Summary Basis of Decision for Prolia ™
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:
ProliaTM
Denosumab, 60 mg/mL solution for injection
Amgen Canada Inc.
Submission control no: 121139
Date issued: 2011-01-17
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):
- 02343568
- 02343541
Therapeutic Classification:
Non-medicinal ingredients:
Sorbitol, acetate, polysorbate 20, water for injection [United States Pharmacopeia (USP)], and sodium hydroxide.
Vial:
Sorbitol, acetate, water for injection (USP), and sodium hydroxide.
Submission type and control no:
Control Number: 121139
Date of Submission:
Date of authorization:
2 Notice of decision
On August 6, 2010 Health Canada issued a Notice of Compliance to Amgen Canada Inc. for the drug product Prolia.
Prolia contains the medicinal ingredient denosumab, which is a human immunoglobulin G2 (IgG2) monoclonal antibody that targets and binds with high affinity and specificity to the Receptor Activator for Nuclear κ B Ligand (RANKL), preventing it from activating its receptor Receptor Activator for Nuclear κ B (RANK), on the surface of osteoclasts and their precursors. Prevention of RANKL-RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption.
Prolia is indicated for the treatment of postmenopausal women with osteoporosis at a high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, Prolia reduces the incidence of vertebral, non-vertebral, and hip fractures.
Osteoporosis is associated with systemic low bone mass and compromised bone strength leading to an increased risk of fracture. With age and particularly with the reduction of estrogen levels in postmenopausal women, bone resorption accelerates. Osteoclasts play an important role in bone loss associated with postmenopausal osteoporosis
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy of Prolia was based on data obtained from one pivotal clinical study and its seven sub-studies. The pivotal study was an international, multicentre, randomized, double-blind, and placebo-controlled clinical trial which assessed Prolia as compared to placebo in reducing the risks of new vertebral, non-vertebral, and hip fractures in postmenopausal women with osteoporosis. Osteoporosis was defined as a bone mineral density (BMD) T-score -2.5 to -4.0 standard deviations below the average BMD value for young healthy women at the lumbar spine, the total hip, or both locations. The study enrolled 7,808 women aged 60-91 years. Subjects were randomized (1:1) in a double-blinded fashion to receive either Prolia (60 mg) or placebo subcutaneously every 6 months for 3 years (last dose at month 30; follow-up to month 36). Randomization was stratified by age at entry: 60 to 64 years, 65 to 69 years, 70 to 74 years, and ≥75 years. Subjects received daily calcium (≥1 g) and vitamin D (≥400 IU) supplementation. The primary efficacy variable was the incidence of new vertebral fractures over 3 years.
The results of the study pertaining to the primary endpoint, indicated that Prolia, when taken with calcium and vitamin D over 36 months significantly reduced (p< 0.0001) the incidence of new vertebral fractures as compared to the placebo group which received calcium and vitamin D alone (new vertebral fracture incidence: Prolia 2.3% versus [vs.] placebo 7.2%). The absolute reduction in risk of vertebral fractures was 4.8% and the relative reduction was 68%.
The efficacy of Prolia in the treatment of postmenopausal women with osteoporosis at high risk for fracture was also evaluated as a sub-group analysis. Subjects were classified as having a high fracture risk if they met at least two of the following three criteria: age >70 years; baseline BMD T-score of -3.0 or lower at the lumbar spine, total hip, or femoral neck; and prevalent vertebral fracture at baseline. Of the 7,808 subjects enrolled, 3,513 or 45% of subjects (1,761 in the Prolia group and 1,752 in the placebo group) met the above criteria. Prolia significantly reduced (p< 0.0001) the incidence of new vertebral fractures over 36 months (new vertebral fracture incidence: Prolia 3.5% vs. placebo 10.0%). The decreased absolute risk of new vertebral fractures in this high risk fracture subpopulation was 6.5% with a relative risk reduction of 65%.
Prolia (60 mg/mL, denosumab) is a clear, colourless to slightly yellow solution presented in a prefilled syringe or vial. The recommended dose of Prolia is a single subcutaneous injection of 60 mg, once every 6 months. Dosing guidelines are available in the Product Monograph.
