Summary Basis of Decision for Adynovate

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 Adynovate is located below.

Recent Activity for Adynovate

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Adynovate

Updated: 2023-11-10

The following table describes post-authorization activity for Adynovate, a product which contains the medicinal ingredient antihemophilic Factor VIII (recombinant), 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.

Antihemophilic Factor VIII (Recombinant), PEGylated

250, 500, 750, 1,000, 1,500, 2,000, and 3,000 International Units (IU) per vial, kit, powder for solution, intravenous administration

Drug Identification Number (DIN):

DIN 02459035 - 250 IU/vial, 5 mL diluent

DIN 02459043 - 500 IU/vial, 5 mL diluent

DIN 02459051 - 1,000 IU/vial, 5 mL diluent

DIN 02459078 - 2,000 IU/vial, 5 mL diluent

DIN 02498537 - 250 IU/vial, 2 mL diluent

DIN 02498545 - 500 IU/vial, 2 mL diluent

DIN 02498553 - 750 IU/vial, 2 mL diluent

DIN 02498561 - 750 IU/vial, 5 mL diluent

DIN 02498588 - 1,000 IU/vial, 2 mL diluent

DIN 02498596 - 1,500 IU/vial, 2 mL diluent

DIN 02498618 - 1,500 IU/vial, 5 mL diluent

DIN 02498626 - 3,000 IU/vial, 5 mL diluent

 

Post-Authorization Activity Table (PAAT)

 

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 275133

2023-05-09

Issued NOC 2023-09-19

Submission filed as a Level II – Supplement (Safety) to update safety information in the PM. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 259100

2021-11-29

Issued NOL 2022-03-03

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

SNDS # 259343

2021-12-07

Issued NOC 2022-02-24

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information from studies 261204, 261302, and 261303. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 245031

2020-10-08

Issued NOC 2021-11-05

Submission filed as a Level I – Supplement to update the PM with new safety and efficacy data from studies 261204, 261302, and 261303. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Clinical Trials section of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

Drug product (DIN 02498596) market notification

Not applicable

Date of first sale: 2021-08-27

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 02459078, 02498588, 02498545) market notification

Not applicable

Date of first sale: 2021-08-13

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 02498537) market notification

Not applicable

Date of first sale: 2021-07-16

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 02498626) market notification

Not applicable

Date of first sale: 2021-02-23

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

NDS # 242234

2020-08-04

Issued NOC 2021-01-15

Submission filed to change the name of the drug sponsor from Shire Pharma Canada ULC. to Takeda Canada Inc. and to update the inner and outer labels. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 241946

2020-07-17

Issued NOL 2020-10-26

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in reference standards for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 231976

2019-09-30

Issued NOC 2020-05-01

Submission filed as a Level I – Supplement for the addition of three new strengths (750, 1,500, and 3,000 IU/vial) and a new 2 mL diluent. The submission was reviewed and considered acceptable, and an NOC was issued. New DINs (02498537, 02498545, 02498553, 02498588, 02498596, 02498561, 02498618, and 02498626) were issued. A Regulatory Decision Summary was published.

Drug product (DIN 02459051) market notification

Not applicable

Date of first sale:

2019-03-21

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 02459078) market notification

Not applicable

Date of first sale:

2018-11-21

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 02459043) market notification

Not applicable

Date of first sale:

2018-11-12

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

SNDS # 211971

2017-12-08

Issued NOC

2018-11-21

Submission filed as a Level I – Supplement for an expanded indication: Pediatrics (<12 years of age). The safety and efficacy of Adynovate in routine prophylaxis and the treatment of bleeding episodes were studied in 66 patients under the age of 12. The submission was reviewed and considered acceptable, and an NOC was issued. Regulatory Decision Summary published.

NC # 213799

2018-02-19

Issued NOL

2018-05-11

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

NDS # 214426

2018-03-02

Issued NOC

2018-04-20

Submission filed to change the name of the drug sponsor from Baxalta Canada Corporation to Shire Pharma Canada ULC. An NOC was issued.

