Summary Basis of Decision for Nivestym

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 Nivestym is located below.

Recent Activity for Nivestym

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.

Summary Basis of Decision (SBD) for Nivestym

Date SBD issued: 2020-07-30

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

Filgrastim

Drug Identification Number (DIN):

  • DIN 02485575 - 300 mcg/0.5 mL, solution, subcutaneous or intravenous administration, a single-use prefilled syringe
  • DIN 02485583 - 480 mcg/0.8 mL, solution, subcutaneous or intravenous administration, a single-use prefilled syringe
  • DIN 02485591 - 300 mcg/mL, solution, subcutaneous or intravenous administration, a single-use vial
  • DIN 02485656 - 480 mcg/1.6 mL, solution, subcutaneous or intravenous administration, a single-use vial

Pfizer Canada ULC

New Drug Submission Control Number: 214080

On April 16, 2020, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for Nivestym, a biosimilar to Neupogen (the reference biologic drug). The terms "biosimilar biologic drug" and "biosimilar" are used by Health Canada to describe subsequent entry versions of a Canadian approved innovator biologic drug with demonstrated similarity to a reference biologic drug. Biosimilars were previously referred to as subsequent entry biologics in Canada. Both Nivestym and Neupogen contain highly similar versions of the medicinal ingredient, filgrastim.

Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. For a biosimilar, the weight of evidence is provided by the structural and functional studies. The non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, pharmacokinetic and pharmacodynamic, and clinical studies. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought.

For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.

In this drug submission, Neupogen is the reference biologic drug. Similarity between Nivestym and Neupogen was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Within the drug submission, the sponsor requested authorization of Nivestym for the same indications currently authorized for Neupogen.

The market authorization of Nivestym was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. Similarity was established through data derived from comparative structural, functional, non-clinical, and clinical studies. Based on Health Canada's review, the benefit-risk profile of Nivestym is considered to be highly similar to that of the reference biologic drug, for use in the treatment of the following patient populations:

  • Cancer patients receiving myelosuppressive chemotherapy

  • Nivestym (filgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs.

  • Nivestym is indicated in adult and pediatric patients with cancer receiving myelosuppressive chemotherapy.

  • A complete blood count (CBC) and platelet count should be obtained prior to chemotherapy, and twice per week during Nivestym therapy to avoid leukocytosis and to monitor the neutrophil count. In Phase III clinical studies, filgrastim therapy was discontinued when the absolute neutrophil count (ANC) was >10 x 109/L after expected chemotherapy-induced nadir.

  • Patients with acute myeloid leukemia

  • Nivestym is indicated for the reduction in the duration of neutropenia, fever, antibiotic use and hospitalization, following induction and consolidation treatment for acute myeloid leukemia.

  • Cancer patients receiving myeloablative chemotherapy followed by bone marrow transplantation

  • Nivestym is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients undergoing myeloablative therapy followed by bone marrow transplantation.

  • A CBC and platelet count should be obtained at a minimum of three times per week following marrow infusion to monitor marrow reconstitution.

  • Cancer patients undergoing peripheral blood progenitor cell (PBPC) collection and therapy

  • Nivestym is indicated for the mobilization of autologous peripheral blood progenitor cells in order to accelerate hematopoietic recovery by infusion of such cells, supported by Nivestym, after myelosuppressive or myeloablative chemotherapy.

  • Patients with severe chronic neutropenia (SCN)

  • Nivestym is indicated for chronic administration to increase neutrophil counts and to reduce the incidence and duration of infection in patients with a diagnosis of congenital, cyclic or idiopathic neutropenia.

  • Patients with human immunodeficiency virus (HIV) infection

  • Nivestym is indicated in patients with human immunodeficiency virus (HIV) infection for the prevention and treatment of neutropenia, to maintain a normal ANC (e.g., between 2 x 109/L and 10 x 109/L).

