Summary Basis of Decision for Jetrea
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 Jetrea is located below.
Recent Activity for Jetrea
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.
Post-Authorization Activity Table (PAAT) for Jetrea
Updated:
The following table describes post-authorization activity for Jetrea, a product which contains the medicinal ingredient ocriplasmin. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02410818 - 2.5 mg/mL, solution, intravitreal injection
- DIN 02452154 - 1.25 mg/mL, solution, intravitreal injection
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| DIN (02452154) cancelled (post-market) | Not applicable | Discontinuation date:2020-03-20 | The manufacturer notified Health Canada that sale of the drug has been discontinued post-market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations. |
| DIN (02410818) cancelled (post-market) | Not applicable | Discontinuation date:2020-03-10 | The manufacturer notified Health Canada that sale of the drug has been discontinued post-market. Health Canada cancelled the DIN(s) pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations. |
| Drug product (DIN 02410818) market notification | Not applicable | Date of first sale:2019-09-24 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| Drug product (DIN 02452154) market notification | Not applicable | Date of first sale:2019-05-08 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 218435 | 2018-08-13 | Issued NOC2018-09-27 | Submission filed to transfer ownership of the product (that is [i.e.] drug sponsor name) from Alcon Canada Inc. to ThromboGenics N.V. An NOC was issued. |
| NC # 206902 | 2017-06-23 | Issued NOL2017-09-27 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 193101 | 2016-03-07 | Issued No Objection Letter2016-05-18 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to create a secondary reference standard. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 192807 | 2016-03-01 | Issued No Objection Letter2016-04-12 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) to reflect revisions in the company core safety data sheet. As a result of the NC, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| NC # 190150 | 2015-12-03 | Issued No Objection Letter2016-03-01 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to extend the expiry dating on the original formulation. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| SNDS # 185490 | 2015-06-26 | Issued NOC2016-02-16 | Submission filed as a Level I - Supplement for a new ready-to-use formulation of the drug product that does not require dilution prior to use. The new formulation has an identical composition to the diluted original drug formulation and will replace the original formulation. The data were reviewed and considered acceptable, and an NOC was issued. |
| NC # 187578 | 2015-09-08 | Issued No Objection Letter2015-11-13 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to provide information to support the addition of Drug Product Testing Responsibilities for the alternate drug product manufacturing site, identified in SNDS # 180910. The submission was reviewed and considered acceptable. A No Objection Letter was issued. |
| SNDS # 180910 | 2014-12-22 | Issued NOC 2015-08-10 | Submission filed as a Level I - Supplement to add an alternate manufacturing site for the production of the drug product, and to update the Dosage and Adminstration section of the Product Monograph. The data were reviewed and considered acceptable, and an NOC was issued. |
| NC # 181963 | 2015-02-19 | Issued No Objection Letter2015-03-06 | Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Product Monograph (PM) based on post-market safety information. Additional text was added to the PM with regard to the following adverse drug reactions: impairment of the pupillary reflex, and visual disturbances. The submission was reviewed and considered acceptable. A No Objection Letter was issued. |
| Drug product (DIN 02410818) market notification | Not applicable | Date of first sale:2013-11-20 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 161356 | 2012-12-24 | Issued NOC2013-08-13 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Jetrea
Date SBD issued: 2013-10-25
The following information relates to the new drug submission for Jetrea.
Ocriplasmin, 2.5 mg/mL, solution, intravitreal injection
Drug Identification Number (DIN):
- 02410818
- 02452154
Alcon Canada Inc.
New Drug Submission Control Number: 161356
On August 13, 2013, Health Canada issued a Notice of Compliance to Alcon Canada Inc. for the drug product, Jetrea.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Jetrea is favourable for the treatment of symptomatic vitreomacular adhesion (VMA).
1 What was approved?
Jetrea, an ophthalmologic biologic product, was authorized for the treatment of symptomatic vitreomacular adhesion (VMA). Ocriplasmin is a recombinant truncated form of human plasmin obtained from microplasminogen produced in a Pichia pastoris expression system by recombinant deoxyribonucleic acid (DNA) technology.
