Summary Basis of Decision for Opdivo

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Opdivo is located below.

Recent Activity for Opdivo

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Opdivo

Updated: 2024-05-23

The following table describes post-authorization activity for Opdivo, a product which contains the medicinal ingredient nivolumab. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Numbers (DINs):

DIN 02446626 – 40 mg/vial, nivolumab, solution, intravenous administration

DIN 02446634 – 100 mg/vial, nivolumab, solution, intravenous administration

 

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NC # 281961 2023-12-11 Issued NOL 2024-02-09 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in a cell bank/seed bank manufacturing site. The submission was reviewed and considered acceptable, and an NOL was issued.
PBRER-C # 279072 2023-09-13 Filed 2024-01-19 Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C for the period 2022-07-04 to 2023-07-03. The information was reviewed and found acceptable.
SNDS-C # 273578 2023-03-22 Issued NOC under NOC/c Guidance 2023-12-06 Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c) and as outlined in the LOU dated 2022-06-09, issued under SNDS # 253652 for the adjuvant treatment of adult patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection of urothelial carcinoma. The sponsor provided results from the pivotal Study CA209274. The submission was reviewed and considered acceptable, and an NOC under the Guidance Document: Notice of Compliance with Conditions (NOC/c) was issued.
SNDS # 272504 2023-02-15 Issued NOC  2023-12-29 Submission filed as a Level I – Supplement for an expanded indication. The indication authorized was: Opdivo, as monotherapy, is indicated for the adjuvant treatment of adult patients with Stage IIB or IIC melanoma following complete resection. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 270348 2022-12-05 Issued NOC 2023-09-19 Submission filed as a Level II – Supplement (Safety) to update the PM. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration and Clinical Trials sections of the PM. An NOC was issued.
NC # 278012 2023-08-04 Issued NOL 2023-09-12 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance release or shelf‐life specifications. The submission was considered acceptable, and an NOL was issued.
NC # 275752 2023-05-25 Issued NOL 2023-08-28 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was considered acceptable, and an NOL was issued.
SNDS-C # 270778 2022-12-16 Issued NOC under NOC/c Guidance 2023-08-11 Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c) by providing the final study report for Study CA209835 as outlined in the LOU dated 2017-11-08, issued under SNDS # 203286 for the treatment of relapsed classical Hodgkin Lymphoma. The submission was reviewed and considered acceptable, and an NOC under the Guidance Document: Notice of Compliance with Conditions (NOC/c) was issued.
NC # 274212 2023-04-06 Issued NOL 2023-07-10 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the modification to a facility involved in the manufacture of a drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS-C # 270857 2022-12-20 Issued NOC 2023-03-22 Submission filed as a Level I – Supplement to remove the following indication: Opdivo as monotherapy for the treatment of adult patients with advanced (not amenable to curative therapy or local therapeutic measures) or metastatic hepatocellular carcinoma (HCC) who are intolerant or have progressed on sorafenib therapy. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS-C # 259148 2021-11-30 Issued NOC under NOC/c Guidance 2022-12-19 Submission filed as a Level I – Supplement to amend commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c) and outlined in the LOU dated 2017-11-08, issued under SNDS # 203286 for the treatment of relapsed classical Hodgkin Lymphoma. The sponsor provided the protocol for the proposed alternate confirmatory Study S1826. The submission was reviewed and considered acceptable, and an NOC under the Guidance Document: Notice of Compliance with Conditions (NOC/c) was issued.
PBRER-C # 267773 2022-09-09 Filed 2022-12-09 Submission filed in response to commitments made as per the provisions of the Guidance Document: Notice of Compliance with Conditions (NOC/c). PBRER-C for the period 2021-07-04 to 2022-07-03. The information was reviewed and found acceptable.
NC # 266751 2022-08-05 Issued NOL
2022-09-14

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug product manufacturing process. The submission was considered acceptable, and an NOL was issued.
SNDS # 261300 2022-02-08 Issued NOC
2022-08-18

Submission filed as a Level I – Supplement for a new indication. The submission was reviewed under the Priority Review of Drug Submissions Policy, and the following indication was approved: in combination with platinum-doublet chemotherapy, for the neoadjuvant treatment of adult patients with resectable non-small cell lung cancer (NSCLC) (tumors ≥4 cm or node positive). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 257103 2021-09-29 Issued NOC
2022-07-25

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with either ipilimumab or with fluoropyrimidine- and platinum-containing chemotherapy, treatment of adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC), with tumour cell programmed death-ligand 1 (PD-L1) expression ≥1% as determined by a validated test, and no prior systemic therapy for metastatic ESCC. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 255937 2021-08-19 Issued NOC
2022-07-07

Submission filed as a Level I – Supplement to add an alternative flat dose regimen for nivolumab for patients with metastatic non-small cell lung cancer (NSCLC) expressing programmed death-ligand 1 (PD-L1) ≥1%, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumour aberrations and no prior systemic therapy, in combination with ipilimumab. In addition, the submission was filed to update the PM with new safety and efficacy data. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 253652 2021-06-10 Issued NOC under NOC/c Guidance
2022-06-27

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: monotherapy for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC. The submission was reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance.
SNDS-C # 254893 2021-07-19 Issued NOC under NOC/c Guidance
2022-06-02

Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The submission provided updated safety and efficacy data from study CA209205. Updated efficacy results were consistent with those report initially, and no new safety signals were identified. The data were reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance.
NC # 260638 2022-01-21 Issued NOL
2022-02-28

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the storage conditions for the drug product. The submission was considered acceptable, and an NOL was issued.
NC # 260769 2022-01-25 Issued NOL
2022-02-14

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance and drug product. The submission was considered acceptable, and an NOL was issued.
NC # 259361 2021-12-08 Cancellation Letter Received
2021-12-22

