Summary Basis of Decision for Mircera ™
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:
MirceraTM
Methoxy polyethylene glycol-epoetin beta, solution
Hoffmann-La Roche Ltd.
Submission control no: 106461
Date issued: 2009-01-19
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:
50 µg/mL, 100 µg/mL, 200 µg/mL, 300 µg/mL, 400 µg/mL, 600 µg/mL, 1000 µg/mL
Single-dose pre-filled syringes:
50 µg/0.3 mL, 75µ:g/0.3mL, 100 µ:g/0.3 mL, 150 µ:g/0.3 mL, 200 µ:g/0.3 mL, 250 µ:g/0.3 mL, 400 µ:g/0.6 mL, 600 µ:g/0.6 mL
Dosage form:
Route of administration:
Drug identification number(DIN):
- 50 µ:g/mL - 02307995
- 100 µ:g/mL - 02308002
- 200 µ:g/mL - 02308010
- 300 µ:g/mL - 02308029
- 400 µ:g/mL - 02308037
- 600 µ:g/mL - 02308045
- 1000 µ:g/mL - 02308053
- 50 µ:g/0.3 mL - 02308061
- 75µ:g/0.3 mL - 02308088
- 100 µ:g/0.3 mL - 02308096
- 150 µ:g/0.3 mL - 02308118
- 200 µ:g/0.3 mL - 02308126
- 250 µ:g/0.3 mL - 02308134
- 400 µ:g/0.6 mL - 02308142
- 600 µ:g/0.6 mL - 02308150
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
™Trade-Mark of F. Hoffmann-La Roche AG, used under license.
2 Notice of decision
On March 31, 2008, Health Canada issued a Notice of Compliance to Hoffman La-Roche Ltd. for the drug product, Mircera.
Mircera contains the medicinal ingredient methoxy polyethylene glycol-epoetin beta which is the first long half-life Continuous Erythropoietin Receptor Activator under the therapeutic classification: Erythropoiesis Stimulating Agent (ESA).
Mircera is indicated for the treatment of anemia associated with chronic kidney disease (CKD). This indication is based on data from correction of anemia and maintenance of hemoglobin in patients with CKD not previously treated with ESAs, on dialysis and not on dialysis as well as maintenance of hemoglobin levels in dialysis patients previously treated with other ESAs. Like other ESAs, Mircera stimulates erythropoiesis through interaction with the erythropoietin receptor on progenitor cells in the bone marrow. As a primary growth factor for erythroid development, the natural hormone erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, the natural hormone erythropoietin interacts with erythroid progenitor cells to increase red cell production.
The market authorization was based on quality, non-clinical and clinical information submitted.
The efficacy and safety of Mircera have been assessed in six Phase III randomized multicentre clinical studies for the treatment of anemia in adult patients with CKD including patients on dialysis and not on dialysis. Two studies evaluated the efficacy and safety of Mircera in patients with CKD not currently treated with an ESA and four studies assessed the ability of Mircera to maintain hemoglobin concentrations in patients with CKD who had been receiving another ESA. Administration of Mircera once a month, was shown to be non-inferior to the comparator drug in maintaining hemoglobin concentrations in the study target range. Mircera was generally well tolerated, with a safety profile characteristic of the patient population. Hypertension is a common adverse drug reaction. Patients with uncontrolled hypertension should not be treated with Mircera.
Mircera is presented as a solution. There are various strengths for single-dose vials (50 µg/mL, 100 µg/mL, 200 µg/mL, 300 µg/mL, 400 µg/mL, 600 µg/mL, 1000 µg/mL) and the single-dose pre-filled syringes (50 µg/0.3 mL, 75µg/0.3mL, 100 µg/0.3 mL, 150 µg/0.3 mL, 200 µg/0.3 mL, 250 µg/0.3 mL, 400 µg/0.6 mL, 600 µg/0.6 mL). The recommended starting dose to achieve a haemoglobin range of 100-120 g/L in patients who are on not currently treated with an ESA is 0.4 mg/kg body weight, administered once every 2 weeks, as a single IV injection for patients who are on dialysis; or 0.6 mg/kg body weight, administered once every 2 weeks, as a single SC injection for patients who are not on dialysis. If the hemoglobin range is reached for the individual patient, Mircera may be administered once monthly using a dose equal to twice the previous, once every two weeks dose. As shown in the clinical trial program, patients on hemodialysis and treated with another ESA may be converted to Mircera administration once a month as a single intravenous or subcutaneous injection. Dosing guidelines are available in the Product Monograph. To reduce the risks for cardiovascular and thromboembolic events, titrate dose of Mircera that will gradually increase hemoglobin concentration to the lowest level sufficient to avoid blood transfusions. The hemoglobin concentration should not exceed 120 g/L; the rate of hemoglobin increase should not exceed 10 g/L in any 2 week period.