Prolia is contraindicated for patients with hypocalcaemia, or for those who are hypersensitive to the drug or to any component of the product. Prolia 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 Prolia 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 Prolia is favourable for the indication stated above. As part of the market authorization, Health Canada has required a Risk Management Plan to ensure that the benefits continue to outweigh any risk.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Denosumab is a full-length, IgG2 human monoclonal antibody with high affinity and specificity for RANKL, a transmembrane or soluble protein that is essential for the formation, function and survival of osteoclasts, the sole cell type responsible for bone resorption. Osteoclasts play an important role in bone loss associated with postmenopausal osteoporosis (PMO). Denosumab binds with high affinity and specificity to RANKL, preventing RANKL from activating its receptor RANK, which is located on the surface of osteoclasts and their precursors. Prevention of RANKL-RANK interaction results in reduced osteoclast numbers and function, and thereby decreases bone resorption.
Manufacturing Process and Process Controls
The drug substance is generated by recombinant technology.
The denosumab manufacturing process is performed and has been validated at two different manufacturing sites. The process implemented at each site differs slightly due to facility-related differences and design constraints. Each process consists of cell culture, harvest, recovery, and purification stages, including viral inactivation/removal steps. Process validation data demonstrate that the manufacturing processes operate in a consistent manner, yielding product of acceptable quality. In addition, as there are differences between manufacturing sites, comparability studies have been performed. Data demonstrate that denosumab manufactured at both sites is comparable from a quality perspective.
The drug substance manufacturing process has been scaled-up and optimized during development. Different manufacturing sites have also been used for clinical supply and to support commercialization. The process changes introduced at each generation of the process were adequately described and comparatively assessed. Lot release, stability and characterization data have also been used to support the comparability assessment.
The materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing process consistency is ensured through defined production procedures, critical quality tests, in-process limits, and denosumab certificate of analysis specifications. Microbial control is maintained throughout the manufacturing process by testing for bio-burden as well as for bacterial endotoxins. In-process controls performed during the manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
Detailed characterization studies were performed to provide assurance that denosumab consistently exhibits the desired characteristic structure and biological activity.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of denosumab are considered acceptable.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicated that the impurities of the drug substance were adequately under control.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance container closure is considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed shelf-life and storage conditions for the drug substance were adequately supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Prolia (60 mg/mL, denosumab) is a sterile, preservative-free, clear, colourless to slightly yellow solution. It is supplied in a single-use prefilled syringe (PFS) or in a single-use vial. Prolia is intended for administration by subcutaneous (SC) injection.
Each 1.0 mL single-use PFS of Prolia contains 60 mg denosumab, 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, water for injection, and sodium hydroxide to adjust to a pH of 5.2.
Each 1.0 mL single-use vial of Prolia contains 60 mg denosumab, 4.7% sorbitol, 17 mM acetate, water for injection (USP), and sodium hydroxide to adjust to a pH of 5.2
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Prolia, rationale for choice of formulation, manufacturing process including packaging, information on batches used for in vitro studies for characterization and discussion on the effect of formulation change on the safety and/or efficacy of Prolia. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Parameters relevant to the performance of the drug product were not affected by the changes described.
Data pertaining to the physico-chemical characteristics and biological activity demonstrated biocomparability between the development and commercial batches.
Manufacturing Process and Process Controls
The drug product manufacturing process essentially consists of diluting the drug substance to a target concentration of 60 mg/mL, filtration, and filling into vials or syringes. In the case of the PFS presentation, polysorbate 20 is also added during preparation of the formulated bulk to mitigate particle formation in the PFS container closure system. The drug product manufacturing process used to manufacture each of the presentations (vial and PFS) has been adequately validated and is capable of consistently generating product that meets release specifications.
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
Each lot of Prolia drug product is tested for appearance, content, identity, potency, purity, and impurities. Established test specifications and validated analytical test methods are considered acceptable.
Through Health Canada's lot release testing and evaluation program, manufactured final product lots were tested and found to meet the established drug product specifications and demonstrate consistency in manufacturing.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed 30-month shelf-life at 2 to 8°C for Prolia (vial and PFS) is considered acceptable.
