provide sponsors with specific guidance for the proposed submission; help uncover any major foreseeable concerns or deficiencies with the submission in turn, help improve the quality of incoming submissions; help determine the drug product classification and the regulatory authority responsible for regulating the sale of the product in Canada (e.g., VDD at Health Canada versus the Canadian Food Inspection Agency versus Pest Management Regulatory Agency), if applicable; and discuss the best approach to the presentation and formatting of data in the submission. Notwithstanding the above, it should be noted that pre-submission meetings are not intended for presentation, discussion and pre-evaluation of actual data that have been generated from studies conducted by the sponsor but rather to provide further clarification and guidance on the type of studies and data needed in support of the submission. Page 12 of 43

13 7.1.1 Request for a pre-submission meeting The diagram below provides an overview of pre-submission meeting process. The sponsor can send a meeting request to VDD at any time. As indicated in the diagram above, a pre-submission meeting, would take place approximately 60 calendar days from the date of the request. Sponsors should take this time frame into account when planning to request a pre-submission meeting with VDD. The meeting request should be sent to VDD by mail or by fax using the meeting request template in Appendix D. Adequate product-related information should be provided to enable the review divisions to assess the meeting request and to select appropriate meeting attendees from VDD. The meeting request will be logged in and assigned with submission and file numbers. Upon receipt of the pre-submission meeting request, VDD will provide a written reply within 15 calendar days for options to coordinate the meeting. If a meeting is required, the sponsors will be requested to provide a pre-submission meeting package within 20 calendar days from the date of VDD s acceptance letter. Sponsors should note that pre-submission meetings are limited to 2 hours including a slide presentation (if any) of no longer than 30 minutes. Therefore, when submitting premeeting packages, the sponsors should ensure that the information submitted is comprehensive. It is recommended that the package be limited to 40 pages in length and it should contain the required information described below: a cover letter outlining the purpose of the pre-meeting package; a copy of the proposed meeting agenda; the names and functions of the company s representatives that will attend the Page 13 of 43

14 meeting; a list of specific items or questions where guidance is being sought from VDD (grouped by scientific disciplines); a brief summary of the drug product (strength, dosage form, therapeutic claims and the intended species); a comprehensive summary of the drug product concerning the chemistry and manufacturing, target animal safety and efficacy, and human safety (applicable if intended for use in food-producing animals) aspects of the product; a copy of the proposed product label, if available; an overview of the product registration status in Canada and in foreign countries; proposed submission plan for which the meeting is being called; a copy of the presentation slides/handouts that are to be used during the meeting (if applicable); and any other information that would be helpful for the meeting (can be discussed with VDD representatives in advance of the meeting). Shortly after receipt of the pre-submission package, VDD will contact the sponsor in order to discuss and reach an agreement on the date when the pre-submission meeting will take place. Whenever possible, the date of the pre-submission meeting will be set within 25 calendar days from the date of receipt of the pre-submission meeting package Minutes of the pre-submission meeting Once the pre-submission meeting is held, the sponsor is required to provide VDD with a draft copy of the minutes of the meeting within 15 calendar days. The meeting minutes should consist of, but not limited to, the following elements: a cover letter; meeting date, agenda and attendees from VDD and the submission sponsor; a copy of presentation/handouts during the meeting (if not previously provided or different from that submitted in the pre-meeting package); a summary of key discussion items and outcome; a list of follow-up items (if applicable); and a version date for the first set of draft minutes. Upon receipt of the first set of draft meeting minutes, the attendees from VDD are to review and provide a set of consolidated comments or a reply to accept the draft meeting minutes within 15 calendar days. The official record of the minutes will require their acceptance by meeting attendees from VDD and the sponsors. 7.2 Initial processing of original NDS, ABNDS, SNDS, SABNDS submissions and responses to screening and review decision letters As specified in Appendix B, all submission-related documents should be sent to the Submission Page 14 of 43