Mircera is contraindicated in patients with uncontrolled hypertension, with known hypersensitivity to the active substance or any of the excipients, or who develop Pure Red Cell Aplasia (PRCA) following treatment with any ESA. Mircera is not indicated for the treatment of anemia due to cancer chemotherapy. Mircera 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 Mircera are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Mircera is favourable for the treatment of anemia associated with CKD with above limitations.
3 Scientific and Regulatory Basis for Decision
A New Drug Submission (NDS) for Mircera (methoxy polyethylene glycol-epoetin beta) was filed with Health Canada on June 12, 2006. Deficiencies in the clinical studies were identified which precluded a complete review and establishing a benefit/risk analysis. Therefore, the submission received a Notice of Deficiency (NOD). In response to the NOD, the sponsor submitted additional data and addressed adequately the concerns that led to the NOD. The indication, clinical use and the dosing regimens were modified in the Product Monograph as a result of the relevant information provided in the response to the NOD. A Notice of Compliance (NOC) was subsequently issued for Mircera on March 31, 2008.
Mircera is indicated for the treatment of anemia associated with chronic kidney disease (CKD). This indication is based on data from studies conducted for correction of anemia and maintenance of hemoglobin in patients with CKD not previously treated with ESAs, on dialysis and not on dialysis as well as maintenance of hemoglobin levels in dialysis patients previously treated with other ESAs.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
The natural hormone erythropoietin, a primary growth factor for erythroid development, is produced in the kidney and released into the bloodstream in response to hypoxia. It interacts with erythroid progenitor cells to increase red blood cell (RBC) production.
Methoxy polyethylene glycol-epoetin beta, the medicinal ingredient of Mircera, is an erythropoiesis stimulating agent (ESA). Like other ESAs, Mircera stimulates erythropoiesis through interaction with the erythropoietin receptor on progenitor cells in the bone marrow.
Manufacturing Process and Process Controls
The manufacturing process is considered to be adequately controlled within justified limits.
In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
The structure of methoxy polyethylene glycol-epoetin beta is considered to be 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 methoxy polyethylene glycol-epoetin beta are considered acceptable.
Stability
Stability study results based on accelerated and long-term testing show that methoxy polyethylene glycol-epoetin beta is a stable compound when packaged as proposed, and over the proposed storage period. The bulk drug is also stable under the proposed storage conditions.
3.1.2 Drug Product
Description and Composition
Mircera is formulated in an aqueous solution which is clear, and colorless to slightly yellowish in colour.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of methoxy polyethylene glycol-epoetin beta with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Data pertaining to the physico-chemical characteristics and biological activity demonstrated biocomparability between the developmental and commercial batches.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
All 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
The test specifications are considered acceptable to control the drug product, and the impurity limits were set according to ICH recommendations.
The review of the Lot Release Documentation (e.g. test protocol format for the release package, certificate of analysis, and/or any safety certifications) is considered to be acceptable.
Stability
Based on the long-term stability data submitted, the proposed 24 months shelf-life at 2-8°C for Mircera is considered acceptable.
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.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of facilities involved in the manufacture and testing of Mircera has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.
All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
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 Mircera 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
Pharmacodynamic (PD) studies were conducted comparing the PD properties of Mircera to epoetin beta. In vitro studies revealed that the total binding affinity to soluble recombinant erythropoietin receptor (srEPOR) for Mircera was very low when compared to epoetin beta, i.e., approximately 45-fold lower. It was determined that this was dependent on different association rate constants; epoetin beta associated much faster to srEPOR than Mircera. Dissociation rates were within a similar range for both compounds, with Mircera dissociating from srEPOR at ~1.5 times faster than epoetin beta. The lower binding affinity of Mircera will result in reduced receptor mediated elimination and therefore a longer half-life. Based on these data, it was concluded that in vivo potency would be high and therefore there would be continuous activation of the erythropoietin receptor. This was verified in a number of in vivo animal studies.
