Summary Basis of Decision for Vidaza ®
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:
Vidaza®
Azacitidine, 100 mg/vial, Powder for suspension, Subcutaneous injection
Celgene
Submission control no: 127108
Date issued: 2010-06-22
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):
- 02336707
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On October 23, 2009, Health Canada issued a Notice of Compliance to Celgene for the drug product, Vidaza®.
Vidaza® contains the medicinal ingredient azacitidine, a pyrimidine analogue that is an antineoplastic agent. Azacitidine is believed to exert its antineoplastic effects by multiple mechanisms including cytotoxicity on abnormal hematopoietic cells in the bone marrow and hypomethylation of deoxyribonucleic acid.
Vidaza® is indicated for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation with:
- Intermediate-2 and High-risk Myelodysplastic Syndrome according to the International Prognostic Scoring System.
- Acute Myeloid Leukemia with 20-30 % blasts and multi-lineage dysplasia, according to the World Health Organization classification.
The market authorization was based on quality, non-clinical, and clinical information submitted. The pivotal study was an international, multicentre, controlled open-label, randomized (1:1), parallel-group, Phase III comparative study. In the intent-to-treat analysis of 358 patients, Vidaza® treatment was associated with a median survival of 24.46 months compared to 15.02 months for those receiving conventional-care regimens (CCR), resulting in a difference of 9.4 months. The Vidaza® group had a reduced risk of death compared with patients in the CCR group. The hazard ratio for the treatment effect was 0.58. The two-year survival rates were 50.8% in the Vidaza® group compared to 26.2% in the CCR group.
Vidaza® (100 mg/vial, azacitidine) is presented as a powder for solution, for subcutaneous injection. Before administration, patients should be premedicated with anti-emetics for nausea and vomiting. Note that Vidaza® has not been studied in patients with impaired hepatic or renal function. The dosage given should be adjusted according to tolerability. The recommended starting dose for the first treatment cycle, for all patients regardless of baseline haematology laboratory values, is 75 mg/m2 of body surface area, injected subcutaneously, daily for 7 consecutive days, followed by a rest period of 21 days (28-day treatment cycle). It is recommended that patients be treated for a minimum of 6 cycles unless unacceptable toxicities occur. Treatment should be discontinued if associated toxicities cannot be managed with dose delays/adjustments or standard supportive care such as transfusions, growth factors, or antibiotics. Treatment should be continued as long as the patient continues to benefit or until disease progression. Dosing guidelines are available in the Product Monograph.
Vidaza® is contraindicated for patients with advanced malignant hepatic tumours, or patients who are hypersensitive to azacitidine or to any ingredient in the formulation or component of the container.
Vidaza® 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 Vidaza® are described in the Product Monograph.
Priority Review status was granted for the evaluation of Vidaza® as it appeared to provide effective treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating disease or condition for which no drug is presently marketed in Canada.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Vidaza® is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Azacitidine, the medicinal ingredient of Vidaza®, is a pyrimidine analogue with an antineoplastic effect. Azacitidine is believed to exert its antineoplastic effects by multiple mechanisms including cytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of deoxyribonucleic acid (DNA). Azacitidine also has the ability to restore normal function to genes that are critical for differentiation and proliferation of haematopoietic cells.
Manufacturing Process and Process Controls
Azacitidine is manufactured via a multi-step synthesis. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of azacitidine has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of azacitidine are considered acceptable.
Validation reports are considered satisfactory for all analytical procedures used for in-process, release, and stability testing of the drug substance.
Batch analysis results were reviewed and are within the proposed acceptance criteria.
The proposed packaging components are considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed retest period for the drug substance was supported and is considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Each vial of Vidaza® contains 100 mg of azacitidine and 100 mg mannitol as a sterile white lyophilized powder for reconstitution as a suspension for subcutaneous (SC) injection.
Vidaza® (azacitidine for injection) is supplied in 100 mg single-use vials packaged in individual cartons.
