Summary Basis of Decision for Cyramza

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 Cyramza is located below.

Recent Activity for Cyramza

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 Cyramza

Updated:

2022-12-22

The following table describes post-authorization activity for Cyramza, a product which contains the medicinal ingredient ramucirumab. 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 that are found in PAATs.

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

Drug Identification Number (DIN):

  • DIN 02443805 - 10 mg/mL, ramucirumab, solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
NC # 2666122022-08-09Issued NOL
2022-10-04

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the working reference standard qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued

NC # 2642982022-05-16Issued NOL
2022-07-26

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to transfer a quality control test to a new facility. The submission was considered acceptable, and an NOL was issued.

SNDS # 2601292022-01-07Issued NOC
2022-06-09

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.

SNDS # 2591892021-12-17Issued NOC
2022-03-25

Submission filed as a Level II – Supplement (Safety) to update the PM. The changes were in response to an Advisement Letter issued by Health Canada dated 2021-12-03, requesting revisions related to arterial (including aortic) aneurysms, dissections, and rupture. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM. An NOC was issued.

NC # 2577072021-10-18Issued NOL
2022-01-31

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the drug substance manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 2368992020-03-06Issued NOL
2020-05-25

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 Adverse Reactions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

New safety reviewNot applicableStarted between
2021-03-01

Health Canada started a safety review for Avastin and Cyramza, related to arterial aneurysm (balloon-like bulge in the wall of a blood vessel [artery]), arterial dissection (separation of the layers of a blood vessel [artery]), and aneurysm rupture (aneurysm that is leaking or has burst open).

NC # 2324552019-10-10Issued NOL
2020-01-24

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, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 2244372019-02-06Issued NOC
2019-07-30

Submission filed as a Level I – Supplement for a new drug substance manufacturing site, and to transfer a quality control test to a new facility. The data were reviewed and considered acceptable, and an NOC was issued.

NC # 2241692019-01-29Issued NOL
2019-05-21

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 Adverse Reactions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 2247202019-02-14Issued NOL
2019-04-30

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 2158102018-04-26Cancellation Letter Received
2018-05-10		Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM. The changes were not in scope of an NC. The submission was not necessary and it was cancelled by the sponsor.
NC # 1997232016-10-27Issued NOL
2017-01-26		Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM. As a result of the NC, modifications were made to the Warnings and Precautions, Adverse Reactions, and Clinical Trials 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 # 1952612016-05-18Issued NOL
2016-09-02		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 1874702015-09-04Cancellation Letter Received
2016-08-12		Submission filed as a Level I - Supplement for an expanded indication: use of Cyramza in combination with Folfiri (irinotecan, folinic acid, and 5-fluorouracil) for the treatment of patients with metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. A NON was recommended based on the uncertainty of the robustness of the efficacy analyses in the pivotal study, weighed against the risks of therapy in the overall benefit/risk assessment. The sponsor cancelled the submission.
SNDS # 1871972015-09-02Cancellation Letter Received
2016-08-11		Submission filed as a Level I - Supplement for a new indication: Cyramza, in combination with docetaxel, is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum based chemotherapy. A NON was recommended based on uncertainty of the robustness and clinical significance of the efficacy results, resulting in an unfavourable risk versus benefit assessment. The sponsor cancelled the submission.
SNDS # 1902552015-12-07Issued NOC
2016-07-27		Submission filed as a Level I - Supplement for a new drug substance manufacturing site. There were no changes to the drug substance specifications as a result of the proposed changes. The information was reviewed and considered acceptable. An NOC was issued.
NC # 1911422016-01-07Issued No Objection Letter
2016-04-08		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update the analytical methods for drug substance and drug product specifications. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 1900882015-11-30Issued No Objection Letter
2016-03-01		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to replace an analytical procedure in the drug substance and drug product specifications. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 1891002015-10-30Issued No Objection Letter
2016-02-04		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the reference standard qualification protocol. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 1891672015-11-03Issued No Objection Letter
2016-01-27		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change controls applied to the drug product. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 1888622015-11-02Issued No Objection Letter
2016-01-25		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change in-process controls. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Drug product (DIN 02443805) market notificationNot applicableDate of first sale:
2015-09-10		The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 1768102014-07-28Issued NOC
2015-07-16		Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Cyramza

Date SBD issued: 2015-08-20

The following information relates to the new drug submission for Cyramza.

