potential risk of ‘Systemic corticosteroid effect’ (infection, hypertension and impaired healing) has already been included in the EU RMP v 7.0. Allergan believes that current EU RMP v 7.0 (along with the ASA v2.0) adequately addresses any safety concern(s) arising out of use of Ozurdex in Australia. It is recommended that the important potential risk: ‘Off use’ be included as a new ongoing safety concern given the sponsor is not seeking to register the EU approved indications (that is the treatment of adult patients with macular oedema following either Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO) and for the treatment of adult patients with inflammation of the posterior segment of the eye presenting as non-infectious uveitis). Consideration must be given as to what pharmacovigilance and risk minimisation activities will be proposed for this new ongoing safety concern and only the ASA need be revised accordingly. The sponsor agrees that post approval of Ozurdex in Australia for the proposed indication there is a potential for off label use for the remaining approved indications in the EU and the US (macular oedema following BRVO or CRVO and uveitis). However, the sponsor argues that safety concerns (if any) associated with the use of Ozurdex in adult patients with macular oedema following BRVO or CRVO and posterior uveitis will be similar, if not, less than those expected with its usage in diabetic macular oedema patients. On this basis the sponsor refuses to amend Section 2 of the ASA as recommended. It is agreed that routine and risk minimisation are appropriate for this new ongoing safety concern specific to Australia. Nevertheless to ensure that it is appropriately monitored by routine it is reiterated that ‘Off label use’ should be included as an important potential risk, which need only be reflected in a revised ASA preferably before this application is approved. The EU RMP states the following for Version 3.0 dated May 2013: “Systemic The sponsor states: “While in EU RMP v4.0, Allergan This is acceptable.
pressure, Glaucoma, Ocular Hypertension’ and ‘Endophthalmitis (infectious/ non-infectious)’ in Australia, as some inconsistency is observed in the EU RMP on this matter (for example the tables included in Part V.1: ‘Risk minimization measures by safety concern’, Table 9 16: ‘Summary Table of Risk Minimization Measures’ and Table 9 19: ‘Summary Table of Risk Minimization Measures’). between two and seven days following the injection. The proposed Australian PI provides no such detail. Consequently this remains outstanding and should be adequately addressed preferably before this application is approved. The current UK SmPC states: “The safety and efficacy of Ozurdex administered to both eyes concurrently have not been studied. Therefore administration to both eyes concurrently is not recommended”. This precautionary statement is cross referenced to the ‘Posology and method of administration’ section of the UK SmPC and was related to the former ongoing safety concern: ‘Systemic corticosteroid effects’. However, a similar precautionary statement does not appear to be included in the proposed Australian PI, but is included in the proposed Australian CMI. The sponsor should correct this oversight and amend the proposed Australian PI accordingly. The sponsor states: “The assessor’s observation is addressed in the updated Australian PI, and the following sentence has been added to the draft PI under Dosage and Administration: “The safety and efficacy of Ozurdex administered to both eyes concurrently have not been studied. Therefore, administration to both eyes concurrently is not recommended.” It is observed that this information is in fact now included in the Precautions section, not in the dosage and administration section, of the proposed Australian PI. This is not entirely satisfactory and it is reiterated that these precautionary statements should also be cross referenced to the dosage and administration section of the proposed Australian PI. Furthermore Table 3–1: ‘Differences between the risk minimisation activities
Given these differences in registration details it would also be expected that the sponsor will conduct a physician survey in Australia to assess the effectiveness of the prescriber educational materials as a measure to reduce all the specified important identified risks. Consequently the sponsor should provide to the TGA for review the details of the nature (quantitative) and content of the survey testing to be conducted in Australia, including the specific review period, the criteria used to verify success and how the results of this testing will be reported to the TGA. Section 3: ‘RMP’ of the ASA should be revised accordingly. The sponsor states: “The overall AE reporting rate, as well as the injection procedure related adverse rate, will be used as a measure of effectiveness of these educational materials. A decrease in overall reporting rate, as well as frequency and severity of injection procedure related