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Economic evaluation of photodynamic therapy with verteporfin
Ophthalmology Volume 110, Number 4, April 2003 No recurrences have been seen after 1-2 years. This has been reported by other investigators with similar results.2 No corneal melts or corneal epithelial sequelae have been reported from use of the medication. Dr. Yamamoto and his colleagues are to be commended for their work. We recommend topical interferon be considered in the armamentarium of treatment for CIN.
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BARRY A. SCHECHTER, MD ROBERT S. NAGLER, MD Pompano Beach, Florida References 1. Schechter BA, Schrier A, Nagler RS, et al. Regression of presumed primary conjunctival and corneal intraepithelial neoplasia with topical interferon alfa-2b. Cornea 2002;21:6 –11. 2. Karp CL, Moore JK, Rosa RH Jr. Treatment of conjunctival and corneal intraepithelial neoplasia with topical interferon␣2b. Ophthalmology 2001;108:1093–98. ●
Author reply Dear Editor: We thank Drs. Schechter and Nagler for their advice. We are familiar with the reports about the successful treatment of conjunctival intraepithelial neoplasia (CIN) with interferon. Because we encountered the reported case in 1997, before the publication of reports on interferon, we followed the treatment of CIN recommended at the time, mitomycin-C and 5-Fluorouracil therapy. If we encounter a similar case in the future, we will certainly consider the use of interferon. NORIAKI YAMAMOTO, MD Aichi-ken, Japan
Economic evaluation of photodynamic therapy with verteporfin Dear Editor: The analysis of Sharma et al, reported in the November 2001 issue,1 is the first published economic evaluation of photodynamic therapy (PDT) with verteporfin (Visudyne), a new technology offering effective treatment and prevention of vision loss due to choroidal neovascularisation secondary to age-related macular degeneration (AMD).2 There is only one other proven treatment option, laser photocoagulation. However, this is suitable for only a minority of subfoveal lesions. Furthermore, laser photocoagulation is associated with a risk of immediate and permanent vision loss in the hope of a delayed rate of vision loss in later months. Although Sharma et al present a well-conducted analysis, this analysis should not be regarded as automatically transferable to other jurisdictions, either in Australia, the US or other countries outside Canada. There are several reasons for this, as follows: ●
626
The perspective adopted by the authors is very narrow. The decision to use a third-party insurer perspective excludes resource use that will be important to decision-makers who are interested in resource implications for governments and in out-of-pocket expenses to patients and their families. Such resource use sav-
●
●
ings include reduced need for nursing homes or home care for the visually impaired, and reduced treatment costs associated with falls (which increase in frequency and severity as visual acuity decreases). The cost savings arising from reduced resource use in these areas is likely to be substantial. The authors did not have access to the full range of data from the Treatment of Age-Related Macular degeneration with photodynamic therapy investigation (TAP) study and so were restricted in analysing the efficacy of PDT with verteporfin. There are more patient-relevant ways to present the difference in efficacy than the three-line decline in vision used in their paper. One such method is to investigate the effect of PDT with verteporfin in preventing severe vision loss or legal blindness. These outcomes are likely to be more patient-relevant, and they are also likely to have implications for the utility values obtained. The choice of a 3-line loss of vision represents a relatively modest change in vision when viewed in terms of the natural progression of AMD. A subgroup analysis of the Laser Photocoagulation Trial identified the population that is most similar to the trial population in the TAP study and found that 53 percent of the patients in the placebo arm had a vision loss of at least 30 letters (6 lines) after 24 months.3 This is at least double the loss in visual acuity used in the utility analysis by Sharma et al. The valuation method employed by the authors meant that the utility values were derived for the minimum gain achieved by patients who achieved a greater than three-line improvement, rather than the average gain. Sharma et al report the 2-year results of the economic evaluation as the baseline results. This could be misleading, as results of the 11-year model were reported as being robust against changes to key variables. In such a case it would be normal practice to report the 11-year results also as baseline results, considering that these better reflect the trade-off between increased resource use and improvements in quality of life (among other health outcomes) that flow from the treatment of AMD with PDT plus verteporfin. The 11-year results show PDT with verteporfin to be far more cost-effective, especially in patients who present with a visual acuity of 20/40 in the second and betterseeing eye (base case 1).
