Summary Basis of Decision (SBD) for Imjudo

As outlined in the What steps led to the approval of Imjudo? section, the clinical review of the New Drug Submission for Imjudo was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

Clinical Pharmacology

Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) is a negative regulator of T‑cell activity that is primarily expressed on the surface of T lymphocytes. The interaction of CTLA-4 with its ligands, cluster of differentiation (CD) 80 (CD80) and CD86, limits effector T-cell activation, through a number of potential mechanisms, but primarily by limiting co-stimulatory signalling through CD28. Tremelimumab, the medicinal ingredient in Imjudo, is a selective, fully human immunoglobulin G2 (IgG2) antibody that blocks CTLA-4 interaction with CD80 and CD86, thus enhancing T-cell activation and proliferation, which may result in increased T-cell diversity and enhanced antitumour immune activity.

The clinical pharmacology assessment of Imjudo (tremelimumab) in combination with durvalumab included pharmacokinetic, pharmacodynamic, and immunogenicity analyses.

The pharmacokinetics of Imjudo was investigated in the pivotal HIMALAYA study and in 16 supportive studies that included patients with different types of solid tumours. The studies investigated the following dose range: 300 mg single-dose, 75 mg every 4 weeks (Q4W), 1 mg/kg Q4W, 750 mg Q4W, and 10 mg/kg every 2 weeks. The pharmacokinetic analysis suggested dose-dependent exposure to Imjudo, however, no significant covariates on exposure of Imjudo were identified through population pharmacokinetic modelling.

The HIMALAYA study also compared the pharmacokinetics of durvalumab monotherapy, and 300 mg and 75 mg doses of Imjudo when dosed with durvalumab (D vs. T300+D versus [vs.] T75+D). Based on data from the HIMALAYA study, administration of Imjudo plus durvalumab had no impact on the exposure of durvalumab. An exposure-response analysis for overall survival (OS) and progression-free survival (PFS) was conducted with data from patients who received D, T75+D and T300+D in the HIMALAYA study. Imjudo area under the concentration-time (AUC) curve at Cycle 1 (AUC_{dose 1}) and maximum concentration (C_max) at Cycle 1 (C_{max,dose 1}) were found to be associated with OS and PFS, respectively, at the Imjudo T300 dose. The data therefore supported selection of a single 300 mg Imjudo dose plus durvalumab. Following a single 300 mg dose of Imjudo, exposures as measured by geometric mean AUC and C_max were 763 µg•day/mL and 86.5 µg/mL, respectively.

The flat 300 mg dose of Imjudo for patients above 30 kg was also supported by Study D4190C00022 (Study 22), where a similar C_max and trough concentration (C_trough) were observed following the weight‐based and the equivalent fixed dosing regimen of Imjudo and durvalumab. Dose adjustment for individuals weighing less than 30 kg was recommended given that the body weights of all patients in the HIMALAYA study and in Study 22 were above 30 kg and there were no data available on the safety and tolerability of this dose regimen in patients with extremely low body weight (≤30 kg). Therefore, in order to prevent over exposure in these patients, it was recommended that patients with a body weight of 30 kg or less at the start of treatment receive a weight‐based dosing of Imjudo 4 mg/kg and durvalumab 20 mg/kg for the combination dose at Cycle 1.

The pharmacodynamics assessment was based on Study 22 in which increases in CD8+Ki67+ T cells by durvalumab were enhanced by Imjudo at 300 mg, and this was concomitant with the highest objective response rate in the Imjudo plus durvalumab (T300+D) arm. This increase may indicate an enhanced antitumour immune activity provided by Imjudo.

The effect on electrocardiogram intervals was evaluated in a Phase I, open‑label study of Imjudo (at 1, 3 or 10 mg/kg) in combination with durvalumab (at 3, 10, 15 or 2  mg/kg) administered to patients with advanced non-small cell lung cancer, and no relationship was observed between tremelimumab concentration and QTc intervals.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs], which have the potential to neutralize the biological activity of the drug). There was no identified clinically significant effect of anti-tremelimumab antibodies on the pharmacokinetics or safety of Imjudo in the HIMALAYA study; however, the effect of anti‑drug antibodies and neutralizing antibodies on the effectiveness of Imjudo remains unknown.

