Summary Basis of Decision for Obizur

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 Obizur is located below.

Recent Activity for Obizur

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 Obizur

Updated: 2024-02-20

The following table describes post-authorization activity for Obizur, a product which contains the medicinal ingredient antihemophilic factor (recombinant), porcine sequence. 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 (DIN):

DIN 02447401 - 500 Units/mL, antihemophilic factor (recombinant), porcine sequence, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 271748

2023-01-24

Issued NOL 2023-04-28

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

NC # 271400

2023-01-13

Issued NOL 2023-04-19

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the qualification of a new lot of reference standard against the approved reference standard and a change to reference standard qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 268812

2022-10-18

Issued NOC 2023-03-10

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Contraindications and Adverse Reactions 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 # 259106

2021-11-29

Issued NOL 2022-02-25

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

SNDS # 251749

2021-04-19

Issued NOC 2021-09-22

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.

Drug product (DIN 02447401) market notification

Not applicable

Date of first sale: 2021-06-08

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

NC # 239919

2020-05-26

Issued NOL 2020-07-15

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. The submission was reviewed and considered acceptable, and an NOL was issued.

NDS # 240729

2020-06-22

Issued NOC 2020-07-14

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

NC # 234901

2020-01-06

Issued NOL 2020-04-06

Submission filed as a Level II (90 day) Notifiable Change to update the PM. As a result of the NC, modifications were made to the Warnings and Precautions; Adverse Reactions; and Overdosage 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.

NC # 231945

2019-09-25

Issued NOL 2019-12-20

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in cell bank/seed bank manufacturing site. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 226868

2019-04-25

Issued NOC 2019-12-10

Submission filed as a Level I – Supplement for the addition of a drug product manufacturer/manufacturing facility. The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DIN 02447401) market notification

Not applicable

Date of first sale: 2019-05-08

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

NC # 219267

2018-08-16

Issued NOL

2018-10-30

 

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

NDS # 214824

 

2018-03-23

Issued NOC

2018-05-04

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

NC # 202408

2017-02-01

Issued NOL

2017-04-28

 

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update an in-process control used in the manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 199056

2016-10-11

Issued NOL

2017-01-13

 

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 02447401) market notification

Not applicable

Date of first sale:

2016-11-30

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

NDS # 177290

2014-08-15

Issued NOC

2015-10-14

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

Date SBD issued: 2015-12-03

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

Antihemophilic Factor (Recombinant), Porcine Sequence
500 Units/mL, powder for solution, intravenous

Drug Identification Number (DIN):

  • 02447401

Baxalta Canada Corporation

New Drug Submission Control Number: 177290

 

On October 14, 2015, Health Canada issued a Notice of Compliance to Baxalta Canada Corporation for the drug product, Obizur.

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 Obizur is favourable for treatment of bleeding episodes in patients with Acquired Hemophilia A (AHA).

 

1 What was approved?

 

Obizur [Antihemophilic Factor (Recombinant), Porcine Sequence] is an antihemmorrhagic agent indicated for the treatment of bleeding episodes in patients with Acquired Hemophilia A (AHA). Obizur temporarily replaces the inhibited endogenous factor VIII that is needed for effective hemostasis in patients with AHA.

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.

Acquired Hemophilia A is typically a geriatric disease (average age 70 years old) where patients can have multiple co-morbidities and concomitant medications. Clinical studies in this population suggest that Obizur is safe and effective. Obizur should be dosed according to the clinical response independent of the age of the patient.

The safety and efficacy of Obizur have not been established in pediatric patients.

Obizur is contraindicated in patients with known anaphylactic reactions to the active substance, any ingredient in the formulation, hamster protein, or any component of the container. Obizur was approved for use under the conditions stated in the Obizur Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Obizur [Antihemophilic Factor (Recombinant), Porcine Sequence, 500 Units/mL] is presented as a powder for solution. In addition to the active ingredient, the powder also contains calcium chloride, Polysorbate 80, sodium chloride, sucrose, tris, 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 Obizur Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Obizur approved?

