Summary Basis of Decision for Idelvion

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 Idelvion is located below.

Recent Activity for Idelvion

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 Idelvion

Updated:

2023-02-28

The following table describes post-authorization activity for Idelvion, a product which contains the medicinal ingredient Coagulation Factor IX (Recombinant), Albumin 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 that are found in PAATs.

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

Drug Identification Number (DIN):

  • DIN 02451336 - 250 IU/vial, Coagulation Factor IX (Recombinant), Albumin Fusion Protein, powder for solution, intravenous administration
  • DIN 02451344 - 500 IU/vial, Coagulation Factor IX (Recombinant), Albumin Fusion Protein, powder for solution, intravenous administration
  • DIN 02451352 - 1,000 IU/vial, Coagulation Factor IX (Recombinant), Albumin Fusion Protein, powder for solution, intravenous administration
  • DIN 02451360 - 2,000 IU/vial, Coagulation Factor IX (Recombinant), Albumin Fusion Protein, powder for solution, intravenous administration
  • DIN 02489627 – 3,500 IU/vial, Coagulation Factor IX (Recombinant), Albumin Fusion Protein, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NC # 261572 2022-02-16 Cancellation Letter Received 2022-02-24 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to the manufacture of the drug substance. The changes were not in scope of an NC but were considered to be Level III changes. The sponsor cancelled the submission administratively.
NC # 253788 2021-06-15 Issued NOL 2021-08-20 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 248963 2021-01-28 Issued NOL 2021-05-05 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 242888 2020-08-13 Issued NOL 2020-09-29 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the controls applied during the drug substance manufacturing process, and the specifications for the materials. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 241052 2020-06-25 Issued NOL 2020-09-29 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 233069 2019-10-31 Issued NOC 2020-09-22 Submission filed as a Level I – Supplement to update the PM with data from study 3003. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, Dosage and Administration, Action and Clinical Pharmacology, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
NC # 239557 2020-05-14 Issued NOL 2020-08-17 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change to a primary container closure system. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 238110 2020-04-15 Issued NOL 2020-07-17 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.
SNDS # 235824 2020-02-05 Issued NOC 2020-04-15 Submission filed as a Level I – Supplement to revise the inner and outer labels. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 234411 2019-12-12 Issued NOL 2020-03-23 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug product, the controls applied during the drug product manufacturing process, and the manufacture of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 234252 2019-12-06 Issued NOL 2020-03-05 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance and the controls applied during the drug substance manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 230729 2019-08-14 Issued NOL 2019-10-15 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.
Drug product (DIN 02451352) market notification Not applicable Date of first sale: 2019-07-04 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 226965 2019-04-18 Issued NOL 2019-06-26 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 221567 2018-11-01 Issued NOC 2019-06-18 Submission filed as a Level I – Supplement for a scale-up of the drug substance and drug product manufacturing processes, and a new strength (3,500 IU/vial). The data were reviewed and considered acceptable, and an NOC was issued. A new DIN (02451352) was issued for the new strength.
NC # 222737 2018-12-05 Issued NOL 2019-02-05 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications used to release the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 219951 2018-09-07 Issued NOL 2019-01-10 Submission filed as a Level II (120 day) Notifiable Change to update the PM. As a result of the NC, modifications were made to the Serious Warnings and Precautions Box, and Action and Clinical Pharmacology sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 214449 2018-03-13 Issued NOC
2018-05-18		 Submission filed as a Level I - Supplement to propose revisions to the printed packaging material. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 203434 2017-03-03 Issued NOL
2017-04-26		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the Adverse Reactions, and Pharmaceutical Information sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 201528 2016-12-23 Issued NOL
2017-01-12		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Adverse Reactions, and Dosage Forms Composition and Packaging sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
NDS # 180793 2015-02-09 Issued NOC
2016-01-26		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Idelvion

Date SBD issued: 2016-03-09

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

Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP)
250 IU/vial, 500 IU/vial, 1,000 IU/vial, and 2,000 IU/vial
Powder for solution, intravenous

Drug Identification Number (DIN):

  • DIN 02451336 - 250 IU/vial,
  • DIN 02451344 - 500 IU/vial,
  • DIN 02451352 - 1,000 IU/vial
  • DIN 02451360 - 2,000 IU/vial

CSL Behring Canada Inc.