The elderly population has been studied in clinical studies. No dose adjustment is required.
The safety and efficacy of Jetrea in the pediatric population with symptomatic VMA have not been established. No data are available.
Jetrea is contraindicated for patients who have a hypersensitivity to ocriplasmin or to any of the excipients, or patients who have active or suspected ocular or periocular infections.
Jetrea (2.5 mg/mL ocriplasmin) is a solution for intravitreal injection, after dilution. In addition to the medicinal ingredient, ocriplasmin, the solution contains citric acid, mannitol, sodium hydroxide, and water.
For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Jetrea Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Jetrea approved?
Health Canada considers that the benefit/risk profile of Jetrea favourable for the treatment of symptomatic vitreomacular adhesion (VMA).
The elderly population, ≥65 years of age, has been studied in clinical studies and no dose adjustment is required. The safety and efficacy of Jetrea in the pediatric population with symptomatic VMA have not been established. Therefore, no data are available.
Vitreomacular adhesion (VMA) is a medical condition where the vitreous gel of the human eye creates an abnormally strong adhesion to the retina. The created adhesion can result in pulling forces on the retina causing vitreomacular traction and result in severe ocular damage. Patients with VMA may complain of metamorphopsia (distorted vision), decreased visual acuity and central visual field defect. If left untreated, the condition can lead to irreversible retinal damage, and possible blindness.
The goal of the therapy is to relieve tractional effects on the macula with subsequent functional improvement. The only active treatment option available currently is surgery (vitrectomy), whereby any adhesions are dissected from the macular surface with aspiration of the vitreous.
Ocriplasmin has proteolytic activity against protein components of the vitreous body and the vitreoretinal interface (VRI) (for example; laminin, fibronectin and collagen), thereby dissolving the protein matrix responsible for the abnormal VMA.
The efficacy and safety of Jetrea was demonstrated in two Phase III, multicentre, randomized, double-masked, placebo-controlled, 6-month studies in patients with symptomatic VMA, Study TG-MV-006 and Study TG-MV-007.
The primary efficacy endpoint for both studies was the proportion of patients with VMA resolution in the study eye at Day 28. In both studies, results showed that following a single dose of 125 mcg ocriplasmin, the rate of VMA resolution at Day 28 was more than double compared to the placebo group. Based on the statistical analysis, the differences between two groups were statistically significant in both studies. In Study TG-MV-006, the results were 27.9% and 13.1% for the Jetrea and placebo groups, respectively; and in Study TG-MV-007, the results were 25.3% and 6.2% for the Jetrea and placebo groups, respectively. It should be noted that the primary efficacy endpoint is a surrogate endpoint for the prevention of the deterioration of vision and its long term clinical relevance is uncertain.
The most frequently reported Adverse Events (AEs) were vitreous floaters, conjunctival hemorrhage, eye pain, and photopsia. The majority of AEs that were reported by ≥2% or ≥1% of subjects were reported by Jetrea subjects at a rate of ≥2 times the rate of the placebo subjects, which included vitreous floaters, eye pain, photopsia, vision blurred, vision impairment, retinal edema, photophobia, ocular discomfort, iritis, dry eye, metamorphopsia, and retinal degeneration. This difference on reporting rate may indicate a drug-related effect, in addition to the intraocular injection.
Based on clinical review of the efficacy and safety data, the overall benefit/risk profile of Jetrea is found acceptable for treatment of symptomatic vitreomacular adhesion (VMA).
Jetrea has an acceptable risk/benefit profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Jetrea 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 Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Jetrea?
The sponsor filed a request for Priority Review Status for Jetrea under the Priority Review Policy for the review of new drug submissions. Priority Review Status was denied on December 11, 2012 due to insufficient evidence to meet the following criteria required for priority review:
- an effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada; OR
- a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada.
On March 5, 2013, the sponsor filed a reconsideration request for Priority Review Status. The submission was granted priority review status on March 21, 2013.
