NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

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1 NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE Health Technology Appraisal Erythropoietin for anaemia induced by cancer treatment Response to public comments on the ACD Consultee / Commentator Academic Researcher Academic Researcher Section Comment Response Consideration of the Evidence Research The committee are correct in noting that several HRQOL studies have been poor quality, yet these have generally improved in the last three years, providing somewhat stronger (but not absolute) evidence for the benefits of EPO on QOL (Bottomley A, Thomas R, Van Steen K, Flechtner H, Djulbegovic B. Human recombinant erythropoietin and quality of life: A wonder drug or something to wonder about? The Lancet Oncology 2002;3(3):145-53). It is also important that the committee are aware that there could well exist publication bias towards positive QOL results. It is also a common observation that much repeated publication of trial results are in the literature, which unless critically evaluated could bias any reader. There is also a flood of sub-optimal, none systematic EPO reviews focused on QOL. However, with that said, better QOL evidence in beginning to emerge, although often studies report unplanned sub-analysis, etc. The committee should therefore give stronger recommendations for better quality research into QOL addressing many of the limitations noted in the Bottomley et al and several other independent reviews. These were also noted in a small part in the ASCO/ASH guideline I suggest making more significant statement for the need for high quality in QOL studies, in order to address common mistakes seen in RTC of QOL research. The Committee has recommended that further research be conducted into the effects of erythropoietin on health related quality of life (see FAD paragraph 5.1) 1

2 Academic Researcher Academic Researcher Beating Bowel Cancer Implementation & Audit Review Date It is not clear to what extent other groups, that is, ASCO and ASH have been consulted in producing this guidance and it may be valuable to consider other efforts before finalizing this. Given that new data for EPO use is fast emerging, and the value that this treatment can offer patients, it may be better that this review is re-visited in 2007 rather than Beating Bowel Cancer, the UK s leading charity for bowel cancer patients. urges NICE to reconsider their provisional guidance that erythropoietin products are not recommended for use in people with cancer-treatment induced anaemia. Comments noted and FAD amended accordingly (paragraph ). The Committee feels that the review date is appropriate in view of ongoing clinical studies. Beating Bowel Cancer General Beating Bowel Cancer is committed to safeguarding the quality of life for people with bowel cancer and believes that by removing a safe and effective treatment for cancer-treatment induced anaemia, more patients will suffer from the debilitating symptoms of anaemia, such as fatigue. Fatigue is an incapacitating condition that makes even simple daily tasks, such as getting out of bed, a major challenge. Up to 78% of cancer patients suffer from fatigue. Anaemia, and its associated symptoms, are often cited as the most disruptive side effects of treatment more so than the pain associated with the cancer itself. When every day counts, patients do not want to be too tired to live. The Committee has considered these comments and fully appreciated the degree to which anaemia may contribute to feelings of fatigue in cancer patients. It also understood that there are a variety of other causes of fatigue in this patient group and therefore decided not to change its recommendation. Beating Bowel Cancer Beating Bowel Cancer believes that patients should have as broad a choice in their treatment regimen as possible. Currently in the UK, blood transfusions have been the only other treatment choice for people with cancer-treatment induced anaemia. Presently, many patients receive little choice over treatment for cancer-treatment induced anaemia. By removing the use of erythropoietin products in the treatment of cancertreatment induced anaemia, the options for patients are being reduced still further. 2

3 Beating Bowel Cancer Beating Bowel Cancer believes that patients should be free to choose the best and most effective treatments for their condition irrespective of cost. By removing erythropoietin products as a treatment option, cancer patients with moderate to severe anaemia will be forced to undergo lengthy and inconvenient blood transfusions often requiring a hospital stay, which can further impact quality of life and cause difficulties for patients to return to work or care for their families. Erythropoietin products have been seen to have a greater effect on haemoglobin levels than blood transfusion, are effective for longer, and reduce the need for blood transfusion. Although respect for autonomy, and individual choice, are important for the and its users, they should not have the consequence of promoting the use of interventions that are not clinically and/or cost effective (Social Value Judgements - Principles for the development of NICE guidance; principle 5) Carer 1 As a carer of a myeloma suffer I am very concerned at the prospect of the withdrawal of EPO. This will mean multiple transfusions may be required in the future to control the anaemia and fatigue synonymous with this condition. Blood transfusions these days pose a very significant risk. I therefore urge you to reconsider your decision and continue to allow the prescribing of this category of drugs for all patients where their medical practitioners deem it necessary. Carer 2 It should specifically state that this does not affect its use as part of the cancer treatment for cancers like my wife s multiple myeloma, which can affect the body s natural production, to avoid misinterpretation. In such cases chemotherapy may exacerbate the condition and one can see some bureaucrat interpreting that if any percentage of the anaemia might have been caused by the treatment then the drug should be withdrawn whether or not it was already being used prior to treatment. Please note that this appraisal only covers the treatment of anaemia which is caused by cancer treatment and does not cover all cancer-induced anaemia. A sentence has been added in the Guidance section of the FAD to clarify this. 3

