Summary Basis of Decision for Removab ®
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:
Removab®
Catumaxomab, 0.1 mg/mL, Concentrate for solution for infusion, Intraperitoneal
Fresenius Biotech GmbH
Submission control no: 142629
Date issued: 2012-12-20
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02385724 - 10 µg
- 02385732 - 50 µg
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
Removab® is a registered trademark of Fresenius Biotech GmbH
2 Notice of decision
On May 11, 2012, Health Canada issued a Notice of Compliance to Fresenius Biotech GmbH for the drug product Removab.
Removab contains the medicinal ingredient catumaxomab, a monoclonal antibody that acts as an antineoplastic agent.
Removab is indicated for the palliative management of malignant ascites via intraperitoneal infusion in patients with epithelial cell adhesion molecule (EpCAM) positive carcinomas where standard therapy is not available or no longer feasible. Catumaxomab is specifically directed against the EpCAM and the CD3 antigen. The EpCAM antigen is overexpressed on most carcinomas. CD3 is expressed on mature T-cells as a component of the T-cell receptor. A third binding site in the Fragment crystallizable (Fc) region enables interaction with accessory immune cells. Due to catumaxomab's binding properties, tumour cells, T-cells, and accessory immune cells come in close proximity promoting a concerted immunoreaction against tumour cells, thereby resulting in the destruction of tumour cells.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy of Removab was demonstrated in a two-arm, randomized, multicentre, open-label clinical study in 258 patients with symptomatic malignant ascites due to EpCAM-positive carcinomas of whom 170 were randomized to Removab treatment. The efficacy of the treatment with paracentesis plus Removab was statistically significantly superior to that with paracentesis alone in terms of puncture-free survival and it is supported by the results from time to first need for therapeutic ascites puncture. The difference on median puncture-free survival is considered clinically meaningful in the clinical setting.
Removab (0.1 mg/mL, catumaxomab) is presented as a solution for intraperitoneal infusion in doses of 10 µg and 50 µg in single-use pre-filled syringes. The dosing schedule is comprised of four intraperitoneal infusions:
- 1st dose 10 µg on Day 0
- 2nd dose 20 µg on Day 3
- 3rd dose 50 µg on Day 7
- 4th dose 150 µg on Day 10
Removab has to be administered under the supervision of a qualified health professional as constant rate intraperitoneal infusion with an infusion time of 6 hours. An interval of at least two days must elapse between infusions. The interval between the infusion days can be prolonged in case of relevant adverse reactions. The overall treatment period should not exceed 20 days. Dosing guidelines, including the use of pre-medication of analgesic/antipyretic/nonsteroidal anti-inflammatory medicinal products and the monitoring of the patient after each infusion, are available in the Product Monograph.
Removab is contraindicated for patients who are hypersensitive to this drug, to murine (rat and/or mouse) proteins or to any ingredient in the formulation or component of the container. Removab should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Removab are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Removab is favourable for the palliative management of malignant ascites via intraperitoneal infusion in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Catumaxomab, the medicinal ingredient of Removab, is a monoclonal antibody that acts as an antineoplastic agent. Catumaxomab is used for palliative management of malignant ascites, a condition which occurs in patients with metastasizing cancer. Malignant ascites is the abnormal accumulation of fluid within the peritoneal cavity usually caused by various types of advanced abdominal tumours growing in the peritoneal cavity or other advanced tumours which spread to the peritoneal cavity.
Catumaxomab has the unique ability to bind to three different cell types: tumour cells, T-cells, and accessory cells. Catumaxomab has two different antigen-binding specificities: one for the epithelial cell adhesion molecule (EpCAM) found on tumour cells and one for the CD3 antigen found on T-cells. A third binding site in the fragment crystallisable (Fc) -region (Fc gamma receptors, or FcγR) facilitates interaction with accessory immune cells. Due to catumaxomab's unique binding properties, tumour cells, T-cells and accessory immune cells all come into close proximity of one another. This concerted grouping of the three cells results in an immunoreaction against tumour cells and ultimately leads to the destruction of these tumour cells.
