Summary Basis of Decision for Osnuvo
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Osnuvo is located below.
Recent Activity for Osnuvo
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Summary Basis of Decision (SBD) for Osnuvo
Date SBD issued: 2020-04-24
The following information relates to the new drug submission for Osnuvo.
Teriparatide
Drug Identification Number (DIN):
- DIN 02495589 - 250 mcg/mL, solution, subcutaneous administration
AVIR Pharma Inc.
New Drug Submission Control Number: 215409
On January 13, 2020, Health Canada issued a Notice of Compliance to AVIR Pharma Inc. for Osnuvo, a biosimilar to Forteo (the reference biologic drug). The terms "biosimilar biologic drug" and "biosimilar" are used by Health Canada to describe subsequent entry versions of a Canadian approved innovator biologic drug with demonstrated similarity to a reference biologic drug. Biosimilars were previously referred to as subsequent entry biologics in Canada. Both Osnuvo and Forteo contain highly similar versions of the medicinal ingredient teriparatide (recombinant deoxyribonucleic acid [rDNA] origin).
Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. For a biosimilar, the weight of evidence is provided by the structural and functional studies, whereas the non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, pharmacokinetic and pharmacodynamic, and clinical studies. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought.
For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.
In this drug submission, Forteo is the reference biologic drug. Similarity between Osnuvo and Forteo was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Within the drug submission, the sponsor requested the authorization of Osnuvo for the same indications currently authorized for Forteo.
The market authorization of Osnuvo was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. Similarity was established through data derived from comparative structural, functional, non-clinical, and clinical studies. Based on Health Canada's review, the benefit-risk profile of Osnuvo is considered to be highly similar to the reference biologic drug. Accordingly, Osnuvo is indicated:
- For the treatment of postmenopausal women with severe osteoporosis who are at high risk of fracture or who have failed or are intolerant to previous osteoporosis therapy.
- To increase bone mass in men with primary or hypogonadal severe osteoporosis who have failed or are intolerant to previous osteoporosis therapy. The effects of teriparatide on risk for fracture in men have not been demonstrated.
- For the treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in men and women who are at increased risk for fracture.
1 What was approved?
Osnuvo, a bone formation agent, was authorized:
- For the treatment of postmenopausal women with severe osteoporosis who are at high risk of fracture or who have failed or are intolerant to previous osteoporosis therapy.
- To increase bone mass in men with primary or hypogonadal severe osteoporosis who have failed or are intolerant to previous osteoporosis therapy. The effects of teriparatide on risk for fracture in men have not been demonstrated.
- For the treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in men and women who are at increased risk for fracture.
Osnuvo is a biosimilar to Forteo. Both drugs contain the medicinal ingredient, teriparatide. Teriparatide is a polypeptide consisting of the first 34 amino acids of human parathyroid hormone. The 1-34 N-terminal fragment is produced in Escherichia coli using recombinant deoxyribonucleic acid (DNA) technology.
Similarity between Osnuvo and the reference biologic drug Forteo has been established through comparative structural and functional studies, comparative non-clinical studies, a comparative pharmacokinetic study in non-pregnant healthy premenopausal women, and a comparative Phase III study in patients with osteoporosis at high risk of fracture, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Health Canada has not authorized an indication for use in pediatric patients (younger than 18 years of age) or in young adults with open epiphyses. Moreover, the use of Osnuvo in these populations is contraindicated (as listed below).
No significant differences in bone response and no new safety findings were seen in geriatric patients (65 years of age and older) receiving teriparatide (rDNA origin) as compared to younger patients. In geriatric patients, no dose adjustment is required.
Osnuvo is contraindicated for:
- hypersensitivity to teriparatide, any excipients in the formulation or component of the container
- pre-existing hypercalcemia
- severe renal impairment
- metabolic bone diseases other than primary or glucocorticoid-induced osteoporosis (including hyperparathyroidism and Paget's disease of the bone)
- unexplained elevations of alkaline phosphatase
- prior external beam or implant radiation therapy involving the skeleton
- bone metastases or a history of skeletal malignancies
- pregnancy and nursing mothers
- pediatric patients or young adults with open epiphyses
Osnuvo was approved for use under the conditions stated in its Product Monograph, taking into consideration the potential risks associated with the administration of this drug product.
Osnuvo (250 mcg/mL [600 mcg in 2.4 mL solution] teriparatide [rDNA origin]) is presented as a solution. In addition to the medicinal ingredient, the solution contains acetic acid (glacial), mannitol, metacresol, hydrochloric acid (for pH adjustment), sodium acetate (trihydrate), sodium hydroxide (for pH adjustment), and water for injections.
For more information, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.