15 Office at VDD. Upon receipt into VDD, the Submission Office will stamp the submission with a receipt date. This starts the screening clock applicable to the submission provided there is no administrative hold placed on the submission. The submission and the related information will then be assigned with a submission and a file number. An acknowledgement of receipt will be sent to the sponsors within 7 calendar days from the date of receipt. 7.3 Screening of original NDS, ABNDS, SNDS, SABNDS submissions and responses to screening and review decision letters All submissions and related information (including responses to screening and review decision letters) are subject to screening before being accepted for review. The purpose of the screening is to ensure that submissions are prepared in an acceptable format and contain sufficient supporting information. If the submission is screened and found to be deficient, the sponsor is notified early in the process that the submission has omissions or inadequacies that will introduce interferences to a substantive and meaningful review by the review divisions. Responses to MIRs undergo an administrative screen for tracking purposes only Screening of original NDS, ABNDS, SNDS and SABNDS VDD will target to screen the original submissions within 45 calendar days from the date of receipt in VDD. The screening is based on applicable regulatory and scientific requirements outlined in the Food and Drugs Act and Regulations as well as any applicable policies and guidelines. Upon the completion of screening, VDD will proceed with one of the following three screening decisions: Screening findings No deficiencies found Deficiencies found Submission is significantly deficient Screening decision and next step Issuance of an Acceptance for Review letter by fax only. The submission is to be forwarded to the relevant review divisions for evaluation. (screening clock of 1 st screening cycle stops and review clock starts on the date of the Acceptance for Review letter) Issuance of a Screening Deficiency Notice (SDN) by fax and mail. The sponsor is required to submit all the requested information within 45 calendar days from the date of SDN. (screening clock of 1 st screening cycle stops on the date of SDN) Issuance of a Screening Rejection Notice (SRN) by fax and mail. The submission is rejected at screening. If the sponsor decides to refile this submission at a future time, it will be processed as a new submission. (screening clock of 1 st screening cycle stops on the date of SRN) Page 15 of 43

16 Issuance of a Screening Deficiency Notice (SDN) A decision to issue a Screening Deficiency Notice will mainly be based on, but not be limited to, the following conditions: omission of elements that are required in accordance with the Food and Drugs Act and Regulations; administrative omission or incomplete submission of required regulatory forms including Submission Evaluation Fee assessment; scientific inadequacies in the submission such as omission of critical data, information or analysis needed to evaluate the quality, animal safety and efficacy and human safety of the drug; poor presentation of a section that will preclude a proper review; references to information or data submitted previously in a submission that is under review; and failure to address submission-related deficiencies that have been clearly communicated to the sponsor by VDD during a pre-submission meeting or in regulatory correspondence prior to the sponsor filing the submission Issuance of a Screening Rejection Notice (SRN) Decision to issue a Screening Rejection Notice will be made based on, but not be limited to, the following conditions: upon completion of the screening process, if the submission is considered significantly incomplete and could not be reviewed without major modifications; and the response to SDN is unsatisfactory or the sponsor fails to provide a response to SDN within 45 calendar days Screening of responses to Screening Deficiency Notice Following the receipt of a SDN, the sponsor is required to provide a complete response within 45 calendar days to address the deficiencies noted at screening. When a response to a SDN is received in VDD, a new 14 calendar day screening period (2 nd screening cycle) will commence. There are two possible outcomes to the screening process: Page 16 of 43

17 Screening findings Response to a SDN is complete and does not contain unsolicited data Response to a SDN is incomplete, deficient, or contains unsolicited data. OR No response to a SDN Screening decision and next step Issuance of an Acceptance for Review letter by fax only. The submission is to be forwarded to the relevant review divisions for evaluation. (screening clock of 2 nd screening cycle stops and review clock starts on the date of the Acceptance for Review letter) Issuance of a Screening Rejection Notice (SRN) The submission is rejected at screening. If the sponsor decides to refile the submission at a future time, it will be processed as a new submission. (screening clock of 2 nd screening cycle stops) Screening of responses to review decision letters [Notice of Deficiency (NOD)] The same management principles, procedures and decision criteria described in Sections 7.3 to of this document will apply when VDD screens responses to review decision letters. The table below provides an overall summary of the process. Responses to Acknowledgement Target screening Maximum Acceptance for review decision of receipt period number of review letter letters issued (calendar days) SDN issued issued before SRN Minor Information Request (MIR) Yes *Not applicable as no screening will be done for responses to MIR. Notice of Deficiency (NOD) Yes 45 1 Yes *Note: As indicated in below, the issuance of a MIR does not stop the review clock. Therefore, responses to MIR will be forwarded to the review division(s) upon receipt. 7.4 Reviewing original submissions (NDS, ABNDS, SNDS, SABNDS) and responses to review decision letters Once the submission is screened and found acceptable for review, it is forwarded to the appropriate review divisions for review. VDD will target to issue a final response letter within VDD s target performance standards outlined in Appendix A of this document. The final response letter for the NDS, ABNDS, SNDS or SABNDS submission will be based on the review Page 17 of 43

