Belimumab for the treatment of autoantibody-active systemic lupus erythematosus

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1 National Institute for Health and Clinical Excellence Comment 1: the draft remit Single Technology Appraisal (STA) Belimumab for the treatment of autoantibody-active systemic lupus erythematosus Response to consultee and commentator comments on the draft remit and draft scope (pre-referral) Section Consultees Comments Action Appropriateness British Association of Dermatologists British Society for Yes, we feel it would be appropriate. Yes. No action No action CSAS This is appropriate No action GlaxoSmithKline We believe the remit is appropriate. No action LUPUS UK Yes. No action NHS Bolton Yes there is a need for guidance in this area of medicine, it is appropriate. No action National Institute for Health and Clinical Excellence Page 1 of 30

2 Section Consultees Comments Action Primary Care Society Yes this would be appropriate. Any Proposals which will lead to either the appropriate introduction of new therapies for SLE or lead to heightened awareness/improved standards of care to help us support our patients throughout their lifetime illness would be very appropriate. From the Primary Care perspective, although these are rare conditions, this is a very important area to address. Present drug regimes are often only partially effective, and toxicity of all these drugs including steroids are a major problem for both primary and secondary care in supporting these patients. Aditionally, the rarity of SLE can make it a difficult condition to detect. Not all patients present with the symptoms that are described in the Background as being "very general'. Some may have very few symptoms at onser, or silent i.e renal disease. There are two particular areas to address which are relevant to new technology. Firstly is an acknowledgment of the toxicity of current therapies. Many patients wil be taking significant amounts of oral steroids, with the additional complications of this drug treatment that are managed in primary care i.e. acne, diabetes, weight gain, cataract and effects on mood and appearance. These effects are particualry relevant to the population predominately affected by SLE, namely young women. Therefore any new technology which can act as an effective "steroid sparing agent" is urgently needed. Secondly, the "gold standard" treatments, with agents such as Cyclophosphamide, incur a risk of infertility, and any new treatment which avoids this risk is a major advance. Thirdly, one of the major overwhelming symptoms that affects our Lupus patients is Fatigue. Often this does not respond to conventional drug treatment, is multifactorial, and is a particular difficult problem to manage in Primary Care. Any new drug which improves Fatigue in this setting is a major advance. Finally we are aware of the major increased mortality (not mentioned in the Background) of secondary Cardiovascular disease in SLE, likely due to the effects of uncontrolled inflammation but also long term steroid exposure. Following the final referral from the Department of Health, the appraisal will be planned into the technology appraisal schedule to allow as timely as possible guidance to the NHS. See comments on comparators (page 13) and on outcomes (page 14-18). National Institute for Health and Clinical Excellence Page 2 of 30

3 Section Consultees Comments Action Wording Renal Association British Association of Dermatologists British Society for This is the only new drug which has demonstrated a positive benefit in a randomised controlled trial. There is a great need for new medications with low toxicity in this challenging relapsing remitting condition. However, I'm not sure that the current level of data is adequate to justify a NICE appraisal. Yes, we feel it does. There are some errors: "seropositive" refers to positive ANA or anti-ds DNA antibodies not rheumatoid factor and indicates diagnostic of lupus and antidsdna antibodies can be used as a disease activity marker. Change "South East Asian" to "South Asian" (includes patients from India and Pakistan, relevant to UK). Mainly affects people aged years not 40years. Median age in large cohorts is about 42 years in UK. Treatment options are to control disease activity and reduce chronic damage and complications from the disease (thereby reducing symptoms and signs and preventing disability). It was agreed at the scoping workshop that an appraisal of belimumab for the treatment of autoantibodyactive systemic lupus erythematosus was appropriate. No action Scope amended accordingly. CSAS Yes. No action GlaxoSmithKline We believe the wording of the remit is appropriate. No action LUPUS UK Yes. No action NHS Bolton Yes - it should include SLE as the abbreviation. No action National Institute for Health and Clinical Excellence Page 3 of 30

4 Section Consultees Comments Action Primary Care Society Yes. No action Timing Issues Renal Association British Association of Dermatologists British Society for Yes. We do not feel that there is an undue urgency for this proposed appraisal. The suggested timing for submission of evidence seems appropriate 2 trials have met their primary end-point and license has been applied for from EMEA and FDA, so timing seems appropriate No action Following the final referral from the Department of Health, the appraisal will be planned into the technology appraisal schedule to allow as timely as possible guidance to the NHS. No action CSAS Unclear No action GlaxoSmithKline There has been little therapeutic innovation in treatments for Systemic Lupus Erythematosus (SLE) for several decades. SLE is associated with significant impact on morbidity and mortality. Belimumab has demonstrated efficacy in the management of SLE in two phase III clinical trials. GSK believe that belimumab will be a valuable treatment in the management of SLE. LUPUS UK Timing would seem appropriate. No action National Institute for Health and Clinical Excellence Page 4 of 30

