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PrPERJETA

Contact: Office of Regulatory Affairs, Biologics and Genetic Therapies Directorate

Summary Basis of Decision (SBD)

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

Recent activity for Perjeta

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 decision was negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle. At this time, no PAAT is available for Perjeta. When the PAAT for Perjeta becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Perjeta

The following information relates to the original authorization of the new drug submission for Perjeta.

Date SBD Issued: 2013/07/10

Pertuzumab
420 mg/14 mL vial Concentrate for solution for infusion, intravenous
Drug Identification Number (DIN): 02405016
Hoffmann-La Roche Limited
New Drug Submission Control Number: 158419

On April 12, 2013, Health Canada issued a Notice of Compliance to Hoffmann-La Roche Limited for the drug product, Perjeta.

Perjeta (pertuzumab) is a recombinant humanized monoclonal antibody based upon the human IgG1(κ) framework sequence and is a first-in-class human epidermal growth factor receptor 2 (HER2) dimerization inhibitor.

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 Perjeta in combination with Herceptin (trastuzumab) and docetaxel is favourable for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

  1. What was approved?
  2. Why was Perjeta approved?
  3. What steps led to the approval of Perjeta?
  4. What follow-up measures will the company take?
  5. What post-authorization activity has taken place for Perjeta?
  6. What other information is available about drugs?
  7. What was the scientific rationale for Health Canada's decision?

1. What was approved?

Perjeta (pertuzumab) is a targeted molecular biologic agent and antineoplastic agent, and is a first-in-class human epidermal growth factor receptor 2 (HER2) dimerization inhibitor. Perjeta in combination with Herceptin (trastuzumab) and docetaxel was authorized for the treatment of patients with HER2- positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

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

Perjeta (420 mg/14 mL, pertuzumab) is presented as a concentrated solution for dilution for infusion. In addition to the medicinal ingredient, the solution also contains glacial acetic acid, L-histidine, polysorbate 20, sucrose, 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 Perjeta Product Monograph, approved by Health Canada and available through the Drug Product Database.

2. Why was Perjeta approved?

Health Canada considers that the benefit/risk profile of Perjeta in combination with Herceptin (trastuzumab) and docetaxel is favourable for the treatment of patients with human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

In 2011, breast cancer was diagnosed in approximately 23,400 Canadian women and 5,100 women died from this disease (Canadian Cancer Statistics 2011). Human epidermal growth factor receptor 2 (HER2) positive breast cancer represents 15-20% of breast cancer and is associated with aggressive tumour growth and poor clinical outcome. Although a decline of breast cancer mortality has been observed in recent years, metastatic breast cancer (MBC) remains largely incurable. The median survival of MBC patients in 2011 was approximately 18-24 months.

Perjeta has been shown to be efficacious in HER2 positive MBC. The efficacy data provided demonstrated that the addition of Perjeta to Herceptin and docetaxel offered a statistically significant and clinically meaningful prolongation of progression-free survival in patients with HER2-positive metastatic breast cancer. The results from the second interim analysis of overall survival have also shown a statistically significant difference of hazard ratio in favour of the group treated with Perjeta. The clinical benefits have also been observed from the subgroup analyses and are further supported by the results of other secondary endpoints.

The most common adverse drug reactions (>30%) seen in patients treated with Perjeta in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash and peripheral neuropathy. The most common serious adverse reactions were febrile neutropenia, neutropenia and diarrhea.

The addition of Perjeta to Herceptin and docetaxel did not alter the safety profile of Herceptin and docetaxel; however, diarrhea, rash, mucosal inflammation and febrile neutropenia were more common in the Perjeta treatment group. Higher incidence of grade ≥3 febrile neutropenia and diarrhea, and serious adverse events (mainly febrile neutropenia and infections) were observed in the Perjeta treatment group compared to the placebo treatment group. The number of deaths due to reasons other than disease progression was similar in both treatment groups. From the pivotal clinical study, there is currently no indication that the addition of Perjeta to Herceptin and docetaxel significantly increased the risk of cardiotoxicity.

A Risk Management Plan (RMP) for Perjeta was submitted by Hoffmann-La Roche Limited 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.

Appropriate warnings and precautions are in place in the approved Perjeta Product Monograph to address the safety concerns that have been identified up to the time of authorization. A Black Box Warning addresses the potential risk of embryo-fetal toxicity.

Based on the review of data on clinical efficacy and safety, the risk-benefit profile of Perjeta, in combination with Herceptin and docetaxel in adult patients with HER2-positive metastatic breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease, was considered to be positive.

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 Next link will take you to another Web site 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 Perjeta?