4 Carer 2 Carer 2 Myeloma is notoriously difficult to treat and requires the use of whatever treatments are available at the maximum strength the patient can withstand. Anything less may compromise the outcome and require earlier further treatment than should have been required costing the more. Suggesting lowering the dosage to avoid anaemia when there is a perfectly effective support drug is wasting resources and endangering lives unnecessarily (there seem to be only so many drugs which myeloma responds to but only partially as it develops "immunity" to thema lower dosage may affect the patients state of health and encourage the development of "immune" strains. Surely if a European dimension is to be included then European practice and use of the drugs should be identified as well. On the basis of this evidence alone is this not an argument for it being recommended for lymphoma/myeloma and gynaecological cancers. The comment regarding the adjustment of treatment regimens is not intended to be prescriptive. It simply describes what sometimes happens in clinical practice at present. The systematic review of clinical effectiveness included studies from all over the world. The Committee acknowledged that erythropoietin appears to be more widely used in other countries but still feels that its recommendation is appropriate on the basis of the currently available evidence. Carer 2 Assuming that the treatment levels have been correctly identified on clinical grounds how can adjusting them be a real option - are you suggesting that the uses unreasonable levels of treatment and if so surely this should be the subject of another investigation. Carer 2 Does not also identify the physical difficulties of giving severely emaciated patients large numbers of transfusions. Carer 2 The Technologies The 70kg patient is misleading - the majority of cancer patients loose a great deal of weight - my wife dropped to 35kg was on a feeding tube and on a special anti-sore bed. This is the difference between guestimates and reality which seems to permeate this document! The comment regarding the adjustment of treatment regimens is not intended to be prescriptive. It simply describes what sometimes happens in clinical practice at present. 4

5 Carer 2 Clinical Effectiveness implies that insufficient clinical effectiveness information exists - this means that you have not yet found out/done enough work to identify whether the drug is a life saver or a waste of money. There is enough evidence to suggest that it has some valuable uses but I am appalled that you should decide to not recommend based on your lack of information to the contrary because the drugs are expensive. Carer 2 Cost Effectiveness this appears to be statistical gobbledygook - is the committee hiding behind jargon and misdirection regarding cost effectiveness? Carer 2 Consideration of the Evidence Carer 2 Carer 2 Carer 2 Consideration of the Evidence Research Research despite being persuaded that transfusion therapy to achieve a sustained and prolonged increase in haemoglobin levels would be time consuming and inconvenient for most patients, and trials of this type would be difficult to undertake the committee is recommending that instead of trials this should be the way it has to be done for those who require it if it is not within the scope of this appraisal to consider the relative cost effectiveness of erythropoietin how can it come to a reasonable recommendation based on costs. 5.1 Is this not what the committee needs before issuing its recommendations. A bit like closing the stable door In an environment where clinicians cannot use this because of the committee s recommendations who is going to fund the research - this has to be identified if any independent research is to take place. Carer 2 Resource Impact If the committee is recommending research it is increasing the costs to the - if it is not then section 5 needs amendment. Carer 2 Implementation & Since you have already stated that your clinical data is not without Audit prejudices how can implementation and audit based on recommendations based on that really take place. Carer 2 Related Guidance I am amazed that you consider no guidance to be necessary - how will you explain this to patients like my wife and their families. I read this shambles of a document with declared poor clinical data and wonder what recommendation you would come to as to whether there should be hospitals - is there real evidence that they are worth their cost? This section has been reworded in the FAD to clarify its meaning. (see FAD ). Carer 2 Review Date Is this when you expect research to be completed by? 5

6 Professional 1 Professional 2 Evidence & Interpretation I am a Haemato-oncology Clinical Nurse Specialist at a large acute trust. We have many patients with Myeloma under our care as we have a large Renal unit. I strongly disagree with the preliminary decision regarding the use of EPO in treating anaemia in people with Myeloma. Many of my previous and existing patients have benefited from the use of EPO. It has an enormous positive impact on their quality of life. The use of EPO maintains their Hb at a constant level. Because of the kidney damage caused by the Myeloma patients usually have low levels of naturally occurring EPO. Myeloma patients should receive special consideration.. I sincerely hope NICE will reconsider there decision. I am concerned that your guidance on the use of erythropoietin for chemotherapy induced anaemia if implemented will disadvantage many patients with Myeloma. There needs to be a clear distinction between chemotherapy induced anaemia as is seen in the treatment of solid tumours and that seen in haemopoetic malignancies when the chemotherapy induced anaemia is compounded by marrow infiltration. In Myeloma however the picture is further complicated by the renal impairment which commonly accompanies this disease; % at presentation < 50 % at sometime in the illness. As a result patients with myeloma are usually exquisitely sensitive to EPO and often do not need the full manufacturers recommended dose. Thus the cost / benefit analysis in this group of patients is considerably in favour of its use and there are great quality of life gains. Please note that this appraisal only covers the treatment of anaemia which is caused by cancer treatment and does not cover all cancer-induced anaemia. The Committee discussed whether subgroups of patients may be treated cost-effectively with erythropoietin but felt that the evidence base was currently insufficient to support subgroup recommendations. The recommendations were therefore unchanged. The Committee discussed whether subgroups of patients may be treated cost-effectively with erythropoietin but felt that the evidence base was currently insufficient to support subgroup recommendations. The recommendations were therefore unchanged. 6