The model is therefore limited by the lack of data and the approach taken regarding the perspective and duration of the mode. This restricts its applicability. An analysis that takes into account likely resource savings and a more patient-relevant efficacy endpoint would be likely to show that PDT with verteporfin is significantly more cost-effective than is reported by the authors. MICHAEL J. LEES, BAGRECON(HONS) MCOM GRAILY J. R. ALDRIDGE, BSC(HONS) PETER J. DAVEY, BA MA(ECON) MENDE GORGIEVSKI, BCOM(HONS) Sydney, Australia
Letters to the Editor References 1. Sharma S, Brown GC, Brown MM, et al. The cost-effectiveness of photodynamic therapy for fellow eyes with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology 2001;108:2051–9. 2. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: twoyear results of two randomized clinical trials—TAP report 2. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Arch Ophthalmol 2001; 119:198 –207. 3. Visual outcome after laser photocoagulation for subfoveal choroidal neovascularization secondary to age-related macular degeneration. The influence of initial lesion size and initial visual acuity. Macular Photocoagulation Study Group. Arch Ophthalmol 1994;112:480 – 8.
Author reply Dear Editor: Dr. Lees et al raise some points that are not only relevant to our particular cost-utility models1 but also to the interpretation of health technology assessment in general. The first issue that is raised by the authors is the belief that the results of our analyses may not be generalizable to other jurisdictions, given the perspective adopted to create our models. In my opinion, from a clinical epidemiological perspective, the internal validity of a study should never be sacrificed at the expense of its external validity or potential generalizability. This rings true not only for traditional forms of clinical research including case-controlled, cohort studies, and clinical trials, but also for ones based on humanistic outcomes such as health-related quality of life measurement through instruments or utility valuation. When critically appraising a cost-utility analysis, it is imperative that one understands the issue of perspective,2 as the results of a cost-utility analysis may be more relevant to some decision makers and less so to others. Our model answers the specific question that it was designed to answer from the managed care perspective. While one may or may not have philosophical differences with the concept of managed care, these organizations now represent a dominant force in the delivery of healthcare in the US. Rightfully or wrongfully, these organizations exist to create shareholder value by increasing the efficiency and effectiveness of healthcare. Some may argue that they do so through quality reductions in healthcare. However, if managed care providers do so at the cost of patient quality-of-life, they will be penalized by an efficient capital market. While I agree that the results of our models may not be directly applicable to other jurisdictions, they are certainly relevant to managed care organizations in the US. To answer the question of whether verteporfin therapy is cost-effective from the societal standpoint, another analysis needs to be conducted. We are currently obtaining primary costing information in an attempt to make cogent evidencebased policy recommendations regarding verteporfin therapy from the societal perspective. To do so members of our research team are collecting pertinent costs directly from all
relevant stakeholders, including payers, governments, patients and their caregivers. An economic evaluation, be it a cost-effective, a cost-minimization, or a cost-utility analysis, is a form of secondary analysis when created in an expected-value framework. As with any secondary analysis, it is wholly dependent on the accuracy of the inputting data. Our model was created using data available through the peer-reviewed literature, in conjunction with our own primary patientderived utilities. Lees et al are quite correct in their assessment that lack of access to the primary data can generally cause difficulty in the creation of an economic model. However, it is important to note that research designed to evaluate the efficacy of pharmaceutical agents is funded by their manufacturers, themselves, and that data derived through these trials are proprietary. It is also important to note that Friedberg and associates have also recently noted that pharmaceutical company-sponsored economic studies were significantly less likely than nonprofit-sponsored studies to report unfavorable qualitative conclusions derived from the economic assessment of oncologic drugs.3 I would disagree with Lees et al’s statement that “there are more patient-relevant” ways to evaluate the outcomes than the ones used in our models. Although there are many methods used to obtain utilities, including expert panel, surrogate responders, and healthy volunteers,4 our utilities were directly obtained from patients who suffered from the disutility of AMD, themselves. In fact, given that our recent research has demonstrated that ophthalmologists dramatically underestimate the disutility associated with vision loss5 would suggest that there is no way to get more “patient-relevant” quality-of-life data than from talking directly to patients who suffer from this disabling condition themselves. Furthermore, I cannot agree with Lees et al’s assessment that, given our choice of methodology, our models represent minimalist gains in quality-of-life. Firstly, our models evaluated the expected change in utility on the primary outcome of the TAP study, a 3-line visual loss. This outcome was chosen by investigators of the TAP study themselves, and is one that is clinically relevant. More importantly, our models were all based on the assumption that the lesion being treated was in the worse-seeing eye (we assumed that the other eye had a disciform scar). This perspective essentially assumed the best possible case for the treatment. If a model were also populated with individuals who had a lesion in the better-seeing eye, the incremental improvement in qualityof-life would fall significantly, and its cost-utility ratio would rise. Finally, our base-case analysis was performed over a 2-year time frame because we wanted to create a model that was based on the results of level 1 scientific evidence (randomized clinical trials with a low type I error).6 While it is true that the therapeutic effects of photodynamic therapy may persist over a much longer time period, we are simply unsure of the efficacy of this treatment over longer periods of time. In addition, increased numbers of treatments may be needed in the later years in models of longer duration, and, therefore, any incremental quality improve-