No significant issues were identified in the clinical pharmacology data. The clinical pharmacology data support the use of Imjudo for the recommended indication.

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

Clinical Efficacy

Pivotal Study

The efficacy of Imjudo in combination with durvalumab was evaluated in the pivotal HIMALAYA study, an ongoing Phase III, randomized, open-label, multicentre study in patients with confirmed unresectable hepatocellular carcinoma (uHCC) who did not receive prior systemic treatment for hepatocellular carcinoma (HCC). The study included patients with Barcelona Clinic Liver Cancer (BCLC) Stage C or B (not eligible for locoregional therapy), Child-Pugh Score Class A, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (fully active or restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature).

A total of 1,171 patients were randomized (1:1:1) to the Imjudo plus durvalumab (T300+D) arm (total number [n] = 393), the durvalumab (D) monotherapy arm (n = 389) or the sorafenib (S) monotherapy arm (n = 389). Patients were stratified by macrovascular invasion (MVI), etiology of liver disease (confirmed hepatitis B virus [HBV] versus [vs.] confirmed hepatitis C virus [HCV] vs. others) and by ECOG Performance Status (0 vs. 1). Of the randomized patients, 83.7% were male, and 50.4% were over 65 years of age with a median age of 64 years (range: 18 to 88 years). The majority were white (44.6%) or Asian (50.7%), and 1.7% were black or African American. The baseline ECOG performance status was 0 for 63.8% of patients and 1 for the other 37.2%. Patient distribution by BCLC stage was 19.2% Stage B and 80.8% Stage C, while distribution by liver disease etiology was 30.6% HBV, 27.2% HCV, and 42.2% others. Taking into consideration other important prognostic factors at baseline, 25.2% of patients had MVI, 53.4% had extrahepatic spread (EHS), 34.5% had alpha-fetoprotein (AFP) ≥400 ng/mL, 46.8% had an albumin-bilirubin (ALBI) score of 2, and 0.5% with ALBI score of 3. Imbalances between arms were observed in terms of the demographics and baseline disease characteristics in HCV patients.

Patients treated with the combination therapy of Imjudo plus durvalumab received a single dose of Imjudo 300 mg in combination with durvalumab 1500 mg, followed by durvalumab 1500 mg as a single agent every 4 weeks. Patients in the two other arms received either durvalumab 1500 mg as a single agent every 4 weeks or sorafenib 400 mg orally twice daily. Patients were treated until the occurrence of disease progression or unacceptable toxicity.

The primary efficacy endpoint was overall survival (OS) comparing the T300+D arm and the S arm for superiority in the intention-to-treat (ITT) population. The key secondary endpoint was OS comparing the D arm and the S arm for superiority.

Initially, data from the final OS analysis were submitted which presented an analysis of the primary endpoint based on the unadjusted stratified Cox model. The median follow-up in T300+D, D and S was 33.2, 32.7 and 32.2 months, respectively. In the ITT population, death occurred in 66.7%, 72.0% and 75.3% of patients in the T300+D, D, and S arms, respectively, while the median OS was 16.4, 16.6 and 13.8 months, respectively. A statistically significant OS improvement was shown for the T300+D compared to S, with a hazard ratio (HR) of 0.78 (95% confidence interval [CI]: 0.66, 0.92, p-value: 0.0035) and a moderate improvement in median OS of 2.6 months. Conversely, D alone failed to show superiority as compared to S with a HR of 0.86 (95% CI: 0.73, 1.02, p‑value: 0.0674); however, non-inferiority was achieved as the upper bound of the 95% CI fell within the prespecified non-inferiority margin of 1.08.