  • Nivestym therapy reduces the clinical sequelae associated with neutropenia (e.g., bacterial infections) and increases the ability to deliver myelosuppressive medications used for the treatment of HIV and its associated complications. It is recommended that complete blood counts and platelet counts be monitored at regular intervals (e.g., initially twice weekly for 2 weeks, once weekly for an additional 2 weeks, then once monthly thereafter, or as clinically indicated) during Nivestym therapy.

1 What was approved?

Nivestym, a granulocyte colony-stimulating factor, was authorized for use in cancer patients receiving myelosuppressive chemotherapy, patients with acute myeloid leukemia, cancer patients receiving myeloablative chemotherapy followed by bone marrow transplantation, cancer patients undergoing peripheral blood progenitor cell collection and therapy, patients with severe chronic neutropenia, and patients with human immunodeficiency virus infection.

Nivestym is a biosimilar to Neupogen. Both drugs contain the medicinal ingredient filgrastim. Filgrastim is a recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF), produced in Escherichia coli cells using recombinant deoxyribonucleic acid (DNA) technology. Endogenous G-CSF is a glycoprotein produced by monocytes, fibroblasts, and endothelial cells. It regulates the production of neutrophils within the bone marrow and has been shown to have minimal direct in vivo or in vitro effects on the production of other hematopoietic cell types.

Similarity between Nivestym and the reference biologic drug, Neupogen, has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, two comparative pharmacokinetic and pharmacodynamic studies in healthy adult volunteers, and one comparative immunogenicity study in healthy adult volunteers, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Nivestym is contraindicated in patients with known hypersensitivity to Escherichia coli-derived products, filgrastim, pegfilgrastim, or to any ingredient in the formulation, including any non-medicinal ingredient.

Nivestym was approved for use under the conditions stated in its Product Monograph, taking into consideration the potential risks associated with the administration of this drug product.

Nivestym (filgrastim 300 mcg/0.5 mL and 480 mcg/0.8 mL in single-use prefilled syringes, and 300 mcg/mL and 480 mcg/1.6 mL in single-use vials) is presented as a solution. In addition to the medicinal ingredient, the solution contains acetate, polysorbate 80, sodium, sorbitol, and water for injection.

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

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

2 Why was Nivestym approved?

Health Canada considers that the benefit-risk profile of Nivestym is highly similar to that of the reference biologic drug Neupogen. Similarity between Nivestym and Neupogen was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Nivestym is indicated for use in the treatment of the following patient populations:

  • cancer patients receiving myelosuppressive chemotherapy,
  • patients with acute myeloid leukemia,
  • cancer patients receiving myeloablative chemotherapy followed by bone marrow transplantation,
  • cancer patients undergoing peripheral blood progenitor cell collection and therapy,
  • patients with severe chronic neutropenia, and
  • patients with human immunodeficiency virus infection.

The New Drug Submission filed for Nivestym sought authorization for the same indications and clinical uses currently authorized for Neupogen.

Based on comparative structural and functional studies, Nivestym and the reference biologic drug were judged highly similar in terms of quality attributes.

Comparable pharmacokinetics and pharmacodynamics of Nivestym and Neupogen authorized in the United States (US Neupogen) were established in one single-dose and one multiple-dose comparative pharmacokinetic/pharmacodynamic study conducted in healthy volunteers. In terms of immunogenicity, Nivestym was demonstrated to be non-inferior to US Neupogen in a parallel-arm, multiple-dose, non-inferiority study in healthy volunteers. The reference product, US Neupogen, was used as a suitable proxy for the Canadian reference product in the clinical studies.

The safety profile of Nivestym is generally consistent with the known safety profile of Neupogen. No new safety signals were observed in healthy volunteers from the submitted clinical studies. The Adverse Reactions section of the Nivestym Product Monograph is based on the clinical experience with the reference biologic drug. As found in the Product Monograph for Neupogen, a Serious Warnings and Precautions box has been included in the Product Monograph for Nivestym. This section warns of reported occurrences of splenic rupture, including fatal cases, and severe sickle cell crises in patients with sickle cell trait or sickle cell disease, in some cases resulting in death.

