Draft Guidance for Industry on Management of Regulatory Submissions

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Cover Letter

Introduction

Health Canada's Veterinary Drugs Directorate (VDD) has prepared this Draft Guidance for Industry - Management of Regulatory Submissions document for stakeholder consultation. Its purpose is to clarify the requirements for key steps in the process and enable drug sponsors to improve the quality of their submissions.

The draft guidance defines how VDD manages regulatory submissions and related information filed by sponsors in accordance with the Food and Drugs Act and Regulations. It clearly describes the process that both VDD staff and sponsors must follow for all submission-related activities.

This will result in a submission process which is more efficient and effective for both the sponsors and VDD staff. By improving the quality of veterinary drug submissions which currently vary significantly, VDD staff will be able to work in a more efficient, cost effective manner.

Stakeholder consultation on this draft guidance document is being launched at this time.

Background

This document was developed in accordance with stakeholder requests for a clear set of procedures. In addition, these guidelines were developed in response to the need for a department-wide tracking system. Once this guidance document has been finalized, VDD will phase in its implementation in an appropriate and workable manner for all parties.

Content

This guidance document 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 (S/NDS);
• Abbreviated New Drug Submission (ABNDS);
• Abbreviated Supplemental New Drug Submission (ABS/NDS); and
• Notifiable Change (NC).

For each of the above submission types, this document provides a procedural outline on the following stages of the submission process:

• Pre-submission Phase;
• Initial Processing of Submissions;
• Screening of Submissions;
• Review of Submissions; and
• Final Review Decision.

Please note that Investigational New Drug Submissions (INDS) and Experimental Studies Certificates (ESC) are not included in this policy.

Submission Coordination Committee

VDD's internal Submission Coordination Committee (SCC), comprised of review Division Chiefs, was formed to:

• develop policy;
• synchronize the work of divisions;
• develop implementation plans for new policies;
• provide ongoing monitoring for policy effectiveness; and
• draft Standard Operating Procedures (SOPs) for these policies.

Implementation

The closing date for stakeholder comment is April 1, 2004. VDD will finalize the document and develop next steps, taking stakeholder comments into consideration. It is expected that implementation of the Guidance for Industry - Management of Regulatory Submissions document will take place in the fourth quarter of 2004/05. VDD is concurrently developing a tracking system for submission management. This system will provide data to assist VDD in working with industry to implement performance targets.

Achieving a reduction in review times will be a joint effort shared by VDD and the veterinary drug industry. Collaboration ensures that this progress will continue in a positive and energetic fashion.

Cover Page

Draft Guidance For Industry
Management of Regulatory Submissions

Veterinary Drugs Directorate
Health Products and Food Branch
Health Canada

Draft Date for External Consultation: November 25, 2003
Effective Date: TBD

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Table of Contents

Forward

1. Introduction

2. Purpose

3. Scope

4. An Overview of the Regulatory Requirements for Filing Drug Submissions with VDD

4.1 Request for authorization to sell-marketing authorization
4.2 Request for authorization to sell a drug that does not have a DIN
4.3 Post-approval obligations: Scientific amendments to initial product registration
4.4 Post-approval obligations: Administrative amendments to initial product registration for all drugs

5. Procedure for Sending ALL Regulatory Submissions and Related Information to VDD

5.1 Sending information by mail or fax
5.2 Sending information by electronic mail (e-mail)

6. Submission Holds

6.1 During initial processing
6.2 During screening
6.3 During the NOC and/or DIN issuance stage

7. Review and Approval Process for NDS, ABNDS, SNDS and SABNDS

7.1 Pre-Submission meeting
7.2 Initial processing of original NDS, ABNDS, SNDS, SABNDS submissions and responses to screening and review decision letters
7.3 Screening of original NDS, ABNDS, SNDS, SABNDS submissions and responses to screening and review decision letters
7.4 Reviewing original submissions (NDS, ABNDS, SNDS, SABNDS) and
responses to review decision letters
7.5 Additional points to consider when responding to a SDN, MIR, NSL