The compatibility of the drug product with the container closure systems was demonstrated through compendial testing and stability studies. The container closure systems met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The drug substance is manufactured at two different facilities. On-Site Evaluations (OSEs) for the denosumab drug substance facilities were waived because both facilities have been subjected to relatively recent and successful OSEs.
An OSE of the facility involved in the manufacture and testing of the drug product has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.
The design, operations and controls of the facility and equipment that are involved in the production of Prolia are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
The denosumab 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). Steps from the purification process designed to remove and inactivate viruses are adequately validated.
Raw materials of animal and recombinant origin used in the manufacturing process are adequately tested to ensure freedom from adventitious agents. 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 Prolia 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 Pharmacodynamics
Pharmacodynamic (PD) studies demonstrated that denosumab binds to human RANKL with high affinity and specificity. There was no evidence of interactions between denosumab and other members of tumour necrosis factor (TNF) family. Denosumab effectively suppressed osteoclast formation driven by human RANKL but not murine RANKL. No effect was observed on the proliferation and survival of osteoblast-like cell lines. Denosumab does not appear to recognize murine or rodent RANKL, and had no obvious effects on the normal mouse or rat skeleton.
It was demonstrated that denosumab increases bone mass and density and inhibits bone resorption in human RANKL knock-in mice (genetically modified to express a human/chimeric form of RANKL that is inhibited by denosumab).
In a representative animal model for osteoporosis, ovariectomized (OVX) cynomolgus monkeys were treated with denosumab by SC administration at doses of 25 or 50 mg/kg bodyweight (bw)/month for 16 months. Both dose levels were well tolerated, without any adverse effects on bone. Treatment with denosumab elicited positive effects on cortical and cancellous bone mass as determined by in vivo BMD measurements and by ex vivo histomorphometric architectural parameters. Bone strength and quality was increased at clinically relevant sites including the lumbar spine, the femoral neck, and the femoral diaphysis.
The effects of changing treatment from alendronate (ALN) to denosumab were assessed in OVX cynomolgus monkeys. Treatment with ALN for 6 months followed by treatment with denosumab resulted in further reduction in bone resorption, leading to further increases in BMD of the whole body, lumbar spine, and distal radius. There was no negative effect on bone strength or bone quality. Treatment with either ALN or denosumab resulted in slight decreases in serum calcium levels; however, these changes were within physiologically normal ranges. The data from this study revealed that transition from treatment with ALN to denosumab did not modify the activity of denosumab, and did not result in any adverse effects with respect to serum calcium or bone strength/quality.
Safety Pharmacology
There were no treatment-related cardiovascular or respiratory effects observed in male cynomolgus monkeys following SC administration of denosumab at concentrations of 0.3, 3.0 or 30.0 mg/kg bw.
3.2.2 Pharmacokinetics
At the time of review, pharmacokinetic (PK) studies in humans had been completed which were considered more relevant than the non-clinical PK studies. As a result, the non-clinical PK studies were not reviewed for this submission.
3.2.3 Toxicology
All in vivo toxicity studies were conducted in cynomolgus monkeys and the majority utilized the SC route of administration to support the intended clinical use. The dose levels were chosen to provide substantial challenge to the test animals. Low doses were intended to provide no-observed-effect and/or no-observed-adverse-effect levels (NOEL, NOAEL). The circulating half-life of denosumab and potential for immunogenicity in the test species were also taken into consideration. Doses in the longer duration studies were adjusted upward to accommodate for the immune response to the drug, thus maintaining adequate exposure to active drug. Overall, adequate margins of drug exposure were achieved in each study to facilitate an adequate risk assessment.
Repeat-Dose Toxicity
Repeat-dose toxicity testing was carried out for 1 month at dose levels of 0.1, 1.0, and 10 mg/kg bw/week; and for 6 and 12 months (combined study) at dose levels of 1, 10, and 50 mg/kg bw/month.
Dose levels in the repeat-dose studies were generally well-tolerated and findings were generally consistent after treatment for 1, 6, or 12 months. Findings included: an increase in BMD; increased bone mass and biomechanical strength; increases in cortical area, cortical thickness and bone mineral content (BMC); decreased serum calcium and alkaline phosphatase; and decreases in serum and urine markers of bone turnover. The degree of reduction in bone resorption markers was slightly greater than for the bone formation marker; therefore, it is likely that the bone formation response was coupled to the resorption response.
