A systematic review of the clinical effectiveness and cost effectiveness of Pharmalgen® for the treatment of bee and wasp venom allergy

Aetiology, pathology and prognosis

Apidae (bees), Vespidae (wasps and hornets) and Formicidiae (ants) form part of the order Hymenoptera. Bees and wasps have a modified ovipositor at the terminal end of their abdomen that gives them the ability to sting other organisms. Bees possess a barbed stinger, which, together with their venom sac, remains in their victim’s skin after they sting. This means that bees are able to sting only once, and die soon afterwards. Wasps’ stingers are not barbed and they are therefore capable of delivering more than one venom-injecting sting in their lifetime. Bee and wasp stings contain allergenic proteins. In wasps, these are predominantly phospholipase A1,1 hyaluronidase1 and antigen 52 and, in bees, phospholipase A2 and hyaluronidase. 3 It has been estimated that each bee sting contains 147 μg of venom and each wasp sting contains 17 μg of venom. 4

The symptoms produced following a sting can be classified into non-allergic and allergic reactions. All envenomated individuals are likely to experience local burning and pain followed by erythema (redness) and a small area of oedema (swelling) at the site of the sting. These are caused by vasoactive components of venom and the mechanism is toxic rather than allergic. 4

Following an initial sting, some individuals generate an immune response, which produces antibodies of the IgE class. These antibodies sensitise cells, particularly histamine-containing mast cells, so that allergen re-introduced by a subsequent exposure can bind to the preformed IgE molecules, triggering the cells to produce a rapid inflammatory response (this is referred to as a ‘type 1’ or ‘immediate-type’ hypersensitivity reaction). These allergic reactions in venom-sensitised individuals can be local or systemic, can vary in severity and are typically of rapid onset. 5–8 The term ‘anaphylaxis’ is applied to the most severe reactions. These frequently occur within 15 minutes of a sting; initial symptoms are usually cutaneous (flushing, urticaria, angioedema) followed by hypotension (with light-headedness, fainting or collapse) and/or respiratory symptoms (due to an asthma-like response or laryngeal oedema). Progression to fatal cardiorespiratory arrest can occur within several minutes. 5 Anaphylaxis occurs more commonly in males and in people under 20 years of age,6 and the species that cause the most frequent allergic reactions in humans following a sting are the Apidae (bees) and the Vespidae (wasps and hornets). 7

In addition to local and systemic allergic reactions, individuals may also experience allergic reactions due to circulating immune complexes or delayed hypersensitivity reaction. This is uncommon, and presents as skin rashes and sickness-like symptoms occurring within 3 days to 2 weeks post sting. 5

Severity of systemic reactions to Hymenoptera venom can be measured using the Mueller grading system,8 which is summarised in Table 1. The grading system classifies the reaction to a sting according to the severity of symptoms. Severity ranges from grade 1 (symptoms of skin and mucous membranes) to grade 4 (cardiovascular symptoms).

Epidemiology

In the UK, insect stings are the second most frequent cause of anaphylaxis outside of medical settings,9 and Hymenoptera venoms are one of the three main causes of fatal anaphylaxis in both the USA and the UK. 10 It is estimated that the prevalence of bee and wasp sting allergy is between 0.4% and 3.3%. 11

The prevalence rates of large local reactions (LLRs) in the general population have been estimated at between 2.4% and 26.4%, and up to 38% in beekeepers. 10 Children are reported to have lower rates of both large local and systemic reactions to Hymenoptera stings, at between 11.5% and 19% and between 0.15% and 0.8%, respectively. 5 After a LLR, 5–15% of people will go on to develop a systemic reaction when next stung. 12

The prevalence of systemic reactions to Hymenoptera venom is not reliably known, but estimates range from 0.5% to 3.3% in the USA,12,13 and from 0.3% to 7.5% in Europe. 10 Differences in rates of systemic allergic reactions in children and adults have been reported: up to 3% of adults and almost 1% of children have a medical history of severe sting reactions. 11,13 In people with a mild systemic reaction, the risk of subsequent systemic reactions is thought to be between 14% and 20%. 12 Within the USA, severe life-threatening reactions occur in 0.4–0.8% of children and 3% of adults. 14