7 Professional 2 Professional 2 Professional 2 Clinical Effectiveness We have audited a mixed group of haematology patients and I will attach this audit for your information. We found that myeloma patients were the most likely to benefit and that they needed a smaller amount of EPO that recommended to achieve the desired effect. We have reduced the number of visits to hospital for these patients Given the skeletal problems of myeloma patients often resulting in severe pain and immobility it is a considerable benefit to these patients not to have to travel up to hospital be portered to a day unit to spend hours sitting in less than an ideal environment. Use of Erythropoietin also means that there is a steady level of haemoglobin and thus performance something usually difficult to achieve with blood transfusion. The other point that has not been examined as closely as it should is the inconsistency of the advice not to use erythropoietin at a time when medical staff are being exhorted to reduce use of blood. Blood is scarce and likely to become more so. Why would we want to use blood when there is an alternative which is better and safer for patients and if used judiciously is cost effective as well? Results noted. The Committee discussed the impact of this guidance on the supply of blood for transfusion but decided not to change its recommendation (see FAD paragraph ) Professional 2 I would urge the group to reconsider their decision and especially to consider the complex mechanisms of anaemia in different patient groups to which the guidance must be sensitive. The Committee discussed whether subgroups of patients may be treated cost-effectively with erythropoietin but felt that the evidence base was currently insufficient to support subgroup recommendations. The recommendations were therefore unchanged. 7

8 Professional 3 Clinical Effectiveness The first process flaw appears to have been in the search strategy for trials. Missing out the major European Cancer meetings in favour of the American ones is very obvious (e.g. ESTRO, ESMO, ECCO). Even when you have told us that a meeting has been searched (e.g. ASCO 2004), you have missed trials. Can I suggest that as a minimum you add to your review Professional 3 Professional 3 Clinical Effectiveness 1 - the meta-analysis of Clark O. BMC Cancer Sep 24;2(1):23.Erythropoietin, uncertainty principle and cancer related anaemia. This was a Systematic Review (SR) of the published literature on the role of EPO in cancer-related anaemia. 2- the randomised trial of Antonadou D, Cardamakis E, Puglisi M, Malamos N, Throuvalas N. Erythropoietin enhances radiation treatment efficacy in patients with pelvic malignancies. Final results of a randomised phase III study. Eur J Cancer. 2001;37(suppl 6):s144. I worry that your conclusion appears to suggest that the licence for the use of Epos in anaemic cancer patients is without evidence and unsafe outside a trial. Does the EMA and FDA endorse this? The second issue is with the grouping together of all Epo trials in cancer into one meta-analysis You have claimed in the NICE appraisal document that there were good reasons why these trials should all be reviewed together. If you analyse these trial groups separately, then if the outcome is the same, the review will be believed. If the analysis is different for these groups, then the biological plausibility that NICE has suggested is not easy to defend. The Committee requested that further analysis be undertaken to determine the impact of restricting the survival metaanalysis to RCTs reflecting the licensed indications and the appraisal scope. Professional 3 Clinical Effectiveness In terms of trial searches, were the panel aware of the body of evidence for transfusion correction of anaemia having impact on cancer control? These studies are the justification for the standard UK and international practice to transfuse cancer patients during curative radiotherapy and chemo-radiotherapy. 8

9 Professional 3 Professional 3 Clinical Effectiveness Cost Effectiveness Issues with biologically plausible clinical and pre-clinical studies that Epo could promote cancer growth. The quickest way to answer this would be to have a meta-analysis of trials to show that Epo, when used in anaemic patients, had worse rates of tumour control to control non-epo arms of trials. Again, separate anaemic patients with solid cancers and haematological malignancy. Many trials had tumour response or local control data to analyse this simply. The first Cochrane review of 2004 suggested a benefit of improved response in Epo arms over control for anaemic patients. 385 patients from the Greek study would add even more data to secure this endpoint. NICE seems to have taken the most extreme use likely for Epos. My experience, and that of ECAS, is that few patients start cancer treatment anaemic, but many will fall into the NCCN/ASCO/ASH/EORTC guideline levels after 2-3 cycles of treatment. Prescriptions would therefore be likely for weeks, not six months. This would affect the process of CE analysis. The text regarding the cost of a course of treatment has been amended in the FAD to reflect these comments. The Committee discussed the impact of changing the assumption regarding the number of cycles of chemotherapy used in economic model with the Assessment Group and heard from the Assessment Group that this was unlikely to have a significant impact on the results of the costeffectiveness analysis. This assumption therefore remains unchanged. Professional 3 Cost Effectiveness Did you survey current UK and European prescribing patterns for the analysis, or was this left out of the process? 9