Histopathological examination of the tibia, sternum, and femur after 6 and 12 months of treatment revealed a decrease of osteoblasts and osteoclasts, and decreased chondroclasis at the epiphyseal growth plate, with increased thickness of the epiphysis. These findings were expected effects attributable to the pharmacological activity of denosumab and were not considered to be adverse effects.
In the 6-/12-month study, two males died in the 50 mg/kg bw/month group. Upon examination, it was revealed that one male had cardiac pathology. The other male was sacrificed moribund, due to exacerbation of a protozoal infection. Although these were isolated incidences, it could not be ruled out with certainty that the cause of the two mortalities was secondarily related to the administration of denosumab, such as (i.e.), exacerbation of sub-symptomatic existing disease, and exacerbation of the protozoal infection. In addition, there was an increased incidence of abscesses observed in the teeth and jaws of females in the 10 mg/kg bw and 50 mg/kg bw groups. These findings were considered to be possibly a secondary result of treatment with denosumab, i.e., as a result of immune suppression.
Genotoxicity and Carcinogenicity
Genotoxicity and carcinogenicity studies have not been conducted with denosumab in accordance with the guidelines of the International Conference on Harmonisation (ICH) Guidance S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.
Direct evaluation of the carcinogenic potential of denosumab is precluded by the limited species reactivity of denosumab which does not recognize murine or rodent RANKL. In addition, there was no gross evidence of hyperplastic lesions in OVX monkeys treated for up to 16 months with denosumab at doses of up to 50 mg/kg bw/month or gross or microscopic evidence in male and female monkeys treated for 12 months at doses up to 50 mg/kg bw/month.
Immunotoxicity
Immunotoxicity testing revealed no adverse effects of denosumab in lymphocyte subsets, serum immunoglobulin levels, or T-cell dependent antibody response to keyhole limpet hemocyanin (KLH). Collective data indicate that denosumab does not pose a meaningful risk for immunotoxicity on functional immune responses, circulating lymphocyte subpopulations or distribution of T- and B-lymphocytes in lymphoid tissue.
Reproductive and Developmental Toxicity
Reproductive toxicity studies were conducted at dose levels of 2.5, 5.0, and 12.5 mg/kg bw. There were no treatment-related effects on general maternal toxicity, female mating, female fertility, menstrual cycle length, serum hormone levels or embryo-foetal development. In addition, there was no effect on sperm motility, which was assessed in the 6-/12-month repeat-dose cynomolgus monkey toxicity study at doses of up to 50 mg/kg bw.
Denosumab was not teratogenic at any dose level tested. A pre- and post-natal developmental study was not conducted due to the species specificity of denosumab (that is to say, only an extremely low number of juvenile monkeys would be available for evaluation) and also since there were no adverse findings identified in the embryo-foetal study. However, results obtained in a safety pharmacology study in 2-week old rats, utilizing the test material human osteoprotegerin (huOPG-Fc; a surrogate molecule for the pharmacological effects of denosumab) provided preliminary evidence to suggest that denosumab has the potential to inhibit skeletal growth and tooth eruption in infants or children. In addition, denosumab was quantified in the cord blood of foetuses at Day 100 of pregnancy. As an IgG2 human monoclonal antibody, it is considered unlikely that denosumab crosses the placenta during the first trimester; however, transfer progressively increases during the second and third trimester. Therefore, it would have been useful to conduct a pre- and post-natal study to confirm the noted findings in young rats after treatment with denosumab and to characterize any other potential effects on pre- and post-natal animals. These studies could have been conducted in genetically engineered, huRANKL knock-in mice.
Local Tolerance
Local tolerance of SC injections of denosumab was investigated following monthly SC administration of denosumab at 50 mg/kg bw. There was no evidence of substantive irritation observed at the injection sites.
3.2.4 Summary and Conclusion
In conclusion, the above studies have characterized the pharmacological properties of denosumab, demonstrating its ability to inhibit the interaction of RANKL and RANK.