Ramucirumab, 10 mg/mL, solution, intravenous

Drug Identification Number (DIN):

  • 02443805

Eli Lilly Canada Inc.

New Drug Submission Control Number: 176810

On July 16, 2015, Health Canada issued a Notice of Compliance to Eli Lilly Canada Inc. for the drug product, Cyramza.

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 Cyramza is favourable as a single agent or in combination with paclitaxel for the treatment of patients with advanced or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma with disease progression on or after prior platinum and fluoropyrimidine chemotherapy.

1 What was approved?

Cyramza is an antineoplastic agent, a recombinant human monoclonal antibody (IgG1) that specifically binds to vascular endothelial growth factor (VEGF) receptor 2. Cyramza as a single agent or in combination with paclitaxel was authorized for the treatment of patients with advanced or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma with disease progression on or after prior platinum and fluoropyrimidine chemotherapy.

No overall differences in safety or effectiveness have been observed between the elderly (≥65 years of age) and younger patients, but greater safety sensitivity of some older individuals cannot be ruled out.

The safety and effectiveness of Cyramza in children and adolescents (<18 years of age) have not been established.

Cyramza is contraindicated for patients with a known hypersensitivity to ramucirumab or to any other ingredient used in the formulation. Cyramza was approved for use under the conditions stated in the Cyramza Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Cyramza (10 mg/mL ramucirumab) is presented as a solution for intravenous infusion in 10 mL or 50 mL single-use vials. Each vial contains either 100 mg ramucirumab in 10 mL (10 mg/mL) or 500 mg ramucirumab in 50 mL (10 mg/mL). In addition to the medicinal ingredient, ramucirumab, the solution also contains glycine (E640), histidine, histidine monohydrochloride, polysorbate 80 (E433), sodium chloride, 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 Cyramza Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Cyramza approved?

Health Canada considers that the benefit/risk profile of Cyramza (ramucirumab) as a single agent or in combination with paclitaxel is favourable for the treatment of patients with advanced or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma with disease progression on or after prior platinum and fluoropyrimidine chemotherapy.

Ramucirumab is a recombinant human monoclonal receptor-targeted antibody (IgG1) that specifically blocks vascular endothelial growth factor (VEGF) receptor 2, the key mediator of VEGF-induced angiogenesis. Similar to bevacizumab (Avastin), which has been authorized by Health Canada for the treatment of metastatic colorectal cancer, non-small cell lung cancer, and glioblastoma; ramucirumab blocks angiogenesis, and therefore inhibits tumour growth.

Gastric cancer is the fifth most common cancer in the world and is a major cause of cancer-related death. There were approximately one million new cases of stomach cancer worldwide in 2008 with 736,000 deaths, making it the third-leading cause of cancer death globally in men and the fifth in women. The clinical development of Cyramza is particularly relevant in gastric cancer where VEGFs are highly expressed and there is a significant unmet medical need.

Cyramza has been shown to be efficacious in patients with advanced or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma with disease progression on or after prior platinum and fluoropyrimidine chemotherapy. The market authorization was based on two pivotal Phase III, multicentre, randomized, double-blind studies. When Cyramza was used as a single agent, the improvement in overall survival (OS) was 1.4 months, an increase in median survival to 5.2 months for Cyramza from 3.8 months for placebo, with the reduced risk of death by 22%. The improvement in progression-free survival (PFS) was 0.8 months with a reduced risk of disease progression by 52%. When Cyramza was combined with paclitaxel therapy, the improvement in OS was 2.27 months, an increase in median survival to 9.63 months for Cyramza plus paclitaxel from 7.36 months for placebo plus paclitaxel, with the reduced risk of death by 19%. The improvement in PFS was 1.5 months with a reduced risk of disease progression by 37%. In both studies, Cyramza demonstrated clinically and statistically significant improvements for OS and PFS.

The safety profile is consistent with what is expected from an angiogenesis antagonist. A higher incidence rate of adverse events was observed when Cyramza was combined with paclitaxel therapy compared to Cyramza as a single agent. In the Cyramza plus paclitaxel group versus (vs.) the paclitaxel group, the incidence rate of hypertension was 25.1% vs. 5.8%, bleeding was 41.9% vs. 17.9%, and proteinuria was 16.8% vs. 6.1%. Nevertheless, the risks were considered to be acceptable with the demonstrated improvement in OS and PFS.

