Summary Basis of Decision for Fulphila
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Fulphila is located below.
Recent Activity for Fulphila
The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.
The following table describes post-authorization activity for Fulphila, a product which contains the medicinal ingredient pegfilgrastim. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).
For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.
Updated: 2024-04-24
Drug Identification Number (DIN):
DIN 02484153 – 10 mg/mL, pegfilgrastim, solution, subcutaneous administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
NDS # 273627 |
2023-03-23 |
Issued NOC 2023-05-15 |
Submission filed to transfer ownership of the drug product from BGP Pharma ULC to Biosimilar Collaborations Ireland Limited (BCIL). An NOC was issued. |
|
SNDS # 269946 |
2022-11-21 |
Issued NOC 2023-05-12 |
Submission filed as a Level I – Supplement a scale-up of the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
SNDS # 268399 |
2022-10-03 |
Issued NOC 2023-03-09 |
Submission filed as a Level I – Supplement to update the outer labels (carton and blister labels). The submission was reviewed and considered acceptable, and an NOC was issued. |
|
NC # 267236 |
2022-08-22 |
Issued NOL 2022-11-30 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the cell bank/seed bank qualification protocol, cell banks, and cell bank/seed bank testing site. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
SNDS # 261801 |
2022-03-25 |
Issued NOC 2022-09-08 |
Submission filed as a Level I – Supplement to update the PM to align with that of the reference biologic drug, Neulasta, and migrate it to the 2020 format. The changes were in response to an Advisement Letter issued by Health Canada to BGP Pharma ULC, dated February 25, 2022, requesting revisions related to the increased risk of Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in breast and lung cancer patients when used in conjunction with chemotherapy and/or radiotherapy. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions and Adverse Reactions sections of the PM. An NOC was issued. |
|
NC # 262083 |
2022-03-07 |
Issued NOL 2022-03-07 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 237134 |
2020-03-13 |
Cancellation Letter Received 2020-05-25 |
Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. Health Canada determined that the proposed changes to the PM did not align with the PM of the reference biologic drug, Neulasta, and the sponsor cancelled the submission. |
|
SNDS # 232297 |
2019-10-07 |
Issued NOC 2020-05-15 |
Submission filed as a Level I – Supplement for the addition of an alternate drug substance manufacturing site and a scale up of the drug substance and drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
Drug product (DIN 02484153) market notification |
Not applicable |
Date of first sale: 2020-02-07 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NC # 225219 |
2019-03-01 |
Issued NOL 2019-06-07 |
Submission filed as a Level II (90 day) Notifiable Change to correct an error in the PM. As a result of the NC, modifications were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable. |
|
NC # 224148 |
2019-01-28 |
Issued NOL 2019-05-02 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug product (release and stability). The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 224215 |
2019-01-30 |
Issued NOL 2019-04-12 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the parameters of an approved holding step or addition of a new holding step. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NDS # 200807 |
2016-12-05 |
Issued NOC 2018-12-24 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Fulphila
Date SBD issued: 2019-05-29
The following information relates to the New Drug Submission for Fulphila.
Pegfilgrastim
Drug Identification Number (DIN):
- DIN 02484153 - 10 mg/mL, solution, subcutaneous administration
BGP Pharma ULC
New Drug Submission Control Number: 200807
On December 24, 2018, Health Canada issued a Notice of Compliance (NOC) to BGP Pharma ULC for Fulphila, a biosimilar to Neulasta (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 Fulphila and Neulasta contain highly similar versions of the medicinal ingredient, pegfilgrastim.
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 biosimilars, 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 biosimilar assessment to rely on the safety and efficacy information of the reference biologic drug in the indications authorized.
For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.
In this drug submission, Neulasta is the reference biologic drug. Similarity between Fulphila and Neulasta was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Within this drug submission, the sponsor requested the authorization of Fulphila for the indication that is currently authorized for Neulasta.
The market authorization 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 Fulphila is considered to be highly similar to the reference biologic drug for decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs.
1 What was approved?
Fulphila, a granulocyte colony-stimulating factor, was authorized for decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs.
Fulphila is a biosimilar to Neulasta. Both drugs contain the medicinal ingredient pegfilgrastim, which is produced in Escherichia coli cells using recombinant deoxyribonucleic acid (DNA) technology. Pegfilgrastim is a long-acting, covalent conjugate of recombinant human granulocyte colony-stimulating factor (GCSF, also known as filgrastim) and polyethylene glycol (PEG).