5 Section Consultees Comments Action Additional comments on the draft remit NHS Bolton No comments. No action Primary Care Society Renal Association British Association of Dermatologists We are aware from Web-based news feeds that FDA have granted fast-track appraisal. If approval is given, it would be appropriate to have in place guidance from NICE to guide Primary Care funding/commissioning decisions in connection with this new technology. Not currently urgent. None Following the final referral from the Department of Health, the appraisal will be planned into the technology appraisal schedule to allow as timely as possible guidance to the NHS. It was agreed at the scoping workshop that an appraisal of belimumab for the treatment of autoantibodyactive systemic lupus erythematosus was appropriate. No action National Institute for Health and Clinical Excellence Page 5 of 30

6 Section Consultees Comments Action British Thoracic Society Although lung involvement is common in lupus, it is uncommon for severe or progressive pulmonary disease to be the dominant manifestation of disease and it is unlikely therefore that chest physicians would be in a position to consider prescribing belimumab in SLE. A possible exception is shrinking lung syndrome and it would be of interest, from a pulmonary perspective, to know if there are data on the efficacy of belimumab in this condition. Renal Association I think it is too early for this drug to be appraised. We need more data and longer follow up. It was agreed at the scoping workshop that an appraisal of belimumab for the treatment of autoantibodyactive systemic lupus erythematosus was appropriate. National Institute for Health and Clinical Excellence Page 6 of 30

7 Comment 2: the draft scope Section Consultees Comments Action Background information British Association of Dermatologists British Society for CSAS This section appears reasonable. Several points on the epidemiology: good UK data on prevalence is available and there is a clear gradient according to ethnicity. Most common in Afro- Caribbeans and Chinese, then Africans then Indo-Asians. Prevalence likey to be increasing due to inward migration and better survival. Severity of SLE is also greater in these minorities. Severity also greater in males and children. The female:male proponderance is 13:1 in UK. It is worth noting that long-term damage accrues as a result of persistent disease activity and also due to cumulative effects of steroids. Also, see comments above on wording as it is this section which needs revising. The background is incorrect and states that belimumab is for people with rheumatoid factor positive disease; it is for people seropositive for ANA and/or anti-dna and anti-sm antibodies. No action Scope amended accordingly. Scope amended accordingly. National Institute for Health and Clinical Excellence Page 7 of 30

8 GlaxoSmithKlin e The draft scope acknowledges the importance of renal disease in patients with SLE. The 15 year survival rate is 80%, with a 2.4 times higher mortality risk than the general population (1,2). It is worth noting that with the current management of SLE patients, the use of immunosupressants and corticosteriods are associated with an increased incidence of infection and cardiovascular disease. These effects contribute towards significant increases in morbidity and mortality in SLE patients. Regarding the sentence 'Seropositive SLE means that the rheumatoid factor blood test is positive, and indicates a more severe disease course', rheumatoid factor is specific for rheumatoid arthritis not SLE. In GSK trials, 'seropositive' or 'serologically active' is defined as Hep-2 ANA 1:80 and/or anti-dsdna 30 IU/mL. This sentence was removed from the scope as belimumab is being studied in patients with autoantibody-positive SLE. The management of SLE patients is complex with a variety of agents currently used as standard of care. In order to accurately reflect this, mycophenolate mofetil should be included in the list of immunosupressive agents as it is now commonly used in the management of SLE patients. Although there is limited evidence to support its use, rituximab is routinely used in the more severe patient population and should therefore be considered as a potential comparator treatment. Of the current treatments used for the management of SLE, only prednisolone, azathioprine and hydroxychloroquine have an indication for SLE, whereas the other interventions routinely used are unlicensed for this indication. Hydroxychloroquine is spelt incorrectly. Mycophenolate mofetil was added to standard therapy in the comparators in the scope. The following comparators were added to the scope: For people in whom rituximab is considered appropriate: Rituximab plus standard care For people in whom cyclophosphamide is considered appropriate: Cyclophosphamide plus standard care. Scope amended accordingly. National Institute for Health and Clinical Excellence Page 8 of 30

9 LUPUS UK Accurate, but see Population below. No action NHS Bolton Primary Care Society The background is incorrect and states that belimumab is for people with rheumatoid factor positive disease; it is for people seropositive for ANA and/or anti-dna and anti-sm antibodies. Perhaps standard therapy should also include unlicensed alternatives also. Rituximab (unlicensed) is sometimes used in practice for more severe cases of SLE. There is an innacuracy in the description of the term "Seropositive" SLE. The correct description of this terminology is that an Anti-nuclear Antibody test is present i.e. it is not the Rheumatoid Factor test that is positive and it is not connected with prognosis Hydroxychloroquine is mis-spelt in the draft. It would be appropriate to highlight in the Background the difficulties that GPs and also some Specialists can face in both recognising, and assessing, whether their patients symptoms are due to SLE or not. This difficulty is a reflection of the large number of body systems that the illness can affect, and the lack of one single disease-monitoring blood tests, which can make the designation of either active or inactive disease difficult, particulary in Primary Care. It would also be appropriate for the Background to make reference to the additional impact on general health aside from the direct impact of disease activity, including the adverse effects of long term steroid, the potential effects of current (cytotoxic) drugs on fertility, the impact of fatigue, and the long term cardiovascular risks of this condition. Scope amended accordingly. The following comparators have been added to the scope: For people in whom rituximab is considered appropriate: Rituximab plus standard care For people in whom cyclophosphamide is considered appropriate: Cyclophosphamide plus standard caresome Scope amended accordingly. National Institute for Health and Clinical Excellence Page 9 of 30