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacturing process. The changes were not in scope of an NC, but were considered to be Level III changes. The sponsor cancelled the submission administratively.
SNDS # 248147 2021-01-08 Issued NOC
2021-12-01

Submission filed as a Level I – Supplement to update the PM with new efficacy data. The submission was reviewed and considered acceptable, and an NOC was issued.
PBRER-C # 256670 2021-09-15 Filed
2021-11-03

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2020-07-04 to 2021-07-03. The information was reviewed and found acceptable.
SNDS # 247339 2020-12-11 Issued NOC
2021-10-28

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with fluoropyrimidine and platinum containing chemotherapy, for the treatment of adult patients with advanced or metastatic gastric, gastroesophageal junction or esophageal adenocarcinoma. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
SNDS # 245851 2020-10-29 Issued NOC
2021-10-13

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with cabozantinib, for the first-line treatment of adult patients with advanced (not amenable to curative surgery or radiation therapy) or metastatic renal cell carcinoma. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 255095 2021-07-23 Issued NOL
2021-09-03

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a new drug product manufacturing suite at an approved site. The submission was considered acceptable, and an NOL was issued.
SNDS # 246805 2020-11-25 Issued NOC
2021-07-09

Submission filed as a Level I – Supplement to add an alternate manufacturing site of the drug substance. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 247045 2020-12-04 Issued NOC
2021-07-02

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer in patients who have residual pathologic disease following prior neoadjuvant chemoradiotherapy (CRT). The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
PBRER-C # 244286 2020-09-21 Filed
2021-06-21

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2019-07-04 to 2020-07-03. The information was reviewed and found acceptable.
SNDS # 243600 2020-09-03 Issued NOC
2021-05-28

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with ipilimumab, the treatment of adult patients with unresectable malignant pleural mesothelioma (MPM) who have not received prior systemic therapy for MPM. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 250975 2021-03-31 Issued NOL
2021-05-20

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add an alternate site for drug substance testing. The submission was considered acceptable, and an NOL was issued.
Summary Safety Review Not applicable Posted
2021-05-19

Summary Safety Review posted for Opdivo (nivolumab) (Assessing the potential risks of certain blood disorders, and cytokine release and tumor lysis syndromes).
SNDS # 244059 2020-09-17 Issued NOC
2021-05-04

Submission filed as a Level I – Supplement to add an alternate manufacturing site of the drug product. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 240984 2020-06-24 Issued NOC
2021-04-30

Submission filed as a Level I – Supplement to update the PM with pediatric pharmacokinetic and safety data. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 245588 2020-11-18 Issued NOC
2021-04-12

Submission filed as a Level II – Supplement (Safety) to update the PM. The submission was in response to an Advisement Letter issued by Health Canada dated 2020-10-28, requesting PM revisions related to aplastic anemia, cytokine release syndrome, and tumour lysis syndrome. As a result of the submission, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM and to Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 238976 2020-04-29 Issued NOC
2021-03-22

Submission filed as a Level I – Supplement to update the PM with new safety and efficacy data. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS-C # 237337 2020-03-20 Issued NOC
2021-03-01

Submission filed as a Level I – Supplement to remove the conditions from the NOC that was issued under the NOC/c Guidance for SNDS # 189307. The submission provided the final report from confirmatory study CA209067. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued 2016-10-26.
SNDS # 239474 2020-05-13 Issued NOC under NOC/c Guidance
2021-02-11

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with ipilimumab, the treatment of adult patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer after prior fluoropyrimidine-based therapy in combination with oxaliplatin or irinotecan. The submission was reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance. A Regulatory Decision Summary was published.
SNDS # 242653 2020-08-12 Issued NOC
2020-12-03

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 234228 2019-12-06 Issued NOC
2020-11-18

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: treatment of metastatic non-small cell lung cancer (NSCLC) expressing programmed death-ligand 1 (PD-L1) ≥1%, as determined by a validated test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumour aberrations and no prior systemic treatment for metastatic NSCLC, when used in combination with ipilimumab. The submission was reviewed and considered acceptable. A Regulatory Decision Summary was published.
SNDS-C # 233053 2019-10-31 Issued NOC under NOC/c Guidance
2020-09-18

Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The submission filed the final report from study CA209040. Updated efficacy results were consistent with those reported initially, and no new safety signals were identified. The data were reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance.
SNDS # 235186 2020-01-16 Issued NOC
2020-08-07

Submission filed as a Level I – Supplement for a change to a drug product manufacturing facility. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 236255 2020-02-19 Issued NOC
2020-08-06

Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy, the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, and no prior systemic therapy for metastatic NSCLC. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
NC # 237825 2020-03-31 Issued NOL
2020-06-02

Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, a Serious Warnings and Precautions Box was added to the PM, and modifications were made to the Adverse Reactions section. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 228818 2019-06-20 Issued NOC
2020-05-29

Submission filed as a Level I – Supplement to provide data from studies CA209238 and CA209067. The data were reviewed and considered acceptable, and an NOC was issued.
NC # 237744 2020-03-27 Issued NOL
2020-05-26

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS-C # 229065 2019-06-24 Issued NOC under NOC/c Guidance
2020-05-26

Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The submission filed interim results of study CA209835. No new safety concerns were identified. The data were reviewed and considered acceptable, and an NOC was issued under the NOC/c Guidance.
New safety review Not applicable Started between
2020-03-01

Health Canada started a safety review for Opdivo related to autoimmune hemolytic anemia.
NC # 234219 2020-01-13 Issued NOL
2020-03-19

The submission was filed as a Level II (90 day) Notifiable Change to update the PM. The submission was in response to an Advisement Letter issued by Health Canada dated 2019-12-06, requesting PM revisions related to reports of hemophagocytic lymphohistiocytosis. As a result of the NC, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM and to Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
New safety review Not applicable Started between
2020-02-01