Venom immunotherapy

In addition to the measures detailed above, people with a history of a systemic allergic reaction to Hymenoptera venom can be considered for specific allergen immunotherapy. It is recommended that venom immunotherapy (VIT) is considered ‘when positive test results for specific IgE antibodies correlate with suspected triggers and patient exposure’. 26 VIT is intended to prevent or reduce the severity of future systemic allergic reactions and can be administered using a variety of products and according to a variety of protocols. Currently, the only products licensed for use in the UK are Pharmalgen products (Table 2).

Venom immunotherapy consists of subcutaneous injections of increasing amounts of venom, and treatment is divided into two periods: the updosing phase and the maintenance phase. VIT is normally discontinued after 3–5 years, but adjustments to the treatment regime may be necessary when treating people with intense allergen exposure (such as beekeepers) or those with individual risk factors for severe reactions. There are 44 centres across the UK that provide PhVIT to people for bee and wasp sting allergy. 27 From the findings of the latest UK audit,14 it is clear that there is no single standard approach to the delivery of PhVIT; different centres appear to follow different dosing and administration protocols and every treatment package is tailored to the requirements of the individual patient.

In 1978, the first randomised controlled trial (RCT)28 assessing the effectiveness of VIT in the treatment of insect venom allergy was published, in which people were randomised to either VIT or placebo. Systemic reactions following re-sting occurred in 7 of 12 people receiving placebo and in 1 of 18 people receiving VIT. As a direct result of this study, it is now considered unethical to randomise people eligible for VIT to receive placebo treatment.

Assessing the effectiveness of venom immunotherapy

The impact of VIT can be assessed using both clinical and psychological outcomes. Clinical outcomes relate to the effectiveness of VIT in reducing the rate of reaction to subsequent stings and the psychological outcomes relate to quality of life (QoL) and anxiety related to fear of future stings.

The effectiveness of VIT has been assessed using various methods. A method frequently used in clinical trials is that of a hospital sting challenge (SC), in which a patient is purposely stung, in a controlled environment, by a living insect of the species to which they have been desensitised. Any reaction to the sting is then reported and treated if necessary. Another measure of effectiveness is that of patient-reported reactions to accidental field stings (FSs). Other methods include the measurement of serum IgE and skin tests similar to those used in the diagnosis of venom allergy. However, there is no completely reliable method of predicting which people will be at risk of further anaphylactic reactions and which will remain anaphylaxis free in the long term, following VIT. 26

Local or systemic adverse reactions (ARs) may occur as a result of VIT. They normally develop within 30 minutes of the injection, but occasionally delayed reactions can occur after several hours. Each patient is monitored closely following each injection to check for ARs. These reactions inform the rate of progression to increased doses during the updosing phase of treatment.

Relevant national guidelines

Pharmalgen products are produced by ALK Abelló and have had UK marketing authorisation for the diagnosis (using skin testing/intracutaneous testing) and treatment (using PhVIT) of IgE-mediated allergy to bee venom (Pharmalgen Bee Venom) and wasp venom (Pharmalgen Wasp Venom) since March 1995 (marketing authorisation number PL 10085/0004). 31 The active ingredient is freeze-dried Apis mellifera venom in Pharmalgen bee venom and partially purified, freeze-dried Vespula spp. venom in Pharmalgen wasp venom, each provided with a solvent to prepare for injection.

Before treatment is considered, allergy to bee or wasp venom must be confirmed by case history and diagnostic testing as outlined previously. Treatment with Pharmalgen bee or wasp venom is performed by subcutaneous injection. The treatment is carried out in two phases: the updosing phase and the maintenance phase.