Submission Milestones: Jetrea
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2012-10-02 |
| Request for priority review status | |
| Filed: | 2012-11-15 |
| Rejection issued by Director: | 2012-12-11 |
| Request for reconsideration of priority review status: | 2013-03-05 |
| Priority review status granted: | 2013-03-21 |
| Submission filed: | 2012-12-24 |
| Screening | |
| Screening Acceptance Letter issued: | 2013-02-15 |
| Review | |
| Quality Evaluation complete: | 2013-08-12 |
| Clinical Evaluation complete: | 2013-08-12 |
| Labelling Review complete: | 2013-08-08 |
| Notice of Compliance issued by Director General: | 2013-08-13 |
The Canadian regulatory decision on the non-clinical and clinical review of Jetrea was based on a critical assessment of the Canadian data package. The publicly available foreign reviews completed by the United States Food and Drug Administration (FDA) were used as an added reference.
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.
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 and have been market notified (that is, the company has told Health Canada the product is being marketed).
- 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 Clinical basis for decision
Clinical Pharmacology
Ocriplasmin (the medicinal ingredient of Jetrea) has proteolytic activity against protein components of the vitreous body and the vitreoretinal interface (for example; laminin, fibronectin and collagen), thereby dissolving the protein matrix responsible for the abnormal vitreomacular adhesion.
A pharmacokinetic (PK) study evaluated the PK properties of intravitreal ocriplasmin 125 mcg dose when administered at different time points prior to the planned primary pars plana vitrectomy (PPV). As expected, the results showed that ocriplasmin was inactivated quickly in vitreous humor. Ocriplasmin activity levels were decreased about 4-fold after 4 hours and decreases more than 20-fold after 24 hours. Detectable levels of ocriplasminin in systemic circulation are not expected after intravitreal injection.
For further details, please refer to the Jetrea Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Jetrea (ocriplasmin) was demonstrated in two Phase III, multicentre, randomized, double-masked, placebo-controlled, 6-month studies in patients with symptomatic vitreomacular adhesion (VMA). A total of 652 patients (Jetrea 464, placebo 188) were randomized in these 2 studies (TG-MV-006 and TG-MV-007). Randomization was 2:1 for Jetrea and placebo, respectively, in Study TG-MV-006; and 3:1 in Study TG-MV-007.
In both studies, the majority of the patients were female and Caucasian. The mean age was 71.3 years in Study TG-MV-006 and 72.0 years in Study TG-MV-007. The mean best corrected visual acuity (BCVA) at baseline was 64.8 letters in Study TG-MV-006 and 63.8 letters in Study TG-MV-007. The proportion of patients with full thickness macular hole (FTMH) at baseline was 27.3% in Study TG-MV-006and 19.6% in Study TG-MV-007. In Study TG-MV-006, the proportion of pseudophakic patients was 41.6% in the Jetrea group and 27.1% in the placebo group, while in Study TG-MV-007, the proportion was 33.1% in the Jetrea group and 29.6% in the placebo group.
The primary efficacy endpoint for both studies was the proportion of patients with vitreomacular adhesion (VMA) resolution in the study eye at Day 28. In both studies, the proportion of patients who achieved VMA resolution at Day 28 was significantly higher in the Jetrea group after a single dose of 125 mcg compared to the placebo group. In Study TG-MV-006, the results were 27.9% and 13.1% for the Jetrea and placebo groups, respectively; and in Study TG-MV-007, the results were 25.3% and 6.2% for the Jetrea and placebo groups, respectively. It should be noted that the primary efficacy endpoint is a surrogate endpoint for the prevention of the deterioration of vision and its long term clinical relevance is uncertain.
The key secondary efficacy endpoint is proportion of patients with total posterior vitreous detachment (PVD) at Day 28, as determined by masked Investigator assessment of B-scan ultrasound.
The other secondary endpoints were exploratory with no pre-defined specified statistical plan to demonstrate statistical significance, which included the following:
- Proportion of patients not requiring vitrectomy.
- Proportion of FTMHs that closed without vitrectomy as determined by the Central Reading Centre.
