Italy approves bevacizumab for reimbursement, sparking controversy

Matteo Piovella, MD, explains the SOI position in favor of the decision, while Paolo Lanzetta, MD, gives an opposing view.

Matteo Piovella

Bevacizumab has been officially approved for intravitreal use in the treatment of “exudative maculopathy and neovascular glaucoma” and will be fully reimbursed by the National Health Service in Italy.

This provision is raising some controversy within the ophthalmic community.

Avastin (bevacizumab, Genentech/Roche) is an approved cancer treatment. It is used off-label worldwide in the treatment of neovascular age-related macular degeneration, with the support of a number of small studies suggesting that it is well-tolerated and effective; however, no randomized clinical trial has established its safety and long-term efficacy for ocular use.

Other anti-VEGF agents, namely Macugen (pegaptanib, OSI/Pfizer) and Lucentis (ranibizumab, Genentech), have been approved by the U.S. Food and Drug Administration and the European Medicines Agency (EMEA) for intraocular use. But those drugs are currently available in Italy as only “class C” medications, which means they are not reimbursable and can only be purchased and administered by public hospitals with no payment from the NHS.

Pro: Approval a step forward

The May 28 approval of bevacizumab is an important social and medical achievement, according to one surgeon in Italy.

Intravitreal therapy of exudative maculopathies, due to medical urgency and a lack of effective alternative treatments, has increased in popularity without following the normal course of pharmacological agents, Matteo Piovella, MD, secretary of the Italian Society of Ophthalmology (SOI), which represents 7,000 Italian eye doctors, told Ocular Surgery News.

Bevacizumab was available and largely used for treating advanced AMD even before pegaptanib and ranibizumab hit the market, according to Dr. Piovella. The Italian provision, he noted, brings this practice “in the light of day,” making anti-VEGF therapy available and affordable within the NHS and mitigating some of the concerns about the liability issues related to the off-label use of the drug.

“From now on, there will be no need to justify the use of Avastin with diagnoses that do not correspond to reality,” he said.

The SOI played a primary role in the approval of intravitreal bevacizumab in Italy. The SOI ethics committee examined the case, gave its formal consent and discussed it with the Italian Pharmaceutical Agency (AIFA). At the end of this process, bevacizumab was included in a special list of “innovative medications,” eligible for special reasons to be approved – and fully reimbursed – in the absence of specific, official data from large-scale clinical trials.

“The AIFA was already working at the inclusion of 19 other off-label drugs in this list,” Dr. Piovella said. “Most of them were approved, standard medications that awaited the possibility of NHS reimbursement for pediatric use. We have done nothing but add bevacizumab, which was similarly approved and reimbursable in oncology and only needed an extension of its indications to ophthalmology. We gave ‘exudative maculopathy’ as an indication to remain on a fairly general definition, which saves us from having to write false diagnoses.”

Affordability may prevent discrimination

Obtaining reimbursement for bevacizumab, Dr. Piovella explained, was easier than it would have been for pegaptanib and ranibizumab.

“Avastin had already gone through the whole series of bureaucratic procedures to obtain reimbursement as a colorectal cancer treatment. The next step from there was only short,” he said.

In addition, bevacizumab is cheaper than both of the other medications.

“We are comparing an estimated treatment cost of €20 to €30 per injection with bevacizumab to a cost of €1,000 or more per injection with either pegaptanib or ranibizumab. Although cost should not be the first priority, it is certainly an issue and a challenge to our health systems,” Dr. Piovella said.

Within the Italian NHS system, the maximum coverage provided for ophthalmic treatments is €2,500, he said.

“Multiple treatments with Macugen or Lucentis, more often than not in combination with photodynamic therapy, would be far beyond those limits, unless the patients pay for themselves, which would create a huge discrimination between those who can and those who cannot afford to be cured,” he said.

“Needless to say,” he said, “industries have a huge financial interest in pleading the cause of Macugen and Lucentis, but the scientific and political communities should remain independent.”

With a disease such as age-related maculopathy, Dr. Piovella said it is necessary to consider the price of the therapy to ensure all patients receive a valid treatment.

SOI provides guidelines, insurance

The SOI technical committee provided the guidelines for the intravitreal use of bevacizumab, and the insurance department offered special coverage for off-label intravitreal use of the drug.

“All 2,400 Italian ophthalmologists who are insured with SOI have 100% coverage in case they perform this treatment on their patients,” Dr. Piovella said.

He said he is aware that these provisions and the position of the SOI created some controversy. But to those who argue that there are no properly controlled, double-masked data for both the safety and efficacy of bevacizumab, Dr. Piovella said that “the clinical trials on the other anti-VEGF drugs have not been completed, and the data we have at present are limited.”

In his opinion, at least a few more years are necessary to draw the first reliable conclusions on anti-VEGF drugs. Only then will it be possible to make more definitive, documented choices and create pressure on governments to translate them into official provisions.

“We have no preferences and no preclusions. This is a period of transition, and the future will provide us with the answers we are looking for. But at present we must face the emergency. Also, there are some doctors, who used Avastin without specific guidelines but with outstanding results for a longer period and with more patients compared with the other drugs available today, who are supporting for nonethical reasons the need to use only the more expensive drugs, without giving real information to the patients about all the alternatives. If we have the opportunity of saving the vision of thousands of people who cannot afford to pay the high cost of FDA- or EMEA-approved drugs, then I think we should take it,” he said. “Also, if in doing so we can protect ourselves from liability, I think we have the right to do so.”