In the updosing phase, the dose is increased stepwise until the maintenance dose (the maximum tolerable dose before an allergic reaction, or a maximum dose of 100 μg, whichever is the smaller) is achieved. ALK Abelló recommends the following dosage protocols: ‘conventional’, ‘modified rush’ (clustered) and ‘rush’ updosing. In conventional updosing, the patient receives one injection every 3–7 days. In modified rush (clustered) updosing, the patient receives two to four injections once a week. If necessary, this interval may be extended up to 2 weeks. The two to four injections are given with an interval of 30 minutes. In rush updosing, while hospitalised, the patient receives injections at 2-hour intervals and a maximum of four injections per day may be given in the updosing phase. An ultra-rush protocol has also been used in some studies in which hospitalised patients receive all injections in one day at 30-minute intervals. 32

The updosing phase ends when the individual maintenance dose has been attained and the interval between the injections is increased by 2, 3 or 4 weeks. This is called the maintenance phase, and the maintenance dose is then given every 4–6 weeks for at least 3 years.

In the UK, treatment is carried out in hospital, either as an outpatient for conventional updosing or as an inpatient for rush protocols. Treatment is administered by a specialist, and emergency resuscitation equipment should be available in case it is required to treat any systemic reaction. Venom from ALK Abelló is used in most clinics in the UK, with 92% of clinics employing the conventional 12-week updosing protocol and the remainder employing a clustered (7- to 8-week) updosing protocol. 14

For bee venom-sensitised people, the relevant PhVIT preparation costs £54.81 during the updosing phase and then £15.94 per injection during the maintenance phase. For wasp venom-sensitised people, PhVIT costs £67.20 during the updosing phase and then £20.51 per injection during the maintenance phase.

Search strategy

A comprehensive search strategy using a combination of index terms (e.g. Pharmalgen) and free-text words (e.g. allerg$) was developed and used to interrogate the following electronic databases:

• EMBASE (1980 to 2011 Week 4)

• MEDLINE (1948 to February Week 3 2011)

• The Cochrane Library (February 2011).

The results were entered into an Endnote X4 library (Thomson Reuters, CA, USA) and the references were de-duplicated. Full details of the search strategies and the number of citations returned for each search are presented in Appendix 1.

Data abstraction strategy

Data relating to both study design and quality were extracted by one reviewer (JH) into a Microsoft Access 2007 database (Microsoft Corporation, Redmond, WA, USA) and were cross-checked by a second reviewer (GC). Where multiple publications of the same study were identified, data were extracted and reported as a single study.

Critical appraisal strategy

The quality of the included clinical effectiveness studies was assessed by one reviewer (JH) and checked by a second reviewer (GC) according to criteria based on CRD (Centre for Reviews and Dissemination) Report 4. 34 The checklist used to critically appraise the included studies is specific to RCTs; for the non-RCT studies a modified version of this checklist was used. All relevant information was tabulated and summarised within the text of the report. Full details and results of the quality assessment strategy for clinical effectiveness studies are reported in Appendix 4.

Methods of data synthesis

The results of the data extraction are summarised in structured tables and as a narrative description. A standard meta-analysis was planned if sufficient clinically and statistically homogeneous data were available from the included studies. The primary outcomes identified for our evidence synthesis were systemic reaction to FS or SC during treatment and/or ARs to VIT. Secondary outcomes included LLR to VIT, LLR to FS or SC, number of stings and deaths.

We planned to extract number of events for each outcome and total number of people in each treatment arm in order to calculate odds ratios and the corresponding 95% confidence intervals for each study. Studies with no events in both arms would be excluded from analysis. All analyses were planned based on the intention-to-treat (ITT) population where possible. Where appropriate, the levels of clinical and methodological heterogeneity would be investigated, and statistical heterogeneity would be assessed using Q- and I²-statistics. 35,36 Given the small number of trials available, a fixed-effects model was planned using the ‘metan’ command within Stata Version 9.2 (StataCorp LP, College Station, TX, USA) where pooling was appropriate.