10 Professional 3 Cost Effectiveness The significant benefit of keeping patients out of bed, and with unrestricted activity doesn't seem to be reflected in the NICE analysis of simpler outcomes than QOL scores. The effect of this on patients carers, families and on hospital admissions doesn't seem to have been part of the process of review. This aspect alone could contribute towards and UK government targets for reducing unplanned admissions to hospitals. Mike Richards, the National Cancer "Czar" told us that on any one day people with cancer are occupying a hospital bed and 50% of the total spent on cancer services is spent on hotel costs and associated nursing care". [Richards M. The Challenges Ahead. RT Managers development. London. 1st Feb, 2005]. Professional 3 Professional 3 Professional 4 General The process is supposed to look at equity of access. What now is the target for correcting anaemia in renal failure compared with cancer? Overall cancer doctors and nurses are not great advocates for investigating or treating cancer fatigue. Studies show that even when we have been told that a patient rates pain and fatigue as the equal top priority for treatment, we rank pain first and leave the fatigue issues fifth! Will it be still available for the Jehovah s witness patients undergoing chemotherapy, radiotherapy and surgery as it currently? The consideration of the use of erythropoietin in patients with renal failure is outside the scope of this appraisal. 10

11 Professional 5 Professional 5 Professional 5 Professional 5 Professional 5 Research Anaemia for many patients that I treat with or without cancer is disabling and long term. I have in my practice many patients with cancer related anaemia whose Qol has been greatly enhanced by EPO. They have little need to come to Hospital, require less hospital admissions for transfusion or its follow on complications and are more adjusted to their treatment. There are many hidden costs of transfusions which become apparent later on during clinical course of the illness such as iron overload or transfusion reactions, infections etc. Also EPO can downstage disease categories and may delay institution of chemotherapy. I feel that this is a worthwhile therapy for the restricted resources that many patients want and feel immensely grateful for. Restriction of its use as is current practice in the is disheartening to the clinicians like myself and to the patients who have a lot to cope with their illness. With successful therapy many of the patients require only small maintenance doses which are as cost effective as fast disappearing blood transfusion stocks. Who is going to fund these needed research? The whose focus is on balancing financial books or the Industry whose motives are viewed as suspicious? There are other non malignant conditions where profound anaemia occurs such as Diabetes, Rheumatoid Arthritis that respond as well to EPO. I feel that these should have been considered as well as it will take another decade before these unrecognised groups in terms of political profile are looked at. Clinical Effectiveness The data out there show that EPO is a very useful agent in patients with anaemia secondary to cancer. The initial studies were not powered to answer survival questions which is what the government think thank want to see. In patients with malignant conditions QOL is a big issue and many are grateful for a shorter well spent life than long life with restrictions Many patients will prefer not to have blood given choice. It is less convenient. Hospital car parks are overfilled with people coming in for this procedure. There are also many hidden costs of transfusion that providers do not take into account when calculating cost effectiveness of EPO such as Iron overload, line related infections. The Committee discussed the cost of blood transfusion and were satisfied that it had not been substantially underestimated. The consideration of the use of erythropoietin in patients other than those with cancer treatment induced anaemia is outside the scope of this appraisal. The Committee discussed this issue and felt that quality of life was addressed as adequately as possible within the utility component of the Assessment Group s economic model. This issue has been considered by the Committee (see FAD 4.3.3) 11

12 Professional 5 Professional 5 The Technologies Resource Impact Many responsive patient such as Lymphoma, myeloma become transfusion independent with successful treatment of the underlying process so that it is not a recurrent cost. In many cases, a small maintenance dose is required which is less costly such as 4,00iu/week EPO This will have a major impact on resources but would lead to a healthier Nation. Our neighbours in Nordic counties are using EPO in a less restricted manner and we all attribute their healthy state to access to "" cutting edge""2 medical care. If they can fund it, so should the UK in my personal opinion. The Committee acknowledged that erythropoietin appears to be more widely used in other countries but still feels that its recommendation is appropriate on the basis of the currently available evidence. Professional 5 Professional 6 Review Date Too long. There are numerous patients with malignant and non malignant conditions who are awaiting the outcome of this review. They will be disappointed to know that for another 3 yrs, their access to a drug which has been show to impact on their health has been denied. Lack of data to support survival does not mean absence of proof. I agree that well designed large scale studies are needed but in short term NICE should issue out guidance on use of EPO in patients already on the ground who deserve these therapy. The appraisal consultation document on Erythropoietin for anaemia induced by cancer treatment appears to display a touching faith in the efficacy of blood transfusion. It is disappointing that, in an otherwise objective study, there was no critical assessment of the supposed benefits of blood transfusion. This may be because the claims that blood transfusions save lives and ameliorate the symptoms of anaemia have been accepted at face value. I have been unable to find any objective evidence to support these beliefs. If there is no evidence to justify transfusion, then the comparisons made in this document with the cost of transfusion as an alternative to erythropoietin therapy for anaemia will have been false. Unless the are demonstrable benefits to the patient as a result of transfusion in cancer-therapy then perhaps the practice should be more actively discouraged. The Committee feels that the review date is appropriate in view of ongoing clinical studies. 12

