Summary Basis of Decision for Jivi

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 Jivi is located below.

Recent Activity for Jivi

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.

The following table describes post-authorization activity for Jivi, a product which contains the medicinal ingredient antihemophilic factor (recombinant, B-domain deleted, PEGylated). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

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

Updated: 2023-10-12

Drug Identification Number (DIN):

  • DIN 02481758 - antihemophilic factor 250 IU/vial, powder for solution, intravenous administration
  • DIN 02481766 - antihemophilic factor 500 IU/vial, powder for solution, intravenous administration
  • DIN 02481774 - antihemophilic factor 1,000 IU/vial, powder for solution, intravenous administration
  • DIN 02481782 - antihemophilic factor 2,000 IU/vial, powder for solution, intravenous administration
  • DIN 02481790 - antihemophilic factor 3,000 IU/vial, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 265962

2022-07-11

Issued NOC 2023-08-03

Submission filed as a Level II – Supplement (Safety) to update the PM with long-term safety and efficacy data and to migrate the PM to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions; Clinical Pharmacology; Clinical Trials; and Non-Clinical Toxicology sections of the PM. An NOC was issued.

NC # 269587

2022-11-09

Issued NOL 2023-01-27

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

NC # 268458

2022-10-03

Issued NOL 2022-12-09

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for an alternate primary container closure system. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 258302

2021-11-03

Issued NOL 2022-02-15

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the drug substance and drug product release or shelf‐life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02481766) market notification

Not applicable

Date of first sale: 2020-04-08

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

Drug product (DINs 02481774, 02481782) market notification

Not applicable

Date of first sale: 2020-03-11

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

Drug product (DIN 02481790) market notification

Not applicable

Date of first sale: 2020-01-27

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 210935

2017-11-03

Issued NOC 2018-10-18

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Jivi

Date SBD issued: 2019-03-15

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

Antihemophilic factor (recombinant, B-domain deleted, PEGylated)

Drug Identification Number (DIN):

  • DIN 02481758 - 250 IU/vial, powder for solution, intravenous administration
  • DIN 02481766 - 500 IU/vial, powder for solution, intravenous administration
  • DIN 02481774 - 1,000 IU/vial, powder for solution, intravenous administration
  • DIN 02481782 - 2,000 IU/vial, powder for solution, intravenous administration
  • DIN 02481790 - 3,000 IU/vial, powder for solution, intravenous administration

Bayer Inc.

New Drug Submission Control Number: 210935

 

On October 18, 2018, Health Canada issued a Notice of Compliance to Bayer Inc. for the drug product Jivi.

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 Jivi is considered favourable for use in previously treated adults and adolescents (≥12 years of age) with hemophilia A (congenital factor VIII deficiency) for:

  • Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes
  • Control and prevention of episodic bleeding
  • Perioperative management of bleeding (surgical prophylaxis)

Jivi does not contain von Willebrand factor and is not indicated for the treatment of von Willebrand disease. The safety and efficacy of Jivi have not been studied in previously untreated patients.

 

1 What was approved?

 

Jivi is a recombinant, B-domain deleted, PEGylated antihemophilic factor. It was authorized for use in previously treated adults and adolescents (12 years of age and over) with hemophilia A (congenital factor VIII deficiency) for:

  • Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes
  • Control and prevention of episodic bleeding
  • Perioperative management of bleeding (surgical prophylaxis)

The safety and efficacy of Jivi have not been established in pediatric patients younger than 12 years of age. It is not indicated for use in children younger than 12 years of age due to a greater risk for hypersensitivity reactions.

Clinical studies of Jivi did not include subjects aged 65 years and over. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Jivi is contraindicated in patients who have had prior anaphylactic reaction to the drug or its components, or to mouse or hamster protein.

Jivi 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.

Jivi (250, 500, 1,000, 2,000, or 3,000 IU/vial antihemophilic factor [recombinant, B-domain deleted, PEGylated]) is presented as powder for solution. In addition to the medicinal ingredient, the powder contains calcium chloride, glycine, histidine, polysorbate 80, sodium chloride and sucrose.

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 Jivi Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Jivi approved?