The drug submission for Perjeta was reviewed under the Priority Review Policy. Perjeta in combination with Herceptin and docetaxel demonstrated a significant increase in effectiveness with an improved benefit/risk profile compared to existing therapies for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer, a condition that is not adequately managed by a drug marketed in Canada.

Submission Milestones: Perjeta
Submission Milestone Date
Pre-submission meeting: 2011/12/11 and 2011/12/14 
Request for priority status
Filed: 2012/07/23
Approval issued by Director 2012/08/22
Submission filed: 2012/08/31
Screening
Screening Acceptance Letter issued: 2012/10/15
Review
On-Site Evaluation: 2013/03/18 to 2013/03/22
Quality Evaluation complete: 2013/04/12
Clinical Evaluation complete: 2013/04/12
Labelling Review complete: 2013/04/12
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate 2013/04/12

The Canadian regulatory decision was based on a critical assessment of the Canadian data package that included quality, non-clinical, and clinical data. The United States Food and Drug Administration (FDA) reports which were based on a different clinical data package and were available in the public domain were used as a reference during the clinical assessment. The foreign review completed by the European Union's centralized procedure was only available to the Health Canada clinical reviewers at the late stage of the assessment.

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?

In addition to requirements outlined in the Next link will take you to another Web site Food and Drugs Act and Next link will take you to another Web site Regulations, commitments include (but are not limited to) the following:

  1. The sponsor will submit annual reports on the global Perjeta Pregnancy Pharmacovigilance Program within the Periodic Safety Update Report (PSUR), as well as copies of the annual reports on the MotHER Pregnancy Registry in the United States.
  2. The sponsor will provide data from an ongoing clinical trial to investigate whether the addition of hormonal therapy increases the efficacy of pertuzumab-based therapy in the hormone receptor-positive, HER2-positive metastatic breast cancer to Health Canada.
  3. The sponsor will provide the final efficacy and safety information of two on-going studies to Health Canada when further interim/final analyses are performed. The final analysis for Study W020697 is expected in Q4 2014. The final analysis of Study B022280 is expected in Q1 2016.

5. What post-authorization activity has taken place for Perjeta?

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.

At this time, no PAAT is available for Perjeta. When available, the PAAT will be incorporated into this SBD.

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?

Clinical Basis for Decision

Clinical Pharmacology

Human epidermal growth factor receptor 2 protein (HER2) -positive breast cancer is associated with aggressive tumour growth. Perjeta (pertuzumab) specifically targets HER2 and inhibits intracellular signalling which can result in cell growth arrest and apoptosis.

Twelve studies involving approximately 444 patients provided more than 3,800 samples for a comprehensive evaluation of the pharmacokinetics of pertuzumab, both alone and in combination with other drugs as well as the potential of drug-drug interactions. In single agent and combination studies, pertuzumab demonstrated linearity at doses between 2 and 25 mg/kg. Although the pharmacokinetics of pertuzumab were primarily correlated with lean body weight and serum albumin, these two covariates had so little influence on the targeted trough concentration of 20 µg/mL that a fixed dosing schedule could be justified.

The clinical pharmacological data support the use of Perjeta for the specified indication.

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

Clinical Efficacy

The clinical efficacy and safety were primarily based on one Phase III study (Study WO20698/TOC4129g), and one Phase II study (Study B017929).

Study WO20698/TOC4129g

Study WO20698/TOC4129g was a multicentre, randomized, double-blind, placebo-controlled Phase III clinical study conducted in 808 patients with HER2-positive metastatic or unresectable breast cancer who had not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Breast tumour specimens were required to show HER2 overexpression defined as a score of 3+ by immunohistochemistry (IHC) or in situ hybridization (ISH) amplification ratio ≥2.0 as determined at a central laboratory. Patients were randomized 1:1 to receive placebo, Herceptin, and docetaxel (Pla+T+D); or Perjeta, Herceptin, and docetaxel (Ptz+T+D). Randomization was stratified by prior treatment status (de novo or prior adjuvant/neoadjuvant therapy) and geographic region (Europe, North America, South America and Asia). Patients with prior adjuvant or neoadjuvant therapy were required to have a disease free interval of at least 12 months before enrolment into the study.

Perjeta was given intravenously as an initial loading dose of 840 mg, followed every three weeks thereafter by 420 mg. Herceptin was given intravenously as an initial loading dose of 8 mg/kg, followed every three weeks thereafter by 6 mg/kg. Patients were treated with Perjeta and Herceptin until disease progression, withdrawal of consent or unmanageable toxicity. Docetaxel was given as an initial dose of 75 mg/m2 intravenous infusion every 3 weeks for at least 6 cycles. The dose of docetaxel could be escalated to 100 mg/m2 at the investigator's discretion if the initial dose was well-tolerated.

