Summary Basis of Decision for Lucentis
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:
Lucentis
Ranibizumab, 10 mg/mL, Solution, Intravenous
Novartis Ophthalmics, Novartis Pharmaceuticals Canada Inc.
Submission control no: 110233
Date issued: 2007-12-21
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrLUCENTIS, Ranibizumab, Solution, Novartis Ophthalmics, Novartis Pharma Canada Inc.
No de contrôle de la présentation 110233
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):
- 02296810
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
LUCENTIS is a registered trademark of Genentech Inc., used under permission by Novartis Pharmaceuticals Canada Inc.
2 Notice of decision
On June 26, 2007, Health Canada issued a Notice of Compliance to Novartis Ophthalmics, Novartis Pharmaceuticals Canada Inc. for the drug product, Lucentis.
Lucentis contains the medicinal ingredient ranibizumab which is an anti-neovascularisation agent.
Lucentis is indicated for the treatment of neovascular (wet) age-related macular degeneration (AMD). Ranibizumab, a humanised monoclonal antibody fragment, binds to human vascular endothelial growth factor-A (VEGF-A) isoforms, thereby preventing binding of VEGF-A to its receptors, VEGFR-1 and VEGFR-2.Binding of VEGF-A to its receptors leads to endothelial cell proliferation and neovascularisation, as well as vascular leakage, all of which are thought to contribute to the progression of the neovascular (wet) form of AMD.
The market authorization was based on quality, non-clinical, and clinical information submitted. The clinical safety and efficacy of Lucentis were assessed in three randomized, double-masked, sham- or active-controlled studies with a total of 1,323 neovascular (wet) AMD patients. Almost all of the patients treated with Lucentis maintained their visual acuity at Month 12, and a significant number of treated patients also experienced a clinical significant, sustained improvement in vision.
Lucentis (10 mg/mL, ranibizumab) is presented as a solution for injection. The recommended dose for Lucentis is 0.5 mg (0.05 mL). Lucentis 0.5 mg is recommended to be administered by intravitreal injection once a month. Treatment may be reduced to one injection every 3 months after the first three injections if monthly dosing is not feasible. Dosing guidelines are available in the Product Monograph dated June 26, 2007.
Lucentis is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container, patients with active or suspected ocular or periocular infections, and patients with active intraocular inflammation.
Lucentis 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 Lucentis are described in the Product Monograph.The drug submission for Lucentis was reviewed under the Priority Review Policy. Lucentis demonstrated an improved benefit/risk profile compared to existing therapies for neovascular (wet) AMD, a condition that is not adequately managed by a drug marketed in Canada.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Lucentis is favourable for the treatment of neovascular (wet) AMD.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Ranibizumab, the medicinal ingredient of Lucentis, is a humanized monoclonal antibody Fab fragment (IgG1) targeted against human vascular endothelial growth factor A (VEGF-A). Binding of VEGF-A to its receptors leads to endothelial cell proliferation and neovascularisation, as well as vascular leakage, all of which are thought to contribute to the progression of the neovascular (wet) form of age-related macular degeneration (AMD), one of the leading causes of blindness. The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors VEGFR-1 and VEGFR-2 on the surface of endothelial cells.
Manufacturing Process and Process Controls
Ranibizumab is produced in Escherichia coli cells by standard recombinant DNA technology. The manufacture of ranibizumab is based on an E. coli master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants in accordance with ICH guidelines. Results of these tests confirmed cell line identity and absence of adventitious agents contaminants. Genetic characterization also demonstrated stability of the master cell bank ranging from storage to production at the limit of in vitro cell age.
The manufacture of ranibizumab comprises of a series of steps which include cell culture, harvest, and purification. The purification is performed via chromatographic steps. The manufacturing process consistency is ensured through defined production procedures, critical quality tests, in-process limits, and is evidenced by the ranibizumab certificate of analysis. Microbial control is maintained throughout the manufacturing process by testing for bioburden as well as for bacterial endotoxins. In-process controls performed during manufacture were reviewed and 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 ranibizumab is consistently exhibiting the desired characteristic structure. Results from process validation studies also indicate that the methods used during processing are adequately controlling the levels of product and process-related impurities. The impurities that were reported and characterized were found to be within established limits. The nutrient medium used during the cell culture process contains the antibiotic tetracycline. However, tetracycline is not detectable in the final product.