A lack of significant immunogenicity was observed in the clinical studies, which is in line with the immunogenicity profile of the reference product. While significant immunogenicity concerns are not expected with filgrastim products (as the intended patient populations include immunocompromised patients), an ongoing monitoring of the clinical safety of Nivestym and a continued risk-benefit assessment are required during the post-approval phase.

The risk of dosing errors was also identified for Nivestym, since a volume of less than 0.3 mL (180 mcg) of Nivestym cannot be accurately measured or injected subcutaneously using Nivestym graduated prefilled syringes. In order to avoid potential dosing errors in the clinical practice, appropriate warnings were added to the Nivestym Product Monograph.

Serious adverse reactions identified in the post-marketing setting in patients receiving filgrastim are also listed in the Nivestym Product Monograph.

The final regulatory decision for this product was based on the totality of evidence, including structural, functional, non-clinical, pharmacokinetic and pharmacodynamic, and clinical comparisons. Furthermore, the scientific rationale provided by the Sponsor to support the authorization of Nivestym for the indications held by the reference biologic drug is considered adequate and in line with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

A Risk Management Plan (RMP) for Nivestym was submitted by Pfizer Canada ULC 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, Nivestym, was accepted.

Overall, the benefit-risk profile of Nivestym is considered favourable for the same indications, doses, and routes of administration authorized for the Canadian reference product, Neupogen.

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 Quality (Chemistry and Manufacturing), Non‑clinical, and Clinical Basis for Decision sections.

3 What steps led to the approval of Nivestym?

Submission Milestones: Nivestym

Submission MilestoneDate
Pre-submission meeting:2017-03-15
Submission filed:2018-02-28
Screening
Screening Acceptance Letter issued:2018-04-16
Review
Review of Risk Management Plan complete:2018-10-16
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2019-02-06
Quality Evaluation complete:2019-02-07
Clinical Evaluation complete:2019-02-08
Patent Hold
Submission placed on Patent Hold:2019-02-08
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate:2020-04-16

The Canadian regulatory decision on the review of Nivestym was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the United States Food and Drug Administration (FDA) were used as added references.

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.

The onus is on the sponsor to monitor the post-market safety profile of Nivestym as well as the Product Monograph of the reference biologic drug for safety signals that could affect the biosimilar and make safety updates to the Nivestym Product Monograph, as appropriate. New safety issues that are first identified with the use of the biosimilar, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both the biosimilar and the reference biologic drug. For more information, refer to the Fact Sheet: Biosimilars.

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

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 decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

At this time, no PAAT is available for Nivestym. 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?
7.1 Quality Basis for Decision

Nivestym was developed as a biosimilar to the reference biologic drug, Neupogen. In addition to a typical chemistry and manufacturing data package that is submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity with the reference biologic drug.

Comparative Structural and Functional Studies

The sponsor provided data to support two presentations of Nivestym: a single-dose prefilled syringe available in two strengths, 300 mcg/0.5 mL and 480 mcg/0.8 mL, and a single-dose vial available in two strengths, 300 mcg/mL and 480 mcg/1.6 mL. Neupogen licensed in the United States (US Neupogen) was used as the non-Canadian reference biologic drug. The reference product is available in the same presentations and strengths as those of Nivestym.

The biosimilarity assessment involved comprehensive structural and functional characterization of Nivestym and US Neupogen. Both strengths of each presentation were equally represented in the comparative analytical testing. The assessment included development, clinical, and process performance qualification (PPQ) lots of Nivestym. All of these lots have been placed in the stability program. The reference product lots used in the comparative non-clinical and clinical studies were also included in the biosimilarity assessment studies. Side-by-side physicochemical and biological characterization and comparative stability assessment studies were conducted through an array of state-of-the-art methods. The characterization tests used suitable predefined acceptance criteria.

There are no new impurities detected in Nivestym drug substance or drug product compared to US Neupogen. The major product-related impurities, including oxidized, deamidated, succinimide, isomerized and reduced variants, and aggregates, are tested at release and on stability samples.

