Summary Basis of Decision for Eloctate

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 Eloctate is located below.

Recent Activity for Eloctate

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 Eloctate

Updated: 2024-02-06

The following table describes post-authorization activity for Eloctate, a product which contains the medicinal ingredient, antihemophilic factor (recombinant BDD), Fc fusion protein. 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.

Drug Identification Number(s) (DINs):

  • DIN 02430290 - 250 IU/vial, antihemophilic factor (recombinant BDD), Fc fusion protein, powder for solution, intravenous administration
  • DIN 02430304 - 500 IU/vial, antihemophilic factor (recombinant BDD), Fc fusion protein, powder for solution, intravenous
  • DIN 02430312 - 750 IU/vial, antihemophilic factor (recombinant BDD), Fc fusion protein, powder for solution, intravenous administration
  • DIN 02430320 - 1,000 IU/vial, antihemophilic factor (recombinant BDD), Fc fusion protein, powder for solution, intravenous administration
  • DIN 02430339 - 1,500 IU/vial, antihemophilic factor (recombinant BDD), Fc fusion protein, powder for solution, intravenous administration
  • DIN 02430347 - 2,000 IU/vial, antihemophilic factor (recombinant BDD), Fc fusion protein, powder for solution, intravenous administration
  • DIN 02430355 - 3,000 IU/vial, antihemophilic factor (recombinant BDD), Fc fusion protein, powder for solution, intravenous administration

Post-Authoriation Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 265121

2022-06-10

Cancellation Letter Received 2022-06-27

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The changes were not in scope of an NC but were considered to be Level III changes. The sponsor cancelled the submission administratively.

Drug product (DIN 02430290) market notification

Not applicable

Date of first sale: 2022-05-20

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 02430355) market notification

Not applicable

Date of first sale: 2022-01-13

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 02430339) market notification

Not applicable

Date of first sale: 2021-11-10

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

SNDS # 247043

2020-12-04

Issued NOC 2021-11-08

Submission filed as a Level I – Supplement to update the PM with safety and efficacy data from Study 997HA306 for the use of Eloctate in previously untreated patients with hemophilia A, to migrate the PM to the 2020 format, and to update the labels to meet the Plain Language Labelling requirements. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications; Warnings and Precautions; and Adverse Reactions sections of the PM. An NOC was issued.

Drug product (DIN 02430320) market notification

Not applicable

Date of first sale: 2021-11-03

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 02430347) market notification

Not applicable

Date of first sale: 2021-10-29

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

NC # 254081

2021-06-21

Issued NOL 2021-09-23

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes affecting the quality control testing of the drug substance and drug product (release and stability). The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02430304) market notification

Not applicable

Date of first sale: 2021-09-13

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 02430312) market notification

Not applicable

Date of first sale: 2021-09-10

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

NC # 243241

2020-08-21

Issued NOL 2020-11-20

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

NDS # 242603

2020-08-07

Issued NOC 2020-09-25

Submission filed to transfer ownership of the drug product from Bioverativ Canada Inc. to sanofi-aventis Canada Inc. An NOC was issued.

SNDS # 223089

2018-12-17

Issued NOC 2019-11-21

Submission filed as a Level I – Supplement to update the PM with long-term safety and efficacy data via the final study reports for Studies 997HA307 and 997HA309, and extension study 8HA01EXT. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions and Clinical Trials sections of the PM. An NOC was issued.

NC # 227808

2019-05-15

Issued NOL 2019-09-05

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to reference standard qualification protocol and a change to a drug substance manufacturing facility. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02430312) market notification

Not applicable

Date of first sale: 2018-06-21

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 02430304) market notification

Not applicable

Date of first sale: 2018-03-30

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 02430339) market notification

Not applicable

Date of first sale: 2018-02-08

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 02430320, 02430355) market notification

Not applicable

Date of first sale: 2017-12-07

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 02430347) market notification

Not applicable

Date of first sale: 2017-11-09

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

NC # 208458

2017-08-14

Issued NOL 2017-10-06

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC, modifications were made to the Contraindications, Warnings and Precautions, and Adverse Reactions sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 201192

2016-12-15

Issued NOC 2017-10-04

Submission filed as a Level I – Supplement for the approval of an alternate manufacturing site of the drug product. Drug product manufactured at the new site is comparable to product manufactured at the current site. The data were reviewed and considered acceptable, and an NOC was issued.