Denosumab was generally well tolerated in repeat-dose toxicity studies at doses of up to 50 mg/kg bw/month. However, in the 6-/12- month repeat-dose study, two male cynomolgus monkeys died in the 50 mg/kg bw group and there was an increased incidence of abscesses in the teeth and jaws for females in the 10 and 50 mg/kg bw/month groups. These findings were considered to possibly be a secondary result of treatment with denosumab. Hence, it cannot be ruled out that the administration of denosumab may possibly increase the risk of infection. Adequate safety precautions should be taken against immunomodulatory activity which may be seen in patients undergoing treatment.
There was no evidence of denosumab-associated maternal toxicity, embryo-foetal toxicity or teratogenicity observed in reproductive toxicity studies conducted in cynomolgus monkeys at doses up to 12.5 mg/kg bw; however, pre- and post-natal studies were not conducted, and results obtained in safety pharmacology studies indicated that denosumab has the potential to inhibit skeletal growth and tooth eruption in infants and children. Based on this data, it is recommended that special consideration be given to women wanting to become pregnant who are being treated with denosumab. Women who are pregnant should not be treated with denosumab. In addition, breastfeeding should be discouraged in lactating women who are being treated with denosumab.
The non-clinical studies submitted were considered adequate to assess the safety profile of Prolia (denosumab) and support is use in humans, provided that adequate safety precautions are taken, as described in Section 3.3.4 Clinical Safety.
The toxicity database for Prolia is complete and is in accordance with ICH Guidance S6.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The pharmacodynamics of Prolia was investigated in healthy subjects (women) with or without signs of osteoporosis and in postmenopausal women with low bone mass. Bone turnover markers were measured to assess bone metabolism. The marker serum C-telopeptide of type I collagen (CTX) was measured to assess the degree of bone resorption.
The results of the studies showed that within 6 hours of SC administration of 60 mg of Prolia, a rapid reduction in CTX of approximately 70% was observed, with reductions of approximately 85% occurring by 3 days. Levels of CTX were below the limit of assay quantitation (0.049 ng/mL) in 39 to 68% of subjects 1 to 3 months after treatment with Prolia. Bone turnover markers (bone resorption and formation markers) generally reached pre-treatment levels within 9 months after the last 60 mg SC dose. Upon re-initiation, the degree of inhibition of CTX by Prolia was similar to that observed in patients initiating Prolia treatment.
3.3.2 Pharmacokinetics
In dose-ranging studies, denosumab exhibited nonlinear, dose-dependent pharmacokinetics for doses between 0.01 to 3.0 mg/kg inclusive. Clearance or apparent clearance (mL/hr/kg was higher at lower doses and had a linear inverse relationship with dose on a log-log plot. Exposures (SC dosing) based on area under the serum denosumab concentration-time curve (AUC) increased greater than dose-proportionally from 0.01 to 1 mg/kg (700-fold for the 100-fold increase in dose), but approximately dose-proportionally from 1 to 3 mg/kg (3.9-fold for the 3-fold increase in dose).
3.3.3 Clinical Efficacy
To support the authorized indication, efficacy data was obtained from one pivotal clinical study and its seven sub-studies.
Pivotal Study
The pivotal study (FREEDOM) was a Phase III, international, multicentre, randomized, double-blind, and placebo-controlled clinical trial which compared Prolia to placebo for reducing the incidence of vertebral, non-vertebral, and hip fractures in postmenopausal women with osteoporosis. Osteoporosis was defined as a BMD T-score -2.5 to -4.0 standard deviations below the average BMD value for young healthy women at the lumbar spine, the total hip, or both locations. The study enrolled 7,808 women aged 60-91 years (mean age 72 years). Of the patients enrolled, 23.6% had prevalent vertebral fractures.
Patients were randomized (1:1) in a double-blinded fashion to receive either Prolia (60 mg) or placebo subcutaneously every 6 months for 3 years (last dose at month 30; follow-up to month 36). Randomization was stratified by age at entry: 60 to 64 years, 65 to 69 years, 70 to 74 years, and ≥ 75 years. Patients received daily calcium (≥1 g) and vitamin D (≥400 IU) supplementation.
The primary efficacy endpoint of the pivotal study was the incidence of new vertebral fractures over 3 years. Secondary efficacy endpoints included the incidence of non-vertebral fracture and hip fracture, assessed over 3 years. The study was powered to detect a 45% reduction in the incidence of new vertebral fractures, a 40% decrease in the risk of non-vertebral fractures, and a 40% decrease in the risk of hip fractures. Women with other diseases or on therapies that may affect bone (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget's disease) were excluded from this study.