Manufacturing Process and Process Controls
The monoclonal antibody catumaxomab is produced via a mouse/rat hybrid-hybridoma cell line. The manufacturing process consists of a series of stages which include cell culture, harvesting, purification (including viral inactivation/removal steps), and formulation.
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.
Process validation data demonstrate that the manufacturing process operates in a consistent manner, yielding product of acceptable quality.
Characterization
Detailed characterization studies were performed to provide assurance that catumaxomab consistently exhibits the desired characteristic structure and biological activity.
The drug substance manufacturing process was scaled-up and optimized during the pharmaceutical development. The manufacturing process changes introduced were adequately described and comparatively assessed. Lot release, stability and extended characterization data were used to support the comparability assessment.
Control of Drug Substance
The drug substance acceptance criteria, and analytical methods used for the evaluation of the identity, composition, potency and purity of catumaxomab are considered acceptable.
Copies of the analytical method protocols and, where appropriate, validation reports were provided for all analytical procedures used for release and stability of catumaxomab, and are considered satisfactory.
Batch analysis results were reviewed and were found to comply with specifications demonstrating consistent quality of the batches produced.
Stability
Based on stability studies provided, the proposed shelf-life and storage conditions for catumaxomab are supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
The drug product Removab is a sterile, clear and colourless, preservative-free concentrate solution (0.1 mg/mL) of catumaxomab for intraperitoneal infusion provided in doses of 10 µg and 50 µg.
In addition to the active ingredient catumaxomab, each Removab dose contains the following non-medicinal ingredients: citric acid monohydrate, polysorbate 80, sodium citrate, water for injections.
All excipients found in the drug product are acceptable for use in drugs according to the Canadian Food and Drug Regulations. The compatibility of catumaxomab with the excipients and the container closure system is supported by the provided stability data.
Removab is supplied in single-use pre-filled syringes. The container closure system consists of a siliconized glass container, a siliconized plunger stopper and a closure system composed of a siliconized tip cap, a luer lock and a tamper proof seal.
In order to ensure the proper use of components recommended for the dilution and administration of Removab, an infusion kit will be provided with the final product presentation.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. The data include composition of Removab, rationale for choice of formulation, manufacturing process, including packaging, and compatibility with the infusion system.
Manufacturing Process and Process Controls
The Removab drug product manufacturing process essentially consists of sterile filtration of the formulated drug substance, aseptic filling into sterile syringes, labelling and packaging. Notably, the drug product is completely formulated at the drug substance stage.
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters are adequately described in the submitted documentation and are found acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
The drug product manufacturing process has been adequately validated and is capable of consistently generating product that meets release specifications.
Control of Drug Product
Removab is tested to verify that its appearance, content, identity, purity, potency and sterility are within acceptance criteria. The acceptance criteria were adequately justified and the analytical methods were appropriately validated.
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
Based on stability data submitted, the proposed 24-month shelf-life for Removab, when stored at 2-8°C and protected from light is considered acceptable.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the active ingredient, catumaxomab, has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.
An OSE for the drug product facility was not warranted since the facility was recently evaluated for another product produced by the company within the last three years.
3.1.4 Adventitious Agents Safety Evaluation
The catumaxomab manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Purification process steps designed to remove and inactivate viruses are adequately validated.
Except for the components which are a part of the cell bank culture, no raw materials of animal or human origin are used in the manufacture of Removab. The excipients used in the drug product formulation are not of animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Removab has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Primary pharmacodynamic (PD) in vitro cellular assays demonstrated that catumaxomab binds to human EpCAM on epithelial tumour cells, binds to human CD3 on T-cells, and binds to FcγR I, IIa and III on accessory cells.
Catumaxomab showed anti-tumour activity in vitro against epithelial tumour cell lines expressing high to low levels of EpCAM. The effects mediated by catumaxomab were found to be superior when compared to both parental antibodies, either alone or in combination, that is (i.e.), anti-EpCAM, and anti-CD3 monospecific antibody.
