Verteporfin, powder for I.V. infusion, 15 mg, Visudyne®, November 2005
Public Summary Document for verteporfin, powder for I.V. infusion, 15 mg, Visudyne® November 2005
Page last updated: 20 February 2017
Public Summary Document
Product: Verteporfin, powder for I.V. infusion, 15 mg, Visudyne®
Sponsor: Novartis Pharmaceuticals Australia Pty Ltd
Date of PBAC Consideration: November 2005
1. Purpose of Application
The submission sought Section 100 listing of verteporfin under a special program for subfoveal choroidal neovascularisation (CNV) due to age-related macular degeneration (AMD) and other macular diseases.
Section 100 of the National Health Act 1953 provides for drugs to be made available under arrangement outside of the normal PBS process where appropriate.
2. Background
The drug had not previously been considered by the PBAC.
However, at its August 2001 meeting, the Medical Services Advisory Committee (MSAC) recommended verteporfin be approved for reimbursement via Medicare for patients with predominantly classic (>50%) subfoveal choroidal neovascularisation secondary to macular degeneration. Cabinet approved funding for verteporfin through subsidised access via a three-year Health Program Grant (HPG) from June 2002, which was extended until 30 June 2006.
3. Registration Status
Currently, Verteporfin is registered by the TGA for the treatment of patients with predominantly classic or occult subfoveal choroidal neovascularisation due to age-related macular degeneration, or with subfoveal choroidal neovascularisation caused by other macular diseases.
4. Listing Requested and PBAC’s View
Section 100 (Special Program) Private hospital authority required
Treatment of subfoveal choroidal neovascularis ation (CNV) secondary to age-related macular degeneration where the CNV is composed, predominantly (>50%), of classic lesions as defined by fluorescein angiography;
Treatment of occult with no classic or minimally classic subfoveal choroidal neovascularisa tion (CNV) secondary to age-related macular degeneration where the lesion size is less than or equal to 4 Macular Photocoagulation Study disc areas as defined by fluorescein angiography;
Treatment of patients with subfoveal choroidal neovascularisation caused by other macular diseases.
The requested wording and populations proposed for listing presented here is only one of four options proposed by the Sponsor in their submission, each with different patient subgroups of lesion types and sizes.
See Recommendations and Reasons for PBAC’s view.
5. Clinical Place for the Proposed Therapy
Photodynamic therapy in conjunction with verteporfin is an approved treatment for subfoveal CNV, most commonly caused by age-related macular degeneration.
6. Comparator
The submission nominated standard care (no treatment or watchful waiting) as the main comparator. The PBAC considered this was appropriate.
7. Clinical Trials
The submission presented five head-to-head randomised trials comparing verteporfin and placebo and four non-randomised studies. Of the five randomised trials, four compared verteporfin and placebo in the treatment of CNV secondary to age-related macular degeneration (AMD) and the remaining trial compared verteporfin and placebo in the treatment of CNV secondary to pathologic myopia (PM). Two of the non-randomised studies were open-label extension studies of randomised trials presented in the submission and one non-randomised study and extension assessed the effectiveness of verteporfin in the treatment of CNV secondary to ocular histoplasmosis syndrome.