Effects on Fracture Incidence
Primary Analysis (Intent-to-Treat Patient Population)
Vertebral Fracture Incidence
Vertebral fractures were determined radiologically by a pair of validated independent blinded radiologists using a semi-quantitative method.
Over 36 months, patients who were treated with Prolia (in combination with daily calcium and vitamin D supplementation) demonstrated a statistically significantly reduced incidence of new vertebral fractures (2.3%; 86/3706 patients) compared to the placebo group which received calcium and vitamin D supplementation alone (7.2%; 264/3691 patients) (p <0.0001). The absolute reduction in risk of vertebral fractures was 4.8% [95% Confidence Interval (CI): 3.9, 5.8] and the relative risk reduction was 68% (95% CI: 59, 74; p <0.0001). The number needed to treat (NNT) over 3 years to prevent one new vertebral fracture was 20.7 (95% CI: 17.3, 25.8).
Hip Fracture Incidence
The incidence of hip fracture was 1.2% for the placebo group compared to 0.7% for the Prolia group. The observed absolute reduction in the risk of hip fracture over 3 years was 0.3%, with a 95% CI across the zero (-0.1%, 0.7%), and the relative risk reduction was 40% (95% CI: 3, 63; p = 0.0362).
Non-Vertebral Fracture Incidence
The incidence of non-vertebral fractures was 8.0% for the placebo group compared to 6.5% for the Prolia group. The observed absolute reduction in risk of non-vertebral fractures over 3 years was 1.5% (95% CI: 0.3, 2.7). The relative risk reduction was 20% (95% CI: 5, 33; p = 0.0106).
Sub-group Analysis: Postmenopausal Women with Osteoporosis at a High Risk for Fracture
Patients were classified as having a high fracture risk if they met at least two of the following three criteria: age >70 years; baseline BMD T-score of -3.0 or lower at the lumbar spine, total hip, or femoral neck; and prevalent vertebral fracture at baseline. Of the 7,808 patients enrolled, 3,333 (45%) of patients (1,761 in the Prolia group and 1,752 in the placebo group) met the above criteria.
Vertebral Fracture Incidence
Prolia significantly reduced the incidence of new vertebral fractures over 36 months from 10.0% in the placebo group to 3.5% in the Prolia group. The decreased absolute risk of new vertebral fractures was 6.5% (95% CI: 4.8, 8.2) with a relative risk reduction 65% (95% CI: 0.26, 0.47; p <0.0001).
Hip Fracture Incidence
The incidence of hip fracture was 1.9% the placebo group compared to 1.0% for the Prolia group. The observed absolute risk reduction was 0.9%, and the relative risk reduction was 48% (95% CI: 0.29, 0.91; p = 0.0208).
Non-Vertebral Fracture Incidence
The incidence of non-vertebral fractures was 8.6% for the placebo group compared to 7.7% for the Prolia group. The observed absolute risk reduction was 0.9%, and the relative risk reduction was 12% (95% CI: 0.70, 1.11; p = 0.2901).
Sub-studies
The results obtained from the seven sub-studies conducted within the pivotal trial did not reveal an impact on the efficacy and safety of Prolia; however, in the "Bone histology and histomorphology sub-study", markedly reduced bone formation rates were observed. The long-term consequences of this degree of suppression of bone remodelling are unknown.
3.3.4 Clinical Safety
The safety of Prolia was evaluated in the pivotal clinical study described in section 3.3.3 Clinical Efficacy.
Pivotal Study
The incidence of serious adverse events (SAEs) was 25.8% in the Prolia group and 25.1% in the placebo group. A higher incidence of fatality was not observed in patients treated with Prolia [1.8% vs. 2.3% placebo].
Adverse events (AEs) leading to treatment discontinuation occurred in 4.9% of women in the Prolia group and 5.2% of women in the placebo group. The most common AEs leading to treatment discontinuation for both groups were breast cancer which was observed in 0.5% of Prolia-treated patients and 0.3% of placebo-treated patients, back pain (0.2% Prolia vs. 0.3% placebo), and constipation (0.2% Prolia vs. 0.2% placebo). Cardiac disorders leading to discontinuation were reported in 14 patients (0.4%) in the Prolia group and 3 patients (<0.1%) in the placebo group.