Comparative stability studies performed under intended, accelerated, and stress conditions as well as under mechanical stress and light exposure stress conditions showed similar profiles. The data support the sponsor's assertion that Nivestym is highly similar to the reference product US Neupogen. A clear linkage between the non-Canadian reference biologic drug, US Neupogen, and the Canadian Neupogen has been established As a result, Nivestym is considered to be a biosimilar to Neupogen from a quality perspective.

Characterization of the Drug Substance

The medicinal ingredient in Nivestym is filgrastim, a recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF). Filgrastim is a 175 amino acid protein with a molecular weight of 18,800 Da. Its amino acid sequence is identical to the natural sequence predicted by a human deoxyribonucleic acid (DNA) sequence analysis, except for the addition of an N-terminal methionine, which is needed for expression in Escherichia coli.

Detailed characterization studies were performed to provide assurance that filgrastim 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 the established and acceptable limits.

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

Filgrastim is produced in a strain of Esherichia coli, engineered by recombinant DNA technology. The manufacturing process involves bacterial fermentation, during which the drug substance is expressed in the form of inclusion bodies. Isolation of the inclusion bodies from the harvest broth is achieved by cell disruption and centrifugation. Subsequently, the inclusion bodies are solubilized and the protein is folded to its active conformation during a refolding step. The solubilization reagents are removed by ultrafiltration. Capture of the target protein and its further purification are performed using chromatography steps. The material is then desalinated via ultrafiltration and diluted with buffer to the target protein concentration. The drug substance bulk solution is filtered and filled into polyethylene terephthalate glycol (PETG) bottles. The drug substance is either stored on site at 2ºC to 8ºC to subsequently enter the drug product manufacturing process or shipped frozen (≤-65°C) to the second drug product manufacturing site.

Process validation studies demonstrated that a drug substance of acceptable quality is consistently manufactured at the proposed manufacturing site.

Manufacturing of the drug product contained in single-use prefilled syringes consists of compounding, sterile filtration, aseptic filling and plunger stoppering, followed by visual inspection, labelling, syringe assembly, and packaging. For manufacture of the drug product contained in single-use vials, the frozen drug substance is thawed and subjected to compounding, sterile filtration, aseptic filling and stoppering, capping, visual inspection, labelling, and packaging.

Process validation studies demonstrated that a drug product of acceptable quality is consistently manufactured at the proposed manufacturing sites.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and 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 filgrastim 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. Analytical procedures are validated and in compliance with International Council for Harmonisation (ICH) guidelines.

Nivestym is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. As part of this program, final product lots were tested using a subset of release methods and shown to be fit for purpose.

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 satisfactory.

When stored at 2ºC to 8ºC, the shelf life is 30 months for the Nivestym single-use prefilled syringes and 24 months for the Nivestym single-dose vials.

Nivestym may be allowed to reach room temperature for a maximum of 15 days.

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 facilities and equipment involved in the production are considered suitable for the activities and products manufactured.

On-site evaluations of the drug substance and drug product manufacturing and testing facilities have been conducted by Health Canada, with satisfactory ratings.

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

Adventitious Agents Safety Evaluation

Adequate control measures are incorporated in the manufacturing process of filgrastim to prevent contamination and maintain microbial control.

The prokaryotic expression system used does not support the growth of viral adventitious agents. Bacteriophage, bioburden and endotoxin testing procedures are integrated in the control strategy and meet relevant guidelines and requirements.

The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy or other human pathogens.

7.2 Non-Clinical Basis for Decision

For biosimilars, the degree of similarity at the quality level determines the scope and the breadth of the required non-clinical data. Non-clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty.