Health Canada started a safety review for Opdivo related to aplastic anemia, cytokine release syndrome, and tumour lysis syndrome.
PBRER-C # 231170 2019-08-29 Filed
2020-02-25

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2019-01-04 to 2019-07-03. The information was reviewed and found acceptable.
NC # 233129 2019-11-01 Issued NOL
2020-02-13

Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Dosage and Administration sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 228578 2019-06-12 Issued NOC
2019-12-19

Submission filed as a Level I – Supplement to add alternate drug substance manufacturing and testing sites, and a manufacturing scale-up. The stability profiles of the drug substance and drug product remain unchanged. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 215535 2018-04-17 Cancellation Letter Received
2019-11-26

Submission filed as a Level I – Supplement for a new indication: the treatment of adult patients with advanced or recurrent gastric or gastroesophageal junction cancer after two or more prior systemic therapies. The sponsor cancelled the submission and a Summary of Cancellation was published.
PBRER-C # 226344 2019-03-29 Cleared
2019-11-05

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2018-07-04 to 2019-01-03. The information was reviewed and found acceptable.
NC # 228644 2019-06-13 Issued NOL
2019-10-30

Submission filed as a Level II (120 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions and Dosage and Administration sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 226152 2019-03-27 Issued NOC
2019-10-08

Submission filed as a Level I – Supplement to change the dosage regimens for the treatment of advanced or metastatic hepatocellular carcinoma and adjuvant melanoma, with no changes to the authorized indications. The submission was reviewed and considered acceptable, and an NOC was issued.
Summary Safety Review Not applicable Posted
2019-06-24

Summary Safety Review posted for Opdivo (nivolumab) and Yervoy (ipilimumab) used alone or in combination (Assessing the potential risk of hemophagocytic lymphohistiocytosis [HLH]).
SNDS-C # 204349 2017-03-31 Cancellation Letter Received
2019-04-15

Submission filed as a Level I – Supplement in response to commitments made as per the provisions of the NOC/c Guidance. The submission filed the results of confirmatory study CA209067. The sponsor cancelled the submission and a Summary of Cancellation was published.
PBRER-C # 220118 2018-09-13 Cleared
2019-03-19

Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2018-01-04 to 2018-07-03. The information was reviewed and found acceptable.
NC # 222714 2018-12-05 Issued NOL
2019-03-13		 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 216241 2018-05-14 Issued NOC
2019-02-01		 Submission filed as a Level I - Supplement in response to a post-marketing commitment in the Post-Decision Letter dated 2015-09-29, to provide biomarker assay results from two studies: CA209038 and CA209066. The analyses from both studies did not alter the benefit/risk assessment of Opdivo for the indication that was approved under NDS # 180828. No changes to the PM were necessary. An NOC was issued.
SNDS-C # 213548 2018-02-08 Issued NOC
2019-01-23		 Submission filed as a Level I - Supplement is response to a commitment in the Letter of Undertaking (LOU) dated 2017-11-08, issued under SNDS # 203286, to provide updated follow-up data from Phase II trial CA209205. The benefit/risk assessment of Opdivo in the treatment of patients with classical Hodgkin Lymphoma refractory to or relapsed after 3 or more treatments including autologous stem cell transplantation remained unchanged. The risk-benefit assessment remains favourable as initially determined in SNDS # 203286 and this commitment meets the NOC criteria. The data were reviewed and considered acceptable. Appropriate changes were made to the PM. An NOC was issued.
SNDS # 217830 2018-06-29 Cancellation Letter Received
2018-12-06		 Submission filed in response to a Post-Decision Letter dated 2015-09-29, to provide analyses from Study CA209066. An NOD was recommended. The sponsor cancelled the submission.
SNDS # 211838 2017-12-01 Issued NOC
2018-11-15		 Submission filed as a Level I - Supplement for new indication: for the adjuvant treatment of adult patients after complete resection of melanoma with regional lymph node involvement, in transit metastases/satellites without metastatic nodes, or distant metastases. Regulatory Decision Summary published.
SNDS # 217657 2018-07-03 Issued NOC
2018-09-07		 Submission filed as a Level I - Supplement to update the inner and outer labels. The submission was reviewed and considered acceptable, and an NOC was issued.
New safety review started by Health Canada Not applicable Started between
2018-08-01		 Health Canada started a safety review for Opdivo between 2018-08-01 and 2018-08-31.
PBRER-C # 214260 2018-03-06 Cleared
2018-08-21		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2017-07-04 to 2018-01-03. The information was reviewed and found acceptable.
SNDS # 218184 2018-07-13 Cancellation Letter Received
2018-08-20		 Submission filed as a Level I - Supplement for a new dosing regimen. The submission was cancelled by the sponsor.
NC # 218033 2018-07-09 Issued NOL
2018-08-16		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 212067 2017-12-13 Issued NOC
2018-07-06		 Submission filed as a Level I - Supplement for new indication: in combination with ipilimumab, for the treatment of adult patients with intermediate / poor-risk advanced or metastatic renal cell carcinoma. Regulatory Decision Summary published.
SNDS # 206639 2017-06-15 Issued NOC
2018-05-24		 Submission filed as a Level I - Supplement to make changes to the dosing schedule. The changes recommended in this submission do not change the previously established favourable benefit/risk assessment of Opdivo for the specified indication. The data were reviewed and considered acceptable. Appropriate changes were made to the PM, and an NOC was issued.
NC # 212891 2018-01-17 Issued NOL
2018-04-24		 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 213152 2018-01-26 Issued NOL
2018-04-05		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes related to a release test for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS-C # 206974 2017-06-27 Issued NOC under NOC/c Guidance
2018-03-23		 Submission filed as a Level I - Supplement for new indication: for the treatment of adult patients with advanced or metastatic hepatocellular carcinoma who are intolerant to or have progressed on sorafenib therapy. Regulatory Decision Summary published.
NC # 211925 2017-12-07 Issued NOL
2018-03-12		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS-C # 203973 2017-03-21 Issued NOC
2018-02-21		 Submission filed as a Level I - Supplement to remove the conditions from the NOC for the indication: for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The submission provided the final clinical study report for CHECKMATE-037. The review of this SNDS-C fulfills the commitments that were made by the sponsor under SNDS # 183397. The data were reviewed and considered acceptable. As a result of the submission, the conditions were removed from the NOC that had been issued 2016-04-29.
SNDS # 211471 2017-11-21 Issued NOC
2018-01-26		 Submission filed as a Level I - Supplement to update the package insert. The package insert was reviewed and considered acceptable, and an NOC was issued.
SNDS # 203593 2017-03-09 Cancellation Letter Received
2018-01-19		 Submission filed as a Level I - Supplement for new indication: for use in patients with locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of prior platinum-containing therapy. Summary of Cancellation published.
NC # 210301 2017-10-17 Issued NOL
2018-01-22		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 209488 2017-09-20 Issued NOL
2017-12-20		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add sites for quality control testing of the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 203286 2017-02-27 Issued NOC under NOC/c Guidance
2017-11-10		 Submission filed as a Level I - Supplement for new indication: monotherapy for the treatment of adult patients with classical Hodgkin Lymphoma that has relapsed or progressed after autologous stem cell transplantation (ASCT) and brentuximab vedotin, or three or more lines of systemic therapy including ASCT. Regulatory Decision Summary published.
PBRER-C # 208678 2017-08-23 Cleared
2017-09-15		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2017-01-04 to 2017-07-03. The information was reviewed and found acceptable.
NC # 207862 2017-07-25 Issued NOL
2017-09-01		 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 205282 2017-05-04 Issued NOC
2017-06-22		 Submission filed as Level I - Supplement to make updates to the carton labels. The information was reviewed and considered acceptable. An NOC was issued.
SNDS # 199379 2016-10-18 Issued NOC
2017-05-12		 Submission filed as a Level I - Supplement for new indication: for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in adults progressing on or after platinum-based therapy. Regulatory Decision Summary published.
SNDS # 198926 2016-10-03 Issued NOC
2017-05-15		 Submission filed as a Level I - Supplement for a new drug substance manufacturing site and to make updates to the manufacturing process of the drug product. The information was reviewed and considered acceptable. An NOC was issued.
PBRER-C # 203631 2017-03-10 Cleared
2017-04-03		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2016/07/04 to 2017/01/03. The information was reviewed and found acceptable.
NC # 203415 2017-03-02 Issued NOL
2017-04-03		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 201030 2016-12-09 Issued NOL
2017-03-13		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to fulfill a quality-related post-authorization commitment. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 200902 2016-12-02 Issued NOL
2017-02-17		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to extend the room temperature / room light storage time after dilution to 8 hours, and to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Warnings and Precautions and Dosage and Administration sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 199792 2016-10-31 Issued NOL
2017-01-23		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to fulfill several quality-related post-authorization commitments. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 193121 2016-03-08 Issued NOC
2017-01-23		 Submission filed as a Level I - Supplement to provide the results of analyses conducted in studies CA209066 and CA209037. These are the sponsor's analyses of efficacy and safety of Opdivo based on programmed death ligand 1 (PD-L1) expression in these two studies of metastatic melanoma. Based on the evaluation, no changes to the Opdivo indications or the PM are required. An NOC was issued.
SNDS # 189307 2015-11-06 Issued NOC under NOC/c Guidance
2016-10-26		 Regulatory Decision Summary published.
NC # 196247 2016-06-22 Issued NOL
2016-08-26		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 196910 2016-07-19 Cancellation Letter Received
2016-07-29		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to scale up the drug product manufacturing process. The submission exceeded the scope of an NC and was therefore cancelled administratively by the sponsor, so as to be filed as an SNDS.
NC # 193813 2016-03-29 Issued NOL
2016-07-05		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NDS # 183397 2015-03-31 Issued NOC under NOC/c Guidance
2016-04-29		 Regulatory Decision Summary published.
SNDS # 189821 2015-11-20 Issued NOC
2016-04-25		 Regulatory Decision Summary published.
NC # 189898 2015-11-24 Issued No Objection Letter
2016-02-29		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to propose the implementation of a new Working Cell Bank (WCB) for the manufacture of nivolumab drug substance. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NDS # 186625 2015-07-31 Issued NOC
2016-02-26		 Regulatory Decision Summary published.
NC # 192149 2016-02-10 Cancellation Letter Received
2016-02-18		 Submission filed as a Level II (120 day) Notifiable Change to provide the results of analyses conducted in study CA209066. The submission exceeded the scope of a Notifiable Change and was therefore cancelled administratively by the sponsor, so as to be filed as a Supplemental New Drug Submission.
Drug product (DINs 02446626, 02446634) market notification Not applicable Date of first sale:
2015-10-23		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 180828 2014-12-19 Issued NOC
2015-09-25		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Opdivo

Date SBD issued: 2016-01-08

The following information relates to the New Drug Submission for Opdivo.

Nivolumab, 40 mg and 100 mg, solution, intravenous

Drug Identification Number (DIN):

  • DIN 02446626 - 40 mg/vial
  • DIN 02446634 - 100 mg/vial

Bristol-Myers Squibb Canada

New Drug Submission Control Number: 180828

 

On September 25, 2015 Health Canada issued a Notice of Compliance to Bristol-Myers Squibb Canada for the drug product, Opdivo.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Opdivo is favourable for the treatment of unresectable or metastatic BRAF V600 wild-type melanoma in previously untreated adults.

 

1 What was approved?

 

Opdivo, an antineoplastic agent, was authorized for the treatment of unresectable or metastatic BRAF V600 wild-type melanoma in previously untreated adults.