Serious and/or Adverse Events of Interest
Hypocalcaemia
Declines of serum calcium concentrations to less than the normal range were reported in 1.6% of women in the Prolia group and 0.4% women in the placebo group.
Infections
The incidence of non-fatal serious infections was 4.0% in the Prolia group and 3.3% in the placebo group. Hospitalizations due to serious infections were reported more frequently in patients treated with Prolia. These included infections of the skin (particularly, erysipelas and cellulitis) (0.4% Prolia vs. <0.1% placebo); abdomen (0.9% Prolia vs. 0.7% placebo); urinary tract (0.7% Prolia vs. 0.5% placebo]; and ear (0.1% Prolia vs. 0.0% placebo). Other serious infections occurred more frequently in patients treated with Prolia. These included endocarditis which was reported in 0.1% of Prolia-treated patients receiving Prolia vs. 0.0% placebo patients.
Oedema
Oedema was reported in 4.9% of women in the Prolia group and 4.0% of women in the placebo group.
Anaemia
Anaemia was reported in 3.3% of women in the Prolia group and 2.8% of women in the placebo group.
Dermatologic
A significantly higher number of patients treated with Prolia developed epidermal and dermal AEs (10.8% of the Prolia group vs. 8.2% in the placebo group, p <0.0001) including dermatitis, eczema, and rashes. Most of these events were not specific to the injection site (see also Infections above).
Osteonecrosis of the Jaw
Osteonecrosis of the jaw was rarely reported in the open-label osteoporosis clinical trial program in patients treated with Prolia.
Cardiovascular Disorders
The incidence of positively adjudicated cardiovascular SAEs was 4.8% for Prolia and 4.6% for placebo. The incidence for acute coronary syndrome was 1.2% for Prolia vs. 1.0% for placebo; congestive heart failure: 0.7% for Prolia vs. 0.6% for placebo; and arrhythmia: 1.3% for Prolia vs. 1.2% placebo.
Fracture Healing
The incidence of delayed fracture healing events for non-vertebral fractures was 0.8% for the Prolia group and 0.4% for the placebo group. One percent (1 out of 104) of patients in the Prolia group and 0% (0 out of 116) of patients in the placebo group had delayed distal radius fracture healing.
Malignancies
The overall incidence of new malignancies was 4.8% for the Prolia group and 4.3% for the placebo group. The most common malignancies were related to the breast (0.9% of Prolia patients vs. 0.7% of placebo patients), reproductive system (0.5% Prolia vs. 0.2% placebo), and gastrointestinal systems (0.9% Prolia vs. 0.6% placebo). Specific cancers occurred more commonly in Prolia-treated patients. These included pancreatic, gastric, gynaecologic and recurrent breast cancers, and lentigo maligna.
Pancreatitis
Pancreatitis was reported in 0.2% of Prolia-treated patients and 0.1% of placebo-treated patients. Of these reports, one patient in the placebo group and all 8 patients with pancreatitis in the Prolia group had serious events including two deaths in the Prolia group.
Laboratory Abnormalities
The most frequent laboratory abnormalities were reduction of serum calcium with compensatory physiological changes in serum phosphorus and a reduction of alkaline phosphatase.
3.3.5 Additional Issues
As part of the marketing authorization for Prolia, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. Commitments include (but are not limited to):
- Submitting to Health Canada, in accordance with Canadian Regulations, all serious AEs (including malignancies, infections, et cetera) that occurred in all clinical trials with Prolia.
- Submitting to Health Canada as Supplemental New Drug Submissions any study reports pertaining to the long-term efficacy and safety of Prolia for the treatment of postmenopausal osteoporosis as they become available.
- Providing to Health Canada concise safety reports every three months, including copies of reports provided to other regulatory agencies, once the product is launched, in addition to the Periodic Safety Update Reports.
- Providing to Health Canada the protocol and the full operational aspects of the prospective, post-marketing, observational adherence Study 20090413, anticipated to include Canadian subjects with postmenopausal osteoporosis. In addition, the sponsor commits to address any Health Canada's comments regarding the design and the conduct of this study.
