Irregular monitoring, infrequent reinjections affect real-world outcomes of anti-VEGF therapy for AMD

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.

But the introduction to the guidelines for the management of neovascular AMD, released in September by the European Society of Retina Specialists, highlights a disconnect. According to the report, “The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance.”

“The therapeutic benefit is accompanied by significant economic investments, unresolved medicolegal debates about the use of off-label substances and overwhelming problems in large population management,” the authors wrote.

The SEVEN-UP study, a follow-up to the ANCHOR, MARINA, and HORIZON trials, retrospectively evaluated the results at 7 years of a group of patients previously involved in the trials. Compared with baseline, almost half of eyes were stable, whereas one-third had lost 15 or more letters. In the 3 to 4 years since the end of the HORIZON trial, patients had received a mean of 6.8 anti-VEGF injections. Better results were correlated to more frequent treatments.

Clinical trials are not the real world

“For a number of reasons, the results of clinical trials cannot be replicated in real-world clinical settings,” Sobha Sivaprasad, MD, senior author of the recently published AURA study, said. “In the best scenario, this is because while inclusion and exclusion criteria are very robust in clinical trials, in our practices we include most patients, almost everyone who comes through the door.”

Irregular monitoring and undertreatment are other problems reported in the AURA and other real-world studies.

The AURA study retrospectively reviewed the follow-up and results of 2,227 patients treated in eight countries: Canada, France, Germany, Ireland, Italy, the Netherlands, the United Kingdom and Venezuela.

“What we found was that ranibizumab (Lucentis, Genentech/Novartis) had a definite beneficial effect, particularly the loading doses, but it was hard to maintain the results at 1 year, and at 2 years, VA was back to baseline. Still good, because if left untreated, these eyes would have lost 15 letters, but we would like to do better,” ivaprasad said.

The lower visual acuity gain reported in some countries was partly due to a ceiling effect.

“However, monitoring and treatment practices had a high impact, reflected in the different outcome of countries with comparable baseline scores,” Sivaprasad said.

Image: Sivaprasad S

Overall, 10 visual acuity tests were performed over the study duration, and patients received a mean of five injections in the first year and two injections in the second year. Countries had substantial differences in injection frequency. More frequent visits and injections were associated with greater improvements in visual acuity.

The U.K., Sivaprasad said, was top of the list for follow-up visits, injection frequency and consequently visual outcomes.

“Ours is quite an exceptional situation in which regular follow-up visits and free treatment are given under NHS coverage to all, even monthly if necessary. When insurance comes into it or patients have to pay, results are very different. Other countries cannot cope with the workload and the frequency of treatment,” she said.

Trial criteria unrealistic in practice

According to Francesco Bandello, MD, there are reasons for the gap between clinical trial and real-life outcomes that are inherent to the scope and nature of clinical trials themselves. Multinational pharmaceutical companies are currently the only entities capable of producing evidence-based medicine data through large-scale, multicenter investigations. They have an interest in optimizing efficacy data to allow pharmacotherapies to be approved, registered and reimbursed, and therefore they may adopt inclusion and exclusion criteria as well as follow-up and treatment modalities that are not realistically applicable to the clinical practice.

“The result is that patients in real life do a lot worse than in the trials,” Bandello said.

On the other hand, independent studies that meet evidence-based medicine criteria have unaffordable costs, he said. Studies such as CATT and IVAN are unique standalone cases.

Bandello is one of the investigators of the LUMINOUS study, the largest observational global study on ranibizumab in routine clinical practice to treat AMD, diabetic macular edema and retinal vein occlusion. 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 first interim analysis of 2,112 patients with wet AMD followed for 1 year was released at the 2014 Association of Research in Vision and Ophthalmology meeting. 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 and seven visits were recorded.

According to Bandello, LUMINOUS study results do not entirely reflect reality.

“In this kind of study, there is no control on data entry. The investigator bias always plays a role in prospective studies, and wishful thinking makes us overlook negative outcomes quite often when we report on our own work,” he said.

Reimbursement issues, logistical problems

Another recently published report, the COMPASS study, was based on a data set of 1,729 patients from 451 centers in Germany. After a fixed pre-loading phase of three monthly injections, treatment decisions were at the discretion of the physician and patient. The overall study time was 15 months.

“There was an increase in VA during the loading phase, with a progressive decline over time after the initial phase. What we obtained, overall, was stabilization,” study author Armin Wolf, MD, said.

Only a minority of patients (71 of 1,729) underwent OCT during the maintenance phase, and a mean of 1.5 additional injections were given after the loading doses.

“More than half of the patients did not receive additional injections,” Wolf said.

The current German health insurance scheme requires most patients to individually apply for treatment reimbursement. The long intervals between application, approval and actual reimbursement seems to be a major cause of undertreatment.

“The insurance pays, but it takes time,” Wolf said. “New regulations are going to be enforced before the end of October, and this will hopefully change the situation.”

Logistical issues are another problem, particularly for those who live outside city areas. More than 40% of the patients reported in a questionnaire that problems with transportation and high cost made the burden of monthly visits too high.