627
●
BARRY A. SCHECHTER, MD ROBERT S. NAGLER, MD Pompano Beach, Florida References 1. Schechter BA, Schrier A, Nagler RS, et al. Regression of presumed primary conjunctival and corneal intraepithelial neoplasia with topical interferon alfa-2b. Cornea 2002;21:6 –11. 2. Karp CL, Moore JK, Rosa RH Jr. Treatment of conjunctival and corneal intraepithelial neoplasia with topical interferon␣2b. Ophthalmology 2001;108:1093–98. ●
Author reply Dear Editor: We thank Drs. Schechter and Nagler for their advice. We are familiar with the reports about the successful treatment of conjunctival intraepithelial neoplasia (CIN) with interferon. Because we encountered the reported case in 1997, before the publication of reports on interferon, we followed the treatment of CIN recommended at the time, mitomycin-C and 5-Fluorouracil therapy. If we encounter a similar case in the future, we will certainly consider the use of interferon. NORIAKI YAMAMOTO, MD Aichi-ken, Japan
Economic evaluation of photodynamic therapy with verteporfin Dear Editor: The analysis of Sharma et al, reported in the November 2001 issue,1 is the first published economic evaluation of photodynamic therapy (PDT) with verteporfin (Visudyne), a new technology offering effective treatment and prevention of vision loss due to choroidal neovascularisation secondary to age-related macular degeneration (AMD).2 There is only one other proven treatment option, laser photocoagulation. However, this is suitable for only a minority of subfoveal lesions. Furthermore, laser photocoagulation is associated with a risk of immediate and permanent vision loss in the hope of a delayed rate of vision loss in later months. Although Sharma et al present a well-conducted analysis, this analysis should not be regarded as automatically transferable to other jurisdictions, either in Australia, the US or other countries outside Canada. There are several reasons for this, as follows: ●
626
The perspective adopted by the authors is very narrow. The decision to use a third-party insurer perspective excludes resource use that will be important to decision-makers who are interested in resource implications for governments and in out-of-pocket expenses to patients and their families. Such resource use sav-
●
●
ings include reduced need for nursing homes or home care for the visually impaired, and reduced treatment costs associated with falls (which increase in frequency and severity as visual acuity decreases). The cost savings arising from reduced resource use in these areas is likely to be substantial. The authors did not have access to the full range of data from the Treatment of Age-Related Macular degeneration with photodynamic therapy investigation (TAP) study and so were restricted in analysing the efficacy of PDT with verteporfin. There are more patient-relevant ways to present the difference in efficacy than the three-line decline in vision used in their paper. One such method is to investigate the effect of PDT with verteporfin in preventing severe vision loss or legal blindness. These outcomes are likely to be more patient-relevant, and they are also likely to have implications for the utility values obtained. The choice of a 3-line loss of vision represents a relatively modest change in vision when viewed in terms of the natural progression of AMD. A subgroup analysis of the Laser Photocoagulation Trial identified the population that is most similar to the trial population in the TAP study and found that 53 percent of the patients in the placebo arm had a vision loss of at least 30 letters (6 lines) after 24 months.3 This is at least double the loss in visual acuity used in the utility analysis by Sharma et al. The valuation method employed by the authors meant that the utility values were derived for the minimum gain achieved by patients who achieved a greater than three-line improvement, rather than the average gain. Sharma et al report the 2-year results of the economic evaluation as the baseline results. This could be misleading, as results of the 11-year model were reported as being robust against changes to key variables. In such a case it would be normal practice to report the 11-year results also as baseline results, considering that these better reflect the trade-off between increased resource use and improvements in quality of life (among other health outcomes) that flow from the treatment of AMD with PDT plus verteporfin. The 11-year results show PDT with verteporfin to be far more cost-effective, especially in patients who present with a visual acuity of 20/40 in the second and betterseeing eye (base case 1).
The model is therefore limited by the lack of data and the approach taken regarding the perspective and duration of the mode. This restricts its applicability. An analysis that takes into account likely resource savings and a more patient-relevant efficacy endpoint would be likely to show that PDT with verteporfin is significantly more cost-effective than is reported by the authors. MICHAEL J. LEES, BAGRECON(HONS) MCOM GRAILY J. R. ALDRIDGE, BSC(HONS) PETER J. DAVEY, BA MA(ECON) MENDE GORGIEVSKI, BCOM(HONS) Sydney, Australia
Letters to the Editor References 1. Sharma S, Brown GC, Brown MM, et al. The cost-effectiveness of photodynamic therapy for fellow eyes with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology 2001;108:2051–9. 2. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: twoyear results of two randomized clinical trials—TAP report 2. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Arch Ophthalmol 2001; 119:198 –207. 3. Visual outcome after laser photocoagulation for subfoveal choroidal neovascularization secondary to age-related macular degeneration. The influence of initial lesion size and initial visual acuity. Macular Photocoagulation Study Group. Arch Ophthalmol 1994;112:480 – 8.