If the data allowed, a mixed-treatment comparison (MTC) of relevant comparators to PhVIT would be considered. A MTC analysis allows for the synthesis of data from direct and indirect comparisons, and allows for the ranking of different treatments in order of efficacy and estimation of the relative treatment effect of competing interventions. This approach assumes ‘exchangeability’ of treatment effect across all included trials, such that the observed treatment effect for any comparison could have been expected to arise if it had been measured in all other included trials. This approach fulfils the objective of providing simultaneous comparison of all of the relevant treatment alternatives, and can provide information about the associated decision uncertainty or sufficient information for economic evaluation. Hence, for the purposes of decision-making, a Bayesian MTC framework would be adopted to synthesise information on all technologies simultaneously using Markov chain Monte Carlo (MCMC) methods to estimate the posterior distributions for our outcomes of interest. The MCMC simulation begins with an approximate distribution and, if the model is a good fit to the data, the distribution converges to the true distribution. As with all meta-analyses, MTC may be conducted using either fixed- or random-effects models. Random-effects models allow for the possibility that the true treatment effect may differ between trials. The model fit will be assessed based on residual deviance and deviance information criteria.

WinBUGS version 1.4 statistical software37 (MRC Biostatistics Unit, Cambridge, UK) was planned for use in the MTC. 38 Two chains would be used to ensure that model convergence was met after 50,000 iterations with a burn-in of 100,000. Formal convergence of the models would be assessed using trace plots and the Gelman–Rubin approach39 and through inspection of the history plots.

Data would be pooled only if it was felt that the studies were measuring the same effects and if the studies had the same study design. When meta-analysis was considered unsuitable for the data that were identified (e.g. because of the heterogeneity of the studies, or because no reliable data were presented in the report), a narrative synthesis approach would be employed.

Quantity and quality of research available

The electronic searches identified 1397 citations, which, after de-duplication, included 1065 individual papers, of which 799 were excluded after scanning titles and abstracts in stage 1. The full papers of 266 references were obtained and screened using the previously described inclusion criteria. Of the 266 papers screened at stage 2, 11 papers (nine studies) met the revised inclusion criteria. Of the remaining 255 excluded papers, the majority (161) were not comparative studies of PhVIT; other reasons for exclusion included inappropriate outcomes and irrelevant patient populations (Figure 1).

FIGURE 1.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart.

There were 38 excluded papers that require further mention in this report as they met the majority of the inclusion criteria but were studies of non-PhVIT. These 38 papers included 16 papers that compared two non-PhVIT treatments and 12 papers that compared non-PhVIT with no VIT [placebo, AAI prescriptions or whole bee extract (WBE)] and are described in the clinical effectiveness section (see Comparative studies of venom immunotherapy other than Pharmalgen). Seven papers provided data on QoL and three were economic papers (see Figure 1).

Nine comparative studies, reported in 11 publications,32,40–49 met the inclusion criteria for this review. The references discussed in the text refer to the primary papers and any other publications of the study are listed by study in Appendix 3. A summary of the included studies is shown in Table 4.

Clinical effectiveness

Observational studies of Pharmalgen

In addition to the comparative studies of PhVIT included in this review the searches identified 17 observational studies of PhVIT in the treatment of bee and wasp venom allergy (Table 13). It is likely that some of these papers are multiple publications from the same studies but in the following description they are assumed to be independent. All 17 studies assessed the rate of systemic reactions to subsequent stings, either FS or SC, after or during PhVIT.

All but one study54 was conducted in Europe and all studies used a maintenance dose of 100 μg/ml Pharmalgen. The number of people receiving treatment ranged from 10 to 562 and the number of re-stings reported in each study ranged from 3 to 290. Three studies55–57 included only children. Five studies58–62 split results by insect venom type and a further two63,64 reported outcomes only for individuals with a bee venom allergy.