Mannitol is a good bulking agent for use in preparation of lyophilized drug products. Mannitol is acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of azacitidine with mannitol is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The manufacturing equipment, in-process manufacturing steps, and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Vidaza® is tested to verify that its identity, appearance, content uniformity, assay, foreign particulate matter, sterility, moisture content, levels of degradation products, drug-related impurities, and bacterial endotoxins are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
Validation results of the analytical methods used for the determination of azacitidine and the drug-related impurities are considered acceptable. Although related substances limits are not considered qualified as per current regulatory requirements, the clinical assessment has concluded that they are considered acceptable for the indicated patient population. Should the sponsor file a submission requesting market authorization for other indications/patient population, the impurity limits may need qualifications.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed 48-month shelf-life at 15-30°C for Vidaza® is considered acceptable.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Vidaza® are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Vidaza® 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
The primary pharmacodynamic activities of azacitidine are the inhibition of DNA methylation and cytotoxicity. The published literature supports the proposed modes of action for azacitidine.
Studies have shown that:
- azacitidine cellular entry is required and facilitated by a nucleoside transport system;
- enzymatic sequential phosphorylation is required to yield azacitidine-5'-triphosphate;
- the phosphorylated form of azacitidine is incorporated into ribonucleic acid (RNA) and deoxyribonucleic acid (DNA).
The mechanism of anticancer activity has been suggested to be due to:
- demethylation of cellular DNA leading to reactivation of silenced genes initiating apoptosis and/or differentiation;
- induction of DNA damage due to the formation of irreversible, covalent enzyme-DNA adducts initiating apoptosis;
- disruption of protein synthesis secondary to effects on RNAs.
In an in vivo cardiovascular study conducted in dogs given single intravenous doses of azacitidine ≥ 2 mg/kg, increases in heart rate and the ECG QTc, and increased serum creatinie kinase (CK) and CK isozyme 2 (CK-MB) concentrations were observed. No in vitro studies [human Ether-à-go-go Related Gene (hERG), canine Purkinje fiber assay) were performed to rule out the effect of Vidaza® on QT prolongation. While the interpretation of the dog study is limited by concurrent confounding effects associated with toxicity elicited by high exposures to azacitidine, the possibility of QTc interval prolongation cannot be ruled out. The Warnings and Precautions and Toxicology sections of the Product Monograph include the observations of QTc prolongation in conscious dogs, and indicate that no thorough clinical QT/QTc study or in vitro studies were performed to rule out the effect of Vidaza on QT prolongation.
3.2.2 Pharmacokinetics
The non-clinical pharmacokinetic (PK) evaluation was limited. There were no studies of the clinical formulation or substantive evaluation of bioavailability after SC administration. Distribution and excretion of azacitidine were well-characterized in mice following intraperitoneal (IP) administration. Azacitidine was rapidly distributed and eliminated almost exclusively in the urine.
The characterization of potential impact of azacitidine on the cytochrome P450 (CYP) system is more comprehensive than the PK evaluation. The results show in vitro that azacitidine, at concentrations well exceeding the human maximum drug concentration in plasma (Cmax), is not a substrate of CYP isoenzymes, does not inhibit the metabolism of CYP substrate, and is not an inducer of CYP. Catabolism of azacitidine via the cytidine deaminase system is well documented in the literature.
3.2.3 Toxicology
The majority of the non-clinical toxicology data is derived from published scientific literature. Most of the toxicity studies were conducted during the 1970s and early 1980s according to guidelines and standards in place during that period. They were not conducted according to current scientific/regulatory standards [non-Good Laboratory Practices (GLP) compliant] or guidelines. The routes of administration used in the in vivo studies included IP, intravenous (IV), and oral, but not SC routes.