Results from the subgroup analysis by the stratification factor of liver disease etiology suggested a lack of OS treatment benefit of T300+D relative to S in patients with HCV-positive uHCC (n = 214, HR: 1.06). Substantial baseline imbalances were identified among the three arms in this HCV-positive uHCC subgroup with respect to EHS, ALBI score, AFP and BCLC. In the presence of randomization within this subgroup, such imbalances are unlikely. Health Canada requested that the sponsor explain these imbalances and did not accept the provided explanation. To account for the impact of these imbalances, a stratified Cox model adjusting for EHS, ALBI score, AFP and BCLC was conducted. Based on the results of the adjusted Cox model, the estimated OS HR for HCV-positive uHCC subgroup comparing T300+D to S was 0.92 (95% CI: 0.65, 1.30). The findings for the HCV-positive uHCC subgroup did not suggest a treatment benefit and were not consistent with the findings from the other two liver disease etiology subgroups, in which the OS HR for HBV is 0.60 and the OS HR for others is 0.78. The observed baseline imbalances also suggested that the unadjusted Cox regression model analysis of OS for the ITT population was not appropriate as it did not account for these imbalances. On March 10, 2023, a Notice of Non-Compliance was issued as Health Canada concluded that substantial evidence supporting the benefit of Imjudo in combination with durvalumab for the treatment of uHCC could not be established at that time. Health Canada requested that the sponsor reanalyze the primary endpoint of OS using an adjusted Cox regression model, which is deemed to produce more robust and reliable results.

In their response to the NON, the sponsor accepted this recommendation and submitted OS HR results from the adjusted Cox regression model presented for both the final analysis and the subgroup analysis by liver disease etiology. The ITT findings between the adjusted and the unadjusted models were substantially different for D vs. S. With the adjusted analysis, a statistically significant OS treatment benefit was shown for the D arm. Based on the results from the adjusted Cox model accounting for the observed baseline imbalances, a statistically significant OS improvement as compared to the control arm (S) was demonstrated for both the T300+D combination therapy (HR: 0.76 [95% CI: 0.64, 0.90, p value: 0.0013]) and the D monotherapy (HR: 0.83 [95% CI: 0.70, 0.98, p-value: 0.0293]. This represents a 24% and 17% reduction in the risk of death, with T300+D and D therapy, respectively. Of note, uncertainty remains regarding the treatment effect of Imjudo, given the small difference in the OS treatment benefit between the T300+D arm (HR: 0.76) and the D arm (HR: 0.83) relative to the S arm. In the presence of substantial baseline imbalances, the findings from the adjusted Cox regression model were deemed to be more appropriate for decision making and labelling. In their response to the NON, the sponsor submitted a revised Product Monograph for Imjudo in which OS HR results from the adjusted Cox regression model are presented in both the final analysis and the subgroup analysis by liver disease etiology.

Supportive Study

Study 22 was a Phase I/II study examining the safety, tolerability, and clinical activity of Imjudo (T) and durvalumab (D) as monotherapy, or Imjudo in combination with durvalumab (T300+D) in patients with advanced HCC who had progressed on, were intolerant of, or refused sorafenib-based therapy. The study was composed of four parts. Data from parts 2 and 3 were combined and the overall response rate (ORR) was reported to be 24% in the T300+D arm (n = 75), 12% in the D arm (n = 104), and 7% in the T arm (n = 69).

Overall, the results were considered as supportive only, due to the following: there was no formal statistical testing of efficacy endpoints; the pooling of data from parts 2 (non-randomized) and 3 (randomized) was inadequately justified; it was an exploratory Phase I/II study with a relatively small sample size; the study population was different from the pivotal study (first and second lines versus [vs.] first line); and the results of the T arm provided limited support for the efficacy of Imjudo in the T300+D regimen due to different dosing (10 mg/kg every four weeks followed by every 12 weeks for the T arm in Study 22).

Indication

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

Imjudo (tremelimumab for injection) in combination with Imfinzi (durvalumab) is indicated for the treatment of patients with unresectable hepatocellular carcinoma (uHCC).

To support safe and effective use of the product, Health Canada approved the following indication:

Imjudo (tremelimumab for injection) in combination with durvalumab is indicated for the first‑line treatment of adult patients with unresectable hepatocellular carcinoma (uHCC) who require systemic therapy.

When using Imjudo in combination with durvalumab, consult the Product Monograph for Imfinzi (durvalumab) for further information on this drug.