Dr. Piovella does not consider it a problem that bevacizumab is not yet available in a specific single-dose vial for intravitreal use.

“The same applies to many other medications that we currently use. Hospital pharmacies are perfectly capable of preparing the single doses we need under sterile conditions, avoiding any risk of contamination,” he said.

Con: Approval a step backward

In the era of evidence-based medicine, the Italian provision that supports and gives NHS coverage to use intravitreal bevacizumab is a step backward toward empiric, unscientific and unethical practice, according to Paolo Lanzetta, MD, an associate professor at Udine University.

“State governments have the duty to protect and promote their citizens’ health but should do it with all due respect to the criteria validated and accepted by the scientific community; in other words, on the grounds of evidence-based medicine,” he said in an interview with OSN.

Dr. Lanzetta said bevacizumab has not withstood the scrutiny of a large-scale, multicenter, randomized clinical trial for intraocular use, and this raises legitimate concerns about its safety and long-term efficacy.

“Macugen and Lucentis, following a rigorous process of validation, have received the approval of both the FDA and EMEA. Lucentis, in particular, has shown results that are extremely encouraging, with 95% of the patients maintaining or improving their vision,” he said.

“The AIFA, the organization that ‘facilitates the access to innovative medications and promotes the safe and appropriate use of drugs,’ has denied the reimbursement of pegaptanib and ranibizumab, which have been specifically developed, researched and validated for ocular use,” Dr. Lanzetta said.

“Instead,” he noted, “AIFA has granted approval and reimbursement to a drug that has completely different indications and only anecdotal evidence to support its use in ophthalmology.”

Dr. Lanzetta emphasized that there are no evidence-based guidelines concerning the dosage of intravitreal bevacizumab and that little is known of the pharmacokinetics of the drug in the eye. Preliminary data suggest that after intravitreal injection, bevacizumab may enter the blood circulation system in quantities that are potentially capable of producing systemic effects.

‘Vague, contradictory statements’

The AIFA got around the problem of granting NHS coverage to a drug that lacked the evidence of properly controlled, double-blind data by including it in a special list of “innovative” off-label medications that, by governmental decree, were judged to be eligible for use and reimbursement within the NHS.

Bevacizumab, in particular, has received approval as a treatment for “exudative maculopathy and neovascular glaucoma” and has been included in a group of medications “to be used for different indications than those officially approved [ie, in this case, for colorectal cancer], under full coverage by the NHS provided that no other validated alternative treatment is available,” as printed in the official announcement released by the AIFA.

This offers room for dispute, starting from “the vague and contradictory statements used in this document,” according to Dr. Lanzetta.

Exudative maculopathy means nothing, he said. It is not a definition of a disease but rather a description of a morphological condition secondary to many diseases of the retina.

Moreover, “the existence of other approved available alternative treatments is undeniable and, in fact, so evident that the statement sounds preposterous,” he added.

Finally, the bevacizumab dosage suggested by the AIFA (1 mg, 1.25 mg, 1.5 mg, 2 mg or 2.5 mg) is “meaningless, inaccurate and arbitrary,” according to Dr. Lanzetta.

“The commercially available vial is conceived for single use in a single patient. Dividing it into smaller multiple doses means incurring all the risks of kitchen pharmacy, first of all the possibility of contamination. Using only what is needed for one patient and throwing away the rest of the vial would, on the other hand, raises the cost of the therapy, considerably reducing the advantage of bevacizumab over other more expensive anti-VEGF medications,” he said.

Safety, efficacy should outweigh cost

Dr. Lanzetta emphasized that the advantage of the potentially lower cost of AMD treatment with bevacizumab as compared with pegaptanib or ranibizumab is a matter that should not be discussed before the top priority issues of safety and benefit have been properly investigated.

“Cost is an important parameter to be considered but should come secondary to the evaluation of safety and efficacy of a treatment,” he said.

“As a matter of fact, the Italian provision sounds very much like a way of bypassing the obstacle of economic issues by offering to our patients ‘the drug of the poor,’” he noted.

While other European countries are taking the necessary steps to make approved anti-VEGF medications available within their NHS systems, the “poor relations” who cannot afford them are taking the shortcut of a low-cost alternative, he said.

“As an ophthalmologist and a citizen, I fully understand that the sustainability of innovative therapies and the rights for health and vision are relevant issues in modern societies. Health authorities, professional societies, physicians, citizen representatives and patient associations should take part in the decision process for the reimbursement of medications, and the review procedure should be made public,” Dr. Lanzetta said.

“The sad scenario that is being delineated in our country is that where a few will be able to afford the treatment with pegaptanib or ranibizumab, all the others will be offered the class-B medication, bevacizumab,” he said.

For more information:

• Paolo Lanzetta, MD, can be reached at Università di Udine, Clinica Oculistica, Udine, Italy; e-mail: paolo.lanzetta@uniud.it. Dr. Lanzetta is a consultant for Allergan, Iridex, NeoVista, Novartis and QLT.
• Matteo Piovella, MD, can be reached at C.M.A, Centro di Microchirurgia Ambulatoriale, Via Donizetti 24, 20052 Monza (Mi), Italy; +39-039-389-498; fax: + 39-03-9230-0964; e-mail: piovella@piovella.com. Dr. Piovella has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

• Michela Cimberle is an OSN Correspondent based in Treviso, Italy, who covers all aspects of ophthalmology. She focuses geographically on Europe.