In normocythemic mice, a single injection of Mircera resulted in a substantial increase in reticulocytes and a subsequent increase in erythrocytes, the magnitude of which was twice that of epoetin beta. In addition, the duration of the response was longer and was dose-dependent. The response after subcutaneous (SC) or intravenous (IV) administration was comparable and the effects were erythrocyte-specific. Repeated injections, i.e., once a week, once every two weeks or once every three weeks, resulted in dose-dependent cyclic elevations in reticulocytes, which was similar to elevations seen after administration of epoetin beta three times per week. However, the magnitude of the response was greater with Mircera. Peak reticulocyte response was observed 4 to 5 days post-injection. There was also a more pronounced increase in erythrocyte levels after administration of Mircera, when compared to epoetin beta. However, the response was not cyclical, but rather the RBC levels remained elevated throughout the treatment period (attributed to the 45-day survival time of the mature mouse erythrocyte). There was a gradual decrease in peak elevations noted after once weekly injections of either Mircera or epoetin beta. This was attributed to either exhaustion of the bone marrow precursor cells or possibly formation of neutralizing antibody. This decrease was less pronounced when Mircera was injected once every other week or every third week, indicating that less frequent dosing allows expansion of the progenitor pool between injections. Reduced immunogenicity was demonstrated when compared to treatment with epoetin beta.
In normocythemic rats, once weekly SC or IV injections of Mircera resulted in a similar, dose-related increase in reticulocyte count (maximal response on day 6) which was maintained for the duration of the treatment period. In addition, erythrocyte count increased continuously in a dose-related manner. Findings were comparable to those seen after epoetin beta was administered three times every week, indicating higher potency of Mircera. Similar results were observed in nephrectomized rats. There was a dose-dependent increase in reticulocyte count, and a dose- and time-dependent increase in erythrocyte count. When compared to epoetin beta, it was demonstrated that Mircera was a more potent erythropoietic agent than epoetin beta when the dosing interval was prolonged to once weekly administration.
Findings in dogs were consistent with longer-lasting stimulation of erythropoiesis by Mircera, when compared with epoetin beta. However, IV administration resulted in a more pronounced increase in reticulocyte count than after SC administration. In addition, a safety pharmacology study in beagles demonstrated that acute administration of Mircera did not elicit any adverse, treatment-related effects on cardiovascular or respiratory parameters.
Bridging studies in mice demonstrated therapeutic equivalence between the preliminary and final formulations.
In conclusion, results of the PD studies demonstrated that Mircera was a more potent erythropoietic agent than epoetin beta, manifest as an increase in the magnitude and duration of the erythropoietic response.
3.2.2 Pharmacokinetics
ELISA assays were developed for measurement of Mircera in the serum of rats, rabbits and dogs. Assays were shown to be acceptable with respect to sensitivity, specificity, reproducibility and accuracy for the assessment of pharmacokinetics, and to support the toxicology studies of Mircera in the relevant species.
In addition, an ELISA assay was developed for the measurement of anti-Mircera antibodies in rat serum. This assay, which was previously validated in human serum, was partially validated in rat serum for use in a 4-week formulation comparability study.
PK studies were conducted in rats and dogs. For rats, Mircera was administered to males only as a single IV or SC injection at dose levels of 0.25, 2.5 or 25 μg/kg bw. After IV injection, approximately dose proportional increases in the area under the curve (AUC) were observed between the doses of 2.5 to 25 μg/kg bw (~ 27-fold increase was seen between the 0.25 and 2.5 μg/kg bw doses). The apparent terminal t1/2 was about 2-fold longer than that of epoetin beta (18-27 vs. 11-17 hours). The apparent volume of distribution was only 7-10% of total body water volume and 1/5 of the epoetin beta value indicating a limited distribution of Mircera. The systemic clearance of Mircera was 1/10 of the epoetin beta value. After SC administration, slightly greater than dose proportional increases in AUC were evident between the doses of 2.5 to 25 μg/kg bw (~ 64-fold increase was seen between the 0.25 and 2.5 μg/kg bw doses). As compared with epoetin beta, Tmax (24 hours) was delayed about 12 hours indicating slower depot absorption. Systemic clearance was significantly lower than that of epoetin beta (~ 10-fold). Bioavailability was lower than that of epoetin beta, i.e., 31-45% vs. 77%, respectively.