Control of Drug Substance
Satisfactory validation reports were submitted for the analytical procedures used for in-process and release testing of ranibizumab. The drug substance specifications, and analytical methods used for quality control of ranibizumab are considered acceptable.
Stability
Based upon real-time and accelerated stability studies, the proposed shelf-life and storage conditions for ranibizumab are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Lucentis is a sterile, clear, colourless to pale yellow and preservative-free aqueous solution for injection. Each mL of Lucentis contains 10 mg ranibizumab as the medicinal ingredient. The non-medicinal ingredients are α,α-trehalose dihydrate, histidine hydrochloride monohydrate; histidine; polysorbate 20; and water for injection.
The drug product contains 3.0 mg ranibizumab in 0.3 mL solution for injection, and is packaged in a single-use glass vial (colourless type I glass) with a chlorobutyl rubber stopper. One package contains one 0.3 mL vial and one filter needle for withdrawal of the vial contents.
The excipients (non-medicinal ingredients) used in the Lucentis formulation comply with either the US Pharmacopoeia (USP), National Formulary (NF), or European Pharmacopoeia specifications, except for α,α-trehalose dihydrate, which complies to an acceptable non-compendial set of specifications.
Pharmaceutical Development
The Lucentis formulation as well as the container closure configuration have changed during development. These changes were implemented in order to reduce overfill, improve dosing accuracy, and to ensure that vials are for single-use only. The quality of Lucentis was not negatively affected by these changes.
Manufacturing Process and Process Controls
Lucentis is formulated and filled into vials using proper aseptic process techniques, and conventional pharmaceutical equipment and facilities. All manufacturing equipment, in-process manufacturing steps and detailed operating parameters are adequately described in the submitted documentation and are considered acceptable. The validated process is capable of consistently generating product that meets specifications.
Control of Drug Product
Lucentis is tested to verify its appearance, identity, purity, sterility, and potency, as well as the formulation-relevant parameters: protein content, pH, and osmolality. The validation reports submitted for the analytical procedures used for in-process and release testing of Lucentis are satisfactory and justify the specifications of the drug product.
Analytical testing results from final batch analyses were reviewed and considered to be acceptable according to the specifications of the drug product.
Stability
Based on the real-time and accelerated stability data submitted, an expiration period of 24 months is justified for Lucentis when stored at the recommended temperature of 2oC to 8oC. Lucentis should be protected from prolonged exposure to intense light.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment which are involved in the production are considered suitable for the activities and products manufactured. All facilities are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
E. coli cells do not support the replication of mammalian viruses; therefore, there is no risk from adventitious animal viruses during the production of ranibizumab and the drug product Lucentis.
Pre-harvest culture fluid from each lot is tested to ensure freedom of adventitious microorganisms (e.g. bacteriophages, yeast, mold, Gram negative or positive organisms).
Raw materials of animal origin that are used in the manufacturing process have been adequately tested to ensure freedom of adventitious agents and are subjected to a validated heat-sterilization process. 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 Lucentis 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
Ranibizumab is a recombinant, monoclonal IgG1 antibody antigen-binding fragment (Fab) designed to bind and inhibit all active forms of human vascular endothelial growth factor (VEGF). Ranibizumab binds with high affinity to the VEGF-receptor binding site on multiple isoforms of VEGF such as VEGF110, VEGF121, and VEGF165, thereby preventing binding of VEGF to its receptors VEGFR-1 and VEGFR-2. All three isoforms were shown to stimulate human endothelial cell proliferation, while ranibizumab neutralized this proliferation in a dose-dependent manner.
A modified Miles assay revealed that intravitreally injected ranibizumab blocks VEGF-induced vascular permeability, with 90% inhibition occurring when ranibizumab concentrations were 4-7 times greater than the VEGF concentrations.
