The First-Instance Court of Athens recently found an ophthalmologist liable for injury suffered by his patient when the latter lost vision from one eye following the intraocular administration of the medicine Avastin.
The claimant, a 60-year old woman suffering from macular oedema due to retinal vein occlusion, underwent treatment by the defendant. This treatment included intraocular injections of the substance bevacizumab, sold under the tradename Avastin, an anti-angiogenic factor (anti-VEGF). The first injection was made in 2006 in the operating room of a hospital and dramatically improved the claimant's visual acuity. The second injection, a couple of years later, was made in a specially equipped sterilised room in the doctor's office and was successful. Six months later, when the claimant's visual acuity deteriorated again, another injection was made in the same room in the doctor's office. While the first two injections improved the claimant's visual acuity, the third did not; instead, the claimant's eyesight gradually deteriorated. A fourth intravitreal injection of Avastin was administered a couple of months later, again at the doctor's office. The next day the claimant's vision had severely deteriorated and by early afternoon, when she arrived at the defendant's office, it was lost. The doctor diagnosed the claimant with endophthalmitis (an infectious and serious inflammation of the intraocular fluids) and proceeded to administer intraocular antibiotics with no result. On the defendant's recommendation, the patient was sent to another ophthalmologist's vitrectomy surgery the next evening, during which time the vitreous cavity was thoroughly cleansed and a recurrence avoided, but the eye was lost. The claimant sought €400,000 in moral compensation.
The court carefully examined the arguments put forward by the parties. The claimant admitted that the defendant had fully disclosed to her that Avastin had no regulatory approval for intraocular use and was officially registered for treating various metastatic forms of cancer before he administered the first injection at the beginning of her treatment. He also told her that the drug was widely used in this off-label manner (ie, used outside the terms of its licence) by ophthalmologists worldwide in order to treat macular degeneration, the disease from which she suffered, and that the principal but very rare side-effect was endophthalmitis.
Further, the court noted that apart from Avastin, another medicine, Lucentis (ranibizumab – also an anti-VEGF), was used for the treatment of macular oedema – the difference being that the latter had regulatory approval for this specific use. Lucentis obtained approval from the European Medicines Agency on January 22 2007 for only two causes of macular oedema (ie, wet age-related macular degeneration (AMD) and diabetic macular oedema). It obtained approval for macular oedema due to retinal vein occlusion (from which the claimant suffered) only in 2011. This means when the defendant administered Avastin to the claimant, no on-label drug existed for the disease from which the claimant suffered, except Macugen (pegaptanid) – a far less effective medicine. On the other hand, the apparently safe and effective Avastin continues to be part of mainstream medical practice worldwide, despite its intraocular administration being entirely off-label and the fact that Lucentis came onto the market as an on-label option many years ago.
The court also considered the fact that while there were no controlled trials on Avastin's ophthalmological use when the claimant underwent treatment, the results of a two-year extensive clinical trial published in 2012 comparing Avastin and Lucentis labelled "Comparison of AMD Treatments Trials" showed no statistically significant differences either in efficiency or adverse effects between the two drugs (endophthalmitis occurred in 0.7% of the subjects treated with Lucentis and in 1.2% of the subjects treated with Avastin).
The court then assessed whether, on the basis of the evidence produced by the parties, an increased risk of infection existed in the intraocular use of Avastin as a result of its packaging. As the drug was packaged in 4 millilitre (ml) and 16ml vials, suitable for its on-label use as an intravenous infusion for cancer treatment, it had to be repackaged in 1ml vials and diluted with sodium chloride for its off-label use as an intravitreal injection. In this specific case, the doctor had used the content of the same vial of Avastin on seven other patients (none of whom presented any adverse effects). This preparation increased the risk of microbial infections, as the repackaging of a sterile medicine through a potentially inadequately aseptic process compromised the drug's sterility. The court also found that the defendant had delayed in providing the claimant with the proper treatment for endophthalmitis, as she was admitted to the other surgery nearly 48 hours after she presented the first symptoms of the infection.
The court found the defendant to be liable for the loss of the claimant's eyesight, saying that the use of Lucentis was inherently safer compared to Avastin's because, as there was no need for repackaging when using the former, the risk of infectious endophthalmitis was lower. The court decided that the defendant and his professional liability insurer, which was summoned to the trial by the insured doctor, were jointly liable to pay to the claimant €30,000 for moral compensation.
'Off-label' use is defined as the unapproved use of a medicinal product which has regulatory approval for other medical uses (and should not be confused with unapproved or unlicensed products which have no approval for any medical condition). In the controversy over the off-label use of medicines, the Avastin versus Lucentis debate holds a prominent position.
The main reasons that a medicine will be prescribed for off-label use are because:
- no drug has approval for the treatment of the relevant condition; or
- the drugs approved for this condition have not benefited the patient.
A 2009 study found that more than half of paediatric office visits included off-label prescriptions, and in 2014 the American Academy of Paediatrics Committee on Drugs stated to paediatricians that "off-label use is neither incorrect nor investigational if based on sound scientific evidence, expert medical judgment, or published literature". The number of off-label prescriptions given to children results from the fact that an overwhelming number of drugs still have no information regarding use in paediatrics. Psychiatry is another area where off-label prescriptions are common.