For dogs, Mircera was administered to both males and females as a single IV or SC injection at dose levels of 3.0, 7.5 (IV only) or 10 μg/kg bw. The systemic clearances from the 3 and 10 μg/kg bw groups were reduced about 7 to 20-fold, respectively, which significantly prolonged the elimination t1/2 from 6 hours (epoetin beta) to 41-70 hours (Mircera). The volume distribution of Mircera was about 60% of the epoetin beta value, indicating a limited tissue uptake of Mircera. Exposures between the 3 and 7.5 μg/kg bw groups appeared dose proportional, implying linear kinetics. However, non-linear kinetics were apparent between the doses of 7.5 and 10 μg/kg bw. After SC administration, dose proportional increases in AUC and Cmax were observed. Bioavailability of Mircera at 10 μg/kg bw was lower than at 3 μg/kg bw, i.e., 46% vs. 80%, respectively. Serum concentration increased slowly and reached maximum concentration at 48 hours whereas Tmax was 24 hours for unmodified epoetin beta, suggesting that pegylation substantially decreased the rate of absorption. The absolute bioavailability was higher in males than in the females, i.e., 98% (males) and 68% (females) vs. 66% (males) and 36% (females) at 3 and 10 μg/kg bw, respectively.
In a study conducted to evaluate the in vivo stability of Mircera, it was demonstrated that Mircera (60 kDa) remains intact in the serum. Mircera reached the bone marrow target as a 60 kDa molecule and was excreted in the urine as the intact 60 kDa molecule or a 30 kDa PEG molecule. Unconjugated human epoetin beta was not detected in the serum, urine or bone marrow.
A tissue biodistribution study was conducted in male rats at the dose of 0.674 mg/animal, which indicated that the highest radioactivity concentrations were observed in the lymph nodes, testes, blood, adrenal glands and spleen. Low concentrations were observed in the brain indicating that the radioactivity crossed the blood/brain barrier, but at low levels. Urine was the primary route of elimination. At 336 hours, urine, feces and residual carcass accounted for 57.6%, 8.59% and 33.3% of the administered dose (AD), respectively.
Tissue distribution studies were also conducted in pregnant rats at the dose level of 0.8 mg/animal. Results indicated that radioactivity was widely distributed in most maternal tissues. However, the amount of radioactivity detected in the brain and fetus was limited, indicating that the radioactivity crossed the blood/brain and blood/placental barriers, but at low levels. Within a 336 hour collection period, radioactivity in the whole fetus was less than 0.3% of the AD and never exceeded 0.01% of the AD in any fetal tissue. In lactating rats, radioactivity was detected in the milk at 4 hours post-dose and in the serum at 2 hours post-dose. Concentrations in milk and serum increased until Cmax was reached at 48 hours post-dose, with mean values of 1.18 and 12.3 μg equivalents 14C-Mircera /g, respectively. Concentrations declined with time, but were still detectable at 168 hours post-dose.
3.2.3 Toxicology
The acute non-lethal dose of Mircera when administered by IV injection to mice or rats was determined to be > 750 μg/kg bw (the highest dose tested, ~300 times the anticipated human single dose). All animals survived the duration of the study period, and treatment-related findings in either species were considered secondary to the pharmacological effect of the test material, i.e., increased reticulocyte count, RBC count, hemoglobin and hematocrit, enlarged spleens and extramedullary hematopoiesis.
Sub-chronic testing was conducted in rats (13 and 26 weeks) and dogs (13 weeks). Sub-chronic testing in rats and dogs was carried out for 13 weeks, either by IV or SC administration, followed by an 8-week recovery period, at dose levels of 1, 3 and 10 μg/kg bw/week. An interim sacrifice was carried out at 4 weeks, which also included an additional high dose group of 30 μg/kg bw/week.
For rats, seven animals were found dead or were sacrificed moribund in the 10 μg/kg bw/week group after IV administration. After SC administration, one animal in the 1 μg/kg bw/week group, and one animal in the 10 μg/kg bw/week group were sacrificed moribund. All deaths occurred after study day 36, were associated with extreme polycythemia, or anemia due to neutralizing anti-erythropoietin antibody formation, and were therefore attributed to the exaggerated pharmacological activity of the drug. For dogs, one animal was sacrificed in the 10 μg/kg bw/week group after SC administration (day 83) and was associated with extreme polycythemia. There were no other mortalities.