- Achievement of ≥2 and ≥3 lines improvement in best corrected visual acuity (BCVA) without need for vitrectomy.
- Improvement in BCVA.
- Improvement in the National Eye Institute (NEI) 25-Item Visual Function Questionnaire.
The key secondary endpoint was total PVD at Day 28. A statistically significantly higher percentage of patients treated with Jetrea achieved total PVD at Day 28 compared to patients treated with placebo in Study TG-MV-006 [16% versus (vs.) 6%] and in Study TG-MV-007 (11% vs. 0%). The other secondary endpoints were exploratory with no pre-defined specified statistical plan to demonstrate statistical significance.
Patients treated with Jetrea were less likely to require vitrectomy, at the discretion of the treating physician, by the end of the study (Month 6) compared with placebo-treated patients (Study TG-MV-006: 20.5% vs. 29.0%, respectively; Study TG-MV-007: 23.5% vs. 15.1%, respectively).
FTMH closure was an exploratory endpoint. No pre-specified statistical assessment was planned to determine the statistical significance. In addition, there was only a subset of subjects who had FTMH at Baseline, and the sample sizes were small. No conclusion can be made based on currently available data.
The number of patients with ≥2 lines and ≥3 lines increase in visual acuity was numerically higher in the Jetrea group compared to placebo group in both studies; however, the number of patients with ≥2 lines and ≥3 lines decrease in visual acuity was also higher in the Jetrea group in one of the studies.
The mean increases from baseline in BCVA letter scores were generally small and comparable between treatment groups; no notable treatment differences were observed at Month 6 in both studies.
Patients treated with Jetrea in both studies generally achieved numerically larger changes from baseline in subscale and composite scores of the VFQ-25.
Overall, the two Phase III clinical studies (Studies TG-MV-006 and TG-MV-007) demonstrated that a single injection of Jetrea 125 mcg is superior to placebo in terms of the primary efficacy endpoint and the key secondary endpoint (VMA resolution and a total PVD at Day 28). The results from the other exploratory endpoints were inconclusive, and it was concluded that Jetrea cannot be recommended for the treatment of FTMH associated with VMA.
The sponsor's proposed indication for this priority New Drug Submission was to seek approval for the marketing of Jetrea for intravitreal injection for the treatment of symptomatic VMA, including when associated with macular hole. Instead, the indication granted by Health Canada is as follows, "Jetrea (ocriplasmin) solution for intravitreal injection is indicated for the treatment of symptomatic vitreomacular adhesion (VMA)."
For more information, refer to the Jetrea Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
Jetrea (ocriplasmin) solution for intravitreal injection is indicated for the treatment of symptomatic vitreomacular adhesion (VMA). Jetrea is a recombinant truncated form of human plasmin which retains protease activity and is intended to facilitate the induction of a total posterior vitreous detachment (PVD).
The pivotal studies, TG-MV-006 and TG-MV-007, were both multicentre, randomized, placebo-controlled, double-blind, 6-month studies that investigated the safety and efficacy of a single intravitreal injection of Jetrea 0.125 mg in patients with symptomatic vitreomacular adhesion. The two studies were identical in design (except for allocation ratio of 2:1 in TG-MV-006 and 3:1 in TG-MV-007) and conduct (except for geography). A total of 652 patients were randomized (188, placebo; 464, Jetrea); of these, 93.1% patients completed the studies. A total of 16 (8.5%) patients in the placebo group and 29 (6.3%) patients in the ocriplasmin group were discontinued from the studies. The mean age was 71.7 years (median 72 years; range 18 to 97 years).
The objective of these clinical studies was to evaluate the safety and efficacy of a single intravitreal injection of ocriplasmin 125 mcg in subjects with VMA [that is (i.e.); focal VMA leading to symptoms].
Most adverse drug reactions (ADRs) were ocular, which is consistent with the intravitreal route of administration, rapid inactivation and limited systemic bioavailability; and most occurred within 0 to7 days post injection. The most common ADRs were consistent with pharmacologic vitreolysis such as vitreous floaters, photopsia, or were due to inflammation/irritation resulting from either the injection procedure and/or the drug. The majority of ADRs were non-serious, mild in intensity and resolved.