No overall differences in safety or efficacy have been reported between elderly (≥65 years) and younger patients (<65 years).

The safety and effectiveness of Opdivo have not been established in pediatric patients.

Opdivo is contraindicated for patients who are hypersensitive to nivolumab or to any ingredient in the formulation or component of the container. Opdivo was approved for use under the conditions stated in the Opdivo Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Opdivo (nivolumab, 40 mg/vial and 100 mg/vial) is presented as solution for intravenous infusion. In addition to the medicinal ingredient, nivolumab, the solution also contains hydrochloric acid, mannitol (E421), pentetic acid, polysorbate 80, sodium chloride, sodium citrate, sodium hydroxide, and water for injection.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Opdivo Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Opdivo approved?

 

Health Canada considers that the benefit/risk profile of Opdivo is favourable for the treatment of unresectable or metastatic BRAF V600 wild-type melanoma in previously untreated adults.

Opdivo should be administered under the supervision of physicians experienced in the treatment of cancer.

Melanoma is a malignant tumour of melanocytes. Melanocytes are cells derived from the neural crest that are responsible for producing the pigment melanin in our skin. Each year, several thousand new cases of melanoma are diagnosed and although melanoma represents just a small fraction of all cases of skin cancer, it accounts for almost three quarter of all skin-cancer deaths.

Over the past several years, several therapies have been developed for the treatment of unresectable or metastatic melanoma. These therapies include either anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) blocking antibodies or small molecular therapies targeting the BRAF kinase pathways. While these therapies have significantly improved progression free survival (PFS) and overall survival (OS) in patients with unresectable or metastatic melanoma, patients often relapse from these treatments. As such, there remains an unmet medical need for other treatment options.

Based on previous scientific research, it is noted that approximately half of patients with metastatic melanoma harbour an activating mutation of the intracellular signaling kinase, BRAF V600. BRAF, a member of the RAF family, is a protein kinase that is encoded by the BRAF gene. BRAF plays an important role as an intermediary in the RAS-RAF signaling pathway, a pathway responsible for normal cell differentiation and growth. The BRAF V600 mutation in melanoma is thought to be implicated in different mechanisms underlying disease progression [that is (i.e.) initiation malignant transformation, tumour-progression, and metastasis].

Opdivo, a fully human monoclonal immunoglobulin G4 (IgG4) antibody (HuMAb) has been shown to control tumour-specific inhibition of T cell responses to tumours. Expression of programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2) by tumours, such as that of melanoma, allows the tumour to evade immune-mediated destruction. Opdivo acts by binding to the programmed cell death-1 receptor (PD-1) and inhibits the interaction between PD-1 receptor and its ligands, PD-L1 and PD-L2. By inhibiting the PD-1 receptor from binding to PD-L1 and PD-L2, Opdivo restores T cell activity and enables T cells to mount a direct immune attack against tumour cells. This T cell attack results in the death of the tumour cell.

Opdivo has been shown to be efficacious, as a single agent, for the treatment of patients with advanced (unresectable or metastatic) melanoma. The market authorization was based on a Phase III, randomized, double-blind study (CA209066) conducted in 418 patients with previously untreated BRAF wild-type, unresectable or metastatic melanoma. The primary endpoint of the study was overall survival (OS). Key secondary endpoints included PFS and overall response rate (ORR). Based on formal interim analysis for OS that occurred when 146 deaths were observed, the CA209066 study showed patients randomized to Opdivo had clinically meaningful and statistically significant improvements in OS compared to patients treated with dacarbazine. Median OS was not yet reached for Opdivo compared to 10.8 months for dacarbazine. The estimated OS rates at 12 months were 73% and 42%, respectively. Overall survival was demonstrated regardless of PD-L1 tumour cell membrane expression levels. Statistically significant improvements were also seen in the relevant secondary endpoints of PFS and ORR in the Opdivo compared to the dacarbazine treatment arm.

A Phase I, dose-escalation study, MDX1106-03 (conducted in solid tumour malignancies across several tumour types) also provided additional support for efficacy and safety in patients with advanced stage melanoma. Study results from this study supported those results observed in the Phase III CA209066 study.

Given its mechanism of action, Opdivo is most commonly associated with immune-related adverse reactions resulting from increased or excessive immune activity. Some of these events include: immune-mediated endocrinopathies, immune-related gastrointestinal reactions, immune-related hepatic reactions, immune-related pulmonary reactions, immune-mediated renal reactions, and immune-mediated rash. Most of these adverse reactions, including severe reactions, resolved rapidly following initiation of appropriate medical therapy or withdrawal of Opdivo.

Adverse events, most frequently reported, in Study CA209066 (occurring at ≥15%) were fatigue, nausea, diarrhea, pruritus, and rash. The majority of adverse reactions were mild to moderate in nature.

A Risk Management Plan (RMP) for Opdivo was submitted by Bristol-Myers Squibb Canada to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Opdivo has been deemed acceptable.

Overall, the therapeutic benefits seen in the CA209066 study is promising and the benefits of Opdivo therapy are considered to outweigh the risks. Opdivo has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Opdivo Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Opdivo?

 

The drug submission for Opdivo was reviewed under the Priority Review Policy. Opdivo represents a novel direction for the treatment of patients with advanced (unresectable or metastatic) melanoma. Opdivo demonstrated a significant increase in effectiveness with an improved benefit/risk profile compared to existing therapies for treatment of unresectable or metastatic BRAF V600 wild-type melanoma in previously untreated adults, a condition that is not adequately managed by a drug marketed in Canada.

