Summary Basis of Decision for Beqvez

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.


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Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Beqvez is located below.

Recent Activity for Beqvez

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle. At this time, no PAAT is available for Beqvez. When the PAAT for Beqvez becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Beqvez

Date SBD issued: 2024-10-06

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

Fidanacogene elaparvovec

Drug Identification Number (DIN): 02544156 - 1 x 1013 genome copies/mL, solution, intravenous administration

Pfizer Canada ULC

New Drug Submission Control Number: 275853

Submission Type: New Drug Submission (New Active Substance) - Priority Review

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): B02 Antihemorrhagics

Date Filed: 2023-06-01

Authorization Date: 2023-12-27

On December 27, 2023, Health Canada issued a Notice of Compliance to Pfizer Canada ULC for the drug product Beqvez.

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 Beqvez is favourable for the treatment of adults (aged 18 years or older) with moderately severe to severe hemophilia B (congenital Factor IX [FIX] deficiency) who are negative for neutralizing antibodies to variant adeno‑associated virus (AAV) rhesus serotype 74 (Rh74).

1 What was approved?

Beqvez, an antihemorrhagic, was authorized for the treatment of adults (aged 18 years or older) with moderately severe to severe hemophilia B (congenital Factor IX [FIX] deficiency) who are negative for neutralizing antibodies to variant adeno‑associated virus (AAV) rhesus serotype 74 (Rh74).

The safety and efficacy of Beqvez in children under 18 years of age have not been studied.

The safety and efficacy of Beqvez in patients 65 years of age or older have not been established. Caution should be used when treating geriatric patients.

Beqvez (fidanacogene elaparvovec 1 x 1013 genome copies/mL) is an adeno-associated viral vector-based gene therapy. It is presented as a concentrate solution. The concentrate solution requires dilution prior to intravenous infusion. In addition to the medicinal ingredient, the solution contains disodium phosphate heptahydrate, monosodium phosphate monohydrate, poloxamer 188, sodium chloride, and water for injection.

The use of Beqvez is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient or component of the container.

The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Beqvez Product Monograph is available through the Drug Product Database.

For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

2 Why was Beqvez approved?

Health Canada considers that the benefit-risk profile of Beqvez is favourable for the treatment of adults (aged 18 years or older) with moderately severe to severe hemophilia B (congenital Factor IX [FIX] deficiency) who are negative for neutralizing antibodies to variant adeno‑associated virus (AAV) rhesus serotype 74 (Rh74).

Hemophilia B is a bleeding disorder caused by mutations in the gene for Factor IX located on the long arm of the X chromosome, primarily inherited via the germline and therefore occurs almost exclusively in males. The mutations result in a lack of production of or a dysfunctional Factor IX coagulation protein, leading to abnormally decreased blood clot formation and prolonged bleeding. Bleeding episodes may occur spontaneously or after a traumatic event. The World Federation of Hemophilia (WFH) annual global survey of 2021 identified 37,998 individuals with hemophilia B globally, 727 of whom (across all disease severities) are in Canada. The estimated incidence of hemophilia B is 5.0 cases per 100,000 males for all severities, and 1.5 cases per 100,000 males for severe hemophilia B (where Factor IX activity is less than 1% of normal values).

In Canada, children and adults with hemophilia B currently rely primarily on intravenously administered Factor IX replacement therapies to treat and prevent bleeding episodes. Patients with severe disease (less than 1% of normal Factor IX activity) or moderately severe disease (1% to less than 2% of normal Factor IX activity) are the most likely to require routine prophylaxis with Factor IX. Individuals with moderate disease (2% to 5% of normal Factor IX activity) or mild disease (6% to less than 50% of normal Factor IX activity) may only need periodic treatment with Factor IX replacement therapy to treat random bleeds, or to use before surgery (episodic use).