At the time of the primary analysis, the mean number of cycles of study treatment received in the Pla+T+D group was 16.2 and in the Ptz+T+D group was 19.9.

The primary endpoint of the study was progression-free survival (PFS) as assessed by an independent review facility (IRF) and defined as the time from the date of randomization to the date of disease progression or death (from any cause) if the death occurred within 18 weeks of the last tumour assessment.

Key secondary efficacy endpoints were overall survival (OS), progression-free survival (PFS, investigator-assessed), and objective response rate (ORR).

Patient demographic and baseline characteristics were balanced between the two treatment groups.

Treatment with Ptz+T+D resulted in a statistically significant improvement in IRF-assessed PFS [hazard ratio (HR) = 0.62, 95%, confidence interval (CI) 0.51, 0.75; p <0.0001] with a clinically meaningful increase in median PFS of 6.1 months (median PFS of 12.4 months in the Pla+T+D group versus (vs.) 18.5 months in the Ptz+T+D group). The results of the pre-specified subgroup analyses, based on stratification factors, key baseline demographic and disease characteristics, were generally consistent with the results seen in the intent-to-treat population, except for differences seen in PFS between the visceral and non-visceral disease status subgroups.

Overall survival (OS) was analyzed in the first interim analysis at the primary data cut-off date and the results did not meet the pre-defined significance level determined using the Lan-DeMets alpha-spending function with the O'Brien-Fleming stopping boundary. However, after an additional one-year follow-up, the OS results at the second interim analysis demonstrated a HR = 0.66, 98.62% (adjusted) CI: 0.49, 0.90; p = 0.0008; stratified by prior treatment status and region which crossed the pre-defined O'Brien-Fleming stopping boundary for the Lan-DeMets alpha-spending function (HR ≤0.739; p ≤0.0138), and therefore demonstrated a statistically significant benefit for patients randomised to Ptz+T+D. The median time to death was 37.6 months in the Pla+T+D group but had not been reached in the Ptz+T+D group. A clear separation of the survival curves for the Ptz+T+D and Pla+T+D groups can be seen from the Kaplan-Meier plot. These differences are considered clinically meaningful. Subgroup analyses of OS are consistent with the results for all patients, except for the comparison of the visceral and non-visceral subgroups. These results have been captured in the Perjeta Product Monograph.

The ORR (complete response + partial response) was also in favour of the Ptz+T+D treatment group (80.2%) when compared to the Pla+T+D group (69.3%); however, the analysis of ORR is considered descriptive (and not inferential) due to the pre-determined sequential testing approach used to adjust for multiple statistical testing of IRF-assessed PFS, OS and ORR at the final PFS analysis, and the fact that the difference in OS was not statistically significant at the primary data cut-off date. The results from the duration of the objective response between the two groups were also supportive.

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

Clinical Safety

The safety of Perjeta was evaluated in the Phase III Study WO20698/TOC4129g (described in the Clinical Efficacy section) and in Phase I and Phase II studies conducted in more than 1,400 patients with various malignancies and predominantly treated with Perjeta in combination with other antineoplastic agents.

In Study WO20698/TOC4129g, the overall incidence of adverse events (AEs) during the treatment period was 98.5% of patients in the Pla+T+D group vs. 99.8% of patients in the Ptz+T+D group. The total number of AEs reported in the Ptz+T+D group (6,048 events) was higher than in the Pla+T+D group (5,300 events). The most common AE by patient was alopecia (60.5% for Pla+T+D; 60.9% for Ptz+T+D). Other frequently occurring AEs in both treatment groups were diarrhea, neutropenia, nausea, fatigue and rash. The incidence of diarrhea, rash, mucosal inflammation, dry skin and febrile neutropenia was higher in the Ptz+T+D group than in the Pla+T+D group, whereas peripheral edema and constipation were more commonly reported in the Pla+T+D group than in the Ptz+T+D group. The proportion of patients with at least one Grade ≥3 AE was 72.8% in the Pla+T+D group and 74.2% in the Ptz+T+D group. The majority of these were blood and lymphatic system disorders, particularly neutropenia.

The number of deaths due to causes other than progressive disease was 13 and 12 from the Pla+T+D group and Ptz+T+D group, respectively.

The incidence of left ventricular systolic dysfunction (LVSD) was similar in the two treatment groups (four patients each); however, more patients in the Pla+T+D group had investigator-assessed LVSD than in the Ptz+T+D group; seven patients (1.8%) vs. four patients (1.0%), respectively.