18 outcomes from ALL appropriate review divisions. Review divisions Review focus Clinical Evaluation Division (CED) Animal Safety and Efficacy Labelling - lead review division Manufacturing and Chemical Evaluation Division (MCED) Chemistry, manufacturing and controls Labelling Human Safety Division (HSD) Human safety: toxicology, residue, microbiological safety Labelling Communications during the review between the Sponsor and VDD Upon the start of review of a submission, VDD will send the sponsor a fax to inform them that the review has begun. The assigned reviewer in each of the appropriate review divisions will review the data submitted. During the course of the review, the individual review division may send a Minor Information Request (MIR) to the sponsor requesting further information or clarification that would facilitate the completion of that review stream. All MIRs will be sent by fax only and will be sent by the manager responsible for the appropriate review division. Review outcome Minor deficiencies found - the applicable review stream was not completed. Review decision and next step Issuance of a Minor Information Request (MIR). The sponsor is required to submit all the requested information within 15 calendar days from the date of MIR. (no impact on review clock) Issuance of a Minor Information Request (MIR) A MIR will only be used to request further clarification to facilitate the appropriate divisions review of a submission; The information requested should be readily available - the sponsor does not need to conduct new studies or to generate new data. Responses to MIRs should be addressed to the Submission Office. Upon receipt of a MIR, the sponsor is required to provide a complete response to VDD within 15 calendar days from the date the MIR was issued. A sponsor s failure to respond to a MIR will result in the issues or remaining issues contained in the MIR to be addressed through a Page 18 of 43

19 Notice of Deficiency Response letter from VDD Upon the completion of VDD s review of the submission (by all appropriate review divisions), there are three possible decision letters that can be sent to the sponsor: Review outcome No deficiencies found based on reviews done by applicable divisions. Review decision and next step The issuance of a Notice of Compliance. (review clock of the 1 st review cycle stops) Significant deficiencies found. Deficiencies remaining following review of responses to a NOD. OR No responses to a NOD. Issuance of a Notice of Deficiency (NOD). The sponsor is required to submit all requested information within 90 calendar days from the date the NOD was issued. (review clock of the 1 st review cycle stops) Issuance of a Notice of Non-Compliance (NON). If sponsor decides to refile the submission at a future time, it will be processed as a new submission. (review clock of the 2 nd review cycle stops) Issuance of a Notice of Deficiency (NOD) - C (1) (b) of the Food and Drug Regulations Only one NOD will be issued per submission and will be based on the following condition: upon the completion of VDD s review of the submission by all applicable review divisions, where outstanding deficiencies remain making the submission not compliant with the Food and Drug Act and Regulations. The NOD is to be issued to the sponsor by fax and mail. The sponsor is required to provide a complete response to a NOD within 90 calendar days from the date the NOD was issued Issuance of a Notice of Non-Compliance (NON) - C (3) (b) of the Food and Drugs Regulations Only one NON will be issued per submission based on the following conditions: Page 19 of 43

20 a sponsor s failure to respond to a NOD within 90 calendar days; following a complete review of the response to a NOD by the applicable review divisions, the submission remains deficient. A NON is issued under the signature of the Director General and will include a rationale as to why the submission is considered not compliant with the Food and Drugs Act and Regulations along with a list of the specific deficiencies upon which the decision is based. Upon receipt of a NON, the sponsor may choose one of the following two options: Refile the submission at a future time. The refiled submission will be considered as a new submission. The sponsor should follow the instructions outlined in Section 13 of this document prior to refiling. File an appeal in accordance with the document entitled: Blueprint for the Veterinary Drug Submission Appeal Process Issuance of a Notice of Compliance (NOC) Pursuant to Sections C (1)(a) and C (3)(a) of the Food and Drug Regulations, a NOC will be issued if the submission is found to be in compliance with the regulations after a complete review of the submission by all applicable review divisions. 7.5 Update Notices If it becomes evident that the review of the submission will not commence prior to the Health Canada performance target date, an Update Notice will be issued by VDD. At that time information may be added or removed from the original NDS, SNDS, ABNDS or SABNDS in the updated submission. The updated submission must stay within the scope of the original submission. VDD will not accept information in response to an Update Notice such as addition of new species or production types or changes which would normally result in the creation of a separate submission. Sponsors should note that update packages are subject to screening and fee adjustments, as applicable. If the update package is determined to be deficient at the screening stage, the entire submission may be placed on hold (see Section ) pending receipt of a satisfactory response to a Screening Deficiency Notice (SDN), or may be rejected (see Section ). 7.6 Additional points to consider when responding to a SDN, MIR, NOD Upon the receipt of a SDN, MIR or NOD, the sponsor must respond within the time specified. A detailed scientific explanation must be provided in the absence of the requested information. The sponsor is encouraged to contact the designated person listed in the letter for clarification. It Page 20 of 43

