Qualifying Notice - Veklury

Therapeutic Product Directorate
Holland Cross, Tower "B"
6th Floor, 1600 Scott Street
Address Locator #3106B
Ottawa, ON K1A 0K9

Dossier ID: e240551

[employee's name removed]
[employee's title removed]
Gilead Sciences Canada Inc.
6711 Mississauga Rd, Suite 600
Mississauga, ON L5N 2W3

Dear [employee's name removed]:

This Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN), issued in accordance with the Health Canada Guidance Document: Notice of Compliance with Conditions (NOC/c), is to advise you that information submitted in support of the New Drug Submission for Veklury (remdesivir), Control Number 240551, for the indication of "treatment of coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) with pneumonia requiring supplemental oxygen", qualifies to be considered for authorization in accordance with the NOC/c Guidance. In light of the public health emergency caused by the COVID-19 pandemic and because there are no currently approved therapeutic options, Health Canada is prepared to grant, on exceptional basis, flexibility in the application of the NOC/c Guidance and allow conditions for both the safety and quality profile of VEKLURY. In keeping with the provisions outlined in the NOC/c Guidance, the following additional information is requested to complete the assessment:

1. A letter, signed by the Chief Executive Officer or designated signing authority of Gilead Sciences Canada Inc., indicating that you agree to have this submission considered under the NOC/c Guidance. Please be reminded that in agreeing to accept a Notice of Compliance (NOC) under the NOC/c Guidance, Gilead Sciences Canada Inc. consents to the posting of this NOC/c-QN on Health Canada's website once market authorization has been received.
2. A Letter of Undertaking signed by the Chief Executive Officer or designated signing authority of Gilead Sciences Canada Inc., having a form and content satisfactory to Health Canada, as indicated in NOC/c Guidance, including commitments to provide the following:

Confirmatory Studies

1. In order to confirm the efficacy and safety of remdesivir, the sponsor should submit the final clinical study report (CSR) of Study CO-US-540-5776 (NIAID-ACTT1) [information removed].
2. In order to confirm the efficacy and safety of remdesivir in patients on IMV/ECMO, the sponsor should submit the published final Day 28 mortality data by ordinal scale categories of Study CO-US-540-5776 (NIAID-ACTT1) [information removed]. In addition, the sponsor should discuss potential imbalance in the use of corticosteroids and effect modification in Study CO-US-540-5776 [information removed].
3. In order to confirm the efficacy and safety of remdesivir, the sponsor should submit the final CSR for Part A (Day 28) of Study GS-US-540-5773 [information removed].
4. In order to confirm the efficacy and safety of remdesivir, the sponsor should submit the final CSR for Part A (Day 28) and any available data from the Extension Treatment Group of Study GS-US-540-5774[information removed].
5. In order to confirm the safety profile of remdesivir, the sponsor should submit in Module 2.7.4,[information removed],an analysis of all available safety data from clinical trials CO-US-540-5776, GS-US-540-5773, GS-US-540-5774 and CO-US-540-5758 when completed, including case narratives, detailed information about adverse reactions, exposure data as well as an analysis of occurrence and aggravation of adverse events (AEs), Serious Adverse Events (SAEs) and Adverse Drug Reactions (ADRs) associated with increasing exposure.
6. In order to confirm the safety profile of remdesivir, the sponsor should submit the CSR for a Phase I study in uninfected volunteers with moderate and severe hepatic impairment [information removed].
7. In order to confirm the safety profile of remdesivir, the sponsor should submit the CSR for a Phase I study in uninfected volunteers with severe renal impairment and end-stage renal disease (ESRD) on dialysis[information removed].

Progress Reports of Confirmatory Trials and Other Ongoing Trials

8. On an annual basis, within 60 calendar days of the market authorization anniversary or a date agreed upon at the time of the issuance of the market authorization, status reports on the progress of ongoing confirmatory trials, as per section 3.2 and Appendix 4 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The details of the requirements for filing and termination of the annual status report as agreed upon by Gilead Sciences Canada Inc. and Health Canada must be outlined in the Letter of Undertaking.