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

Clinical Safety

The clinical safety of Imjudo was primarily evaluated in the pivotal HIMALAYA study described in the Clinical Efficacy section.

In the safety analysis set, the median duration of treatment was 5.5 months (range: 0.4, 42.7), 5.5 months (range: 0.2, 44.4), and 4.1 months (range: 0.1, 38.6) months in the T300+D, D, and S arms, respectively.

The most common adverse events (AEs) reported in at least 10% of the patients who received Imjudo in combination with durvalumab (T300+D) were pruritus, diarrhea, rash, fatigue, decreased appetite, pyrexia, increased aspartate aminotransferase (AST), hypothyroidism, nausea, abdominal pain, insomnia, and asthenia. Of all patients in this arm, 50.5% reported Grade 3 or 4 AES, with the most common (occurring in at least 5% of patients) being increased lipase and AST. Adverse events leading to dose delays or interruption of any study treatment were reported in 34.5% of patients in this arm and 13.7% reported discontinuation due to an AE. Serious adverse events (SAEs) occurred in 40.5% of patients receiving T300+D, with the most commonly reported SAEs (reported in at least 1% of patients) being pneumonia (1.8%), anaemia (1.3%), diabetes mellitus (1%), pneumonitis (1%), ascites (1%), upper gastro-intestinal haemorrhage (1.8%), sepsis (2.1%), diarrhea (2.3%), death (1%), and pyrexia (1%).

The safety results from the HIMALAYA study demonstrated that the frequencies of AEs in the T300+D and D were higher with increasing age. Adverse events possibly related to treatment were 72.1%, 79.8%, and 85.7% for patients younger than 65 years, 65 years to less than 75 years, and 75 years or older, respectively. There was a higher rate of fatal AEs in patients 65 years or older (10.6%) relative to patients who were younger than 65 years (4.0%). In addition, there was a higher rate of AEs leading to discontinuation in patients 65 years or older (18.6%) relative to patients who were younger than 65 years (8.4%).

Adverse events with outcome of death occurred in 7.7% of patients treated with T300+D vs. 6.7% of patients treated with durvalumab (D) monotherapy and 7.2% of patients treated with sorafenib (S) monotherapy. Fatal adverse events possibly related to treatment as assessed by the investigator in T300+D occurred in 2.3% of patients and included hepatitis, myocarditis, immune-mediated hepatitis (2 patients), pneumonitis, myasthenia gravis, nervous system disorder, acute respiratory distress syndrome, and hepatic failure. By comparison, no treatment-related fatal AEs were reported in the D arm, and 0.8% were observed in the S arm. The majority of these events were attributed to disease progression, metastases or viral etiology, but the role of study treatment could not be definitively ruled out.

Immune-mediated adverse reactions (imARs) were reported in 35.8% of patients treated with T300+D (Grade 3 or 4 events 12.6%) and 16.5% of patients treated with D monotherapy (Grade 3 or 4 events 6.4%).

Increased toxicity was seen with the T300+D combination therapy as compared to the durvalumab monotherapy. The safety profile observed with T300+D in the HIMALAYA study was generally consistent with the known safety profiles for both Imjudo (a CTLA-4 blocker) and durvalumab (a PD-L1 blocker), characterized by immune-mediated adverse events. The identified safety concerns include the risk of severe and fatal imARs, including enterocolitis, intestinal perforation, hepatitis, dermatitis, Stevens-Johnson syndrome, endocrinopathy, pneumonitis, interstitial lung disease, myocarditis, neuropathy, encephalitis, myasthenia gravis, as well as toxicities in other organ systems. The life-threatening and fatal imARs that were reported in the T300+D arm of the HIMALAYA study are considered clinically significant and serious safety hazards. As such, Health Canada recommended the inclusion of a Serious Warnings and Precautions box in the Imjudo Product Monograph as early diagnosis and timely intervention of imARs are important for managing the risks associated with Imjudo. This issue was raised as one of the concerns in the NON. In their response to the NON, the sponsor acknowledged Health Canada’s concern and included a Serious Warnings and Precautions box in their revised Imjudo Product Monograph that describes the possibility of severe and fatal imARs. Recommendations are also included for the management of these risks, including monitoring, and how to manage imARs.