In more complex in vitro 3-dimensional tumour cell models (spheroids), peripheral blood mononuclear cells (PBMCs) in combination with catumaxomab, but not PBMCs alone, effectively penetrated EpCAM-positive tumour spheroids, generated a decrease in spheroid volume, and induced apoptosis of tumour cells.
The in vivo anti-tumour activity of catumaxomab was confirmed in an immunologically compromised murine xenograft model of ovarian carcinoma, where tumour development was delayed by a single intraperitoneal treatment with catumaxomab and human PBMCs.
It was demonstrated that the anti-tumour activity of catumaxomab is dependent on the presence of PBMCs, indicating the importance of the immunostimulatory effects [for example (e.g), cytokine release] of catumaxomab and their contribution to anti-tumour activity.
It was shown that catumaxomab activates T-cells and stimulates their proliferation in the presence of tumour cells. Catumaxomab also stimulates the release of pro-inflammatory cytokines from blood cells, and induces granzyme B and perforin release by T-cells, which results in the killing of tumour cells. Catumaxomab also binds to and activates FcγR-positive accessory cells (type I, IIa or III FcγR), which contribute to tumour cell killing, and activates antigen-presenting dendritic cells and natural killer (NK) cells. Catumaxomab stimulates FcγR-positive accessory cells to eliminate tumour cells by direct phagocytosis [antibody-dependent cellular phagocytosis (ADCP)], which is dependent on EpCAM expression by the tumour target cells.
In vitro PD drug interaction studies have shown that the anti-tumour effect of catumaxomab is synergistic with other chemotherapeutic drugs and that the use of anti-inflammatory drugs reduces catumaxomab-induced cytokine release.
No unexpected binding of catumaxomab to normal human tissues was observed in tissue cross reactivity studies.
3.2.2 Pharmacokinetics
Review of the human pharmacokinetic (PK) data was considered more relevant in assessing the PK profile of catumaxomab for human use. See section 3.3.2 Pharmacokinetics.
3.2.3 Toxicology
The non-clinical safety program for catumaxomab was designed in accordance with the International Conference on Harmonisation (ICH) S6 guidelines, and most toxicology studies were conducted in accordance with the principles of Good Laboratory Practice (GLP). It has been demonstrated that catumaxomab specifically binds to the human EpCAM antigen and the human CD3 antigen on T-lymphocytes, and there are no appropriate animal species which exhibit a full pharmacologically active response to catumaxomab. Hence, the toxicology studies performed with catumaxomab provide information about non-specific toxicity. For the assessment of potential toxicity mediated by binding to CD3 or accessory cells, the variant antibody BiLu, which has an equivalent structure but binds to mouse CD3 instead of human CD3, was used in toxicity studies in immunocompetent mice. The toxicology studies utilized the intraperitoneal (IP) route of administration since this is the intended clinical route of exposure. The intravenous (IV) route was also utilized, since it was assumed to represent maximal systemic exposure.
Single-Dose Studies
Acute, single-dose toxicology studies utilizing catumaxomab were conducted on mice, rats, guinea pigs, and monkeys at doses exceeding the human therapeutic dose range. The concentration that was lethal to 50% of the experimental animals (LD50) was higher than the highest dose tested, i.e., LD50 values were >5.2 mg/kg body weight (bw) for mice, >5.0 mg/kg bw for rats and > 300 µg/kg bw for the monkey.
Two single-dose-escalation toxicity studies, utilizing both the IP and IV routes of administration, were conducted in mice using the variant antibody BiLu in order to assess any potential toxicity mediated by binding to CD3 or accessory cells. In the first study, doses utilized were 0.2, 0.4, 1.0 and 3.0 µg/kg bw (~0.1-fold the human equivalent dose); 2, 4, 10 and 30 µg/kg bw (~ equal to the human equivalent dose); and 20, 40, 100 and 300 µg/kg bw (~ 10-fold the human equivalent dose). The surrogate antibody, BiLu, was generally well-tolerated in the escalating dose toxicity studies in mice at doses up to 10 times the human equivalent dose. The primary findings were those associated with the pharmacological activity, manifest as transient decreases in the percentage of CD4 positive cells and concomitantly, a slightly lower mean CD4/CD8 ratio, with a return to baseline levels at the end of a treatment-free period. For males only, spleen weight was increased, and there was a tendency towards increased liver weights. In addition, centrilobular necrosis and megakaryocytic haemopoiesis were observed in the spleen of males only. These results indicate that male mice are more sensitive than females.