10 Section Consultees Comments Action Renal There are errors of fact in the background. The sentence "SLE is This Association characterised by unpredictable flares and is the most common form of sentence was removed from lupus" does not make sense. The sentence "Seropositive SLE means that the rheumatoid factor blood test is positive, and indicates a more severe disease course" is the scope. Scope amended accordingly. erroneous - SLE requires the presence of an ANA not rheumatoid factor and indeed the phrase "seropositive" isn't usually used in SLE. The technology/ intervention British Association of Dermatologists British Society for Standard drugs include Mycophenolate mofetil rather than methotrexate. It appears to be. Yes: note it is a monthly IV infusion currently given in hospitals but there is a low infusion reaction rate. It was agreed at the scoping workshop that both methotrexate and mycophenolate mofetil constitute standard therapy for the treatment of SLE. No action No action CSAS This appears accurate. Could add dose and frequency of administration. GlaxoSmithKlin e In the description of the technology the draft scope mentions 'In SLE, elevated BLyS levels contribute to the production of autoantibodies' it is also worth noting that elevated BLyS levels have been associated with increased SLE disease activity (3). Scope amended accordingly. LUPUS UK Yes. No action NHS Bolton This appears to be accurate. Could include dose and frequency of administration. National Institute for Health and Clinical Excellence Page 10 of 30

11 Section Consultees Comments Action Primary Care Society Yes. No action Population Renal Association British Association of Dermatologists British Society for CSAS GlaxoSmithKlin e Yes. Perhaps consideration should be given to also including SLE patients who do not have a circulating rheumatoid factor. Yes: should consider the SLE population as a group although it would be reasonable to exclude patients with active lupus nephritis as these were excluded from the trials This appears complete. Seropositivity isn't required for diagnosis of SLE and so reportedly by implication this treament is reserved for consideration in severe disease only. May need to consider at what stage belimumab would be considered, i.e. NSAIDs would often be administered first line followed by hydroxychloroquine and/or prednisone and then immunosuppressives. SLE is a multi-organ disease and there may be certain sub-groups within the anticipated licensed indication which NICE may wish to consider separately. These include those patients with high disease actvity and/or those with major organ involvement associated with increased morbidity and mortality. No action It was agreed at the scoping workshop that the population should be defined as adults with autoantibody-positive systemic lupus erythematosus. It was agreed at the scoping workshop that the population should be defined as adults with autoantibody-positive systemic lupus erythematosus. It was agreed at the scoping workshop that no subgroups should be defined separately in the scope. LUPUS UK We believethat the figure of 15,000 people with SLE is too low. National Institute for Health and Clinical Excellence Page 11 of 30

12 NHS Bolton This appears complete. Seropositivity is not required for diagnosis of SLE and so reportedly by implication this treatment is reserved for consideration in severe disease only. In addition this treatment should be considered for higherrisk patients only due to the cost implications this is likely to have, being a biologic type drug. Criteria for commencing treatment would need to be defined e.g. at what stage belimumab would be considered (i.e. NSAIDs would often be administered first line followed by hydroxychloroquine and/or presnisolone and then immunosuppresives). Previous drug therapies/failure of these/intolerances should also be considered. Primary Care Society Renal Association Royal College of Physicians We are not aware of any information regarding specific subgroups in whom Belimumab is likely to be more effective. However, the disproportional prevalence of the disease in non-white UK populations specifically African- Caribbean and South East Asian should be noted. No - patients should be defined according to standard criteria - this would currently be the ACR definition of SLE. "seropositive" patients is an inadequate description. It would be very interesting to review patients with lupus nephritis separately but there is no good evidence as yet The scoping exercise may limit itself to adults. This is a potential weakness as lupus is a disease that affects children and ultimately the long term implications are greater if optimum treatment is not used. It was agreed at the scoping workshop that the population should be defined as adults with autoantibody-positive systemic lupus erythematosus. It was agreed at the scoping workshop that no subgroups should be defined separately in the scope. It was agreed at the scoping workshop that the population should be defined as adults with autoantibody-positive systemic lupus erythematosus. The proposed marketing authorisation for belimumab is for adult patients only. It was agreed at the scoping workshop that the population should be defined as adults with autoantibody-positive systemic lupus erythematosus. National Institute for Health and Clinical Excellence Page 12 of 30