Despite the shortcomings of most of these studies/reports compared with current GLP safety pharmacology and toxicology study standards and regulatory guidelines, the sponsor indicates that little would be gained at this time by the conduct of further non-clinical studies based on the large amount of existing safety data available for the administration of azacitidine in humans. Additional or longer term toxicology studies would have to be conducted at doses that are multiples below the clinical dose and thus would not provide any additional relevant safety information. The sponsor's justification that further animal studies likely are not necessary at this time is acceptable, due to the adequate human safety database obtained from the clinical studies.
Single-Dose and Repeat-Dose Toxicity
Based on the in vitro studies and non-clinical animal studies in which azacitidine was administered parenterally (for the majority of studies), it is concluded that azacitidine has a moderate to marked order of acute single-dose toxicity with signs potentially indicative of central nervous system (CNS) effects at higher dose levels tested in rodents; and toxicity at lower dose levels following repeat-dosing compared with single doses.
Severe toxicity and deaths following repeat dosing primarily reflect effects on bone marrow and haematopoietic cells of all lineages as would be expected based on the pharmacologic propensity of azacitidine for cytotoxicity. Toxicity in animals, including effects on target organs (bone marrow, lymphoid tissues, liver, and kidney) occurred at administered dose levels in animals that were considerably lower than the intended clinical dose of 75 mg/m2.
Mutagenicity
Azacitidine was mutagenic and clastogenic in bacterial and mammalian cells. Mice and rats treated with azacitidine had an increased incidence of tumours of the lymphoreticular system, lung, mammary gland, testes, and skin.
Reproductive and Developmental Toxicity
Azacitidine has shown the potential to produce adverse effects on male reproduction and fertility, including decreased testes and epididymides weights, decreased sperm counts, and decreased pregnancy rates. In embryofoetal development studies in mice and rats, azacitidine caused embryotoxicity, embryolethality, and teratogenicity.
3.2.4 Conclusion
The mechanism of action for azacitidine has been well-established in in vitro and in vivo non-clinical pharmacology studies. Non-clinical studies were not conducted to characterize the pharmacokinetics of the clinical formulation, nor was there a substantive evaluation of bioavailability after SC administration (the intended clinical route).
Toxicity effects on target organs (bone marrow, lymphoid tissues, liver and kidney), carcinogenicity, and severe reproductive toxicity occurred in animals at administered dose levels that were considerably lower than the intended clinical dose of 75 mg/m2. Adequate statements are in place in the Product Monograph to address the identified safety concerns.
In view of the intended use of Vidaza®, there are no pharmacological/toxicological issues within the submission which preclude approval of the requested product indication. The non-clinical studies together with the clinical studies are considered sufficient to characterize the safety profile of Vidaza®.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The primary pharmacodynamic effects of interest in the treatment of MDS are:
- Inhibition of DNA methylation;
- Cytotoxicity by incorporation of azacitidine into DNA and RNA and inhibition of protein synthesis.
Clinical pharmacodynamic studies were not conducted. Importantly, no thorough QT/QTc study was conducted to rule out an effect of Vidaza on the QT interval. For more information, see section 3.2.1 Pharmacodynamics.
3.3.2 Pharmacokinetics
The pharmacokinetics of azacitidine were characterized based on one study in six patients with MDS and two studies described in published papers. All three studies with their advantages and/or limitations in some cases, contributed to the understanding of the absorption, distribution, metabolism and excretion of azacitidine. After 30 minutes of bolus administration of radiolabelled azacitidine, plasma levels of radioactivity were 70% of the concentration at 5 min. However, < 2% of the radioactivity was associated with the parent drug (radiolabelled azacitidine) indicating a rapid metabolism or degradation. At least two metabolites or degradation products were found in the plasma. Cytosolic metabolism was responsible for the breakdown of the drug. In vitro studies with incubations of azacitidine with mouse or human hepatic S9 fractions indicated that the metabolism of azacitidine was not CYP-mediated. The studies with radiolabelled azacitidine also demonstrated that 73% to 98% of the administrated doses were excreted in the urine 1 to 3 days following administration and that the plasma level decline of azacitidine was multiphasic with rapid distribution of the drug following administration.