 

Health Canada considers that the benefit/risk profile of Obizur is favourable for the treatment of bleeding episodes in patients with Acquired Hemophilia A (AHA).

Acquired hemophilia A (AHA) is a rare, but potentially life-threatening, bleeding disorder caused by the development of autoantibodies directed against coagulation factor VIII (FVIII). It occurs in approximately 0.2-1.0 case per 1 million persons per year. Although approximately half of reported cases are idiopathic, several conditions are associated with this disorder including malignancies, autoimmune disease, postpartum, and following drug exposures generally. Treatment involves control of bleeding and treating the underlying condition when possible. The AHA patient population tends to be older (≥65 years of age) with significant co-morbidities.

Obizur is a porcine B-domain deleted recombinant factor VIII (rPFVIII) product and is manufactured in baby hamster kidney cells. Like human FVIII, porcine FVIII activates factor IX in the coagulation cascade, resulting eventually in the development of a fibrin clot and thus promoting coagulation. Porcine FVIII has been of particular therapeutic interest because patients with congenital hemophilia can develop inhibitory alloantibodies to human FVIII, which when bound to an exogenous FVIII product administered to the patient, limit the ability of the FVIII product to function in the coagulation cascade. Patients with AHA acquire this bleeding disorder as a result of the development of autoantibodies to endogenous FVIII which render the patients' own FVIII ineffective.

Currently, there are no approved replacement therapies for AHA patients with inhibitors in Canada. Multiple other bypassing products are used to treat bleeding episodes in AHA patients, including activated prothrombin complex concentrate, FEIBA NF (a Factor VIII Inhibitor Bypassing Agent). Various steroids and chemotherapeutic immunosuppressants are used to eradicate the inhibitors. Unlike the available therapies (bypassing agents), Obizur re-establishes the normal physiologic clotting mechanism by correcting the hemostatic defect via the intrinsic coagulation pathway even in the presence of inhibitors to human factor VIII. The choice of using of a recombinant factor VIII with excipients containing no animal-derived products of the final active substance presents an advantage with regard to viral safety.

Obizur has been shown to be efficacious for treating serious bleeding events in patients with AHA. The market authorization was based on an international, multicentre, open-label, single-cohort, prospective, Phase II/III study where a total of 28 patients with AHA were regarded as evaluable for efficacy. Patients diagnosed with AHA with autoimmune inhibitory antibodies to human factor VIII and experiencing serious bleeding requiring hospitalization were considered evaluable for efficacy. The efficacy of Obizur was assessed primarily by patient response to treatment after 24 hours, both clinically and their FVIII levels achieved. Of the 28 AHA patients, 100% (28/28) had a positive response to treatment at 24 hours, meaning an effective or partially effective response with bleeding stopped or reduced. Data from this pivotal study support the benefit of Obizur treatment for response and effective control of serious bleeding episodes in patients with AHA. The submission contained insufficient data to assess the efficacy of this product to treat subsequent bleeds or to treat bleeds in specific sites, such as intra cranial haemorrhage.

The risks of treatment with Obizur are allergic reactions, the development of inhibitory antibodies to porcine FVIII, and thrombogenicity.

The development of anti-porcine antibodies may reduce the efficacy of this product to treat bleeds; however, the inhibitory antibodies against porcine FVIII were not associated with increased incidence of adverse events, and the maximum increase in titres was not related to dose.

A Risk Management Plan (RMP) for Obizur 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.

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

Overall, the therapeutic benefits seen in the pivotal study are positive and the benefits of Obizur therapy are considered to outweigh the potential risks. Obizur 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 Obizur 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 Obizur?

 

The sponsor filed a request for Priority Review Status under the Priority Review Policy for the review of the new drug submission (NDS) for Obizur. An assessment was conducted to determine if sufficient evidence was provided demonstrating that the drug provides:

  1. an effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada; or
  2. a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for patients with Acquired Hemophilia A, a disease or condition that is not adequately managed by a drug marketed in Canada.