8. Review and Approval Process for Scientific Amendments to Product Registration - SNDS, SABNDS and NC Submissions

8.1 Consultation - Pre-submission
8.2 Initial processing of original SNDS, SABNDS and NC submissions and responses to screening and review decision letters
8.3 Screening of original submissions and responses to screening and review decision letters
8.4 Reviewing of original SNDS, SABNDS and NC submissions

9. Administrative Amendments to Submissions Under Review

10. Final Label Review

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
11.2 Annual drug notification - Products that are marketed
11.3 Cancellation of the DIN
11.4 Changes to the product's brand name or changes to DIN ownership
11.5 Transfer of business product lines
11.6 Changes to a company's address and contact name

12. Withdrawing a Submission Prior to Approval

13. Refiled Submission

13.1 Data requirement

14. Screening of Unsolicited Amendments to Submissions Under Review

15. Appeal Process

16. Access to Submission-Related Information

16.1 Submission status

17. Establishment License (E.L.) Requirement

18. 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

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

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Forward

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 principles and 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.

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 or Abbreviated 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;
• Final review decision.

As shown in the diagram below, all submissions and related information undergo a similar review and approval process.

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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.

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: http://www.hc-sc.gc.ca/vetdrugs-medsvet/index-eng.php

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.01.014 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.01.014.1(2) of the Food and Drug Regulations;
• A New Drug Submission (NDS) pursuant to Section C.01.014.1(3) and C.08.002 and C.08.005.1 of the Food and Drug Regulations; and
• An abbreviated NDS (ABNDS) pursuant to Section C.01.014.1(3) and C.08.002(1) and C.08.002.1 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.08.013 and C.08.014 of the Food and Drug Regulations;
• A Pre-Clinical Submission [referred to as an Investigational New Drug (IND) submission] pursuant to Sections C.08.005 and C.08.005.1of 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.08.010 of the Food and Drug Regulations.

4.3 Post-approval obligations: Scientific amendments to initial product registration

4.3.1 After a sponsor has received a marketing authorization for a new drug product pursuant to Section C.08.004 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.08.003 of the Food and Drug Regulations.

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

4.3.2 If a sponsor receives a marketing authorization for a drug product pursuant to Section C.01.014.2 of the Food and Drug Regulations, the sponsor is required to file updated information about the drug in accordance with Section C.01.014.4 of the Food and Drug Regulations.

4.4 Post-approval obligations: Administrative amendments to initial product registration for all drugs

4.4.1 Notification of commencement of sale

Pursuant to Section C.01.014.3 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.

4.4.2 Annual drug notification for products that have been marketed

Pursuant to Section C.01.014.5 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.

4.4.3 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.01.014.6 of the Food and Drug Regulations.

4.4.4 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.

4.4.5 Changes to the product's brand name and DIN ownership

Pursuant to Section C.01.014.1 (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.

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 for urgent reasons, these documents 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 (e-mail)

Over the past several years, the use of e-mail 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 e-mail cannot be considered as a substitute for the official hard copy submission that is necessary for VDD's records. Similarly, the e-mail documents sent by VDD staff cannot be considered an official record of decisions made by the Directorate.

In addition, the e-mail 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 e-mails to correspond with VDD about regulatory issues.

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

Before filing a submission, the sponsors may request a meeting with VDD to seek regulatory guidance on specific items. The purpose of the meeting would be to:

• familiarize VDD review staff with the general information to be submitted;
• provide sponsors with general 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.

7.1.1 Request for a pre-submission meeting

The diagram below provides an overview of pre-submission meeting process.

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The sponsor can send a meeting request to VDD at any time. As indicated in the diagram above, a pre-submission meeting, if granted, 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 to advise the sponsor whether the meeting request is accepted or refused. If a meeting is granted, 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 pre-meeting 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 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.

