Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Refer bevacizumab to NICE!
- James P Raftery, Andrew Lotery (10 February 2007)
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Industry as a Good Corporate Citizen
- Padmanabhan Badrinath (19 February 2007)
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RE:- Editorial - “Treatments for neovascular acute macular degeneration” authored by Professors Chakravarthy and Lim (BMJ 2007; 334; 269-270 - 9th February 2007).
- Tim Cave (21 February 2007)
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Re: RE:- Editorial - “Treatments for neovascular acute macular degeneration” authored by Professors Chakravarthy and Lim (BMJ 2007; 334; 269-270 - 9th February 2007).
- Surinder Sethi (26 February 2007)
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Re: RE:- Editorial - “Treatments for neovascular acute macular degeneration” authored by Professors Chakravarthy and Lim (BMJ 2007; 334; 269-270 - 9th February 2007).
- Christopher J McCabe, University of Leeds (28 February 2007)
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The other side of the coin - Lucentis in NHS today
- Victor Chong (1 March 2007)
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The NHS has a right to conduct its own trials
- Daphne I Austin (6 March 2007)
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New treatments for neovascular acute macular degeneration
- Usha Chakravarthy, Jennifer Lim (8 March 2007)
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James P Raftery, Professor of Health Technology Assessment University of Southampton, SO17 1SG, Andrew Lotery
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Dear Editor We welcome the editorial point that the price of bevacizumab is likely to be less than that of ranibizumab, but think the editorial could have said more about the pricing of these two drugs. Both drugs are owned by a single company, Roche/Genentech, which has no intention of licensing the cheaper. The US price of ranibizumab is $1950 or roughly £1,000 per injection. Monthly injections would cost £12,000 per patient. Bevacizumab which is licensed for cancer treatment could cost as little as £17 per injection, as the dosages used for eyes are minute compared to cancer. In the US, off-license bevacizumab is estimated to cost $17-$50 (£8-£25) including the costs of splitting up the larger cancer doses. By refusing to license bevacizumab for macular degeneration, Roche/Genentech is raising the price by an unprecedented factor of over 50! Given the lack of data directly comparing these two drugs, we support the call for a head-to-head trial (indeed we are part of a team bidding to do such a trial). We wish to make three further points. First, we have modelled how more effective bevacizumab would have to be relative to lucentis in order to meet the NICE threshold of £30k/QALY. Using best estimates of current US prices of $1950 and (a high) $50, lucentis would need to be 2.5 times more efficacious to meet NICE’s threshold. This seems highly unlikely, given the similarity of the two drugs and the observational data that exists on the effectiveness of avastin. Even if ranibizumab’s price was reduced to $500, it would have be more than 5% better than bevacizumab to be cost effective. Second, the review by NICE of ranibizumab versus standard care for patients with the predominantly classic form of macular degeneration, due to report by October 2007, could imperil any head-to-head trial in the UK. Should NICE find in favour of ranibizumab, then those patients may well prefer to be treated with ranibizumab rather than being randomised. Any UK trial must recruit quickly. Third, bevacizumab has been excluded from the NICE review due to it being unlicensed. Exclusion of unlicensed drugs is normally sensible due to lack of data. However, given that Roche/Genentech, which owns both drugs, has no plans to license the cheaper, an exception should be considered. Even if a trial was to show bevacizumab as equivalent to ranibizumab, it would require Department of Health authorisation before bevacizumab could be widely used. The Department should urgently consider referring bevacizumab for NICE appraisal. Competing interests: Both JR and AL are part of bid for funding of a head-to-head comparison of bevacizumab and ranibizumab. |
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Padmanabhan Badrinath, Consultant in Public Health Medicine & Affiliated Clinical Lecturer Suffolk PCT & University of Cambridge, IP33 1YJ