In a monkey model of laser-induced CNV (choroidal neovascularization), there was a lower incidence of CNV development in animals injected intravitreally with 0.5 mg of ranibizumab every second week before laser induction of CNV, supporting the anti-angiogenic effects of the compound. In addition, ranibizumab inhibited vascular leakage from the CNV lesions. When verteporfin photodynamic therapy (PDT) was given before, after, or concomitantly with ranibizumab, there was an additive effect on the inhibition of vascular leakage without any apparent increase in side effects.
In summary, the pharmacodynamic (PD) studies demonstrated that ranibizumab binds to and inhibits the biological activity of several forms of VEGF involved in stimulating endothelial cell proliferation and enhancing vascular permeability.
3.2.2 Pharmacokinetics
After intravitreal (ITV) injection, the pharmacokinetics (PK) of ranibizumab appeared to be dose-linear in the vitreous humor, aqueous humor, retinal tissues and serum at all dose levels tested in rabbits and monkeys. In addition, data from the multiple-dose studies in monkeys demonstrated steady-state profiles in vitreous fluid and serum, indicating the absence of both non-linear PK and unexpected accumulation. In rabbits and monkeys, serum levels were >1000-fold lower than vitreous concentrations and declined in parallel with those in the vitreous humor, consistent with absorption rate-limited systemic elimination. The levels in the aqueous humor and the retina were 2.5 to 4-fold lower than levels in the vitreous humor. The terminal half-life was approximately 2-3 days in all ocular matrices, and there was rapid penetration into retinal tissues. In monkeys, the estimated bioavailability after ITV administration was approximately 100%, which suggests that in this model intraocular metabolism is limited.
Microautoradiographic analysis of ocular tissues demonstrated that ranibizumab was present in/on the following structures: perivascularly in the optic nerve head and extending a variable distance into the optic nerve; vitreous; retina, including the retinal pigment epithelium cells; ciliary body epithelium and stroma; anterior and posterior lens capsule; zonula fibers; iris epithelium and stroma; and corneal endothelium. Radioactive Fab reached the blood vessels in the choroids, with no alteration noted in the fenestration in the choroids capillaries. Electron microscopy indicated that Fab fragments injected into the vitreous penetrated the retina and diffused intracellularly through the different layers. Anti-ranibizumab antibodies were detected in the vitreous body and serum after a single ITV administration in rabbits, but did not affect the PK of ranibizumab. In monkeys, anti-ranibizumab antibodies were only detected after repeat administration.
3.2.3 Toxicology
Single-Dose Toxicity,
Single-dose ocular studies were conducted in rabbits at the dose level of 2000 µg/eye. In these studies, the treatment-related effects were limited to ocular inflammation.
Repeat-Dose Toxicity
Four sub-chronic ocular toxicity studies (4-, 13-, 16- and 26-weeks in duration) were conducted in monkeys, with dose levels ranging from 250-2000 µg/eye. The test material (various doses of ranibizumab or vehicle control) was administered by ITV injection once in each eye (50 µL/eye) once every two weeks.
Other than the development of antibodies towards ranibizumab, there were no apparent systemic effects in any study at systemic exposures 400 to 1000-fold over the clinical maximum exposure. There were also no consistent decreases in ocular VEGF levels in animals. Consequently, from a systemic view-point, there were sufficient safety margins, and hence the lack of standard systemic toxicology studies is acceptable.
The highest exposure level without any adverse effects (NOEL) could not be determined in any of the studies, since ocular inflammation was observed at all dose levels tested. Ocular inflammation in the anterior chamber was transient and occurred relatively rapidly, i.e., peaked by day 2 post-injection, whereas in the vitreous, the response was more persistent and slower, i.e., peaked 7 days post-injection. In the shorter studies, the inflammation was most severe after the first injection and subsided thereafter. Seven days post-dose, there was no, or only a mild anterior chamber inflammation, whereas vitreal cells were present during the entire course of the studies. However, in the 26-week study, the inflammatory response increased with the number of injections and at the highest investigated dose (2000 µg/eye) a number of animals were prematurely discontinued due to a severe vitreous inflammation with vitreal protein and inflammatory debris severely impairing the view of the fundus. In the 13-week study, only the lowest dose tested gave an inflammatory response that subsided to levels comparable to that observed in vehicle-injected animals while the animals were still receiving treatment. These findings suggest that the 2-week dosing interval was not long enough to allow the eye to fully recover from the inflammatory reactions before the next dose. The proposed clinical interval is one month, and so this finding does not appear to be a serious safety concern. During the recovery period, anterior chamber inflammation decreased or disappeared, and a decrease in vitreous and tissue inflammatory cells was observed.