For routine prophylaxis in individuals who require regular therapy, Factor IX replacement therapy is administered intravenously every 2 to 3 days (for products with standard half‑life) or every 5 to 7 days (for products with extended half‑life). Although replacement therapy can be effective, it is also burdensome, particularly in very young patients where adequate venous access may be challenging and a central line is required (or preferred) for the administration of the Factor IX product. For other patients, Factor IX replacement therapy is still not adequate to prevent or control bleeding episodes leading to chronic joint pain, which can eventually result in crippling disabilities. In rare instances, internal bleeding such as intracranial hemorrhages can occur, which could be fatal.

Beqvez (fidanacogene elaparvovec) is a gene therapy consisting of the hyperactive human coagulation Factor IX Padua variant (R338L), which is packaged within a recombinant adeno-associated virus (AAV) rhesus serotype 74 (Rh74var), under the control of a liver promoter. The gene encoding the Padua variant of human Factor IX is reported to result in a 5 to 10-fold increase in Factor IX activity compared to the wild-type Factor IX gene sequence. Beqvez is intended to be used as a single dose infusion to provide relatively stable endogenous expression of Factor IX to help reduce or eliminate dependence on Factor IX therapy, although long-term follow-up is ongoing to determine if effective bleeding control can be maintained over many years without requiring Factor IX replacement therapy.

The market authorization of Beqvez was primarily based on efficacy and safety data derived from one pivotal Phase III, open-label, single-arm study (C0371002). This study enrolled 45 adult male hemophilia B patients with moderately severe or severe disease (defined as Factor IX activity less than or equal to 2%) who were negative for neutralizing antibodies to variant AAV serotype Rh74. Patients completed at least 6 months of standard of care lead‑in Factor IX prophylaxis prior to receiving a single intravenous infusion of 5 x 1011 (vg/kg) of Beqvez.

The primary efficacy endpoint of the study was the annualized bleeding rate (ABR) for total bleeds (ABRtotal; treated and untreated) from Week 12 to Month 15 versus usual care Factor IX prophylaxis replacement regimen, comparing pre‑ and post‑Beqvez infusion. The non-inferiority of Beqvez compared to the lead-in treatment with prophylactic Factor IX was demonstrated as the upper bound for the 95% confidence interval of the treatment difference in ABRtotal (post‑Beqvez - lead‑in Factor IX prophylaxis) was lower than the pre‑specified non‑inferiority margin of 3. The model‑based estimate of the ABRtotal post‑infusion of Beqvez was 2.17 (95% confidence interval [CI]: 0.64, 3.70) compared to 4.51 (95% CI: 1.85, 7.17) with Factor IX prophylaxis (treatment difference: -2.34 [95% CI: -4.97, 0.29]).

The most frequently reported adverse reaction with Beqvez was transaminitis (hepatotoxicity), which is thought to be caused by an immune‑related response to AAV vector transduction. In Study C0371002, 62% (28/45) of patients received corticosteroids due to presumed immune‑mediated events including the elevation of liver enzymes and/or reduction in Factor IX. The use of corticosteroids was associated with numerically lower mean Factor IX activity.

Although not observed in patients, theoretical risks of Beqvez include the potential for insertional mutagenesis which could lead to the development of malignancies, particularly liver cancer due to integration of the liver‑targeting AAV vector. The Beqvez Product Monograph recommends that patients with pre-existing risk factors for liver cancer should receive regular abdominal ultrasound screenings and be monitored annually for alpha-fetoprotein elevations for five years following treatment of Beqvez.

Shedding of Beqvez viral/transgene DNA into semen has been reported. Since viral/transgene DNA was detected in the semen of patients up to 154 days following a dose of 5 x 1011 (vg/kg) of Beqvez, the Product Monograph recommends the use of barrier contraception for male patients and their female partners of child-bearing potential for one year after Beqvez treatment.

A Risk Management Plan (RMP) for Beqvez was submitted by Pfizer Canada ULC to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme, and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.

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

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Beqvez was accepted.

Beqvez 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 Beqvez 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 issued 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 Beqvez?