21 should be noted that unofficial responses from sponsors will not be accepted by VDD. All responses should be prepared in a question and answer format with appropriate references to relevant sections of the original submission or information submitted previously (e.g., volume and page numbers). Although faxed responses are considered acceptable, the sponsor should follow the procedure outlined in Section 5 of this document. If a response to a SDN, MIR or NOD cannot be provided in the time specified, the sponsor may withdraw the submission. A request to temporarily inactivate a submission is not acceptable. Submission sponsors should ensure that all relevant data is present at the time of filing or is available when the data is requested by the Directorate. A temporary inactivation mechanism would offer little benefit to the sponsor and prolongs the life cycle of an incomplete submission which may have been filed prematurely. 8. Review and Approval Process for Scientific Amendments to Product Registration - SNDS, SABNDS and NC Submissions A flow diagram for the review and approval process for SNDS, SABNDS is outlined in Appendix C. The flow diagram for NC submission process is outlined in Appendix E. 8.1 Consultation - Pre-submission Prior to filing a SNDS, SABNDS or NC submission, the sponsors should consult the applicable guidelines to ensure that the proposed change qualifies for the submission type under which the sponsors plan to file. The sponsors may contact VDD to seek guidance if unsure of the classification of the proposed submission. For all inquiries on submission classification, the sponsors are required to send in a Request for Regulatory Guidance to VDD by mail or by fax. A copy of the request template can be found in Appendix F. Adequate information should be provided to enable VDD to assess the significance of the changes proposed without the need for further clarification from the sponsor. Upon receipt of a Request for Regulatory Guidance, VDD will target to provide a response to the sponsor within 60 calendar days from the date when the request is considered to be complete for assessment by VDD. A copy of the Request for Guidance and VDD s reply should be included when filing the upcoming submission. It is the sponsors responsibility to provide adequate supporting data for the proposed change in order to demonstrate that the changes do not pose any adverse impact on the chemistry and manufacturing, target animal safety and efficacy and human safety aspects of the drug product. VDD will provide guidance based on the information provided by the sponsors. Verification of the submission classification will be done based on the actual information provided at the time of the submission filing. The submission may be re-classified if it contains additional changes and Page 21 of 43

22 if the overall changes are considered beyond the scope of the current classification. 8.2 Initial processing of original SNDS, SABNDS and NC submissions and responses to screening and review decision letters Upon receipt of the above referenced submissions, the Submission Office will stamp the submission with a receipt date which starts the applicable screening clock. The submission or related information will then be assigned with a submission and a file number. An acknowledgement of receipt will be sent within seven calendar days from the date of receipt. 8.3 Screening of original submissions and responses to screening and review decision letters All SNDS, SABNDS and NC submissions and related information (including response to screening and review decision letters) are subject to screening before being accepted for review as described in Section 7.3 of this document Screening of original submissions VDD will target to screen the original SNDS, SABNDS and NC submissions as detailed below: Submission Types Target Screening Period (calendar days from the date of the receipt) SNDS, SABNDS 45 NC 14 The screening is based on the applicable regulatory and scientific requirements outlined in the Food and Drugs Act and Regulations as well as in applicable guidelines. The submissions are also screened to ensure that the correct submission type has been filed for the changes proposed, i.e., not beyond the scope of the classification of the submission. Upon the completion of screening, VDD will proceed with one of the following three screening decisions: Screening findings No deficiencies found Screening decision and next step Issuance of an Acceptance for Review letter by fax only. The submission is to be forwarded to the relevant review divisions for evaluation: (screening clock of 1 st screening cycle stops and review clock starts on the date of the Acceptance for Review letter) Page 22 of 43