The incidence of serious adverse events (SAEs) was higher in the Ptz+T+D group than in the Pla+T+D group; 34.4% (140/407 patients) vs. 26.2% (104/397 patients) and this difference is primarily due to an increased incidence of febrile neutropenia (FN) in the Ptz+T+D group. The difference in incidence of FN between the two treatment groups was more marked in Asian patients than in other patients. Specifically, the incidence of FN in the Ptz+T+D group was 26% for Asian patients vs. 8.2% for non-Asian patients, while the incidence of FN in the Pla+T+D group was 11% for Asian patients vs. 5.7% for non-Asian patients. The reasons for such difference are unknown, but these results have been included in the Perjeta Product Monograph.

The safety data from the Phase II studies did not reveal new safety concerns. The safety profile of Perjeta in combination with chemotherapy was consistent with that of chemotherapy alone and of the known profile of Perjeta monotherapy.

Appropriate warnings and precautions are in place in the approved Perjeta Product Monograph to address the identified safety concerns. A Black Box Warning addresses the potential risk of embryo-fetal toxicity.

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

Non-Clinical Basis for Decision

Studies utilizing the mouse xenograft model for tumour assessment revealed that pertuzumab, the active ingredient in Perjeta, is active as a single agent against various human tumours including breast, lung, ovarian and prostate cancers. Pertuzumab demonstrated anti-tumour activity in both trastuzumab-sensitive and trastuzumab-resistant xenografts.

Pertuzumab was generally well-tolerated in 4-, 7- and 26-week repeat-dose toxicity studies at doses up to 150 mg/kg body weight (bw) in monkeys. After 7 and 26 weeks of treatment, there was an increase in the incidence of liquid and/or non-formed feces at all dose levels. The only other finding was an increase in blood urea nitrogen (BUN) levels which was observed in all repeat dose studies, at all dose levels, and was also seen in association with the poor clinical condition associated with diarrhea and dehydration in 3 animals in the 26-week study, one of which was euthanized moribund. Levels of BUN were also increased for dams in the embryo-fetal toxicity study, and all fetuses at all dose levels had adverse, renal histopathological changes. Additional findings in the embryofetal toxicity study, observed at all dose levels, included a dose-related increase in the incidence of abortions, a decrease in fetal body weight, decreased external measurement parameters, decreased placental weight and oligohydramnios. In addition, the length of the ossified long bones was decreased at all dose levels, and limb anomalies were observed in the 33.3 and 100 mg/kg bw groups, consistent with uterine growth restriction secondary to oligohydramnios.

In conclusion, the non-clinical toxicology data base was considered adequate to assess the safety profile of Perjeta and support its use for metastatic breast cancer in humans. Based on the adverse effects observed in all treated fetuses, Perjeta should not be administered to pregnant or lactating females.

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

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

Quality Basis for Decision

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that pertuzumab consistently exhibit the desired characteristic structure.

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

Pertuzumab (drug substance) is produced by recombinant deoxyribonucleic acid (DNA) technology in Chinese hamster ovary (CHO) cells. The manufacture of pertuzumab is based on a CHO 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 Conference on Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

Quality by Design principles were applied during the pertuzumab development lifecycle. Accordingly, new risk assessments and decision tools were used to define critical quality attributes, critical process parameters, acceptable process parameter ranges, the Drug Substance and Drug Product control systems, and process monitoring. These tools have been developed as part of an integrated risk management system building on concepts expressed in ICH Q8, Q9 and Q10.

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

The manufacturing process of the drug product (Perjeta) also consists of a series of steps which include thawing, pooling, and mixing of the contents of the drug substance followed by sterile filtration and then filling into vials using proper aseptic process techniques, and conventional pharmaceutical equipment. As the drug substance is already formulated at the appropriate concentration required for filling, this is a relatively simple process for which suitable controls are in place.

Control of the Drug Substance and Drug Product

Release specifications and analytical procedures have been carefully selected according to their ability to confirm the safety, efficacy, and activity of pertuzumab Drug Substance and Drug Product. The methods were validated in full accordance with the ICH guidelines for method validation [ICH Q2(R1)].

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.

Analytical testing results, from final batch analyses, were reviewed and considered to be acceptable according to the specifications of the drug product.

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 Perjeta is considered acceptable when vials are refrigerated at 2-8°C protected from light.

Facilities and Equipment

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of the drug substance (pertuzumab) was successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada and determined to be acceptable.

An OSE of the facility involved in the manufacture and testing of the drug product was not performed as part of the current application due to the short review time (Priority Review), in addition to the lack of issues identified during the review process.

Adventitious Agents Safety Evaluation

The pertuzumab 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.

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