Post Market Safety Monitoring

9. Provision of monthly safety reports for remdesivir that contain updated safety data on patients treated outside of clinical trials including safety data from spontaneous sources, the compassionate use program and the expanded access program. The submission of monthly reports should begin one month following marketing authorization in Canada and the reports should be submitted monthly until the time of submission of the first Periodic Benefit-Risk Evaluation Report (PBRER) or Periodic Safety Update Report (PSUR).
10. Report all serious adverse drug reactions (ADRs) that occurred in Canada and all serious unexpected ADRs that occurred outside of Canada within 15 days to the Marketed Health Products Directorate, in accordance with the current Food and Drug Regulations (C.01.017) and guidance documents.
11. Provision of PBRERs or PSURs every 6 months for the first 2 years of marketing following authorization in Canada. The frequency of submission of subsequent PSURs/PBRERs will be determined according to the information available at the time of review. The PSUR(s) or PBRER(s) should be submitted within 70 calendar days of the data lock point according to the ICH E2C(R2) guidelines and the submission should include cumulative data on relevant unlisted adverse reactions from the date of marketing to the time of the report. A PSUR should however be submitted as soon as possible, should the sponsor identify a change in the benefit risk profile of the drug that will require modifications to the pharmacovigilance or risk mitigation activities.
12. Provision of the pregnancy safety report with data from the compassionate use (IN-US-540-5755) and expanded access program (GS-US-540-5821) within the first PSUR [information removed]. Subsequent available interim and cumulative pregnancy data will be presented in future PSURs.
13. Notify the Marketed Health Products Directorate of all foreign regulatory actions related to safety within 15 days and submit a report on the issue within 30 days, as outlined in Section 3.4.4, Post-Market Commitments: Notification and Reporting of Specific Issues of Concern, of the Health Canada NOC/c Guidance.

Chemistry, Manufacturing, and Controls

14. Submit, as a Supplemental New Drug Submission (SNDS-C), the response to the comments below:

All responses to the quality-specific obligations and quality recommendations described in annex 1 of the European Public Assessment Report (EPAR) should be submitted to Health Canada within [information removed], except when the comments pertain to labelling.

In addition, you are requested to address the following Health Canada comments:

Drug Substance

15. The drug substance specifications should be revised as follows in order to ensure acceptable quality of the drug substance and suitability for the intended use:
    1. The proposed limit of not more than (NMT) [information removed] for each of the unspecified degradation products is higher than the acceptable ICH Q3A limit of 0.10%. Based on the justification provided in the dossier and the fact that remdesivir is indicated for a life-threatening condition and has a short treatment duration of 10 days, TPD considers the proposed limit as tentatively qualified for general toxicity for the identified impurities to be controlled as unspecified impurities. However, the assessment of these impurities as per ICH M7 and applicable Q3 guidelines are required for a full approval of remdesivir. In addition, given that at a proposed limit of [information removed], the 200 mg dose will result in a dose of the impurity being greater than [information removed]; the sponsor must also demonstrate the lack of clastogenicity of these unspecified impurities. Alternatively, the limit can be tightened to 0.15%.
    2. As noted in the EMA specific obligations, the specification limit for unknown impurities should be adjusted to comply with ICH Q3A.
16. The proposed storage conditions for the drug substance should be revised to include a temperature range (e.g., upper and lower temperature limits) as per Health Canada's Quality Guidance Document. Thus, you are requested to revise [information removed]. Please update all relevant documents, including the Certified Product Information Document (CPID).

Remdesivir for injection

17. The drug product specifications should be revised as follows in order to ensure acceptable quality of the drug product and suitability for the intended use:
    1. It is noted that the reconstitution time is reported in the batch analysis as maximum [information removed], thus a specification limit of [information removed] is a wider limit. You are requested to tighten the limit.
    2. The proposed limit [information removed] for each of the unspecified degradation products is higher than the acceptable ICH Q3B limit of 0.2%.
       1. An attempt should be made to identify any unknown degradation products observed above the identification threshold and these degradation products should be specified in the drug product specifications.
       2. Qualification of these impurities above the ICH threshold would require an assessment as per ICH M7 and applicable Q3 guidelines. In addition, given that at a proposed limit of [information removed], the 200 mg dose will result in a dose of the impurity being greater than [information removed]; the sponsor must also demonstrate the lack of clastogenicity of these unspecified impurities. Alternatively, the limit can be tightened to 0.2%.
       3. A limit of 0.2% should be applied for unknown degradation products.
18. In-use stability data for remdesivir powder have not been provided. In light of the dilution instructions specific to the remdesivir powder (i.e. use of a 100 mL bag) and the limited aqueous solubility of remdesivir at [information removed]. You are requested to provide in use stability data for remdesivir powder that supports the proposed range of concentrations (0.4 mg/mL to 2 mg/mL) and the proposed storage conditions for any diluent included in the Canadian Product Monograph (PM). Results should be provided for appearance, pH, Assay and Degradation products, as well as particulate matter as per the USP <788> for all your in use stability data. If you are proposing Di(2-ethylhexyl) phthalate (DEHP) containing bags, you are also requested to provide results for DEHP content released. Also please note that in-use stability study should also be performed with the drug product at the end of its shelf-life.
19. Incomplete information was provided for the container closure system. You are requested to provide the following details:
    1. Information regarding the composition, specifications including drawings, details of washing procedures and their validation should be submitted for the proposed ready to sterilize rubber closures [information removed]. Alternatively, reference can be made to Canadian master files.
    2. The information requested above should allow for determination of absence of the rubber vulcanization accelerator 2-Mercaptobenzothiazole (2-MBT) and related compounds, as well as any known nitrosamine precursors. Alternatively, a statement that they are free from 2-MBT and related compounds, as well as any known nitrosamine precursors, can be submitted.
    3. Similarly, details should be provided for the 30 mL, Type I, clear glass vial with 20 mm finish including any information on the [information removed]. The qualitative composition of the [information removed] should be provided in the submission or cross-referenced to a Canadian Master File.