23 Screening findings Deficiencies found Screening decision and next step Issuance of a Screening Deficiency Notice (SDN) by fax and mail. (screening clock of 1 st screening cycle stops) Submission is significantly deficient Incorrect submission type has been filed For NC: A complete response is due within 30 calendar days. For SNDS, SABNDS: A complete response is due within 45 calendar days. Issuance of a Screening Rejection Notice (SRN) by fax and mail. (screening clock of 1 st screening cycle stops on the date of SRN) The submission is rejected at screening. If the sponsor decides to refile the submission at a future time, it will be processed as a new submission Issuance of a Screening Deficiency Notice (SDN) The issuance of a SDN for SNDS, SABNDS and NC submission types follows the same management principles and decision criteria as that described in Section of this document. Only one SDN may be issued per submission. A SDN will be issued under the conditions outlined below: the data provided is considered insufficient in support of the proposed change(s); and upon screening, it is determined that additional changes other than those stated in the submission have been made and no supporting data has been provided Issuance of a Screening Rejection Notice (SRN) A Screening Rejection Notice will be issued under the following conditions: a sponsor s failure to respond to a SDN; a submission is significantly deficient and cannot be accepted for review without major modifications; the proposed change is beyond the scope of the class of submission under which it is filed (e.g., should be a SNDS instead of a NC); the related NDS or ABNDS is still under review or the approval of the submission is dependent on a previously filed submission that is still under review; and the product is registered under a DIN owner that is different from the one identified in the submission filed (e.g., NC, SNDS or SABNDS). Page 23 of 43

24 8.3.2 Screening of responses to Screening Deficiency Notice Upon receipt of a SDN, the sponsors are required to provide a complete response within the time specified below. A new screening period (2 nd screening cycle) will commence following the receipt of a response to a SDN. Response to Target due date Acknowledgement New screening SDN for for sponsor of receipt issued? period (2 nd screening cycle) SNDS, SABNDS 45 Yes 14 NC 30 No 14 Upon the completion of the screening of responses to a SDN, there are two possible outcomes for the screening process to progress: Screening findings Response to a SDN is complete and does not contain unsolicited data Response to a SDN is incomplete, deficient, or contains unsolicited data OR No response to a SDN Screening decision and next step Issuance of an Acceptance for Review letter by fax only. The submission is to be forwarded to the relevant review divisions for evaluation: (screening clock of 2 nd screening cycle stops and review clock starts on the date of the Acceptance for Review letter) Issuance of a Screening Rejection Notice (SRN) The submission is rejected at screening. If the sponsor decides to refile the submission at a future time, it will be processed as a new submission. (screening clock of 2 nd screening cycle stops) Screening of responses to review decision letters (Notice of Deficiency (NOD)) The same management principles and decision criteria described in Section 7.3. to of this document will apply when VDD screens responses to review decision letters. The table below provides an overall summary of the process. Page 24 of 43

25 Responses to Acknowledgement Target screening Maximum Acceptance review decision of receipt period number of for review letters issued (1 st screening cycle) SDN issued letter issued (calendar days) before SRN Minor Information Request (MIR) - Used for SNDS and SABNDS only Yes *Not applicable as no screening will be done for responses to MIR Notice of Deficiency (NOD) Yes 45 days for SNDS and SABNDS 14 days for NC 1 Yes *Note: As indicated in below, the issuance of MIR does not stop the review clock. Therefore, responses to MIR will be forwarded to the review division(s) upon receipt. 8.4 Reviewing of original SNDS, SABNDS and NC submissions Review of SNDS, SABNDS and responses to related review decision letters The same management principles, decision criteria and the review and approval process for the NDS and ABNDS submissions apply to the SNDS and SABNDS. Please refer to Sections 7.0 to 7.5 of this document Review of NC and responses to related review decision letters Once the NC submission is accepted for review, it is forwarded to the applicable review division for review based on the nature of the changes proposed. If the submission is subject to a joint review by 2 or 3 review divisions, a consolidated set of review comments will be communicated to the sponsor. VDD will target to issue a response letter within VDD s target performance standards outlined in Appendix A of this document Response letter from VDD Upon the completion of VDD s review of a NC submission by all applicable divisions, one of three possible decision letters can be sent to the sponsor: Page 25 of 43

26 Final review outcome No deficiencies found based on reviews done by applicable division(s) Deficiencies found Review decision and next step The issuance of a No Objection Letter (NOL). (review clock of 1 st review cycle stops) Issuance of a Notice of Deficiency (NOD). The sponsor is required to submit all the requested information within 30 calendar days from the date of NOD. (review clock of 1 st review cycle stops) Deficiencies remaining following review of responses to a NOD. OR No responses to a NOD. Issuance of a Notice of Non-Compliance (NON). The sponsor may refile the submission at a future time but it will be processed as a new submission. (review clock of 2 nd review cycle stops) Issuance of a Notice of Deficiency (NOD) - C (1)(b) of the Food and Drug Regulations Only one NOD will be issued per submission and the decision to issue NOD will be based on the following condition: upon the completion of all applicable review divisions, it is found that the remaining deficiencies will preclude VDD from issuing a NOL for the submission. The NOD is to be issued to the sponsor by fax and mail. The sponsor is required to provide a complete response to a NOD within 30 calendar days from the date of the NOD Issuance of a Notice of Non-Compliance (NON) - C (3)(b) of the Food and Drugs Regulations Only one NON will be issued per submission and will be based on the following conditions: sponsor s failure to respond to a NOD within 30 calendar days; and following the review of the responses to NODs by the applicable review divisions, the submission remains deficient. The NON will contain reasons and a list of deficiencies that resulted in the decision not to issue a NOL. Page 26 of 43