 

Submission Milestones: Opdivo

Submission Milestone Date
Pre-submission meeting: 2014-10-28
Request for priority status  
Filed: 2014-11-10
Approval issued by Director: 2014-12-01
Submission filed: 2014-12-19
Screening  
Screening Deficiency Notice issued: 2015-02-02
Response filed: 2015-03-02
Screening Acceptance Letter issued: 2015-03-30
Review  
On-Site Evaluation:  
Quality Evaluation complete: 2015-09-25
Clinical Evaluation complete: 2015-09-25
Labelling Review complete: 2015-09-24
Notice of Compliance issued by Director General: 2015-09-25

 

The Canadian regulatory decision on the non-clinical and clinical review of Opdivo was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Opdivo?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Opdivo is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Melanoma is a malignant tumour of melanocytes, which are cells derived from the neural crest that are responsible for producing the pigment melanin in our skin.

Opdivo is a fully human monoclonal immunoglobulin G4 (IgG4) antibody which binds to programmed cell death-1 receptor (PD-1) and blocks the interaction between PD-1 receptor and its ligands, PD-L1 and PD-L2. The upregulation of PD-1 ligands occurs in some tumours and signaling through this pathway can contribute to inhibition of active T cell immune surveillance of tumours. By inhibiting the PD-1 receptor from binding to PD-L1 and PD-L2, Opdivo reactivates tumour-specific cytotoxic T lymphocytes in the tumour microenvironment and reactivates anti-tumour immunity.

The effects of various covariates on the pharmacokinetics of nivolumab (the medicinal ingredient of Opdivo) were assessed in a population pharmacokinetic analysis. The following factors appear to have no clinically important effect on the clearance of Opdivo: age, gender, race, tumour type, tumour size, mild or moderate renal impairment, and mild hepatic impairment. Eastern Cooperative Oncology Group (ECOG) status and body weight were noted to have a modest effect on nivolumab clearance. These effects are unlikely to be clinically relevant, given the flat exposure-response relationships for both efficacy and safety.

Opdivo has not been studied in patients with moderate or severe hepatic impairment. For further information, please consult the Warnings and Precautions and Dosage and Administration sections of the Opdivo Product Monograph.

Overall, the clinical pharmacological data support the use of Opdivo in patients with unresectable or metastatic BRAF V600 wild-type melanoma. For further details, please refer to the Opdivo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Opdivo was primarily evaluated in a Phase III, multicentre, randomized, double-blind study, Study CA209066. Patients enrolled in this study consisted of adult patients with confirmed, treatment-naïve, Stage III or IV BRAF wild-type, (advanced unresectable or metastatic) melanoma and with an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1.

The primary objective of the study was to compare the clinical benefit, as measured by overall survival (OS), provided by Opdivo compared to dacarbazine. The study was conducted in regions where dacarbazine was considered first-line standard of care for patients with previously untreated, unresectable or metastatic melanoma.

Key secondary endpoints included duration of investigator-assessed progression-free survival (PFS) and investigator-assessed objective response rate (ORR) of Opdivo versus dacarbazine.

A total of 418 patients were randomized in a 1:1 ratio to receive one of the following two dosing regimens:

  • Opdivo administered intravenously over 60 minutes at 3 mg/kg every 2 weeks [Number of patients (n) = 210] or;
  • Dacarbazine 1,000 mg/m² administered intravenously every 3 weeks (n = 208).

Baseline demographic and disease characteristics of the study population were balanced between the Opdivo and dacarbazine groups. Among all randomized patients, the median age was 65.0 (range: 18 to 87) years. The majority of patients were white (99.5%) and male (58.9%). Prior adjuvant therapy, neo-adjuvant therapy, surgery related to cancer, and radiotherapy were balanced across treatment groups.

Treatment was continued as long as clinical benefit was observed or until treatment was no longer tolerated. Treatment after disease progression was permitted for patients who had clinical benefit and did not have substantial adverse effects with the study drug, as determined by the investigator. Tumour assessments, according to the Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, were conducted 9 weeks after randomization and continued every 6 weeks for the first year and then every 12 weeks thereafter.

The submitted results from Study CA209066 were based on an interim analysis with a clinical cut-off date of June 24, 2014. At the time of data cut-off, 206 patients had received at least 1 infusion of Opdivo and 205 patients had received at least 1 infusion of dacarbazine. The majority of patients (91.3%) in the Opdivo group and 52.2% of patients in the dacarbazine group received ≥ 90% of the initial intended dose. The median number of doses received was 12 (Opdivo) vs. 4 (dacarbazine). The median duration of study therapy was 6.5 months [95% Confidence Interval (CI): 4.9, not reached] for Opdivo treatment and 2.1 months (95% CI: 1.9, 2.4) for dacarbazine treatment.

Interim results demonstrated Opdivo to be superior in OS compared with dacarbazine in previously untreated patients with BRAF wild-type advanced (unresectable or metastatic) melanoma with a clinically meaningful and statistically significant observed Hazard Ratio (HR) of 0.42 (99.79% CI: 0.25, 0.73); p<0.0001. Median OS was not reached in the Opdivo group and was 10.84 months in the dacarbazine group.

In addition, a clinically meaningful and statistically significant improvement in PFS was observed in the Opdivo group compared to the dacarbazine group [HR of 0.43 (99.79% CI: 0.29, 0.64); p<0.0001]. The median PFS was 5.06 months (95% CI: 3.48, 10.81) in the Opdivo group and 2.17 months (95% CI: 2.10, 2.40) in the dacarbazine group.

The investigator-assessed ORR using RECIST v1.1 criteria was also significantly higher in the Opdivo group than in the dacarbazine group, 40.0% (95% CI: 33.3, 47.0) compared to 13.9% (95% CI: 9.5, 19.4) respectively, with a difference in ORRs of 26.1% (99.79% CI: 13.4, 38.7; p<0.0001). A higher proportion of patients had a complete response (CR) in the Opdivo group 7.6% (16/210) compared to the dacarbazine group 1.0% (2/208).

Supportive Study
Supportive Dose-Escalation Study MDX1106-03

The MDX1106-03 study was designed as a Phase I open-label, dose-escalation study to evaluate the safety and clinical activity of Opdivo in patients with prior-treated solid tumour malignancies. After identifying a signal of clinical activity in several tumour types, the study was expanded to further evaluate safety and clinical activity.