NDS # 203855

2017-03-27

Issued NOC 2017-05-17

Submission filed to transfer ownership of the product (that is [i.e.] drug sponsor name) from Biogen Canada Inc. to Bioverativ Canada Inc. An NOC was issued.

NC # 194251

2016/04/12

Issued No Objection Letter

2016/06/14

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, Adverse Reactions, and Special Handling Instructions sections of the PM. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.

SNDS # 186957

2015/08/18

Issued NOC 2016/07/08

Submission filed as a Level I – Supplement to extend the use of Eloctate to children less than 12 years of age and to use in perioperative management for all age groups. Regulatory Decision Summary published.

Drug product (DIN(s) 02430290,

02430304,  02430320, 02430339,  02430347, 02430355) market notification

Not applicable

Date of first sale: 2016/01/15

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

NC # 188660

2015/10/19

Issued No Objection Letter 2016/01/20

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to propose a new working reference standard, and include additional testing at approved testing facilities. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.

SNDS # 183662

2015/04/10

Issued NOC  2015/11/20

Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the drug substance and a manufacturing scale-up. The stability profiles of the drug substance and drug product remain unchanged. The data were reviewed and considered acceptable, and an NOC was issued.

NC # 183135

2015/03/31

Issued No Objection Letter 2015/06/04

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add sites for Quality Control testing of the drug product and to update excipient specifications for Eloctate. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.

NC # 182522

2015/02/25

Issued No Objection Letter 2015/04/08

Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Product Monograph (PM) based on post‑market safety information. As a result of the submission, changes were made to the Warnings and Precautions, Adverse Reactions, Drug Interactions, Dosage and Administration, Storage and Stability, Clinical Trials, Toxicology, and Part III Consumer Information sections of the PM. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.

NDS # 163447

2013/07/30

Issued NOC 2014/08/22

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

Date SBD issued: 2014-10-21

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

Antihemophilic Factor (Recombinant BDD), Fc Fusion Protein, 250, 500, 750, 1,000, 1,500, 2,000, 3,000 IU/vial, powder for solution, intravenous

Drug Identification Number (DIN):

  • DIN 02430290 - 250 IU/vial, powder for solution
  • DIN 02430304 - 500 IU/vial, powder for solution
  • DIN 02430312 - 750 IU/vial, powder for solution
  • DIN 02430320 - 1,000 IU/vial, powder for solution
  • DIN 02430339 - 1,500 IU/vial, powder for solution
  • DIN 02430347 - 2,000 IU/vial, powder for solution
  • DIN 02430355 - 3,000 IU/vial, powder for solution

Biogen Idec Canada Inc.

New Drug Submission Control Number: 163447

 

On August 22, 2014, Health Canada issued a Notice of Compliance to Biogen Idec Canada Inc. for the drug product, Eloctate.

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 Eloctate is favourable for use in adults and children (≥12 years) with Hemophilia A for the routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes and the control and prevention of bleeding episodes.

 

1 What was approved?

 

Eloctate, which belongs to the class of drug antihemorrhagic blood coagulation factor VIII, was authorized for use in adults and children (≥12 years) with Hemophilia A (congenital factor VIII deficiency) for:

  • Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes
  • Control and prevention of bleeding episodes.

Eloctate does not contain von Willebrand factor and therefore is not indicated in patients with von Willebrand's disease.

Clinical studies did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be individualized.

No data are available for patients below the age of 12 years.