The efficacy results provided from the pivotal studies did not provide evidence of a significant increase in efficacy over existing therapies. In addition, from the safety data provided, it was not possible to judge what safety advantage, if any, is provided by the use of Obizur as opposed to other existing therapeutic options. For these reasons, the informal adjudicator committee determined that the submission did not meet the criteria for Priority Review and therefore the request was denied. The submission was subsequently filed and reviewed as a regular NDS.

The drug submission was placed on Regulatory Hold on September 25, 2015, and communicated to the sponsor on September 28, 2015, to allow a response to the On-Site Evaluation (OSE) Exit Notice for the drug product facility. The response to the OSE Exit Notice was received on October 1, 2015, and the Regulatory Hold was released on October 2, 2015. The submission target date was adjusted from October 8, 2015, to October 14, 2015, due to implementation of this Regulatory Hold. The NDS was issued a Notice of Compliance (NOC) on October 14, 2015.

 

Submission Milestones: Obizur

Submission Milestone Date
Pre-submission meeting: 2013-12-20
Request for priority status  
Filed: 2014-04-30
Rejection issued by Director: 2014-05-29
Refiled: 2014-07-14
Rejection issued by Director: 2014-08-08
Submission filed: 2014-08-15
Screening  
Screening Deficiency Notice issued: 2014-10-10
Response filed: 2014-10-29
Screening Acceptance Letter issued: 2014-12-12
Review  
On-Site Evaluations: 2015-07-20 - 2015-07-24
Quality Evaluation complete: 2015-10-09
Clinical Evaluation complete: 2015-06-23
Labelling Review complete: 2015-10-07
Regulatory Hold  
Submission placed on Regulatory Hold: 2015-09-25
Notice of Compliance issued by Director General: 2015-10-14

 

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.

 

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

 

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 Obizur 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

 

Pharmacologie clinique

Les patients atteints d'hémophilie A acquise (HAA) sont porteurs de gènes normaux du facteur VIII, mais produisent des auto-anticorps dirigés contre leur propre facteur VIII. Ces auto-anticorps neutralisent le facteur VIII humain circulant et créent ainsi un déficit fonctionnel en cette protéine procoagulante. Obizur remplace temporairement le facteur VIII endogène inhibé qui est nécessaire pour une hémostase efficace chez les patients ayant fait l'objet d'un diagnostic d'HAA.

La pharmacodynamique d'Obizur a été évaluée dans le cadre de l'analyse des données sur l'efficacité décrite à la section Efficacité clinique. Aucune étude pharmacocinétique officielle d'Obizur n'a été menée auprès de patients ayant fait l'objet d'un diagnostic d'HAA.

Pour obtenir des renseignements supplémentaires, consultez la monographie du produit Obizur, approuvée par Santé Canada et accessible par l'intermédiaire de la Base de données sur les produits pharmaceutiques.

Efficacité clinique

L'efficacité et l'innocuité d'Obizur pour le traitement d'épisodes hémorragiques graves chez des sujets atteints d'HAA et porteurs d'anticorps inhibiteurs auto-immuns dirigés contre le facteur VIII humain ont été évaluées lors d'une étude de phase II/III internationale, multicentrique, ouverte, à cohorte unique et prospective (n = 29). Les patients atteints d'HAA et porteurs d'anticorps inhibiteurs auto-immuns contre le FVIII humain, qui présentaient un saignement grave nécessitant une hospitalisation, ont été considérés comme étant admissibles pour l'analyse de l'efficacité. Alors qu'un des patients avait été jugé admissible au début de l'étude, il a été établi par la suite qu'il n'était pas atteint d'HAA, ce qui a ramené à 28 le total de patients admissibles pour l'analyse de l'efficacité.