To address the major safety concerns, a Serious Warnings and Precautions box containing increased risks of hemorrhage, gastrointestinal perforation and impaired wound healing was added to the Cyramza Product Monograph.

A Risk Management Plan (RMP) for Cyramza was submitted by Eli Lilly Canada Inc. 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.

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

Overall, the therapeutic benefits seen in the pivotal studies are positive and the benefits of Cyramza therapy are considered to outweigh the potential risks. Cyramza 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 Cyramza 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 theClinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Cyramza?

Submission Milestones: Cyramza

Submission MilestoneDate
Pre-submission meetings:2013-08-15 - 2014-01-24
Submission filed:2014-07-28
Screening
Screening Acceptance Letter issued:2014-09-19
Review
Biopharmaceutics Evaluation complete:2015-06-25
Quality Evaluation complete:2015-07-15
Clinical Evaluation complete:2015-06-02
Biostatistics Evaluation complete:2015-06-22
Labelling Review complete:2015-07-15
Notice of Compliance issued by Director General:2015-07-16

The Canadian regulatory decision on the non-clinical and clinical review of Cyramza was based on a critical assessment of the Canadian data package. The European Medicines Agency (EMA) review (Day 120 and Day 180 Questions and Responses) and the United States Food and Drug Administration (FDA) (Summary of FDA Information Requests and Responses) documents were reviewed and considered during the evaluation and recommendation for Cyramza.

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.

As part of the marketing authorization for Cyramza, Health Canada requested that the sponsor provide the following information when available:

  • Data on studies to explore the efficacy and safety of higher doses of Cyramza. 
  • Safety assessment for hypothyroidism from the current or future clinical studies.
  • Data and information supporting the understanding of regional differences in the incidence of proteinuria and neutropenia with combined therapy when available.
  • Available data and information supporting the possible potentiation on hypertension and proteinuria associated with the use of chemotherapy agents combined with Cyramza.

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

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 Cyramza 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

Vascular endothelial growth factor receptor 2 (VEGFR-2) is the key mediator of VEGF induced angiogenesis. Cyramza (ramucirumab) is a human receptor-targeted antibody that specifically binds VEGFR-2, and blocks binding of VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGFR-2 and its downstream signalling components, including p44/p42 mitogen-activated protein kinases, neutralizing ligand-induced proliferation and migration of human endothelial cells. In gastric cancer, VEGFs are highly expressed.

The impact of ramucirumab on the VEGFR-2 signalling pathway was demonstrated in non-clinical studies conducted using a proof-of-principle surrogate antibody (DC101) for ramucirumab since ramucirumab is species-specific and does not bind to the murine VEGFR-2 as used in nonclinical studies. This approach was considered relevant to the primary pharmacology of ramucirumab. In in vivo animal models, DC101 inhibited angiogenesis, and inhibited tumour growth.

Sparse and intensive data from eight studies were available to characterize the clinical pharmacokinetics; the data were also pooled together for a population pharmacokinetic analysis. The pharmacokinetic parameter estimates derived from the non-compartmental analysis were generally comparable to those estimated from the population pharmacokinetic approach. No dose modifications are considered necessary for gender, age or race. No formal studies were conducted to evaluate the effect of renal or hepatic impairment on the pharmacokinetics of ramucirumab. This has been addressed in the Cyramza Product Monograph.

For further details, please refer to the Cyramza Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Cyramza (ramucirumab) as a single agent, and in combination with paclitaxel, for the treatment of patients with advanced gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma after prior chemotherapy was based on two pivotal clinical studies (REGARD and RAINBOW). The primary objective of both studies was to evaluate the overall survival (OS) with the main secondary objective to assess the progression-free survival (PFS).

The REGARD study was a Phase III, multicentre, randomized, double-blind, single-agent study of Cyramza plus best supportive care (BSC) versus (vs.) placebo plus BSC. The study randomized (2:1) 355 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the GEJ) who previously received platinum- or fluoropyrimidine-containing chemotherapy. Patients were required to have experienced disease progression either within 4 months after the last dose of first-line therapy for locally advanced or metastatic disease or within 6 months after the last dose of adjuvant therapy. Patients were also required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients received either an intravenous infusion of Cyramza 8 mg/kg [number of patients (n) = 238)] or placebo solution (n = 117) every 2 weeks. The patients were treated with Cyramza or placebo until disease progression, the development of unacceptable toxicity, noncompliance, or withdrawal of consent by the patient. The median duration of treatment was 8 weeks in the Cyramza group and 6 weeks in the placebo group. The primary endpoint was OS and secondary endpoints included progression-free survival (PFS) and 12-week PFS rate.