Drug product (DINs 02459043, 02459051, 02459078) market notification

Not applicable

Date of first sale:

2018-03-06

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

NC # 209601

2017-09-22

Issued NOL

2017-12-12

Submission filed as a Level II (90 day Notifiable Change (Moderate Quality Changes) to propose two new reference standards. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 208684

2017-08-22

Issued NOC

2017-10-26

Submission filed as a Level I – Supplement to provide a labelling update as requested in a Post-Decision Letter from Health Canada dated November 23, 2016 for NDS # 189709. The submission was reviewed and considered acceptable, and an NOC was issued.

NDS # 189709

2015-12-02

Issued NOC

2016-11-17

Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Adynovate

Date SBD issued: 2016-12-30

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

Antihemophilic Factor VIII (Recombinant), PEGylated
250 IU/vial, 500 IU/vial, 1,000 IU/vial, and 2,000 IU/vial, kit, Powder for solution, intravenous

Drug Identification Number (DIN):

  • DIN 02459035 - 250 IU/vial
  • DIN 02459043 - 500 IU/vial
  • DIN 02459051 - 1,000 IU/vial
  • DIN 02459078 - 2,000 IU/vial

Baxalta Canada Corporation

New Drug Submission Control Number: 189709

 

On November 17, 2016, Health Canada issued a Notice of Compliance to Baxalta Canada Corporation for the drug product, Adynovate.

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 Adynovate is favourable for patients (≥12 years) with hemophilia A (congenital Factor VIII deficiency) for:

  • Control and prevention of bleeding episodes
  • Prophylaxis to prevent or reduce the frequency of bleeding episodes
  • Perioperative management

 

1 What was approved?

 

Adynovate, an antihemorrhagic blood coagulation Factor VIII, was authorized for patients (≥12 years) with hemophilia A (congenital Factor VIII deficiency) for:

  • Control and prevention of bleeding episodes
  • Prophylaxis to prevent or reduce the frequency of bleeding episodes
  • Perioperative management

Adynovate is a human recombinant Factor VIII (rFVIII) conjugated with a polyethylene glycol (PEG) reagent. More specifically, the rFVIII used for the conjugation is the active substance of Baxalta's medicinal product Advate approved by Health Canada in 2006. Advate is a full-length human rFVIII. The PEG moiety is conjugated to the Advate molecule to increase the plasma half-life of the product.

Adynovate is not indicated for the treatment of von Willebrand disease.

Treatment should be administered under the supervision of a qualified health professional who is experienced in the use of coagulation agents and in the management of bleeding disorders.

Clinical studies of Adynovate did not include patients aged 65 and over.

The safety, efficacy, or pharmacokinetic profiles of Adynovate have not been established in pediatric patients less than 12 years old or in previously untreated patients (PUPs).

Adynovate is contraindicated for patients who have had prior anaphylactic reaction to Adynovate, to the parent molecule Advate, mouse or hamster protein, or excipients of Adynovate (tris, calcium chloride, mannitol, sodium chloride, trehalose dehydrate, glutathione, histidine, and polysorbate 80). Adynovate was approved for use under the conditions stated in the Adynovate Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Adynovate (250 IU/vial, 500 IU/vial, 1,000 IU/vial, and 2,000 IU/vial, PEGylated recombinant human Factor VIII) is presented as a powder for solution. Adynovate is formulated as a sterile, non-pyrogenic, preservative-free, white to off-white powder for intravenous injection and is supplied in a single-use vial. Adynovate is reconstituted with 5 mL sterile Water for Injection.