New Drug Submission Control Number: 180793

On January 26, 2016, Health Canada issued a Notice of Compliance to CSL Behring Canada, Inc. for the drug product Idelvion.

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 Idelvion is favourable for patients with hemophilia B (congenital Factor IX deficiency) or Christmas disease for:

  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes
  • Control and prevention of bleeding episodes
  • Control and prevention of bleeding in the perioperative setting

Clinical studies were performed only in previously-treated patients.

1 What was approved?

Idelvion, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is an antihemorrhagic blood coagulation Factor IX (FIX) product. Idelvion was authorized for patients with hemophilia B (congenital FIX deficiency) or Christmas disease for:

  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes
  • Control and prevention of bleeding episodes
  • Control and prevention of bleeding in the perioperative setting

Clinical studies were performed only in previously-treated patients.

Idelvion is contraindicated in patients who have a known hypersensitivity to Idelvion, any of its components, excipients or hamster protein. Idelvion was approved for use under the conditions stated in the Idelvion Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Idelvion (250 IU, 500 IU, 1,000 IU, and 2,000 IU of the active substance rIX-FP) as a powder for solution is presented in single-use vials.

In addition to the medicinal (active) ingredient, the powder for solution contains mannitol, polysorbate 80, sucrose, and tri-sodium citrate.

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

2 Why was Idelvion approved?

Health Canada considers that the benefit/risk profile of Idelvion is favourable for patients with hemophilia B (congenital Factor IX deficiency) or Christmas disease for:

  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes
  • Control and prevention of bleeding episodes
  • Control and prevention of bleeding in the perioperative setting

Clinical studies were performed only in previously-treated patients.

Inherited Factor IX (FIX) deficiency (also known as hemophilia B or Christmas disease) is a sex-linked recessive disorder one quarter as common as hemophilia A (Factor VIII deficiency). Patients with severely affected phenotypes (≤2% endogenous FIX activity) are prone to unprovoked bleeding into joints or major organs which is at best disabling, at worst life-threatening. Treatment by replacing the deficient plasma factor can reduce the risk considerably leading to a more normal quality of life and life expectancy. Currently available replacement FIX preparations have limited plasma half-lives and require dosing 2 to 3 times per week, a burden for children with the disease.

Idelvion (Coagulation FIX [Recombinant], Albumin Fusion Protein [rIX-FP]) is a recombinant protein purified from Chinese Hamster Ovary (CHO) cells and is generated by the genetic fusion of human albumin to human coagulation FIX. The purpose of this genetic fusion is to prolong the half-life of FIX as compared with that of endogenous plasma FIX. The activity of the rIX-FP is similar to that of native FIX but its half-life is prolonged.

Idelvion has been shown to be efficacious in previously-treated patients with severe hemophilia B (≤2% endogenous FIX activity). The market authorization was based on a prospective, open-label, multicentre clinical study. Idelvion was shown to be an effective replacement for inherited deficiency of FIX when used either as a treatment for bleeding episodes or in a prophylactic role. Both the 7-day prophylaxis and 14-day prophylaxis regimens with Idelvion in the reduction in the number of spontaneous bleeds per year were demonstrated to be effective.

Idelvion was generally well-tolerated. The most common adverse reaction reported in four clinical studies was headache (1.9%). Other treatment-related adverse reactions included dizziness, rash, and infusion reaction. No neutralizing antibodies to FIX or antibodies to CHO host cell protein have been detected with the use of Idelvion. No events of anaphylaxis or thrombosis were reported.

A Risk Management Plan (RMP) for Idelvion was submitted by CSL Behring 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.

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

The benefit conferred by Idelvion as compared with other FIX products is the potential for a greatly improved quality of life resulting from reduced dose frequency and possible reduction in the total annual dose required for equal effect. For pediatric patients especially, these two factors are of major importance.

The safety profile of Idelvion is acceptable and there is no indication that Idelvion has unique risks over and above those of other FIX products in current use. Appropriate warnings and precautions are in place in the Idelvion 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 Idelvion?

Submission Milestones: Idelvion

Submission Milestone Date
Submission filed: 2015-02-09
Screening  
Screening Acceptance Letter issued: 2015-04-01
Review  
On-Site Evaluation: 2015-11-02 - 2015-11-06
Quality Evaluation complete: 2016-01-21
Clinical Evaluation complete: 2016-01-07
Labelling Review complete: 2016-01-14
Notice of Compliance issued by Director General: 2016-01-26

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.