 

Health Canada considers that the benefit-risk profile of Jivi is favourable for use in previously treated adults and adolescents (12 years of age and older) with hemophilia A (congenital factor VIII deficiency) for:

  • Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes
  • Control and prevention of episodic bleeding
  • Perioperative management of bleeding (surgical prophylaxis)

Jivi does not contain von Willebrand factor and is not indicated for the treatment of von Willebrand disease. The safety and efficacy of Jivi have not been studied in previously untreated patients.

Hemophilia A is an X-linked recessive disease characterized by deficiency of coagulation factor VIII (FVIII) that results in bleeding complications. Bleeding tends to occur in joints (where recurrent bleeds lead to hemophilic arthropathy), muscles, oropharynx, gastrointestinal tract, genitourinary tract, and rarely, brain. The severity of the disease is defined according to the patient's FVIII level, which is an important predictor of clinical manifestations.

Standard treatment for hemophilia A patients is the replacement of the missing protein by infusion of either plasma-derived FVIII or recombinant FVIII. This increases the plasma concentrations of FVIII, thereby enabling a temporary correction of the factor deficiency and reversal of the bleeding tendencies. Typical treatment regimens have been either on-demand therapy (given when a bleed occurs) or regularly scheduled prophylactic infusions two to four times per week.

The drug substance of Jivi is antihemophilic factor (recombinant, B-domain deleted, PEGylated), also known as damoctocog alfa pegol. Functional characterization of Jivi shows comparable mechanism of action to that of a recombinant FVIII product with an extended plasma half-life. As a result, Jivi is longer-acting and was developed for intravenous FVIII replacement therapy or prophylaxis given on a less frequent basis than standard hemophilia A regimens.

Jivi has been shown to be efficacious in patients with severe hemophilia A. The market authorization was primarily based on data derived from an open-label, uncontrolled, partially randomized Phase II/III study (PROTECT VIII) conducted in male adolescent and adult (aged 12 to 65 years) patients with severe hemophilia (defined as coagulation FVIII activity level of <1%). These patients had been previously treated with other FVIII products for ≥150 exposure days and had no history of FVIII inhibitors. Part A of the study evaluated the efficacy of Jivi for on-demand treatment and routine prophylaxis of bleeding. An optional extension was offered to patients who had completed Part A in order to accumulate at least 100 exposure days to Jivi. Part B evaluated the efficacy of Jivi in the prevention of bleeding during major surgical procedures. The primary efficacy variable was the annualized number of total bleeds (annualized bleeding rate).

Three dosing regimens of Jivi were evaluated in the prophylaxis arm of the study: 30 to 40 IU/kg twice a week, 45 to 60 IU/kg every 5 days, and 60 IU/kg every 7 days. Patients assigned to the every-7-days prophylaxis group experienced bleeding events that caused 26% of these patients to change regimen to a higher frequency of administration as they had a higher mean annualized bleed rate. Accordingly, this dosing regimen is not specifically recommended and has not been included in the Jivi Product Monograph. The recommended initial regimen is 30-40 IU/kg twice weekly. Based on the bleeding episodes, the regimen may be adjusted to 45-60 IU/kg every 5 days. A regimen may be further individually adjusted to more or less frequent dosing.

The safety of Jivi was evaluated in 221 patients with hemophilia A. Known safety concerns associated with the use of all FVIII products include the risks of hypersensitivity reactions and development of neutralizing antibodies (inhibitors) to FVIII. In addition, a new risk reported during clinical studies with Jivi is an immune response to polyethylene glycol (PEG). The immune response to PEG was characterized by the development of immunoglobulin M (IgM) antibodies directed against the PEG, resulting in loss of efficacy of the drug and decreased FVIII recovery. Moreover, this immune response was accompanied by hypersensitivity reactions in some patients and occurred mainly in children below 6 years of age. In approximately half of the cases, the affected patients were found to have anti-PEG IgM antibodies prior to first exposure to the study drug. The aforementioned safety concerns have been addressed in the Warnings and Precautions section of the Jivi Product Monograph.

In completed clinical studies with 73 pediatric previously treated patients with severe hemophilia A, adverse reactions due to an immune response to PEG were observed in some children who were younger than 6 years of age. In 23% of patients in this age group, loss of drug effect due to neutralizing anti-PEG IgM antibodies occurred during the first 4 exposure days. Furthermore, in 7% of patients younger than 6 years of age, the loss of drug effect was concurrent with hypersensitivity reactions. In view of these findings, the sponsor has requested market authorization of Jivi only for individuals 12 years of age and older.