The list of trials published at the time of the submission are as follows:
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
| Arnold J, | Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: One-year results of 2 randomized clinical trials - TAP report 1. | Archives of Ophthalmology 1999; 117:1329-45. |
| Arnold J, | Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: Two-year results of 2 randomized clinical trials - TAP report 2. | Archives of Ophthalmology 2001; 119:198-207. |
| Bressler NM, | Verteporfin therapy of subfoveal choroidal neovascularization in patients with age-related macular degeneration: Additional information regarding baseline lesion composition's impact on vision outcomes - TAP report no. 3. | Archives of Ophthalmology 2002; 120:1443-54. |
| Rubin GS, | Effects of verteporfin therapy on contrast sensitivity: Results from the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) investigation - TAP Report No. 4 | Retina 2002; 22:536-44. |
| Blumenkranz MS, | Verteporfin therapy for subfoveal choroidal neovascularization in age-related macular degeneration: Three-year results of an open-label extension of 2 randomized clinical trials - TAP report no. 5. | Archives of Ophthalmology 2002; 120:1307-14. |
| Bressler SB, | Natural History of Minimally Classic Subfoveal Choroidal Neovascular Lesions in the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Investigation: Outcomes Potentially Relevant to Management - TAP Report No. 6. | Archives of Ophthalmology 2004; 122:325-9. |
| TAP & VIP study group | Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP Report No. 1 | American Journal of Ophthalmology 2003; 136: 407-418. |
| Bressler NM. | Photodynamic therapy of subfoveal choroidal neovasularisation with verteporfin: fluorescein angiographic guidelines for evaluation and treatment – TAP and VIP Report No. 2. | Archives of Ophthalmology 2001; 121:1253-68. |
| TAP & VIP study group | Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration - Meta-analysis of 2-year safety results in three randomized clinical trials: Treatment of age-related macular degeneration with photodynamic therapy and verteporfin in photodynamic therapy study report No. 4. | Retina 2004; 24:1-12. |
| Arnold J, | Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: Two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization - Verteporfin in photodynamic therapy report 2. | American Journal of Ophthalmology 2001; 131:541-60. |
| Bressler NM. | Verteporfin therapy of subfoveal choroidal neovascularisation in age-related macular degeneration two year results of a randomised clinical trial including lesions with occult with no classic choroidal neovascularisation – verteporfin in photodynamic therapy report 2. | American Journal of Ophthalmology , 2002, 133:168-9. |
| Azab-M, | Verteporfin Therapy of Subfoveal Minimally Classic Choroidal Neovascularization in Age-Related Macular Degeneration: 2-Year Results of a Randomized Clinical Trial. | Archives of Ophthalmology 2005; 123(4): 448-57 |
| Bressler NM. | Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin: 1-year results of a randomized clinical trial VIP report no. 1. | Ophthalmology 2001; 108:841-52. |
| Blinder KJ, | Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-Year results of a randomized clinical trial - VIP report no. 3. | Ophthalmology 2003; 110:667-73. |
| VIP-Study-Group | Verteporfin in Photodynamic Therapy: Report no. 5 (VIP report No. 5). | Ophthalmology 2004; 111:2144. |
| Saperstein DA, | Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin in the ocular histoplasmosis syndrome: One-year results of an uncontrolled, prospective case series. | Ophthalmology 2002; 109:1499-505. |
| Rosenfeld PJ, | Photodynamic therapy with verteporfin in ocular histoplasmosis: Uncontrolled, open-label 2-year study. | Ophthalmology 2004; 111: 1725-1733. |
8. Results of Trials
The results of the key trials for the indications for which PBS listing was sought are summarised in the tables below. In patients with CNV due to AMD, verteporfin was associated with a significant reduction in the risk of visual loss compared with placebo. For patients with predominantly (>50%) classic CNV (currently funded by the MBS), the reduction in risk of visual loss was statistically significantly greater at both 12 and 24 mo nths. For patients with occult CNV and ≤4 Macular Photocoagulation Study Disc Areas (MPS DA) lesion size, the reduction in risk of visual loss was only statistically significant at 24 months. For patients with minimally classic CNV and ≤4 MPS DA lesion size, the reduction in risk of visual loss was not statistically significant at either 12 or 24 months. For patients with CNV due to PM, the statistically significant reduction in risk of visual loss at 12 months did not persist at 24 months.