Author reply Dear Editor: Dr. Lees et al raise some points that are not only relevant to our particular cost-utility models1 but also to the interpretation of health technology assessment in general. The first issue that is raised by the authors is the belief that the results of our analyses may not be generalizable to other jurisdictions, given the perspective adopted to create our models. In my opinion, from a clinical epidemiological perspective, the internal validity of a study should never be sacrificed at the expense of its external validity or potential generalizability. This rings true not only for traditional forms of clinical research including case-controlled, cohort studies, and clinical trials, but also for ones based on humanistic outcomes such as health-related quality of life measurement through instruments or utility valuation. When critically appraising a cost-utility analysis, it is imperative that one understands the issue of perspective,2 as the results of a cost-utility analysis may be more relevant to some decision makers and less so to others. Our model answers the specific question that it was designed to answer from the managed care perspective. While one may or may not have philosophical differences with the concept of managed care, these organizations now represent a dominant force in the delivery of healthcare in the US. Rightfully or wrongfully, these organizations exist to create shareholder value by increasing the efficiency and effectiveness of healthcare. Some may argue that they do so through quality reductions in healthcare. However, if managed care providers do so at the cost of patient quality-of-life, they will be penalized by an efficient capital market. While I agree that the results of our models may not be directly applicable to other jurisdictions, they are certainly relevant to managed care organizations in the US. To answer the question of whether verteporfin therapy is cost-effective from the societal standpoint, another analysis needs to be conducted. We are currently obtaining primary costing information in an attempt to make cogent evidencebased policy recommendations regarding verteporfin therapy from the societal perspective. To do so members of our research team are collecting pertinent costs directly from all
relevant stakeholders, including payers, governments, patients and their caregivers. An economic evaluation, be it a cost-effective, a cost-minimization, or a cost-utility analysis, is a form of secondary analysis when created in an expected-value framework. As with any secondary analysis, it is wholly dependent on the accuracy of the inputting data. Our model was created using data available through the peer-reviewed literature, in conjunction with our own primary patientderived utilities. Lees et al are quite correct in their assessment that lack of access to the primary data can generally cause difficulty in the creation of an economic model. However, it is important to note that research designed to evaluate the efficacy of pharmaceutical agents is funded by their manufacturers, themselves, and that data derived through these trials are proprietary. It is also important to note that Friedberg and associates have also recently noted that pharmaceutical company-sponsored economic studies were significantly less likely than nonprofit-sponsored studies to report unfavorable qualitative conclusions derived from the economic assessment of oncologic drugs.3 I would disagree with Lees et al’s statement that “there are more patient-relevant” ways to evaluate the outcomes than the ones used in our models. Although there are many methods used to obtain utilities, including expert panel, surrogate responders, and healthy volunteers,4 our utilities were directly obtained from patients who suffered from the disutility of AMD, themselves. In fact, given that our recent research has demonstrated that ophthalmologists dramatically underestimate the disutility associated with vision loss5 would suggest that there is no way to get more “patient-relevant” quality-of-life data than from talking directly to patients who suffer from this disabling condition themselves. Furthermore, I cannot agree with Lees et al’s assessment that, given our choice of methodology, our models represent minimalist gains in quality-of-life. Firstly, our models evaluated the expected change in utility on the primary outcome of the TAP study, a 3-line visual loss. This outcome was chosen by investigators of the TAP study themselves, and is one that is clinically relevant. More importantly, our models were all based on the assumption that the lesion being treated was in the worse-seeing eye (we assumed that the other eye had a disciform scar). This perspective essentially assumed the best possible case for the treatment. If a model were also populated with individuals who had a lesion in the better-seeing eye, the incremental improvement in qualityof-life would fall significantly, and its cost-utility ratio would rise. Finally, our base-case analysis was performed over a 2-year time frame because we wanted to create a model that was based on the results of level 1 scientific evidence (randomized clinical trials with a low type I error).6 While it is true that the therapeutic effects of photodynamic therapy may persist over a much longer time period, we are simply unsure of the efficacy of this treatment over longer periods of time. In addition, increased numbers of treatments may be needed in the later years in models of longer duration, and, therefore, any incremental quality improve-
627