Une dose initiale de 200 unités d'Obizur par kilogramme a été administrée par voie intraveineuse pour le traitement des épisodes hémorragiques initiaux graves. La durée du traitement variait selon la réponse. Le traitement a été instauré pour dix-neuf épisodes de saignement intramusculaire ou articulaire, deux chirurgies, quatre épisodes hémorragiques post-chirurgicaux, deux épisodes intracrâniens, une hémorragie rétropéritonéale et un saignement périorbitaire.

Lors de cette étude, l'efficacité d'Obizur pour la maîtrise des hémorragies graves a été évaluée auprès de sujets atteints d'HAA, d'une part par la réponse au traitement 24 heures après l'administration (telle que déterminée par l'état clinique et les taux d'activité du FVIII), et d'autre part par la fréquence, la dose totale, le nombre de perfusions d'Obizur et le délai requis pour atteindre l'hémostase. Une évaluation efficace ou partiellement efficace était considérée comme une réponse positive avec arrêt de l'hémorragie (taux de FVIII ≥ 50 % du taux normal) ou une réduction de l'hémorragie (taux de FVIII ≥ 20 % du taux normal).

Sur les 28 sujets atteints d'HAA admissibles pour l'analyse de l'efficacité, 100 % (28/28) de ceux qui présentaient initialement des épisodes hémorragiques ont obtenu une réponse positive au traitement à 24 heures. Dans la plupart des cas d'hémorragie, une réponse positive était observée dans les 8 ou 16 heures suivant la première perfusion; 95 % (19/20) des sujets évalués ont obtenu une réponse positive en 8 heures, et 100 % (18/18) en 16 heures. En plus de la réponse au traitement, la réussite globale du traitement était déterminée par le chercheur en fonction de sa capacité à arrêter ou à réduire la dose et/ou la fréquence posologique d'Obizur. En tout, 24 sujets sur 28 (soit 86 %) ont réussi à traiter l'épisode hémorragique initial. Parmi ces sujets traités par Obizur en première intention, c'est-à-dire n'ayant jamais reçu d'agents antihémorragiques immédiatement avant le premier traitement par Obizur, 16 sujets sur 17 (94 %) ont rapporté que le traitement avait fonctionné dans les 8 à 16 heures après la première perfusion. Onze sujets ont rapporté avoir reçu des antihémorragiques avant le premier traitement par Obizur. Sur ces 11 sujets, huit (73 %) ont confirmé l'efficacité du traitement dans les 8 à 16 heures.

Pendant la période initiale de 24 heures, un nombre médian de trois perfusions (dose médiane : 200 unités par kilogramme) a été administré au cours de l'étude clinique. Lorsque le traitement était nécessaire après 24 heures, une médiane de 10,5 perfusions (dose médiane : 100 unités par kilogramme) a été administrée pendant une période médiane de six jours pour maîtriser un épisode hémorragique.

Selon les renseignements fournis, Obizur semble être sûr et offrir un avantage thérapeutique aux patients atteints d'HAA. Il n'existe aucune mention, dans les études cliniques, de réaction d'hypersensibilité ou allergique, d'évènement thromboembolique confirmé ou d'anticorps aux cellules rénales de hamster nouveau-né (BHK).

La dose initiale de 200 unités par kilogramme, associée à l'objectif de maintien du taux du FVIII à 50 % ou plus (≥ 80 % en cas de saignements graves menaçant le pronostic vital) s'est avérée suffisante pour atteindre l'hémostase lors du traitement d'épisodes hémorragiques graves initiaux. Les données étaient insuffisantes pour évaluer le traitement des saignements chez les patients dont les titres en anticorps anti-porcins étaient supérieurs à 20 unités Bethesda. De même, elles n'ont pas permis d'évaluer l'efficacité d'Obizur pour traiter les épisodes hémorragiques graves suivants, car cette étude ne portait que sur trois de ces évènements, dont deux ont donné des résultats probants (soit 67 %). L'étiquetage le signale et évoque également une thérapie parallèle en cas de réponse clinique non adéquate.