Results of the AMD comparative randomised trials: primary outcome (loss of < 15 letters) at 12 and 24 months
|
Trial |
Verteporfin |
Placebo |
ARD (95% CI)
|
RR (95% CI)
|
NNT (95% CI)
|
|---|---|---|---|---|---|
|
12 months |
|||||
| TAP A a |
122/204 (59.8) |
49/107 (45.8) |
(2.4, 25.6) |
(1.03, 1.65) |
|
| TAP B a |
124/198 (62.6) |
47/100 (47.0) |
(3.7, 27.5) |
(1.05, 1.65) |
|
| TAP A&B (pooled) a |
246/402 (61.2) |
96/207 (46.4) |
(6.5, 23.1) |
(1.12, 1.56) |
|
| ≥50% classic a |
107/159 (67.3) |
33/83 (39.8) |
(14.7, 40.3) |
(1.27, 2.25) |
|
| <50% classic | |||||
| ≤4 MPS DA b |
50/77 (64.9) |
19/40 (47.5) |
17.4% (-1.4, 36.2) |
1.37 (0.95, 1.97) |
NA |
| >4 MPS DA b |
60/122 (49.2) |
36/61 (59.0)/ |
-9.8% (-25.0, 5.4) |
0.83 (0.63, 1.10) |
NA |
| VIP AMD c |
111/225 (49.3) |
52/114 (45.6) |
3.7% (-7.5, 15.0) |
1.08 (0.85, 1.38) |
NA |
| Occult no classic c |
81/166 (48.8) |
41/92 (44.6) |
4.2% (-8.5, 16.9) |
1.09 (0.93, 1.44) |
NA |
| ≤ 4 MPS DA d |
45/80 (56.3) |
17/39 (43.6) |
12.7% (-6.3, 31.6) |
1.29 (0.86, 1.94) |
NA |
| >4 MPS DA d |
35/84 (41.7) |
24/52 (46.2) |
-4.5% (-21.7, 12.7) |
0.90 (0.61, 1.33) |
NA |
| Classic containing c |
28/57 (49.1) |
11/22 (50.0) |
-0.9% (-25.5, 23.7) |
0.98 (0.60, 1.61) |
NA |
| VIM e |
60/77 (77.9) |
22/40 (55.0) |
(4.9, 40.9) |
(1.04, 1.92) |
|
| Meta-analysis (RevMan) f |
417/704 (59.2) |
170/361 (47.1) |
(6.0, 18.0) |
(1.11, 1.43) |
|
|
24 months |
|||||
| TAP A a |
104/204 (51.0) |
42/107 (39.3) |
11.7% (0.2, 23.2) |
1.30 (0.99, 1.70) |
9 (4, 500) |
| TAP B a |
109/198 (55.1) |
36/100 (36.0) |
(7.4, 30.7) |
(1.14, 2.04) |
|
| TAP A&B (pooled) a |
213/402 (53.0) |
78/207 (37.7) |
(7.1, 23.5) |
(1.15, 1.71) |
|
| ≥50% classic a |
94/159 (59.1) |
26/83 (31.3) |
(15.2, 40.4) |
(1.34, 2.66) |
4 (3, 7) |
| <50% classic | |||||
| ≤4 MPS DA b |
44/77 (57.1) |
16/40 (40.0) |
17.1% (-1.6, 35.9) |
1.43 (0.93, 2.19) |
NA |
| >4 MPS DA b |
49/122 (40.2) |
28/61 (45.9) |
-5.7% (-21.0, 9.5) |
0.88 (0.62, 1.24) |
NA |
| VIP AMD c |
104/225 (46.2) |
38/114 (33.3) |
(2.1, 23.7) |
(1.03, 1.86) |
|
| Occult no classic c |
75/166 (45.2) |
29/92 (31.5) |
(1.5, 25.8) |
(1.02, 2.02) |
|
| ≤4 MPS DA d |
44/80 (55.0) |
11/39 (28.2) |
(9.0, 44.6) |
(1.14, 3.34) |
|
| >4 MPS DA d |
29/84 (34.5) |
18/52 (34.6) |
-0.1% (-16.5, 16.4) |
1.00 (0.62, 1.60) |
NA |
| Classic containing c |
27/57 (47.4) |
9/22 (40.9) |
6.5% (-1.7, 30.8) |
1.16 (0.65, 2.05) |
NA |
| VIM e |
46/77 (59.7) |
16/40 (40.0) |
19.7% (1.0, 38.5) |
1.49 (0.98, 2.28) |
5 (3, 100) |
| Meta-analysis (RevMan) f |
363/704 (51.6) |
132/361 (36.6) |
(9.0, 21.0) |
(1.21, 1.64) |
|
Statistically significant differences are highlighted by bolded font.