Similarity between Fulphila and the reference biologic drug, Neulasta, has been established on the basis of comparative structural and functional studies, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
The safety and effectiveness of Fulphila have not been established in pediatric patients (<18 years of age).
Fulphila is contraindicated in patients with known hypersensitivity to E. coli-derived proteins pegfilgrastim filgrastim, or any other component of the product.
Fulphila 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.
Fulphila (10 mg/mL pegfilgrastim, supplied as a solution [0.6 mL] containing 6 mg pegfilgrastim) is presented as a sterile solution for injection. In addition to the medicinal ingredient, the formulation contains polysorbate 20, sodium acetate, 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 Fulphila Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Fulphila approved?
Health Canada considers that the benefit-risk profile of Fulphila is highly similar to that of the reference biologic drug, Neulasta, for decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs. Similarity between Fulphila and Neulasta was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Fulphila is considered to be biosimilar to Neulasta. Neulasta is authorized and marketed in Canada specifically for the treatment of febrile neutropenia in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs. The New Drug Submission (NDS) filed for Fulphila requested authorization for the same indication that is currently authorized for Neulasta. The indication sought has been authorized on the basis of demonstrated similarity between Fulphila and Neulasta, the reference biologic drug.
Neutropenia is an abnormally low number of neutrophils in the blood. These cells represent a type of white blood cell with a central role in the innate immune system. Since neutropenia weakens the immune system, affected patients are at an increased risk of developing an infection or sepsis. Neutropenia may have various causes, but it is often a consequence of myelosuppressive chemotherapy, and its occurrence represents a dose-limiting factor in chemotherapy regimens. The development of severe neutropenia (classified as Grade 3 or 4) during chemotherapy often leads to dose reduction or dose interruption for the patient, which can interfere with the success of treatment.
Pegfilgrastim, the medicinal ingredient in Fulphila, is the PEGylated, longer-acting form of the recombinant human granulocyte colony-stimulating factor filgrastim (GCSF). PEGylation refers to the addition of a methoxy polyethylene glycol (mPEG) moiety to a biological molecule. Filgrastim acts on hematopoietic cells by binding to specific cell surface receptors, stimulating proliferation, differentiation, commitment, and end-cell functional activation, including the proliferation of neutrophils. Due to the added mPEG moiety, pegfilgrastim has reduced renal clearance and an extended half-life, which prolongs its pharmacological effect. Therefore, while filgrastim requires daily administration, pegfilgrastim may be administered once per cycle of chemotherapy.
At the time of authorization of Fulphila, one other drug was also authorized in Canada as a biosimilar to Neulasta.
The biosimilar and the reference biologic drug were determined to be highly similar in terms of quality attributes (based on comparative structural and functional studies). Comparative bioavailability and comparative pharmacodynamic studies demonstrated similarity in healthy volunteers. Additionally, comparative clinical trials ruled out clinically meaningful differences in safety and immunogenicity between the biosimilar and the reference biologic drug, in patients with Stage II/III breast cancer receiving myelosuppressive chemotherapy in the neoadjuvant or adjuvant settings. The demonstration of similarity enables the biosimilar assessment to rely on the safety and efficacy information of the reference biologic drug in the indication authorized.
Fulphila has demonstrated a comparable safety profile with the reference product, Neulasta. Therefore, the Adverse Reactions section of the biosimilar Product Monograph is based on the clinical experience with the reference biologic drug. As with Neulasta, the major identified safety concerns include splenic rupture and severe sickle cell crises. These risks have been listed in the Serious Warnings and Precautions box in the Fulphila Product Monograph, as can be found in the Neulasta Product Monograph.
A Risk Management Plan (RMP) for Fulphila was submitted by BGP Pharma 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 Fulphila was accepted.
Overall, Fulphila is considered to have a benefit-risk profile comparable to that which has been established for the claimed indication of its reference biologic drug, Neulasta. The benefits of Fulphila are considered to outweigh the potential risks in the target patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Fulphila Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.
3 What steps led to the approval of Fulphila?
A Notice of Deficiency (NOD) was issued in the first review cycle of this submission due to scheduling issues which could not be resolved in time to meet the review target date. (See Facilities and Equipment).
The sponsor filed a response to the NOD, and Health Canada conducted an OSE within the second review cycle to address the outstanding concerns. The information provided in the NOD and the results of the OSE were acceptable, and a Notice of Compliance (NOC) was issued for this submission.