In the REGARD study, the median OS was 5.2 months in the Cyramza group and 3.8 months in the placebo group, with an improvement in OS of 1.4 months for Cyramza. The hazard ratio was 0.776 [95% Confidence Interval (CI) 0.603-0.998] with a stratified Log-rank p-value of 0.0473. The median PFS was 2.1 months in the Cyramza group and 1.3 months in the placebo group, with a hazard ratio of 0.483 (95% CI 0.376-0.620) and a stratified Log-rank p-value of <0.0001. The 12-week PFS rate was 40.1% in the Cyramza group and 15.8% in the placebo group.

RAINBOW was a Phase III, multicentre, randomized, double-blind study of Cyramza plus paclitaxel vs. placebo plus paclitaxel. The study randomized (1:1) 665 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the GEJ) who previously received platinum- and fluoropyrimidine-containing chemotherapy, with or without anthracycline. The selection of paclitaxel as a combination partner for Cyramza was based on data from non-randomized, single-arm Phase II studies that were available at the time of the study design in 2010. Paclitaxel was shown to have similar activity to other single-agents (including docetaxel and irinotecan) or combination chemotherapy regimens used in second-line treatment of advanced gastric cancer. For the RAINBOW study, the patients were required to have experienced disease progression during, or within 4 months after the last dose of, first-line therapy. Patients were also required to have ECOG performance status of 0 or 1. Patients received either an intravenous infusion of Cyramza at 8 mg/kg (n = 330) or placebo (n = 335) every 2 weeks (on days 1 and 15) of a 28-day cycle. Paclitaxel at 80 mg/m2 was administered by intravenous infusion on Days 1, 8, and 15 of each 28-day cycle. Patients underwent radiographic assessment of disease status approximately every 6 weeks following the first dose of study therapy for 6 months and approximately every 9 weeks thereafter. Patients were treated until there was evidence of disease progression, unacceptable toxicity, withdrawal of consent, or until other withdrawal criteria were met. The primary endpoint was OS and the secondary endpoints included PFS and overall response rate.

In the RAINBOW study, the median OS was 9.63 months in the Cyramza plus paclitaxel group, and 7.36 months in the placebo plus paclitaxel group, with an improvement in OS of 2.27 months for the Cyramza plus paclitaxel group. The hazard ratio was 0.807 (95% CI 0.678-0.962) with a stratified Log-rank p-value of 0.0169. The median PFS was 4.4 months in the Cyramza plus paclitaxel group and 2.9 months in the placebo plus paclitaxel group, with a hazard ratio of 0.635 (95% CI 0.536-0.752) and a stratified Log-rank p-value of < 0.0001. The overall response rate was 27.9% in the Cyramza plus paclitaxel group, and 16.1% in the placebo plus paclitaxel group.

In conclusion, the REGARD and RAINBOW clinical studies demonstrated clinically and statistically significant improvements in both OS and PFS.

The original proposed indication by the sponsor for Cyramza was: "Cyramza as a single agent or in combination with paclitaxel is indicated for the treatment of patients with advanced or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma after prior chemotherapy." Health Canada recommended the following indication to accurately reflect the pivotal data: "Cyramza as a single agent or in combination with paclitaxel is indicated for the treatment of patients with advanced or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma with disease progression on or after prior platinum and fluoropyrimidine chemotherapy."

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

Clinical Safety

The clinical safety of Cyramza (ramucirumab) as a single agent, and in combination with paclitaxel, for the treatment of patients with advanced gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma after prior chemotherapy was evaluated in two pivotal clinical studies (REGARD and RAINBOW). Both of the clinical studies are described in the Clinical Efficacy section.

The most common adverse reactions observed with Cyramza-treated patients were fatigue/asthenia, neutropenia, leukopenia, diarrhea, epistaxis, and hypertension.