The timing of the sting differed between studies and as such has an important bearing on the rates of systemic reaction reported. Four54,60,64,65 reported re-sting during maintenance, four59,62,63,66 during updosing and maintenance, five57,61,67–69 after PhVIT, two55,70 during or after PhVIT and two56,58 during and after PhVIT.

The reported rates of systemic reaction ranged between 0.0% and 32.7%. This large range reflects differences in the timing of re-stings, with 12 studies reporting data on re-stings before the completion of PhVIT. For the studies reporting systemic reactions after PhVIT, three smaller studies67–69 reported no systemic reactions, two larger studies reported 4/200 (2.0%)56 and 8/274 (2.9%)58 systemic reactions, and the remaining two studies reported 1/29 (3.4%)57 and 25/200 (12.5%)61 systemic reactions.

Comparative studies of venom immunotherapy other than Pharmalgen

Although the remit of this review was to assess the clinical effectiveness and cost-effectiveness of PhVIT for the treatment of bee and wasp venom allergy, as discussed in Chapter 1, Venom immunotherapy, there are other VIT products that are available to treat bee and wasp venom allergy. The searches for this review identified one meta-analysis71 and two systematic reviews33,72 reporting on comparative studies of non-PhVIT products in the population of interest, and an overview of the publications is given in Table 14.

The AG assessed the systematic reviews33,72 for quality using the Database of Abstracts of Reviews of Effects (DARE) quality assessment tool. 88 Both were shown to be of high quality (Table 15). One of the high-quality reviews was a Cochrane review that is ongoing, and the AG have worked in collaboration with this group on a number of systematic reviews.

Both of the systematic reviews33,72 and the meta-analysis71 conclude that VIT is effective in preventing future systemic reactions to venom in venom-allergic people.

Vespid Allergy Quality of Life questionnaire

In a study of 29 people with a history of LLR to yellow jacket sting, Oude Elberink et al. 87 reported that 53% had a significant improvement in QoL score (an increase of at least 0.5 points in VQLQ) at 1 year in the immunotherapy group compared with 8% in the control group. Mean VQLQ at the end of treatment was 5.84 in the immunotherapy group and 4.53 in the control group. In an abstract publication82 the same research group reported a mean difference in QoL score change of a 0.96-point improvement on a 1–7 scale after 1 year of yellow jacket immunotherapy in 50 people compared with a 0.37-point deterioration in a control group of 51 people, all of whom had a history of systemic allergic reaction. A further publication83 by the same research group in 69 people with a history of systemic reaction to yellow jacket sting reported that 74% had a significant improvement in QoL score (an increase of at least 0.5 points in VQLQ) at 1 year with immunotherapy compared with 9% in the control group. Mean VQLQ at the end of treatment was 4.35 in the immunotherapy group and 2.90 in the control group. A meta-analysis of the two studies for the outcome change in VLQL over time significantly favoured VIT over EpiPen (test for overall effect: z = 36.25 p < 0.00001).

Acceptability of treatment

The studies of Oude-Elberink et al. 82–84,87 reported patient views of the burden of treatment in both VIT and control arms using a 7-point scale in which a score of 1–3 was classed as a ‘positive’ view of treatment and a score of 4–7 as negative or neutral view of treatment. In their 2006 study84 of people with a history of systemic reaction to yellow jacket sting, 44/47 (94%) immunotherapy-treated people had a positive overall assessment of their treatment after 1 year compared with 22/46 (48%) people in the control group (p < 0.001); similarly, in their 2009 study87 of people with a history of LLR to yellow jacket sting, 93% of immunotherapy-treated people and 42% of those in the control group had a positive overall assessment of their treatment at 1 year.

Overview of Assessment Group model

An overview of the AG’s de novo economic model is given in Table 17.

Economic model

The economic model is constructed as a 1-year cohort decision tree that can be extrapolated to have a horizon of multiple years with the only changes being a reduction in the size of the cohort at the end of each year as a result of sting-related death or death from other causes. The average age of the cohort increases with the time horizon of the model with all-cause mortality rates changing as the average age of the cohort increases. 96 Development of a Markov model was not appropriate for disease modelling of the decision problem. To illustrate, with the exception of death, there is no transition into a state that results in changes to the key parameters, for example being stung does not change the probability of experiencing a systemic reaction from future stings.

