Qualifying Notice for Adcetris
Biologics and Genetic Therapies Directorate
200 promenade Tunney's Pasture Driveway
Address Locator 0701A
Friday December 7, 2012
File No.: 9427-S3125\1-22
Control No.: 154851
Document No.: 787857
Seattle Genetics, Inc.
21823-30th Drive S. E.
Bothell, Washington, USA 98021
Notice of Compliance with Conditions - 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 for Adcetris (brentuximab vedotin), Control Number 154851, filed by SPharm Inc., on behalf of Seattle Genetics, Inc., for the indication of treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one multi-agent chemotherapy regimen, 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:
- A letter, signed by the Chief Executive Officer or designated signing authority of Seattle Genetics, Inc., indicating that you agree to have this submission considered under the NOC/c Policy. Please be reminded that in agreeing to accept a NOC under the NOC/c Policy, Seattle Genetics, Inc. consents to the posting of the NOC/c-QN on Health Canada's website.
- A draft Letter of Undertaking signed by the Chief Executive Officer or designated signing authority of Seattle Genetics, 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:
a) Submit, as an SNDS, the final report of the completed trial entitled: 'A randomized phase 3, double-blind, placebo-controlled trial of SGN-35 (brentuximab vedotin) in combination with CH-P versus CHOP as frontline therapy in patients with CD30-positive mature T- and NK-cell lymphomas including systemic ALCL (sALCL).' Enrollment of approximately 300 patients is expected with a primary endpoint of progression free survival (PFS) as determined by an independent blinded review facility (IRF). Overall survival (OS) is a key secondary endpoint. It is important to ensure that the study is powered for both PFS per IRF and OS.
- This trial should ensure that the number of sALCL patients enrolled in the trial is sufficiently large to allow an adequate assessment of the efficacy and safety profile of Adcetris in this population.
- The diagnostic evaluation of ALCL should always include ALK protein status. The number of ALK-positive and ALK-negative patients should be balanced between arms.
b) Submit, as an SNDS, the final report of the completed trial entitled: 'A randomized phase 3 trial of SGN-35 (brentuximab vedotin) in combination with AVD versus ABVD as frontline therapy in patients with advanced Hodgkin Lymphoma.' Enrollment of at least 880 patients is expected with a primary endpoint of progression free survival determined by an independent blinded review facility. Overall survival is a key secondary endpoint. Ensure that the study is powered for both PFS per IRF and OS.
Additionally, acknowledge that Seattle Genetics, Inc. is aware that the indications for Adcetris (HL and/or sALCL) can be withdrawn if either or both studies are unsuccessful.
c) Submit, as an SNDS-C, the final report for the ongoing placebo-controlled AETHERA trial entitled: ' A Phase 3 Study of Brentuximab Vedotin (SGN-35) in Patients at High Risk of Residual Hodgkin Lymphoma Following Stem Cell Transplant'. This trial will be considered as supportive evidence of clinical efficacy, but will not be sufficient to remove the conditional status of approval on its own.
d) Submit, as an SNDS-C, the final report for the clinical trial, SGN35-008B entitled: 'A Phase I study of Pharmacokinetics in CD30-Positive Hematologic Malignancies for Patients with Hepatic or Renal Impairment (Dosing q3w)'.
e) The severity, duration and reversibility of neuropathy should be characterized in a prospective trial. The ongoing placebo-controlled AETHERA trial safety results may be utilized to address this Post Market Requirement (PMR). The data should be submitted as an SNDS-C. 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) Submit safety updates for ALL on-going clinical trials with Adcetris.
g) 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).