Two types of treatment-related posterior segment changes were observed. The first form was a response characterized by single to multifocal, perivenous retinal hemorrhages typically with white centres in the far peripheral retina. These lesions usually appeared 48 hours after the first dose, resolved by one week after dosing, and generally did not reoccur or were diminished on subsequent injections, even with an increased dose. The second form was a dose- and time-related focal to mutifocal, white, perivascular sheathing around peripheral retinal venules with varying amounts of white inflammatory material over the surface of the optic disc. This was considered secondary to the posterior segment inflammation and more chronic in nature. Changes diminished, but did not resolve, during recovery.
In the 26-week study, several cases of cataracts were observed in animals receiving 1000 or 2000 µg/eye. In all cases, the cataracts developed only after a relatively long period of intense inflammation suggesting that the changes to the lens were also secondary to chronic inflammation. Similar findings were not observed in animals dosed with 500 µg/eye.
Intravitreal injection of either ranibizumab or vehicle caused immediate and marked increases (2- to 5-fold) in intraocular pressure (IOP) due to an acute increase in intraocular volume. IOP returned to normal at the next measurement as early as 15 minutes after dosing in all groups.
There were no toxicologically significant findings on electroretinogram evaluation.
Histopathological examinations revealed inflammatory cell infiltrates (neutrophils, macrophages, plasma cells, lymphocytes and/or eosinophils) in different ocular tissues. Following a recovery period, all inflammatory responses were reversed or reduced.
Serum antibodies to ranibizumab were detected in some animals in many studies. Antibodies were detected in the vitreous in one study at doses ≥ 750 µg/eye. No cross reactive binding of humanized monoclonal antibody rhuMAb VEGF was observed to any human tissues. Ranibizumab at concentrations of up to 20 mg/mL did not cause hemolysis of human erythrocytes, and was compatible with monkey and human serum and plasma, and human vitreal fluid.
Genotoxicity and Carcinogenicity
There were no genotoxicity or carcinogenicity studies available. Systemic exposure was low and it would be difficult to perform the relevant studies obtaining both high systemic and intraocular exposure.
Reproductive and Developmental Toxicity
Reproductive and developmental toxicology studies were not performed since the median age of the AMD population was over 70 years of age.
3.2.4 Summary and Conclusion
All relevant assays were shown to be sensitive, specific, reproducible and accurate enough for the assessment of PK and PD studies, and to support the toxicology studies of ranibizumab in the relevant species. Ranibizumab has been shown to bind to several VEGF-A isoforms all of which are involved in stimulating endothelial cell proliferation and enhancing vascular permeability.
The non-clinical pharmacology and toxicology program for Lucentis demonstrated that the compound is relatively safe for humans. Ranibizumab administered by ITV injection did not result in any apparent systemic effects in any study at systemic exposures 400 to 1000-fold over the maximum clinical exposure. Treatment-related findings were only observed in ocular tissues, manifesting as a dose-dependent inflammation in both the anterior and posterior segments of the eye. In the monkey studies, it was demonstrated that 0.5 mg ranibizumab/eye was the maximum tolerated dose. In these studies, the incidence and severity of anterior chamber inflammation and vitreal cell findings were much less than those seen at higher doses. At histopathological examination, the degree of inflammatory cell infiltration was mostly minimal to slight, and the incidence was less than that seen at higher doses. No abnormal IOP, cataract or fluorescein leakage changes were noted. In consideration of the differences between the human and monkey eye with respect to vitreal volume (human - 4.5 mL vs. monkey - 1.5 mL) and dosing frequency (human - once a month vs. monkey - every two weeks), it was concluded that the non-clinical data were adequate to support the proposed clinical use of this drug.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Plasma VEGF levels were measured as a pharmacodynamic (PD) endpoint to investigate the potential effect of ranibizumab on systemic VEGF activity. Prior to ranibizumab administration, concentrations of VEGF ranged from approximately 40 pg/mL to 171 pg/mL. Following ranibizumab administration, VEGF plasma levels fluctuated somewhat, without a discernible pattern, suggesting that the systemic levels of ranibizumab did not have a significant impact on circulating VEGF.