13 Comparators British Association of Dermatologists British Society for CSAS GlaxoSmithKlin e We feel this is the case. We do not feel that there is an unequivocal 'best drug'. Standard therapy is all off-licence including antimalarials, steroids, immunosuppressives including azathioprine, cyclophosphamide (also given by IV route), methotrexate, mycophenolate mofetil ciclosporin and rituximab. All are used routinely in active patients. The studies were drug against placebo with continued background immunosuppression with prednisolone, hydroxychloroquine, azathioprine, methotrexate or mycophenolate is varing combinations. These are current standard drugs though only prednisolone and hydroxychloroquine are licensed for lupus. Comparator should be standard therapy plus placebo. Standard therapy would be NSAIDS and hydroxychloroquine and/or prednisone, which are currently licensed. Immunosuppressives may be added. Other newer treatments being researched include mycophenolate mofetil (CellCept) and the use of stem cell therapy. Mycophenolate mofetil should also be considered as as part of standard of care, as it is routinely used in the management of SLE. As mentioned previously, rituximab is routinely used in the management of more severe SLE patients and is therefore an appropriate comparator. It is worth noting that in the pivotal phase III trials, belimumab was used in addition to standard of care, not instead of standard of care. No action It was agreed at the scoping workshop that the comparators should be defined as: Standard therapy without belimumab For people in whom rituximab is considered appropriate: Rituximab plus standard care For people in whom cyclophosphamide is considered appropriate: Cyclophosphamide plus standard caresome See comment above. See comment above. National Institute for Health and Clinical Excellence Page 13 of 30

14 Outcomes LUPUS UK Yes. No action NHS Bolton Primary Care Society Renal Association British Association of Dermatologists Comparator should be standard therapy plus placebo. Standard therapy would be NSAIDs and hydroxychloroquine and/or prednisolone, which are currently licensed. Immunosuppresssives may be added (methotrexate, azathioprine, ciclosporin, tacrolimus, cyclophosphamide (all unlicensed). Standard treatments should be defined for specific degrees of SLE i.e. for severe, moderate forms. Other newer treatments being researched include mycophenolate mofetil (CellCept), and the use of stem cell therapy. In addition rituximab (unlicensed) has been used for this indication in more severe patients. Any associated costs for these treatments should be considered. Yes. However, of all the comparator drugs listed, we are not aware that one specific agent could be selected as the "single" specific comparator. Each of the comparator drugs have specific indications depending on the type of organ affected and the severity. The current data on Belimumab involves comparison with a variety of "standard" treatments, none of which are licenced apart from Hydroxychloroquine and steroids. In the UK these would include hydroxychloroquine, prednisolone, mycophenolate mofetil, azathioprine, cyclophosphamide, and antiinflammatories. It depends on the manifestation of lupus as to which would be considered best alternative care The stated outcome measures appear reasonable. It was agreed at the scoping workshop that the comparators should be defined as: Standard therapy without belimumab; For people in whom rituximab is considered appropriate: Rituximab plus standard care For people in whom cyclophosphamide is considered appropriate: Cyclophosphamide plus standard caresome See comments above. See comments above. No action National Institute for Health and Clinical Excellence Page 14 of 30

15 British Society for CSAS Also assess steroid sparing properties as this has a huge impact on long-term outcomes. Consider long-term damage using SLICC damage index. Not clear what is meant by disease progression. Studies involved reduction in disease activity and prevention of flares which is appropriate as well as assessment of quality of life, fatigue (?), and adverse events. Insufficient numbers and duration to address mortality. Better definition of disease progression is Renal, neurological, lung or heart or haematological involvement could be the primary focus of this outcome. Disease activity also needs better definition, e.g. whether this refers to number of flare-ups, time to first flare-up or severity of flare-ups, or to specific disease features. Validated scales should be used where possible. SRI response as an outcome should be added. Reduced use of corticosteroids and changes to the biomarkers of disease have also been considered as outcomes in trials identified. Workshop participants consdiered that the outcome measures should be: disease activity; incidence and severity of flares; healthrelated quality of life, including fatigue; adverse effects of treatment; and mortality. Consideration will be given to the reduction in steroids, if evidence allows. It was also considered that disease progression should be removed from the outcomes in the scope. See comments above. National Institute for Health and Clinical Excellence Page 15 of 30