Additional information may be found in the Osnuvo Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Osnuvo approved?
Health Canada considers that the benefit-risk profile of Osnuvo is highly similar to the reference biologic drug Forteo. Similarity between Osnuvo and Forteo was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
Osnuvo is indicated:
- for the treatment of postmenopausal women with severe osteoporosis who are at high risk of fracture or who have failed or are intolerant to previous osteoporosis therapy
- to increase bone mass in men with primary or hypogonadal severe osteoporosis who have failed or are intolerant to previous osteoporosis therapy. The effects of teriparatide on risk for fracture in men have not been demonstrated.
- for the treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in men and women who are at increased risk for fracture.
The diagnosis of severe osteoporosis may be confirmed by the finding of low bone mass or the presence or history of osteoporotic fracture. While non-vertebral fractures are usually clinically apparent, vertebral fractures may also be manifested by back pain, height loss, or kyphosis.
The New Drug Submission filed for Osnuvo requested authorization for the same indications and clinical uses currently authorized for Forteo. The indications for Osnuvo have been authorized on the basis of demonstrated similarity between Osnuvo and the reference biologic drug.
Osnuvo and the reference biologic drug were judged highly similar in terms of quality attributes, based on comparative structural and functional studies.
Evidence of pharmacokinetic similarity of Osnuvo and Forteo was provided from a comparative pharmacokinetic study in non-pregnant healthy premenopausal women.
A comparative Phase III study conducted in patients with osteoporosis at high risk of fracture ruled out clinically meaningful differences in efficacy, safety and immunogenicity between the biosimilar and the reference biologic drug. The comparability in efficacy of the two products was established based on the percent change in lumbar spine (L2-L4) bone mineral density, a clinically relevant phamacodynamic parameter. The difference in the percent change of the adjusted mean (two-sided 95% confidence interval) in lumbar spine (L2-L4) bone mineral density between the Osnuvo and Forteo groups was -0.65% (-2.17% to 0.87%), which met the prespecified equivalence margin of ±2.8%.
The type, incidence, onset time, severity and outcome of adverse events and adverse drug reactions were comparable between the biosimilar and the reference biologic drug. Anti-teriparatide antibodies were not detected in any of the patients in the Osnuvo group. In the Forteo group, two patients had anti-teriparatide antibodies that did not exhibit neutralizing activity.
Osnuvo has demonstrated a comparable safety profile with its reference product, Forteo. Therefore, the Adverse Reactions section of the biosimilar Product Monograph is based on the clinical experience with the reference biologic drug. As found in the Product Monograph for Forteo, a Serious Warnings and Precautions box has been included in the Product Monograph for Osnuvo. This section warns that Osnuvo should be prescribed only to patients for whom the potential benefits outweigh the potential risks. Furthermore, it highlights that, in rats, teriparatide caused an increase in the incidence of osteosarcoma, dependent on the dose and treatment duration, at systemic exposures ranging from 3 to 60 times the exposure in humans administered a dose of 20 µg teriparatide. Additionally, it warns that Osnuvo should not be prescribed to patients who are at increased baseline risk for osteosarcoma.
A Risk Management Plan (RMP) for Osnuvo was submitted by AVIR Pharma Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Osnuvo was accepted.
Overall, the benefits of Osnuvo therapy are expected to be similar to the known benefits of the reference biologic drug, Forteo, and are considered to outweigh the potential risks. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Osnuvo Product Monograph to address the identified safety concerns.
This 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. For more information, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical for Decision sections.
3 What steps led to the approval of Osnuvo?
The New Drug Submission for Osnuvo was accepted for review on June 1, 2018. The submission package did not include data from a comparative clinical efficacy and safety study, which precluded a complete benefit-risk assessment of Osnuvo. Therefore, a Notice of Deficiency was issued on January 24, 2019. In a response to the Notice of Deficiency, accepted for review on March 19, 2019, the sponsor provided results of a phase III clinical study RGB1023O31 (described in the Comparative Clinical Efficacy, Safety and Immunogenicity section). Following review of the sponsor's response to the Notice of Deficiency, a Notice of Compliance for Osnuvo was issued on January 13, 2020.