In addition, the sponsor has agreed to provide reports on two ongoing studies to add to the safety data and to complete evidence on inadequately studied groups: that is (i.e.) pediatric patients (study 3002) and previously untreated patients (study 3003) as well as to provide more robust data on the possible development of inhibitory antibodies in long-term use (study 3003). A small sub-group in study 3003 may transition to a 21-day infusion cycle.

The sponsor has also committed to carrying out additional analysis and method development related to measuring amounts of different forms of Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP).

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

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 Idelvion 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

Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased levels of Factor IX (FIX) and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy, the plasma levels of FIX are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

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

Pharmacokinetic studies in adults confirmed a prolonged half-life (104 hours) as compared with historical data for plasma derived FIX or recombinant FIX, both at 18 hours. A slightly lower half-life (91 hours) was reported with children (1 to <12 years of age) who received Idelvion.

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

Clinical Efficacy

The clinical efficacy of Idelvion (Coagulation Factor IX [Recombinant], Albumin Fusion Protein [rIX-FP]), was evaluated in a prospective, open-label, multicentre clinical study. This study compared episodic (on-demand) treatment to weekly routine prophylaxis, compared weekly routine prophylaxis to every 10- or 14-day routine prophylaxis, determined hemostatic efficacy in the treatment of bleeding episodes, and determined hemostatic efficacy during perioperative management of patients undergoing surgical procedures.

A total of 63 male previously-treated patients with severe hemophilia B (≤2% endogenous FIX activity), between 12 and 61 years of age (median 30 years) received Idelvion for up to 27 months. Forty patients in the prophylaxis arm received weekly routine prophylaxis at an initial dose of 35-50 IU/kg, with median dose of 40 IU/kg of Idelvion at the end of the weekly prophylaxis period. Twenty-six of the 40 patients in the prophylaxis arm subsequently crossed-over to an every 10- or 14-day routine prophylaxis and received 50-75 IU/kg of Idelvion after approximately 26 weeks of weekly prophylaxis. Twenty-three patients in the on-demand arm received Idelvion as needed for the treatment of bleeding episodes, 19 patients subsequently crossed-over to weekly prophylaxis after approximately 26 weeks of episodic treatment. If a patient required a surgical procedure during the study, the patient could be enrolled in the surgical substudy.

The primary efficacy endpoint was the annualized spontaneous bleeding rate (AsBR) for treated bleeding episodes during on-demand treatment compared with that during routine prophylaxis treatment.

Routine Prophylaxis

Routine prophylaxis with once-weekly Idelvion reduced the AsBR by 100% compared to on-demand treatment (primary efficacy population, p<0.0001). The median (Q1, Q3) AsBR was 15.43 (7.98, 17.96) for on-demand treatment and 0.00 (0.00, 0.96) for weekly prophylaxis treatment. Fewer patients experienced spontaneous bleeding episodes during prophylaxis treatment compared with their on-demand treatment (9/19 or 47.4% versus [vs.] 19/19 or 100.0%, respectively). The median AsBR was 0.0 in both the 7-day prophylaxis and 14-day prophylaxis regimens, therefore, both regimens were demonstrated to be effective. The 10-day prophylaxis regimen had only six patients and did not provide adequate supporting data.

Treatment of Bleeding Episodes

A total of 358 bleeding episodes, including 5 iliopsoas bleeds, were evaluated for treatment with Idelvion.

Most bleeding episodes requiring treatment were successfully treated with 1 or 2 injections of Idelvion resulting in an overall probability of success of 98.6%. Similar findings were observed regardless of cause (spontaneous [98.5%], traumatic [99.3%], unknown [92.9%]) or location (joint [99.2%], muscle [97.1%], or other [96.2%]) of bleeding episodes. Overall, 93.6% of bleeding episodes were successfully treated with 1 infusion with similar rates observed across all treatment regimens. The median dose per injection required to resolve bleeding episodes was 46.73 IU/kg. The Investigator's assessment of hemostatic efficacy of Idelvion in the treatment of bleeding episodes was either excellent (83.0%) or good (11.2%) for the majority of bleeding episodes. There were no major life-threatening bleeding episodes reported in this study.