Of the 306 patients enrolled in this study, 107 had advanced melanoma and received Opdivo at a dose of 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg. Tumour responses were centrally assessed by the sponsor using RECIST v1.0 based on tumour measurements collected by investigators. Data from this study are based on a minimum of 21 months follow-up.

In the advanced melanoma patients, across all dose levels studied, the objective response was reported in 34 patients (32%) with the median duration of response of 22.9 months. Seventeen (17) advanced melanoma patients were treated at the proposed clinical dosing regimen of 3 mg/kg every 2 weeks. At this dose, 7 of 17 (41.2%) patients were considered responders, with a median duration of response of 17.5 months.

The results from the MDX1106-03 study provided additional support that Opdivo monotherapy in previously treated advanced melanoma resulted in durable anti-tumour activity.

Overall Analysis of Efficacy

Study CA209066 demonstrated a clinically and statistically significant improvement in OS in patients treated with Opdivo compared to dacarbazine. This result was supported by improvements in PFS and ORR. Furthermore, results from the MDX1106-03 study also provided additional support to the results observed in the CA209066.

For more information, refer to the Opdivo Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Opdivo was primarily evaluated in the CA209066 study previously described in the Clinical Efficacy section. The safety analyses included all treated patients (411 in total; 206 patients in the Opdivo group and 205 patients in the dacarbazine group). Per study protocol, the analyses of adverse events (AEs) were conducted for events reported up to 30 days and up to 100 days (extended follow-up) after the last dose of study medication.

At the time of data cut-off, 53.9% (111/206) patients treated in the Opdivo group and 93.7% (192/205) patients treated in the dacarbazine group had discontinued study treatment. The most common reason for discontinuation was disease progression: 46.6% Opdivo and 85.4% dacarbazine.

A total of 22.8% (47/206) patients in the Opdivo group and 46.8% (96/205) patients in the dacarbazine group died prior to the time of data cut-off. Disease progression was the most common cause of death in both treatment groups; 21.4% (44/206) of patients in the Opdivo group and 44.9% (92/205) of patients in the dacarbazine group. Other reasons for death were provided by the investigator for 3 patients in the Opdivo group. Reasons were heart failure, sepsis with multi-organ failure, and subarachnoid bleeding (suspected but not proven). Two patients died in the dacarbazine group (due to respiratory failure and acute diarrheic syndrome).

The overall frequency of AEs was comparable in the Opdivo group and the dacarbazine group (93.2% vs 94.6%). The most frequently reported AEs (≥20% of patients) were fatigue, diarrhea, constipation, nausea, pruritus, and rash in the Opdivo group and nausea, constipation, vomiting, fatigue, and diarrhea in the dacarbazine group.

Grade 3 and 4 AEs occurring up to 30 days after the last dose were reported in 34.0% of patients in the Opdivo group and 38.0% of patients in the dacarbazine group. No Grade 3 and 4 AEs occurred in ≥5% of patients in the Opdivo group. Thrombocytopenia was the only Grade 3 and 4 AE that occurred in the dacarbazine group (5.4%).

The overall frequency of serious adverse events (SAEs) was lower in the Opdivo group than in the dacarbazine group (31.1% vs. 38%). There were 20.9% Grade 3 and 4 SAEs and 2.9% Grade 5 SAEs in the Opdivo group compared to 26.3% Grade 3 and 4 SAEs and 5.9% SAEs in the dacarbazine group.

Description of Selected Adverse Reactions

The following Grade 3 to 4 immune-mediated events of special interest were seen in Study CA209066: hyperthyroidism (1), hypophysitis (1), diarrhea (2), colitis (1), alanine aminotransferase (ALT) increased (2), aspartate aminotransferase (AST) increased (1), gamma-glutamyl transpeptidase (GGT) increased (1), acute renal failure (1), pruritus (1), rash (1), and maculo-papular rash (1). Further details on these selected adverse reactions are discussed below.

Immune-Mediated Endocrinopathies

Severe endocrinopathies, including thyroid and adrenal disorders, have been observed with Opdivo treatment. In Study CA209066, Grade 3 hyperthyroidism and hypophysitis were reported in 2 of 206 patients. Thereby it is important to monitor patients for signs and symptoms of endocrinopathy such as fatigue, weight change, or headache.

Immune-Mediated Gastrointestinal Adverse Reactions

Severe diarrhea or colitis has been observed with Opdivo treatment. In Study CA209066, Grade 3 colitis or diarrhea was reported in 3 of 206 patients. As such, it is important to monitor patients for diarrhea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool.

Immune-Mediated Hepatic Adverse Reactions

Severe hepatotoxicity has been observed with Opdivo treatment. In Study CA209066, Grade 3 hepatic related events were reported in 3 of 206 patients. Therefore, it is important to monitor patients for signs and symptoms of hepatotoxicity, such as transaminase and total bilirubin elevations.

Immune-Mediated Pulmonary Adverse Reactions

Severe pneumonitis or interstitial lung disease, including fatal cases, have been observed with Opdivo treatment. In study CA209066, AEs were mild to moderate (Grade 1 and 2). As such, it is important to monitor patients closely for signs and symptoms of pneumonitis, such as radiographic changes [for example (e.g.,) focal ground glass opacities, patchy filtrates], dyspnea, and hypoxia.

Immune-Mediated Renal Adverse Reactions

Severe nephrotoxicity, including nephritis and renal failure, has been observed with Opdivo treatment. In Study CA209066, Grade 3 acute renal failure was reported in 1 of 206 patients. Therefore, it is important to monitor patients for signs and symptoms of nephrotoxicity. Most patients present with asymptomatic increase in serum creatinine.