Study FVF2428g investigated the effects of ranibizumab administered as multiple intravitreal injections in combination with verteporfin photodynamic therapy (PDT). Patients were randomized to receive ranibizumab (0.5 mg/monthly) in combination with verteporfin PDT or a sham injection in combination with verteporfin PDT. Plasma levels of VEGF were assessed as a PD endpoint. Similar decreases in VEGF plasma levels were observed in both the control and treated group following the first dose. These decreases could be related to other physiologic effects such as those related to stress. The effect of ranibizumab on CNV lesion size and leakage was assessed in secondary endpoints. In general, the results demonstrated that ranibizumab had a favourable effect on these parameters compared to sham control. Ranibizumab in combination with verterporfin PDT was also shown to improve CNV lesion size and/or leakage compared to verterporfin PDT alone.
3.3.2 Pharmacokinetics
The serum pharmacokinetics (PK) of Lucentis following an ITV dose in humans impacts mainly on the assessment of safety from the potential systemic inhibition of VEGF activity by ranibizumab rather than on the assessment of the dose-effect response of ranibizumab within the eye. The assessment of the systemic exposure to ranibizumab in humans was based on a population PK analysis of scarce serum samples from Phase I, II, and III clinical studies. The sampling scheme was insufficient to adequately define both the peak drug concentration (Cmax) and the overall serum profile of ranibizumab. Following monthly ITV doses of 0.5 mg, serum levels of ranibizumab appeared to remain generally below the threshold thought to be necessary to inhibit the biological activity of VEGF by 50% (11-27 ng/mL, as assessed in an in vitro cellular proliferation assay). In the clinical studies, plasma levels of VEGF were profiled following ITV administration of ranibizumab and no effect was observed on the plasma levels of VEGF. Although systemic exposure from a 0.5 mg dose is expected to be low, it remains unclear whether or not the Cmax can reach a clinically significant level.
Consequently, the risk of systemic adverse events based on the serum PK profile of ranibizumab cannot be adequately assessed from the PK data included in this drug submission. A large amount of safety information is available from the clinical studies conducted with Lucentis independent of the limited systemic PK data available. Any deficiencies identified in the PK review are thus not considered detrimental to the authoriziation of Lucentis for the proposed indication, dose, and route of administration in the treatment of AMD.
3.3.3 Clinical Efficacy
Three pivotal studies (n=1323) were submitted to support this New Drug Submission (NDS): Study FVF2598 (MARINA), Study FVF2587 (ANCHOR), and Study 3192 (PIER). Five non-pivotal studies involving 254 patients using Lucentis for periods up to two years were reviewed for safety only.
Study MARINA was a Phase III, multicentre, randomized, double-masked, sham injection-controlled study (n=716) of the efficacy and safety of Lucentis in patients with minimally classic or occult subfoveal neovascular AMG. Eligible patients were randomized in a 1:1:1 ratio to receive 0.5 mg ranibizumab, 0.3 mg ranibizumab, or a sham injection. The study had a 2-year treatment period. The results for the first 12 months were used for the primary efficacy endpoint analysis as well as for the analyses of the secondary and exploratory endpoints. The 24-month results were used for the analyses of the secondary and exploratory endpoints. The analyses of safety results were done at both 12 and 24 months.
Study ANCHOR was a Phase III, multicentre, randomized, double-blind, active treatment-controlled study (n=423) of the efficacy and safety of Lucentis compared with verteprofin photodynamic therapy (PDT) in patients with predominantly classic subfoveal neovascular AMG. Eligible patients were randomized in a 1:1:1 ratio to receive 0.3 mg ranibizumab and sham PDT with saline infusion, 0.5 mg ranibizumab and sham PDT with saline infusion, or sham injection of ranibizumab and active verteporfin PDT. The study had a 2-year treatment period. The results for the first 12 months were used for the primary endpoint analysis as well as for the analyses of the secondary and exploratory endpoints. The analyses of safety results were done at both 12 and 24 months.