Eloctate is contraindicated in individuals who have manifested severe hypersensitivity reactions, including anaphylaxis, to the product or its components. Severe hypersensitivity reactions were not observed in clinical studies; however, these have been known to occur with use of other factor VIII replacement products. Eloctate was approved for use under the conditions stated in the Eloctate Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Eloctate contains the active ingredient Antihemophilic Factor (Recombinant BDD), Fc Fusion Protein. Each single-use vial contains nominally 250, 500, 750, 1,000, 1,500, 2,000 or 3,000 IU of Elocate. Once reconstituted with the provided diluent, the product also contains sucrose, sodium chloride, L-histidine, calcium chloride dihydrate, and polysorbate 20.

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

 

2 Why was Eloctate approved?

 

Health Canada considers that the benefit/risk profile of Eloctate is favourable for adults and children (≥12 years) with Hemophilia A (congenital factor VIII deficiency) for:

  • Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes,
  • Control and prevention of bleeding episodes.

Hemophilia A is a rare congenital bleeding disorder occurring predominantly in males, characterized by a deficiency of factor VIII (FVIII), which results in abnormal clot formation, causing prolonged and abnormal bleeding. Bleeding may be life-threatening or result in significant morbidity. Currently, there is no cure for Hemophilia A. The treatment focuses on the replacement of FVIII with FVIII containing coagulation products.

Eloctate has been shown to be efficacious in Hemophilia A patients in routine prevention and control of bleeding episodes. The market authorization was based primarily on one multicentre, open-label study (997HA301) which assessed the efficacy of Eloctate for routine prophylactic or episodic (on-demand) treatment of bleeding episodes and perioperative management in patients aged 12 years and older with Hemophilia A. The benefits of Eloctate have been shown in routine prevention and control of bleeding episodes. The median annualized bleeding rate was <2 under individualized prophylaxis treatment regimen, and <4 under the weekly prophylaxis regimen. The responses to the majority of Eloctate injections for the bleeding episodes were assessed as "excellent" or "good" by the patients.

The clinical safety of Eloctate was evaluated in two open-label studies (998HA101 and 997HA301). The safety profile derived from the two studies was considered acceptable. None of the patients (110 patients with ≥50 exposure days) developed FVIII inhibitors. No serious adverse events of allergic reactions or anaphylaxis were reported.

A Risk Management Plan (RMP) for Eloctate was submitted by Biogen Idec Canada Inc. 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.

Overall, the therapeutic benefits seen in study 997HA301 are considered positive and the benefits of Eloctate therapy outweigh the potential risks. Eloctate was shown to have an acceptable safety profile based on the non-clinical data and clinical studies. The benefit/risk analysis is considered favourable for Eloctate to be used as an alternative therapy for Hemophilia A patients aged ≥12 years old for prophylactic and on-demand treatment of bleeding episodes.

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 Eloctate?

 

Submission Milestones: Eloctate

Submission Milestone Date
Pre-submission meeting: 2013-05-22
Submission filed: 2013-07-30
Screening  
Screening Deficiency Notice issued: 2013-09-18
Response filed: 2013-10-02
Screening Acceptance Letter issued: 2013-10-29
Review  
On-Site Evaluation: 2014-06-16 - 2014-06-20
Quality Evaluation complete: 2014-08-20
Clinical Evaluation complete: 2014-08-19
Biostatistics Evaluation complete: 2014-08-19
Labelling Review complete: 2014-08-19
Notice of Compliance issued by Director General: 2014-08-22

 

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 Eloctate, 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)providing updates on the stability data for FcRn binding and FcRn integrity attributes as they are completed, and to update the post-approval stability protocol. Additional comments were issued to address minor corrections to the Certified Product Information Document regarding revised drug product release parameters and corresponding method validation.

 

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

 

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

The PAAT for Eloctate 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

Hemophilia A is a bleeding disorder characterized by a deficiency of functional clotting factor VIII (FVIII), which leads to prolonged clotting time in the activated partial thromboplastin time assay, a conventional in vitro test for the biological activity of FVIII. Eloctate is used as a replacement therapy to increase plasma levels of factor VIII, thereby enabling a temporary correction of the factor deficiency and the bleeding tendency.