The volume of distribution values obtained in these studies agrees with the low organic/aqueous partition coefficient of the drug and its low binding (<1%) to human albumin.
Good bioavailabilty for azacitidine when administered by the SC route was demonstrated in the PK study with six MDS patients. The apparent (SC) clearance and systemic (IV) clearance of azacitidine far exceeded the glomerular filtration rate and total renal blood flow in the average adult indicating that non-renal elimination [for example (e.g.), metabolism/ hydrolysis/degradation] played a role in the elimination of the parent drug.
Most AEs reported from this study were mild (Grade 1) or moderate (Grade 2) in intensity. There were a total of 24 AEs reported in five MDS patients during the study. The most frequently reported AEs were nausea and vomiting, both observed with IV and SC administration; injection site bruising, SC administration only; and arthralgia, IV administration only.
One concern is the possible effects of renal dysfunction (98% of azacitidine is excreted in the urine) or hepatic dysfunction (rapid metabolism of degradation of azacitidine by cytosolic enzymes) on the pharmacokinetics of azacitidine. The effects of hepatic insufficiency or renal insufficiency on the pharmacokinetics of azacitidine were not studied. Hepatic or renal dysfunction may contribute to azacitidine toxicity because of decreased metabolism or degradation of azacitidine, and decreased elimination of the drug and its metabolic products, respectively.
No formal drug interaction studies were conducted with azacitidine. Based on in vitro data, such interactions are considered unlikely.
3.3.3 Clinical Efficacy
The pivotal study (AZA-001) was an international, multicentre, controlled open-label, randomized (1:1), parallel-group, Phase III study. The purpose of this study was to evaluate the SC administration of azacitidine in combination with best supportive care (BSC) versus conventional care regimens (CCR) plus BSC for the treatment of higher-risk patients with MDS. The patients had an International Prognostic Scoring System (IPSS) classification of Intermediate-2 or High Primary MDS diagnosed as Refractory Anaemia with Excess Blasts (RAEB) or Refractory Anaemia with Excess Blasts in Transformation (RAEB-T) according to the French American British classification. Under the current World Health Organization (WHO) classification system, RAEB-T patients (20-30 % blasts in the bone marrow) are now considered to be acute myeloid leukemia (AML) patients with 20% to 30% blasts and multi-lineage dysplasia.
Of the 358 patients randomized, 179 received Vidaza® plus BSC and 179 received CCR plus BSC (105 BSC alone, 49 low-dose cytarabine, and 25 chemotherapy with cytarabine and anthracycline). Patients who received Vidaza® were administered a SC dose of 75 mg/m2 daily for 7 consecutive days, followed by a rest period of 21 days for a median of 9 cycles. It was recommended that patients be treated for a minimum of 6 cycles unless unacceptable toxicities occur.
The primary endpoint was overall survival. Secondary efficacy endpoints included time to AML transformation, haematologic status and episodes of infections requiring IV antibiotics and/or antivirals, time to relapse after complete remission (CR) or partial remission (PR), or disease progression according to response criteria.
In the Intent-to-Treat (ITT) population of 358 patients, the Kaplan-Meier median overall survival was 24.5 months in the Vidaza® group compared with 15.0 months in the combined CCR group. Treatment with Vidaza® was statistically superior to the CCR treatment for prolonging survival, with an increase in median overall survival of 9.4 months. As estimated from the stratified Cox proportional hazards model, the Vidaza® group had a 42% reduced risk of death compared with patients in the combined CCR group. The two-year survival rates were 50.8% in patients receiving Vidaza® versus 26.2% in patients receiving CCR treatment. The survival benefits of Vidaza® were consistent regardless of the CCR treatment option (BSC alone, low-dose cytarabine, or standard induction chemotherapy) utilized in the control arm. The results of this clinical study demonstrated substantial clinical benefit of Vidaza® when compared to conventional care regimens in prolonging overall survival (the primary endpoint).