16 GlaxoSmithKlin e LUPUS UK The following outcomes should be considered for inclusion: flares, fatigue and steriod sparing. Flares in a patient's disease have a significant impact on quality of life, therefore it would be appropriate to include flares as an outcome to be considered. Fatigue has been mentioned by patients as contributing significantly to a decrease in their quality of life and therefore should be included as a separate outcome measure. The ability of an intervention to demonstrate efficacy in steriod sparing (reduction in steriod dose), may have significant impact on the long term outcomes of SLE patients. It is also worth noting that there is a need for an efficacy endpoint in the clinical development for SLE, which is able to measure improvement in disease activity, while at the same time accounting for potential effects on other aspects of the disease and on patient well-being. With this in mind, the phase III belimumab studies have a composite primary efficacy endpoint. Patient response rate at week 52, as defined by: a reduction from baseline in the SELENA SLEDAI score of at least 4 points (which indicates a clinically important reduction in SLE disease activity); no worsening in Physician s Global Assessment (with worsening defined as an increase in PGA of more than 0.30 points from baseline); no new BILAG A organ domain score and no more than 1 new BILAG B organ domain score compared with baseline (to ensure no significant worsening within organ systems). Health-related quality of life is particularly important. A reduction in steroids and immunosuppresents being used will benefit patients. See comments above. See comments above. National Institute for Health and Clinical Excellence Page 16 of 30

17 Section Consultees Comments Action NHS Bolton Better definition of disease progression/activity is required e.g. whether activity See refers to number of flare-ups, time to first flare-up or severity of flare-ups, or to comments above. specific disease features. Validated scales should be used where possible (e.g. BILAG scale). Outcomes should be based on other conditions/effects related to this condition as primary outcomes e.g. degree of renal impairment, neurological, lung or heart or haematology involvement. Treatment failure should be defined to ensure treatment is not continued inappropriately, perhaps the scoring e.g. BILAG could used to define this and also the severity of the condition requiring the treatment (i.e. when to commence treatment). SLE Responder Index (SRI) as an outcome should be added. Reduced use of corticosteroids and changes to the biomarkers of disease have also been considered as outcomes in trials identfied. Assessment of QoL outcomes should support assessment of response but should not define it, as this can be subjective. Primary Care Society Some of these proposed outcome measures e.g. death will not be a frequent event to allow differentiation in current trial data. The term "disease progression" - if this refers to developing new features of active disease whilst on treatment - would be very valid. Given the varied nature of symptoms and organ involvement, the use of composite or global disease activity scores across several domains would be appropriate. Renal function is an important outcome (unless severe renal disease was an exclusion in the Belimumab trials) Cleary the Secondary Care specialist input into this draft will have more expertise in commenting on these specific areas. See comments above. It was agreed at the scoping workshop that renal disease should not be included as an outcome in the scope. National Institute for Health and Clinical Excellence Page 17 of 30

18 Section Consultees Comments Action Renal Mortality is a rare event in lupus especially the milder forms so far See Association included in Belimumab trials and is probably an inappropriate measure. comments above. There are well defined outcome measures in lupus - indices of disease activity, accumulated damage and quality of life - these would be the most relevant outcome measures. They should be system specific as well as global as the treatment may not benefit all aspects but might have specific benefits. Economic analysis British Association of Dermatologists British Society for The terms of the economic analysis seem reasonable. An appropriate time horizon may run into years. The time horizon of about 10 years seems appropriate. The 10 yr survival is approx 85-90%. Need a lot of time to prevent damage and mortality (eg. 3-5 years) but may be able to address improved quality of life. Could be clearer that there is economic data available. No action The appraisal will be carried out in accordance with the NICE guide to the methods of technology appraisal. No changes to the scope CSAS Short and long term effects should be considered See comments above. GlaxoSmithKlin e No comment. No action LUPUS UK As the 10yr survival rate is around 90% a 10yr time horizon seems appropriate. The appraisal will be carried out in accordance with the NICE guide to the methods of technology appraisal. No changes to the scope National Institute for Health and Clinical Excellence Page 18 of 30

19 Section Consultees Comments Action NHS Bolton Short and long term effects should be considered. Additional costs associated The with the drug should be considered i.e. bed days if required for administration appraisal will be carried out in of the drug, would this be given by a homecare company?, any associated accordance with the NICE monitoring costs (if any). These factors should all be taken into account when guide to the methods of devising ICERs and ultimately QALYs. These factors should also be included technology appraisal. No in any review of evidence for standard treatments, including comparison to changes to the scope presently used unlicensed preparations e.g. rituximab It was agreed during the scoping workshop that all drug costs and administrative costs would be included in the economic analysis. Equality and Diversity Renal Association British Association of Dermatologists British Society for Lupus is a desease predominantly affecting women of child bearing age over a period of years - economic analysis needs to take a long term view (years) regarding ability to work / have children as well as more standard analyses such as hospital admissions / adverse events etc We have no comments Severity is increased in all the minority groups with SLE i.e. ethnic minorities, males and children. Therefore a highly effective therapy will help with disease stability in the most at risk groups. There is also evidence that adherence to therapy is poorer in patients from ethnic minorities and patients from deprived backgrounds so an IV therapy may help address this. The drug should be available if approved equally to all groups indpendent of postcode/pct. The appraisal will be carried out in accordance with the NICE guide to the methods of technology appraisal. No changes to the scope No action It was agreed during the scoping workshop that no equality issues needed to be addressed separately. CSAS No issues No action National Institute for Health and Clinical Excellence Page 19 of 30