The clinical pharmacokinetics of Eloctate in patients with severe Hemophilia A was evaluated in 28 subjects in study 997HA301, and compared with a currently available FVIII product. Together, the clinical and pharmacological data support the use of Eloctate for routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes, and the control and prevention of bleeding episodes in patients aged 12 years and older with Hemophilia A.

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

Clinical Efficacy

The clinical efficacy of Eloctate was evaluated in a multicentre, open-label, study (997HA301). The design of this study was to assess the efficacy of Eloctate in the treatment and prevention of bleeding episodes in each of two prophylactic treatment arms (Fixed weekly and individual interval). A total of 164 previously treated male patients (PTPs) with severe Hemophilia A [defined as ≤1% IU/dL endogenous factor VIII (FVIII) or a genetic mutation consistent with severe Hemophila A], received at least one dose of Eloctate in the study. Patients were aged 12 to 65 years, including 13 adolescent patients aged 12 to 17 years. Patients were asked to use an electronic patient diary (eDiary) throughout the duration of the study to record details of Eloctate administration, any bleeding episodes, and responses to Eloctate for bleeding episodes.

Patients who were on a prophylaxis therapy prior to study entry were assigned to Arm 1 [individualized prophylaxis regimen, number of patients (n) = 117]. Patients who were on an episodic regimen prior to study entry were either assigned to the individualized prophylaxis group (Arm 1) or randomized to either the weekly prophylaxis group (Arm 2; n = 24) or episodic (on-demand) therapy (Arm 3; n = 23). Patients from Arm 1, 2, or 3 who had major surgery during the study were considered for enrollment in the perioperative management subgroup provided they met the inclusion criteria. The duration of the study was 54 weeks. The primary efficacy endpoint was the annualized number of bleeding episodes or annualized bleeding rate (ABR).

Efficacy in Routine Prophylaxis

A total of 140 patients received prophylactic Eloctate; 117 patients in the individualized interval arm (Arm 1) and 23 patients in the weekly interval arm (Arm 2). The median ABR per patient was 1.60 (range 0.0 to 18.2) for the patients in Arm 1, and 3.59 (range 0.0 to 58.0) for the patients in Arm 2.

Eighty-seven patients had a prophylaxis treatment regimen 12 months prior to the start of the study and during the study. The number of bleeding episodes per patient in the 12 months prior to study start was estimated based on patient-reported historical data. The ABR during the study in 70/87 patients was either reduced or did not change compared to the number of bleeds 12 months prior to the study. The ABR in 16 patients increased by 1 to 7 bleeds, with the on study ABR ranging from 2 to 18. The on study ABR in 1 patient was unknown. The mean ABR for Eloctate (2.91±3.93 for Arm 1, n = 117) was in line with the reported ABR for another approved product from the same class of drugs.

Although the historical pre-study bleeding information was obtained retrospectively and was not acquired as rigorously as the on-study data, the overall efficacy of Eloctate for prophylactic use was considered acceptable.

Efficacy in Control of Bleeding

A total of 880 injections were administered during the study to treat 757 bleeding episodes in Arms 1, 2, and 3 combined. Of the 880 injections, 860 of them were evaluated by the patient using a 4-point scale ("excellent", "good", "moderate" or "no response"); 667 (77.6%) of them were assessed by patients as an "excellent" or "good" response.

The treatment response was also analyzed by the type of bleeds and location of bleeds. The treatment injections for 79.2% spontaneous bleeds and 74.4% traumatic bleeds were assessed by patients as "excellent" or "good". In addition, 77% to 89% of injections were assessed as "excellent" or "good" for joint, muscle, soft tissue and skin/mucosa bleeds. However, only 54.5% injections for internal bleeds were assessed as "excellent/good".

Overall, the efficacy of Eloctate for bleeding episode (on-demand) treatment is considered acceptable.