7.1.2 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 Office at VDD. Upon receipt, 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.

7.3.1 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:

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7.3.1.1 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.

7.3.1.2 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.

7.3.2 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:

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7.3.3 Screening of responses to review decision letters [Not Satisfactory Letter (NSL)]

The same management principles, procedures and decision criteria described in Sections 7.3 to 7.3.2 of this document will apply when VDD screens responses to review decision letters. The table below provides an overall summary of the process.

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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 outcomes from ALL appropriate review divisions.

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7.4.1 Communications during the review between the Sponsor and VDD

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.

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7.4.1.1 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.

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 Not Satisfactory Letter.

7.4.2 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:

View three possible decision letters that can be sent to the sponsor Table
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7.4.3 Issuance of a Not Satisfactory Letter (NSL) - C.08.004 (1) (b) of the Food and Drug Regulations

Only one NSL 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 NSL is to be issued to the sponsor by fax and mail. The sponsor is required to provide a complete response to a NSL within 60 calendar days from the date the NSL was issued.

7.4.4 Issuance of a Notice of Non-Compliance (NON) - C.08.004 (3) (b) of the Food and Drugs Regulations

Only one NON will be issued per submission based on the following conditions:

• a sponsor's failure to respond to a NSL within 60 calendar days;
• following a complete review of the response to a NSL 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".

7.4.5 Issuance of a Notice of Compliance (NOC)

Pursuant to Sections C.08.004 (1)(a) and C.08.004 (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 Additional points to consider when responding to a SDN, MIR, NSL

Upon the receipt of a SDN, MIR or NSL, 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 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 NSL 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 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.

8.3.1 Screening of original submissions

VDD will target to screen the original SNDS, SABNDS and NC submissions as detailed below:

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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:

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8.3.1.1 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 7.3.1.1 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.

8.3.1.2 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).

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.

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Upon the completion of the screening of responses to a SDN, there are two possible outcomes for the screening process to progress:

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8.3.3 Screening of responses to review decision letters (Not Satisfactory Letter (NSL)

The same management principles and decision criteria described in Section 7.3. to 7.3.3 of this document will apply when VDD screens responses to review decision letters. The table below provides an overall summary of the process.

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8.4 Reviewing of original SNDS, SABNDS and NC submissions

8.4.1 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.

8.4.2 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.

8.4.2.1 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:

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8.4.2.1.1 Issuance of a Not Satisfactory Letter (NSL) - C.08.004 (1)(b) of the Food and Drug Regulations

Only one NSL will be issued per submission and the decision to issue NSL 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 NSL is to be issued to the sponsor by fax and mail. The sponsor is required to provide a complete response to a NSL within 30 calendar days from the date of the NSL.

8.4.2.1.2 Issuance of a Notice of Non-Compliance (NON) - C.08.004 (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 NSL within 30 calendar days; and
• following the review of the responses to NSLs 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.

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.

8.4.2.1.3 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;
• 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 final version of any labels including package inserts. 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.

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.01.014.3 of the Food and Drug Regulations.

11.2 Annual drug notification - Products that are marketed

Pursuant to Section C.01.014.5 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 TPD's Web site at: http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/annualfees_e.html.

11.3 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.01.014.6 of the Food and Drug Regulations.

11.3.1 Cancellation of DIN by DIN owner

Pursuant to Section C.01.014.7 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.

11.3.2 Cancellation of DIN by VDD

The Directorate may cancel the DIN under the following circumstances:

• the DIN owner has failed to return the annual drug notification form as required by Section C.01.014.5 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.

11.4 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.

11.5 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 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.

13.1 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.

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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 7.3.1 to 7.3.2 and 8.3.1 to 8.3.2 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".

16. Access to Submission-Related Information

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: 613-941-8845, or fax at: 613-946-1125 or e-mail at SKMD-SO_DGPS-CP@hc-sc.gc.ca. 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:
http://www.hc-sc.gc.ca/dhp-mps/compli-conform/index-eng.php.