Clinically relevant reactions (including Grade ≥ 3) associated with antiangiogenic therapy observed in Cyramza-treated patients across the clinical studies were proteinuria, infusion-related reactions, and gastrointestinal perforations. The risks of hemorrhage, gastrointestinal perforations, and impaired wound healing are listed in a Serious Warnings and Precautions box in the Cyramza Product Monograph.

In the REGARD study where Cyramza was used as a single agent, the overall rate of treatment-emergent adverse events (TEAEs, of any grade) was higher in the Cyramza group (94.5%) compared with the placebo group (87.8%). The most common TEAEs (any grade) occurring at a higher rate in the Cyramza group compared to the placebo group were hypertension [15.3% versus (vs.) 7.8%], diarrhea (14.4% vs. 8.7%), and headache (9.3% vs. 3.5%).

In the RAINBOW study where Cyramza was used in combination with paclitaxel, the overall proportion of patients experiencing toxicity from treatment was greater in the Cyramza plus paclitaxel group compared to the placebo plus paclitaxel group. While the proportion of patients with ≥1 TEAEs was similar in both groups (99% vs. 98%), the incidence of Grade ≥3 TEAEs was higher in the Cyramza plus paclitaxel arm (82% vs. 63%).

There was a much higher incidence of adverse reaction events from the combined Cyramza plus paclitaxel therapy compared to the Cyramza monotherapy.

The incidence of proteinuria was 16.8% in the Cyramza plus paclitaxel group (6.1% in the placebo plus paclitaxel group), much higher than the observed 3% in the group treated with Cyramza as a single agent. Although paclitaxel is not known to cause proteinuria, it may possibly further increase the incident rate of proteinuria when it is used with Cyramza. The incidence of bleeding was 41.9% in the Cyramza plus paclitaxel group and 17.9% in the placebo plus paclitaxel group.

The incidence of hypertension was 25.1% in the Cyramza plus paclitaxel group compared to 16.1% in the group treated with Cyramza as a single agent, and similar in the control groups of RAINBOW (5.8%, placebo plus paclitaxel) and REGARD (7.8%, placebo). This finding is suggestive of possible potentiation of hypertension associated with the use of paclitaxel, when combined with Cyramza.

Regional differences were observed in the safety analyses. The RAINBOW safety population consisted of 402 (61.3%) White and 228 (34.8%) Asian patients. The incidence of proteinuria in Asian patients was higher (26.6%) than White patients (12.1%). Of the 4 patients associated with Grade 3 proteinuria, all were Asian patients. There was also a higher incidence of neutropenia in Asian than White patients, with the incidence of neutropenia at 77.1% in Asian and 43.7% in White patients. In the REGARD study, the incidence of neutropenia was low (3.8% in the Cyramza group and 0.9% in the placebo group) and the difference could not be reliably assessed. Despite discussions with the sponsor and exploration of various possible causes with the available data from clinical studies, the underlying mechanisms for the regional (racial) differences in the incidence of proteinuria and neutropenia with combined therapy remain unknown.

The review assessment included additional safety data from eight non-pivotal studies (five Phase I-II single-arm studies, two Phase II randomized open-label studies, and one Phase III, randomized double-blind study) in which ramucirumab was administered as a single agent or in combination with a chemotherapeutic agent. Although some differences in the toxicity profiles were observed in different disease settings, the results were generally consistent with the safety data from the Cyramza pivotal studies. Some of this additional data provided evidence for adding to or strengthening the proposed safety information in the Warnings and Precautions section of the Cyramza Product Monograph.

Overall, the safety profile of Cyramza as a single agent or in combination with paclitaxel is acceptable and manageable for the treatment of patients with advanced or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma with disease progression on or after prior platinum and fluoropyrimidine chemotherapy. Appropriate warnings and precautions are in place in the approved Cyramza Product Monograph to address the identified safety concerns.

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

7.2 Non-Clinical Basis for Decision

A common battery of in vitro studies was employed to characterize the non-clinical pharmacology of ramucirumab (the active ingredient in Cyramza), including its binding and blocking activity at VEGFR-2, and functional inhibition of VEGF/VEGFR-2 signaling by ramucirumab. Overall, the non-clinical pharmacodynamic data demonstrated that ramucirumab binds specifically and with high affinity to VEGFR-2. It is capable of inhibiting cellular responses that result from VEGFR-2 activation by VEGF, thereby having the potential to be a potent inhibitor of angiogenesis in human tumours.