Remdesivir solution for injection

20. In use stability data should include results for particulate matter as per the USP <788>. Therefore, you are requested to provide results for this test to support the proposed concentration range recommended in the PM.
21. You are requested to confirm that an in-use stability study will also be performed with drug product at the end of its shelf-life.
22. The drug product specifications should be revised as follows in order to ensure acceptable quality of the drug product and suitability for the intended use:
    1. The proposed limit of [information removed] for each of the unspecified degradation products is higher than the acceptable ICH Q3B limit of 0.2%.
       1. An attempt should be made to identify any unknown degradation products observed above the identification threshold and these degradation products should be specified in the drug product specifications.
       2. Qualification of these impurities above the ICH threshold would require an assessment as per ICH M7 and applicable Q3 guidelines. In addition, given that at a proposed limit of [information removed], the 200 mg dose will result in a dose of the impurity being greater than[information removed]; the sponsor must also demonstrate the lack of clastogenicity of these unspecified impurities. Alternatively, the limit can be tightened to 0.2%.
       3. A limit of 0.2% should be applied for unknown degradation products.
23. Based on the stability data, a shelf-life of 12 months is considered to be appropriate at this time. You are requested to update the documentation to identify a 12 month shelf-life and the correct storage conditions ("Store in a refrigerator (2 °C to 8 °C)").
24. Incomplete information was provided for the container closure system. You are requested to provide the following details:
    1. Information regarding the composition, specifications including drawings, details of washing procedures and their validation should be submitted for the proposed rubber closures, [information removed] (full description of this closure is not provided). Alternatively, reference can be made to a Canadian master file.
    2. The information requested above should allow for determination of absence of the rubber vulcanization accelerator 2-Mercaptobenzothiazole (2-MBT) and related compounds, as well as any known nitrosamine precursors. Alternatively, a statement that these are free from 2-MBT and related compounds, as well as any known nitrosamine precursors, can be submitted.
    3. You are requested to confirm which vial size will be used (20 or 25 mL) and justify the selection of a 20 mL vial when the fill volume is over 20 mL.
25. [information removed].
26. The CPID should be revised to reflect your responses to the above comments. You are requested to provide an annotated CPID, highlighting revisions made to the CPID dated [information removed], in the upcoming SNDS-c.

3. A draft of the Product Monograph (PM) that is consistent with the requirements outlined in section 5.2.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). Please note that boxed text should appear on the cover page as well as at the beginning of each major section of the Product Monograph (Parts I, II and III, as applicable), disclosing the nature of the authorization granted for Veklury (remdesivir) for the indication of "treatment of coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) with pneumonia requiring supplemental oxygen".
4. A final mock-up of the Package Insert (if applicable), in line with the requirements outlined in Health Canada's Guidance Document, Questions and Answers: Plain Language Labelling Regulations (Q&A: PLL), containing boxed text disclosing the nature of the authorization granted for Veklury (remdesivir) for the indication of "treatment of coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) with pneumonia requiring supplemental oxygen".

I wish to advise you that this Qualifying Notice is being issued in accordance with Health Canada's guidance documents on the Management of Drug Submissions and Applications and Notice of Compliance with Conditions. Please submit a complete response with the requested information as soon as possible.

In order to facilitate and to ensure proper processing, please include a revised Submission Certificate with your response, quote the product name and control number, and address all correspondence to the Office of Submissions and Intellectual Property, Therapeutic Products Directorate, Health Canada, Finance Building, 101 Tunney's Pasture Driveway, Address Locator 0201A1, Ottawa, Ontario, K1A 0K9.

Yours sincerely,

Dr. J. Patrick Stewart, MD, CCFP(EM)
Director General
Therapeutic Products Directorate