The submitted non-clinical data included three in vitro functional assays and one in vivo repeat-dose toxicity study (MPI 1550-060). Study MPI 1550-060 was a 4-week, comparative, repeat-dose toxicity study that evaluated Nivestym versus Neupogen (sourced from the United States [US Neupogen]) administered subcutaneously in Sprague-Dawley rats. The study demonstrated comparability of Nivestym and US Neupogen in terms of their toxicity, local tolerance, pharmacokinetic and pharmacodynamic profiles, and immunogenicity. No new toxicological findings were observed for Nivestym. The non-clinical data were in compliance with the requirements for non-clinical studies of biosimilars, as outlined in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The results of the comparative non-clinical studies have been included in the Nivestym Product Monograph. In view of the intended use of Nivestym, no pharmacological or toxicological issues were identified within this submission to preclude authorization of the product.

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

7.3 Clinical basis for decision

For a biosimilar, the purpose of the clinical program is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The structural complexity of the biologic drug and the availability of a relevant and sensitive pharmacodynamic endpoint determine the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Three clinical studies were conducted in healthy volunteers to support comparability of Nivestym to Neupogen sourced from the United States (US Neupogen). This reference product was used as a suitable proxy for the Canadian reference product.

Comparative Pharmacokinetics and Pharmacodynamics

Comparability in terms of the pharmacokinetics and pharmacodynamics of Nivestym and the reference product was established in two studies conducted in healthy adult volunteers following subcutaneous administration of a single dose (C1121002) or multiple doses (C1121003). Safety and immunogenicity were also assessed in these studies.

Single-dose study in healthy volunteers (C1121002)

Study C1121002 was an open-label, randomized, single-dose, two-way crossover, comparative pharmacokinetic and pharmacodynamic study of Nivestym versus US Neupogen following a single subcutaneously administered dose of 5 mcg/kg. It included 24 healthy adult volunteers (12 subjects per treatment sequence: Nivestym followed by US Neupogen [Nivestym/US Neupogen] or US Neupogen followed by Nivestym [US Neupogen/Nivestym]). The two study periods were separated by a washout of at least 28 days. Given that one subject from the Nivestym/US Neupogen treatment sequence did not complete the study, the statistical comparisons included data from 23 subjects.

Pharmacokinetic comparability of Nivestym with the reference product was demonstrated in this study. The ratio of geometric means (GMR) for the maximum serum concentration (Cmax) and the 90% confidence interval (CI) for the area under the concentration versus time curve from time zero to the last measurable time point (AUC0-last) were within the equivalence margins of 80.0% to 125.0%. The pharmacokinetic comparability standards were met on both measured (potency uncorrected) data (GMR for Cmax: 111%; 90% CI for AUC0-last: 105% to 123%) and potency corrected data (GMR for Cmax: 112%; 90% CI for AUC0-last: 106% to 124%).

Pharmacodynamic comparability of Nivestym with the reference product was also demonstrated, based on the assessment of the absolute neutrophil count (ANC) as a relevant pharmacodynamic marker for the activity of granulocyte colony-stimulating factor (G-CSF). Both the 95% CI for the area under the effect curve (AUEC) for the ANC (AUECANC) (95% CI: 94% to 103%) and the 95% CI for the maximum effect (ANCmax) (95% CI: 92% to 104%) were within the equivalence margins of 80.0% to 125.0%.

Multiple-dose study in healthy volunteers (C1121003)

Study C1121003 was an open-label, randomized, multiple-dose, two-way crossover, comparative pharmacokinetic and pharmacodynamic study that compared Nivestym to US Neupogen in 60 healthy adult volunteers (30 subjects per treatment sequence: Nivestym/US Neupogen or US Neupogen/Nivestym). Each subject received five consecutive subcutaneous doses of 5 mcg/kg/day of either Nivestym or US Neupogen in each period of the study. The two study periods were separated by a washout of at least 28 days. Three subjects from the Nivestym/US Neupogen treatment sequence and one subject from the US Neupogen/Nivestym treatment sequence did not complete the study, which led to inclusion of data from 56 subjects in the statistical comparisons.