The most frequently reported adverse events (AEs)/ADRs mainly were vitreous floaters, conjunctival hemorrhage, eye pain, and photopsia. The majority of AEs that were reported by ≥2% or ≥1% of subjects were reported by ocriplasmin subjects at a rate of ≥2 times the rate of the placebo subjects, which including vitreous floaters, eye pain, photopsia, vision blurred, vision impairment, retinal edema, photophobia, ocular discomfort, iritis, dry eye, metamorphopsia, and retinal degeneration. This difference on reporting rate may indicate an ocriplasmin related effect in addition to the intraocular injection.
Serious adverse events (SAEs) were reported for 62 (13.3%) and 24 (12.8%) patients in the Jetrea and placebo groups, respectively in the two pivotal studies. The incidence of drug-related SAEs was 3.2% in each treatment group. For SAEs regardless of causality, the majority were ocular events and these occurred in the study eye. The SAEs reported most frequently for Jetrea were macular hole [including progression of macular hole (5.2%)], vitreous adhesions [that is (i.e.) vitreomacular traction progression (1.1%)] and for placebo, macular hole (8.6%) and retinal detachment (1.6%).
Adverse events (AE) that led to withdrawal were four (0.9%) in the ocriplasmin group and two (1.1%) in the placebo group for the pivotal studies.
All deaths were due to systemic medical conditions. There are no significant differences in the rates of non-fatal SAEs between ocriplasmin-treated subjects and placebo-treated subjects. The majority of AEs that led to study withdrawal were systemic medical conditions.
Two other ocular AEs of special interest were noted, the anatomic/functional retinal and intraocular inflammation. The majority of the anatomic/functional retinal findings were reported by ocriplasmin subjects at a rate of ≥2 times the rate of the placebo subjects, such as retinal/macular edema, retinal pigment epitheliopathy, retinal/macular degeneration, vision blurred, visual impairment, metamorphopsia, and scotoma. The overall incidence of intraocular inflammation AEs was higher in the ocriplasmin group than in the placebo group.
The most notable safety findings were those related to visual function changes (i.e. visual impairment, dyschromatopsia and/or electroretinogram changes). Most of these findings were non-serious, of mild intensity and resolved.
No formal studies have been conducted with Jetrea in patients with hepatic or renal impairment. No dose adjustment or special considerations are anticipated for patients with either impairment.
Overall, there were more patients who received ocriplasmin that reported AEs, ADRs, best corrected visual acuity worsening, anatomic and functional retinal related AEs, and intraocular inflammation AEs, compared to patients who received vehicle. A much higher rate of AEs in the ocriplasmin group suggests a drug-related effect. However, most of these findings were non-serious and resolved spontaneously. The potential benefits of ocriplasmin to the patients outweigh the risks of the product.
Based on clinical review of the efficacy and safety data, the overall benefit/risk profile of Jetrea is found acceptable for treatment of symptomatic vitreomacular adhesion (VMA).
For more information, refer to the Jetrea Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical pharmacology, safety pharmacology, pharmacokinetic, and toxicology program conducted with ocriplasmin (the medicinal ingredient of Jetrea) is considered to be sufficient to support the intended clinical use of Jetrea for the specified indication.
Rabbits, monkeys and mini-pigs were used for the evaluation of intravitreal toxicity of a single dose of ocriplasmin (dose range from 2.3 to 797 mcg/mL vitreous). There was no evidence of systemic toxicity resulting from intravitreal injection of ocriplasmin following a single dose of up to 797 mcg/mL vitreous. Ocular findings after a single intravitreal injection of ocriplasmin included attenuated retinal vessels with retinal atrophy in rabbits only; lens subluxation in all three species; and changes in intraocular pressure, inflammation, and electroretinogram (ERG) changes in rabbits and monkeys. The exposure doses of ocriplasmin for the findings of inflammation, ERG changes, and lens subluxation observed in animals after a single intravitreal dose were low, and ranged from concentrations lower than the proposed human dose to 1.5-2 fold of the proposed human dose. In monkeys, a second intravitreal administration of ocriplasmin (4 weeks apart) resulted in an increase incidence of lens subluxation, sustained increases in intraocular pressure, and a series of adverse microscopic findings in the eye. Appropriate warnings and precautionary measures are in place in the Jetrea Product Monograph to address these identified safety concerns.