13 Professional 7 Professional 7 Professional 8 Professional 9 Clinical Effectiveness Cost Effectiveness In pou hospital we have seen a benefit from a quality of life perspective with a high percentage of patients - (especially Myeloma patients ) receiving Erythropoietin, this has led to less symptoms during treatment and fewer admissions to hospital. From a cost effectiveness perspective, It must be more cost effective to administer a regular injection than risk complications of anaemia which lead patients being admitted into hospital for a number of days, Patients often require admission throughout their cancer journey, if we can limit the number of admission it not only benefits the organisation but gives a the patient more time at home supported by their family I am concerned that all cancer related anaemia may not be treated with such drugs. For example in myeloma, anaemia can be caused by a variety of causes, some of which a very amenable to EPO. Health authorities may let myeloma patients be categorised in the guidance because they have received chemotherapy and ignore the other causes which would deny them appropriate treatment and put them to inconvenience and risk of blood product associated complications. Many patients benefit significantly from the use of Epo to combat chemotherapy/radiotherapy induced anaemia. Anaemia significantly reduces the QOL and experience of cancer treatment for a large % of such patients and therefore should be available for use if clinically indicated. In addition there are some conditions such as myeloma where the cause of anaemia is multifaceted and this will create a grey area when confronted by PCT s making decisions on who should and who shouldn t have access to EPO. A sentence has been added in the Guidance section of the FAD to clarify this. A sentence has been added in the Guidance section of the FAD to clarify this. 13

14 Professional 10 Professional 11 Professional 11 Professional 11 Clinical Effectiveness Clinical Effectiveness The situation for myeloma is different to that in other cancers - please refer to the UK Myeloma Forum & The Nordic Myeloma Study Group Guidelines on the Diagnosis and Management of Multiple Myeloma There is good evidence, including double blind studies, for the use of EPO in myeloma patients with symptomatic anaemia whilst undergoing chemotherapy. I note that there is no haematologist on the Appraisal Committee. My clinical experience is that erythropoietin is a very effective drug for alleviating the fatigue of some patients with cancer-treatment related anaemia. Many patients benefit a lot, some gain a little benefit and others do not feel any improvement. The preliminary decision from NICE will deny all patients the chance to obtain relief of symptoms from anaemia. There is no acceptable alternative because there are no data to suggest that blood transfusion improves patients quality of life in this setting although transfusion can rescue patients from life-threatening, severe anaemia. The provisional decision of NICE will also deny access to erythropoietin to those patients who for religious (Jehovah s witnesses) or personal choice reasons will not accept blood transfusions. One of the experts at the meeting on June 7th said that he did not use erythropoietin for people with potentially curative tumours. I do not know of other people expressing the same concern and I know that across the world the erythropoietic agents are widely used for patients with curable diseases such as lymphoma. Please note that this appraisal is restricted to anaemia induced by cancer treatment. It does not cover anaemia in cancer patients which is not related to treatment. The Appraisal Committee is a standing committee whose membership remains the same for each topic under consideration. The Committee relies on participating consultees and invited experts to provide specialist expertise. 14

15 Professional 11 Professional 11 Professional 11 Professional 12 Professional 12 Research Resource Impact Recommendation You suggest that further research is needed on both quality of life and survival. Many studies addressing this latter issue are in progress or close to being reported. Most people feel that the quality of life data in the large randomized trials is of high quality even though it does not look at utility scores. It is increasingly difficult or impossible to do randomized trials of the erythropoietic agents looking at quality of life in many European countries because it is deemed unethical because so much data already exist. This analysis assumes that all patients treated with erythropoietin will be treated for a full course at full dose. One third of patients do not respond and will have treatment stopped after 4-8 weeks. I hope very much that the NICE conclusion can be reversed. If not you should make it absolutely clear (which it is not in your conclusion) that the ruling applies only to anaemia induced by treatment in patients with cancer and that the role of erythropoietin in cancer associated anaemia (non-treatment related), post transplant, in myelodysplasia, and other settings is not included in the analysis. Epo is currently being used to treat disease related anaemia (such as in myeloma) and although this guidance relates to treatment related anaemia there could be confusion. How will the anaemia be differentiated in order to use Epo for disease related anaemia as oppose to treatment related? Clinical need appears to strongly indicate the need for Epo especially in haematological cancers where anaemia is an extremely common issue. The resource impact section is being been updated by the NICE Costing Unit. A sentence has been added in the Guidance section of the FAD to clarify this. The Committee discussed whether subgroups of patients may be treated cost-effectively with erythropoietin but felt that the evidence base was currently insufficient to support subgroup recommendations. The recommendations were therefore unchanged. 15