Immune-Mediated Rash

Severe rash (including rare cases of fatal toxic epidermal necrolysis) has been observed with Opdivo treatment. It is therefore important to monitor patients for rash.

Other Immune-Mediated Adverse Reactions

Other clinically significant immune-mediated adverse reactions have been observed with Opdivo treatment. In less than 1% of patients treated with Opdivo in clinical studies across doses and tumour types, the following immune-mediated adverse reactions were reported: diabetes mellitus, diabetic ketoacidosis, hypopituitarism, uveitis, Guillain-Barré syndrome, adrenal insufficiency, pancreatitis, autoimmune neuropathy (including facial and abducens nerve paresis), demyelination, myasthenic syndrome, and encephalitis.

Infusion Reactions

Severe infusion reactions have been reported in clinical studies of Opdivo. In case of a severe infusion reaction (Grade 3 or 4), Opdivo infusion needs to be discontinued and appropriate medical therapy administered. Patients with mild or moderate infusion reaction may receive Opdivo with close monitoring and use of premedication according to local treatment guidelines for prophylaxis of infusion reactions.

Special Populations

Opdivo has not been studied in children under the age of 18, patients with moderate or severe hepatic impairment, or in patients with severe renal impairment. These issues within patient populations have been identified and addressed through appropriate labelling in the Opdivo Product Monograph.

Pregnant and Nursing Women

There are no data on the use of Opdivo in pregnant and nursing women. An animal study conducted with nivolumab (the medicinal ingredient of Opdivo) has shown reproductive toxicities. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss. These results indicate a potential risk that treatment with Opdivo during pregnancy could cause fetal harm, including increased rates of abortion or stillbirth.

Human immunoglobulin G4 (IgG4) is known to cross the placental barrier. Nivolumab is an IgG4; therefore nivolumab has the potential to be transmitted from mother to the developing fetus.

Opdivo is not recommended during pregnancy unless the clinical benefit outweighs the potential risk to the fetus. Women of childbearing potential should use effective contraception during treatment with Opdivo and for at least 5 months after the last dose of Opdivo.

It is not known if Opdivo is secreted in human milk. As many drugs are secreted in human milk, a decision to discontinue breast-feeding or to discontinue Opdivo should be made, taking into account the benefit of breast-feeding to the child and the benefit of Opdivo therapy for the mother.

For more information, refer to the Opdivo Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

In animal models, inhibition of programmed cell death 1 (PD-1) signaling increased the severity of some infections and enhanced inflammatory responses. Notably, mycobacterium tuberculosis - infected PD-1 knockout mice exhibited markedly decreased survival compared with wild-type controls. Programmed cell death-1 receptor knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus. Data describing these animal models of infection are adequately captured in the Opdivo Product Monograph.

In an enhanced pre- and post-natal development study, dose-related increases in pregnancy losses, particularly in the third trimester, were observed in Opdivo-treated monkeys. Increase in neonatal death during the two first postnatal weeks was also reported in the low dose group (10 mg/kg) compared with controls. Interstitial inflammation and thyroid follicular hypertrophy/hyperplasia were noted in one fetus from a 10 mg/kg dam that aborted on gestational day 124. The Lowest Observed Adverse Effect Level (LOAEL) was established at 10 mg/kg for developmental toxicity. The risk of embryofetal toxicity and the potential risk to pregnant women are adequately addressed in the Opdivo Product Monograph.

Ex vivo studies using human peripheral blood mononuclear cells demonstrated increased antigen responsiveness following primary and secondary antigen exposure in the presence of Opdivo. An increase in sensitivity to pulmonary re-challenge by ovalbumin was also shown in a mouse PD-1 knockout model.

The mutagenic and carcinogenic potential of Opdivo have not been evaluated. Fertility studies have not been performed with Opdivo.

Overall, the results of the non-clinical studies as well as the potential risks to humans have been included in the Opdivo Product Monograph. In view of the intended use of Opdivo, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Opdivo Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

Opdivo (nivolumab) is a fully human monoclonal IgG4 antibody (HuMAb) that binds to the PD-1 receptor. The programmed cell death-1 (PD-1) receptor has important T cell regulatory functions and mediates tumour-specific inhibition of T cell responses, but does not mediate antibody-dependent cell-mediated cytotoxicity (ADCC) of activated human T cells. Engagement of the PD-1 receptor by its ligands PD-L1 and PD-L2 is a key interaction that allows tumours to evade immune-mediated destruction. Both PD-L1 and PD-L2 are expressed on the cell surface of multiple tumours. Binding of these ligands to the PD-1 receptor, results in an inhibition of T cell proliferation, survival and cytokine secretion. The binding of nivolumab to the PD-1 receptor inhibits multiple PD-1 ligand interactions and restores T cell responsiveness as well as the ability to mount a direct T cell immune attack against tumour cells.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that nivolumab, the drug substance, consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

The drug substance, nivolumab, is manufactured based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The manufacturing process of the drug substance consists of a series of stages which include cell culture, harvest, purification stages including viral inactivation/removal steps, and formulation. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.

The Opdivo drug product manufacturing process includes preparing buffer solution, pooling, sterile filtration, aseptic filling into vials, capping, and visual inspection using conventional pharmaceutical equipment and facilities.

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.

In-process controls and lot release tests for the drug substance and drug product were established and validated.

The materials used in the manufacture of the drug substance and drug product (including biological-sourced materials) are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing processes are considered to be adequately controlled within justified limits.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the nivolumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with ICH guidelines.

Each lot of Opdivo drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24 month shelf-life for Opdivo, when stored at 2 to 8°C and protected from light, is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.

On-Site Evaluations of the facilities involved in the manufacture and testing of the drug substance and drug product were not warranted since the facilities are known to be compliant with Good Manufacturing Practices and are currently evaluated in good standing.

Adventitious Agents Safety Evaluation

The nivolumab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.

 

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