Local Tolerance
Investigation of local tolerance indicated that there were no treatment-related local reactions at the injection sites following IV or IP administration of up to 300 μg/kg bw.
Genotoxicity and Carcinogenicity Toxicity
Genotoxicity and carcinogenicity studies were not conducted with catumaxomab. The range and type of genotoxicity studies routinely conducted for pharmaceuticals are generally not considered applicable to biotechnology-derived pharmaceuticals (refer to ICH S6). It is not expected that catumaxomab would interact directly with deoxyribonucleic acid (DNA) or other chromosomal material. In addition, standard carcinogenicity bioassays are generally considered inappropriate for biotechnology derived pharmaceuticals. Catumaxomab does not have the potential to induce proliferation of EpCAM-positive or CD3-positive tumour cells. There is no potential concern for the accumulation of spontaneously mutated cells with catumaxomab.
Reproductive and Developmental Toxicity
Studies to investigate reproductive and developmental toxicity were not performed due to the lack of appropriate animal species, the intended patient population and the late stage of the malignant disease.
3.2.4 Summary and Conclusion
The non-clinical studies for this drug submission are considered acceptable. The anti-tumour activity of catumaxomab has been demonstrated in both in vitro and in vivo non-clinical pharmacology studies. The non-clinical data base was considered adequate to assess the safety profile of catumaxomab and support its use in humans.
3.3 Clinical basis for decision
The Canadian regulatory decision on the clinical efficacy and safety of Removab was based on a critical assessment of the Canadian data package. The foreign reviews completed by the European Union's centralized procedure European Medicines Agency (EMA) and Australia's regulatory authority Therapeutic Goods Administration (TGA) were used as an added reference.
3.3.1 Pharmacodynamics
The anti-tumour activity of Removab (catumaxomab) was demonstrated in the non-clinical studies. See section 3.2.1 Pharmacodynamics.
3.3.2 Pharmacokinetics
The PK report focused on the concentration of Removab with time in the plasma after IP administration, although Removab concentrations were also determined in the ascites fluid. The relationship between ascites fluid and plasma was best summarized by the sponsor with the following observations: "There was no clear relationship between the measured concentrations of catumaxomab (Removab) and cytokines, between cytokine concentrations and clinical parameters, or between catumaxomab plasma concentrations and clinical parameters".
When administered into the peritoneal cavity, it was expected that the level of binding and retention of the drug would likely be influenced by the amount of target cells. Therefore, the variability in tumour loads of malignant ascites at this location would likely have influenced the variability of the PK profiles that were observed in the plasma.
Of the 13 patients, 10 of them had detectable PK profiles in the plasma. This was observed after the third and fourth IP administration of Removab, or equivalently 6 to 11 days after the first administered dose. The most relevant PK parameter in this context was the median of the apparent half-life of elimination from the plasma which was 2.19 days (0.73-17.5 days).
3.3.3 Clinical Efficacy
The efficacy of Removab was demonstrated in a two-arm, randomized, multicentre, open-label clinical study in 258 patients with symptomatic malignant ascites due to EpCAM-positive carcinomas of whom 170 were randomized to Removab treatment. This study compared efficacy and safety of paracentesis plus Removab versus paracentesis alone (control) in the management of malignant ascites. EpCAM positivity was determined in the ascites fluid via immunohistological staining. The threshold for positivity was set at 400 EpCAM positive cells in 106 total cells of ascites.