16 Professional 12 Professional 12 Professional 12 Evidence & Interpretation Evidence & Interpretation Resource Impact The use of Epo has a far less detrimental effect on patients daily life as oppose to blood transfusion which means additional visits to hospital and short stays. Patients with haematological malignancies benefit hugely from the use of Epo in their general well being and quality of life Survival should not be a strong factor but quality of life for these patients. It is obvious there is a clear need for further research however in the interim the use of Epo should continue as it is Although cost is an important consideration and there is a finite financial resource perhaps the use of Epo could be considered in haematological malignancies. These patients frequently need numerous transfusions and the impact on their quality of life is huge whereas the use of Epo would be managed out of the hospital setting The Committee acknowledges this in paragraph of the FAD. The Committee discussed whether subgroups of patients may be treated cost-effectively with erythropoietin but felt that the evidence base was currently insufficient to support subgroup recommendations. The recommendations were therefore unchanged. Professional 13 Professional 13 Research It is unfortunate that the appraisal has been so restrictive as there are many patients with cancer (not currently having treatment, and including myelodysplastic syndrome) who actually benefit from erythropoietin. In addition the product is used pre-operatively to improve haemoglobin and is used post transplant in BMT to maintain haemoglobin in some cases. Patients with anaemia of chronic disease also respond. International bodies such as the American Society of Haematology and Clinical Oncology have both published guidelines which support its role in exactly this setting. Studies cannot be carried out in North America or Europe where erythropoietin would be randomised against best supportive care as this would be considered un-ethical. The products are widely used across Europe and North America for this indication - do we believe that they have interpreted the data incorrectly. The consideration of the use of erythropoietin in patients other than those with cancer treatment induced anaemia is outside the scope of this appraisal. 16

17 Professional 13 There is no question that anaemia is a clinical problem in cancer care. if a non cancer patient came to clinic with a haemoglobin of 8.5-9g/dl significant investigation would occur and attempts would be made to normalise the haemoglobin to 12g/dl. Because epo is not funded these patients receive 3-4 units of blood, however the cancer patient has to accept the anaemia or be told that fluctuation will occur and that they may need a transfusion to get them to g/dl. Patients are under transfused. In section 2.6 it is suggested that the underlying cancer regimen is modified. This is an unacceptable as the whole point of protocols is that they are delivered at full dose and on time. The aim in many disorders is curative and the idea of modification is counterintuitive. Many patients with cancer have iron overload already and iron supplementation may give rise to cardiac toxicity. Transfusion is an option but societal costs as well as the limited local resource costs need to be factored in. The Better Blood HSC 2002/009 emphasises avoiding blood transfusion and making sure that patients are informed of their choices - we are doing neither. The SHOT report emphasizes the real risk The comment regarding the adjustment of treatment regimens is not intended to be prescriptive. It simply describes what sometimes happens in clinical practice at present. Social and personal economic costs do not form part of the NICE reference case (Guide to the Methods of Technology Appraisal, section 5.3.3) The Committee discussed the potential for this guidance to conflict with the Better Blood initiative but decided not to change its recommendation (see FAD paragraph ). 17

18 Professional 13 The Technologies The product is very safe and has been used in thousands of cases worldwide. Patients die or have significant morbidity with blood transfusion. Blood transfusion as safe as we think it is has significant side effects. the cost per treatment 3.8 is an overestimate and would be closer to 2500 as most patients will only require it for some of the cycles. If there was no response it would be stopped. The text regarding the cost of a course of treatment has been amended in the FAD to reflect these comments. The Committee discussed the impact of changing the assumption regarding the number of cycles of chemotherapy used in economic model with the Assessment Group and heard from the Assessment Group that this was unlikely to have a significant impact on the results of the costeffectiveness analysis. This assumption therefore remains unchanged. 18

19 Professional 13 Clinical Effectiveness Epo increase haemoglobin in all the studies. However unlike renal disease it does not do it in all cases and identifying these cases has been problematic. the relative comparison with blood transfusion is flawed as few patients were optimally transfused to say g/dl, so, there was an unmet need. This a supportive care drug and the studies were never really powered to show survival. The drug increases haemoglobin and quality of life and if societal costs were included Epo would appear more attractive. The NBS have spent millions on universal leucodepletion, sourcing plasma from abroad, stopping people donating blood if they received transfusion post 1980, all to reduce the risk of vcjd, not obviate it. Our aim should be where possible to avoid unnecessary use of blood. Erythropoietin is one part of the armamentarium. If a CJD test was introduced in the future the blood supply would be significantly affected - we need to have the option of Epo in this setting now. No comment is made around religious groups who are unwilling to accept blood. This has to commented on. 19

