Qualifying Notice for Gavreto

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

Dossier ID: e239724

[employee name removed]
[employee title removed]
Hoffmann-La Roche Limited
7070 Mississauga Road
Mississauga, Ontario
L5N 5M8

[employee 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 Gavreto (pralsetinib), Control Number 243731, for the indication of the treatment of adult patients with rearranged during transfection (RET) fusion-positive locally advanced unresectable or metastatic non-small cell lung cancer (NSCLC). 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 Hoffmann-La Roche Limited 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, Hoffmann-La Roche Limited 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 Hoffmann-La Roche Limited having a form and content satisfactory to Health Canada, as indicated in NOC/c Guidance, including commitments to provide the following:

Confirmatory studies

1. Submit, as a Supplement to a New Drug Submission (SNDS)-confirmatory (SNDS-c), the final reports including datasets from clinical studies to confirm and further characterize the clinical benefit of pralsetinib for the treatment of patients with RET fusion-positive non-small cell lung cancer (NSCLC) with 1) treatment-naïve RET fusion-positive NSCLC and with 2) RET fusion-positive NSCLC who have previously received platinum chemotherapy to provide a more precise estimation of the blinded independent central review (BICR) assessed overall response rate and duration of response after all responders in the population of patients with treatment-naïve NSCLC (approximately 120 patients) have been followed for at least 12 months from the date of initial response (or until disease progression, whichever comes first) and after all responders in the population of patients with NSCLC previously treated with platinum therapy (87 patients) have been followed for at least 6 months.
   1. Hoffmann-La Roche Limited should provide the approximate date of completion of the confirmatory study and should commit to an approximate date of filing of the SNDS-c.
   2. Hoffmann-La Roche Limited should provide annual progress reports of confirmatory trials.
   3. Hoffmann-La Roche Limited should acknowledge that the indication authorized under the NOC/c pathway for Gavreto under control number 243731 can be withdrawn or revised if the aforementioned results do not confirm clinical benefit of pralsetinib for the treatment of patients with RET fusion-positive NSCLC who are treatment-naïve or who have previously received systemic therapy.
2. Submit, as an SNDS-c, the final report including datasets from a multi-center, randomized trial comparing pralsetinib to physician's choice of platinum-based chemotherapy treatment regimens based on standard of care treatment for the first-line treatment of RET fusion-positive, metastatic NSCLC. The results from this trial may inform product labeling.
   1. Hoffmann-La Roche Limited should provide the approximate date of completion of the confirmatory study and should commit to an approximate date of filing of the SNDS-c.
   2. Hoffmann-La Roche Limited should provide annual progress reports of confirmatory trials.
   3. Hoffmann-La Roche Limited should acknowledge that the indication authorized under the NOC/c pathway for Gavreto under control number 243731 can be withdrawn or revised if the aforementioned results do not confirm clinical benefit of pralsetinib for the treatment of patients with RET fusion-positive NSCLC who are treatment-naïve or who have previously received systemic therapy.

Additional studies requested by Health Canada

3. Conduct a comprehensive analysis evaluating and characterizing the incidence, clinical presentation, management, and outcome of the potential serious risk of pralsetinib associated gastrointestinal perforations and fistulas. Submit an integrated final report containing data from patient level and pooled analyses of on-going and completed clinical trials, postmarketing reports and/or literature reports and a comprehensive pharmacovigilance assessment for this potential serious risk. The results from this report may inform product labelling.
   1. Hoffmann-La Roche Limited should provide the approximate date of completion of the study and should commit to an approximate date of filing of the SNDS-c.

Post market safety monitoring studies

4. Provision of annual Periodic Benefit-Risk Evaluation Reports (PBRER-Cs) or Periodic Safety Update Reports (PSUR-Cs) in a manner deemed consistent with E2C ICH Guidelines, until such time as all conditions for market authorization under the NOC/c Guidance have been removed. The annual PBRER-Cs or PSUR-Cs should include cumulative data on relevant unlisted Adverse Reactions (ARs) from the date of marketing to the time of the report.
5. Notification and reporting on specific issues of concern, 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.
6. Report(s) of all serious adverse drug reactions (ADRs) that occurred in Canada and all serious unexpected ADRs that occurred outside of Canada should be forwarded within 15 days to the Marketed Health Products Directorate, in accordance with the current Food and Drug Regulations (C.01.017) and guidance documents.

Additional information

7. Receive pre-clearance by the Pharmaceutical Advertising Advisory Board (PAAB) for all promotional material related to Gavreto (pralsetinib) authorized under the NOC/c policy as per section 5.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
8. An outline of the agreed-upon advertising, labelling or distribution requirements, including a commitment to file revised Product Monographs under the appropriate submission type as information is made available as per section 4.3 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
9. An up-to-date, complete listing of ongoing additional clinical trials related to Gavreto (pralsetinib), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance Document: Notice of Compliance with Conditions (NOC/c).
10. Copies of any marketing authorizations for Gavreto (pralsetinib), from any other drug regulatory authority as per Section 4.6 of the Guidance Document: Notice of Compliance with Conditions (NOC/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 Gavreto (pralsetinib), for the indication of the treatment of adult patients with locally advanced unresectable or metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC).
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 Gavreto (pralsetinib), for the indication of the treatment of adult patients with locally advanced unresectable or metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC).

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. Sponsors are instructed to submit a complete response [refer to Guidance Document: Notice of Compliance with Conditions (NOC/c)] with the requested information within 30 calendar days of the date of this letter.

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
JPS/oh