Efficacy in Perioperative Management

During the original filing of this New Drug Submission, the sponsor initially sought approval for routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes; for control and prevention of bleeding episodes, as well as for perioperative management (surgical prophylaxis). Health Canada revised the indication to exclude perioperative management as the current available data regarding the perioperative management was not considered sufficient to support this indication and not considered sufficient according to internationally established guidelines.

Overall, the clinical efficacy data supports the use of Eloctate for routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes, and the control and prevention of bleeding episodes in patients 12 years and older with Hemophilia A.

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

Clinical Safety

The clinical safety of Eloctate was evaluated in a Phase I/ II open-label study (998HA101) and the pivotal Phase III open-label study (997HA301, described in the Clinical Efficacy section).

Study 998HA101 evaluated the safety and pharmacokinetics (PK) of a single dose of a frozen liquid formulation of Eloctate in previously treated patients with severe Hemophilia A [defined as ≤1 IU/dL (≤1%) endogenous FVIII], ≥12 years of age, with =100 previous exposure days (EDs). Fifteen patients were included in the PK analysis, 6 of them received 25 IU/kg and 9 received 65 IU/kg of a comparator product and a frozen liquid formulation of Eloctate. Following a single dose of 65 IU/kg Eloctate, 23 adverse events (AEs) were reported by 2/10 patients. All AEs were reported by 1/10 patients, except for myalgia and headache which were reported by 2/10 patients. No Factor VIII inhibitors were reported.

Study 997HA301, evaluated the safety of Eloctate in 164 patients. The patients used an eDiary throughout the study to record details of Eloctate administration, any bleeding episodes, and responses to Eloctate for bleeding episodes. Of the 164 patients, 108 (65.9%) reported at least one AE, with a total of 295 AEs. Adverse Events judged by the investigator to be at least possibly related to Eloctate were reported in 10/164 patients (6.1%). These AEs included malaise and arthralgia [each reported in 2 patients (1.2%)], bradycardia, lower abdominal pain, chest pain, feeling cold, feeling hot, procedural hypotension, increased brain natriuretic peptide, joint swelling, myalgia, dizziness, dysgeusia, headache, cough, rash, angiopathy, and hypertension [each reported in 1 patient (0.6%)]. In addition, 2 events had a missing relationship assessment and both were counted as related AEs, upper abdominal pain and retinal disorder. None of the 110 patients with ≥50 exposure days of Eloctate developed FVIII inhibitors during the study. No serious adverse events (SAEs) of allergic reactions or anaphylaxis were reported during the study. One patient experienced mild venous thrombosis after 74 Eloctate injections. This event was considered resolved while the patient continued in the study and the event was assessed by the investigator as being unrelated to Eloctate treatment. A total of 5 patients (3.0%) reported rash/urticaria, and 5 patients (3.0%) reported hypertension/hypertensive emergency. For both events, 4/5 patients reported the events on the day of the Eloctate injection or the following day of the injection.

Overall, the safety profile derived from the two clinical studies was considered acceptable and similar to other products in the same class of products.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

An extensive non-clinical program with Eloctate was performed in mice, rats, dogs, and monkeys to support clinical development and registration for the proposed indications, as well as to support manufacturing changes. The non-clinical program included pharmacokinetic, pharmacology, and toxicology studies. The route of administration in the non-clinical program was intravenous which matched the route of administration in clinical studies.

Based on the results of these pharmacokinetic (PK) studies, in vitro and in vivo pharmacology studies, and toxicology studies, Eloctate has been adequately characterized. The non-clinical program supports the clinical development and marketing authorization of Eloctate for the treatment of Hemophilia A.

No local tolerance study was conducted. However, in three repeat-dose toxicology studies, the injection site (intravenous injection) was examined. All dose groups (including the vehicle group) had similar findings.

The genotoxicity and carcinogenicity were not assessed in animals. In addition, the thrombogenic potential of Eloctate was not assessed in animals, and is not generally required.

