Arzerra - Notice of Compliance with Conditions - Qualifying Notice - 2015 - Health Canada

Biologics and Genetic Therapies Directorate
Health Canada
200 promenade Tunney's Pasture Driveway
Address Locator 0701A
Ottawa, Ontario
K1A 0K9

File No.: 9427-G0838-243
Control No.: 128188
Document No.: 720220

January 6, 2012

[employee name removed]
Group Manager, Regulatory Affairs
GlaxoSmithKline Inc.
7333 Mississauga Road
Mississauga, ON
L5N 6L4

Facsimile: 905-819-3339

Notice Of Compliance With Conditions (NOC/c) - Qualifying Notice

Dear [employee name removed]:

This Notice of Compliance with Conditions - Qualifying Notice (NOC/c-QN), issued in accordance with the Health Canada NOC/c policy, is to advise you that information submitted in support of the New Drug Submission (NDS) for Arzerra (ofatumumab), Control Number 128188, for the indication as a single agent, for the treatment of patients with chronic lymphocytic leukemia (CLL) who are refractory to fludarabine and alemtuzumab, qualifies to be considered for authorization under the NOC/c policy. In keeping with the provisions outlined in the NOC/c policy, the following additional information is required to complete the assessment:

1. A letter, signed by the Chief Executive Officer or designated signing authority of GlaxoSmithKline Inc., indicating that you agree to have this submission considered under the NOC/c policy. Please be reminded that in agreeing to accept an NOC under the NOC/c policy, GlaxoSmithKline Inc. consents to the posting of the NOC/c-QN on Health Canada's website.
2. A draft Letter of Undertaking signed by the Chief Executive Officer or designated signing authority of GlaxoSmithKline Inc., having a form and content satisfactory to Health Canada, as indicated in the Guidance for Industry: Notice of Compliance with Conditions, including commitments to supply the following:

Confirmatory Studies

a) Provide the projected date for the final study report for clinical trial Hx-CD20-406 entitled: "A single-arm international, multi-center trial of HuMax-CD20, a fully human monoclonal anti-CD20 antibody, in patients with B-cell Chronic Lymphocytic Leukemia who have failed fludarabine and alemtuzumab" will be available, and commit to submit the final report to the Biologics and Genetic Therapies Directorate (BGTD) as a Supplemental New Drug Submission (SNDS). The final report must include the results of both IRC and clinical investigators' assessments of the objective response rates and duration of response. The sponsor should agree that the authorisation of Arzerra will be withdrawn for the indication, if the final analyses of Hx-CD20-406 result in either of the following:

1. A failure to confirm significant improvement in the objective response rates (ORR) as specified in the statistical analysis plan. That is, the ORR should exceed 30% with a lower 99% confidence bound of greater than 15%, by both IRC and investigators' assessments.
2. A shift in the benefit risk profile (as assessed by Health Canada) that indicates that the benefits of ofatumumab monotherapy, in patients with B-CLL, refractory to fludarabine and alemtuzumab, no longer outweigh the risks associated with the proposed treatment.

b) The sponsor agrees to submit a SNDS based on the results and analyses from the completed study OMB11091 - a phase III open-label, randomized, multi-centre trial of ofatumumab added to chlorambucil versus Chlorambucil monotherapy in previously untreated patients with chronic lymphocytic leukemia” which will serve two purposes in relation to the proposed indication:

1. To verify the clinical benefit of ofatumumab by demonstration of a clinically meaningful effect on PFS and OS.
2. To confirm the clinical safety and efficacy of ofatumumab formulated in an acetate buffer as opposed to a citrate buffer as was used in trial Hx-CD20-406.

c) The sponsor agrees to submit the results of clinical trial OMB112855, a trial of QTc intervals in patients who have been administered ofatumumab: QTc assessments will be performed in patients who have failed at least one fludarabine-containing regimen (at least two cycles) and failed at least one alemtuzumab-containing regimen (a minimum of at least 12 administrations) or who are considered inappropriate for treatment with alemtuzumab due to lymphadenopathy with at least one lymph node> 5 cm and requiring therapy and who receive the dose and schedule of ofatumumab per the approved prescribing information. The number of patients evaluated for QTc interval changes will be at least 12. For the QTc assessments, ECGs will be collected in triplicate at baseline, at steady-state ofatumumab concentrations, periodically on-therapy [for example (e.g.), every 3 months], and at the end of treatment. The final report will be a comprehensive combined report of the results (including primary data) of clinical trial OMB112855 and of the sub-trial assessing QTc intervals in OMBII0911 (see below).