adverse events, will be considered as verification of the success of the educational materials.” This approach is reliant upon data from spontaneous AE reports which are unlikely to be sufficient in measuring the effectiveness of these proposed additional risk minimisation activities. This is due to the under reporting and the lack of reliable exposure (usage) data associated with spontaneous reporting systems, not to mention the information gained from adverse reaction reporting is often incomplete. Consequently this remains outstanding and should be adequately addressed preferably before this application is approved. It would appear that no information detailing how the patient educational materials as a measure to reduce the important identified risks: ‘Increased IOP, glaucoma, ocular hypertension’ and ‘endophthalmitis (infectious/ non-infectious)’ has been provided. Consequently the sponsor should state how the The sponsor “proposes capturing data on identified risks through the targeted questionnaire and spontaneous AE reporting to Allergan’s pharmacovigilance department. Data This approach is reliant upon data from spontaneous AE reports which are unlikely to be sufficient in measuring the effectiveness of these proposed additional risk trial
effectiveness of this additional risk minimisation measure for these ongoing safety concerns will be measured, the criteria used to verify success and how the results of such testing will be reported to the TGA. Section 3: ‘RMP’ of the ASA should be revised accordingly. collected via these channels will be reported to the TGA through established reporting mechanisms if required.” The updated ASA states: “Allergan diligently monitors AEs (related to injection procedure). The overall AE profile, reporting rate, as well as the type and frequency of injection procedure related adverse events will all be used as a measure of effectiveness of these educational materials.” minimisation activities. This is due to the under reporting and the lack of reliable exposure (usage) data associated with spontaneous reporting systems, not to mention the information gained from adverse reaction reporting is often incomplete. Consequently this remains outstanding and should be adequately addressed preferably before this application is approved. In addition the sponsor stated that educational materials were attached as Appendix 1 to the updated ASA. However, it appears that the patient educational materials have not been so attached. The sponsor should correct this oversight. A table summarising the pharmacovigilance and risk minimisation activities for all of the specified ongoing safety concerns and missing The sponsor states: “A table listing all proposed Pharmacovigilance activities (Table 2 1) This is acceptable.
Results, ITT Primary endpoint: BCVA (letters) mean change from baseline (AUC) are shown in Table 11. Table 11. Primary endpoint: BCVA (letters) mean change from baseline (AUC) Study 700 µg 350 µg Sham 010 N mean change difference from Sham (95% CI) 163 4.1 2.1 (0.4, 3.8) 166 4.3 2.3 (0.5, 4.0) 165 1.9 011 N mean change difference from Sham (95% CI) 188 2.9 0.8 ( 0.9, 2.4) 181 2.9 0.7 ( 0.9, 2.4) 185 2.0 Pooled: 700 µg difference from Sham: 1.4 letters, 95% CI (0.2, 2.6) Selected secondary endpoint: Percentage of patients with 15+ letter improvement in BCVA are shown in Table 12. Table 12. Selected secondary endpoint: Percentage of patients with 15+ letter improvement in BCVA 700 µg 350 µg Sham 010 N n (%) 163 36 (22)* 166 31 (19) 165 22 (13) 011 N n (%) 188 42 (22)* 181 33 (18)* 185 20 (11) “*” statistically significantly different from Sham The mean change from baseline, pooled data from Studies 010 and 011 is show in in Figure 7. Figure 7. Mean change from baseline, pooled data from Studies 010 and 011 Results, selected pre specified subgroup analyses Difference from Sham, BCVA (letters) mean change from baseline (AUC) are shown in Table 13.
Table 13. Difference from Sham, BCVA (letters) mean change from baseline (AUC) Study / pre specified subgroup 700 µg versus Sham 350 µg versus Sham 010 Any prior treatment N (Sham N=127) difference from Sham (p value) 123 2.6 (0.011) 126 3.2 (0.002) Pseudophakic eye at baseline N (Sham N=50) difference from Sham (p value) 44 5.9 (<0.001) 47 4.1 (0.007) 011 Any prior treatment N (Sham N=134) difference from Sham (p value) 124 0.7 (0.495) 123 0.8 (0.409) Pseudophakic eye at baseline N (Sham N=51) difference from Sham (p value) 42 3.6 (0.018) 41 4.3 (0.005) Percentage of patients with 15+ letter improvement in BCVA, difference from Sham are shown in Table 14. Table 14. Percentage of patients with 15+ letter improvement in BCVA, difference from Sham 700 µg versus Sham 350 µg versus Sham 010 Any prior treatment N (Sham N=127) difference from Sham (p 123 11% (0.020) 126 10% (0.036) Pseudophakic eye at baseline N (Sham N=50) difference from Sham (p value) 44 18% (0.042) 47 -1% (0.880) 011 Any treatment N (Sham N=134) difference from Sham (p value) 124 10% (0.032) 123 3% (0.410)