Perioperative Management

Seven patients received Idelvion for perioperative management in 9 surgical procedures. The 9 surgical procedures included a double mastectomy, 2 knee replacements, a hemorrhoidectomy, a rhinoplasty, and 3 complicated and 1 uncomplicated dental surgeries. Two of the 4 dental surgeries were performed in children <12 years.

For all surgeries at wound closure and postoperative Day 14, which was the end of the surgical substudy, hemostatic efficacy for surgical prophylaxis was rated as excellent or good by the investigator. The estimated actual intraoperative blood loss and transfusion requirements were close to that predicted by the investigator/surgeon prior to surgery; no other hemostatic interventions or transfusion support were required for any patient. Hemoglobin levels were maintained throughout the surgical period and at levels not unexpected for the type of surgeries performed. Consumption of Idelvion during the postoperative period was low considering the type of surgeries performed. Only 21 infusions were administered over the 14-day postoperative period.

Overall Analysis of Efficacy

Idelvion appears to be an effective replacement for inherited deficiency of FIX when used either as a treatment for bleeding episodes or in a prophylactic role to prevent them. The clinical studies suggest that its efficacy is comparable to or enhanced with respect to FIX preparations previously used by the patients. The submitted data supports 7-day prophylaxis and 14-day prophylaxis regimens.

Indication

The New Drug Submission for Idelvion was filed with the following indication:

Idelvion, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is an antihemophilic factor indicated in all patients with hemophilia B (congenital FIX deficiency) or Christmas disease for:

  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes
  • Control and prevention of bleeding episodes
  • Control and prevention of bleeding in the perioperative setting

Following review of the indication, Health Canada recommended removing the word "all" to accurately reflect the data in the pivotal clinical studies. A statement was added to inform readers that the clinical studies were performed only in previously-treated patients. Health Canada authorized the following indication for the Idelvion Product Monograph:

Idelvion, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is an antihemophilic factor indicated in patients with hemophilia B (congenital FIX deficiency) or Christmas disease for:

  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes
  • Control and prevention of bleeding episodes
  • Control and prevention of bleeding in the perioperative setting

Studies described in this monograph have been performed only in previously-treated patients (PTPs).

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

Clinical Safety

The clinical safety of Idelvion was evaluated in four multicentre, prospective, open-label clinical studies. A total of 107 previously-treated patients (PTPs, exposed to a FIX-containing product for ≥100 exposure days) were evaluated. A total of 6,384 injections were administered over a median of 469 days (range: 25 to 986 days), with a median 3,000 IU per injection (range: (138.9-10,570.0 IU). The median total amount of Idelvion administered was 127,110.0 IU (range: 1,900.0-999,051.4).

Eight of the 107 patients (7.5%) reported treatment-related adverse events. Of these 8 cases, 5 cases were considered related to Idelvion: headache (2, 1.9%), dizziness (1, 0.9%), rash (1, 0.9%), and infusion-related reaction (1, 0.9%) Two patients withdrew from the study due to an adverse reaction (headache, infusion related reaction). No serious adverse events were attributed to Idelvion. No neutralizing antibodies (inhibitors) to FIX or antibodies to Chinese Hamster Ovary (CHO) host cell protein have been detected with the use of Idelvion. No events of anaphylaxis or thrombosis were reported.

Safety and tolerability assessments demonstrated that intravenous infusion of Idelvion had a favourable safety profile and was well tolerated when administered on a 7-, 10-, or 14-day prophylaxis regimen, as on demand treatment, and for the perioperative management of bleeding. During the course of the pivotal study (described in the Clinical Efficacy section), the mean weekly prophylaxis dose was 46.61 (11.02) IU/kg and the safety profile was favourable. No inhibitors to rIX-FP and no antibodies to rIX-P or CHO host cell protein were detected in any patient. The 5 patients that reported the adverse events, related to Idelvion by the investigator, were considered to be of mild or moderate intensity. There were no deaths. There were no thromboembolic adverse events and no signs of increased coagulation activity observed. One hypersensitivity adverse event was reported, but was reviewed by an Independent Data Monitoring Committee and considered most likely to be an infusion reaction. No anaphylactic reactions occurred. Local tolerability assessments of very slight or slight infusion site reaction following infusion of Idelvion were reported in <15% of patients. The available data do not suggest a safety concern for self-administration in the home setting. There were no notable findings related to clinical laboratory or vital sign parameters.