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

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

 

2 Why was Adynovate approved?

 

Health Canada considers that the benefit/risk profile of Adynovate is favourable for patients (≥12 years) with hemophilia A (congenital Factor VIII deficiency) for:

  • Control and prevention of bleeding episodes
  • Prophylaxis to prevent or reduce the frequency of bleeding episodes
  • Perioperative management

Hemophilia A is an X-chromosome linked recessive, congenital bleeding disorder characterized by a deficiency of functional coagulation Factor VIII (FVIII), resulting in a prolonged patient plasma clotting time (as determined by the activated partial thromboplastin time [aPTT]). Hemophilia A is characterized by bleeding episodes predominantly in joints, but also in soft tissues. Factor VIII concentrates (either plasma derived or recombinant) are used in patients with hemophilia A to normalize the aPTT by providing a hemostatic FVIII level sufficient to treat and prevent bleeding episodes over the effective dosing period.

Adynovate is a human recombinant FVIII (rFVIII) conjugated with a polyethylene glycol (PEG) reagent. The rFVIII used for the conjugation is the active substance of Baxalta's Advate, a product already approved by Health Canada. This PEGylated product has the benefit of having a longer half-life than that of Advate. This results in the potential for decreased frequency of infusions of FVIII which could increase compliance and encourage a prophylactic schedule. Prophylaxis is the preferred management as prophylaxis has been shown to decrease bleeding episodes with a potential for less tissue damage, particularly joint damage.

Adynovate has been shown to be efficacious in patients ≥12 years of age with hemophilia A. The market authorization was based on a pivotal, multicentre, non randomized, open label study in adult and adolescent, previously treated male patients with severe hemophilia A. Patients received either prophylactic treatment with Adynovate at a dose of 45±5 IU/kg twice weekly (Arm A) or on-demand therapy with Adynovate at a dose of 10 to 60 IU/kg (Arm B). Of the 137 evaluable patients, more than 100 had ≥50 exposure days to Adynovate. Adynovate was found to be effective in controlling bleeding episodes and prophylactic treatment. The annualized bleeding rate was reduced in the prophylactic arm compared to on-demand treatment. Most bleeding was controlled with one or two injections and effectiveness according to the rating scale was rated as excellent or good. Quality of life assessment scales favoured prophylactic treatment over on-demand treatment. In most cases, surgeons and investigators gave Adynovate excellent ratings for perioperative management.

Adynovate has not demonstrated an increased risk over Advate in clinical studies. Polyethylene glycol and PEGylated products have been used for many years. The size of the PEG molecule used in Adynovate has not been associated with adverse events. In non clinical studies, neither Adynovate nor PEG alone showed any toxicity or unexpected immunogenicity. No neutralizing antibodies (inhibitors) have developed in clinical studies thus far. It is unknown at this time if long term use of Adynovate will result in a decreased or increased risk of inhibitor formation.

A Risk Management Plan (RMP) for Adynovate was submitted by Baxalta Canada Corporation 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. Post marketing follow up will include Periodic Safety Update Reports and Periodic Benefit-Risk Evaluation Reports which will provide updates on safety.

A Look alike Sound alike brand name assessment was performed and the proposed name Adynovate has been deemed acceptable.

Overall, the therapeutic benefits seen in the pivotal study are positive and the benefits of Adynovate therapy are considered to outweigh the potential risks. Adynovate has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and adequate monitoring. Appropriate warnings and precautions are in place in the Adynovate 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 Adynovate?

 

Submission Milestones: Adynovate

Submission Milestone Date
Pre-submission meeting: 2015-05-28
Submission filed: 2015-12-02
Screening  
Screening Acceptance Letter issued: 2016-01-22
Review  
On-Site Evaluation: 2016-08-15 - 2016-08-18
Quality Evaluation complete: 2016-11-11
Clinical Evaluation complete: 2016-11-14
Labelling Review complete: 2016-11-16
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2016-11-17

 

The Canadian regulatory decision on the non-clinical, clinical, and quality sections of the review of Adynovate was based on a critical assessment of the Canadian data package. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference.

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 sponsor has agreed to provide Periodic Safety Update Reports and Periodic Benefit-Risk Evaluation Reports and results from ongoing clinical studies.