In clinical trials in previously treated patients 12 years of age and older, the most frequently reported (≥5%) adverse reactions were headache, cough, nausea, and pyrexia.

A Risk Management Plan (RMP) for Jivi was submitted by Bayer Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. Health Canada requested inclusion of pediatric off-label use (for all children under 12 years of age) as an important potential risk in the next update of the RMP (accompanied with specific messages for educational materials to inform healthcare providers of the age restriction regarding the use of Jivi).

The submitted inner and outer labels, package insert and Patient Medication Information section of the Jivi Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Jivi was accepted.

Based on the non-clinical data and clinical studies, Jivi has an acceptable safety profile for 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 Jivi Product Monograph to address the identified safety concerns.

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

 

3 What steps led to the approval of Jivi?

 

Submission Milestones: Jivi

Submission Milestone Date
Pre-submission meeting: 2017-08-10
Submission filed: 2017-11-03
Screening  
Screening Acceptance Letter issued: 2017-12-22
Review  
Review of Risk Management Plan complete: 2018-07-05
Quality Evaluation complete: 2018-10-16
Clinical Evaluation complete: 2018-10-17
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2018-10-17
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2018-10-18

 

The Canadian regulatory decision on the quality, non-clinical and clinical review of Jivi was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and 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?

 

As part of the marketing authorization for Jivi, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):

  • Inclusion of pediatric off-label use (for all children under 12 years of age) as an important potential risk in the next update of the Risk Management Plan.
  • Submission of Periodic Benefit-Risk Evaluation Reports every 6 months for the first three years following market authorization. These reports will include a dedicated review of pediatric off-label use.

 

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

 

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.

The PAAT for Jivi is found above.

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

 

6 What other information is available about drugs?

 

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

 

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

 

Clinical Pharmacology

The medicinal ingredient in Jivi, a PEGylated form of recombinant B-domain deleted antihemophilic factor, temporarily replaces the missing endogenous coagulation factor VIII (FVIII) needed for effective prevention and control of bleeding episodes in congenital hemophilia A patients. The PEGylation within the A3 domain reduces clearance of FVIII, thereby resulting in an extended half-life and increased area under the concentration-time curve (AUC).

The pharmacokinetics of Jivi was evaluated in previously treated patients aged 18 years of age and older with severe hemophilia A following single-dose administration of 25 IU/kg and 60 IU/kg, and multiple-dose administration of 25 IU/kg twice weekly and 60 IU/kg once weekly for 8 weeks. The pharmacokinetic parameters were based on plasma factor VIII activity measured by the chromogenic substrate and one-stage clotting assays.

The pharmacokinetic profile of Jivi obtained at Week 8, after repeated dosing, was consistent with the pharmacokinetic profile obtained after the first dose. Dose-proportional increases in the dose-normalized area under the curve (AUCnorm) and dose-normalized maximum plasma concentration (Cmax, norm) were observed between the doses of 25 and 60 IU/kg. A pharmacokinetic profile was also obtained in the Phase II/III study (PROTECT VIII, described in the Clinical Efficacy section) in 22 patients after the first dose of 60 IU/kg and in 16 patients after 6 months of prophylaxis treatment with Jivi.

Based on data from Phase I and Phase II/III studies in patients 12 to 65 years of age given 60 IU/kg of Jivi once weekly, Jivi has a prolonged mean half-life of 17.4 hours (measured by one-stage assay) and 17.9 hours (measured by chromogenic substrate assay).

The clinical pharmacology data support the use of Jivi for the recommended indication.

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

Clinical Efficacy

The efficacy of Jivi was evaluated in an open-label, uncontrolled, partially randomized Phase II/III study (PROTECT VIII) conducted in male adolescent and adult (aged 12 to 65 years) patients with severe hemophilia (defined as coagulation factor VIII [FVIII] activity level of <1%). All patients had been previously treated with other FVIII products for ≥150 exposure days and had no history of FVIII inhibitors. Part A of the study evaluated the efficacy of Jivi for on-demand treatment and routine prophylaxis of bleeding. An optional extension was offered to patients who had completed Part A to accumulate at least 100 exposure days to Jivi. Part B evaluated the efficacy of Jivi in the prevention of bleeding during major surgical procedures. The primary efficacy variable was the annualized number of total bleeds (annualized bleeding rate).