What makes the Avastin case special is that its off-label use is based on financial considerations, a parameter which is not perceived as acceptable by medical or regulatory guidelines in most countries. Off-label prescriptions are generally accepted when there is no suitably licensed medicine to meet the patient's needs. However, in the case of anti-VEGF drugs, there are other medicines available on the market to treat AMD and macular oedema. Lucentis (and the more recent Eylea) are officially approved for these indications. However, they are approximately 30 to 50 times more expensive than the off-label Avastin, depending on the country, and this often entails a several thousand euros cost difference over the course of a treatment. Because of the cost difference, while Avastin and Lucentis are considered to have a similar effect, several prominent health authorities – including the World Health Organisation and the International Council of Ophthalmology – have supported the use of Avastin. The plot is thickened by the fact that both substances (ie, Avastin and Lucentis) were discovered and patented by the same company, Genentech, which gave the marketing rights for Avastin to Roche and the rights for Lucentis to Novartis. Roche has denied expanding Avastin's indication, maintaining its stance that Avastin should not be used to treat AMD. In an interesting twist, Roche acquired the majority of Genentech's shares in 2009, thus obtaining a stake in both Avastin and Lucentis. As a result of the above, both Roche and Novartis have been investigated by antitrust authorities in the European Union over their marketing practices regarding Avastin and Lucentis. In Italy, the Competition Authority found that the two companies colluded in order to drive sales for Lucentis and fined them a combined €180 million, while specific measures allowed Avastin to be reimbursed for the off-label treatment of AMD. In France, the National Agency for the Safety of Medicines (ANSM) issued a temporary recommendation of use, a procedure that allows ANSM to recommend a licensed product for additional indications outside the scope of its licence, thus allowing Avastin to be reimbursed in France for its off-label use in AMD. Roche and Novartis challenged the recommendation of use before the French Administrative Supreme Court, but their request was dismissed on February 24 2017.
All of the above were submitted to the First-Instance Court of Athens by the defendant in order to demonstrate that Avastin was a legitimate and safe choice for the claimant's treatment, who, after all, gave her informed consent at a time when no on-label option existed. The claimant's side insisted that while Lucentis is manufactured and delivered as an eye injection and adequately packaged for a single-use intravitreal injection, Avastin must be repackaged into smaller doses for the eye, which raises concerns regarding a greater possibility of infection. Notably, in its defence for not expanding Avastin's indication, Roche has argued that it lacks the expertise, capacity or authorisation to repackage Avastin in quantities appropriate for intraocular injections. The court ruled in favour of the claimant, despite the fact that the defendant had presented the court with details of the steps it followed while repackaging the drug in order to ensure an aseptic procedure, which were never contradicted by the claimant's side.
According to Greek law, in cases of medical malpractice, the injured party must prove a medical act or omission, its injury and a causal link between the act or omission and the injury. Contrarily to what applies in most liability cases, the doctor's fault (in the form of negligence) is presumed, and thus the burden of proof is reversed.
The court found that medical malpractice existed in this case, as the infection which led the claimant to lose her eyesight occurred when the defendant could have opted for (what the court assessed to be) the safer Lucentis. In other words, the court found that the use of an off-label medicine when an on-label product exists amounts to malpractice, although not conceptually, but, in this case, as a result of the defending doctor's failure to prove that using Avastin was as diligent and safe as using Lucentis.
Finally, another noteworthy fact on the Avastin-Lucentis controversy: on February 28 2017 the European Commission published an overdue study report on off-label use of medicines in the European Union.(1) Although the study failed to recommend specific steps to be taken by the member states or at EU-level, it contains a plethora of interesting facts, assessments and general suggestions. It clearly states, for instance, that one of the reasons for the off-label use of drugs is pricing and reimbursement. What is more interesting for the case examined here is that the study addresses the Avastin-Lucentis issue in the context of the abovementioned administrative measures taken in France and Italy, which led to the pharmaceutical industry complaining to the EU Commission. The study acknowledges, on this point, that "beyond purely therapeutically motivated decisions, off-label use of medicines at the healthcare system level can also be driven by financial reasons". As expected, the industry's associations – the European Federation of Pharmaceutical Industries and Associations, the European Confederation of Pharmaceutical Entrepreneurs and EuropaBio – reacted only a few days after publication of the report, emphasising in their statement that economic considerations leading to the reimbursement of off-label medicines when on-label products exist is an unacceptable policy option that jeopardises public health.
For further information on this topic please contact Athanassios Lambrou at Zemberis, Markezinis, Lambrou & Associates by telephone (+30 210 363 6016) or email (firstname.lastname@example.org). The Zemberis, Markezinis, Lambrou & Associates website can be accessed at www.zmlaw.gr.
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(1) The study was commissioned in 2014 by the European Commission as a result of an 2013 EU Parliament resolution instructing the European Medicines Agency to establish guidelines on the off-label use of drugs. For a comprehensive presentation of the study's findings please see:
- "European Commission publishes long-awaited study on off-label use: industry reacts", Evelyn Van Keymeulen of Allen & Overy; and
- "Off-label use of medicinal products in the EU (facts and figures published in an EU study report)", B Fonteyn & D Phan of C/M/S.