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Dear Editor, I wholeheartedly welcome the editorial by Chakravarthy & Lim (1) on treatments for neovascular acute macular degeneration (nAMD). There has been recent media coverage on a high profile case on the same issue (2, 3). It is needless to say that commissioning decisions have to be guided by sound data on clinical and cost effectiveness and we should do all we can to provide the best possible care for our populations within the available resources. At the same time, we need to be careful and do not harm our patients by adopting new innovations without adequate long term appraisal, and have safeguards in place to protect the interests of all concerned. In January the manufacturer of Lucentis wrote (4) to health care providers on the risk of stroke associated with 0.5 mg dose of the drug. According to the manufacturers the macular degeneration drug Lucentis (ranibizumab) may increase the risk for stroke at the Food and Drug Administration approved dose. Patients receiving 0.5 mg of the drug had a 1.2% risk for stroke compared with a 0.3% risk for patients receiving 0.3 mg - a significant difference - after about 8 months of follow-up in an ongoing clinical trial. In a letter to physicians (4), the company reported that patients with a history of stroke faced a higher risk. However, there was no significant increase in the rate of heart attack or vascular-related death between the two doses. I would also like to raise the issue of industry being a good corporate citizen. The health care community should do all it can to make sure that the industry acts in the best interests of the health system and the society in which it operates. We need to ensure that the “concept of corporate citizen” not only applies to the public sector but also to the industrial and commercial operators as every one’s interests are interlinked and dependent. The industry needs to be encouraged to apply for license if a drug could be provided cheaper for a serious condition, in this case bevacizumab for nAMD. I fully agree with the case for this very eloquently expressed by Raftery & Lotery in the BMJ (5). References 1.Chakravarthy U & Lim J I. Treatments for neovascular acute macular degeneration. BMJ 2007;334:269-70. 2.Ex-MP battles NHS over eye drug. http://news.bbc.co.uk/1/hi/england/west_yorkshire/6311701.stm. Accessed on 17th February 3.NHS to reconsider eye drug ruling. http://news.bbc.co.uk/1/hi/england/west_yorkshire/6315329.stm. Accessed on 17th February. 4.http://www.gene.com/gene/products/information/pdf/healthcare- provider-letter.pdf. Accessed on 17th February. 5.Raftery J P & Lotery A. Refer bevacizumab to NICE, BMJ 10th February Dr.P.Badrinath MD BS M.Phil MPH PhD FFPH, Consultant in Public Health Medicine & Affiliated Clinical Lecturer, Suffolk Primary Care Trust & University of Cambridge, United Kingdom. Disclaimer: The views expressed above are personal views of the author ONLY and NOT that of his employing organisation. Competing interests: The author is employed by a Primary Care Trusts (PCT) and PCTs are responsible for commissioning high quality health care to their population within the available resources. |
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Tim Cave, Medical Director Novartis Pharmaceutical Ltd, Frimley, Surrey, GU15 7SR
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Dear Editor I would like to take this opportunity to comment on statements made in the above editorial, regarding bevacizumab (Avastin™) and ranibizumab (Lucentis™), in the treatment of age related macular degeneration (AMD), which affect the conclusions regarding cost and the “priority” need for a controlled clinical trial. 1. Ranibizumab (Lucentis™) is not a derivative of bevacizumab (Avastin™) – They are both molecules derived from a common murine antibody framework that also gave rise to trastuzumab (Herceptin™). Thus it is a false assumption that the sharing of a common ancestor means that they automatically should have similar effects, as evidenced by the different effects of bevacizumab and trastuzumab , ii. Indeed, ranibizumab has been specifically designed for ocular use and shows significant differences to bevacizumab, such that the benefit:risk profile could be very different when both are used in wet AMD patients , e.g. Ranibizumab is smaller in size, has higher binding affinity for VEGF-A isoforms, has a shorter systemic half-life when given intravenously i, 2. As the editorial points out, the current level of evidence for bevacizumab in patients with wet AMD, is derived from case series that are in general, based on small-scale, retrospective analysis, with no controls, and are of short-term and non-systematic follow-up. Importantly, what is lacking in the evidence base for bevacizumab is the following:- 1. Formal ocular toxicology and pharmacology studies in pre-clinical models of eye disease; 2. Formal phase I dose-ranging studies, to establish minimum effective or maximum tolerated doses in humans, that study the proposed dose to be used in later human clinical studies, 3. Formal clinical pharmacology studies to establish pharmacokinetic and pharmacodynamic parameters for single and multiple doses; and 4. Formal randomised, controlled phase II studies to validate evidence of therapeutic benefit and risks, over a control group, in the disease to be tested. In the absence of such critical data, the use of bevacizumab in a large phase III head-to-head study versus ranibizumab, would expose large numbers of patients over a long period of time to a drug for use in a disease state where the benefit:risk has not been explored in a systematic and scientific manner. 