The New Drug Submission (NDS) for Beqvez was subject to an expedited review process under the Priority Review of Drug Submissions Policy. The sponsor presented substantial evidence of clinical effectiveness to demonstrate that Beqvez provides effective treatment of a serious, life‑threatening or severely debilitating disease, and that the overall benefit‑risk profile of Beqvez is improved over existing therapies.

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

Submission Milestones: Beqvez

Submission Milestone

Date

Pre-submission meeting

2023-03-14

Request for priority status filed

2023-04-20

Request for priority status approved

2023-05-18

New Drug Submission filed

2023-06-01

Screening

Screening Acceptance Letter issued

2023-06-30

Review

Review of Risk Management Plan completed

2023-11-21

Non-clinical evaluation completed

2023-12-21

Clinical/medical evaluation completed

2023-12-21

Biostatistics evaluation completed

2023-12-21

Labelling review completed

2023-12-22

Quality evaluation completed

2023-12-22

Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate

2023-12-27
4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Food and Drug Regulations.

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

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

At this time, no PAAT is available for Beqvez. When available, the PAAT will be incorporated into this SBD.

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

6 What other information is available about drugs?

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

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

Clinical Pharmacology

The clinical pharmacology program focussed on two key aspects, the evaluation of vector shedding and the evaluation of vector-derived Factor IX activity for fidanacogene elaparvovec, the medicinal ingredient in Beqvez.

Vector shedding was evaluated by a validated quantitative polymerase chain reaction method. In Study C0371002, Factor IX activity was evaluated by two one-stage activated partial thromboplastin time methods (Actin-FSL, HemosIL SynthASil) and one chromogenic assay method. Supportive studies only employed the one-stage assay using Actin-FSL reagent.

Regarding vector shedding, in Study C0371002 peak vector deoxyribonucleic acid (DNA) concentrations occurred within two weeks of infusion. Plasma, saliva, and semen vector DNA were below the lower limit of quantification (LLOQ) for three consecutive assessments within 1 to 4 months after infusion. Vector DNA remained above the LLOQ in peripheral blood mononuclear cells longer than in other matrices (with time to reach clearance of vector DNA within mean of approximately seven months and a maximum of 513 days). Vector DNA in urine was very low compared to that in plasma and clearance occurred within three weeks of infusion. Vector DNA in semen presents a risk of germ-line transmission. The maximum time to reach clearance of vector DNA from semen was 154 days. Given the small sample size and reliance on the LLOQ to determine clearance rather than the limit of detection, precautions (e.g., contraception) for at least one year are recommended to prevent transmission of vector DNA.

Study C0371002 evaluated Factor IX activity over the course of 15 months in patients who had documented Factor IX activity of 2% or less. The mean steady‑state Factor IX activity as measured by Actin‑FSL assay was 12.62% (geometric mean of values collected from Week 12 to Month 15). The Factor IX steady‑state value as measured by HemosIL SynthASil assay was 25.90% while the chromogenic assay mean steady‑state value was 13.49%. The differences between assays were consistent at different time‑points throughout the study. Accordingly, recommendations have been included in the Beqvez Product Monograph suggesting that patients be monitored using a single assay by a single laboratory.

A compartmental model for gene and protein expression in combination with 3‑compartment models for FIX disposition to account for the contribution of extended half-life and standard half-life FIX products on overall FIX activity adequately described the time-course of fidanacogene elaparvovec derived FIX activity observed in three fidanacogene elaparvovec studies. Body weight was the only dosing factor impacting fidanacogene elaparvovec derived Factor IX activity that was considered clinically important. The labelled dosing recommendations are based on the dosing practices in the clinical studies and limit the dose based on the patient’s body mass index. Patients having a body mass index of 30 kg/m2 or more require a dosing modification.