Increased erythropoiesis was observed at all dose levels tested resulting in increased RBC count, reticulocyte count, hemoglobin and hematocrit, decreased mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, and a functional iron deficiency. Other primary findings included enlarged spleens, increased spleen weights and extramedullary hematopoiesis in the spleen and bone marrow (all dose levels). For dogs, there was also increased hematopoiesis of the myeloid and/or megakaryocytic series in the bone marrow and spleen, and erythroid hypoplasia in the bone marrow was observed in a few animals, at all dose levels. Additional findings considered secondary to the increased erythropoiesis (and subsequent extreme polycythemia) were seen at all dose levels and included one or more of the following: ocular vascular engorgement, congestion of various tissues, hemorrhage and/or erosion of the glandular mucosa of the stomach, valvular inflammation and/or thrombosis in the heart, ossification of the bone marrow and fibroplasia and hyperostosis in the bone (rats only). By the end of the 8-week recovery period, most treatment-related changes had partially or completely reversed. However, for dogs' only, segmental glomerular sclerosis and interstitial fibrosis was observed in the kidneys at all dose levels after recovery, which was considered to be a sequelae to increased tubular basophilia and glomerular thrombi noted at the end of the treatment period.
Sub-chronic testing in rats was also carried out for 26 weeks, by SC administration, followed by a 12-week recovery period, at dose levels of 0, 0.3, 1 and 3 μg/kg bw. Treatment-related findings were the same as those seen in the 13-week study, and were observed at lower doses. Again, by the end of the recovery period, changes had partially or completely reversed.
Standard mutagenicity studies were not performed with Mircera. For biotechnologyproducts, in particular high-molecular-weight recombinant human proteins, genotoxicity tests routinely conducted for traditional pharmaceuticals are not applicable as direct interaction of these products with DNA or other chromosomal material is not expected.
Standard carcinogenicity studies were not conducted since these are considered inappropriate for biotechnology products due to the development of antibodies against human proteins in test animals.
Chronic administration of Mircera to rats for up to 26 weeks did not induce pre-neoplastic changes or hyperplasia in any tissues other than hematopoietic target organs. In addition, a normal human tissue binding study and an in vitro cell proliferation study with human tumour cell lines were conducted to evaluate non-target growth stimulation potential of Mircera in lieu of formal carcinogenicity studies. The results from these studies indicated that it is unlikely that Mircera has the potential to non-specifically stimulate growth of various non-target human cells.
Reproductive, developmental and perinatal/postnatal studies were conducted in rats and/or rabbits at dose levels of 0, 5, 20 and 50 μg/kg bw. These studies indicated that Mircera did not have any effect on estrous cycling or fertility, sperm parameters or reproductive parameters.
However, the developmental studies in rats and rabbits revealed that Mircera was embryo/fetal toxic at all dose levels tested in the absence of maternal toxicity, based on decreased fetal body weights. For rats there was also an increased incidence of reversible developmental delays at all dose levels tested, and an increased incidence of fetal alterations at 50 μg/kg bw. For rabbits, other findings included an increase in the total number of re-absorptions and percent reabsorbed conceptuses per litter at all dose levels, an increased incidence of the variations angulated hyoids and incompletely ossified sternal centra at all dose levels, and an increased incidence of the malformation flat ribs in the 50 μg/kg bw group. In the perinatal/postnatal study, F1 generation pups exhibited reduced body weight gain during lactation and for 3-4 weeks post-weaning at all dose levels. Hence, based on the reproduction data, it is recommended that special consideration should be given to women wanting to become pregnant who are being treated with Mircera. Caution should be exercised when prescribing to pregnant women and Mircera should not be used unless the potential benefits outweigh the risks to the fetus. In addition, breast-feeding should be discouraged in lactating women who are being treated with Mircera.
To summarize, non-clinical toxicity testing demonstrated that Mircera was generally well-tolerated in rats, rabbits and dogs. Treatment-related findings resulted from the development of polycythemia in normocythemic animals receiving Mircera continuously without adjustment of the dosing. However, during clinical use, the dosing schedule can easily be adjusted and hematocrit and hemoglobin concentrations will be closely monitored and maintained within a safe, physiological range. Hence, the noted treatment-related effects should not be a risk to patients.
In conclusion, the non-clinical toxicology data base was considered adequate to assess the safety profile of Mircera and support its use in humans, provided adequate safety precautions are taken, as described above.
3.2.4 Summary and Conclusion
The appropriate non-clinical toxicology studies were performed and are considered adequate. The toxicity findings were consistent with the pharmacological effects of Mircera. The non-clinical pharmacology and toxicology studies support the use of Mircera for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Mircera is a continuous erythropoietin (EPO) receptor activator that possesses distinct structural and physiochemical properties when compared with currently available erythropoetic agents. The molecule binds to and activates receptors on the erythroid progenitor cells in the bone marrow which then develop into mature erythrocytes thus increasing reticulocyte counts, hemoglobin levels and hematocrit in a dose proportional manner.