The available evidence for the key pathway parameters (likelihood of sting, resulting systemic reaction under different treatment arms and the likelihood of death following systemic reaction) is weak. As such, construction of probability distributions around these parameters was not feasible. Instead, a deterministic model was produced using the best available estimates with sensitivity and scenario analyses employed to test the impact of changing the parameters within plausible ranges.

A schematic of the first year of the model for PhVIT + AAI + HDA is shown in Figure 2. The schematic for subsequent years is identical with the exception that the updosing phase of VIT is no longer present and after PhVIT has stopped the maintenance phase ends. The model then simplifies into the number of stings per patient per year with resulting systemic reactions and the number of deaths from other causes. For the other treatment arms the model is essentially this simplified version of the intervention arm. The cohort is defined as 1000 patients who receive a full course of PhVIT; any extra costs due to non-adherence to treatment are considered implicitly if maintenance continues for 5 years rather than 3 years as described in the sensitivity analysis.

FIGURE 2.

The AG’s de novo economic model in the first year.

Treatment options to be evaluated

To provide evidence on treatment pathways we sent out 97 electronic questionnaires to immunology clinicians in allergy clinics in the UK to gather information to inform the economic modelling. The survey and summary results are presented in Appendix 5. This survey identified that approximately 97% (n = 200) of people receiving PhVIT in the responding clinics were provided with an emergency kit that included an AAI and sometimes a HDA.

The intervention of interest is not considered to be PhVIT in isolation but rather PhVIT in combination with an emergency kit of an AAI and a HDA. The emergency kit is assumed to be provided to the patient during PhVIT treatment and for the lifetime of the patient after treatment has ended. The comparators of interest are (1) an emergency kit of an AAI and a HDA or (2) avoidance advice. It is assumed that avoidance advice is provided to all people regardless of receipt of PhVIT or an emergency kit.

Treatment pathways were determined through reviewing the included evidence on effectiveness of PhVIT in Chapter 3, a published audit of allergy clinics in the UK,14 published guidelines97 and our own survey (for results see Appendix 5).

For the PhVIT + AAI + HDA base case, the patient pathway is assumed to start after the individual has been assessed to be suitable for PhVIT. There are two phases to PhVIT – updosing and maintenance. During PhVIT an individual may experience local and systemic ARs. As the cost and QoL considerations for anything but systemic reactions are considered to be zero (discussed below), the pathway and model consider only systemic ARs by Mueller grade50 (details of Mueller grade can be found in Table 1). The cost of treatment of ARs is assumed to vary by Mueller grade.

The patient pathway assumes that each patient will experience an average number of sting events per year during or after PhVIT. A proportion of these stings result in systemic reactions of one of the four Mueller grades. A proportion of the grade 4 systemic reactions can result in death. There is also a probability that each year a patient can die as a result of causes unrelated to his or her sting allergy, which is dependent on the age of the patient.

Patient population

The patient population considered includes people who would be considered for PhVIT as a result of their previous systemic reaction to bee and/or wasp sting and who have positive test results for specific IgE antibodies. This reflects both the licensed indication and the study populations described in the available effectiveness evidence.

The average age of people starting PhVIT is taken from our survey of clinicians in UK allergy clinics. The survey was returned by 32 out of 97 clinics (33.0%), of which 16 responded that they used PhVIT. In these clinics approximately 200 people commence PhVIT for wasp and/or bee sting each year.

For simplicity of completion of the survey, an estimate of the percentage of PhVIT patients starting in the clinic was requested for three age bands. Assuming that people were on average in the middle of each age band (aged 50 years in the 40+ band), a simple average age across responding clinics was estimated to be 37 years. This age is comparable to the average age reported in the trials included in the effectiveness review shown in Table 8. Sensitivity analysis was used to explore how the age of the individual when starting PhVIT influenced results, with a range between 5 and 55 years being explored.