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

Clinical Efficacy

The efficacy of Beqvez was evaluated in the ongoing Phase III, open‑label, single‑dose, single‑arm multicentre Study C0371002 in adult males with moderately severe to severe hemophilia B (defined as Factor IX activity less than or equal to 2%). A total of 45 patients who completed at least 6 months of a lead-in study with standard of care Factor IX replacement therapy proceeded to a single intravenous infusion of 5 x 1011 vg/kg of Beqvez. For participants with a body mass index greater than 30 kg/m2, the dose was calculated based on an adjusted body weight determination that assumes a maximum permissible body mass index of 30 kg/m2.

Study eligibility required that all patients be screened for neutralizing antibodies to the adeno-associated virus (AAV) rhesus serotype 74 (AAVRh74var) using a cell‑based antibody‑mediated neutralization assay. A total of 61.1% of screened patients who were positive for neutralizing antibodies (titer ≥1:1) were excluded from the study. Patients were also excluded if they were less than 18 years of age or older than 65 years of age. Other exclusion factors included, prior history of Factor IX inhibitor or positive Factor IX inhibitor test results at screening, active hepatitis B or C infection, alanine aminotransferase, aspartate transaminase, or alkaline phosphatase greater than two times the upper limit of normal, bilirubin greater than 1.5 times the upper limit of normal, unstable liver or biliary disease defined by the presence of ascites, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis, significant liver fibrosis or significant liver disease (defined as portal hypertension, splenomegaly and hepatic encephalopathy), creatinine greater than 2.0 mg/dL, platelets less than 100,000 cells/mcL and human immunodeficiency virus infection with either CD4+ cell count 200 mm3 or less or a viral load greater than 20 copies/mL. Of the 45 patients enrolled, 33 (73.3%) were White, 7 (15.6%) were Asian, 1 (2.2%) was Black or African American, and 4 (8.9%) did not report their ethnicity.

The primary efficacy endpoint in Study C0371002 was to demonstrate non‑inferiority of Beqvez (from Week 12 to Month 15 post-infusion) compared to lead-in Factor IX replacement prophylaxis with respect to the total annualized bleeding rate (ABRtotal).

During the efficacy evaluation period, 5 of 45 (11.1%) Beqvez-treated patients resumed Factor IX prophylaxis during the Week 12 to Month 15 period (i.e., post‑Beqvez infusion). Given that the resumption of exogenous Factor IX post-Beqvez infusion can bias the estimated treatment effect, these 5 subjects were multiply imputed for the period from the date of resumption to Month 15 in the primary efficacy analysis using a negative binomial distribution under a conservative assumption of mean ABRtotal of 20 (equivalent to bleeding counts during on-demand treatment) with a dispersion parameter of 0.5 to reflect the high variability in bleeding counts under on-demand treatment. The model-based estimate of the ABRtotal was 2.17 (95% confidence interval [CI]: 0.64, 3.70) post‑infusion with Beqvez compared to 4.51 (95% CI: 1.85, 7.17) with Factor IX prophylaxis (treatment difference: -2.34 [95% CI: -4.97, 0.29]).

Based on the above analysis, the pivotal study met the primary endpoint by demonstrating that a single infusion of 5 x 1011 vg/kg of Beqvez was non‑inferior to Factor IX prophylaxis for the ABRtotal in patients with moderately severe and severe hemophilia B who did not have detectable neutralizing antibodies to the AAVRh74var. Non‑inferiority of Beqvez treatment was demonstrated as the upper bound for the 95% confidence interval of the treatment difference in ABRtotal (post‑Beqvez – lead‑in Factor IX prophylaxis) was lower than the pre‑specified non‑inferiority margin of 3. A single infusion of Beqvez increased the percentage of patients without any bleeds compared to Factor IX replacement treatment (64.4% versus 28.9%, respectively). Sixty-four percent of patients did not receive any injections of exogenous Factor IX post‑Beqvez infusion.

Indication

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

Beqvez (fidanacogene elaparvovec) is an adeno-associated viral vector-based gene therapy indicated for the treatment of moderately severe to severe Hemophilia B in patients 18 years of age and older.