In contrast with EPO, Mircera shows a different activity at the receptor level characterized by a slower association to, and faster dissociation from, the receptor, a reduced specific activity in vitro with an increased activity in vivo, as well as an increased circulating half-life. These differential pharmacological properties are relevant in order to achieve a once monthly dosing regimen with Mircera in patients.
3.3.2 Pharmacokinetics
Absorption
Following SC administration to CKD patients, the maximum serum concentrations of Mircera were observed 72 hours after administration. The absolute bioavailability of Mircera after SC administration was 62% in dialysis patients and 54% in patients not on dialysis.
Distribution
In CKD patients, the clearance and volume of distribution of Mircera were not dose-dependent. A study in 400 CKD patients showed that the volume of distribution of Mircera is approximately 5.0 L.
Excretion
Following IV administration to CKD patients, the half-life of Mircera was 134 hours and the total systemic clearance was 0.494 mL/h/kg. Following SC administration the observed terminal elimination half-life was 139 hours in CKD patients.
The PK data from the Phase III studies has been used to study the linearity of dose. The results indicated dose linearity in the PK of Mircera at therapeutic doses.
The site of injection (abdomen, arm or thigh) had no clinically important effects on the PK or PD of Mircera in healthy volunteers when administered SC (dose of 3.0 mcg/kg).
Drug- Drug Interaction
No drug-drug interaction studies were conducted; however, the effects of other drugs on the PK and PD of Mircera were explored using a population analysis approach. There was no indication of an effect of concomitant medications on the PK and PD of Mircera.
Special Populations
No studies were conducted for patients with hemoglobinopathies, severe liver disease, seizures or with platelet levels greater than 500 x 109/L. Mircera is not recommended for use in children and adolescents below 18 years of age.
3.3.3 Clinical Efficacy
Six Phase III randomized, multi-centre clinical studies were submitted for the evaluation of efficacy and safety of Mircera for the treatment of anemia in adult patients with CKD, including patients on dialysis and not on dialysis. Two studies evaluated the efficacy and safety for correction of anemia in patients with CKD not currently treated with an ESA (BA16738 [not on dialysis], BA16736 [on dialysis]), and four studies evaluated the ability of Mircera to maintain hemoglobin concentrations in patients with CKD [all on dialysis] who had received an ESA other than Mircera in the correction phase (BA16739, BA16740, BA17284, BA17283). Data from extension phases of the two Phase III correction trials (BA16736, BA16738) were also provided.
Anemia Correction Studies: Patients not treated previously with an ESA
Study BA16738 compared the efficacy of Mircera and a comparator, darbepoetin alfa in CKD patients who were not on dialysis. A total of 162 patients were treated with Mircera and 162 patients were treated with the comparator. The primary efficacy endpoints were the proportion of patients who experienced a hemoglobin response defined as an increase from baseline hemoglobin ≥10g/L and a hemoglobin concentration of at least 110.0 g/L without RBC transfusion. The starting dose of Mircera was 0.6 µg/kg administered SC once every two weeks, while that of the comparator was 0.45 µg/kg every week. The hemoglobin response was achieved by 97.5% of the 162 patients treated with Mircera compared to 96.3% of the 162 patients in the comparator group. The mean change in hemoglobin from baseline was 21.5 g/L in patients treated with Mircera and 19.9 g/L in those treated with the comparator. The results demonstrate that Mircera was not clinically inferior to the comparator group. The incidence of RBC transfusions during the core treatment period was 2.5% in the Mircera group and 6.8% in the comparator group. The proportion of patients experiencing a hemoglobin level >130 g/L was 11.4% for those treated with Mircera, and 34.0% for those treated with comparator.
Study BA16736 compared the efficacy of Mircera and a comparator, epoetin alfa or epoetin beta in CKD patients who were on dialysis. The primary efficacy endpoint was the proportion of patients who experienced a hemoglobin response defined as an increase from baseline hemoglobin ≥10g/L and a hemoglobin concentration of at least 110 g/L without RBC transfusion. The starting dose of Mircera was 0.4 µg/kg administered IV once every two weeks, while the comparator was 50 Units/kg administered IV three times per week. The hemoglobin response was achieved by 93% of the 135 patients treated with Mircera compared to 91% of the 46 patients in the comparator group. The incidence of RBC transfusions during the core treatment period was 5.2% in Mircera and 4.3% in the comparator group. The proportion of patients experiencing a hemoglobin level >130 g/L was 7.5% for those treated with Mircera, and 17.8% for those treated with comparator.
