Pharmalgen for the treatment of bee and wasp venom allergy

4.3.2 The Committee discussed current clinical practice for the diagnosis of bee or wasp venom allergy. The Committee heard from the clinical specialists that people who have had a systemic reaction following a bee or wasp sting should be referred to an allergy specialist for the diagnosis of venom-specific IgE allergy to bee and/or wasp venom by skin or intradermal testing and serum-specific IgE testing. The clinical specialists stated that raised serum tryptase at baseline (after a reaction to a sting has subsided) is associated with an increased probability of severe systemic reactions to future stings. However the Committee also noted the consultation comment that the immunological condition mastocytosis may be associated with a raised baseline serum tryptase, and a diagnosis of mastocytosis may be a contraindication to Pharmalgen. The Committee understood that before treatment with Pharmalgen, a positive test for specific IgE antibodies is required, and that clinicians would also take into account baseline serum tryptase and other comorbid conditions when deciding whether to offer treatment with Pharmalgen.

4.3.3 The Committee discussed the treatment of bee and wasp venom allergy in current clinical practice. The Committee heard from the clinical specialists that people who have had a moderate or severe systemic reaction to bee or wasp venom are normally given an emergency kit containing adrenaline. The kit can also include other emergency treatments such as a high-dose antihistamine. Clinicians also advise people on how to avoid being stung, but they do not consider this advice to be effective on its own. The Committee discussed the use of venom immunotherapy in current clinical practice in the UK. The Committee heard from the clinical specialists that Pharmalgen, the only venom immunotherapy with a UK marketing authorisation, is an established therapy for venom allergy which should be initiated and monitored by healthcare professionals within a specialist centre with experience in venom immunotherapy and treating systemic reactions. The clinical specialists stated that they give Pharmalgen in accordance with the SPCs, most frequently using a conventional dosing schedule in the initial phase, followed by a maintenance period of 3 years. The Committee heard that in children and adults Pharmalgen is considered to provide immunity for at least 15 years. The Committee understood that the regimen of most relevance to the appraisal was an initial phase using a conventional dosing regimen and a maintenance phase lasting 3 years, with the treatment administered within a specialist centre.

4.3.4 The Committee discussed which patients currently receive Pharmalgen in clinical practice. It heard from the clinical specialists that Pharmalgen is offered to people with a history of severe systemic reactions to bee or wasp venom, or to people with moderate systemic reactions to bee or wasp venom if they have other risk factors such as raised baseline serum tryptase, a high risk of future stings, or anxiety about future stings. The Committee noted consultation comments that following publication of British Society for Allergy and Clinical Immunology guidelines, Pharmalgen may also be offered to people with a history of moderate systemic reactions to bee or wasp venom if they live far from emergency medical care, have certain comorbid conditions or request treatment with Pharmalgen. The Committee heard from the clinical specialists that children generally have a less severe reaction to venom than adults and a better prognosis over time. However, it is not possible to identify in advance which children will 'outgrow' their allergy to bee and/or wasp venom, and therefore Pharmalgen is an appropriate treatment for some children. The Committee understood that Pharmalgen is indicated for both adults and children, and that Pharmalgen is offered to people who have had severe systemic reactions or to people who have had moderate systemic reactions, and have additional risk factors for future systemic reactions such as raised baseline serum tryptase, or an increased risk of future stings, or whose quality of life is affected by anxiety about future stings.

4.3.5 The Committee discussed the impact of an allergy to bee and/or wasp venom on quality of life. The clinical specialists and patient experts stressed how frightening it is to be stung when there is an expectation of a possible systemic reaction following a sting, and that anaphylaxis can be accompanied by a sense of impending doom. The Committee heard from the patient experts that many people who have experienced a systemic reaction to bee or wasp venom are anxious about the possibility of systemic reactions following future stings, regardless of the actual risk of a reaction. The Committee heard that this anxiety affects usual daily activities of those affected and their family members. The Committee heard that people willingly tolerate the adverse effects of Pharmalgen treatment and the length and intensity of the administration schedule to reduce the probability of a systemic reaction to future stings. The Committee heard from patient experts that after treatment with Pharmalgen, anxiety levels return to normal for many people, and that carrying and having to administer an adrenaline auto-injector does not reduce anxiety to the same degree as having venom immunotherapy. The Committee heard from the clinical specialists that published trials have reported an improvement in quality of life in people who received venom immunotherapy compared with those who received an adrenaline auto-injector only. On balance, the Committee was persuaded that although the extent to which people might feel anxious following a systemic reaction would vary, and the risk of a sting might be very low, many people with a history of systemic reactions to bee or wasp venom would be anxious about the possibility of systemic reactions following future stings.