20 Professional 13 Research It is unlikely from the meta-analysis data that significant survival will be accrued and the two studies where there was increased mortality were using the product outwith its licence and should therefore be viewed with some degree of scepticism. The real cost of blood transfusion and societal costs need to be identified and the increased risks to the blood service need to be identified. The Committee requested that further analysis be undertaken to determine the impact of restricting the survival metaanalysis to RCTs reflecting the licensed indications and the appraisal scope. The Committee discussed the cost of blood transfusion and were satisfied that it had not been substantially underestimated. Social and personal economic costs do not form part of the NICE reference case (Guide to the Methods of Technology Appraisal, section 5.3.3) Professional 13 Resource Impact 6.1 The averaging of 1 unit of blood per patient saved belittles the significant impact the product has in some groups of patients. We must ensure that we do not throw the baby out with the bathwater. Very few patients receive the product at present. The PCT s do not formally fund it. The oncology community will increase the stress on the transfusion service by lowering the transfusion thresholds. 20

21 Professional 14 Professional 14 Professional 14 Anaemia is present in 20-30% of patients with myeloma at presentation and will occur during treatment in the majority of patients receiving chemotherapy % of patients will require red cell transfusions and anaemia is a major cause of impaired quality of life. The use of erythropoietin has been associated with improved quality of life which continues to show improvement even beyond the accepted transfusion Hb level of 12gms/dl in patients receiving erythropoietin. The reason for this is unclear but may be due to the fact that there are Epo receptors in the brain. Patients with this disease should not be denied the opportunity to have improved quality of life whilst receiving chemotherapy. At a time when blood stocks with the NBA are at an all-time low every effort must be made to manage the use of blood stacks to ensure supplies during times of emergency are not compromised. Given the recent reports of vcjd transmission and the emergence of this virus in cattle herds in the USA which has been a major source of blood products it is likely that blood supplies are only going to become lower in the years to come. It is not realistic to suggest that adjusting the underlying cancer treatment regimen is an acceptable alternative to managing anaemia when there is evidence to suggest that best responses are seen when chemotherapy is optimised in cancer treatment. The Committee discussed the impact of this guidance on the supply of blood for transfusion but decided not to change its recommendation (see FAD paragraph ) The comment regarding the adjustment of treatment regimens is not intended to be prescriptive. It simply describes what sometimes happens in clinical practice at present. Professional 14 Cost Effectiveness The costs of erythropoietin compares favourably in those patients who respond with the costs of blood products when the additional marginal costs and personnel costs of a blood transfusion are considered. Space in the day ward, or in-patient ward (if the patients are elderly; 50% of patients with myeloma are aged >70years) is at a premium in virtually all hospital department in the UK and erythropoietin allows better management of this limited resource. The Committee were satisfied that the cost of blood transfusion, including the administration costs, had not been substantially underestimated 21

22 Professional 14 Professional 14 Clinical Effectiveness Research The use of any therapeutic intervention is associated with a risk of sideeffects. Blood products are no exception and the risk need always to be balanced against benefit and discussed with the patient when introducing a new treatment to a patient. Myeloma is one of the groups identified as being responsive to erythropoietin. Any test that might be used in the future to identify patients who are amenable to treatment with erythropoietin will incur a cost and is likely to have a false positivity rate. The most efficient way to demonstrate efficacy is to give erythropoietin for a test period and monitor the response. Suitable protocols should be put in place which would ensure appropriate use of this resource. The true cost to society of a blood transfusion has never been identified in any economic analyses. Many patients with myeloma are restricted in their activities making it difficult for them to transfer to the hospital and adding to the cost to the who often provide transportation. In the USA and Europe cancer guidelines recommend the use of erythropoietin in this situation and a randomised study against best standard of care would probably be considered unethical. Best standard care is now considered to be erythropoietin in these places and a randomised study could only be conducted in the UK. In myeloma the QoL data is compelling. Whist there is no data to support the contention that survival is compromised with the use of erythropoietin the trials that have been conducted to date have not been powered to identify any differences in survival. 22

23 Professional 14 Resource Impact These figures are realistic and we would suggest the use of erythropoietin in myeloma patients would be cost neutral. The cost of a blood transfusion has never been precisely calculated because the total cost to social has never been adequately defined. The Committee discussed whether subgroups of patients may be treated cost-effectively with erythropoietin but felt that the evidence base was currently insufficient to support subgroup recommendations. The recommendations were therefore unchanged. Professional 14 Professional 15 Review Date Clinical Effectiveness There is an urgent need for alternative management strategies for anaemia in cancer and should be reconsidered within the next 12-18months. Some flaws - data derived from unlicensed use should be removed, little information on patients views, very limited options available (chemotherapy dose reduction was undertaken within the trials, iron vitamin deficiency were exclusion criteria so not options to reduce anaemia. The Committee discussed the cost of blood transfusion and were satisfied that it had not been substantially underestimated. The Committee feels that the review date is appropriate in view of ongoing clinical studies. The Committee requested that further analysis be undertaken to determine the impact of restricting the survival metaanalysis to RCTs reflecting the licensed indications and the appraisal scope. 23

24 Professional 15 The Technologies / Resource Impact Cost is based on 6 cycles of CT median is 3-4. The text regarding the cost of a course of treatment has been amended in the FAD to reflect these comments. The Committee discussed the impact of changing the assumption regarding the number of cycles of chemotherapy used in economic model with the Assessment Group and heard from the Assessment Group that this was unlikely to have a significant impact on the results of the costeffectiveness analysis. This assumption therefore remains unchanged. Professional 15 Professional 15 Consideration of the Evidence Epo is safe at licensed doses. Standard option is not iron but nothing or blood transfusion(bt)treatment dose reduction can reduce survival and should not undertaken just for anaemia. Problem is exacerbation of anaemia of chronic disease(not iron responsive) and marrow suppression. Hb trigger for BT has consistently dropped now only severe anaemia HB<8 tend to be transfused with only 2-3 units- grossly inadequate. Comment noted. However, as many cancer patients suffer from anaemia related to iron deficiency, the Committee felt that the wording in 2.6 was appropriate 24

25 Professional 15 Professional 15 Professional 15 Professional 16 Professional 16 Professional 16 Evidence & Interpretation 1.3 only outcomes within license to be used.1.6 Stored iron is inactive without epo driver1.8 blinding not possible -not approved by ethics at the time trials conducted within license, as safe indication and problem of placebo injection in these patients.3.2 Fatigue is dominant, other causes depression usually treated anyway. inadequately treated anaemia,and yo-yo of BT, results in persisting cancer related fatigue.3.3 some patients do become BT free 3.4No service would agree repeated BT up to a normal Hb 3.6 cite evidence for debate in cancer, Epo tumour growth is a return of speculation on G-Csf years ago.3.7 consider burden on time wasting rigmarole of ensuring a`safe` BT on patient 3.8 Particular religious groups receive epo why not for other patients who would choose epo over BT?.3.9 necessary to consider relative cost given statement in 4.3.1`need to take into account etc` Resource Impact 6.1 see 3.8 cost more likely per person. See response above. Research More trials with survival endpoint ending 2005/6 Comment noted. Evidence & Data derived from unlicensed use of epos should not be considered. Interpretation Evidence & Interpretation Evidence & Interpretation Evidence & Interpretation Very very limited options are available for this condition. The Committee requested that further analysis be undertaken to determine the impact of restricting the survival metaanalysis to RCTs reflecting the licensed indications and the appraisal scope. The Committee considered the evidence submitted by patient experts, clinical specialists and professional and patient groups in accordance with NICE s Technology Appraisal process Comment noted. 25

26 Professional 16 Professional 16 The Technologies Standard option for anaemia induced by treatment is not iron but nothing or blood transfusion, the problem being exacerbation of anaemia of chronic disease and transient marrow suppression. Six courses would not be the average for advanced solid tumours for example in lung cancer a maximum of four cycles, average of two to three However, as many cancer patients suffer from anaemia related to iron deficiency, the Committee felt that the wording in 2.6 was appropriate The text regarding the cost of a course of treatment has been amended in the FAD to reflect these comments. The Committee discussed the impact of changing the assumption regarding the number of cycles of chemotherapy used in economic model with the Assessment Group and heard from the Assessment Group that this was unlikely to have a significant impact on the results of the costeffectiveness analysis. This assumption therefore remains unchanged. 26

27 Professional 16 Professional 16 Evidence & Interpretation Resource Impact only outcomes within licensed indication should be used epo enables stored iron to be used up which is inactive without the epo studies could not be blinded, ethics committees would not approve placebo injections fatigue is a dominant issue. anaemia is important and correctable, impact of anaemia on fatigue obvious to the patient epo does remove transfusion need in some patients although not all no transfusion service would agree to a RCT is it valid to use outcomes from unlicensed use? where is the evidence of a safety debate in cancer patients in licensed dosing? if the drug is truly unsafe the licence should be withdrawn; tumour cells have steroid receptors but we do not stop using prednisolone! what about the burden on patients and staff of time spent trying to arrange a bed for a transfusion Jehovah s witnesses currently receive epo on religious grounds, why should there be discrimination against other patients? relative cost should be considered Savings likely to be less, probably only 2K-2.5K per person as costs originally based on six courses which average patient does not receive Savings likely to be offset by increased use of beds for transfusion Other 1 General You refer to a document as a source of evidence -Wilson J, Yao G, Raftery J et al. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment. March, I would like to see a copy of this but can t track it down can you give me a full reference please? Patient 1 I am a patient with myeloma and have been using epoetinum alfa for several years. The difference this makes to my life now is tremendous. No more getting run down with anaemia and the chance of picking up more infections. No need to spend an uncomfortable whole day in hospital for blood transfusions, which from my experience do not have the same good effects as EPO. See above. emia_assessment_report.pdf 27