In vivo studies were conducted using a "proof-of-principle" surrogate antibody for ramucirumab (DC101), an antagonist rat anti-mouse VEGFR-2 specific monoclonal antibody whose biochemical and pharmacodynamic properties were close to those of ramucirumab. This antibody exhibited both anti-angiogenic and anti-tumour activities in a broad range of the mouse xenograft models representing the types of human cancers that were under investigation in the human clinical studies.

Key findings of the toxicity studies indicated that ramucirumab induced renal toxicity with prolonged dosing, and caused pathological changes to the epiphyseal growth plate with short- and long-term dosing. The renal toxicity finding is clinically relevant and suggests that prolonged treatment may induce renal impairment. Epiphyseal growth plate pathology could be clinically important if ramucirumab is used in the pediatric population off-label. Both toxicity studies also recorded increased levels of creatine phosphokinase which were suggestive of muscle injury and a possible sign of cardiac damage.

Reproductive and developmental toxicity testing of ramucirumab has not been conducted. The sponsor conducted an assessment of the substantial body of evidence from the scientific literature. Interference with VEGF signaling by antibodies against VEGFR-2 has been shown to block the functioning or development of tissues critical for mammalian reproduction and development. Therefore, administration of Cyramza to patients poses a potential risk to establishing and maintaining pregnancy and to the embryo-fetal development.

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

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

7.3 Quality Basis for Decision

Ramucirumab, the active ingredient of Cyramza, is a recombinant fully human monoclonal antibody of the immunoglobulin G1 subclass, which binds to the extracellular domain of kinase insert domain receptor (KDR), also known as vascular endothelial growth factor receptor 2 (VEGFR-2).

Characterization of the Drug Substance

Ramucirumab was extensively analyzed to determine its structural, physicochemical, and functional characteristics.

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

The drug substance, ramucirumab, is produced in genetically engineered mammalian NS0 cells. The manufacturing process consists of four stages, including cell culture, harvesting, and purification and formulation of the active ingredient. The purification process includes a series of chromatographic, filtration, and chemical treatment steps. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use. The controls associated with each manufacturing process unit operation were adequately described and justified. The performance of the manufacturing process is routinely monitored by in-process testing using validated or qualified analytical methods against justified acceptance criteria. The manufacturing process was validated at the manufacturing scale and/or characterized using qualified small-scale models, amongst others for its capability to remove specific impurities, including viruses.

The drug product, Cyramza, is manufactured by a process that includes buffer compounding, drug substance pooling and dilution, sterilizing filtration, aseptic filling, stoppering and sealing, and then inspection and sampling. The performance of the manufacturing process is routinely monitored by in-process testing against justified acceptance criteria. The manufacturing process performance was validated at the manufacturing scale to establish the overall consistency and effectiveness of aseptic operations.

Control of the Drug Substance and Drug Product

The quality of formulated bulk drug substance is assessed against release specification, which incorporates tests to assess identity, purity, potency, and relevant characteristics of the dosage form. The associated analytical methods were validated or qualified, and the acceptance criteria were appropriately justified. The batch analysis data confirm that the proposed manufacturing process consistently yields drug substance of acceptable quality.

The quality of drug product lots is routinely assessed against release specification, which incorporates tests to assess relevant characteristics of the dosage form, the identity, purity, and potency of the reconstituted active ingredient, excipient composition, and conformance with compendial requirements. The associated analytical methods were validated or qualified, and the acceptance criteria were appropriately justified. The provided batch analysis data confirm that the proposed manufacturing process consistently yields drug product of acceptable quality.

Stability of the Drug Substance and Drug Product

The proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported by the available stability data. The proposed 24-month shelf-life at 2°C to 8°C for the Cyramza drug product is acceptable.

The proposed packaging and components are acceptable.

Facilities and Equipment

The design, operations, and controls of the respective facilities and equipment used in the manufacture of the drug substance and drug product production are acceptable.

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug substance was not warranted since the facility was recently evaluated in good standing.

An OSE of the facility involved in the manufacture and testing of the drug product, Cyramza, was not recommended as an OSE is scheduled for a drug submission currently under review.

Both sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious agents (bioburden, mycoplasma, and viruses). Purification steps designed to remove and/or inactivate viruses are adequately validated.

Raw materials of animal and recombinant origin used in the manufacturing process have been adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.

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