L'évaluation d'Obizur visait à définir son efficacité comme traitement d'urgence d'épisodes hémorragiques chez des patients d'HAA porteurs d'anticorps inhibiteurs auto-immuns contre le FVIII. Pour éviter la récurrence des épisodes hémorragiques, ce médicament doit être utilisé en association avec un immunosuppressif et d'autres thérapies de longue durée. Il n'existe aucune donnée sur l'efficacité à long terme d'Obizur.

Pour conclure, les données sur l'efficacité fournies par les 28 patients atteints d'HAA sont suffisantes pour justifier l'approbation d'Obizur dans le traitement des épisodes hémorragiques chez les patients atteints d'HAA.

Pour de plus amples renseignements, consulter la monographie du produit Obizur, approuvée par Santé Canada et accessible par l'intermédiaire de la Base de données sur les produits pharmaceutiques.

Innocuité clinique

Le profil d'innocuité d'Obizur repose principalement sur l'étude de phase II/III décrite à la section Efficacité clinique.

Sur les 29 patients traités lors de l'étude de phase II/III, l'exposition médiane totale s'élevait à 1842 unités par kilogramme (plage de 150 à 27659). Le nombre médian de perfusions quotidiennes par patient était de 1,8 (plage de 0,2 à 5,6), pour un nombre total médian de perfusions de 15 (plage de 2 à 140).

En tout, 264 évènements indésirables (EI) ont été signalés chez 27 des 29 patients (soit 93 %). La plupart de ces évènements étaient bénins (50,4 %) ou modérés (37,9 %). Les EI les plus fréquents étaient la constipation (douze patients, soit 41 %), la diarrhée (sept patients, soit 24 %), l'hypokaliémie (sept patients, soit 24 %), l'anémie (six patients, soit 21 %) et l'œdème périphérique (six patients, soit 21 %). L'évènement indésirable observé le plus souvent chez plus de 5 % des sujets est le développement d'inhibiteurs au FVIII.

Des EI graves ont été signalés chez six patients (soit 21 %) : des douleurs abdominales (n = 2), de la constipation (n = 2), de l'hypocalcémie (n = 2) et de l'œdème articulaire (n = 2).

Six EI bénins ou modérés pouvant avoir un lien avec Obizur ont été observés chez quatre patients (28 %). Un patient a souffert de tachycardie bénigne et d'hypotension intermittente. Un autre a fait l'objet d'une occlusion du conduit du cathéter central inséré par voie périphérique (CCIP). Enfin, deux autres ont développé des inhibiteurs d'Obizur et ont dû arrêter le traitement.

Sept décès sont survenus pendant l'étude, mais il a été conclu qu'aucun n'avait de lien avec le produit.

Les anticorps inhibiteurs dirigés contre Obizur ont été mesurés avec la modification de Nijmegen de l'épreuve de Bethesda. Parallèlement, un essai d'électrochemiluminescence validé a servi à tester les anticorps liants à la protéine de rein de hamster nouveau-né (BHK) chez les patients.

Sur les 29 sujets traités par Obizur, le test des anticorps anti-facteur VIII porcin était négatif au début chez 19 sujets. Cinq sujets sur les 19 (26 %) ont produit des anticorps anti-facteur VIII porcin après l'exposition à Obizur. Sur les 10 sujets porteurs d'anticorps anti-facteur VIII porcin détectables au début, deux (20 %) ont présenté une augmentation du titre. Aucun patient n'a développé d'anticorps liant à la protéine de BHK.

Des valeurs anormales importantes sur le plan clinique ont été observées chez tous les sujets, lesquelles concordaient avec leurs maladies sous-jacentes. Le chercheur a jugé qu'une anomalie de l'hypocoagulabilité (hypofibrinémie) pouvait avoir un lien avec le traitement.