Relative risk (RevMan) and NNT calculated during the evaluation
NA = not applicable since not statistically significant
Sources: a Table 19, p86 of the submission; b Table 25, p100 of the submission;
c Table 43, p139 of the submission; d Table 49, p153 of the submission;
e Table 61, p175 of the submission; f Table 69, pp186-187 and Figure 19, p187 of the submission (includes the results from TAP A&B (pooled), and the whole VIP AMD and VIM trial population).
Results of the VIP PM trial: primary and secondary outcomes at 12 and 24 months (ITT)
|
Verteporfin n/N (%) |
Placebo n/N (%) |
ARD (95 % CI) |
RR (95% CI) |
NNT (95% CI) |
|
|---|---|---|---|---|---|
|
Loss of <8 letters of visual acuity (primary outcome) |
|||||
| 12 months |
58/81 (71.6) |
17/39 (43.6) |
28.0% (10.0, 46.0) |
1.64 (1.12, 2.41) |
4 (2, 11) |
| 24 months |
52/81 (64.2) |
19/39 (48.7) |
15.0% (-3.0, 34.0) |
1.32 (0.92, 1.89) |
NA |
|
Loss of <15 letters of visual acuity (primary outcome) |
|||||
| 12 months |
70/81 (86.4) |
26/39 (66.7) |
19.8% (3.2, 36.3) |
1.30 (1.02, 1.64) |
5 (3, 31) |
| 24 months |
64/81 (79.0) |
28/39 (71.8) |
7.2% (-9.5, 23.9) |
1.10 (0.88, 1.38) |
NA |
|
BCVA <34 letters (secondary outcome) |
|||||
| 12 months |
5/81 (6.2) |
7/39 (17.9) |
-11.8% (-24.9, 1.4) |
0.34 (0.12, 1.01) |
NA |
| 24 months | 9/81 (11.1) |
4/39 (10.3) |
0.9% (-10.9, 12.6) | 1.08 (0.36, 3.30) | NA |
Statistically significant differences are highlighted by bold font. BCVA – ; best corrected visual acuity.
For most body systems and individual adverse events, the incidence was similar between verteporfin treated and placebo treated patients. Of the different adverse events reported, only visual disturbances (including acute severe visual acuity decrease), injection site reactions, photosensitivity reactions, and infusion-related back pain occurred with a higher incidence in the verteporfin group than the placebo group. Most adverse events were mild to moderate and transient in nature. Undesirable adverse events reported in patients with pathologic myopia and ocular histoplasmosis syndrome were similar to those reported in patients with AMD.
For PBAC’s view see Recommendations and Reasons.
9. Clinical Claim
The submission claimed that in patients with CNV due to AMD,verteporfin had significant advantages in effectiveness over placebo, but had more toxicity. The PBAC agree that in regard to sub-groups of patients with CNV due to AMD, a test for interaction indicated that presence of predominantly classic lesions was a treatment effect modifier (with effects being superior in this sub-group). The therapeutic relativity in patients with CNV due to other macular diseases was not conclusive.
10. Economic Analysis
The submission presented a preliminary economic evaluation. The choice of the cost-effectiveness approach for patients with CNV due to AMD was considered valid. However, the choice of a cost-effectiveness approach for patients with CNV due to PM was considered invalid, given the doubts about the clinical claim in this patient group.