Hemoglobin Maintenance Studies:
Hemoglobin maintenance studies with patients whose anemia was corrected with an ESA other than Mircera
Four randomized and controlled Phase III studies (BA16739, BA16740, BA17284 and BA17283) demonstrated the ability of Mircera compared to other ESAs in maintaining hemoglobin levels within a study target range. Patients with CKD treated with another ESA who had stable hemoglobin levels were randomized to receive Mircera either once every two weeks (Q2W) or once every four weeks (Q4W), or to continue their current ESA dose and schedule in CKD patients receiving dialysis.
Study BA16739 compared Mircera Q2W IV (n=223) or Q4W IV (n=224) with epoetins [epoetin alfa (n=181) or epoetin beta (n=45)] for the maintenance of haemoglobin. Study BA16740 compared Mircera Q2W SC (n=190) or Q4W SC (n=191) with epoetins [epoetin alfa (n=23), epoetin beta (n=168)] for the maintenance of haemoglobin. Study BA17283 compared Mircera Q2W IV (n=157) with darbepoetin alfa (n=156) for the maintenance of haemoglobin. Study BA17284 compared Mircera Q2W IV (n=112) or SC (n=56) in a pre-filled syringe, with epoetins [epoetin alfa (n=104), epoetin beta (n=64)].
Results demonstrated the non-inferiority of Mircera compared with epoetin alfa, epoetin beta, and darbepoetin alfa, regardless of dosing regimen (Q2W or Q4W), route of administration (IV or SC) and mode of presentation (vial or pre-filled syringe).
In the Phase III maintenance studies, the Mircera Q2W groups required dose decreases more often (12.7%-20.0%) than the reference groups (7.6%-14.1%) whereas the Mircera Q4W groups tended to require dose increases (15.5%-23.2%), more often than the reference groups (11.6%-15.7%). This implies that the proposed dosing regimens are not optimal.
Hemoglobin maintenance studies with patients whose anemia was corrected with Mircera
Data from extension phases of the two Phase III correction trials (BA16736, BA16738) were also provided. Mircera was tested in maintenance of hemoglobin in the same group of CKD patients whose anemia was corrected using Mircera. Compared to other ESAs, the results demonstrate that Mircera is effective and safe for the maintenance of appropriate hemoglobin levels in the same CKD patients who have undergone anemia correction with Mircera.
3.3.4 Clinical Safety
The clinical safety studies originally included results from the Phase IIIcorrection & maintenance studies (BA16736, BA16738, BA16739, BA16740, BA17283, BA17284) and the Phase II studies (BA16260, BA16528, BA16285, BA16286). The long-term extensions of the Phase II studies were excluded from the main mortality analysis. The exclusion of these patients did not allow a full comparison of mortality rates between the Mircera and reference treatment groups.
The overall death rates were similar in the Mircera and reference groups (7%and 6.1%, respectively), however the frequencies of sudden death (0.4% and 0.0%, respectively) and septic shock (0.3% and 0.0%) were somewhat greater with Mircera. There was a tendency towards higher hemoglobin levels (≥130 g/L) with Mircera, as well as a higher death rate associated with these higher hemoglobin levels than with the reference medications. Causes of death included: cardiac effects, infections, CNS effects, renal effects, and sudden death. Also in the long-term extensions of the Phase II extension studies, which continued up to 127 weeks of treatment (and had no reference group), the death rate was 14%.
The most common adverse events (AEs) were: hypertension; diarrhea; and nasopharyngitis. AEs seen more frequently with Mircera than with the reference medication were: procedural hypotension; gastrointestinal hemorrhage; and tachycardia. Treatment-related AEs did not demonstrate any clear difference between groups; and the percentage of patients in each group that withdrew due to AEs was 2.5% and 1.8% with Mircera and the reference medication, respectively.
Serious adverse effects (SAEs) seen more frequently with Mircera than with the reference medication were: atrial fibrillation, acute myocardial infarction, unstable angina, gastrointestinal hemorrhage, and hypotension.
Patients on dialysis were slightly more likely to experience AEs than those not on dialysis but no clear group differences were observed with respect to mode of dialysis (hemodialysis or peritoneal), route of administration (IV or SC), or form of presentation (vial or pre-filled syringe). No anti-erythropoietin or anti-Mircera antibodies were detected in any patients. Mircera patients demonstrated a greater reduction in platelets than did the reference patients, but their means and medians remained within the normal range. However, 5% of patients taking Mircera had marked thrombocytopenia compared with 2% in the reference group. QTcR intervals were similar in the Mircera and reference group.