27 Upon receipt of a NON, the sponsor may decide to refile the submission at a future time. The refiled submission will be considered as a new submission. The sponsor should follow the instructions outlined in Section 13. of this document prior to refiling Issuance of a No Objection Letter (NOL) A NOL will be issued if the submission is found to be in compliance with the Food and Drug Regulations after a complete review of the submission by all appropriate review divisions. 9. Administrative Amendments to Submissions Under Review The submission sponsors may at any time provide administrative updates to submissions under review regarding a change for any of the following: DIN owner name submission sponsor (if different from the DIN owner) brand name of the product other regulatory contact information As part of the update, the sponsor is required to submit the following: a cover letter stating the nature of the administrative change; certification form; copies of the revised set of product labels and package inserts to reflect the change (if applicable); and if the sponsorship of a submission has been changed resulting from a corporate merger, buy-out, or license agreement, then a letter is required from the sponsor who filed the submission initially, authorizing the transfer of submission sponsorship to the new sponsor and the extent of the cross-reference permitted. Upon the receipt of the above updates, VDD will assign a new set of submission and file numbers to reflect this change (if necessary). An acknowledgement of receipt will be sent by fax. 10. Final Label Review Following the receipt of a NOC for a NDS or an ABNDS, the DIN owner of the product should submit the completed Drug Notification Form and a final version of all labelling components for all marketed package sizes including package inserts (required within 30 days of the first sale). These final printed labels will be subject to a final label review to ensure that the content and format of the final labelling is comparable to the approved draft labels. VDD will target to complete the final label review within 45 calendar days from the date of receipt. Page 27 of 43

28 Final review of labels also applies to final labels submitted following the approval of a SNDS or a SABNDS (e.g., due to changes to the product labels). 11. Post-Approval Obligations - Administrative Amendments to Initial Product Registration for All Drugs 11.1 Notification of the commencement of sale of a drug product Within 30 calendar days after commencing the sale of a drug, the owner of the DIN is required to sign and date the Drug Notification Form and return this form along with copies of all the final product labels including package inserts to VDD as per Section C of the Food and Drug Regulations Annual drug notification - Products that are marketed Pursuant to Section C of Food and Drug Regulations, every year Health Canada will send an Annual Drug Notification form to the DIN owner of drugs that are currently being marketed in Canada. [Note: This service is provided by the Submission Information Policy Division (SIPD) in the Therapeutic Products Directorate] The annual drug notification form contains a list of drugs and corresponding DIN-related information that are registered under the DIN owner. Prior to signing and returning the forms, the DIN owner is required to review the form for accuracy and indicate any differences where appropriate. Further details are found in the policy entitled: Authority to sell drugs fees, fee reductions, and adjustment requests. The document is available on the Therapeutic Products Directorate s Web site at: Cancellation of the DIN The DIN of a drug can be cancelled either by the Directorate or by the DIN owner in accordance with Section C of the Food and Drug Regulations Cancellation of DIN by DIN owner Pursuant to Section C of the Food and Drug Regulations, the DIN owner of a drug is required to inform the VDD within 30 calendar days from the date that it discontinues the sale of the drug in Canada. VDD will cancel the corresponding DIN of that drug upon receipt of this notification Cancellation of DIN by VDD The Directorate may cancel the DIN under the following circumstances: Page 28 of 43