20 Innovation GlaxoSmithKlin e LUPUS UK As NICE have noted in the draft scope, SLE is more prevalent in women and African-Caribbean, South-East Asian and Chinese populations. The demographic of SLE patients is likely to include a significant portion of women of child-bearing age. Severity is higher in the ethnic monority groups and this often results in greater organ damage and potential risk to life. Evidence suggests that adherance to medication can be a problem for some patients and so IV therapy may help. No equality issues which need to be addressed separately were raised during the workshop. No equality issues which need to be addressed separately were raised during the workshop. NHS Bolton No issues. No action Primary Care Society Renal Association No Specific comments other than the racial differences in prevalence, as above. Lupus is more common in non-northern European ethnic groups. Trials with other drugs have suggested ethnic variations in responses to certain drugs and it will be critically important to have data on ethnic specific responses lest an overall low rate of response masks a particularly good response in one ethnic group or another. No equality issues which need to be addressed separately were raised during the workshop. No equality issues which need to be addressed separately were raised during the workshop. National Institute for Health and Clinical Excellence Page 20 of 30

21 Other considerations British Association of Dermatologists British Society for We have no comments Need for further studies eg lupus nephritis but should not delay evaluation for non-renal lupus. No action CSAS As above No action GlaxoSmithKlin e Do you consider belimumab in the treatment of active seropositive SLE to be innovative in its potential to make a significant and substantial impact on health-related benefits and how it might improve the way that current need is met (is this a step-change in the management of the condition)? Yes. SLE has a significant impact on morbidity and mortality. There has been little therapeutic innovation in treatments for SLE for several decades. The management of SLE includes the use of steriods, which are associated with certain long term adverse effects (osteoporosis, diabetes and cardiovascular disease). Belimumab is a human monoclonal antibody specifically developed for the management of SLE. Belimumab has a novel mode of action that inhibits the biological actvity of BLyS, which contribute to the production of autoantibodies antibodies that attack and destroy the body s own healthy tissues. Belimumab has demonstrated efficacy in the management of SLE in two phase III clinical trials and has been shown to be well-tolerated. It was discussed during the scoping workshop that, if the final referral from the Department of Health is given and the appraisal is planned into the technology appraisal programme, the manufacturer submission should make reference to the innovative aspects of belimumab. LUPUS UK None. No action National Institute for Health and Clinical Excellence Page 21 of 30

22 NHS Bolton Review of rituximab used for this condition. The following comparators were added to the scope: For people in whom rituximab is considered appropriate: Rituximab plus standard care For people in whom cyclophosphamide is considered appropriate: Cyclophosphamide plus standard caresome Primary Care Society Renal Association We recognise that SLE is a medical condition which can be difficult to detect in Primary Care, both due to it's rarity and the multiple ways in which it can present, which can lead to a delay in diagnosis. Even with current "best practice" management, both the disease and treaments have a major impact on quality of life, morbidity and mortality. There is a need for greater awareness of the condition in Primary Care (and this is an area which is being addressed within PCR educational programmes) Is there data to suggest that Belumimab could be an alternative rather than an additional agent for the treatment of SLE? No action The intervention is defined as belimumab in addition to standard therapy as per the scope. Questions for consultation British Association of Dermatologists British Society for We feel the clinical outcomes as stated are reasonable. 1. Assess disease activity using an objective instrument as many symptoms are subjective. 2. Include serology although not all patients are serologically concordant. 3. Damage accrual is important and steroid sparing as well as reductions in No action Workshop participants consdiered that the outcome measures should be: disease activity; incidence National Institute for Health and Clinical Excellence Page 22 of 30

23 need for other immunosuppressive therapies as they can contribute to longterm infection risk and hospialisations. 4. Changes in disease activity measures (eg. BILAG, SLEDAI, physician's global assessment). Data available in abstract form from 2 phase 3 studies and published from phase 2 study (randomised, placebo controlled). 5. Differences in Quality of Life measures - data available as for (1). 6. Differences in damage and mortality during therapy for less than 52 weeks - data not available except open label studies. Should renal function or other specific disease sequelae be considered as outcome measures? - Role in lupus nephritis not studied to my knowledge, only non renal trials to date. should be considered in future. Are there any subgroups of people in whom belimumab is expected to be more clinically effective and cost effective or other groups that should be examined separately? - Need to review data from phase 3 trials. Possibly but may need further trials to explore more than seropositive lupus as these would be posthoc analyses. Are there any issues that require special attention in light of the duty to have due regard to the need to eliminate unlawful discrimination and promote equality? - Drug if approved needs to be equally available in all parts of UK. Analyses may suggest whether or not certain ethnic groups benefit more than others, but studies will not have been powered to confirm this difference if there is one. Do you consider belimumab in the treatment of active seropositive SLE to be innovative in its potential to make a significant and substantial impact on health-related benefits and how it might improve the way tha current need is met (is this a step-change in the management of the condition)? - It is a much needed additional treatment option that should be useful. and severity of flares; healthrelated quality of life, including fatigue; adverse effects of treatment; and mortality. Consideration will be given to the reduction in steroids, if evidence allows. It was also considered that disease progression should be removed from the outcomes in the scope. It was agreed at the scoping workshop that no subgroups should be defined separately in the scope. It was agreed during the scoping workshop that no equality issues needed to be addressed separately. It was discussed during the scoping workshop that, if the final referral from the Department of Health is given and the appraisal is planned into the technology appraisal programme, the National Institute for Health and Clinical Excellence Page 23 of 30