The Canadian regulatory decision on the quality, non-clinical and clinical review of Fulphila was based on a critical assessment of the data package submitted to Health Canada. Review reports from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were consulted for relevant supplementary information.
Submission Milestones: Fulphila
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2016-03-22 |
| Submission filed: | 2016-11-30 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2017-01-27 |
| Review 1 | |
| Quality Evaluation complete: | 2017-10-17 |
| Clinical Evaluation complete: | 2017-10-18 |
| Review of Risk Management Plan complete: | 2017-09-01 |
| Notice of Deficiency (NOD) issued by Director General, Biologics and Genetic Therapies Directorate (scheduling issues): | 2017-10-20 |
| Response filed: | 2018-01-18 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2018-03-05 |
| Review 2 | |
| On-Site Evaluation(s): | 2018-06-18 - 2018-06-22 |
| Quality Evaluation complete: | 2018-12-19 |
| Clinical Evaluation complete: | 2018-12-20 |
| Biostatistics Evaluation complete: | 2018-12-21 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-12-21 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2018-12-24 |
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?
The onus is on the Fulphila sponsor to monitor the post-market safety profile of this biosimilar product as well as the Product Monograph of the reference biologic drug for safety signals that could impact the biosimilar, and make safety updates to the Fulphila Product Monograph as appropriate. New safety issues that are first identified with 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.
In addition to requirements outlined in the Food and Drugs Act and Regulations, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. These commitments include, but are not limited to:
- Submission of a summary report (preferably as a Periodic Benefit-Risk Evaluation Report [PBRER]) every six months, for at least two years
- Preparation of a Canadian Annex, including the target population in Canada and medical practices and methods used to distinguish adverse event reports for Fulphila from those of other licensed products, including the reference product
- Inclusion of glomerulonephritis as an important risk in the RMP
- Follow-up questionnaires for some identified and potential risks
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Quality Basis for Decision
Quality Basis for Decision
Fulphila was developed as a biosimilar to the reference biologic drug, Neulasta. For biosimilars, the weight of evidence is provided by structural and functional studies. 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.
The biological activity of Fulphila is considered to be representative of the mechanism of action and pharmacological effect of Neulasta.
A Notice of Deficiency (NOD) was issued for this submission due to significant gaps in the quality information that could not be resolved in time to meet the review target date. An on-site evaluation (OSE) was scheduled, but could not be carried out on the previously negotiated date because the site was not in operation. The OSE was essential for the review of this submission, as an OSE had never been conducted at this site. There were significant ambiguities in the information that were crucial to the completion of the quality review, which could best be resolved by a team on-site. A NOD was issued, as deferring the OSE would have prevented completion of the review by the target date, and the sponsor declined to withdraw the submission.
The sponsor filed a response to the NOD, and an OSE was performed within the review cycle to address the outstanding concerns. The information in the NOD and the results of the OSE were acceptable, and a Notice of Compliance (NOC) was issued for this submission.
Comparative Structural and Functional Studies
Comparative testing for Fulphila involved pairwise comparisons between Fulphila, Neulasta licensed in the European Union (EU-Neulasta), and Neulasta licensed in the United States (US-Neulasta). The reference product for Fulphila is specifically EU-Neulasta. US-Neulasta was included in tests to provide supportive data.
The quality attributes examined through these tests were categorized according to their potential to affect biological activity, pharmacokinetics, pharmacodynamics, efficacy, immunogenicity, and safety of the drug. Factors expected to have very high to moderate impact on the quality attributes were assessed quantitatively, using a quality range based on the variance observed in the reference biologic, Neulasta. Factors expected to have moderate to low impact were assessed qualitatively, through descriptive statistics or visual assessment. Collectively, the methods and strategy used to establish the similarity criteria are adequately justified.
The structural and functional studies showed that Fulphila is identical to Neulasta with respect to primary sequence. The comparative data also demonstrate that the biosimilar is highly similar with respect to primary, secondary, and tertiary structures, molecular mass, protein content, potency, biological activity, and low molecular weight proteins. Minor differences were observed with regards to high molecular weight proteins. However, these were detected at very low levels and are not expected to impact the biological activity or pharmacokinetics of Fulphila.
The results of the comparative stability study demonstrate that Fulphila and Neulasta have highly similar degradation pathways, responding similarly to temperature, pH, and oxidative, mechanical, and light stress. No new impurities were identified in Fulphila.