4.3.6 The Committee discussed the relevant comparator in the appraisal. The comparator as set out in the scope is a package of care without venom immunotherapy, including advice on avoidance of insect venom, and high-dose antihistamines and/or adrenaline auto-injectors (with training before use) to be used if stung. The Committee heard from the clinical specialists that the British Society for Allergy and Clinical Immunology recently issued guidelines for the treatment of bee and wasp venom allergy. It heard that clinicians advise people with a history of systemic reactions to bee or wasp venom on ways of minimising their risk of further stings, but do not provide advice alone. Instead clinicians offer people an adrenaline auto-injector (and training in its use) to carry and use following a bee or wasp sting that is accompanied by symptoms of a systemic reaction. The Committee concluded that an adrenaline auto-injector given alongside avoidance advice was the most appropriate comparator for Pharmalgen treatment.

4.3.7 The Committee discussed the clinical effectiveness evidence for Pharmalgen and noted that no RCTs or controlled studies had been identified that compared Pharmalgen with standard care without venom immunotherapy, as defined in the scope. The Committee discussed the available non-comparative data for Pharmalgen and the comparative data for non-Pharmalgen venom immunotherapy. The Committee heard from the clinical specialists that they considered that the results of non-Pharmalgen studies would also apply to Pharmalgen, and that venom immunotherapy is associated with changes in IgE production and a reduced risk of a systemic reaction following a sting. The Committee considered that the available evidence base for Pharmalgen was of poor quality and was limited. On balance, it was persuaded that Pharmalgen had demonstrated some efficacy in reducing the rate and severity of systemic reactions following a bee or wasp sting. However, the Committee considered that the relative efficacy could not be quantified with certainty.

4.3.8 The Committee discussed the economic model developed by the Assessment Group. It noted that in the base-case analysis, Pharmalgen plus an adrenaline auto-injector plus high-dose antihistamine and avoidance advice had an ICER of £18,070,000 per QALY gained compared with an adrenaline auto-injector plus high-dose antihistamine and advice. The Committee heard from the Assessment Group that this estimate was robust to changes in parameters associated with costs and effects. However, the estimate was particularly sensitive to assumptions about utility and about how frequently a person is stung. The Committee considered the importance of the assumption in the base-case analysis that Pharmalgen treatment did not affect health-related quality of life. The Committee noted its earlier conclusions that having a venom allergy increases anxiety and affects daily activities, and that treatment with Pharmalgen may reduce some of this anxiety. The Committee concluded that the assumption in the base-case analysis that Pharmalgen had no effect on health-related quality of life underestimated the cost effectiveness of Pharmalgen compared with alternative treatments.

4.3.9 The Committee discussed comments received during the consultation about the robustness of the Assessment Group's model. The Committee noted the consultation comments that some of the inputs in the economic model relating to costs, efficacy and the likelihood of having a systemic reaction while receiving treatment with Pharmalgen were not plausible. The Committee considered that although there are some uncertainties as to the plausibility of assumptions and inputs, the Assessment Group's sensitivity analyses showed that the estimates of cost effectiveness were not sensitive to changes in these parameters. The Committee understood from the Assessment Group that the key drivers of cost effectiveness were assumptions about utility and about how frequently a person is stung. On this basis the Committee concluded that the Assessment Group's model was an appropriate basis for decision-making despite uncertainties around the plausibility of some parameter estimates.

4.3.10 The Committee considered the Assessment Group's scenario analyses that had assumed that people have five bee or wasp stings per year. The Committee heard from clinical specialists that some people are stung at least five times per year. These may include beekeepers plus their children and neighbours, roofers and gardeners. However, the risk of being stung varies. The Committee noted that in these scenario analyses, treatment with Pharmalgen dominated the alternatives (that is, it was more effective and less costly), and that this remained the case until the average frequency of stings dropped to approximately three per year. The Committee concluded that Pharmalgen is an appropriate use of NHS resources for people with IgE-mediated allergy to bee and wasp venom, who have a high risk of stings.

