AMD treatment too high a burden in real-life practice in most Asia-Pacific countries

Anti-VEGF therapy for age-related macular degeneration has been a major breakthrough in the battle against vision loss. The pivotal MARINA and ANCHOR trials showed a mean increase of 7 to 11 visual acuity letters at 1 year, substantially maintained at 2 years, with monthly injections of ranibizumab. In clinical trial settings, optical coherence tomography-guided variable-dosing regimens achieved comparable results. In the VIEW trials, after three monthly loading doses, bimonthly administration of aflibercept produced similar improvement to monthly ranibizumab.

Observational studies, however, show that the real-life scenario of everyday clinical practice rarely mirrors the positive results of the major clinical trials.

There are many reasons for this, according to Tien Y. Wong, MD, MPH, PhD, OSN APAO Edition Assistant Editor and professor and director of the Singapore National Eye Centre, National University of Singapore.

Image: Wong TY

“First of all, clinical studies rely on a highly selected population of patients, very involved and motivated to come back for the follow-up by a strong supporting team. In real life, a lot of patients are older and have multiple medical issues and socioeconomic problems. The majority of them cannot come back for the regular monthly or even bimonthly follow-up,” he said.

Secondly, in clinical trials, drugs are provided free of charge. The high cost of anti-VEGF agents in real life is unaffordable for most patients and too high a burden for many developing nations.

“The contrast between Australia and other countries in the Asia-Pacific region that do not have a national payment scheme is stark. If there is a system in the society that allows you to follow the intense clinical trial protocols, like in Australia, VA improves and is maintained. Where there is no support from the system, the effectiveness is lost,” Wong said.

Lack of health coverage

In most countries, including Singapore, China, the Philippines and India, the treatment for wet AMD and polypoidal choroidal vasculopathy, a common variant in the Asian population, is not covered by government insurance. Taiwan covers up to three injections per year, South Korea up to 10 injections of Lucentis (ranibizumab, Genentech/Novartis) per lifetime and Thailand up to 12 injections of Avastin (bevacizumab, Genentech/Roche).

A retrospective analysis of treatment patterns at the Singapore National Eye Centre, which manages more than 50% of outpatient ophthalmology visits and surgeries in the country, found that a mean of three to four injections are administered per year.

“This is about half of the injections needed for best results because people have to pay for their own follow-up and treatment. Furthermore, most patients are given bevacizumab, which is a cheaper drug. And this happens in Singapore, which can be considered a high-income country, with good health care standards,” Wong said.

“Although the Chinese Medical Association has issued clinical guidelines for AMD, only a small part of patients in China can receive proper treatment due to economic reasons,” Xiaoxin Li, MD, professor at Beijing University and president of the Chinese Ophthalmological Society, said.

In China, 14.9% of the population is older than 60 years, so the incidence of wet AMD is high, she said. The cost of anti-VEGF drugs varies from 9,800 CNY (US$1,500) for ranibizumab to 6,800 CNY (US$1,150) for conbercept. Photodynamic therapy, commonly used in Asia as an adjunctive therapy, is also paid out of pocket. All of these factors limit the treatment of AMD in China.

In Hong Kong, the government provides some safety net for the poorest patients through a special agreement with Novartis: A fixed quota of 250 patients per year can be treated free of charge in public hospitals for up to 24 months.

“For the rest of our population, anti-VEGF treatment is only available as a self-financed drug, at the cost of US$600 to US$2,000, depending on the agent used. Competition with Eylea (aflibercept, Regeneron/Bayer) has made the price of Lucentis go down, while Eylea has gone up to match Lucentis. Avastin is not much cheaper. It cannot be divided in single units because compound pharmacy is illegal, so patients must buy a whole vial or share it with other patients in the same session and throw away what is left,” Timothy Lai, MD, honorary clinical associate professor at The Chinese University of Hong Kong, said.

If compliance with recommendations is relatively good, it is thanks to the strong family values of the Chinese culture, he said. Adult children help their elderly parents with treatment by taking them to appointments and giving them financial help, if needed.

According to the 2013 report of the Asia-Pacific Wet Age-Related Macular Degeneration Coalition Expert Summit, family support of the elderly traditionally has been strong in the entire Asia-Pacific region, but the situation is changing and an increasing number of elderly patients can no longer rely on their family. Where this support still exists, the financial and other burdens associated with AMD treatments are often too great for the family to take on.

Late access to treatment

The same report identifies late access to diagnostics and treatment as a major problem in the region. “Too many AMD patients in the Asia-Pacific region do not have their vision screened until they have already lost vision in one eye,” according to the report.

In India, a coalition of medical societies has launched an awareness campaign for early detection of AMD based on the home use of the Amsler grid eye test.

“We are sending brochures and Amsler grid charts everywhere, instructing people on how to perform the test at home. Too many people in India don’t realize that they are losing vision until late and present late. The Amsler grid would alert them by simply looking at it daily,” Sundaram Natarajan, MD, chairman and managing director of Aditya Jyot Eye Hospital in Mumbai, India, said.

The Amsler grid pattern has been reproduced in Mumbai using flowers and green plants in a vertical “Amsler garden,” recently inaugurated in the presence of international retina specialists and the home minister of India. At the side of the garden is a label with a detailed explanation on how to use it.

“It is part of our awareness campaign. People are attracted, read the label, understand how important it is to use the Amsler test and learn how to do it,” Natarajan said.

Another initiative launched by Aditya Jyot Eye Hospital is a trial for the detection of retinal pathologies in the urban slums of Mumbai. The screening is carried out by non-medical high school students trained to use three types of cameras.

“We are setting up a large reading center in our hospital, which in a couple of years might be able to serve a wide network of clinics in the state. This might encourage more screening initiatives and multicenter studies,” Natarajan said.

There are few studies that have examined treatment patterns and outcomes in a real-life setting in Asians, and more are needed to raise awareness, according to Wong.

In addition, cost-effectiveness studies are needed to educate policymakers about the need to invest in AMD treatment.

“Effective health care policies for AMD are cost-saving in the long term, but these studies are not easy to do and most health care systems and governments are not interested because it does not bring a direct political capital in the shorter term of their mandate,” he said.

Real-life studies

The LUMINOUS study, the largest real-life global study on anti-VEGF treatment in AMD and other retinal pathologies, includes the Asia-Pacific region. Sponsored by Novartis, it only includes cases treated with its approved drug ranibizumab, which limits it to a minority of Asian countries.

The situation is different in Australia, which contributed 44% of patients within the first 1-year global interim analysis for wet AMD. As shown in a poster presented at the Euretina meeting in London, the 938 Australian patients, mostly Caucasians, received a mean of seven injections and gained a mean of 5.6 letters if treatment naïve or maintained baseline vision if previously treated.

When considering the entire population of 2,112 patients with wet AMD, a mean gain of 4.1 letters was achieved at 1 year in the treatment-naïve subgroup, while previously treated patients maintained their initial higher baseline. A mean number of 5.2 injections were recorded.

Data collection is ongoing, and the aim is to enroll 30,000 patients from approximately 600 sites in 41 countries worldwide, followed for 5 years.

The ongoing UNCOVER study is a multicenter study on ranibizumab outcomes more specifically centered in Asia.

“We are evaluating the treatment frequency, patterns of care and clinical outcomes in real-life clinical settings within different medical coverage systems. Various sites in the Middle East and Asia are included. We have already completed recruitment, and the results will be reported next year,” Lai said.

An observational study aimed at capturing the current treatment pattern of exudative AMD in an Asian setting was carried out in Singapore. Due to the high prevalence of polypoidal choroidal vasculopathy, about half of the patients received anti-VEGF treatment in combination with PDT or laser. Among eyes treated with any anti-VEGF, 83.2% received bevacizumab and the rest received ranibizumab.