Study PIER was a Phase IIIb, multicentre, randomized, double-masked, sham
injection-controlled study (n=184) of the efficacy and safety of Lucentis in patients with subfoveal CNV with or without a classic CNV component secondary to AMG. This study has a 2-year treatment period; the second treatment year of the study is ongoing. Eligible patients were randomized in a 1:1:1 ratio to receive 0.3 mg or 0.5 mg ITV injections of ranibizumab or sham injections once a month for three consecutive doses, followed by a dose administered once every three months.
All three pivotal studies, MARINA, ANCHOR, and PIER, demonstrated that Lucentis is an effective medication in treatment of AMD when compared to controls such as placebo or verteprofin PDT therapy.
In both studies, MARINA and ANCHOR, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline. In the MARINA study, the primary endpoint was achieved at 12 months and the results showed that 94.5% of the patients in the 0.3 mg group and 94.6% of the patients in the 0.5 mg group lost fewer than 15 letters from baseline, compared with 62.2% of sham-injection patients, which was clinically and statistically significant for each of the ranibizumab doses over the sham control. In the ANCHOR study at Month 12, 94.3% of patients treated with Lucentis 0.3 mg and 96.4% of patients treated with Lucentis 0.5 mg lost fewer than 15 letters from baseline, compared with 64.3% of verteporfin PDT-treated patients. In the PIER study, the primary efficacy endpoint was the mean change in Best Corrected Visual Acuity (BCVA) score in the study eye from baseline to 12 months. At 12 months, the mean changes in the BCVA from baseline in the study eye were -1.6 and -0.2 letters for the Lucentis 0.3 mg group and 0.5 mg group, respectively compared with -16.3 letters for the sham control group. Analysis of one of the secondary endpoints in the PIER study showed that at 12 months, 83.3% of the patients in the Lucentis 0.3 mg group and 90.2% of patients in the Lucentis 0.5 mg group lost fewer than 15 letters from baseline compared with 49.2% of the patients receiving sham injections. The PIER study also confirmed that the dosage of the medication can be administered once every three months, however Lucentis is not as effective in this regimen as it is for monthly dosing. Analysis of data confirmed that compared to monthly dosing, dosing every 3 months will lead to an approximate 5 letter (1 line) loss of visual acuity benefit, on average, over the following 9 months.
In summary, in all three pivotal studies, the positive results of the primary endpoints were both clinically and statistically significant. There were also multiple secondary and exploratory endpoints. Their results supported the primary endpoint outcome as the majority of them were statistically significant and demonstrated the clinical effectiveness of Lucentis therapy.
3.3.4 Clinical Safety
A total of 1,323 patients were enrolled in the three pivotal studies, FVF2598g (MARINA), FVF2587g (ANCHOR) and FVF3192g (PIER) and followed for up to two years. For a description of these studies, see section 3.3.3 Clinical Efficacy.
There was an increased proportion of patients with adverse events in the active treatment arm as compared with controls. The common ocular adverse reactions reported for the treated eye were eye pain (frequency 0%-28.9%), conjunctival hemorrhage (frequency 0%-18.4%) and vitreous floaters (frequency 1.6%-17.2%). Other common and serious ocular adverse reactions included intraocular inflammation (such as anterior chamber inflammation, hypopyon, iridocyclitis, iritis, uveitis and vitritis with an overall frequency 4.9%-17.2%) and increased intraocular pressure (frequency 3.3%-18.8%). Serious adverse events such as rhegmatogenous retinal detachment, endophthalmitis, retinal tear or traumatic cataract occurred in <0.1% of ITV injections.
The results do not provide a clear picture of the relationship between therapy with Lucentis and arterial thromboembolic events/cerebro-vascular accidents (CVAs). While in general, there are no large imbalances of adverse arterial thromboembolic events between the active treatment and control groups, there was a potential trend of an increase in the patients treated with Lucentis especially with the higher dose (0.5 mg). However, all of these analyses were performed on a small number of cases and this causes difficulty in interpreting the results. Furthermore, the potential increase in thromboembolic events may be a class effect of VEGF inhibitors but because of very low concentrations of Lucentis in the systemic circulation, causal relationship is very difficult to establish with certainty. In an ongoing uncontrolled comparison study of Lucentis 0.3 mg (1174 patients) and 0.5 mg (1211 patients), the 0.5 mg dose of Lucentis does not appear to engender a greater risk of CVA. Further clarification of this must await the final results of the ongoing studies.