 

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

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Adynovate 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

Adynovate, a pegylated form of recombinant antihemophilic factor (Advate), temporarily replaces the missing coagulation Factor VIII needed for effective hemostasis in congenital hemophilia A patients. Adynovate exhibits an extended terminal half-life through pegylation of the parent molecule, Advate, which reduces binding to the physiological Factor VIII clearance receptor (LRP1).

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic (PK) studies. The clinical pharmacological data support the use of Adynovate for the specified indication.

Pharmacokinetic assessments showed that Adynovate has a longer half-life than Advate supported by an increased mean residual time and decreased clearance.

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

Clinical Efficacy

The clinical efficacy of Adynovate was evaluated in a multicentre, open label, prospective, non-randomized, two-arm clinical study. This pivotal study assessed the efficacy of a twice weekly prophylactic treatment regimen, efficacy of on demand treatment, and determined the hemostatic efficacy in the treatment of bleeding episodes. A total of 137 previously treated male patients (12 to 65 years of age) with severe hemophilia A received at least one infusion with Adynovate. Twenty five of the patients were adolescent (12 to <18 years of age).

 

Patients received either prophylactic treatment (number of patients [n] = 120) with Adynovate at a dose of 40-50 IU per kg twice weekly or on-demand treatment (n = 17) with Adynovate at a dose of 10-60 IU per kg for a 6 month period. The mean dose per prophylaxis infusion was 44.4 IU per kg with a median dosing interval of 3.6 days. Of the 98 patients who indicated that their pre-study treatment regimen was prophylaxis with another Factor VIII concentrate, 91 out of 98 (93%) patients experienced a reduction in dosing frequency during the study, with a median reduction of 33.7%. One hundred and eighteen out of 120 (98%) prophylaxis patients remained on the starting recommended regimen without dose adjustment, and 2 patients increased their dose to 60 IU/kg during prophylaxis.

The primary efficacy assessment compared the annualized bleeding rate (ABR) of prophylactic treatment to on demand treatment. The effectiveness (according to a rating scale) and the number of injections needed to control bleeding episodes were also assessed.

One hundred and twenty patients received prophylactic treatment and 17 received on demand treatment. The results demonstrated that Adynovate used at the intended twice-weekly infusion interval and the intended prophylactic dose of 45±5 IU/kg is efficacious in the reduction of the ABR in previously treated patients with severe hemophilia A compared to on-demand treatment in these patients. The mean ABR (for all ages 12-65 years old) in the prophlaxis arm was 4.3 bleeds compared to 43.4 bleeds in the on-demand arm.

Success in the control of bleeding was defined as a rating of excellent or good using the Efficacy Rating Scale for Treatment of Bleeding Episodes measured 24 hours after initiation of treatment for the bleeding episode. A total of 518 bleeding episodes were treated with Adynovate. The median dose per infusion to treat a minor, moderate, severe/major, and all bleeding episodes was 25.5 IU/kg, 30.9 IU/kg, 36.4 IU/kg, and 29.0 IU per kg, respectively. Of the 518 bleeding episodes treated, 85.5% of them required 1 infusion and 10.4% required 2 infusions to control the bleeding. The rate of success to treat the bleeding episodes was excellent or good in 96.1% of the 518 bleeding episodes.

Study results also showed that the number of injections needed to treat bleeding episodes was decreased in the prophylaxis arm compared to the on demand arm. Ratings by the patients were often excellent or good for the treatment of a bleeding episode. With prophylactic treatment, more patients went for a longer time between bleeding episodes. The patient questionnaires for the most part favoured prophylactic treatment over on demand treatment with regards to decrease in pain and severity of bleeding episodes and quality of life issues.

The sponsor also submitted interim data from a prospective, open label multicentre study of Adynovate in surgical or other invasive procedures. An interim analysis was provided which included 11 major surgical procedures. The study is ongoing; 50 procedures in 40 patients are planned. The intraoperative efficacy and the post-operative efficacy on Days 1 and 14 were rated as excellent for the most part by the surgeon, and blood loss was less than expected for the procedures. For both major and minor surgeries, FVIII consumption was as expected. No adverse events were attributed to the use of Adynovate. The data support the use of Adynovate in perioperative management.