Pharmacokinetic comparability of Nivestym with the reference product was demonstrated in the study, as the GMR for Cmax and the 90% CI for the area under the serum filgrastim concentration curve from time zero to 24 hours on Day 5 (AUC0-24) were within the equivalence margins of 80.0% to 125.0%. For measured (potency uncorrected) data, the GMR for Cmax was 103% and the 90% CI for AUC0-24 was 97% to 108%. Similarly, for potency corrected data, the GMR for Cmax equaled 104% and the 90% CI for AUC0-24 was 98% to 109%.

In addition, pharmacodynamic comparability of Nivestym with the reference product in terms of CD34+ count, as a relevant pharmacodynamic marker to show mobilization of autologous hematopoietic progenitor cells, was also demonstrated. The 95% CI for the area under the effect on the CD34+ count versus time curve (AUECCD34+) and the 95% CI for the maximum observed CD34+ count (CD34+max) were within the equivalence margins of 80.0% to 125.0% (97% to 117% for AUECCD34+ and 93% to 122% for CD34+max).

Comparative Immunogenicity

A Phase I, randomized, open-label, two-period, parallel-arm, non-inferiority immunogenicity study (C1121012) evaluated the immunogenicity of multiple subcutaneous doses of Nivestym or US Neupogen in 256 healthy adult volunteers (128 subjects per arm). The study also assessed safety as a secondary objective.

In Period 1 of the study, each subject received five consecutive daily subcutaneous doses (5 mcg/kg) of Nivestym or US Neupogen. In Period 2, each subject received one subcutaneous dose of the same regimen received in Period 1. There was an interval of approximately 1 month between Period 1 Day 1 and Period 2 Day 1. Samples for immunogenicity assessment were collected on Days 0, 10, and 26 of Period 1, on Days 0 and 10 of Period 2, and at the final visit (Day 31). One patient in the US Neupogen arm did not receive the drug. The statistical analysis included data from 255 subjects who received at least one dose of the study drugs.

The primary study endpoint was the proportion of subjects who had a negative baseline anti-drug antibody (ADA) test result and a confirmed post-dose positive ADA test result at any time during the study. There were 15 subjects with a confirmed positive treatment-emergent ADA result, at least once during the study (9 subjects [7.4%] in the Nivestym group and 6 subjects [4.9%] in the US Neupogen group). The non-inferiority of Nivestym versus US Neupogen was established statistically, as the upper bound of the 95% CI for the test-reference (Nivestym-US Neupogen) risk difference for the primary endpoint was below the prespecified non-inferiority margin of 10%. There was no evidence of neutralizing antibodies for any subject.

Immunogenicity was also assessed in the comparative pharmacokinetic and pharmacodynamic studies (described in Comparative Pharmacokinetics and Pharmacodynamics). In study C1121002, serum for ADA testing was collected prior to dosing on Day 1, on Day 12 of each period, Day 28 of Period 1 and Day 28 of Period 2 (final visit). Three subjects in the US Neupogen/Nivestym treatment sequence had a positive ADA test result at least once during the study. The ADA positive samples did not exhibit neutralizing activity. Of note, there are limitations in interpreting immunogenicity data that originate from a study with a single-dose crossover design.

In study C1121003, blood samples for ADA testing were collected prior to dosing on Days 1, 12 and 33 of each period. One subject in Nivestym/US Neupogen treatment sequence was temporarily positive for ADA. This ADA positive sample did not exhibit neutralizing activity.

Overall, the data indicate that there are no meaningful differences in immunogenicity results between Nivestym and US Neupogen.

Comparative Safety

The overall safety profile of Nivestym appears to be comparable to that of US Neupogen, based on the three clinical studies conducted in healthy volunteers (described in Comparative Pharmacokinetics and Pharmacodynamics and Comparative Immunogenicity). There were no new safety concerns raised in these studies. The most frequently reported (≥5%) events were back pain (in studies C1121003 and C1121012), headache (in studies C1121002, C1121003, and C1121012), pyrexia and cough (in study C1121003), and pain in extremity (in study C1121012). Of note, there was a higher incidence of injection site reactions in the US Neupogen arm (number of subjects [n] = 13) as compared to the Nivestym arm (n = 2) in study C1121012. This observation was attributed to randomness in clinical trials, particularly in small studies, rather than to differences in the drug formulations.