Characterization of the Drug Substance
Detailed characterization studies were performed to provide assurance that pegfilgrastim, the medicinal ingredient in Fulphila, consistently exhibits the desired characteristic structure and biological activity. The identity, quality, safety, purity, potency, strength, and composition of pegfilgrastim were confirmed through validated release and stability tests.
Impurities and degradation products arising from manufacturing or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Manufacturing of pegfilgrastim, the medicinal ingredient in Fulphila, begins with the expression and purification of filgrastim from Escherichia coli cells using recombinant deoxyribonucleic acid (DNA) technology. The E. coli culture is initiated from a single working cell bank vial and allowed to expand through a fed-batch process, which prevents nutrient depletion in the culture medium.
At the end of the fermentation process, the cell culture is harvested, and the cells are lysed to retrieve filgrastim. Filgrastim expressed within the E. coli cells forms aggregates known as inclusion bodies, which are isolated, washed, and solubilized. The purification of filgrastim and its restoration to a biologically active configuration are accomplished through a series of steps including refolding of the protein, acid precipitation, and purification through ion exchange chromatography and hydrophobic interaction chromatography.
Pegfilgrastim is produced through the addition of a methoxy polyethylene glycol (mPEG) moiety to filgrastim, a process known as PEGylation. This results in reduced renal clearance and an extended half-life, prolonging the pharmacological effect of pegfilgrastim relative to filgrastim. The newly created pegfilgrastim is purified through cation exchange chromatography.
To produce the drug product, the purified pegfilgrastim (the drug substance) is diluted to 10 mg/mL with a formulation buffer. The solution is purified through sterile filtration, and single-use syringes are filled with the appropriate volume.
The manufacturing process is considered to be adequately controlled within justified limits. No changes were made to the manufacturing process or equipment throughout development.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
All raw materials used to manufacture the drug substance and the drug product are sourced from qualified vendors and meet the appropriate specifications. Materials of biological origin involved in the manufacture of the cell banks, drug substance, and drug product are free of components of animal origin. They do not carry the risk of contamination with transmissible spongiform encephalopathy (TSE) or bovine spongiform encephalopathy (BSE) agents.
Process validation for manufacturing of the drug substance and drug product involved monitoring of the process parameters, in-process testing, and release testing. All process parameters were within the target range, and the results of in-process and release testing complied with established acceptable criteria.
Each lot of Fulphila drug product is tested for identity, quality, safety, potency, purity, strength, and composition. The established test specifications and validated analytical test methods are considered acceptable.
Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing results support the consistency of the manufacturing process and the suitability of the assays for their intended purposes.
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. The proposed 36-month shelf life at 5 ±3ºC for Fulphila is considered acceptable when the product is protected from light.
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.
Facilities and Equipment
An on-site evaluation (OSE) was essential to the review of the submission for Fulphila, as one had not previously been conducted for the manufacturing facilities involved. There were significant ambiguities in the information that were crucial to the completion of the quality review, which could best be resolved by a team on-site.
The OSE could not be carried out in the first review cycle due to scheduling issues. Therefore, it was completed during the second review cycle, following the issuance of a Notice of Deficiency (NOD) and the sponsor's response to the NOD. The OSE was performed while the facility was actively manufacturing Fulphila, and allowed for observation of the control strategy and critical steps of the manufacturing process. The facility was assigned a compliant rating, and the identified issues are considered resolved.
The Chemistry and Manufacturing information submitted for Fulphila has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. The manufacturing facility was found to be able to reliably manufacture the drug substance or the drug product to an acceptable standard. Additionally, a suitable control strategy is in place to verify that the quality of the final product is acceptable for release.
Adventitious Agents Safety Evaluation
The master and working cell banks from which E. coli cells were sourced have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.
Controls have been incorporated throughout the drug substance and drug product production processes to detect and prevent microbial contamination. Materials of biological origin involved in the manufacture of the cell banks, drug substance, and drug product do not contain components of animal origin. They do not carry the risk of contamination with transmissible spongiform encephalopathy (TSE) or bovine spongiform encephalopathy (BSE) agents. The sponsor has also submitted documentation for various chemicals and media used in the manufacture of Fulphila, confirming that these materials do not carry the risk of transmitting TSE or BSE.