Of the 258 randomized patients, the median age was 59 years, 79% were female, and 99% were Caucasian. The median Karnofsky Performance Status was 80.5% of patients had ovarian cancer and 50% had non-ovarian cancer as the underlying disease. Among the non-ovarian cancer patients, the majority had gastric carcinoma. Other non-ovarian carcinomas were pancreas, breast or colon cancer.
Removab was administered as four IP infusions over 6 hours with increased doses of 10, 20, 50 and 150 µg on Days 0, 3, 7 and 10, respectively. Most of the patients (98.1%) were hospitalized for a median duration of 11 days.
The primary efficacy endpoint was puncture-free survival (PFS), which was a composite endpoint defined as the time to first need for therapeutic ascites puncture or death, whichever occurred first. The PFS was calculated from Day 11 (day after last catumaxomab administration) in the Removab group, while the calculation for the control group started at Day 0 after a paracentesis. For ethical reasons, the control patients were offered active treatment in a cross-over period after the first or second therapeutic puncture. Secondary efficacy endpoints were assessments of quality of life (QoL), patient's health state, and timing of the first post-baseline therapeutic ascites puncture.
Based on the pooled populations of ovarian and non-ovarian cancer patients, median PFS in the randomized phase was 44 days [95% confidence interval (CI): 31 days; 49 days] in the Removab group compared to 11 days (95% CI: 9 days; 16 days) in the control group. The hazard ratio (HR) and 95% CI for HR was 0.310 and 0.228-0.423, respectively. The difference was statistically significant [probability (p) <0.0001]. The difference in the median PFS was considered clinically meaningful in the clinical setting. Similar responses were also reported for each stratum (the ovarian cancer patient group and the non-ovarian cancer patient group).
Time to first need for therapeutic ascites puncture (analyzed by censoring death events from PFS) was substantially longer in the Removab treatment group (median and 95% CI: 77 days and 62-104 days versus 13 days and 9-17 days in the control group).
In the randomized phase, compared to the pre-study, the median time to therapeutic puncture was prolonged in the treatment group (71 days and 80 days during the study for the ovarian and non-ovarian groups, respectively, versus 17 and 14 days pre-study); while in control group the median time during the study phase (11.0 and 15 days for the ovarian and non-ovarian groups, respectively) was not significantly better than these observed in pre-study (19.5 and 17.5 days). The same trend in favour of Removab was also observed in the cross-over phase, although the number of patients was relatively small.
At Visit 6 (8 days after the last infusion for the Removab group, 8 days after Day 0 for the control group), fewer patients had ascites signs and/or ascites symptomsin almost all assessment categories in the treatment group. Time to deterioration of QoL scores was delayed through treatment with Removab in an ad hoc analysis.
3.3.4 Clinical Safety
The clinical safety evaluation of Removab was based on results from the pivotal clinical study (see section 3.3.4 Clinical Efficacy) and the other supportive studies submitted. The safety profile was assessed in the context of the targeted patient population and the nature of the clinical study design. The side-by-side comparison of safety profiles between the Removab-treatment group and the control group in the pivotal study was interpreted with caution, due to the asymmetric design and the longer observation period of the Removab group than the control group (median in the full analysis set: 52 versus 11 days from the randomized phase.)
Removab treatment was associated with frequent symptomatic adverse drug reactions (ADRs). Approximately 90% of patients in the overall population and 85% in the pivotal study experienced ADRs. The most commonly reported ADRs were cytokine-release related symptoms (pyrexia, nausea, and vomiting), and symptoms related to the paracentesis (abdominal pain) or events due to the underlying disease (malignant neoplasm progression). The cytokine-release related symptoms were generally mild to moderate in intensity and mostly fully reversible. The incidence and degree of severity [based on Common Terminology Criteria of Adverse Events (CTCAE)] were similar after each infusion. Transient abdominal pain was frequently observed (48.1% of patients, thereof 9.7% with CTCAE Grade ≥3), and was considered to be partially due to the study procedures, such as paracentesis and IP infusions, leading to peritoneal irritation reactions.