Immunoreactivity was demonstrated in a small percentage of patients in all studies and treatment arms. The clinical significance of this phenomenon is unclear but some patients with higher levels of the immunoreactivity also had a higher incidence of intraocular inflammation.
Five non-pivotal studies involving 254 patients using Lucentis for periods up to two years were reviewed to assess safety; however the results are, otherwise, of limited value as most employed a lyophilized preparation of Lucentis which is not to be marketed.
Results were similar to those of the pivotal studies; the predominant problem being intraocular inflammation after injection which occurred in approximately 50% of the cases and was severe in approximately 11%. However, this rapidly subsided and did not appear to have harmful effects on vision, at least in the short term. Only one patient suffered serious loss of vision due to a retinal vein occlusion and this may not have been due to the medication. Other ocular complications (retinal tear, vitreous haemorrhage) were rare and retinal detachment and retinal artery thrombosis did not occur. Intraocular pressure increases were mostly modest and when greater, were successfully managed by conservative measures. No cases of cataract formation were encountered but the studies may not have been long enough to exclude this, and this potential complication needs to be examined during post-marketing surveillance.
Although no serious anaphylactic hypersensitivity reactions occurred in the clinical trials, there is a theoretical risk of hypersensitivity reactions including anaphylaxis/anaphylactoid reactions or angioedema.
Overall, Lucentis appears to be a relatively safe medication. The Periodic Safety Update Reports collected between June 30, 2006 and March 29, 2007 identified no new safety concerns that had not been already described during clinical trials. A comprehensive list of the adverse reactions related to Lucentis therapy is included in the Product Monograph and adequate warnings about thromboembolic events and hypersensitivity reactions were added.
3.3.5 Outstanding Issues
The sponsor has agreed to fulfill the following post-marketing commitments:
- Provide Periodic Safety Update Reports every 6 months and to inform Health Canada of any signals suggesting an increase in adverse reaction rates related to treatment with Lucentis.
- Complete the ongoing studies and provide the results in post-approval submissions including updating the Lucentis Product Monograph as appropriate.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The drug submission for Lucentis was assigned Priority Review Status as Lucentis is indicated for the treatment of neovascular (wet) AMD, a severe debilitating condition. Treatment with Lucentis demonstrated a favourable effect on a serious symptom or manifestation of the condition for which limited treatment options exist.
Neovascular AMD leads to vision loss and decrease of quality of life and in the clinical studies Lucentis positively modified the progression of this disease. The risks encountered with Lucentis consist of intraocular inflammation, other ocular complications and systemic effects e.g., thromboembolic events. This medication has a number of potential side effects, some of which could be very serious. However, the majority of these risks are predictable based on the analyses of adverse reactions and effects provided with the submission. Many of these risks are reversible and can be mitigated or treated when necessary.
Based on the submitted evidence and taking into account the severity and the burden of untreated AMD as well as limited available treatment options, it can be concluded, that the benefits of Lucentis therapy clearly outweigh the risks arising from its use.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Lucentis is favourable in the treatment of neovascular (wet) AMD. 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: Lucentis
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting : | 2006-09-15 |
| Request for priority status | |
| Filed : | 2006-09-29 |
| Approval issued by Director, CERB : | 2006-10-23 |
| Submission filed : | 2006-12-05 |
| Screening | |
| Screening Acceptance Letter issued : | 2006-12-29 |
| Review | |
| Biopharmaceutics Evaluation complete : | 2007-06-20 |
| Quality Evaluation complete : | 2007-06-22 |
| Clinical Evaluation complete : | 2007-06-20 |
| Biostatistics Evaluation complete : | 2007-06-20 |
| Labelling Review complete : | 2007-06-06 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| LUCENTIS | 02296810 | NOVARTIS PHARMACEUTICALS CANADA INC | RANIBIZUMAB 10 MG / ML |