Overall, Idelvion appears to have a safety profile indistinguishable from similar clotting factor products. No serious adverse events attributed to Idelvion have been reported and there is no indication that Idelvion has unique risks over and above those of other FIX products in current use. Because of the rarity of congenital FIX deficiency the numbers currently treated are limited and long-term data are not available. These deficiencies are acknowledged and addressed in the safety risk management plan. Idelvion has also not been studied in previously-untreated patients and its immunogenicity in this population is unknown. The sponsor will be submitting results from two ongoing studies to add to the safety data and to complete evidence on inadequately studied groups; that is pediatric patients and previously-untreated patients, as well as to provide more robust data on the possible development of inhibitory antibodies in long-term use.

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

7.2 Non-Clinical Basis for Decision

The non-clinical program for Idelvion (rIX-FP) included pharmacology, pharmacokinetic, and toxicology studies. It was considered complete and compliant with the International Council for Harmonisation (ICH) S6 guidelines.

Short-term animal studies confirmed pharmacologic activity and tolerance of rIX-FP; a no-observed-adverse-effect-level (NOAEL) of 500 IU/Kg in both rats and non-human primates. Similarly repeat-dose studies for 28 days in the same two species showed no ill effect up to doses of 500 IU/Kg.

In a pharmacokinetic study in monkeys, rIX-FP was administered intravenously at doses of 50 IU/kg and 100 IU/kg. The mean terminal half-life was 42.2 hours, which was more than 3 times longer than the published data for the half-life of recombinant human factor IX (rIX, 12.7 hours).

Overall the animal studies demonstrated a well-tolerated product with evidence of a prolonged half-life for rIX-FP as compared with rIX.

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

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

7.3 Quality Basis for Decision

Idelvion, Coagulation Factor IX (Recombinant), Albumin Fusion Protein (rIX-FP), is a long acting purified protein produced by recombinant deoxyribonucleic acid (DNA) technology, generated by the genetic fusion of recombinant albumin to recombinant coagulation Factor IX (rFIX) expressed by Chinese Hamster Ovary (CHO) cells.

Idelvion is a preservative-free, sterile, non-pyrogenic, lyophilized powder to be reconstituted with Sterile Water for Injection for intravenous injection. It is available in single-use vials in the following presentations: 250 IU, 500 IU, 1,000 IU, and 2,000 IU of the active substance rIX-FP.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that rIX-FP 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 and process-related impurities 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, rIX-FP, is produced by recombinant DNA technology CHO cells. The manufacture is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with ICH guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks

The manufacturing process of the drug substance consists of a series of stages which include fermentation, media harvest, clarification, purification (including two dedicated viral inactivation/removal steps). The manufacturing process is well-defined and has in-process controls and acceptance criteria for each manufacturing step. For each critical process step, critical process parameters, normal operating range, and proven acceptable range of the critical process parameters were defined to ensure the process operated in a consistent manner.

The drug product process mainly consists of final bulk formulation, filling and a lyophilisation process. The formulation process consists of diluting the drug substance to the desired formulation strength and excipient level, with formulation buffer and dilution solution.

The materials used in the manufacture of the drug substance/drug product (including biological-sourced materials) are considered to be suitable and/or meet standards appropriate for their intended use.

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

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with ICH guidelines.

The validation reports are considered satisfactory for all analytical procedures used for in-process, release, and stability testing of the drug substance and the drug product. The specifications are considered acceptable. The sponsor has committed to additional method/specification development for one method controlling levels of different forms of rIX-FP. Adequate interim controls are in place.

Data from batch analyses were reviewed and are within the proposed acceptance criteria. The final release results met the acceptance criteria in the final product specification and support the manufacturing consistency for the drug product process.

Idelvion will be placed in lot release group 2 which requires the sponsor to submit samples for testing as well as documentation for review.

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 2-25°C for the 250 IU and 500 IU presentations, and the proposed 36-month shelf-life at 2-25°C for the 1,000 IU and 2,000 IU presentations for Idelvion are considered acceptable.

The container closure system met all validation test acceptance criteria. The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment 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 and testing of the bulk drug intermediate for Idelvion 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 the Idelvion drug product was waived, based on previous experience with the site.

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

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.

Raw materials of animal and recombinant DNA origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. The excipients used in the drug product formulation are not of animal or human origin.

Report a problem or mistake on this page
Please select all that apply:
Date modified: