5.Robin AL, Novack G, Covert DW, et al. Adherence in glaucoma: Objective measurements of once-daily and adjunctive medication use. Am J Ophthalmol 2007; 144: 533-540.

6.Friedman DS, Okeke CN, Jampel HD, Ying GS, Plyler RJ, Jiang YZ, Quigley HA. Risk factors for poor adherence with eyedrops in electronically monitored glaucoma patients. Ophthalmology 2009; 116: 1097-1105. Epub 2009 Apr 19.

7.Friedman DS, Quigley HA, Gelb L, Tan J, Margolis J, Shah S, Kim EE, Zimmerman T, Hahn SR. Using pharmacy claims data to study adherence to glaucoma medications: Methodology and findings of the Glaucoma Adherence and Persistency Study (GAPS). Invest Ophthalmol Vis Sci 2007; 48: 5052-5057.

8.Stone JL, Robin AL, Novack GD, Covert DW, Cagle GD. An objective evaluation of eyedrop instillation in patients with glaucoma. Arch Ophthalmol 2009; 127: 732-736.

9.Friedman DS, Hahn SR, Gelb L, Tan J, Margolis J, Shah S, Kim EE, Zimmerman T, Quigley HA. Doctor-patient communication, health-related beliefs, and adherence in glaucoma: Results from the Glaucoma Adherence and Persistence Study (GAPS). Ophthalmology 2008; 115: 1320-1327, 1327.e1-3. Epub 2008 Mar 5.

10.Nordstrom BL, Friedman DS, Mozaffari E, Quigley HA, Walker AM. Persistence and Adherence with Topical Glaucoma Therapy Am J Ophthalmol 2005; 140: 598-606.

11.Gurwitz JH, Glynn RJ, Monane M, Everitt DE, Gilden D, Smith N, Avorn J. Treatment for glaucoma: adherence by the elderly. Am J Public Health 1993; 83: 711-716.

12.Schwartz GF, Reardon G, Mozaffari E. Persistency with latanoprost or timolol in primary open-angle glaucoma suspects. Am J Ophthalmol 2004; 137: S13-16.

13.Cramer JA, Mattson RH, Prevey ML, Scheyer RD, Ouellette VL. How often is medication taken as prescribed? A novel assessment technique. JAMA 1989; 261: 3273-3277. [Erratum, JAMA 1989;262:1472.]

14.Kass MA, Meltzer DW, Gordon M, et al. Compliance with topical pilocarpine treatment. Am J Ophthalmol 1986; 101: 515-523.

15.Norell SE. Monitoring compliance with pilocarpine therapy. Am J Ophthalmol 1981; 92: 727-731.

16.DiMatteo MR, Giordani PJ, Lepper HS, Croghan TW. Patient adherence and medical treatment outcomes: a meta-analysis, Med Care 2002; 40: 794-811.

Delivery systems

Jost Jonas, David Greenfield and Ivan Goldberg

Consensus statements

1.Anti-glaucomatous drug delivery systems in the near-term future (less than five years):

Topical medication will remain the foundation for delivery of anti-glauco- matous therapy. Despite limitations that include inconvenience, dependence on patient adherence, and both local and systemic adverse reactions, topical anti-glaucomatous medication is relatively inexpensive and readily available. Topical therapy is generally safe; should adverse reactions occur they are often reversible. Candidate drug delivery systems include: intravitreal injection of soluble or crystalline drugs;1,2 intravitreal implantation or injection of a bioerodible drug reservoir with slow-release modality;3 intravitreal implantation of a non-resolvable slow-release device;4 trans-sclerally fixated drug release devices (coated micro needles);5 transscleral or transconjunc-

tival iontophoresis;6 genetic engineering using transfected intraocular cells to produce a drug of choice; use of siRNA to silence the expression of deleterious genes; subconjunctival or sub-Tenon injection/implantation of a slow release drug; intraocular cell-encoated drug production;7,8 formulation of nano-drugs with enhanced transcorneal passage;9 intraocular lens-derived drug delivery systems;10 lacrimal insert reservoir with controlled release of medical therapy; and contact lens associated drug delivery.11

2.Limitations of intraocular drug injection or delivery systems in glaucoma

•The risk of injection-related infection is approximately 1:2000.12

In contrast to glaucoma, a highly effective topical treatment for macular diseases, such as exudative age-related macular degeneration or diffuse diabetic macular edema, has thus far not been an alternative to intravitreal drug application.

•An important difference between retinal disease and glaucoma is the ‘50% rule’ in glaucoma that implies that approximately 50% of all subjects using anti-glaucomatous medication may not need the therapy or may not have the disease. This is in contrast to the ‘100% rule’ in macular disease that suggests that all patients need treatment. It is easier to justify a potentially severe advese effect under the assumptions of the 100% rule as compared to the 50% rule.

3.Preservatives in topical anti-glaucomatous medicationDevelopment of preservatives with less tissue toxicity is needed to reduce local adverse affects on the ocular surface. Development of preservative-free drug delivery systems suspended in a nano-particle formulation that may be delivered in a spray or suspension and applied once daily is needed.

4.Intraocular lymphatic drainage system

•It remains inconclusive so far whether the recently described rich lymphatic network in the human ciliary body contributes to aqueous and protein drainage from the eye, and whether it can be used as a target for glaucoma treatment.13,14

5.Non-IOP dependent anti-glaucomatous therapy

•Non-IOP dependent therapy for glaucoma, in combination with novel drug delivery systems, remains a high priority unmet medical need in glaucoma management.

References

1.Jonas JB, Hayler JK, Söfker A, Panda-Jonas S. Intravitreal injection of crystalline cortisone as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol 2001; 131: 468-471.

2.Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY. MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355: 1419-1431.

3.Haller JA, Kuppermann BD, Blumenkranz MS, Williams GA, Weinberg DV, Chou C, Whitcup SM. Dexamethasone DDS Phase II Study Group. Randomized controlled trial of an

intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol 2010; 128: 289-296.

4.Jaffe GJ, McCallum RM, Branchaud B, Skalak C, Butuner Z, Ashton P. Long-term follow-up results of a pilot trial of a fluocinolone acetonide implant to treat posterior uveitis. Ophthalmology 2005; 112: 1192-1198.

5.Mello-Filho PA, Guven D, Beeley NR, de Juan E Jr, Erickson SR. Helical intravitreal triamcinolone acetonide implant: a 6-month surgical feasibility study in rabbits. Ophthalmic Surg Lasers Imaging 2009; 40: 160-168.

6.Eljarrat-Binstock E, Raiskup F, Frucht-Pery J, Domb AJ. Transcorneal and transscleral iontophoresis of dexamethasone phosphate using drug loaded hydrogel. J Control Release 2005; 106: 386-390.

7.Tao W, Wen R, Goddard MB Sherman SD, O’Rourke PJ, Stabila PF, Bell WJ, Dean BJ, Kauper KA, Budz VA, Tsiaras WG, Acland GM, Pearce Kelling S, Laties AM & Aguirre GD. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci 2002; 43: 3292-3298.

8.Zhang R, Ma K, Xu L, Wallrapp C, Jonas JB. Intraocular cell-based production of glucagonlike peptide-1 in the anterior chamber. Acta Ophthalmol 2009; Nov 23. [Epub ahead of print]

9.Ottiger M, Thiel MA, Feige U, Lichtlen P, Urech DM. Efficient intraocular penetration of topical anti-TNF-alpha single-chain antibody (ESBA105) to anterior and posterior segment without penetration enhancer. Invest Ophthalmol Vis Sci 2009; 50: 779-786.

10.Molokhia SA, Sant H, Simonis J, Bishop CJ, Burr RM, Gale BK, Ambati BK. The capsule drug device: novel approach for drug delivery to the eye. Vision Res 2010; 50: 680-685.

11.Gulsen D, Chauhan A. Ophthalmic drug delivery through contact lenses. Invest Ophthalmol Vis Sci 2004; 45: 2342-2347.

12.Pilli S, Kotsolis A, Spaide RF, Slakter J, Freund KB, Sorenson J, Klancnik J, Cooney M. Endophthalmitis associated with intravitreal anti-vascular endothelial growth factor therapy injections in an office setting. Am J Ophthalmol 2008; 145: 879-882.

13.Yücel YH, Johnston MG, Ly T, Patel M, Drake B, Gumus E¸ Fraenkl S, Moore S, Tobbia D, Armstrong D, Horvath E, Gupta N. Identification of lymphatics in the ciliary body of the human eye: a novel ‘uveolymphatic’ outflow pathway. Exp Eye Res 2009; 89: 810-819.

14.Lindsey JD, Hofer A, Wright KN, Weinreb RN. Partioning of the aqueous outflow in rat eyes. Invest Ophthalmol Vis Sci 2009; 50: 5754-5758.

sumes that that cost and quality of life are driven by best eye or worst eye. The hypothesis that these are driven by best or worse or binocular vision has not been tested and lack of this data does impair our ability to assess cost effectiveness.

The disease and its costs / the treatment and its costs

There are wide variations in disease costs reported from developed countries, with similar variations seen in direct patient costs.1-4 Wide variations are also seen by disease stage. Most studies estimate direct costs since indirect costs are relevant only to patients or when the societal perspective is mandated; most payors or providers will not be concerned with indirect costs. Unfortunately there do not appear to be any available data from developing countries, but patients are much more likely to be directly paying these costs in these locations. Quick et al. reported that 50-90% of population of developing countries have to pay from their pocket.5 Indirect costs are likely to be a significant factor in developing countries, but this is unknown.

Most of the evidence seems to indicate that there are very important differences in the cost of glaucoma and its treatment between nations, because the differences are largely a function of the level of economic development in the nations (the one exception being between the U.S. and other developed nations).2 Global costs, as in multinational estimates of costs, have little meaning because of the underlying heterogeneity between nations (see above).

For countries with lower levels of economic development, it would also depend upon whether generic versions of medications are available in the country.

There are no estimates regarding the cost of secondary glaucoma; costs may differ from the available information on POAG.

References

1.Kobelt G. Health economics, economic evaluation, and glaucoma. J Glaucoma 2002; 11: 531-539.

2.Lee PP, Kelly SP, Mills RP, Traverso CE, Walt JG, Doyle JJ, Katz LM, Siegartel LR; Costs of Glaucoma Study Group. Glaucoma in the United States and Europe: predicting costs and surgical rates based upon stage of disease. J Glaucoma 2007; 16: 471-478.

3.Lee PP, Walt JG, Doyle JJ, Kotak SV, Evans SJ, Budenz DL, Chen PP, Coleman AL, Feldman RM, Jampel HD, Katz LJ, Mills RP, Myers JS, Noecker RJ, Piltz-Seymour JR, Ritch RR, Schacknow PN, Serle JB, Trick GL. A multicenter, retrospective pilot study of resource use and costs associated with severity of disease in glaucoma. Arch Ophthalmol 2006; 124: 12-19.

4.Berenson K, Kymes S, Walt JG, Siegartel LR. The relationship of mean deviation scores and resource utilization among patients with glaucoma: a retrospective United States and European chart review analysis. J Glaucoma 2009; 18: 390-394.

5.Quick JD, Hogerzeil HV, Velasquez G, Rago L. Twenty-five years of essential medicines. Bull World Health Organ 2002; 80: 913-914.

Cost of medical treatment and comparison with other therapies

for glaucoma (and how medical treatment fits in with the other modalities)

When viewed on a ‘one time basis’ the cost of surgery is of course much larger than the cost of medication.1 The cost of managing surgical complications should be incorporated into the cost of the surgery. However, while it is likely that the cost of managing surgical complications from glaucoma surgery is likely to be significant, the probability of such events seems to be rather low. Properly, the analysis of something like surgery where there is a (relatively) large upfront payment whose benefit is enjoyed over time would be to amortize it over the period during which the benefits are enjoyed. Similarly, the cost of side-effects of surgery or medication should be recognized by multiplying the probability of the side-effect and the cost of that side-effect. This is easily addressed using the decision analytic methods we typically use for conducting cost-effectiveness studies.

However, over time, the cost curves merge (unpublished, Kymes et al.) with the long-term cost of surgery being lower than medication. This will likely change, however, as prostaglandin analogues become generic, with medication gaining an advantage in both the short and long term.

Reference

1.Calissendorff BM. Costs of medical and surgical treatment of glaucoma. Acta Ophthalmol. Scand 2001: 79: 286-288.

Generics and how these will affect cost of glaucoma management throughout the world (including formulation of generics vs. brand drugs and is there any real difference between/ or do we know?)

The introduction of generic prostaglandins will likely reduce the cost of medical treatment of glaucoma from about $1000/year to a few hundred in the U.S. (a bit above the cost of generic Timolol). It will probably reduce the degree of differences we currently see in the cost of prostaglandins between countries.1,2 There is little published evidence regarding the comparative efficacy of generic glaucoma medication versus the original molecule. In a randomized cross over trial in India that compared Xalatan versus one Indian generic latanoprost, Xalatan had better IOP control and lesser side effects.3 On switching there was an increase in IOP by 0.89 mm when switched from Xalatan to the generic and a decrease by 1.1 mm on switching from the generic to Xalatan. From unpublished data from India (courtesy R. Parikh) that studied the effect of switching to a generic medication after the patient was controlled on Xalatan, mean IOP increased by 1.8 mmHg at the end of three months, when subjects were on the

generic.