The resources included were drug costs (3.4 injections in the first 12 months and 2.2 injections in the second 12 months in AMD) and activation using the laser.
The submission presented a trial-based incremental discounted cost/extra vision-year gained over 24 months for nine patient populations. The results for the four patient groups included in the preferred wording of the restriction are as follows:
- Predominantly classic lesions secondary to AMD: $15,000 to $45,000 (currently subsidised)
- Small occult with no classic lesions secondary to AMD: $45,000 to $75,000 (additional group)
- Small minimally classic lesions secondary to AMD: $45,000 to $75,000 (additional group)
- Subfoveal CNV lesions secondary to PM: $75,000 to $105,000 (currently subsidised)
The variations in these ratios reflected the variations of the absolute risk differences reported in the trials.
A modelled economic evaluation was presented. The resources included in the base case analysis were: extended episodes of photodynamic therapy up to 5 years (included drug costs, costs of activation, medical services costs, and fluorescein angiography costs); and falls due to visual impairment. Outcomes of vision-years gained were extrapolated beyond the time horizon of the trials. Utility gains associated with vision-years were estimated on the basis of a study reporting results of a time trade-off exercise in patients with ocular diseases and varying levels of visual acuity.
The submission presented base case modelled incremental discounted cost/vision-year gained for ten patient populations, including PM. With the exception of the incremental ratios for patients with CNV secondary to PM, the modelled incremental ratios were <$15,000/VYG.
The PES evaluator recalculated the modelled incremental ratios assuming treatment extended for 7 years and excluding all cost offsets due to blindness avoided and presented the following modelled incremental discounted cost/extra discounted QALY gained :
- Predominantly classic lesions secondary to AMD: $45,000 to $75,000 (currently subsidised)
- Small occult with no classic lesions secondary to AMD: $15,000 to $45,000 (additional group)
- Small minimally classic lesions secondary to AMD: $45,000 to $75,000 (additional group)
- Subfoveal CNV lesions secondary to PM: > $200,000 (currently subsidised)
For the PBAC’s view see Recommendations and Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated that the likely number of patients/year would be< 10,000 inYear 4 of listing which was considered by the PBAC to be a possible underestimate depending on whether greater awareness of the disease accompanies PBS listing.
The submission estimated that the financial cost/year to the would be between $30 million and $60 million in the fourth year listing, which was considered by the Committee to be a possible underestimate arising from the possible underestimates of numbers of patients.
12. Recommendation and Reasons
The PBAC recommended listing on a cost-effectiveness basis for patients with AMD featuring predominantly classic lesions. The PBAC considered that the incremental cost per extra QALY gained at between $45,000 to $75,000 (excluding cost offsets) was high but acceptable and less uncertain than the estimated cost-effectiveness for the additional patient groups requested for subsidy.
The PBAC noted that, strictly speaking, the requested restriction in minimally classic CNV falls outside the TGA-approved indications. Further, for patients with predominantly (>50%) classic CNV (currently funded by the MBS), the reduction in risk of visual loss is statistically significantly greater at both 12 and 24 months. For patients with occult CNV and ≤4 MPS DA lesion size, the reduction in risk of visual loss is only statistically significant at 24 months. For patients with minimally classic CNV and ≤4 MPS DA lesion size, the reduction in risk of visual loss is not statistically significant at either 12 or 24 months. For patients with CNV due to PM, the statistically significant reduction in risk of visual loss at 12 months did not persist at 24 months. Thus, in terms of both extent and statistical significance of treatment effect, the trial evidence is most compelling for patients with predominantly classic CNV.