The percentage of patients who discontinued study therapy due to Removab-related ADRs was low (7.0%). Overall, 77.5% of the patients in the integrated safety analysis experienced at least 1 adverse event (regardless of the causal relationship to Removab) with a CTCAE Grade ≥3. Malignant neoplasm progression (26.0%), abdominal pain (12.4%), and lymphopenia (9.3%) were the most frequently reported adverse events of CTCAE Grade ≥3.
There were no fatal outcomes related to Removab treatment as determined by the investigators. The percentage of patients with the outcome of death was 32.6% in the integrated safety analysis and 45.2% in the pivotal study. The percentage of patients with the outcome of death was lower (14.8%) in the control group of the pivotal study. Because the deaths were due to disease progression, this difference could be explained by an approximately 5-fold longer observation period in the Removab group.
Transient increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), gammaglutamyltransferase (GGT) and bilirubin as hepatic and hepatobiliary disorders were regularly observed but rarely considered clinically relevant.
3.3.5 Additional Issues
The sponsor has committed to submit results from all on-going clinical studies, as well as the additional clinical study data to support labelling changes with regards to the duration of infusion and use of pre-medication prior to IP infusion.
The submitted Periodic Safety Update Report (PSUR) based on the European Union (EU) market experiences was reviewed by Health Canada's Marketed Health Product Directorate (MHPD); as well as the Risk Management Plan and post-market surveillance strategies developed by the sponsor.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Based on the pivotal study, intraperitoneal infusion of Removab significantly prolonged puncture-free survival (PFS), as well as delayed the time needed for the first therapeutic ascites puncture in patients with malignant ascites due to EpCAM-positive carcinomas. The possibility to reduce the number of painful paracentesis which are often associated with complications and inconveniences is a substantial benefit for these severely ill patients to whom no other authorized medication for management of malignant ascites is available or to whom standard therapy is no longer feasible. In addition, fewer patients had ascites signs and/or ascites symptoms in the treatment group. Time to deterioration of quality of life was also delayed through treatment with Removab.
Treatment with Removab was associated with frequent symptomatic ADRs, most of which were not serious and manageable by standard prophylactic or symptomatic treatment. Since most of the ADRs were related to the mode of action of catumaxomab and/or the puncture/infusion procedures, there is a high level of predictability allowing the treating physician to inform and thoroughly prepare the patient. With regard to onset and duration, most ADRs were limited to the treatment period and did not occur thereafter. Only a minority of ADRs led to hospitalization or prolongation of existing hospitalization. The benefit of Removab in terms of gain in quality of life is not outweighed by additional hospital stays as it was shown that the time in hospital of the patients treated with Removab was comparable to that of the control patients.
Major revisions have been undertaken to ensure that information included in the Removab Product Monograph reflect the current available information on non-clinical study, clinical study including PK/PD, efficacy and safety. The indication and clinical use of the product was revised to reflect the palliative use in clinical practice. The revised Product Monograph based on recommendations by the clinical review team is considered to be acceptable.
Overall, the benefits of Removab treatment outweigh the risks associated with Removab treatment given as monotherapy for the palliative management of malignant ascites where no standard medication is available or the standard care (paracentesis) is no longer feasible in patients with malignant ascites.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Removab is favourable for the palliative management of malignant ascites via intraperitoneal infusion in patients with epithelial cell adhesion molecule (EpCAM) positive carcinomas where standard therapy is not available or no longer feasible. The 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.
4 Submission Milestones
Submission Milestones: Removab®
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2010-12-23 |
| Screening | |
| Screening Deficiency Notice issued: | 2011-02-18 |
| Response filed: | 2011-03-24 |
| Screening Acceptance Letter issued: | 2011-05-20 |
| Review | |
| Quality Evaluation complete: | 2012-05-10 |
| Clinical Evaluation complete: | 2012-02-20 |
| Labelling Review complete: | 2012-05-05 |
| Notice of Compliance issued by Director General: | 2012-05-11 |