4.3.11 The Committee then considered the scenario analyses that included an effect on health-related quality of life related to anxiety about re-stings and Pharmalgen treatment. The Committee noted that in these analyses the ICER for Pharmalgen decreased to less than £30,000 per QALY gained. The Committee was aware that the Assessment Group had been unable to identify any data on anxiety associated with venom allergy or changes in anxiety as a result of venom immunotherapy that could be used in the economic model. Therefore the Assessment Group had used the EQ-5D survey of norms to explore how much disutility was generated when a person went from having no problems with anxiety and daily activities to moderate anxiety with some effect on daily activities (0.16). The Committee considered that the Assessment Group's assumption that fear of being stung would generate a quarter of that value (0.04), and that venom immunotherapy would reduce this anxiety by a quarter (0.01), was plausible and, given the testimony of the patient experts, may even underestimate the gains in utility associated with treatment with Pharmalgen. The Committee concluded that for people who do not have a high risk of future stings the analyses that assume reduced anxiety about re-stings with Pharmalgen treatment are the most appropriate on which to base the most plausible estimate of the ICER.

4.3.12 The Committee considered the 10-year time horizon in the economic model. It was aware that it had not been presented with evidence of the duration of immunity; but it also considered the testimony of the clinical specialists that immunity was likely to be longer than 10 years. The Committee was presented with a scenario analysis with a time horizon of 20 years for people who have a gain in health-related quality of life associated with reduced anxiety about re-stings and treatment with Pharmalgen. In this scenario, the ICER was £13,800 per QALY gained for treatment with Pharmalgen plus an emergency kit plus advice compared with an emergency kit and advice alone. The Committee concluded that it is appropriate to use a time horizon of longer than 10 years, and that with reduced anxiety about re-stings after treatment with Pharmalgen the most plausible ICER would be less than £20,000 per QALY gained. The Committee concluded that Pharmalgen is an appropriate use of NHS resources for people with IgE-mediated allergy to bee and wasp venom, who are anxious about future stings.

4.3.13 The Committee then discussed its conclusions on the cost-effectiveness modelling and the use of Pharmalgen in current clinical practice (see section 4.3.4). The Committee took into account the evidence from the clinical specialists and patient experts. It concluded that it was appropriate to assume a health-related quality of life benefit from Pharmalgen for people with a history of severe systemic reactions and for people who have a history of moderate systemic reactions to bee and/or wasp venom and who have other risk factors for future systemic reactions such as anxiety about the possibility of systemic reactions following future stings, a higher risk of being stung or raised baseline serum tryptase. The Committee therefore concluded that Pharmalgen could be considered an appropriate use of NHS resources for the treatment of people with IgE-mediated bee and/or wasp venom allergy with the above characteristics. The Committee considered that anxiety about the possibility of systemic reactions following future stings should be such that it affects usual daily activities.

4.3.14 The Committee discussed comments received during consultation, noting that Pharmalgen may also be offered to people with a history of moderate systemic reactions to bee or wasp venom if they live far from emergency medical care, have comorbid conditions or request treatment with Pharmalgen. The Committee discussed the patient expert testimony, and concluded that these people would have heightened awareness of their situation and be anxious about the possible effects of having a systemic reaction from future stings. Therefore the Committee concluded that these groups were covered in its recommendation for people with a history of moderate systemic reactions, who are anxious about future stings.

4.3.15 The Committee discussed whether it should make a separate recommendation for people with raised baseline serum tryptase. The Committee noted that people with raised baseline serum tryptase are at higher risk of more severe reactions to future stings but that a person would only be aware of an increased risk once raised baseline serum tryptase had been diagnosed. The Committee also noted the consultation comment that a raised baseline serum tryptase may indicate mastocytosis, which is a possible contraindication for Pharmalgen. The Committee concluded that comorbid conditions, including mastocytosis, would be identified by the responsible clinician when considering whether to offer treatment with Pharmalgen. The Committee concluded that it was appropriate to include in its recommendations raised baseline serum tryptase as an additional risk factor for people who have had a moderate systemic reaction.

4.3.16 The Committee supported the statement made by the clinical specialists that treatment with Pharmalgen should be initiated and monitored in a specialist centre experienced in venom immunotherapy. The Committee discussed comments from consultation about the need for specialist centres to have staff appropriately trained in resuscitation or immediate access to age-appropriate resuscitation facilities. It noted that the SPCs specify that Pharmalgen should be provided under supervision of a doctor experienced in specific immunotherapy and that because of the risk of potentially fatal anaphylaxis, treatment with Pharmalgen must be carried out in clinics or hospitals where full facilities for cardiopulmonary resuscitation are immediately available for use by adequately trained personnel. The Committee therefore concluded that Pharmalgen should be provided within a specialist centre and that the details of the provision of resuscitation equipment were sufficiently specified in the SPC.