18. 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).

Appendix A: Performance Targets

Initial Processing of all Submissions: Seven calendar days

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View Screening and Review of Responses to VDD Screening and Review Decision Letters - Response to SDN, MIR and NSL for NDS, ABNDS, SABNDS, SNDS Table
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Response to Inquiries on Submission Status: Three working days

Appendix B: Mailing and Faxing of Regulatory Submissions and Related Documents

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Appendix C: Process Overview for NDS, ABNDS, SNDS, SABNDS submissions

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Appendix D: Request for Pre-Submission Meeting(NDS, ABNDS, SNDS, SABNDS)

1. Sponsor contact information:

Address

Contact name

Contact telephone number

Contact fax number

Contact e-mail address

2. Name of the DIN owner of the drug product for which the submission is to be filed:

3. Name of the drug (brand name and proper/common/chemical name):

4. Proposed strengths and dosage forms of the drug:

5. Proposed therapeutic classification, proposed indication and species:

6. Purpose of the meeting (check an applicable box):

Pre-New Drug Submission (NDS)
Pre-Supplemental NDS
Pre-Abbreviated NDS (ABNDS)
Pre-Supplemental ABNDS
Other (please specify):

7. Listing of three proposed dates (approximately 2 months following the request date) and the time of the day for each of the proposed meeting date

Date
Time
a.m. or p.m.
Date
Time
a.m. or p.m.
Date
Time
a.m. or p.m.

8. A brief description of the drug product and corresponding submission plan:

9. A copy of the proposed meeting agenda (note: the final agenda should be very similar to the proposed version):

10. A list of specific items or questions that require guidance from VDD (grouped by scientific disciplines):

11. Request to have the meeting with VDD from the following divisions:

Clinical Evaluation Division (animal safety and efficacy)

Human Safety Division (human safety)

Manufacturing and Chemical Evaluation Division (chemistry and manufacturing)

Submission and Knowledge Management Division (general submission information, procedure and process)

Request date:

Requested by:

Appendix E: Process Overview for NC submissions

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Appendix F: Request for Regulatory Guidance - Submission Classification
(SNDS, NC, S/DIN or NDS)

1. Sponsor contact information:

Address

Contact name

Contact telephone number

Contact fax number

Contact e-mail address

2. Purpose of the request (check an applicable box):

updates to NDS (scientific)

updates to NDS (administrative)

updates to DIN (scientific)

updates to DIN (administrative)

Other (please specify):

3. Name of the DIN owner of the drug product for which the submission is to be filed and related original submission number (NDS, DIN, ESC or IND):

4. Name of the drug (brand name and proper/common/chemical name) and DIN#:

5. Proposed change (in specific detail to enable VDD to assess the significance of the changes proposed) are grouped in the following themes:

5.1 Chemistry and Manufacturing
5.2 Human Safety
5.3 Clinical including clinical study protocol
5.4 Labelling

6. List of questions for VDD

[Note: 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 drug product.]

Request date:

Requested by:

Appendix G: Definitions

Drug Identification Number (DIN): an 8-digit numerical code assigned to each drug product.

DIN Owner: the person to whom the DIN number was assigned to for a given drug product.

Sponsor: the applicant who filed a drug submission with VDD.

Under Screening: is referred to the period from the time a submission received in VDD to the time when a screening decision is made on that submission.

1^st Screening Cycle: is referred to the period during which the original submission or the response to Not Satisfactory Letter (NSL) is under screening.

2^nd Screening Cycle: is referred to the period during which the response to a Screening Deficiency Notice (SDN) is under review.

Under Review: is referred to the period from the time a submission is accepted for review to the time when a decision is made on that submission.

1^st Review Cycle: is referred to the period during which the original submission is under review.

2^nd Review Cycle: is referred to the period during which the response to a Not Satisfactory Letter is under review.