Submission Milestones: Osnuvo
| Submission Milestone | Date |
|---|---|
| Pre-Submission Meeting: | 2016-02-23 |
| Submission filed: | 2018-04-16 |
| Screening | |
| Screening Acceptance Letter issued: | 2018-06-01 |
| Review | |
| Review of Risk Management Plan complete: | 2019-01-03 |
| Quality Evaluation complete: | 2019-01-11 |
| Clinical Evaluation complete: | 2019-01-14 |
| Notice of Deficiency (NOD) issued by Director General, Biologics and Genetic Therapies Directorate (comparative clinical efficacy issues): | 2019-01-24 |
| Response filed: | 2019-03-05 |
| Screening of the NOD response | |
| Screening Acceptance Letter issued: | 2019-03-19 |
| Review of the NOD response | |
| On-Site Evaluation: | 2019-06-17 - 2019-06-21 |
| Clinical Evaluation complete: | 2020-01-08 |
| Quality Evaluation complete: | 2020-01-10 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2020-01-10 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2020-01-13 |
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
The onus is on the Osnuvo sponsor to monitor the post-market safety profile of this biosimilar product as well as the Product Monograph of the reference biologic drug for safety signals that could affect the biosimilar, and make safety updates to the Osnuvo Product Monograph as appropriate. New safety issues that are first identified with the biosimilar, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both the biosimilar and the reference biologic drug. For more information, refer to the Fact Sheet: Biosimilars.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Quality Basis for Decision
Osnuvo was developed as a biosimilar to the reference biologic drug, Forteo. In addition to a typical chemistry and manufacturing data package that is submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity with the reference biologic drug.
Comparative Structural and Functional Studies
The sponsor performed biosimilarity studies with a very limited number of batches of Osnuvo and the reference product. Nevertheless, this was deemed justified based on the size and complexity of the molecule. The biosimilarity assessment was conducted for Osnuvo and the reference product, Forsteo, sourced from the European Union (EU-sourced). It encompassed comparative structural, physicochemical and biological analyses, and comparative stressed stability studies.
The sponsor has demonstrated that Osnuvo is highly similar to the reference product, EU-sourced Forsteo. The sponsor has also demonstrated similarity of EU-sourced Forsteo and Japan-sourced Forteo, as the latter was used to verify the comparability of Osnuvo in the comparative clinical efficacy, safety and immunogenicity study.
Characterization of the Drug Substance
The drug substance, teriparatide (recombinant deoxyribonucleic acid [rDNA] origin) is a recombinant 1-34 fragment human parathyroid hormone analogue [rhPTH(1-34)] with an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone.
Detailed characterization studies were performed to provide assurance that teriparatide (rDNA origin) consistently exhibits the desired characteristic structure and biological activity.
Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established and acceptable limits.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Teriparatide (rDNA origin) is manufactured using a strain of Escherichia coli modified by recombinant DNA technology. The manufacturing process involves fermentation, isolation and purification. During the fermentation step, the recombinant protein is expressed in the recombinant Escherichia coli strain as a fusion protein in inclusion bodies. Following fermentation, the inclusion bodies are isolated by high-pressure homogenization and stored as a suspension (i.e., product intermediate) at ≤-15°C. After thawing of the product intermediate and solubilization of the inclusion bodies, the fusion protein is cleaved by β-mercaptoethanol. The purification of the cleaved protein includes chromatography and filtration steps, followed by filling into flexible biobags and storing at ≤-70°C. The sponsor has demonstrated that the proposed drug substance manufacturing site is capable of consistently manufacturing teriparatide (rDNA origin) of acceptable quality. The materials used in the manufacturing of the drug substance are considered suitable and/or meet standards appropriate for their intended use.
The drug product manufacturing involves thawing of the drug substance, diluting in formulation buffer, filtering, and filling into 3 mL glass cartridges, which are stored at 2°C to 8°C. Each cartridge contains at least 28 doses of 20 µg (per 80 µL). This corresponds to 2.4 mL of teriparatide (rDNA origin) solution containing 600 µg of teriparatide (rDNA origin). The pen device and the pen needles are supplied separately.
The sponsor has demonstrated that the proposed manufacturing facility is capable of consistently manufacturing Osnuvo of acceptable quality.
The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are validated and considered to be adequately controlled within justified limits.
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 teriparatide (rDNA origin) with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications. Analytical procedures are validated and in compliance with International Council for Harmonisation guidelines.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed shelf life of 24 months for Osnuvo at 2°C to 8°C is considered acceptable. Once opened, the product may be stored for a maximum of 28 days within its shelf life at 2°C to 8°C.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured.
An on-site evaluation of the facilities involved in the manufacture and testing of the drug substance has been conducted by Health Canada, with a satisfactory rating.
Based on a risk assessment score determined by Health Canada, an on-site evaluation of the facility involved in the manufacture and testing of the drug product was not deemed necessary.
Both sites involved in production are compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
The manufacturing process of teriparatide (rDNA origin) incorporates adequate control measures to prevent contamination and maintain microbial control.
No materials of animal or human origin are used in the manufacture of the drug substance and drug product. The prokaryotic expression system used does not support the growth of viral adventitious agents. Bacteriophage, bioburden and endotoxin testing are integrated in the control strategy and meet relevant guidelines and requirements.