Evidence from published studies suggests that the majority of people undertaking PhVIT are male. In the base case 80% of people are assumed to be male. As effectiveness and cost are not linked to gender, and age-related QoL norms vary only marginally by gender, it was not anticipated that this would have a significant bearing on results. To test this assumption, two scenarios were created: one in which all people were male (‘100% male’) and one in which all people were female (‘100% female’).

Model parameters

The choice of parameters and their values used in the model is based on the available published literature, discussion with UK clinicians and the results of the short economics survey of UK allergy clinics (see Appendix 5).

Model validation

Model parameters and values used in the base case, sensitivity analysis and scenario analysis

Table 25 summarises the parameters that can vary within the model and the values applied in the base case and sensitivity analyses.

Several scenario analyses were undertaken and these are summarised in terms of the difference in parameters from the base case (Table 26).

Results

For the hypothetical cohort of 1000 patients, the total number of systemic ARs to PhVIT, number of stings, severity of systemic reactions to sting, sting-related deaths, total life-years and QALYs over 10 years for each treatment arm for the base case and the two subgroups (‘High Risk of Sting Patients’ and ‘PhVIT Anxiety QoL Improvement’) are shown in Table 27.

The total costs for the hypothetical 1000-patient cohort in terms of intervention costs, treatment costs for ARs to PhVIT and treatment costs for systemic reactions following sting in the base case and two subgroups are provided in Table 28.

The incremental cost between the three treatment arms, incremental QALYs and cost per QALY of PhVIT + AAI + HDA compared with the two treatment alternatives for the base case and two subgroups for a 1000-patient cohort are shown in Tables 29–31 respectively.

Under the base-case assumptions over 10 years, PhVIT + AAI + HDA generates an additional 0.00011 and 0.00029 QALYs per patient compared with AAI + HDA and avoidance advice respectively. This is at an additional cost of £2029 and £2185 per patient compared with AAI + HDA and avoidance advice respectively. The ICER of PhVIT + AAI + HDA is therefore £18,065,527 per QALY gained compared with AAI + HDA and £7,627,835 per QALY gained compared with avoidance advice.

For the ‘High Risk of Sting Patient’ subgroup, at five stings per year, the reduction in costs from systemic reactions to sting over 10 years because of PhVIT outweighs the VIT treatment costs. As PhVIT also generates additional QALYs by reducing sting deaths for this subgroup, PhVIT + AAI + HDA dominates the alternatives.

The subgroup analysis that allows for QoL changes as a result of sting anxiety and the use of PhVIT estimates that PhVIT + AAI + HDA generates an additional 0.0850 and 0.0852 QALYs per patient compared with AAI + HDA and avoidance advice respectively. The incremental cost per patient is the same as in the base case. The ICER for the subgroup with sting anxiety that is partially alleviated with PhVIT + AAI + HDA is therefore £23,868 per QALY gained compared with AAI + HDA and £25,661 per QALY gained compared with avoidance advice only.

Sensitivity analysis

The results of the sensitivity analysis for the base case and two subgroups are presented in Tables 32–34, respectively, and show the impact on the ICER when parameters are varied; PhVIT + AAI + HDA is compared with the two treatment alternatives.

Scenario analysis

The impact of changes on the ICERs for PhVIT + AAI + HDA, under the different scenarios presented, compared with the alternative treatments is provided in Tables 35–37 for the base case, ‘High Risk of Sting Patients’ subgroup and ‘PhVIT Anxiety QoL Improvement’ subgroup respectively.

Summary of economics evidence

• No published economic evaluations relevant to the decision problem were identified by the systematic review of cost-effectiveness studies.

• The manufacturer of PhVIT did not submit any supporting clinical effectiveness or cost-effectiveness evidence to NICE.