The results of a sub-group analysis demonstrated clinical benefit of Vidaza® in AML patients. In the pivotal study, 113 of the 358 patients (median age of 70 years) had a diagnosis of AML with 20-30% blasts and multi-lineage dysplasia. These AML patients were randomly assigned to receive either Vidaza® (n=55) or CCR (n=58). The two groups were well-balanced with respect to age, gender, performance status, and baseline disease characteristics. The patients treated with Vidaza® experienced a median overall survival of 24.5 months versus 16.0 months for those that received CCR treatment, a difference of 8.5 months. The Vidaza® group had a 53% reduced risk of death compared with patients in the CCR group. The two-year survival rates were 50.2% for the Vidaza® group compared to 15.9% for the CCR group. Therefore, Vidaza® was shown to provide an effective therapeutic approach for patients with WHO AML (20-30% blasts and multilineage dysplasia) who are not eligible for stem cell transplantation.
Overall, Vidaza® has been shown to be efficacious for the treatment of MDS patients with higher risk MDS who are not eligible for stem cell transplantation. Patients with high-risk primary MDS and the subgroup of patients with AML with 20-30% blasts and multilineage dysplasia who were treated with Vidaza® experienced an increase in overall survival by 9.4 and 8.5 months, respectively. These patients also experienced improvements in bone marrow function including a reduction in red blood cell transfusion, improvement in cytopaenia, and a delay in time to transformation to AML. The efficacy findings from the pivotal study were further supported by results of another controlled Phase III study and two uncontrolled Phase II studies.
3.3.4 Clinical Safety
The clinical safety of Vidaza® was evaluated from the pivotal study (AZA-001), three supporting studies, including an open-label controlled study (CALGB 9221), and a clinical pharmacology crossover study. The majority of patients in these studies were treated with doses of 75 mg/m2 for 7 days per cycle. In the pivotal study, the median cycle length was increased by 1 week, from 28 days to 34-35 days. The median duration of treatment was longer in the patients treated with Vidaza® compared to those that were treated with only BSC in Study AZA-001 [10.43 versus (vs.) 6.16 months] and in Study CALGB 9221 (7.34 vs. 4.13 months). Patients with hepatic and renal dysfunction were excluded from the studies, and therefore, there is limited information for this patient population.
Consistent with the pharmacology and established safety profile of azacitidine, the Treatment Emergent Adverse Events (TEAEs) reported most frequently in patients treated with Vidaza® were from four system organ classes: blood and lymphatic system disorders, general disorders and administration site conditions, gastrointestinal disorders, and infections and infestations. In the pivotal study, the haematologic TEAEs that occurred at a much higher frequency in the Vidaza® group compared to the BSC group were: thrombocytopaenia (69.7% vs. 34.3%), neutropaenia (65.7% vs. 28.4), and leucopaenia (18.3% vs. 2.0%). Other frequently reported haematologic TEAEs included anaemia (51.4% vs. 44.1%) and febrile neutropaenia (13.7% vs. 10 %), with percentages comparable between the Vidaza® group and BSC group. The majority of the events of thrombocytopaenia, neutropaenia, and leukopaenia were Grade 3 or 4 in intensity. Findings were generally similar in the supportive studies, including those of the controlled Study CALGB 9221. When corrected for differences in exposure to treatment, the rates for events of thrombocytopaenia, neutropaenia, and leukopaenia remained higher for patients treated with Vidaza® compared to patients on BSC, for both studies AZA-001 and CALGB 9221. However, despite the greater frequency of TEAEs such as thrombocytopaenia and neutropaenia, the overall occurrence of events of bleeding and infection was no greater in Vidaza® patients than with the BSC-only patients.