À la lumière des renseignements fournis, Obizur semble être sûr et semble offrir des avantages thérapeutiques aux patients atteints d'HAA. Aucune réaction d'hypersensibilité ou d'allergie ni d'évènement thromboembolique confirmé ou d'anticorps aux protéines de BHK n'ont été signalés dans les études cliniques. Les résultats d'une analyse intégrée de l'innocuité confirment l'innocuité et la tolérabilité d'Obizur pour l'indication proposée du contrôle des épisodes hémorragiques chez les patients atteints d'HAA. Les mises en garde et mesures préventives inscrites dans la monographie de produit approuvée d'Obizur traitent adéquatement de tous les problèmes d'innocuité soulevés.

Pour de plus amples renseignements, consulter la monographie du produit Obizur, approuvée par Santé Canada et accessible par l'intermédiaire de la Base de données sur les produits pharmaceutiques.

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical program consisted of a series of studies to demonstrate the safety and effectiveness of recombinant porcine factor VIII (rPFVIII) in animals. Overall, the non-clinical safety profile of Obizur did not identify any significant concerns. Toxicities that were observed were due to the exaggerated pharmacological effect of excess amounts of coagulation FVIII, which are expected for products in this class.

Repeat-dose toxicity studies were completed with daily dosing of up to 1,000 U/kg for up to 12 weeks (that is, 13.3 times the intended, median prophylactic clinical dose of 75 U/kg) and the product was generally well-tolerated.

Toxicokinetic profiles demonstrated a linear dose-dependent increase in the levels of porcine FVIII, followed by a time-dependent decrease in product levels. This profile was maintained until anti-product antibody formation occurred, resulting in decreased porcine FVIII activity. Although immunologic responses may occur in patients following repeated product administration and are a potential safety concern, the formation of anti-product antibodies in animals is not unexpected and is not predictive of an immunogenic response to rPFVIII in humans.

Based on the intended use of rPFVIII, non-clinical reproductive or developmental toxicity studies, long-term animal studies to evaluate carcinogenic potential, and studies to determine genotoxicity and effects of Obizur on fertility were neither required, according to International Council for Harmonisation (ICH) guidelines, nor performed.

In view of the intended use of Obizur, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Quality Basis for Decision

 

Obizur [Antihemophilic Factor (Recombinant), Porcine Sequence] is a purified protein produced by recombinant deoxyribonucleic acid (DNA) technology. It corresponds to a B-domain deleted porcine FVIII, and is manufactured in cell culture using BHK cells.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that the drug substance 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 manufacturing of the drug substance utilizes a roller bottle cell culture process for cell expansion and recombinant protein expression followed by a series of filtration and chromatographic steps to purify the product from process-related impurities. All raw materials used in the production are sourced from acceptable suppliers and are released against an approved specification. Throughout the cell culture and purification processes, appropriate critical in-process controls and limits are in place to monitor production. The process validation showed adequate control and consistent processing.

The formulated bulk drug substance is further processed for filling, lyophilization, capping, and inspection, and then shipped to another facility for vial labelling and secondary packaging. Throughout the pooling, aseptic filling, lyophilisation, and oversealing, appropriate critical controls and limits are in place to monitor production. The manufacturing process is considered to be adequately controlled within justified limits. In-process controls were established and validated.

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.

Satisfactory validation reports were provided for the key analytical procedures used for release testing of the drug substance and the drug product, and to justify the specifications for both. Data from batch analyses were reviewed and considered to be acceptable according to the specifications of the drug substance and drug product.

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.

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°C to 8°C with light protection and a post-reconstitution stability of 3 hours for the drug product Obizur 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.

On-Site Evaluations of the facilities involved in the manufacture and testing of Obizur were successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada. The process as implemented in the drug substance and drug product facilities was found to be acceptable and all observations issued during the On-Site Evaluations were adequately addressed.

Adventitious Agents Safety Evaluation

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. Two dedicated virus clearance steps are included in the downstream purification process of Obizur, a solvent/detergent treatment step and a nanofiltration step. These steps have been shown to be effective in inactivating or clearing viruses in scaled-down studies.

 

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