Overall, efficacy assessments indicate that Adynovate is an effective Factor VIII replacement therapy and confirm that prophylactic treatment is effective in reducing bleeding episodes, joint bleeds in particular, often with only one injection. Reductions in ABR were demonstrated with prophylactic treatment compared to on demand treatment. The PK studies show that compared to Advate, Adynovate has a longer half-life and this could result in a decreased frequency of injections required for some patients.

The submitted studies support Adynovate for the specified indications of control and treatment of bleeding episodes and for the prophylactic treatment of bleeding episodes in patients with hemophilia A. The recommended indication is the same as the indication filed with the submission.

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

Clinical Safety

The clinical safety of Adynovate was evaluated in 169 previously treated patients with severe hemophilia A (Factor VIII <1% of normal), who received at least one dose of Adynovate in two completed multicentre, prospective, open label clinical studies and three ongoing clinical studies. The median duration of participation per patient was 333 days (min-max: 1-593 days) and the median number of exposure days to Adynovate per patient was 96 (min-max: 1-170 days). The age distribution included 3 patients <6 years of age, 1 patient 6 to <12 years of age, 25 patients 12 to <18 years of age, and 140 patients ≥8 years of age.

 

In the integrated analysis of safety, 300 adverse events were reported in 96 patients. There were no unexpected adverse events in number or type of event. There were 16 serious adverse events in 11 patients. None were assessed as related to Adynovate. There was one death due to an unrelated cancer. The most common adverse events related to Adynovate were headache (3%) and nausea (1.2%). None of the patients developed neutralizing antibodies to FVIII. Binding immunoglobulin G and immunoglobulin M antibodies against FVIII, PEG-FVIII, and PEG, and Chinese Hamster Ovary (CHO) protein were analyzed and any antibodies which developed were transient. Clinical chemistry and hematology parameters remained within normal range for the most part in those without pre-existing abnormalities.

Adynovate has not demonstrated an increased risk over Advate in clinical studies. Polyethylene glycol (PEG) and PEGylated products have been used for many years. The size of the PEG molecule used in Adynovate has not been associated with adverse events. In non-clinical studies, neither Adynovate nor PEG alone showed any toxicity or unexpected immunogenicity. No neutralizing antibodies (inhibitors) have developed in clinical studies thus far. It is unknown at this time if long term Adynovate will result in a decreased or increased risk of inhibitor formation. Post marketing follow-up will include Periodic Safety Update Reports and Periodic Benefit-Risk Evaluation Reports which will provide updates on safety.

Adynovate is considered to have a favourable safety profile based on the data available at this time. The indications and recommendations for use of Adynovate are supported by the non clinical program which has shown the safety of Adynovate and PEG alone in several animal models. Extensive reports have been provided on the clinical and non clinical safety of PEG and on the immunogenicity of Adynovate. At this time there is no increased risk anticipated for this product. Pharmacokinetic studies in both non clinical and clinical studies support the potential for a longer half-life. There have been no inhibitory antibodies formed to date and no worrisome adverse events. The efficacy has been shown for this product for treatment of hemophilia A with no increased risk over other available products. There will be continued pharmacovigilance for this product particularly for the development of inhibitors.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Non-clinical studies investigating the pharmacology, pharmacokinetics, and toxicity of the active substance, human recombinant Factor VIII (rFVIII) conjugated with a polyethylene glycol (PEG) reagent, also referred to as BAX 855, were reviewed.

In vitro studies and in vivo studies in four animal models were used in the non-clinical studies for BAX 855. BAX 855 had a longer circulation time than Advate and there were no unexpected immunogenic or toxicity findings. The conjugation with PEG has not been found to present any safety issues at clinically relevant dose levels.