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 non-clinical database submitted for Fulphila was in compliance with the requirements for non-clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. A pharmacodynamic study in neutropenic rats demonstrated that treatment with Fulphila resulted in similar increases in the number of leukocytes and in the absolute neutrophil count as those observed for the reference product, Neulasta. In addition, the comparable toxicity study showed that Fulphila and Neulasta are generally comparable.
Histopathology analyses revealed enlarged spleens (splenomegaly) in rats and cynomolgus monkeys following repeat-dose studies with Neulasta. This is consistent with post-market reports, which identified splenic rupture as a risk of treatment with pegfilgrastim and its parent compound, filgrastim. Accordingly, enlarged spleen and splenic rupture have been listed in a Serious Warnings and Precautions box in both the Neulasta and Fulphila Product Monographs.
The developmental and reproductive toxicity of pegfilgrastim was studied in pregnant rats and rabbits. In pregnant rabbits, adverse events were observed in response to doses as low as 50 µg/kg pegfilgrastim every other day. An increased incidence of spontaneous abortions was observed following administration of 200 µg/kg or 250 µg/kg pegfilgrastim to pregnant rabbits every other day during the period of organogenesis. In pregnant rats, very low levels of pegfilgrastim were able to cross the placental barrier. Patients are therefore advised to consult a healthcare professional before taking Fulphila if they are pregnant, planning to become pregnant, or breastfeeding.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Fulphila Product Monograph. Considering the intended use of Fulphila, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Fulphila Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Clinical basis for decision
The demonstration of similarity between the biosimilar and its reference biologic drug enables the biosimilar assessment to rely on the safety and efficacy information of the reference biologic drug in the indication authorized.
For biosimilars, 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 degree of similarity at the quality level determines 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.
Comparative Pharmacokinetic and Pharmacodynamic Studies
Pegfilgrastim, a granulocyte colony-stimulating factor, binds to specific receptors on hematopoietic cells to promote their proliferation and differentiation into various types of granulocytes (a type of white blood cell). This elevates the level of granulocytes in the blood, counteracting the effects of febrile neutropenia resulting from treatment with myelosuppressive antineoplastic drugs.
A comparative bioavailability study (MYL-1401H-1001) was conducted in healthy adult volunteers (aged 18-65 years) to evaluate the pharmacokinetic, pharmacodynamic, and safety profiles of Fulphila, Neulasta licensed in the European Union (EU-Neulasta), and Neulasta licensed in the United States (US-Neulasta). Each subject received a 2 mg subcutaneous injection of Fulphila, EU-Neulasta, and US-Neulasta in three distinct periods, separated by a washout period lasting at least four weeks before the next drug was administered. The primary pharmacokinetic endpoints were the area under the concentration-time curve (AUC0-inf) of pegfilgrastim, and the maximum plasma concentration of pegfilgrastim (Cmax). The primary pharmacodynamic endpoints were the absolute neutrophil count (ANC) above the baseline level and the ANC at the Cmax. Pairwise comparisons of the collected data (Fulphila vs. EU-Neulasta, Fulphila vs. U-Neulasta, EU-Neulasta vs. US-Neulasta) indicate that the pharmacokinetic, pharmacodynamic, and safety profiles of the three drugs are similar to one another. No clinically meaningful differences were detected between the biosimilar and the reference biologic drug.
For further details, please refer to the Fulphila Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Clinical Efficacy and Safety
The comparative clinical efficacy and safety of Fulphila and its reference biologic drug Neulasta were evaluated in 194 patients with Stage II/III breast cancer receiving six cycles of a chemotherapy regimen of docetaxel, doxorubicin and cyclophosphamide (i.e., TAC regimen) as neoadjuvant or adjuvant chemotherapy (Study MYL-1401H-3001). Patients were randomized to one of two treatment groups in a 2:1 ratio, to receive either Fulphila or EU-Neulasta. Patients in each group received a 6 mg subcutaneous injection of their assigned drug on Day 2 of each chemotherapy cycle. The study consisted of an 18-week treatment period and a six-week follow-up period, for a total duration of 24 weeks.
A post hoc analysis of the study data showed no clinically meaningful differences between Fulphila and Neulasta relating to the duration of severe neutropenia in the patients. However, this analysis of efficacy is considered exploratory as it was performed after the study ended. Therefore, its results were not included in the Fulphila Product Monograph.