29 the DIN owner has failed to return the annual drug notification form as required by Section C of Food and Drug Regulations for drugs that it registers with the Directorate; the Directorate determines that the evidence submitted by the DIN owner for the product registration is insufficient and warrants the cancellation of DIN; or the drug is a new drug in respect of which the Notice of Compliance has been suspended by the Directorate Changes to the product s brand name or changes to DIN ownership For all drugs, changes to the brand name of the product or the DIN ownership requires the filing of an administrative NDS or a DIN submission. Prior to filing, the sponsor should ensure that the products have a clear registration record (e.g., no outstanding issues/submissions that are still under review). To facilitate the review and approval process, data provided for the administrative submissions should be limited to administrative content. Scientific updates should be filed under NC, SNDS, and SABNDS submissions. The submission process for administrative NDS submissions will be subject to the same management principles, procedures and processes outlined in Sections 7.0 to 7.5 and 8.0 to 8.4 of this document Transfer of business product lines Often in the veterinary drug industry, one company will sell its entire business product line to another company through a commercial purchase transaction. To ensure regulatory compliance, consideration should be given to the following points prior to (or even after) the completion of a business transfer: who owns the product; (It should be noted that there are times when the business owner of the product may not necessarily be the registered DIN owner of the product.) marketing status of the drug; (If the DIN of a product was previously inactivated, the new business owner of the product needs to refile a submission in order to obtain a valid DIN for marketing the product in Canada.); and outstanding submissions that are still under review but were filed by the previous DIN owner/sponsor of the product. (An authorization letter is required from the sponsor of the previously filed submissions in support of the transfer of submission sponsorship, if applicable. It is the new DIN owner s responsibility to determine the impact of the outstanding submissions on its marketing of the product in Canada.) 11.6 Changes to a company s address and contact name When there is a change in company s address and contact name, the company is required to Page 29 of 43

30 submit a letter stating the nature of the changes and provide a list of products that are being affected by the change. The company referred to here can be a DIN owner, importer or any manufacturing site that holds an Establishment License. If the address change is related to the DIN owner, importer and/or distributor that is included on the labelling, revised labelling should also be submitted to reflect the change. 12. Withdrawing a Submission Prior to Approval A sponsor may withdraw a submission at any time. If the submission is to be re-submitted at a future time, it will be processed as a new submission and subject to new submission fees. 13. Refiled Submission A sponsor may refile a submission that has been previously withdrawn, rejected, or for which a Notice of Non-Compliance (NON) was issued. All refiled submissions will be processed as new submissions and assigned with new submission numbers. They are subject to screening and review as per this document. The refiled submissions are subject to new Submission Evaluation fees pursuant to the Veterinary Drug Evaluation Fees Regulations Data requirement A refiled submission is subject to any new policies, guidelines and procedures that may be in effect at the time of refiling. Whether the related original submission was rejected or withdrawn, the sponsor must submit a complete set of information as required for all new submissions. Cross-references to previously submitted information in lieu of resubmitting the information or cross-reference to a submission that has not received a positive clearance (e.g., NOC, DIN or a NOL) is not acceptable. If the submission is related to a NON issued for a previously filed NDS, ABNDS, SNDS or SABNDS submission, data requirements are dependent on when the refiled submission is submitted. Timing of the refiling Data requirement Cross-reference to the original submission? * Page 30 of 43

31 3 years question and answer format to address deficiencies Yes from the date noted in NON of NON certification that the information submitted in the original submission remains unchanged and is upto-date (alternatively, the sponsors should provide a summary of the differences between the original submission and the refiled submissions). > 3 years re-submit a complete set of information as required No from the date for all new submissions of NON *Note: Cross-references to submissions that have not received a positive clearance (e.g., NOC, DIN or a NOL) are not acceptable. 14. Screening of Unsolicited Amendments to Submissions Under Review VDD will not accept unsolicited amendments to submissions that have been accepted for review unless the amendments meet the following screening criteria: the amendment consists only of additional animal safety or human safety only information that will result in modifications to the Contraindications, Warnings, Precautions and Adverse Reaction sections of the product labels and package inserts; and that would enhance the safe use of the product in animals or provide a minimized impact on human safety or the environment. When submitting unsolicited amendments to submissions under review, it is the responsibility of the sponsor to integrate the amended information into the original submission and provide revised copies of the product labels and other affected documents as applicable. To facilitate initial processing and screening, a cover letter should also be provided to indicate the nature of amendments and the reasons for filing the amendments. All unsolicited amendments will be screened subject to the same management principles and procedures outlined in Sections to and to of this document. 15. Appeal Process The sponsor may appeal some of the decisions made by VDD during the screening and review of a submission. For details on the appeal procedure and process, please refer to the document entitled: Blueprint for the Veterinary Drug Submission Appeal Process, available at: Access to Submission-Related Information Page 31 of 43