24 Section Consultees Comments Action Do you consider that the use of belimumab in the treatment of active seropositive SLE can result in any potential significant and substantial healthrelated benefits that are unlikely to be included in the QALY calculation? - Effects on disease activity may not be captured by EQ5D. From the data published to date, it does have the tendency to make a significant and substantial impact on health related benefits, in particular reducing the rate of manufacturer s submission should make reference to the innovative aspects of belimumab. conversion from disease activity to damage (permanent change). Likewise, it is reasonable to believe that it has significant potential for producing a marked increase in health related benefits though these are likely to be above and beyond the QUALY calculations remain uncertain. CSAS As above No action GlaxoSmithKlin e Have the most appropriate comparators for the treatment of active SLE been included in the scope? No, see previous comment about rituximab. How should standard therapy be defined? Current standard therapy for patients with SLE involves a variety of immunosuppressive, antimalarial and cytotoxic agents, including mycophenolate mofetil. More severe pateints may receive rituximab. Should renal function or other specific disease sequelae be considered as It was agreed at the scoping workshop that the comparators should be defined as: Standard therapy without belimumab; For people in whom rituximab is considered appropriate: Rituximab plus standard care For people in whom cyclophosphamide is considered appropriate: Cyclophosphamide plus standard caresome It was National Institute for Health and Clinical Excellence Page 24 of 30

25 Section Consultees Comments Action outcome measures? considered at the scoping The consideration of organ involvement in SLE patients is important, this may workshop that renal disease include renal, CNS, cardiovascular or other important organ systems. The should not be included as an phase III trials showed improvements in certain organ systems, however the outcome in the scope. trials were not designed or powered to evaluate these sub groups. Are there any subgroups of people in whom belimumab is expected to be more clinically effective and cost effective or other groups that should be examined separately? As mentioned previously, patients with high disease activity or those who have major organ involvement (i.e. renal, CNS, cardiovascular) may demonstrate more favourable cost-effectiveness. It was considered at the scoping workshop that no subgroups should be defined separately in the scope. Are there any issues that require special attention in light of the duty to have due regard to the need to eliminate unlawful discrimination and promote equality? As NICE has noted in the draft scope SLE is more prevalent in women and African-Caribbean, South-East Asian and Chinese populations. It was considered at the scoping workshop that no equality issues needed to be addressed separately. National Institute for Health and Clinical Excellence Page 25 of 30

26 GlaxoSmithKlin e Do you consider that the use of belimumab in the treatment of active seropositive SLE can result in any potential significant and substantial healthrelated benefits that are unlikely to be included in the QALY calculation? There are certain aspects of belimumab, SLE and the potential economic evaluation that need to be considered when considering the QALY calculation. In the phase III clinical trials belimumab plus standard of care was compared to standard of care alone. The current standard of care for the management of SLE consists of relatively old treatments (corticosteroids, antimalarials and immunosuppressants), the very low acquisition costs of these treatments make the demonstration of cost-effectiveness particularly challenging within the current NICE cost per QALY methodology. The appraisal will be carried out in accordance with the NICE guide to the methods of technology appraisal. No changes to the scope It was agreed during the scoping workshop that all drug costs and administrative costs would be included in the economic analysis. The standard of care, includes steroids, which when used chronically at high doses are associated with long term adverse effects (osteoporosis, diabetes and cardiovascular disease). Belimumab has demonstrated steroid sparing effects (reduction in steroid dose) during the phase III trials. This occured against a background of a randomised clinical trial in which clinicians may have been cautious to reduce/stop steroids. It is possible that the long term benefit of avoiding high dose steroids is not captured by the clinical trials. Disease activity does not correlate perfectly with quality of life (e.g. fatigue). Fatigue has been identified by patients as contributing significantly to the decrease in their quality of life, but this is currently not well reflected in the EQ- 5D measure. A critical aspect of the management of lupus is the impact of SLE on long term organ damage. Although the phase III clinical trials collected data on organ damage (SLICC scores), this is unlikely to be fully reflective of belimumab's impact on long term damage due to the duration of the trial. This will need to be modelled via belimumab s effects on disease activity and steroid use, with the inherent uncertainties of long term modelling. Workshop participants consdiered that the outcome measures should be: disease activity; incidence and severity of flares; healthrelated quality of life, including fatigue; adverse effects of treatment; and mortality. Consideration will be given to the reduction in steroids, if evidence allows. It was also considered that disease progression should be removed from the outcomes in the scope. National Institute for Health and Clinical Excellence Page 26 of 30