3. It is difficult to understand how the authors have reached their conclusions on the costs of anti-VEGF treatments for many reasons. The figures of over £500 million used by the authors appear to be a factor of 10 too high, when compared to figures used by the Specialist Commissioners having the responsibility of planning such services. Additionally, the authors have not taken into account that the UK licence for ranibizumab states that the dosing regimen is bi-phasic in nature, with initiation of a loading phase (fixed) of 3 injections and a maintenance phase (flexible) where re-injections are administered based on a clinical assessment of visual acuity change of 5 or more letter loss on an ETDRS chart. Based on this dosing regimen, the expected number of injections that would enable the same visual acuity benefits achieved in the MARINA and ANCHOR studies has been estimated from meta-analysis and modelling to be 8 treatments in year 1 and 6 treatments in year 2, significantly lower than the 24 treatments in these studies. Thus, a calculation for the drug acquisition costs alone using reasonable assumptions would give drug costs an order of magnitude lower than that suggested. Finally, it would appear that the authors’ proposal to perform a head to head study of bevacizumab and ranibizumab in wet AMD, is aimed at justifying wide-scale off-label usage of bevacizumab in this patient group in the UK, based upon financial considerations. This would be without any other research that would normally be required to understand the safety, quality and efficacy of this drug in the eye, and thus, obtain a Marketing Authorisation for such use. The regulatory regime regarding product licensing and drug development was introduced to safeguard patient safety and there must be significant concerns that the authors’ proposal is intended to and will circumvent this legislation based on financial reasons only, with a risk of jeopardising patient safety in the longer term. References i Ferrara et al. Retina 26:859–870, 2006 ii Steinbrook R. N Engl. J Med 2006; 355: 1409-1412 Competing interests: The author is an employee of Novartis Pharmaceuticals Ltd. |
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Surinder Sethi, consultant in public health medicine specialised services commissioning - lancs and south cumbria, Preston Business Centre
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New Anti VEGF Drugs for wet AMD- A Commissioning Perspective The development and licensing of the vascular endothelial growth factors (anti VEGF) drugs especially Ranibizumab (Lucentis) increases the number of very effective evidence based treatment options available to all subtypes of patients with wet AMD. However, the treatments are highly expensive, with very significant cost implications for commissioning budgets. In the absence of additional national funds, these will fall on existing PCT budgets and will compete for resources alongside other medical conditions and their treatments. The annual treatment (drug and visits) cost of monthly Lucentis injections per patient has been estimated to be approximately £25 000. At 60% access rates the first and second year costs for the Cheshire and Merseyside population of 2.4million is projected to be £26.5 million and £17.6 million respectively. With Lucentis, two large phase 3 trials (Marina, Anchor) demonstrated significant visual gain. Almost all patients receiving the drug did not progress to moderate vision loss. Moreover, a third to 40% gained vision (an extra 3 lines) relative to baseline. A similar proportion avoided progression to serious visual loss. However, these gains were achieved with monthly injections of Lucentis over two years to which the study patients demonstrated excellent compliance. When the treatment regimen for Lucentis was reduced in the Pier study ( 3 monthly top loading injections followed by quarterly injections) visual gains decreased. The percentage gaining vision reduced to half and initial gains in visual acuity (VA) fell to baseline or just below baseline levels at the end of one year. The number of annual injections in the Pier study was 6. In the US, the FDA approval of Lucentis recommended Lucentis 0.5 mg for intravitreal injection once a month. However, the European commission has approved an individualised dosing regimen based on a 3 monthly initial loading schedule followed by a VA guided flexible dosing. This is expected to average 8 injections in the first year and 6 in the second year of treatment. This regimen is based on the PRONTO study which recruited and observed 40 patients. The different licensing recommendations in the USA and Europe have implications for both clinical and cost effectiveness. Can commissioners and patients assume that both regimens are equally effective and that the European recommendation is actually more cost effective (with a saving equating to £7610 per patient for drug costs alone over 2 years) and convenient? Is the evidence for this as robust as the original phase 3 pivotal trials? Commissioners need answers to these questions urgently. Can these same benefits be realised with Avastin which is much cheaper and biologically similar to Lucentis? The potential for phase 3 research, licensing issues with Avastin and the possibility of driving down costs to a fifth have been described by Raftery and colleagues. The cost stakes and opportunity costs for commissioners and non-AMD patients are high. As they strive, to make accessible these latest drug advances to the wet AMD community of patients-commissioners need to be assured that they are achieving maximum vision outcomes for patients. Here there may be a trade off between clinical and cost effectiveness depending on which dosing regimen is followed. However commissioners need to understand the nature of the trade offs and the affordability choices that are before them. This is another challenge for the NICE review. 1 Chakravarthy U, Lim JL. New Treatments for neovascular acute macular degeneration. BMJ 2007;334:269-70.(10 February) 2 Raftery JP,Lotery A. The cheaper drug, Bevacizumab should be referred to NICE. BMJ 2007; 334:381-382. Competing interests: None declared |
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Christopher J McCabe, Professor of Health Economics Institute of Health Science, University of Leeds
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Sir, Dr. Cave from Novartis Pharmaceuticals is to be congratulated for correctly highlighting the importance of risk:benefit profiles and long term safety issues in licensing processes. As Dr. Cave points out, because ranibuzimab has been specifically developed for ocular use, it could have a very different risk:benefit profile for AMD patients. However, safety and efficacy are not the only aspect of the risk benefit profile relevant to the comparative value of bevacizumab and ranibizumab. The difference in price between the two treatments is estimated by Raftery and Lotery to be in the region of £990. Utilisation of the more expensive treatment for some risks treatment being completely unavailable to others. Accepting, as we must, that resources are limited and that money cannot be spent twice, for every one person treated with ranibizumab rather than bevacizumab, over 100 eyes will go untreated. Thus, at the population level, which is the only level at which a risk:benefit calculation can be made, the health loss from the untreated eyes should be placed into the risk:benefit assessment of bevacizumab. It is frequently pointed out that licensing and reimbursement processes that impose unnecessary evidential burdens on the new treatments, carry a heavy price in health gain foregone due to delayed market access. I hope Dr. Cave will agree that from a population health perspective, if the proposed Phase III trial of ranibizumab and bevacizumab shows the two treatments to have similar effectiveness in treating AMD, and does not identify any substantial new adverse event concerns, then the population risk:benefit assessment will represent a strong reason for licensing bevacizumab for the management of AMD. Given the substantial differential population health benefit from the two therapies it would seem difficult to justify delaying licensing to await long term safety data. A long term monitoring scheme would be a sensible recommendation for post marketing surveillance as part of a risk management plan. Competing interests: None declared |
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Victor Chong, Consultant / Senior Lecturer / Head of Laser and Retinal Research Unit King's College Hospital, London SE5 9RS
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Dear Editor,
Chakravarthy and Lim should be congratulated highlighting the important of macular degeneration. There are about 30,000 new cases in the UK which would benefit from Lucentis. The following points should also be considered.