“It was important to acknowledge through this study that there are issues that need to be addressed, and now we have the data,” Wolf said.

Overloaded hospitals

Other observational studies in individual countries, including the WAVE study in Germany, the LUMIERE study in France and a study in Coimbra, Portugal, reached the same conclusions: The good visual results obtained during the loading phase are lost during the subsequent flexible maintenance phase. Only one-half to one-third of patients received further ranibizumab reinjections, with an average of one to two. Patients are not monitored monthly, OCT is seldom used, and the delay between upload and the first reinjection is several months. The LUMIERE study also found that less than 40% of patients received the recommended treatment of three initial monthly injections.

“The reason why French ophthalmologists didn’t observe the loading dose is unclear. I guess it was partly due to underestimating the importance of the loading phase and partly to the work overload in our retina units. When patients were seen to do well at the first or second follow-up visit, the loading phase protocol was suspended and the maintenance phase started, with very irregular observance,” study investigator Hassiba Oubraham, MD, said.

A second observational study, the TWIN study, collected data from 2010. The same centers that participated in the LUMIERE study were included, and a few were added, for a total of 881 patients.

“The study showed that something was learned from experience. The interval between diagnosis and first injection was shorter, and more than half of the patients received a loading dose. However, patients continued to be monitored and re-treated irregularly. Letter gain was slightly higher, although not significantly,” Oubraham said.

The authors of the WAVE study noted that deficiencies in the adherence to the recommendations of regular monthly monitoring and the insufficient implementation of optimal diagnostic and re-treatment criteria were the reasons for suboptimal treatment outcomes, “which have not only a potentially devastating personal impact but also considerable cost implications.”

Rufino Silva, MD, PhD, senior author of the Coimbra study, said that hospitals, overloaded by the increasing number of AMD patients needing treatment, may be unable to organize appropriate schedules for patients.

“It’s a widespread problem, which might become even greater in the future. We need to reconsider the way we treat,” he said.

One of the solutions adopted in his department included scheduling all the yearly appointments during the first visit.

“If patients take one appointment at a time, it is often difficult to find a time slot within a month, and the chain of delays and irregular visits starts from the beginning,” Silva said.

No shortcut to success

EURETINA guidelines aim to “provide clinically sound, economically acceptable and unbiased diagnostic and therapeutic recommendations to brighten the horizon for patients and physicians worldwide,” but show that there is no shortcut to success in AMD management. The use of anti-VEGF injections is confirmed as the gold standard. Evidence-based recommendations emphasize the importance of a loading dose of three monthly injections with all agents, followed by monthly or bimonthly injection, depending on the agent and/or patient conditions, with as-needed monthly monitoring by visual acuity testing and OCT as an alternative.

Sivaprasad believes that efficacy and efficiency can be increased by better planning and solid investments in health care. According to Bandello, the need for continuous, tight monitoring, the high number of examinations and the frequent reinjections required are a burden that can hardly be sustained, even by the most efficient system.

“We should investigate new treatment schemes,” Wolf said. “Monthly would be an unsustainable burden and a waste of resources because we would overtreat a lot of patients. We have options to improve the PRN, and we should try treat and extend.”

A more decisive and sustainable answer might come from new treatment options.

“Research is aiming at long-lasting drugs, sustained-release delivery systems, new molecules with increased efficacy and easier ways of administration. They will release the pressure on our institutions and start a new era,” Bandello said. – by Michela Cimberle

• References:
• Cohen SY, et al. Graefes Arch Clin Exp Ophthalmol. 2011;doi:10.1007/s00417-010-1553-0.
• 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. 6.
• Holz FG, et al. Br J Ophthalmol. 2014;doi:10.1136/bjophthalmol-2014-305327.
• Kiss S, et al. Ophthalmic Surg Lasers Imaging Retina. 2014;doi:10.3928/23258160-20140709-04.
• 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. Br J Ophthalmol. 2010;doi:10.1136/bjo.2009.159160.
• Oubraham-Mebroukine H, et al. Evolution of visual acuity in patients with wet AMD diagnosed since 2010 and treated with ranibizumab, in current practice. Comparison with LUMIERE study. Presented at Association for Research in Vision and Ophthalmology meeting; May 7, 2013; Seattle.
• Rofagha S, et al. Ophthalmology. 2013;doi:10.1016/j.ophtha.2013.03.046.
• Schmidt-Erfurth U, et al. Br J Ophthalmol. 2014;doi:10.1136/bjophthalmol-2014-305702.
• Wolf A, et al. Graefes Arch Clin Exp Ophthalmol. 2014;doi:10.1007/s00417-013-2562-6.

• For more information:
• Francesco Bandello, MD, can be reached at the Department of Ophthalmology, Vita-Salute University Scientific Institute San Raffaele, Italy; +39-02-2643-2648.
• Hassiba Oubraham, MD, can be reached at 1 rue Pougin de la Maisonneuve, 45200 Montargis, France; email: hassibaoubraham@gmail.com.
• Rufino Silva, MD, PhD, can be reached at Department of Ophthalmology at the Centro Hospitalar Universitário de Coimbra, Av. Bissaya Barreto - Praceta Prof. Mota Pinto. Coimbra, Portugal; +351-239400400; email: rufino.silva@oftalmologia.co.pt.
• Sobha Sivaprasad, MD, can be reached at King’s College Hospital, Denmark Hill, London SE5 9RS, UK; email: senswathi@aol.com.
• Armin Wolf, MD, can be reached at Ludwig-Maximilians-University, Department of Ophthalmology, Klinikum der Universität München, Mathildenstrasse 8, D-80336 Munich, Germany; +49-89-51603811; email: armin.wolf@med.uni-muenchen.de.

Disclosures: Bandello is a consultant to Alcon, Alimera Sciences, Allergan, Bayer, Bausch + Lomb, Genentech, Hoffmann-La Roche, Novagali Pharma, Novartis, Pfizer, Sanofi-Aventis, Théa and ThromboGenics. Oubraham is a consultant to Allergan, Bayer, Novartis and Théa. Silva is consultant to Alcon, Alimera, Bayer, Novartis and Théa. Sivaprasad is a consultant to Allergan, Bayer and Novartis. Wolf is a consultant to Alcon, Bayer and Novartis.

Can European health care systems afford the high cost of approved anti-VEGF drugs?

Current price not too high, considering the benefits

The French Ministry of Health, which provides full reimbursement for approved anti-VEGF therapies, spent in 2013 429 million for Lucentis (ranibizumab, Genentech/Novartis) — the No. 1 investment for drug coverage last year — and 12 million in 3 months for Eylea (aflibercept, Regeneron/Bayer). This financial burden is expected to grow with increasing demand for treatment in future years. Such a high investment has come from the basic consideration that preserving vision is a high priority in our society, as it is for the individual. What anti-VEGFs do in terms of preserving vision has high value, which makes the high price acceptable.

What is nowadays unacceptable is that the price of anti-VEGF drugs varies from country to country. It was decided a long time ago that the price of pharmaceuticals should be established at a national level, as the result of complicated negotiations among pharmaceutical industries, the government and several other third parties, including private insurers, wholesalers, pharmacists and physicians, to mention just a few. The time is ripe to have a European price and to have it clear, open and fair.

I am not in favor of government provisions that may allow the off-label use and reimbursement of Avastin (bevacizumab, Genentech/Roche) to save on the total budget for anti-VEGF therapies. The additional costs related to compounding, storage, traceability and treatment of epidemic infections due to contamination might, in fact, make the final price less remarkable. In addition, there are rules in Europe that establish that off-label drugs should not be used if an approved product is available, and we should respect these rules.

Jean-François Korobelnik, MD, is an OSN Europe Edition Board Member and president of the French Society of Ophthalmology. Disclosure: Korobelnik is a consultant to Bayer, Novartis and Roche.

Governments, taxpayers should not accept inflated price

Every government should, in theory, provide full reimbursement of treatments with the best pharmacological or technological options available. In practice, limited budgets are often allocated and priorities are not always well established. The Italian government has never been generous to ophthalmology and has been slow in embracing technological advances. However, in the case of Lucentis (ranibizumab, Genentech/Novartis), the issue is different because there is in fact no reason why the government and we, as a community of taxpayers, should accept to pay a price that has been blown up disproportionately in relation to the original molecule, Avastin (bevacizumab, Genentech/Roche). Not even the costs of the trials justify the huge difference between the 15 of a split part of an Avastin vial for ocular use (more than 200,000 vials sold in Italy) to the 2,500 of a single dose of Lucentis, which Novartis fixed in 2007 when Lucentis was first available.

A unique situation has been created in which independent studies have shown equivalence of the two drugs in terms of efficacy and safety. And yet, based on a biased interpretation of the CATT findings, a huge case has been built up against the use of Avastin. Safety, which is a sensitive argument, has been used to manipulate public opinion and justify an otherwise indefensible and unacceptable difference in price.

The result is that, after a long battle, we can theoretically use Avastin off label, but the fear of patients of being given an inferior drug and the fear of physicians of being involved in medicolegal claims are causing a huge deadlock, and 100,000 patients in Italy are going untreated. Avastin was a good way of meeting patients’ needs within our limited hospital budgets, with good results and no true safety concerns. We were prepared to take full responsibility for off-label use. But this probably will be restricted, from the practical point of view, due to the decision managed by the Italian Regulatory Agency that is against the off-label use managed under the responsibility of eye doctors and related to the strategy to support pharmaceuticals’ income. This is unacceptable: Worldwide, 75% of drugs are daily used in off-label mode due to lack of a regulatory system and pharmaceuticals’ responsibility. Off-label drug use is a medical doctor’s right to benefit their patients.

Matteo Piovella, MD, is an OSN Europe Edition Board Member and president of the Italian Society of Ophthalmology. Disclosure: Piovella has no relevant financial disclosures.