Part A enrolled 134 patients, 126 of whom completed the study (on-demand arm, number of patients [n] = 18; prophylaxis arm, n = 108). All patients in the prophylaxis arm were treated with twice-weekly infusions of Jivi 25 IU/kg for 10 weeks (the run-in period) to identify patients with lower bleeding risk. Patients who experienced one or no breakthrough bleed (defined as joint or muscle bleeds and no identified trauma) during the run-in period were randomized 1:1 to receive Jivi every 5 days (starting at 45 IU/kg) or every 7 days (a fixed dose of 60 IU/kg) for additional 26 weeks (Week 10 to 36, the main efficacy period). Patients who had more than one breakthrough bleed during the run-in period were not eligible for randomization. These patients continued with an increased dose of 30 to 40 IU/kg twice a week for the additional 26 weeks of the study. Therefore, three dosing regimens of Jivi were evaluated in the prophylaxis arm: 30 to 40 IU/kg twice a week, 45 to 60 IU/kg every 5 days, and 60 IU/kg every 7 days.

During the main efficacy period (Week 10-36), the majority (99/110 [90%]) of patients did not change their treatment regimens. All patients assigned to the every-5-days regimen (43/43) or twice-a-week regimen (24/24) remained in their respective treatment arm until Week 36. Patients assigned to the every-7-days regimen experienced bleeding events that caused 26% of these patients to change treatment regimen to a higher frequency of administration as they had a higher mean annualized bleed rate. Accordingly, this dosing regimen is not specifically recommended and has not been included in the Jivi Product Monograph. The recommended initial regimen for Jivi is 30 to 40 IU/kg twice weekly. Based on the bleeding profile, the patients' regimen may be adjusted from 45 to 60 IU/kg every 5 days. A regimen may be further individually adjusted to more or less frequent dosing.

A total of 386 bleeding episodes were treated with Jivi from Week 0 to Week 36 in the on-demand arm and 316 in all prophylaxis groups combined. The majority of bleeds were successfully treated with one or two infusions in 90.6% of the patients in both the on-demand and prophylaxis groups.

According to interim data from the ongoing Part A extension study, the overall mean annualized bleeding rate was 32.4 for the on-demand group and 3.76 for the prophylaxis group. The overall median annualized bleeding rate for Part A extension was 32.96 for the on-demand group and 1.17 for the prophylaxis group. The majority of bleeds were successfully treated with one or two infusions (on-demand group: 92.4%; prophylaxis group: 92.1%).

In part B, 14 patients underwent 17 major surgeries using Jivi for hemostasis. In the extension study, three patients underwent three major surgeries. For all 20 major surgeries, treatment with Jivi provided "good" or "excellent" hemostatic control. The pre-surgery doses ranged between 2,500 and 5,000 IU. The median total dose per surgery was 16,250 IU (218.8 IU/kg), with a median of 35.1 IU/kg/infusion.

Overall, Jivi demonstrated efficacy in adolescent and adult patients (12 years of age and older) with severe hemophilia for on-demand treatment to control bleeding episodes, routine prophylaxis, and perioperative management of bleeding.

Indication

The New Drug Submission for Jivi was filed by the sponsor with the following indication:

  • Jivi (Antihemophilic Factor [Recombinant], PEGylated) is indicated in previously treated adults and adolescents (≥12 years of age) with hemophilia A (congenital factor VIII deficiency) for:
    • Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes
    • Control and prevention of episodic bleeding
    • Perioperative management of bleeding (surgical prophylaxis)

To ensure safe and effective use of the product, Health Canada approved the following indication:

  • Jivi (Antihemophilic Factor [Recombinant, B-domain deleted, PEGylated]) is indicated in previously treated adults and adolescents (≥12 years of age) with hemophilia A (congenital Factor VIII deficiency) for:
    • Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes
    • Control and prevention of episodic bleeding
    • Perioperative management of bleeding (surgical prophylaxis)


    Jivi does not contain von Willebrand factor and is not indicated for the treatment of von Willebrand disease.