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

As outlined in the What steps led to the approval of Imjudo? section, the review of the non-clinical component of the New Drug Submission for Imjudo was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The sponsor submitted various non-clinical studies to evaluate the mechanism of action, pharmacodynamics, pharmacology, and toxicology of tremelimumab in numerous model systems.

Tremelimumab does not cross-react with murine cytotoxic T-lymphocyte associated antigen 4 (CTLA-4). Therefore, for the in vivo pharmacodynamic studies, a surrogate anti-mouse CTLA-4 monoclonal antibody (mAb) was administered intravenously in a syngeneic mouse model resulting in decreased tumour size. A different surrogate anti-mouse CTLA-4 mAb and a surrogate of anti-mouse programmed death-ligand 1 (PD-L1) mAb were injected intravenously, either separately or simultaneously into various syngeneic mouse tumour models (breast carcinoma, colon carcinoma and fibrosarcoma) to demonstrate variable anti-tumour activity. Furthermore, in all models tested, injection of both antibodies led to an increased proliferation of intratumoural T cells. Although these studies were non-compliant of Good Laboratory Practices (GLP), they were considered supportive in nature.

Single-dose and repeat-dose toxicology studies of tremelimumab at various dosage levels were conducted in cynomolgus monkeys. In the single-dose toxicology studies, monkeys were administered doses intravenously up to 100 mg/kg tremelimumab resulting in loose stools or diarrhea with increased incidence and frequency. Increased leukocyte counts were also observed, but they were reversible in the study with a recovery period.

The toxicology of tremelimumab was also assessed in two separate repeat-dose studies (1-month or 6-months with recovery periods). At doses of 5 mg/kg and higher, gastrointestinal toxicities in the form of loose stools/diarrhea and decreased food consumption were observed. Animals dosed at 50 mg/kg suffered weight loss and a few animals died in this dosing category in the 6-month study due to chronic diarrhea associated with intestinal inflammation. Increased liver toxicities, e.g., aspartate aminotransferase (AST) increases and liver weight increases, were observed at doses of 15 mg/kg and higher (in the 1-month study) and at 5 mg/kg and higher (in the 6-month study). These liver findings correlated with increased periportal mononuclear cell infiltration. In addition, animals in both the 1-month study (5 mg/kg dose and higher) and the 6-month study (15 mg/kg dose and higher) had decreased red blood cells, hemoglobin, and hematocrit levels. In both studies, animals dosed with tremelimumab had hyperplasia in lymphoid organs and increased levels of circulating immune cells. Mononuclear cell infiltrates were observed by histology in multiple organs at doses of 5 mg/kg and higher in the longer study. These immune cell-related tremelimumab-associated findings decreased in the recovery period of both studies (2 month for the 1‑month study and 3 months for the 6‑month study). In the 6‑month study, tremors were noted in some animals in addition to skin toxicities (rash, abrasions, and/or open sores) at 5 mg/kg. Thyroid toxicities (atrophy, decreased triiodothryonine/thyroxine, and increased thyroid stimulating hormone) were noted at 15 mg/kg and higher doses.

An embryo-fetal development toxicity study was performed in pregnant monkeys during the period of organogenesis using doses of up to 30 mg/kg. No maternal or embryo-fetal toxicities were observed at these doses (with the highest being approximately 30 times the human area under the serum concentration-time curve [AUC] at the recommended dose). Human immunoglobulin G2 (IgG2) is known to cross the placenta, therefore the potential exists for maternal-fetal transmission. The potential adverse effects of tremelimumab during breastfeeding are adequately captured in the Imjudo Product Monograph.