Health Canada approved the following indication:

Beqvez (fidanacogene elaparvovec) is an adeno-associated viral (AAV) vector-based gene therapy for the treatment of adults (aged 18 years or older) with moderately severe to severe Hemophilia B (congenital Factor IX deficiency) who are negative for neutralizing antibodies to variant AAV serotype Rh74.

The sponsor’s proposed indication was revised by Health Canada to better align with the patient population enrolled in the C0371002 study.

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

Clinical Safety

The clinical safety of Beqvez was evaluated in 60 patients who received a single intravenous dose of 5 x 1011 vg/kg of Beqvez. The most frequently reported treatment emergent adverse event (TEAE) was transaminitis (43.3%). Overall, 52% (31/60) of the patients in the safety data set received corticosteroids due to presumed immune-mediated elevations of liver enzymes and/or significant reductions in Factor IX. Corticosteroid use was associated with numerically lower Factor IX activity compared to participants who did not require corticosteroids.

Two serious adverse reactions related to Beqvez were anemia and duodenal ulcer hemorrhage in one patient after receiving corticosteroid treatment for the management of transaminase increases, without gastric acid prophylaxis.

Important potential safety concerns with AAV vector-based gene therapies, such as Beqvez, include integration of viral/transgene deoxyribonucleic acid (DNA) into the genome of the host. This has the potential to lead to tumorgenesis, particularly hepatocellular carcinoma from integration of the liver-targeting vector. While Beqvez remains largely in episomal form in cells, DNA integration events have been reported in non-clinical studies. No events of hepatocellular carcinoma, or other malignancies related to Beqvez, were reported in the clinical trials. Nonetheless, it is recommended that patients with pre‑existing risk factors for hepatocellular carcinoma receive regular abdominal ultrasound screenings and are monitored annually for alpha‑fetoprotein elevations in the 5 years following the administration of Beqvez.

Shedding of Beqvez viral/transgene DNA fragments into semen has been observed up to 154 days following a dose of 5 x 1011 vg/kg of Beqvez. To address the potential for germ-line transmission, the Beqvez Product Monograph recommends barrier contraception for male patients and their female partners of child-bearing potential for one year post-Beqvez infusion.

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

7.2 Non-Clinical Basis for Decision

Fidanacogene elaparvovec (also known as Beqvez), is a recombinant adeno-associated viral vector (AAV) containing a codon-optimized deoxyribonucleic acid (DNA) sequence for human coagulation Factor IX variant R338L (hFIX-Padua).

No product‑related adverse findings were observed in a 92‑day single‑dose intravenous general toxicity study in cynomolgus monkeys at doses up to 5 × 1012 vg/kg, using AAV-Spark100[rh74var]-hFIX19-Padua (same capsid and expressed protein as fidanacogene elaparvovec).

No dedicated carcinogenicity studies were conducted with fidanacogene elaparvovec.

A two‑year vector integration study was performed in which cynomolgus monkeys were administered 5 × 1012 vg/kg of fidanacogene elaparvovec (10 times the recommended human dose). There were no product‑related adverse events at two years. Both transgene DNA and co‑purified/co‑packaged DNA impurities (from packaging plasmids) were assessed. There were no indications that integrated DNA resulted in altered liver function, or hepatocellular hyperplasia and carcinoma. The integration profile was considered low risk as the integrations were mostly distributed uniformly throughout the genome. Enrichment was observed in chromosome 7 and 19, and common insertion sites were identified. There was no indication of significant clonal expansion. Overall, integration is estimated at less than 0.1%.

Studies have not been conducted to investigate the impact of Beqvez on reproductive toxicity and impairment of fertility. Quantitative real-time polymerase chain reaction was used to detect human Factor IX DNA in the semen of New Zealand rabbits infused with up to 1 × 1013 vg/kg of AAV‑Spark100‑hFIX19‑Padua or AAV‑Spark100‑hFIX16 (expresses the wild‑type form of Factor IX transgene). Transgene DNA was observed for up to five months in one animal. This study used up to 20 times the recommended human dose.