    Safety and efficacy for previously untreated patients have not been studied.

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

Clinical Safety

The safety of Jivi was evaluated in 221 patients with hemophilia A (in three studies, including the Phase II/III study PROTECT VIII, which is described in the Clinical Efficacy section). Patients who received Jivi for perioperative management (number of patients [n] = 17) with treatment period of one to three weeks were excluded from pooled safety analysis. However, these patients were included in the analysis of factor VIII (FVIII) inhibitor development. The median number of exposure days for adults and adolescents (12 years of age and older) was 131 exposure days (range: 1-309) per patient and the median number of exposure days for patients younger than 12 years of age was 53 exposure days (range: 1-68) per patient.

In addition to the risks of hypersensitivity reactions and development of neutralizing antibodies (inhibitors) to FVIII, which are known safety concerns associated with the use of all FVIII products, a new risk reported during clinical studies with Jivi is an immune response to polyethylene glycol (PEG). The immune response to PEG was characterized by the development of immunoglobulin M (IgM) antibodies directed against the PEG, resulting in loss of efficacy of the drug and decreased FVIII recovery, and was accompanied by hypersensitivity reactions in some patients. In approximately half of the cases, the affected patients were found to have anti-PEG IgM antibodies prior to first exposure to the study drug. The aforementioned safety concerns have been conveyed in the Warnings and Precautions section of the Jivi Product Monograph.

In completed clinical studies with 73 pediatric previously treated patients with severe hemophilia A (44 patients younger than 6 years of age; 29 patients aged 6 to younger than 12 years), adverse reactions due to an immune response to PEG were observed in some children who were younger than 6 years of age. In 23% of patients in this age group, loss of drug effect due to neutralizing anti-PEG IgM antibodies occurred during the first 4 exposure days. Furthermore, in 7% of patients younger than 6 years of age, the loss of drug effect was concurrent with hypersensitivity reactions. In view of these findings, the sponsor has requested market authorization of Jivi only for individuals 12 years of age and older.

Development of neutralizing antibodies (inhibitors) to FVIII is a known complication in the management of individuals with hemophilia A. The neutralizing antibodies are usually IgG immunoglobulins that inhibit the FVIII procoagulant activity. They are quantified in Bethesda Units (BU) per mL of plasma using the modified Bethesda assay. Appropriate monitoring and laboratory tests are recommended in the Jivi Product Monograph.

There was no development of treatment-related FVIII inhibitors in adult, adolescent and pediatric previously treated patients. Two patients who had low-titer FVIII antibodies prior to surgery had successful surgical outcomes with rising titers following exposure to the study drug. Due to the presence of pre-existing FVIII antibodies, the observed change in antibody titer was not considered related to the study drug. In the pediatric age groups, no patient developed FVIII inhibitor titers greater than the prespecified threshold of 0.6 BU/mL.

In clinical trials in previously treated patients 12 years of age and older, the most frequently reported (≥5%) adverse reactions were headache, cough, nausea, and pyrexia.

Overall, the safety profile of Jivi is considered acceptable for previously treated adolescent and adult patients (12 years of age and older) with severe hemophilia. Appropriate warnings and precautions are in place in the approved Jivi Product Monograph to address the identified safety concerns. Due to the greater risk of hypersensitivity reactions Jivi is not indicated for use in children younger than 12 years of age. The sponsor has outlined a communication plan to inform prescribers about the age restriction associated with Jivi.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Jivi is a B-domain deleted recombinant human coagulation factor VIII (FVIII) molecule which is site-specifically conjugated with a 60 kDa polyethylene glycol (PEG-60) to prolong its half-life in circulation while retaining full biological coagulant activity.

The non-clinical development program of Jivi evaluated its pharmacological, safety pharmacology, pharmacokinetic/toxicokinetic, and toxicological properties. Although the PEG-60 content in a human dose of Jivi is very low (approximately 2-4 µg/kg in the dose of 60 IU/kg, resulting in a maximal amount of 8 µg/kg/week), supplementary toxicology and pharmacokinetic/biodistribution studies were conducted to separately evaluate the safety of the PEG-60 component used in Jivi.