In vitro non-clinical studies support the safety of the PEG molecule at the size being used and the absence of an increased risk for the development of inhibitory (neutralizing) antibodies or antibodies to PEG, FVIII, FVIII-PEG or Chinese Hamster Ovary (CHO) cells.

Overall, the non-clinical studies support the safety of BAX 855 in clinical use. The results of the non-clinical studies as well as the potential risks to humans have been included in the Adynovate Product Monograph. In view of the intended use of Adynovate, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Quality Basis for Decision

 

The active substance in Adynovate (BAX 855) is a human recombinant factor VIII (rFVIII) conjugated with a polyethylene glycol (PEG) reagent. More specifically, the rFVIII used for the conjugation is the active substance of Baxalta's medicinal product Advate approved by Health Canada in 2006. Advate is a full length human rFVIII. The protein component of Advate is derived from a Chinese Hamster Ovary (CHO) cell line using a plasma-protein-free method and a virus inactivation step. The PEG reagent used has a size of 20 kDa with a branched structure and is covalently attached to primary amines, primarily lysine residues, of the rFVIII.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that the drug substance BAX 855 consistently exhibits the desired characteristic structure and biological activity.

Impurities and degradation products arising from manufacturing and/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

The drug substance manufacturing process consists of four major steps: buffer exchange chromatography, PEGylation, cation exchange chromatography, and ultra/diafiltration. The manufacturing process is well-defined and has in-process controls and acceptance criteria for each manufacturing step and sub-step. The selection of the critical steps and control parameter and ranges are justified.

The drug product manufacturing process mainly consists of the formulation of the bulk drug substance utilizing two buffer solutions, normalization buffer and potency dilution buffer, to reach target excipient and protein concentrations, followed by sterile filtration, aseptic filling, lyophilization, capping, bulk packaging, labelling and packaging. All in-process control parameters met the acceptance criteria and release results met the release specification.

Control of the Drug Substance and Drug Product

Many of the materials used for Adynovate are already being used by Baxalta to produce Advate for the Canadian market, including the Advate drug substance that is used as a substrate for the PEGylation to produce the active ingredient of Adynovate. Overall, the materials proposed for use in the Adynovate manufacture are of appropriate quality, and under adequate control.

The commercial drug substance process was validated across seven consecutively manufactured batches. Overall, the results demonstrated the capacity for the commercial process to consistently prepare the drug substance BAX 855 of acceptable quality.

Nine validation runs (batches) were conducted for the Adynovate drug product process. A comprehensive process validation plan was assessed and conducted to confirm the suitability and robustness of the manufacturing process to consistently produce drug product with the appropriate quality attributes, including strength, identity, purity, potency, and microbiological safety. The batch analysis data support the manufacturing consistency of the Adynovate drug product process. The established test specifications and validated analytical test methods are considered acceptable. The results for all of the batches were within the proposed specification limits.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final Adynovate product lots were tested using a subset of release tests. The test results confirmed that the manufacturing process of Adynovate at the proposed Baxalta's manufacturing sites is able to consistently manufacture Adynovate meeting the acceptable quality criteria and positively supported the quality review recommendation.

Stability of the Drug Substance and Drug Product

Based on review of the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were considered adequately supported and are satisfactory. The proposed 24-month shelf life for Adynovate final container drug product at 2°C to 8°C including up to 3 months at room temperature not to exceed 30°C is considered acceptable.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

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

An On-Site Evaluation (OSE) of the facility involved in the manufacture of the drug substance for Adynovate from the Advate drug substance was conducted. The OSE concluded that a positive recommendation from a facility perspective was warranted. The drug product filling site is currently an approved filling site for Advate, and due to the similarities of process from filling forwards, an OSE was not deemed necessary.

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

Adventitious Agents Safety Evaluation

All of the viral clearance data for Adynovate pertain to the purification process for Advate. Adequate data is present to provide assurance that any endogenous or adventitious agent contamination is adequately addressed by the manufacturing process for the Advate drug substance.

 

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