The types and frequencies of adverse events reported in this study for Fulphila and Neulasta are consistent with the known safety profile of Neulasta. The most frequently reported treatment-emergent adverse events (TEAEs) were skin and subcutaneous disorders, musculoskeletal and connective tissue disorders, and gastrointestinal disorders. The majority of reported TEAEs were resolved during the course of the study. In the group receiving Fulphila, four patients discontinued the study due to TEAEs (erysipelas, venous thrombosis, abnormal liver function tests, and pneumonitis), and two patients discontinued treatment with the study medication due to TEAEs (influenza and increased alanine aminotransferase [ALT] enzyme). Adverse events leading to these discontinuations were determined to be unrelated to the study medication. No discontinuations occurred in the group receiving Neulasta.
Bone pain is a known effect of treatment with pegfilgrastim, and was the most frequently reported TEAE which was considered related to the study medication. Most reports were for Grade 1 or 2 bone pain. Grade 3 bone pain was reported in three patients, and all three cases were resolved at the time of data analysis.
Eight patients receiving Fulphila (8/127 or 6.3%) and one patient receiving Neulasta (1/67 or 1.5%) experienced serious adverse events during the study. Seven of these patients experienced febrile neutropenia. Six of the seven patients received Fulphila (6/127, or 4.7%), and one received Neulasta (1/67, or 1.5%). All cases of febrile neutropenia lasted less than five days. There were no infections or cases of sepsis observed in parallel, and all cases resolved without the need for rescue therapy. Other serious adverse events were reported in two patients receiving Fulphila. Erysipelas was reported in one patient, and hypokalemia and anemia were reported in another patient. All serious adverse events reported in this study were determined to be unrelated to the study medication.
A low incidence of treatment-emergent anti-drug antibodies (ADAs) was observed in both treatment groups (0.8% in the Fulphila group, and 3% in the Neulasta group). None of the positive sera tested positive for neutralizing antibodies.
As with Neulasta, the major identified safety concerns for Fulphila include the risk of splenic rupture, and the risk of severe sickle cell crises in patients with sickle cell trait or sickle cell disease. These concerns have been associated with pegfilgrastim and its parent compound, filgrastim, and were detected post-market in patients who received Neulasta. Splenic rupture and severe sickle cell crises have been highlighted in a Serious Warnings and Precautions box in the Fulphila and Neulasta Product Monographs.
Overall, the safety profile of Fulphila is considered to be comparable to that which has been established for the reference biologic drug, Neulasta. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warning and Precautions section of the Fulphila Product Monograph, as they are in the Neulasta Product Monograph.
For more information, refer to the Fulphila Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Immunogenicity
The immunogenicity of Fulphila was compared to that of US-Neulasta in Study MYL-1401H-1002, which was conducted in 50 healthy adult volunteers (aged 19-65 years). Subjects were randomized to one of two treatment groups in a 1:1 ratio, and received two 6 mg subcutaneous injections of either Fulphila or US-Neulasta, administered four weeks apart.
For each administration period, plasma concentration of ADAs was measured on the day before the dose was administered, as well as seven, 14, and 21 days after administration. The concentration of ADAs was also measured 28 days after the administration of the second dose. Samples which tested positive for ADAs were further examined for the presence of neutralizing antibodies.
In both treatment groups, the number of subjects testing positive for ADAs at any time was 8/25 (32%), and ADA titre was low (up to 30). Treatment-emergent neutralizing antibodies were detected in one subject after receiving the first dose of US-Neulasta. The comparative immunogenicity study did not reveal any clinically meaningful differences in immunogenicity between the biosimilar and the reference biologic drug.
Indications
Fulphila is considered to be biosimilar to Neulasta, the reference biologic drug. Neulasta is authorized and marketed in Canada for decreasing the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive antineoplastic drugs.
Within this drug submission, the sponsor requested the authorization of Fulphila for the same indication currently authorized for Neulasta.
Similarity between Fulphila and Neulasta 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 biosimilar assessment to rely on the safety and efficacy information of the reference biologic drug. These data support the authorization of the same indication for the biosimilar drug.
The indication has been authorized for Fulphila on the basis of demonstrated similarity to Neulasta with respect to structural and functional attributes, mechanism of action, pharmacological effect, pathophysiological mechanisms of the conditions involved, safety profile, dosage regimen, and clinical experience with the reference biologic drug.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| FULPHILA | 02484153 | BIOSIMILAR COLLABORATIONS IRELAND LIMITED | PEGFILGRASTIM 10 MG / ML |