The PBAC noted that based on stratifying patients into the requested sub-groups, lesion
size is not demonstrated to be a treatment effect modifier. The Pre-Sub-Committee
Response emphasised that, in regression-based exploratory analyses (based on outcomes
other than the primary outcome), a statistically significant interaction was seen
between treatment size and lesion size. Overall, the PBAC considered that the post
hoc analyses of the evidence available suggested the possibility of treatment effect
modification, but these were not conclusive because they were exploratory rather than
confirmatory in nature and different analyses yielded conflicting results.
There were a number of concerns noted by the PBAC, in relation to the utilities and
the cost off-sets used in the model. In particular, the claimed cost off-sets for
nursing homes (due to falls) were rejected and the PBAC noted that any claims for
other cost off-sets, which were also likely to have been over-estimated, had relatively
small impact. The PBAC also noted that that there were grounds to consider that the
derivation of the utility estimates are likely to have favoured verteporfin, but judged
that the extent of impact of this uncertainty was not a major driver of the model.
In view of the above clinical uncertainties and uncertainties about the model, the PBAC was not convinced that the modelled ratios of incremental cost per extra QALY gained effectiveness calculated for patients with small (≤4 MPS DA) minimally classic or occult CNV lesion were reliable. Even though the ratio for patients with small occult CNV lesions (but not small minimally classic lesions) was numerically less than the incremental cost per extra QALY gained of between $45,000 to $75,000 for predominantly classic CNV, the trial-based evaluations for both patient groups were numerically greater than the incremental cost per extra vision-year gained over 24 months.
Thus, given the uncertainty over the incremental cost-effectiveness ratios (ICER) on both occult and minimally classic disease (and the fact that the latter is not a TGA-registered indication for verteporfin) and the unacceptable incremental cost per extra QALY gained of over $200,000 for CNV due to other macular diseases, the PBAC decided to reject these other indications.
The PBAC noted that the patient group with predominantly classic lesions secondary to AMD were currently subsidised through the Medicare Benefits Scheme (MBS) as were the patients with subfoveal CNV lesions secondary to other macular diseases (PM) . Based on the unacceptably high and uncertain cost-effectiveness associated with treatment of this latter group, the PBAC considered that grandfathering these patients onto the PBS would be inappropriate, however acknowledged that such patients under current treatment would need to be catered for in some way to allow completion of the current course of treatment.
The PBAC also noted that the restriction for the recommended group of patients would need to be developed in consultation with the sponsor and specialist clinicians, taking into account an appropriate limitation on the number of treatments per treatment course, and whether further treatment courses should be subsidised following initial treatment.
Recommendation
VERTEPORFIN, powder for I.V. infusion, 15 mg,
Restrictions and details of administration of supply yet to be finalised
| Restriction: | Section 100 Treatment, in conjunction with photo-therapy, of subfoveal choroidal neovascularisation (CNV) secondary to age-related macular degeneration where the CNV is composed predominantly (≥50%) of classic lesions as defined by fluorescein angiography; |
| Pack Size: | 1 |
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC dec ision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.
14. Sponsor’s Comment
Novartis welcomes the decision by the PBAC regarding the PBS listing for patients with predominantly classic lesions secondary to AMD. However, Novartis is disappointed by the PBAC’s rejection of the listings for patients with other lesion types.
The two main elements of concern to Novartis are:
- The refusal to accept any cost-offsets due to blindness avoided in the modelled economic evaluation. This appears to be inconsistent with standard approaches to economic evaluation and is an unrealistic assumption given the clinical reality of visual impairment. Novartis maintains that the data presented in the submission on falls avoided due to blindness avoided were supported by the evidence, and the errors identified during the evaluation process were corrected in the sponsor’s pre-PBAC response.
- The failure to consider a listing for the overall occult lesion patient group once the PBAC had identified concerns with the sub-group analysis for those patients with small lesions. Novartis had requested in its submission that the PBAC consider a listing for the occult lesion patient group, in the event that the PBAC rejected the sub-group analysis.
Novartis remains committed to providing access to therapies for AMD to Australian patients and will work with the PBAC to ensure this occurs.