- Providing to Health Canada the protocols and the full operational aspects of the long-term observational study in administrative databases to prospectively evaluate the incidence of serious infection including skin infection, dermatologic AEs, and over-suppression of bone turnover in postmenopausal women administered Prolia.
- Providing to Health Canada the protocols and the full operational aspects of the long-term surveillance study in postmenopausal women administered Prolia to prospectively evaluate the incidence of serious infection including skin infections, dermatologic adverse events and over-suppression of bone turnover.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The benefit/risk assessment for the use of Prolia was based exclusively on its effects in postmenopausal women with osteoporosis at a high risk of fracture.
Overall, Prolia has been studied in a large population base with over 7000 patients having enrolled in the pivotal clinical study. The most efficacious and potent drugs for the treatment of osteoporosis exhibit efficacy with high levels of significance for all types of fractures: vertebral, non-vertebral, and hip. The pivotal clinical study demonstrated that Prolia reduces the incidence of vertebral, non-vertebral and hip fractures in postmenopausal women with osteoporosis at a high risk for fracture; however, the efficacy of Prolia varies for each type of fracture measured, with highest significance for vertebral fractures, but relatively lower levels of effects for non-vertebral and hip fractures. The results of the clinical study did not achieve the expected reduction of non-vertebral fractures for which the study was powered (i.e. the relative risk reduction of non-vertebral fractures was 20% as opposed to the expected 40%); however, given that non-vertebral fractures were shown to be both numerically and statistically significantly less frequent in patients treated with Prolia, it cannot be denied that there is an effect of Prolia on reducing non-vertebral fractures.
Prolia has been approved in multiple international jurisdictions, including approval from the United States Food and Drug Administration (FDA). All jurisdictions, including the FDA, have concluded that Prolia has a beneficial effect on the prevention of all types of osteoporotic fractures, including non-vertebral fractures.
The major safety issues identified during the review of the submitted data are: hypocalcaemia; serious infections (particularly skin infections); dermatologic AEs (immunogenic); osteonecrosis of the jaw; suppression of bone turnover with the risk of atypical fractures and delayed fracture healing; malignancies; and pancreatitis. These safety issues have been properly addressed in the Product Monograph, included in the Risk Management Plan, and have been recommended to be closely monitored post-marketing. Most of the risks are comparable to those associated with bisphosphonate treatments, with apparently similar incidences. An advantage of Prolia is the reversibility of these AEs. After approximately four months following administration of Prolia, most of the denosumab drug substance has been eliminated from the circulation and, while its pharmacodynamic effects continue for the entire period, there is added safety in that the effects of each dose are no longer discernible after six months. Bisphosphonates have a long residence time in bone and are associated with some unpleasant gastrointestinal AEs which tend to influence both compliance and adherence to therapy. It is hoped that the once every six months self-administration dosing regimen for Prolia will increase adherence and compliance; however, this remains to be seen in the long term and will need to be monitored once Prolia is marketed.
The benefits of Prolia for the treatment of postmenopausal women at high risk for fracture were judged to outweigh the risks. In order to ensure that the benefits of Prolia continue to outweigh any risk, a Risk Management Plan has been required which includes several post-approval commitments. Some of these commitments are listed in section 3.3.5 Additional Issues.
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 Prolia is favourable in the treatment of postmenopausal women with osteoporosis at a high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, Prolia reduces the incidence of vertebral, non-vertebral, and hip fractures.
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: ProliaTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2008-08-26 |
| Pre-submission meeting: | 2008-11-14 |
| Submission filed: | 2009-01-14 |
| Screening | |
| Screening Acceptance Letter issued: | 2009-03-02 |
| Review | |
| On-Site Evaluation: | 2009-10-12 - 2009-10-15 |
| Biopharmaceutics Evaluation complete: | 2010-05-08 |
| Quality Evaluation complete: | 2009-12-23 |
| Clinical Evaluation complete: | 2010-05-08 |
| Biostatistics Evaluation complete: | 2010-05-08 |
| Labelling Review complete: | 2010-02-02 |
| Notice of Compliance issued by Director General: | 2010-08-06 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| PROLIA | 02343541 | AMGEN CANADA INC | DENOSUMAB 60 MG / ML |