27 LUPUS UK NHS Bolton Primary Care Society Improved quality of life such as ability to retain employment. LUPUS UK Members Survey achieved a 53% response rate. Which includes important data regarding quality of life, symptoms and economic status. This will be a licensed preparation, where currently the only option for more severe disease may be rituximab, but this would depend on individual PCTs agreeing to fund individual cases, therefore decision to treat can vary across the country. A licensed product would help support equality for all patients who fit into the criteria. The criteria included for commencement of treatment should be very clear and only include patients who will benefit, considering clinical and cost-effective use of NHS resources. The condition of SLE is rare and therefore the number of patients this is likely to be suitable for this treatment is going to be low. In addition, clear criteria for reviewing treatment and stopping ineffective treatment should be clear to reduce unnecessary ongoing prescribing of a high-cost drug. We would consider that Belimumab has the potential, given the positive outcomes where this drug has been added to "standard care", to be substantially improve the current care of this condition. In addition to direct treatment benefits, seconary benefits such as reduction in steroid dosage, the potential avoidance of cytotoxic drugs, and reduction in flares of disease are likely to lead to a substantial health improvement. The only data we are aware of is the BLISS 52 and 76 trial data presented in abstract form at scientific meetings Health related quality of life is included in the outcomes listed in the scope. Following the final referral from the Department of Health, the appraisal will be planned into the technology appraisal schedule to allow as timely as possible guidance to the NHS. Workshop participants consdiered that the outcome measures should be: disease activity; incidence and severity of flares; healthrelated quality of life, including fatigue; adverse effects of treatment; and mortality. Consideration will be given to the reduction in steroids, if evidence allows. It was also considered that disease progression should be removed from the outcomes in the scope. National Institute for Health and Clinical Excellence Page 27 of 30

28 Additional comments on the draft scope. Renal Association British Association of Dermatologists British Society for Relevant clinical outcomes would be a meaningful improved response of important symptoms / complications of SLE in those treated with Belimumab compared with those just receiving standard therapy. From a renal perspective this would mean faster / longer sustained induction of remission of nephritis compared to standard therapy and ideally allowing a minimisation or avoidance of steroids. My understanding of the data available is that there are data from different time points in a large RCT - BLISS-52 and 76 representing the data at 52 weeks and 76 weeks respectively. The outcomes were assessed by a composite patient response score using several different scoring systems to define relatively small overall differences in response. Renal function should certainly be considered as an outcome measure and whilst current data inform about function, patients with lupus nephritis were largely excluded from the trial. Hence effectiveness in renal lupus cannot be assessed at this stage. There is a great need to eliminate chronic steroid usage - early use of Belumimab to control early lupus and avoid the long term use of steroids should be evaluated. ie was Belumimab particularly effective in the milder patients who were only otherwise receiving NSAIDs? The approved use of a biological in the treatment of SLE is a step change in treatment of SLE. None From the data that has been published so far, it is not clear that belimumab is likely to favour to one particular organ or system over another in terms of its inducing benefits. Belimumab is a most interesting drug because it targets a B cell activating See comment above. It was considered at the scoping workshop that renal disease should not be included as an outcome in the scope. Consideration will be given to the reduction in steroids, if evidence allows. No action No action National Institute for Health and Clinical Excellence Page 28 of 30

29 factor which is highly likely to be developed in the development of lupus. Its attraction intellectually, therefore, is that it is attacking a logical target which on theoretical grounds ought to be beneficial in the treatment of the disease. GlaxoSmithKlin e Primary Care Society Renal Association References: 1) Abu-Shakra M et al. Mortality studies in systemic lupus erythematosus. Results from a single center. I. Causes of death. J Rheumatol Jul;22(7): ) Bernatsky S et al. Mortality in systemic lupus erythematosus. Arthritis Rheum. 2006;54: ) Petri M et al. Association of plasma B lymphocyte stimulator levels and disease activity in systemic lupus erythematosus. Arthritis Rheum. 2008;58: There are likely to be additional benefits from introduction of any new technology in this disease area, as it it will further focus clinicians on achieving the very best outcomes for their patients. There is an analogy here with the NICE anti-tnf guidance in RA, which has enshrined the assessment of formal disease activtity scores (DAS), enabling both GPs and their patients to judge whether the Specialist care they are receiving has resulted in either a remission or a low disease activity state, and also led to better utilisation of existing drugs. Although SLE is a less prevalent (and more difficult to treat) condition than RA, introduction of any new technology is also likely to facilitate similar knock-on benefits. I think the questions are generally well constructed but am not sure the data yet exist to address them - particularly the need to judge economic benefit over years rather than months. No action Following the final referral from the Department of Health, the appraisal will be planned into the technology appraisal schedule to allow as timely as possible guidance to the NHS. National Institute for Health and Clinical Excellence Page 29 of 30