Post Market Safety Monitoring Studies
h) Submit to MHPD the Periodic Safety Updates Reports - for NOC/c Products (PSUR-Cs) for Adcetris on an annual basis until such time as conditions associated with the market authorization are removed. The PSUR-cs should include an analysis of the Adverse Drug Reactions as per the Pharmacovigilance Plan and safety updates from ALL ongoing clinical trials with Adcetris. The PSUR-cs should be prepared in accordance with the E2C ICH Guideline, including format and content, as per Section 3.4.2 of the Guidance for Industry, Notice of Compliance with Conditions (NOC/c).
i) Provide any updates to the Canadian Risk Management Plan (RMP) when available.
j) Comply with the notification and reporting of specific issues of concern as outlined in Section 6.2.4 of the Guidance for Industry: Notice of Compliance with Conditions and section 6Eiii of the NOC/c policy.
k) Provide an up-to-date, complete listing of ongoing additional clinical trials related to Adcetris (brentuximab vedotin), appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance for Industry: Notice of Compliance with Conditions.
l) Provide copies of any marketing authorizations or other regulatory actions for Adcetris (brentuximab vedotin) from any other drug regulatory authority as per Section 4.6 of the Guidance for Industry: Notice of Compliance with Conditions.
m) Provide 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 Adcetris (brentuximab vedotin) and the need to conduct confirmatory studies.
n) Provide the MMAE whole body radioautography study for review and to support related Product Monograph (PM) updates.
o) Perform analyses or design new studies to investigate potential adverse effects of brentuximab vedotin on functions of pituitary gland, adrenal gland, pancreas, thyroid, and male reproductive systems, based on the tissue distribution profile of MMAE. Furthermore, some adverse drug reactions in humans and clinical observations in animals, for example (e.g.), hyperglycemia, hypothyroidism, hyponatremia, hypogonadism, testicular toxicity and hypospermatogenesis may be explained by either direct toxicity to these organs or indirectly by toxicity to pituitary gland. In addition, vincristine, another microtubule disrupting agent, was reported to cause hyponatremia, possibly by improper release of pituitary ADH.
Adrenal insufficiency may further increase the risk of severe infection and sepsis in patients whose immune systems are compromised due to brentuximab vedotin-related cytopenia. Evidence that supports this concern includes histology findings in animal studies (e.g., hyperplasia) and adverse events in clinical trials (e.g., Addison's disease).
Taken together, the collective evidence, although not conclusive, warrants further investigation to confirm or rule out adverse effects of brentuximab vedotin therapy on the above organs.
p) In non-clinical studies, the levels of ATA reduced ADC plasma concentration and correlated with increased free plasma MMAE. However, such correlations were not found in humans, which may be because only a small number of patients showed positive ATA.
It is recommended that the impact of ATA on brentuximab vedotin PK and safety be further investigated in on-going studies.
q) MMAE time-dependently inhibited CYP3A in vitro, for which the mechanism is not understood.
It is recommended that the mechanism underlying the time-dependent inhibition of CYP3A by MMAE be further explored. A better understanding of the issue will facilitate the safe use of brentuximab vedotin, e.g., by preventing potential drug/drug interactions via CYP3A inhibition.
r) In a non-clinical study based on primary human hepatocyte culture, MMAE inhibited all tested CYP enzymes. The mechanism of the broad CYP inhibition is unclear. In the response to a clarification request concerning this issue, Seattle Genetics, Inc. cited a lack of inhibition of CYP enzymes (except for CYP3) in another study using human liver microsomes. Seattle Genetics, Inc. also concluded that the broad inhibition of other CYP enzymes is not likely to happen in humans treated with brentuximab vedotin at the recommended dose, as the plasma MMAE levels will likely be much lower in humans than the concentrations of MMAE tested in the hepatocyte culture study.
However, without a full understanding of the underlying mechanism, it is not clear if inhibition of other CYP enzymes will not take place at least in some patients. It is recommended that the reported inhibition of CYP enzymes by MMAE in primary hepatocyte cultures be further discussed or investigated for its underlying mechanism and its relevance in humans.
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 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:
Office of Submissions and Intellectual Property
Therapeutic Products Directorate
Finance Building Address Locator 0201A1
101 Tunney's Pasture Driveway,
Dr. Robert Cushman, FRCP (C)
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