32 16.1 Submission status All inquiries regarding submission status should be directed to the Submission Office in VDD. This centralized procedure is to better coordinate, track and efficiently respond to the high volume of administrative calls from submission sponsors. The sponsors should send all the requests by phone at: , or fax at: or at The Submission Office will target to provide a response within 3 working days (i.e., excludes weekends and holidays) to inform the sponsor as to whether or not the review has been initiated in any of the applicable review division. The progress of the review will be communicated at the appropriate time via official review decision letters. It should be noted, however, that VDD will only respond to submission status inquiries for sponsors whose names are listed on the Drug Submission Application form of the submission or to someone who is an authorized agent representing the submission sponsor. No information can be disclosed in response to inquiries from other third parties. In parallel with the process for submission status inquiry, VDD also sends a Notice of Initiation of Review as soon as any of the applicable review division initiates the review of the submission. 17. Establishment License (E.L.) Requirement As outlined in Section C.01A.005 of the Food and Drug Regulations, companies who are involved in fabrication, packaging/labelling, importation, distribution, wholesale, and testing of a drug marketed in Canada are required to obtain a valid Establishment Licence. For guidance, please refer to the Establishment Licensing Framework or the Guidance Document on Establishment Licences, both of which are located on the Health Products and Food Branch Inspectorate Web site: Drug Submission Evaluation Fees Prior to filing a submission, the sponsors should consult with the following documents to ensure appropriate fee assessment is done and the applicable procedures are followed. Guidance Document on Cost Recovery - Veterinary Drug Submission Evaluation Fees (version: February, 2002); Veterinary Drug Evaluation Fees Regulations (SOR/96-143). Page 32 of 43

33 Appendix A: Performance Targets Initial Processing of all Submissions: Seven calendar days Screening and Review of Original Submissions - NDS, ABNDS, SABNDS, SNDS, NC Submission Class Calendar Days Screening (1 st screening cycle) Review (1 st review cycle) NDS AB/NDS SNDS SABNDS NC (90 day) NC (120 day) Administrative NDS Administrative ABNDS Final Label Review Not applicable 45 Screening and Review of Responses to VDD Screening and Review Decision Letters - Response to SDN, MIR and NOD for NDS, ABNDS, SABNDS, SNDS Activity Type Performance Target in Calendar Days (VDD) Performance Target in Calendar Days (Sponsor) Response to SDN Not applicable 45 Screening of response to SDN (2 nd screening cycle) 14 Not applicable Response to MIR Not applicable 15 Response to NOD Not applicable 90 Screening of response to NOD (1 st screening cycle) 45 Not applicable Review of response to NOD (2 nd review cycle) 150 for NDS and ABNDS 120 for SNDS and SABNDS 45 for Administrative NDS and Administrative ABNDS Not applicable Page 33 of 43

34 Screening and Review of Responses to VDD Screening and Review Decision Letters - Response to SDN and NOD for NC submission Activity Type Performance Target in Calendar Days (VDD) Performance Target in Calendar Days (Sponsor) Response to SDN Not applicable 30 Screening of response to SDN (2 nd screening cycle) 14 Not applicable Response to NOD Not applicable 30 Screening of response to NOD (1 st screening cycle) Review of response to NOD (2 nd review cycle) 14 Not applicable 60 Not applicable Pre-Submission Phase - NDS, ABNDS, SNDS, SABNDS, NC Activity Type Performance Target in Calendar Days (VDD) Performance Target in Calendar Days (Sponsor) Meeting request Not applicable 60 prior to the proposed meeting date Written reply 15 Not applicable Pre-meeting pkg Not applicable 30 prior to the meeting date Draft meeting minutes Not applicable 15 Review of draft meeting minutes 15 Not applicable Request for Regulatory Guidance (e.g., submission classification) 60 Not applicable Response to Inquiries on Submission Status: Three working days Page 34 of 43

35 Appendix B: Mailing and Faxing of Regulatory Submissions and Related Documents Submission Types All regulatory submissions and related information except for annual DIN Renewals and Establishment License Applications Address By mail: Submission Office Submission and Knowledge Management Division Veterinary Drugs Directorate Holland Cross Complex, Tower A, Ground Floor Holland Avenue Ottawa, Ontario K1A 0K9 Address Locator A By facsimile: Submission Office Submission and Knowledge Management Division (613) Establishment License Applications Annual DIN Renewal By mail: Submission and Information Policy Division Finance Building #2 Address Locator: 0201A1 Tunney's Pasture Ottawa, Ontario K1A 1B9 By facsimile: Submission Information Policy Division (613) Page 35 of 43

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