Single-dose systemic toxicity studies in healthy adult male rats and rabbits following intravenous administration of Jivi did not result in any adverse findings and there was no evidence of thrombus formation. The no-observed-adverse-effect level (NOAEL) of Jivi was the maximum dose level administered, i.e., 4,000 IU/kg (67 times the recommended maximum prophylactic clinical dose of 60 IU/kg). Repeat-dose systemic toxicity studies in healthy adult male rats and rabbits intravenously administered with Jivi every other day over two weeks did not identify any significant adverse findings. The NOAEL of Jivi was the maximum dose level administered, i.e., 2,250 IU/kg/administration (37.5 times the recommended maximum prophylactic clinical dose). No adverse effects on the coagulation system or any organ system were observed. Notably, the sponsor limited the duration of dosing to two weeks due to the potential development of neutralizing antibodies to the human protein and subsequent loss of its activity. In addition, repeat intravenous dosing (twice weekly for a total of five injections) of up to 1,000 IU/kg/administration of Jivi in healthy neonatal male rats did not result in adverse findings.

However, due to the limited dosing interval (two to four consecutive weeks) of these studies, characterization of the long-term safety profile of Jivi, including the unknown risks of potential PEG accumulation in tissues and fluids (i.e., cerebrospinal fluid), was lacking. The sponsor was therefore requested (by the United States Food and Drug Administration) to evaluate the safety profile of Jivi in a more comprehensive manner by conducting a long-term repeat-dose safety study in immune-deficient rodents to characterize the PEG tissue distribution/accumulation profile and any adverse findings following long-term repeat dosing with Jivi. An audited interim report of this study has been provided to Health Canada and the final audited report is expected in the first quarter of 2019. Immune-deficient male rats were intravenously injected with up to 1,200 IU/kg/administration of Jivi twice weekly for 26 weeks. Subgroups were sacrificed at 13 and 26 weeks. Remaining animals will be sacrificed at 52 weeks, following a 26-week recovery period. Based on the in-life data for all animals up to 26 weeks, and the histopathology data for the animals sacrificed at 13 and 26 weeks, no adverse clinical signs, clinical pathology, or organ histopathology findings were observed. In addition, there was no evidence of tissue vacuolation in any tissue examined and no presence of PEG in the brain (including the choroid plexus), kidney, spleen, or cerebrospinal fluid.

In vitro complement studies with sera obtained from 20 healthy human male donors with or without pre-existing anti-PEG antibodies, showed that Jivi did not induce complement activation (i.e., it did not increase the levels of the complement anaphylatoxin C3a and the soluble terminal complement complex sC5b-9). In an in vitro human tissue cross-reactivity study, Jivi showed no difference in tissue binding in comparison to Kogenate FS (a non-PEGylated recombinant FVIII).

Genotoxicity, carcinogenicity, and developmental and reproductive toxicity studies were not conducted with Jivi. Genotoxicity studies conducted with the PEG component of Jivi showed no indication of genotoxicity.

The safety of the PEG-60 component of Jivi was evaluated in single-dose and repeat-dose (up to 4 weeks of dosing) systemic toxicity studies conducted in healthy adult male rats and rabbits, and a repeat-dose (twice weekly up to 4 weeks) systemic toxicity study in healthy neonatal male rats. The studies employed dose levels that were significantly higher than the amount of PEG-60 (0.002-0.004 mg/kg) present in a single administration of 60 IU/kg of Jivi. There were no significant adverse findings. No immunohistochemical assessment of PEG was performed for the brain or any other organs, tissues, or body fluids. The cellular vacuolation that was observed sporadically in some organs and tissues (testes, kidney, pancreas, parotid glands, choroid plexus, stomach and adrenal cortex of control- and PEG-60-injected animals) was considered incidental by the pathologist.

The non-clinical data support the use of Jivi for the specified indication. In view of the intended use of Jivi, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Quality Basis for Decision

 

Characterization of the Drug Substance

The drug substance of Jivi is antihemophilic factor (recombinant, B-domain deleted, PEGylated), also known as damoctocog alfa pegol. This protein is a B-domain deleted recombinant human coagulation factor VIII (BDD-rFVIII) variant which is site-specifically conjugated with 60 kDa branched polyethylene glycol (PEG) within the A3 domain. The A3 domain was selected for conjugation to provide a consistent coagulation activity, high PEGylation efficiency, and to conceal an epitope region for inhibitors. The molecular weight of the protein is approximately 234 kDa.