Due to the study design, multiple occurrences of the same adverse event in one individual were counted only once. This could have reduced the frequency of serious adverse events especially in the cardiovascular group where most of serious adverse events are short-lived. The treatment effect of this class of drugs has been intensively studied and has been of major concern lately in the clinical literature and in international regulatory decisions.
Chronic Kidney Disease (CKD)
Patients with CKD not requiring dialysis may require lower maintenance doses of Mircera than patients requiring dialysis. These patients may be more responsive to the effects of Mircera, and require judicious monitoring of blood pressure and hemoglobin (i.e., may overshoot target). Renal function and fluid and electrolyte balance should be also closely monitored.
Patients with CKD that require dialysis treated with Mircera may have an increased red blood cell level and decreased plasma volume, which reduces dialysis efficacy, thus requiring possible adjustments in dialysis prescription.
Abnormal Hematological Findings
During treatment with Mircera there was a slight decrease in mean platelet counts from pre-treatment levels, and an increased incidence of thrombocytopenia: platelet counts below 100 x 109/L were observed in 7.5% of patients treated with Mircera and 4.4% of patients treated with other ESAs.
Immunogenicity
In 1789 patients treated with Mircera in clinical studies, antibody testing using an enzyme-linked immunosorbent assay (ELISA) was conducted at baseline and during treatment. Antibody development was not detected in any of the patients.
Cancer
Mircera is not indicated for the treatment of the anemia accompanying cancer chemotherapy. An increased risk of death was observed in a clinical study when other ESAs were administered to achieve hemoglobin of 120 g/L in patients with active malignant disease who were not being actively treated with either chemotherapy or radiation therapy. ESAs also shortened survival in patients with metastatic breast cancer receiving chemotherapy when administered to achieve a hemoglobin level of greater than 120 g/L.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Six Phase III safety and efficacy studies were conducted to evaluate the benefits and risks of Mircera for the treatment of anemia for patients with CKD. The benefits, in patients with CKD, of biweekly dosing of erythropoietic agents for correction, and every four weeks dosing for maintenance of hemoglobin, compared with dosing weekly or several times per week are evident: they reduce inconvenience to the patient and reduce workload in medical facilities. Therefore, if the longer-acting agents can be shown to be safe and effective, then they will be a welcome addition to therapeutic options. Given that patients with CKD are medically fragile, Mircera appears to be reasonably safe and effective provided a range for hemoglobin of 100-120 g/L is respected.
Further studies and rigorous post-marketing surveillance should be performed to determine if long-term use substantiates the above conclusions. Based on the information collected from the studies submitted, Mircera is granted market authorization for the correction of anemia and maintenance of hemoglobin after correction of anemia, in adult patients with CKD (as long as an upper hemoglobin level of 120 g/L is targeted and maintenance therapy is administered every four weeks.
In conclusion, the benefits of Mircera for the treatment of anemia for patients with CKD appear to outweigh the risks. Restrictions to assist in managing risks associated with this drug have been incorporated into the Indication, Labelling, and Product Monograph.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Mircera to be positive for the treatment of anemia associated with chronic kidney disease (CKD). This indication is based on data from correction of anemia and maintenance of hemoglobin in patients with CKD on dialysis or not on dialysis who were not previously treated with erythropoiesis-stimulating agents (ESAs), as well as maintenance of hemoglobin levels (upper hemoglobin level of 120 g/L) in dialysis patients previously treated with other ESAs. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted a Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: MirceraTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2006-03-10 |
| Submission filed: | 2006-06-08 |
| Screening 1: | |
| Screening Acceptance Letter issued | 2006-08-02 |
| Review 1: | |
| Quality Evaluation complete | 2007-02-15 |
| NOD issued by Director General (safety and efficacy issues) | 2007-02-15 |
| Response filed: | 2007-05-17 |
| Screening 2: | |
| Screening Acceptance Letter issued | 2007-06-29 |
| Review 2: | |
| On-Site Evaluation | 2007-09-17 |
| Quality Evaluation complete | 2008-03-28 |
| Clinical Evaluation complete | 2008-03-25 |
| Labelling Review complete | 2008-03-06 |
| NOC issued by Director General NOC issued by Director General | 2008-03-31 |