“The overall number of injections was low at 3.97 over 12 months, ranging from one to nine, with a mean of eight visits. The mean VA improved significantly by 6.5 letters, but 48% of eyes still had activity on OCT at 1 year,” Wong said.

He noted that the situation of undertreatment in the real-life setting is not dissimilar to the U.S. and European countries. Data from the U.S. Medicare system, several European registries and national studies, as well as international studies mostly including Western countries such as the recently published AURA study, have highlighted a high rate of treatment discontinuation within the first year and a low mean number of injections.

Intravitreal anti-VEGF treatment, with its high cost, need for continuous, tight monitoring, high number of examinations and frequent reinjections, is a burden that can hardly be sustained even by the most efficient system.

“A treatment that impacts so heavily on the countries’ medical resources cannot be the end solution for AMD,” Wong said. “We need newer drugs, longer lasting, cheaper, easier to administer, ideally drugs that are capable of preventing AMD. These will be the longer-term solution, and it might be worth investing more money into research rather than continue draining resources for treatment. Funding support should also be given to efforts to develop new and less expensive screening instruments, including portable ones, that could be used effectively by a greater numbers of clinicians in the Asia-Pacific region.” – by Michela Cimberle

References:

Azad R, et al. Indian J Ophthalmol. 2007;doi:10.4103/0301-4738.36479.

Cheung CM, et al. PLoS One. 2014;doi:10.1371/journal.pone.0101057.

Cohen SY, et al. Retina. 2013;doi:10.1097/IAE.0b013e31827b6324.

Finger RP, et al. Acta Ophthalmol. 2013;doi:10.1111/j.1755-3768.2012.02493.x.

Holz FG, et al. Br J Ophthalmol. 2014;doi:10.1136/bjophthalmol-2014-305327.

Li X, et al. Ophthalmology. 2012;doi:10.1016/j.ophtha.2012.05.016.

Mitchell P. Ranibizumab in the real world clinical setting: results from the one year interim analysis of the LUMINOUS study. Presented at: Association for Research in Vision and Ophthalmology meeting; May 6, 2014; Orlando, Fla.

Mitchell P, et al. A cohort of 938 Australian patients with wet AMD in the LUMINOUS trial. Poster presented at: Euretina meeting; 2014; London.

Mitchell P, et al. Br J Ophthalmol. 2010;doi:10.1136/bjo.2009.159160.

Ng WY, et al. Optom Vis Sci. 2014;doi:10.1097/OPX.0000000000000283.

Sunita M, et al. Ophthalmic Epidemiol. 2014;doi:10.3109/09286586.2013.867509.

The Angiogenesis Foundation. Wet Age-Related Macular Degeneration in the Asia-Pacific: Critical Pathways Forward. www.angio.org/wp-content/uploads/2013/10/ap-whitepaper.pdf. Published 2013.

Wolf A, et al. Graefes Arch Clin Exp Ophthalmol. 2014;doi:10.1007/s00417-013-2562-6.

For more information:

Timothy Lai, MD, can be reached at 2010 Retina & Macula Centre, Room 2201-3, 26 Nathan Road, Tsim Sha Tsui, Kowloon, Hong Kong; email: tyylai@cuhk.edu.hk.

Xiaoxin Li, MD, can be reached at People’s Eye Center, People’s Hospital, Peking University, Beijing 100044, China; email: dr_lixiaoxin@163.com.

Sundaram Natarajan, MD, can be reached at Aditya Jyot Eye Hospital, Plot No. 153, Road No. 9, Major Parmeshwaran Road, Opp S.I.W.S. College Gate No. 3, Wadala, Mumbai 400 031, India; +91-22-24181001; email: prof.drsn@adityajyoteyehospital.org.

Tien Y. Wong, MD, MPH, PhD, can be reached at the Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751; +65-63224571; email: tien_yin_wong@nuhs.edu.sg.

Disclosures: Lai is a consultant to Alcon, Bausch + Lomb, Novartis, Bayer and Allergan. Li has no relevant financial disclosures. Natarajan has no relevant financial disclosures. Wong is a consultant to Bayer, Novartis, Pfizer and Allergan.

 

 

What do you believe is the main barrier to improving access to early, effective interventions for wet AMD in your area?

High cost of treatment

I personally feel that cost is the main issue getting in the way of early diagnosis and treatment of patients suffering from AMD in India. Our health care system does not cover the cost of anti-VEGF injections. Because only a minority of wealthy Indians can afford private insurance and only a few insurances reimburse Lucentis or Avastin, the majority of our patients have no coverage and pay out of their own pockets if they need treatment for AMD. Diagnosis, therefore, is often delayed and patients go to the doctor only when the second eye is involved. Once the diagnosis is made and the patient requires treatment in the form of anti-VEGF injections, cost becomes a major hurdle. Most patients cannot afford Lucentis, although the price has been lowered recently and the overall sales of the drug have increased compared to the past. In this regard, Avastin has come to the rescue and can be offered at a minimum cost per injection.

However, wet AMD requires long-term treatment and follow-up. The cost of repeated injections as well as the travel costs of attending regular monitoring visits eventually take their toll, and most patients give up after the initial treatment. Injection frequency is also lower than required in most cases. Intervals between visits are delayed, and we end up injecting patients every 3 to 4 months instead of every month because of cost and travel issues. Extra costs are added if the treatment is administered in the OR rather than in an office setting, as most surgeons prefer for safety reasons. Government’s investments, a reviewed pricing policy specifically addressing the market of developing countries as well as the development of more affordable alternative compounds are needed to deal with the emergency of AMD in India.

 

Manish Nagpal, MS, DO, FRCS, is an OSN APAO Edition Board Member and the Vitreoretinal Consultant, Retina Foundation, Ahmedabad, India. Disclosure: Nagpal is on the advisory board for Novartis.

Lack of awareness

Vision loss due to AMD is preventable if detected early. Advances in the treatment modalities of wet AMD in the last decade have resulted in improved visual outcomes, significantly better with earlier intervention. Unfortunately, many people with AMD are not aware of their condition. In a recent study conducted in Singapore, we found an alarming proportion, as high as 80%, of subjects with vision impairment due to age-related diseases, including AMD, who were not aware of their condition. Lack of awareness may be due to the asymptomatic nature of the early stages of the disease, vision loss in one eye being compensated for some time by the other eye, lack of knowledge about the disease, lack of regular eye examinations and several other reasons. Socioeconomic deprivation, cultural factors such as low health-seeking behavior by the elderly and reduced perception of vision loss compared with other losses in life could also be potential barriers.

Tackling the challenge of reducing preventable blindness due to AMD requires a collaborative care model including patients, public health specialists, eye care specialists, general practitioners, optometrists and policymakers. Public health efforts should focus on increasing the awareness of AMD and spreading eye health messages across populations. This may include information on modifiable risk factors (smoking, low intake of antioxidants, exposure to sunlight, high levels of glucose and cholesterol), the effectiveness of lifestyle modifications, and the need for regular eye examinations for early detection and treatment, in particular among the socially deprived population. At the provider’s level, efforts are needed to train general practitioners to diagnose and refer AMD early and optometrists to promote eye health. Better doctor-patient communication, especially with regards to engaging patients in their care according to their education level and making them aware of low-vision rehabilitation services, and policy changes supporting regular eye examinations could effectively improve eye care in Asia.

 

Ecosse Lamoureux, PhD, is the Head of Population Health and Health Services Research, Singapore Eye Research Institute. Disclosure: Lamoureux has no relevant financial disclosures.