Detailed characterization studies were performed to provide assurance that the drug substance, antihemophilic factor (recombinant, B-domain deleted, PEGylated), consistently exhibits the desired characteristic structure and biological activity.

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

The active protein (or starting molecule), prior to conjugation with polyethylene glycol, is a recombinant B-domain deleted human coagulation factor VIII (BDD rFVIII) produced by recombinant deoxyribonucleic acid (DNA) technology in Baby Hamster Kidney (BHK) cells. The manufacturing process of Jivi consists of three main processes: cell culture, harvest and isolation; purification and drug substance formulation; and final formulation, filling and freeze-drying. Prior to conjugation with the 60 kDa maleimide PEG moiety, the process intermediate is purified from process- and product-related impurities using a series of chromatography and filtration steps, including 20 nm viral filtration. The mono-PEGylated Jivi active molecule is separated from product-related species by chromatography and then formulated by ultrafiltration. The cell culture, PEGylation, purification process and formulation used in the manufacture of Jivi do not use any additives of human or animal origin.

Full-scale conformance (commercial) lots were manufactured and evaluated to demonstrate that the full-scale manufacturing process is reproducible, can be maintained within established parameters, and consistently produces product that meets in-process limits and release specifications.

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

Process validation data and results obtained in comparability studies demonstrate that the process can reproducibly yield Jivi drug product that is of acceptable quality.

Process monitoring and in-process control parameters proposed are those used for validation and are essentially unchanged from the historical controls used for the Phase III clinical trial material. Overall, acceptable information has been provided regarding the control of the process and the control regime is considered appropriate for this type of product.

The chromogenic potency assay is used to measure the rFVIII activity in release and stability testing. The proposed internal potency reference standard is adequately qualified and the potency is assigned against the World Health Organization (WHO) 8th International Standard for Blood Coagulation Factor VIII:C, Concentrate.

Jivi is presented as a lyophilized powder for reconstitution with water as diluent for intravenous injection. The product is supplied in single-use vials containing dosage strengths of 250, 500, 1,000, 2,000 and 3,000 IU. A diluent syringe prefilled with 2.5 mL Sterile Water for Injection and a vial adapter with a 15 µm filter are included with each single-use vial of Jivi. Jivi is formulated with the following excipients: 59 mg glycine, 27 mg sucrose, 8.4 mg histidine, 4.7 mg sodium chloride, 1.0 mg calcium chloride dihydrate, and 0.216 mg polysorbate 80. The pH of the reconstituted product is 6.6 to 7.0. The specific activity of Jivi is approximately 10,000 IU/mg protein.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and the drug product are validated and considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

A comprehensive list of raw materials identifying the compendial and non-compendial items was provided. No raw materials of direct animal or human origin are used in the drug substance or drug product production. Non-compendial reagents are tested to defined specifications.

The drug substance and drug product release specifications provide adequate control over the physical and chemical identity, purity, impurities, potency, safety, and excipients. Satisfactory validation reports were provided for the key analytical procedures used for release testing of the drug substance and drug product.

Jivi is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

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 at 2ºC to 8ºC for the drug product is considered acceptable. Within this period, the product may be stored at room temperature up to 25ºC for 6 months or at room temperature up to 30ºC for 3 months.

The proposed container closure system for the final product was adequately qualified for use in the drug product manufacturing and long-term storage.

Facilities and Equipment

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

An on-site evaluation of the facility involved in the manufacture and testing of Jivi was not warranted since the facility had been recently evaluated and obtained a satisfactory rating.

Adventitious Agents Safety Evaluation

The manufacturing process of Jivi incorporates adequate control measures to prevent contamination and maintain microbial control.

The raw materials used for manufacturing of the drug substance are not of direct animal or human origin. Some materials of animal or human origin were used during early cell line development prior to the preparation of the accession cell bank.

Control of viral agents is achieved through the dedicated process steps of detergent-mediated inactivation and removal via nanofiltration. Additional viral clearance may occur though the immunoaffinity chromatography and anion-exchange chromatography steps. Successful viral clearance was demonstrated using an acceptable panel of model viruses. The overall virus reduction/inactivation capacity is deemed adequate.

 

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