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

 

 

7.3 Quality Basis for Decision

 

Eloctate, Antihemophilic Factor (Recombinant BDD) Fc Fusion Protein (rFVIIIFc), is a fully recombinant fusion protein comprised of recombinant B domain-deleted human Factor VIII (BDD FVIII) covalently linked to the Fc domain of human immunoglobulin G1 (IgG1) and produced by recombinant deoxyribonucleic acid (DNA) technology.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that rFVIIIFc consistently exhibits the desired characteristic structure and biological activity.

The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

Impurities (protein and non-protein) and product variants arising from manufacturing were reported and characterized. These were found to be consistently cleared by the manufacturing process to be within acceptable limits or were controlled by monitoring testing results. The sponsor has successfully demonstrated the capacity of the rFVIIIFc production process to consistently reduce or remove these impurities at the commercial scale. The impurities profile is therefore considered to be acceptable.

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

The drug substance of Eloctate, rFVIIIFc, is produced in Human Embryonic Kidney 293 cells using media, free of animal-derived components, and harvested as a single batch. The process is well defined and has appropriate in process controls for critical steps and intermediates.

The manufacturing process of the drug substance consists of a series of steps that include cell culture, product harvest, viral inactivation, chromatographic purification, viral filtration, formulation and storage. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.

The manufacturing process of the drug product consists of three main steps:

  1. compounding,
  2. sterile filtration, and
  3. aseptic filling and lyophilisation.

Data were provided to support the suitability of container closure components and container closure integrity. Validation data demonstrate the consistency and reliability of the filling process to produce all Eloctate final product strengths.

Media fill data covering recent production were provided and support the manufacturer's capacity to aseptically fill Eloctate.

Data from the Eloctate drug product batch analyses were reviewed and considered acceptable. The quality control results showed a good compliance for all batches within release specifications.

Control of the Drug Substance and Drug Product

The manufacturing process of the drug substance was developed at laboratory-scale and pilot-scale, leading to identification of critical operating parameters and in-process controls for each step, and validated at the commercial scale. Data from batch analysis in process validation adequately demonstrated consistent drug substance manufacture.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.

Potency results obtained by Health Canada were comparable to the sponsor's results when referenced to the Biogen rFVIIIFc reference standard, and are supportive of their capacity to manufacture Eloctate with consistent quality. However, the potency results differed when referenced against two other reference standards that were plasma derived. Based upon these results, it was recommended that the determinations of Eloctate potencies for lot release be evaluated against the Biogen rFVIIIFc reference standard. Eloctate will be placed in lot release group 2 which requires the sponsor to submit samples as well as Certificates of Analysis for Drug Substance, Drug Product and Diluent. These materials are requested for review and testing prior to release on the Canadian market.

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.

Stability data for the drug product supports a shelf life limit of 36 months when stored at 5°C±3°C, which may include 6 months at room temperature up to 30°C, and a 6 hours post reconstitution in use time.

The compatibility of the drug product with the container closure system was demonstrated. The container closure system met all validation test acceptance criteria.

Monitoring of FcRn binding in the bulk drug substance and FcRn integrity in the final drug product was initiated very late in product development. Only the latter stability time points generated FcRn binding (drug substance) and FcRn integrity (drug product) data. As such, insufficient data was available to comment on the stability of the Fc mediated activities. Since the limited commercial scale FcRn integrity results were well above the current release specification, this deficiency did not hinder the approval of the submission. FcRn binding and FcRn integrity results will be monitored during lot release, and additional stability data for the FcRn integrity will be requested upon availability as a post market authorization comment.

Facilities and Equipment

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of the Eloctate drug product has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.

An OSE of the facility involved in the manufacture and testing of Eloctate drug substance was not conducted, as a successful OSE had been recently performed for another product whose manufacturing process was similar.

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

Adventitious Agents Safety Evaluation

The Eloctate manufacturing process incorporates adequate purification steps and control measures to prevent contamination and maintain microbial control. The purification process includes several viral clearance steps. The total reduction factor for relevant and model viruses demonstrates that the manufacturing process provides sufficient viral clearance of potential viruses.

 

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