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

7.3 Quality Basis for Decision

Characterization of the Drug Substance

Fidanacogene elaparvovec, the medicinal ingredient in Beqvez, is a recombinant adeno‑associated virus (AAV) containing a codon-optimized coding deoxyribonucleic acid (DNA) sequence for the human coagulation Factor IX variant R338L (hFIX-Padua).

Detailed characterization studies were performed to provide assurance that fidanacogene elaparvovec consistently exhibits the desired characteristic structure and biological activity. The characterization focused on capsid identity and composition, vector genome identity and composition, biophysical heterogeneity, post‑translational modifications, and biological activity using a wide variety of techniques.

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

Fidanacogene elaparvovec is produced using a human embryonic kidney cell line (HEK293) that is transiently transfected using plasmids encoding fidanacogene elaparvovec components.

Drug Substance

The drug substance manufacturing process consists of an upstream and downstream stage.

The upstream process begins with the thaw of the HEK293 working cell bank. The thawed contents are expanded to a sufficient quantity, transfected with plasmids in solution, cultured, and harvested to generate the AAV-containing process intermediate.

The downstream process involves a series of column chromatography and virus filtration purification steps to remove impurities and potential adventitious viruses, and filtration to exchange buffers and achieve final product concentration. Finally, the process intermediate is formulated, filtered, and dispensed into bottles. The resulting drug substance is stored prior to manufacturing of the drug product.

Drug Product

The drug product manufacturing process begins with the thawing and pooling of the drug substance. The drug substance pool is mixed in a pre‑sterilized bioprocessing container. The bulk drug substance is then transferred through a sterilizing filter into a separate, pre‑sterilized bioprocess container, and aseptically filled into pre‑sterilized vials. Each vial is 100% visually inspected.

The manufacturing processes for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.

None of the excipients found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of the fidanacogene elaparvovec with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

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

The proposed drug substance and drug product specifications were appropriately justified. The tests are appropriate to assess the drug substance and drug product identity, purity, potency, as well as general physiochemical characteristics. The acceptance criteria were appropriately justified, and the analytical methods were validated.

The data reviewed demonstrate a sufficient knowledge of both process- and product-related impurities and an understanding of their potential safety impacts. Impurities are monitored as part of routine drug substance and drug product batch release, and are deemed adequately characterized and/or controlled.

Batch analysis results were submitted and all test results met acceptance criteria. Based on these data, the manufacturing process is considered adequately controlled and able to consistently yield drug substance and drug product of the required quality.

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. The proposed 36 month shelf life when transported at -100°C to -60°C and stored at -90°C to -60°C is considered acceptable. The product must be stored upright in its original package and protected from direct sunlight and ultraviolet light. Additional storage and special handling instructions are included in the Product Monograph.

Facilities and Equipment

A Virtual Evaluation of Process and Facility (VEPF) was conducted remotely at the drug product manufacturing site. The VEPF activities focused on evaluation and witnessing of manufacturing steps, quality control and testing, quality systems, the quality agreements, review issues, facilities, and product development. The facility was issued a compliant rating with no observations. The results of the VEPF supported a positive recommendation following the review of the quality data package of the Beqvez submission.

Adventitious Agents Safety Evaluation

The starting materials, including the HEK293 working cell bank and plasmids, were developed and prepared using traceable materials of animal origin, and were qualified according to applicable guidelines.

Ancillary materials of biological origin are used in the production of fidanacogene elaparvovec. Appropriate biological safety documentation was provided.

The drug substance manufacturing process includes multiple viral clearance steps, including chromatography and virus filtration steps. Virus clearance studies were conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline Q5A(R1).

The drug substance manufacturing process includes an in‑process control at the time of harvest, where a crude harvest sample is analyzed by an in vitro test for adventitious viral agents.

Overall, the control strategy concerning adventitious virus agents and the drug substance manufacturing process was deemed acceptable.

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