The data should be submitted as a SNDS-C if it addresses the original indication or condition of use for which the Notice of Compiance (NOC) will be issued. If the data to be submitted is only safety related, it should be submitted as the appropriate submission type in accordance with the Food and Drug Regulations and the Post-Notice of Compliance (NOC) Changes: Safety and Efficacy Guidance Document.

d) To conduct an assessment of QTc intervals as a sub-trial in clinical trial OMB110911. The total number of patients in OMB110911 with evaluable ECG measurements will be at least 50 (25 per treatment arm). For the QTc assessments, ECGs will be collected in triplicate at baseline, at steady-state ofatumumab concentrations, periodically on-therapy (e.g., every 3 months), and at the end of treatment. The final report will be a comprehensive combined report of the results (including primary data) of the sub-trial assessing QTc intervals in OMB110911 and of clinical trial OMB112855. The data should be submitted as a SNDS-C if it addresses the original indication or condition of use for which the NOC will be issued. If the data to be submitted is only safety related, it should be submitted as the appropriate submission type in accordance with the Food and Drug Regulations and the Post-Notice of Compliance (NOC) Changes: Safety and Efficacy Guidance Document.

e) To conduct an assessment of anti-drug antibody (ADA) response to ofatumumab with a validated assay capable of sensitively detecting ADA responses in the presence of ofatumumab levels that are expected to be present at the time of patient sampling. The following are the BGTD's expectations:

• the ADA response should be evaluated in at least 300 patients, including ofatumumab-treated patients enrolled in clinical trial OMB110911; and
• the final report should include information on the level of ofatumumab in each patient's test sample at each sampling time point.

The data should be submitted as a SNDS-C if it addresses the original indication or condition of use for which the NOC will be issued. If the data to be submitted is only safety related, it should be submitted as the appropriate submission type in accordance with the Food and Drug Regulations and the Post-Notice of Compliance (NOC) Changes: Safety and Efficacy Guidance Document.

f) To submit to Health Canada any other analyses that have been designated as post-marketing commitments to other international authorisation granting agencies as per section 3.4.4 of the Guidance for Industry, Notice of Compliance with Conditions (NOC/c).

g) Provide information in relation to communications and consultations with other agencies, when available as per section 3.4.4 of the Guidance for Industry, Notice of Compliance with Conditions (NOC/c).

h) Provide safety updates for all on-going Arzerra trials.

Post Market Safety Monitoring

i) Provide reports of all serious Adverse Reactions (AR) that occur in Canada and all serious unexpected ARs that occur outside of Canada within 15 days to Health Canada. One copy should be provided to the Marketed Health Products Directorate and another copy to the Centre for the Evaluation of Radiopharmaceuticals and Biotherapeutics in the Biologics and Genetic Therapies Directorate in accordance with current regulations and guidelines (e.g. Guidelines for Reporting Adverse Reactions to Marketed Drugs and the Guidance for Industry: Notice of Compliance with Conditions).

j) Submit Periodic Safety Update Reports - for NOC/c Products (PSUR-Cs) for Arzerra (ofatumumab) on an annual basis until such time as conditions associated with the market authorisation are removed. PSUR-Cs should be prepared in accordance with the E2C International Conference on Harmonisation (ICH) Guideline, including format and content, as per Section 3.4.2 of the Guidance for Industry, Notice of Compliance with Conditions (NOC/c).

k) Implement the Risk Management Plan (RMP) in Canada with the following recommendations and provide an updated RMP:

1. It is requested that detailed pharmacovigilance and risk minimisation plans for posterior reversible encephalopathy syndrome (PRES)/reversible posterior leukoencephalopathy syndrome (RPLS), prolonged B cell depletion and opportunistic infections and reactivation of tuberculosis be included in the current RMP.
2. In the event of exposure during pregnancy, it is recommended that the sponsor systematically attempt to obtain information on outcome of the pregnancy.
3. A brief summary of all non-clinical studies to date should be provided.

l) Comply with the notification and reporting of specific issues of concern as outlined in Section 3.4.4 of the Guidance for Industry: Notice of Compliance with Conditions.

Additional information

m) Provide an up-to-date, complete listing of ongoing additional clinical trials related to Arzerra (ofatumumab), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance for Industry: Notice of Compliance with Conditions.

n) Provide copies of any marketing authorisations or other regulatory actions for Arzerra any other drug regulatory authority as per Section 4.6 of the Guidance for Industry: Notice of Compliance with Conditions.

o) A draft of the “Dear Health Care Professional Letter” detailing the issuance of a Notice of Compliance under the NOC/c Policy for Arzerra (ofatumumab) for the indication as a single agent, for the treatment of patients with B-Cell chronic lymphocytic leukemia (B-CLL) who are refractory to fludarabine and alemtuzumab.

p) A draft of the Product Monograph that is consistent with the requirements outlined in section 5.2.1 and 5.2.2 of the Notice of Compliance with Conditions Guidance. Please note that, if applicable, a boxed text must appear on the cover page, at the beginning of each major section of the Product Monograph (Parts I, II and III), the first page, and the start of the Consumer Information section, disclosing the nature of the authorization granted for Arzerra (ofatumumab) and the need to conduct confirmatory studies.

I wish to advise you that this Qualifying Notice is being issued in accordance with Health Canada's guidances and policies on the Management of Drug Submissions and Notice of Compliance with Conditions, respectively. Sponsors are instructed to submit a complete response (refer to"Guidance for Industry; Notice of Compliance with Conditions") to the outstanding informationwithin 30 calendar days of the date of this letter. It is highly encouraged to consult the BGTD before subsequent submission filings.

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:

Submission and information Policy Division
Therapeutic Products Directorate
Health Canada
Finance Building Address Locator 0201A1
101 Tunney’s Pasture Driveway,
Ottawa, Ontario
K1A 0K9

Sincerely,

Angela Briginshaw
A/Director General