As the submitted comparative studies were carried out in healthy volunteers, a long-term follow-up was not feasible. Consequently, long-term safety data are limited. However, the totality of evidence (the demonstration of clinical pharmacokinetic and pharmacodynamic comparability and analytical similarity) suggests that Nivestym is highly similar to US Neupogen and any differences are unlikely to be clinically meaningful.

The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warnings and Precautions section of the Nivestym Product Monograph, as they are in the Product Monograph for Neupogen.

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

Indications

Within this drug submission, the sponsor provided a written scientific rationale to request the authorization of Nivestym for all of the indications currently authorized for Neupogen. The rationale elaborated on the selective binding of filgrastim to the granulocyte colony-stimulating factor [G-CSF] receptor as the mechanism of action across all of the indications sought. It also outlined the comprehensive biosimilarity exercise undertaken, including extensive physicochemical, non-clinical, and clinical similarity studies in healthy volunteers (as a sensitive population for assessing potential differences in immunogenicity). There were no clinically meaningful differences in terms of pharmacokinetics and pharmacodynamics between Nivestym and US Neupogen in the sensitive population. In addition, no new safety concerns were identified in the comparative clinical studies.

Similarity between Nivestym and Neupogen was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug, and therefore clinical studies are not required to support each indication.

Upon Health Canada's review, Nivestym was authorized for the same indications currently held by the reference biologic drug, Neupogen, as follows:

  • Cancer patients receiving myelosuppressive chemotherapy

  • Nivestym (filgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs.

  • Nivestym is indicated in adult and pediatric patients with cancer receiving myelosuppressive chemotherapy.

  • A complete blood count (CBC) and platelet count should be obtained prior to chemotherapy, and twice per week during Nivestym therapy to avoid leukocytosis and to monitor the neutrophil count. In Phase III clinical studies, filgrastim therapy was discontinued when the absolute neutrophil count (ANC) was >10 x 109/L after expected chemotherapy-induced nadir.

  • Patients with acute myeloid leukemia

  • Nivestym is indicated for the reduction in the duration of neutropenia, fever, antibiotic use and hospitalization, following induction and consolidation treatment for acute myeloid leukemia.

  • Cancer patients receiving myeloablative chemotherapy followed by bone marrow transplantation

  • Nivestym is indicated to reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients undergoing myeloablative therapy followed by bone marrow transplantation.

  • A CBC and platelet count should be obtained at a minimum of three times per week following marrow infusion to monitor marrow reconstitution.

  • Cancer patients undergoing peripheral blood progenitor cell (PBPC) collection and therapy

  • Nivestym is indicated for the mobilization of autologous peripheral blood progenitor cells in order to accelerate hematopoietic recovery by infusion of such cells, supported by Nivestym, after myelosuppressive or myeloablative chemotherapy.

  • Patients with severe chronic neutropenia (SCN)

  • Nivestym is indicated for chronic administration to increase neutrophil counts and to reduce the incidence and duration of infection in patients with a diagnosis of congenital, cyclic or idiopathic neutropenia.

  • Patients with human immunodeficiency virus (HIV) infection

  • Nivestym is indicated in patients with human immunodeficiency virus (HIV) infection for the prevention and treatment of neutropenia, to maintain a normal ANC (e.g., between 2 x 109/L and 10 x 109/L).

  • Nivestym therapy reduces the clinical sequelae associated with neutropenia (e.g., bacterial infections) and increases the ability to deliver myelosuppressive medications used for the treatment of HIV and its associated complications. It is recommended that complete blood counts and platelet counts be monitored at regular intervals (e.g., initially twice weekly for 2 weeks, once weekly for an additional 2 weeks, then once monthly thereafter, or as clinically indicated) during Nivestym therapy.

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