7.2 Non-Clinical Basis for Decision
For biosimilars, the degree of similarity at the quality level determines the scope and the breadth of the required non-clinical data. Non-clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty.
The non-clinical database submitted for Osnuvo was in compliance with the requirements for non-clinical studies of biosimilars, as presented in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.
In vivo studies demonstrated comparability between Osnuvo and Forsteo (the EU-sourced reference biologic drug) in terms of their pharmacodynamic and toxicological properties.
While the systemic exposure and immunogenicity appeared to be greater with Osnuvo than with Forsteo in studies conducted in rats, these characteristics, when assessed in animals, are not necessarily predictive of the drug exposure and immunogenicity in humans. Therefore, the comparability assessment of the exposure and immunogenicity of Osnuvo and the reference drug relied on clinical data.
The results of the comparative non-clinical studies have been included in the Osnuvo Product Monograph. In view of the intended use of Osnuvo, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Osnuvo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Clinical basis for decision
The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in support of the indications being sought, and therefore clinical trials are not required to support each indication.
The purpose of the clinical program for a biosimilar is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The degree of similarity at the quality level determines the scope and the breadth of the required clinical data. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.
Comparative Pharmacokinetics
The comparative pharmacokinetic study RGB-10-001 was a Phase I, randomized, double-blind, single-centre, single-dose (20 µg/80 µL subcutaneous fixed-dose), two-way crossover study that compared the pharmacokinetic profiles of Osnuvo and Forsteo in healthy adult female subjects, aged 18 to 55 years. The comparison met the prespecified criteria for pharmacokinetic similarity: the 94% confidence intervals for the ratios of geometric means of the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) extrapolated to infinity (AUCinf), and the AUC to time of last measurable concentration (AUClast), were within the equivalence margins of 80.0% to 125.0%, thereby demonstrating the pharmacokinetic comparability of Osnuvo and Forsteo.
For further details, please refer to the Osnuvo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Comparative Clinical Efficacy, Safety and Immunogenicity
The comparative clinical efficacy, safety and immunogenicity of Osnuvo and its reference biologic drug Forteo were demonstrated in a multicentre, randomized, active-controlled, rater-blinded, parallel-group, comparative study in patients with osteoporosis at high risk of fracture (Study RGB1023O31). Among the 250 patients of the study full analysis set, 96.4% were women.
The primary objective of the study was to verify the comparability in efficacy of Osnuvo and Japan-sourced Forteo (each treatment arm included 125 patients). The drugs were administered subcutaneously once daily at a dose of 20 µg for 52 weeks. The comparability in efficacy of the two products was established based on the percentage change in lumbar spine (L2-L4) bone mineral density, a clinically relevant phamacodynamic parameter. The difference in the percentage change of the adjusted mean (two-sided 95% confidence interval) in lumbar spine (L2-L4) bone mineral density between the Osnuvo and Forteo groups was -0.65% (-2.17% to 0.87%), which met the prespecified equivalence margin of ±2.8%.
The type, incidence, onset time, severity and outcome of adverse events and adverse drug reactions were comparable between the biosimilar and the reference biologic drug.
Anti-teriparatide antibodies were not detected in any of the patients in the Osnuvo group. In the Forteo group, two patients had anti-teriparatide antibodies that did not exhibit neutralizing activity.
No clinically meaningful differences in efficacy, safety and immunogenicity were observed between Osnuvo and the reference biologic drug.
For more information, refer to the Osnuvo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Indications
Within this drug submission, the sponsor provided a written scientific rationale to request the authorization of Osnuvo for all of the indications currently authorized for Forteo. Similarity between Osnuvo and Forteo was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor's submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug, and therefore clinical trials are not required to support each indication. The indications have been authorized on the basis of demonstrated similarity between Osnuvo and the reference biologic drug in comparative structural and functional studies, comparative non-clinical studies, a comparative pharmacokinetic study in non-pregnant healthy premenopausal women, and a comparative Phase III study in patients with osteoporosis at high risk of fracture.
Upon Health Canada's review, Osnuvo was authorized for the same indications currently held by the reference drug Forteo, as follows:
- For the treatment of postmenopausal women with severe osteoporosis who are at high risk of fracture or who have failed or are intolerant to previous osteoporosis therapy.
- To increase bone mass in men with primary or hypogonadal severe osteoporosis who have failed or are intolerant to previous osteoporosis therapy. The effects of teriparatide on risk for fracture in men have not been demonstrated.
- For the treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in men and women who are at increased risk for fracture.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| OSNUVO | 02495589 | AVIR PHARMA INC. | TERIPARATIDE 250 MCG / ML |