The issue of safety and efficacy of generics is hampered by the non availability of information regarding its cost effectiveness in terms of preventing disease progression. There have been a plethora of studies that have been published on the cost of treatment and the burden of the disease. But the cost of treatment (and burden of disease) only has meaning in the context of what it is being compared to. In assessing if generics are less effective or less safe than branded drugs, we must be consider it in the context of a comparison. What is the value of a mmHg? None of us know because that is a cost-effectiveness question that considers the rate of progression, and we do not have good information on progression currently.

Whether differences in efficacy would influence overall disease costs is a cost-effectiveness question that considers the rate of progression, and we do not have good long term information on progression currently. The EMGT gives us, however, some guidance to this. Basically, if the new medication is no better than a placebo (not likely) we would expect to see a reduction in progression similar to that seen in the EMGT placebo group.4 To the extent that it was simply less effective, we would see a 10% risk of progression for each millimeter of effectiveness lost. Unpublished data (courtesy Steven Kymes) show that given the slowly progressing nature of the disease, it takes considerable loss of efficacy to make an impact on costs alone on a population basis. This might not be true for an individual who has fast progressing visual field loss. The difference in cost is not near as important as the rate of progression or the impact on quality of life in determining the cost-effectiveness of treatment.5 Calculation of utility values would be influenced by cultural differences. Perhaps the most dramatic example came from Gupta et al. which showed that among people with glaucoma in India, they were willing to accept a greater risk of death to cure their illness, than they would accept of becoming blind. Meaning that among this sample, being blind was worse than being dead. Another important issue in determining how cost varies by country is who is paying the bill. In most of the industrialized world, there is a third party payor. While in the developing world, the payor is often the patient him/herself. This substantially changes the way in which costs are measured.

In India, an estimate would be that more than 85% people pay from their pocket and in that scenario, patient’s paying capacity becomes a very important issue in determining or changing therapy. Basically for 35% of population it would be the choice between the cost of the basic necessities of life versus a prostaglandin/prostaglandin analogue to lower eye pressure.

References

1.Rylander NR, Vold SD. Cost analysis of glaucoma medications. Am J Ophthalmol 2008; 145: 106-113.

2.Gao Y, Wu L, Li A. Daily cost of glaucoma medications in China. J Glaucoma 2007; 16: 594-597.

3.Narayanaswamy A, Neog A, Baskaran M, George R, Lingam V, Desai C, Rajadhyaksha V. A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan in comparison with generic Latanoprost (Latoprost) in subjects with primary open angle glaucoma or ocular hypertension. Indian J Ophthalmol 2007; 55: 127-131.

4.Leske MC, Heijl A, Hussein M, Bengtsson B, Hyman L, Komaroff E; Early Manifest Glaucoma Trial Group. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol 2003; 121: 48-56.

5.Kymes SM, Kass MA, Anderson DR, et al. Management of ocular hypertension: a costeffectiveness approach from the Ocular Hypertension Treatment Study. Am J Ophthalmol 2006; 141: 997-1008.

6.Gupta V, Srinivasan G, Mei SS, Gazzard G, Sihota R, Kapoor KS. Utility values among glaucoma patients: an impact on the quality of life. Br J Ophthalmol 2005; 89: 1241-1244.

Glaucoma medical therapy – what are the other costs to consider?

There are a number of other costs potentially associated with the use of glaucoma medications. These include the cost of managing side effects, potentially increased frequency of office visits as compared to surgical therapy and other costs such as caregiver, travel costs and time.1

On a population basis, the cost of managing side-effects of medication are negligible. The cost involves additional office visits and changes in medication choice. This does not add substantially to the total cost of treatment. From the patient’s perspective, Jampel reported the willingness of patients to pay for a side-effect free medication.2 Except for sexual or cardiac side-effects, the amount patients were willing to pay was relatively minor.

Even if patients on medical therapy have an increased frequency of office visits this is not likely to significantly affect the difference in the costs of treatment unless these differences are very large (i.e., two to three visits/year). Again, as the prostaglandins move to generic, more visits will be able to be absorbed. These cost differences may be significant in areas with poor access to eye care where patients have to travel long distances to access eye care. Whether one considers these indirect costs would depend on the perspective of the decision maker. It will also vary by nation/culture. For instance, in the U.S. and most developed nations, there is virtually no incremental cost associated with the travel and time to obtain medication because the medication is either delivered to their home directly or is obtained at the same/time and vendor where they may obtain other items such as groceries. It should also be noted that when we talk about the cost of caregivers, the importance is only relevant to the extent that it is different from the cost of surgery. National differences do exist as Sleath et al. report, in a survey of glaucoma patients from South India, 38% had to travel for half an hour or longer to purchase their medication and 9% traveled more than two hours to purchase their medications.3 The majority of those who participated in this study (60%) were urban residents; the access to pharmacies is likely to be much poorer in rural India.