1. Lucentis is now licensed in the EU, including the UK. So far, I am not aware that NHS is paying for Lucentis. Please do not forget, 30,000 patients are going to go blind between now and the implementation of NICE guidance. We should be focussed on getting Lucentis into the NHS today. 2. I am not certain that a head to head trial is ethical. So far, there is no evidence that Avastin is better than Lucentis, it might be at best similar in efficacy. In theory, the longer half life of Avastin might mean higher risk. The problem was already highlighted by Raftery and Lotery that when Lucentis is available in the NHS (as it should be TODAY), patients would not want to join this head to head clinical trial. 3. Please also do not forget in addition to drug costs, there are also hospital costs to provide the treatment. Both Avastin and Lucentis need similar hospital costs assuming similar efficacy and similar side effect profile. However, if Avastin has a higher stroke rate, for instance, say by 1%, that would mean 300 exact strokes per year. So is it really cheaper? How many patients do we need on the head to head trial to be sure that this 1% extra risk does not exist? Who is going to pay if the patients decide to sue? 4. So a head to head trial has to be robust and similar to regulatory trials with proper trial support. It should be ethical and patients allow to join the study without the fear of not receiving Lucentis if they do not. So how long do you think that it would take and how much is that going to cost? 5. Avastin is only cheaper, as a small amount of the drug is taken from a big bottle. So even after a head to head trial, not only the department of health would need to endorse an off-label drug over a licensed product which is unprecedented, it would have to encourage big scale compound use. We might just as well ask them to ignore patent protection and make Lucentis ourselves. There is law in this land, the regulatory of licensed drugs is in fact European law, making even more difficult for that to happen. Is there no better way to spend research money than such a trial? Competing interests: VC has been on scientific advisory board for Novartis, Genentech, Pfizer and Bayer. The author’s unit receives research support from Novartis, Pfizer and Allergan. |
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Daphne I Austin, Consultant in Public Health West Midlands Specialised Services Agency B16 9RG
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Dear Editor Opposition to the proposed trial for Lucentis and Avastin that has been expressed here, and elsewhere, challenges the legitimacy of the NHS to establish the true value of existing and promising treatments and to pursue solutions to difficult challenges facing health services. When a treatment is effective but associated with very high opportunity costs it is entirely appropriate to seek a means to provide the same health benefits for less cost. That some would consider this unethical in the context of a publicly funded healthcare system is most surprising. Avastin has shown promise as suggested in the following quote from a European Consensus Statement on the treatment of macular degeneration: 1 'Following the publication of highly encouraging data many investigators worldwide are exploring the use of intravitreal [Avastin] with several reports on short term safety and efficacy available in the literature. Also experimental and electrophysiological testing in animals and humans demonstrate absence of toxicity to the retina.' It therefore needs to be recognised that there is considerably more experience with this drug than some of the letters might suggest. Needless to say those who support the trial have carefully considered the risks and the all the implications of the trial. It is of course not possible to state whether Avastin is worse, the same or better than Lucentis. Victor Chong's illustrative scenario that Avastin might give rise to more strokes is supposition. Avastin might give rise to more strokes or it might lead to fewer strokes and clearly it is important to find out which is the case. However Mr Chong's question 'is [Avastin] really cheaper?' stated in the present tense, may be misconstrued. The scientifically accurate version of this question should read: 'do we really know if Avastin is more cost-effective than Lucentis?' The need to find a means to provide treatments that are affordable is one of the most important emerging challenges for healthcare systems. This is illustrated not only by the case under discussion but also Herceptin for use in early breast cancer. At the time of licensing, promising evidence existed that suggested that the benefits of Herceptin could be provided at greatly reduced costs, yet this was completely lost in the public debate. As a consequence, the NHS missed not only its best opportunity to pursue the possibility of a more affordable option--other services may pay for the price for a number of years to come. The UK now has to look to Finland and New Zealand, two countries that have a strong public service ethos underpinning their health services, to find the answer. Some of us would not wish to miss another opportunity. It is quite clear that the NHS cannot look to the Pharmaceutical Industry to help with these issues. The NHS is going to have to help itself. This means more treatments will routinely have to be made available to patients in the context of clinical studies. 