The systemic toxicity of ocriplasmin was evaluated in rats and dogs after intravenous (IV) administration. The no-observed-effect-levels were 10 mg/kg single dose in rats and dogs. These doses are much higher than potential systemic concentration of ocriplasmin in humans after an intravitreal clinical dose of 125mcg. Therefore, the non-clinical data provides support to conclude that systemic toxicity of ocriplasmin is unlikely following a single 125 mcg intravitreal injection in humans. In one toxicology study with dogs, no effects were observed in electrocardiogram (ECG) parameters after 7 doses of IV administrations of 10 mg/kg every other day.
Overall, the results of the non-clinical studies as well as the potential risks to humans have been included in the Jetrea Product Monograph. In view of the intended use of Jetrea, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Jetrea Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Jetrea contains the active component ocriplasmin which is a truncated form of human plasmin with retained protease activity. This product is a recombinant engineered portion of human plasminogen made in the methylotropic yeast Pichia pastoris, and activated with recombinant staphylokinase. Based on the review of the Quality data submitted, Alcon Canada Inc. has provided adequate evidence to support the consistent manufacture of Jetrea of acceptable quality.
Characterization of the Drug Substance
Impurities and degradation products arising from manufacturing were reported and characterized. Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Recombinant human ocriplasmin is produced in transformed yeast Pichia pastoris by standard fermentation technology and purified using standard biotechnology purification procedures. Fermentation of Pichia pastoris results in the secretion of microplasminogen which is purified, then converted to ocriplasmin using an immobilized recombinant staphylokinase activation chromatography column. The active ocriplasmin is then further purified and formulated. All materials used in the manufacture of the ocriplasmin drug substance (including the working cell bank and the recombinant staphylokinase) are considered to be suitable and/or meet standards appropriate for their intended use.
The manufacturing process of the drug product consists of three main steps: compounding by dilution with 5 mM citrate pH 3.1; sterile filtration and aseptic filling; and freezing at ‐70°C. Data was provided to support the suitability of container closure components and container closure integrity. Given the nature of the filling and freezing process, it was verified that samples for testing are handled in a manner representative of the batch, and undergo a freeze thaw cycle prior to testing. Validation data demonstrate consistency and reliability of the filling process to produce the final product.
Adequate data was obtained to support the methods and laboratories used for all analytical procedures used for in-process and release-testing of the drug substance and drug product, and to justify the in-process control parameters and their acceptance limits. Data from batch analyses were also reviewed and considered to be acceptable.
The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are valid and considered to be adequately controlled within justified limits.
Control of the Drug Substance and Drug Product
The established test specifications and validated analytical test methods are considered acceptable. Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
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 18-month shelf-life at ‐20°C ± 5°C for the drug product is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through testing and stability studies. The container closure system met all validation test acceptance criteria.
Facilities and Equipment
An On-Site Evaluation (OSE) was not conducted at the drug substance or drug product manufacturing facilities due to the short review timeline of this priority review and the extremely restricted manufacturing schedule (no drug substance manufacture during review, very limited drug product manufacture). In lieu of being able to visit the sites, pre‐approval inspection reports from the European Medicines Agency (EMA) and United States Food and Drug Administration (FDA) were requested, along with a combination of facility-related data. In combination, the reports solicited and the additional data support the suitability of the facilities involved for the manufacture of Jetrea.
Adventitious Agents Safety Evaluation
Neither the production cell substrate recombinant Pichia pastoris, nor the Escherichia coli system used for producing the recombinant staphylokinase used in the activation process support viral replication.