References

1.Kobelt G. Health economics, economic evaluation, and glaucoma. J Glaucoma 2002; 11: 531-539.

2.Jampel HD, Schwartz GF, Robin AL, Abrams DA, Johnson E, Miller RB. Patient preferences for eye drop characteristics: a willingness-to-pay analysis.Arch Ophthalmol 2003; 121: 540-546.

3.Sleath BL, Krishnadas R, Cho M, Robin AL, Mehta R, Covert D, Tudor G. Patient Reported barriers to glaucoma medication access, use, and adherence in Southern India. Indian J Ophthalmol 2008; 57: 63-68.

Combination dugs – is the cost worthwhile?

There do not appear to be significant differences in the cost of combination drugs as opposed to their individual components.1 Since use of combination therapy is likely to improve compliance, its effect on cost was considered. However, there is no published evidence that show empirically that improved compliance results in improved outcomes, and more importantly, whether this relationship is linear, curvilinear etc. Therefore, there is currently no evidence that could help evaluate the cost-benefit of medication compliance.

Reference

1.Hommer A, Thygesen J, Ferreras A, Wickstrom J, Friis MM, Buchholz P, Walt JG. A European perspective on costs and cost effectiveness of ophthalmic combinations in the treatment of open-angle glaucoma. Eur J Ophthalmol 2008; 18: 778-786.

Failed medical therapy

With regard to failed medical therapy it is apparent that the threshold for surgery or ALT varies from country to country. Kobelt et al. report that among those on monotherapy followed up over a two-year period across nine countries, the rates for ALT/surgery showed wide variations from 11% for Germany to 52% for UK.1 The study was carried out in the pre-prostaglandin era and surgical rates are likely to be lower now across the developed world. Lee et al. report a surgical/ALT rate of 35% over a five-year period in the US and 28% in Europe over similar time frame.2 Patients in this study were nearly equally distributed over disease severity groups. In developing countries, a good proportion of the glaucoma population would be advised to have surgery for socioeconomic reasons. Uncontrolled IOP on a single beta blocker (typically costing one USD) may be an indication for surgical intervention. It is apparent that the definition of failed medical therapy differs from region to region.

One of the confounders is assessing costs in combined cataract and glaucoma surgery since many of these would not qualify as failed medical therapy.

The perspective of the decision being made should be taken into account. If the primary purpose of the surgery is to improve vision, the incremental cost/ charge of glaucoma surgery over that for cataract surgery should be assigned to the glaucoma surgery, and vice-versa. In modeling, if the patient is taken off medical therapy that would be treated as a benefit. If the combined procedure is done in response to a failure of medical therapy, the incremental cost/charge of cataract surgery over the glaucoma surgery shall be charged to the cataract surgery. However most studies have not reported costs from this perspective.

References

1.Kobelt G. Health economics, economic evaluation, and glaucoma. J Glaucoma 2002; 11: 531-539.

2.Lee PP, Kelly SP, Mills RP, Traverso CE, Walt JG, Doyle JJ, Katz LM, Siegartel LR; Costs of Glaucoma Study Group. Glaucoma in the United States and Europe: predicting costs and surgical rates based upon stage of disease. J Glaucoma 2007; 16: 471-478.

Health economics of medical therapy in developing countries

(including pricing of medications in the U.S. and the high cost of developing new medications)

There are a few reports on cost of glaucoma from developing countries. In the absence of reliable estimates it was felt that medical therapy in developing countries is likely to be heavily influenced by drug pricing. Most participants felt that cost was an important consideration in deciding on surgical intervention. Therapeutic options could be limited to the lowest priced medications.

For the developed country markets, the pharmaceutical industry has been able to survive/grow due to ‘cost and pricing shifting’ within the international market (i.e., higher prices and profit margins obtained from US and other developed country markets helping to subsidize new business opportunities but lower margins in developing countries). This strategy may not be viable in the long term (given the current health care debate in the U.S.). It is also our opinion that ‘branded medical therapy’ may not be a viable option for some/ many glaucoma patients in developing countries if ‘discounted’ pricing is not provided by these companies (especially if medical therapy consists of two or more different drops). The pricing of medication in the U.S. does not appear to be directly correlated to the development costs (but targeted to whatever price the market will bear). Since the market in the U.S. is demanding lower overall costs, then prices for medications will have to decrease in the U.S., thereby putting tremendous pressure on the companies. One solution for industry would be to reduce their development costs (thereby increasing the process of farming out clinical trials to the developing countries). Anticipated returns from the market may influence whether new drugs are actually marketed.