1. U Chakravarthy, G Soubrane, F Bandello, V Chong, C Creuzot- Garcher, S A Dimitrakos, J-F Korobelnik, M Larsen, J Monés, D Pauleikhoff, C J Pournaras, G Staurenghi, G Virgili and S Wolf 'Evolving European Guidance on the Medical Management of Neovascular Age Related Macular Degeneration' British Journal of Ophthalmology 2006;90:1188-1196. Competing interests: The author received £600, which was donated to Charity, from Pfizer following a meeting relating to a proposed national cohort study. |
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Usha Chakravarthy, Professor of Ophthalmology Royal Hospitals Belfast BT12 6BA, Jennifer Lim
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Editorials should provoke thought and debate and we are pleased that our editorial has achieved this as seen by the insightful comments from the BMJ readership. We agree with Professor Rafferty that there are economic factors involved that may significantly limit the availability of ranibizumab as compared to a cheaper drug. Yet, safety and efficacy are important concerns for bevacizumab. We thank Mr Cave for pointing out that the annual drug costs that we computed are higher by a factor of 10 and that the true cost is a more affordable 50 million. Even this is a high price for an annual drug bill and if as expected most patients require a second year of dosing, when steady state has been reached the annual cost will be double that of the first year costs. It is unrealistic to expect the manufacturer of bevacizumab to undertake the studies needed for licensing of this drug for the management of neovascular AMD. The lack of toxicology, dose- ranging and pharmacology studies for bevacizumab in the context of managing CNV is a concern. However bevacizumab has been administered systemically to a small group of patients and intravitreally to much larger numbers, with all of the studies consistently reporting benefit. The reality of the situation is that there is widespread use of bevacizumab and there is no data on its safety or efficacy compared with ranibizumab. We also do have a dose that can be delivered intravitreally. With this dose there is no glaring ocular or systemic side effect. Therefore we differ in our opinions from those expressed by Mr Cave that it is premature to undertake a clinical trial comparing the relative efficacies of ranibizumab to bevacizumab. We also disagree with Mr Chong that there is no clear scientific rationale for a trial comparing the two drugs. In the US, the National Eye Institute funded such a trial “the Comparison of age-related macular degeneration treatments trial (CATT) following a rigorous and thorough scientific assessment. Recruitment into the trial imminent. CATT will compare ranibizumab and bevacizumab for efficacy and safety. In addition, the monthly dosing will be compared to a regimen of three monthly doses followed by treatment as needed, addressing some of the concerns that have been expressed in response to our editorial . Individual cost and societal costs are both important. If a drug is shown to have adverse systemic side effects that require hospitalization, the final cost to society may be higher as pointed out by VC. It is therefore extremely important to determine if bevacizumab has a safety profile similar to ranibizumab. CATT will address this issue. We never intended to convey the impression that bevacizumab is identical to Ranibizumab (as pointed out by Mr Cave). The Fab fragment of ranibizumab has a binding site that was affinity matured such that there is a140 fold increase in the binding affinity to VEGF. Also, bevacizumab, has two VEGF binding sites. This aside both stem from a common monoclonal antibody Long term post-marketing surveillance is important and we agree with the eloquently expressed sentiments by Dr Badrinath. As Genentech’s Phase IV SAILOR study has shown, post-marketing surveillance can be useful in identifying safety concerns that the phase III studies did not reveal. We too believe that Genentech was a good corporate citizen in its monitoring and reporting of the safety data. Competing interests: None declared |
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