Non-haematologic AEs frequently reported in the patients treated with Vidaza® in the AZA-001 and CALGB 9221 studies were related to either the administration of the drug (injection site reactions, nausea, and/or vomiting) or consequences of pre-treatment with an anti-emetic drug (i.e., constipation); most were Grade 1 or Grade 2 in severity. These non-haematologic TEAEs are well-recognized events observed with azacitidine treatment.
In Study AZA-001, additional TEAEs of importance occurring in ≥ 2% of patients in the Vidaza® group with a 2-fold greater frequency compared to the BSC group included: bone marrow failure, pancytopaenia, conjunctival haemorrhage, eye haemorrhage, hemorrhoidal haemorrhage, stomatitis, injection site reactions (haemorrhage, inflammation, and/or pruritus), malaise, herpes simplex, neutropaenic sepsis, pharyngitis, sinusitis, myalgia, confusional state, alopaecia, and purpura.
In summary, the most common TEAEs associated with Vidaza® were primarily related to bone marrow suppression, secondary events associated with bone marrow suppression (e.g. infections, and/or haemorrhagic events), and gastrointestinal events which is consistent with the pharmacology of azacitidine. Other common AEs were related to the administration of the drug (injection site reactions) or consequences of pre-treatment with anti-emetics (constipation). Haematological events were more frequently observed during Cycles 1 and 2. Few patients required dose reductions. Most haematologic TEAEs were managed with interruptions or delay of study drug, treatment with concomitant medications, or transfusions. Most patients treated with Vidaza® in the AZA-001 and the CALGB 9221 studies received supportive care for events associated with cytopaenias (transfusions, and/or administration of antibiotics), as well as pre-treatment with anti-emetics to prevent associated nausea and vomiting. The safety findings in AZA-001 were consistent with the CALGB 9221 studies and with the safety data received from the post-market safety database.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Priority review status was granted for Vidaza® based on the efficacy and safety data demonstrated in Study AZA-100 for higher-risk MDS patients who are not eligible for curative treatment with allogeneic haematopoietic stem cell transplantation.
Myelodysplastic syndromes are a heterogeneous group of serious and life-threatening haematopoietic disorders. While allogeneic haematopoietic stem cell transplantation has the potential to cure MDS, it is only an option for a younger population of MDS patients given the associated treatment-related morbidity and mortality. No drug is presently marketed in Canada for the treatment of patients with higher-risk MDS (Intermediate-2 and high-risk MDS according to IPSS) and AML (with 20-30% blasts and multi-lineage dysplasia according to the WHO) who are not eligible for haematopoietic stem cell transplantation. In this population of patients with serious and life-threatening malignancies, the benefit of Vidaza® was demonstrated by superior overall survival when compared to the conventional care options currently available in Canada with an acceptable safety profile. Therefore, the benefit-to-risk ratio is favourable for Vidaza® for the indicated population. Vidaza® was generally well-tolerated by elderly patients and demonstrated a significant and clinically meaningful survival benefit.
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 Vidaza® is favourable in the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation with:
- Intermediate-2 and High-risk Myelodysplastic Syndrome according to the International Prognostic Scoring System.
- Acute Myeloid Leukemia with 20-30 % blasts and multi-lineage dysplasia, according to the World Health Organization classification.
The New Drug Submission (NDS) complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Vidaza®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2009-01-15 |
| Request for priority status | |
| Filed: | 2009-02-03 |
| Approval issued by Director, Bureau/Centre : | 2009-02-17 |
| Submission filed: | 2009-03-26 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2009-04-27 |
| Review 1 | |
| Quality Evaluation complete: | 2009-10-20 |
| Clinical Evaluation complete: | 2009-10-21 |
| Labelling Review complete: | 2009-10-21 |
| Notice of Compliance (NOC) issued by Director General: | 2009-10-23 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| VIDAZA | 02336707 | BRISTOL-MYERS SQUIBB CANADA | AZACITIDINE 100 MG / VIAL |