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

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

As outlined in the What steps led to the approval of Imjudo? section, the review of the quality component of the New Drug Submission for Imjudo was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Characterization of the Drug Substance

Imjudo (tremelimumab) is a fully human anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 or CD152) monoclonal antibody of the immunoglobulin G2a (IgG2a) isotype with a molecular weight of 149 kDa. Tremelimumab blocks CTLA-4 (a cell surface receptor expressed on activated T cells) from binding to the natural B7 ligands (cluster of differentiation [CD] 80 and CD86) on antigen-presenting cells, resulting in enhanced T cell-mediated immune responses (e.g., T cell activation, proliferation, and lymphocyte infiltration into tumours) that can lead to tumour cell death.

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

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

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

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

Drug Substance

The drug substance is manufactured using recombinant deoxyribonucleic acid (DNA) technology. The manufacture is based on a master and working cell bank system (WCB), where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Results from genetic characterization studies also demonstrated stability of these cell banks.

The manufacturing process of the drug substance involves multiple stages. The process is initiated by the thawing of a single WCB vial. The number of WCB cells are expanded through a series of cell growth steps, followed by a harvesting step, and a sequence of purification steps that include chromatography, viral inactivation, and filtration steps. The resulting formulated drug substance is concentrated, filtered, and dispensed into bags if stored at 2 to 8 °C or into cryovessels when stored frozen at -40 °C. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.

The predetermined process validation acceptance criteria were met for all tests, and the manufacturing process parameters remained within defined ranges for all process performance qualification (PPQ) drug substance batch runs that were evaluated. The results from the drug substance process performance validation and ancillary studies show that the manufacturing process is capable of consistently producing drug substance of the desired quality.

Drug Product

The drug product manufacturing process consists of thawing the formulated drug substance, if needed, followed by bioburden reduction filtration, pooling and mixing, filtration, and filling into vials. The vials are then capped and crimped, and undergo visual inspection. Both drug product strengths are filled using the 20 mg/mL drug substance, but with differences in their fill volume and container closure size to adjust for the strength accordingly. The filled vials are stored at 2 to 8 °C before they are shipped to a separate facility where they are labelled, packaged in cartons, and placed in shipping containers where they are stored at 2 to 8 °C until being shipped for distribution.

The predetermined process validation acceptance criteria were met for all tests and the manufacturing process parameters remained within defined ranges for all process performance qualification drug batch runs that were evaluated. This adequately demonstrated that the manufacturing process can consistently produce Imjudo and with an acceptable level of quality.

The manufacturing process is considered to be adequately controlled within justified limits. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of the tremelimumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The control strategy was based on developmental studies and risk assessments to identify the critical process parameters and operating ranges, and to establish in-process acceptance limits and specifications to ensure sufficient control of the critical quality attributes for the desired product safety and efficacy. The control strategy also included appropriate material, facility, equipment, and microbial controls, environmental monitoring, and testing. Ongoing process verification and annual product review evaluations are included in the integrated control strategy to ensure that consistency in manufacturing within the validated state of control and consistency in product quality are maintained throughout the product life cycle.

The proposed drug substance and drug product release and shelf-life specifications were established in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, and based on manufacturing process understanding, prior knowledge, supportive batch analyses data and stability study data. The drug substance and drug product release and shelf-life specifications are closely aligned and include validated assays for assessing identity, quantity, purity, potency, impurities, and safety.

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

Risk assessments were conducted for the presence of nitrosamine and elemental impurities. No safety-related risks were identified for the potential presence of N-nitrosamine and elemental impurities in Imjudo. Accordingly, no confirmatory testing or mitigation plans are required.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.

Imjudo 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.

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 48‑month shelf life is acceptable when Imjudo is stored in the commercial container closure system between 2 to 8 °C, protected from light.

With respect to the microbiological stability, the proposed in-use shelf life for Imjudo diluted with normal saline in the infusion bag is no more than 24 hours stored at 2 to 8 °C or at room temperature (30 °C or less).

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. 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.

Based on a risk assessment score determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

Both sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The tremelimumab 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) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

Raw materials of biologic origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. Two materials of animal origin (fetal bovine serum and bovine serum albumin) were used in the cell line development of the tremelimumab producing clone. The relevant documentation was provided to support the safety of their use. The biologic raw materials originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens. Certification letters attesting to these claims were provided by the sponsor. The excipients used in the drug product formulation are not of animal or human origin.