• The AG developed a de novo economic model to compare PhVIT with currently available NHS treatments in patients with a history of type 1 IgE-mediated systemic allergic reaction to bee and/or wasp venom.

• In the AG’s base case, PhVIT + HDA + AAI reached an ICER of £18,065,527 per QALY gained compared with AAI + HDA.

• In the AG’s base case, PhVIT + HDA + AAI reached an ICER of £7,627,835 per QALY gained compared with avoidance advice only.

• In the AG’s base case the results of the sensitivity analyses and scenario analyses showed that the results of the economic evaluation were robust for every plausible change in parameter made.

• The AG’s ‘High Risk of Sting Patients’ subgroup analysis showed that the PhVIT + HDA + AAI dominates both AAI + HDA and avoidance advice only.

• The AG’s ‘VIT Anxiety QoL Improvement’ subgroup analysis showed that PhVIT + HDA + AAI vs HDA + AAI had an ICER of £23,868 per QALY gained.

• The AG’s ‘VIT Anxiety QoL Improvement’ subgroup analysis showed that PhVIT + HDA + AAI vs avoidance advice only had an ICER of £25,661 per QALY gained.

Prioritisation Group

1. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

2. Professor Imti Choonara, Professor in Child Health, Academic Division of Child Health, University of Nottingham

   Chair – Pharmaceuticals Panel

3. Dr Bob Coates, Consultant Advisor – Disease Prevention Panel

4. Dr Andrew Cook, Consultant Advisor – Intervention Procedures Panel

5. Dr Peter Davidson, Director of NETSCC, Health Technology Assessment

6. Dr Nick Hicks, Consultant Adviser – Diagnostic Technologies and Screening Panel, Consultant Advisor–Psychological and Community Therapies Panel

7. Ms Susan Hird, Consultant Advisor, External Devices and Physical Therapies Panel

8. Professor Sallie Lamb, Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick

   Chair – HTA Clinical Evaluation and Trials Board

9. Professor Jonathan Michaels, Professor of Vascular Surgery, Sheffield Vascular Institute, University of Sheffield

   Chair – Interventional Procedures Panel

10. Professor Ruairidh Milne, Director – External Relations

11. Dr John Pounsford, Consultant Physician, Directorate of Medical Services, North Bristol NHS Trust

    Chair – External Devices and Physical Therapies Panel

12. Dr Vaughan Thomas, Consultant Advisor – Pharmaceuticals Panel, Clinical

    Lead – Clinical Evaluation Trials Prioritisation Group

13. Professor Margaret Thorogood, Professor of Epidemiology, Health Sciences Research Institute, University of Warwick

    Chair – Disease Prevention Panel

14. Professor Lindsay Turnbull, Professor of Radiology, Centre for the MR Investigations, University of Hull

    Chair – Diagnostic Technologies and Screening Panel

15. Professor Scott Weich, Professor of Psychiatry, Health Sciences Research Institute, University of Warwick

    Chair – Psychological and Community Therapies Panel

16. Professor Hywel Williams, Director of Nottingham Clinical Trials Unit, Centre of Evidence-Based Dermatology, University of Nottingham

    Chair – HTA Commissioning Board

    Deputy HTA Programme Director

HTA Commissioning Board

1. Professor of Dermato-Epidemiology, Centre of Evidence-Based Dermatology, University of Nottingham

2. Department of Public Health and Epidemiology, University of Birmingham

3. Professor of Clinical Pharmacology, Director, NIHR HTA programme, University of Liverpool

1. Professor Ann Ashburn, Professor of Rehabilitation and Head of Research, Southampton General Hospital

2. Professor Judith Bliss, Director of ICR-Clinical Trials and Statistics Unit, The Institute of Cancer Research

3. Professor Peter Brocklehurst, Professor of Women’s Health, Institute for Women’s Health, University College London

4. Professor David Fitzmaurice, Professor of Primary Care Research, Department of Primary Care Clinical Sciences, University of Birmingham

5. Professor John W Gregory, Professor in Paediatric Endocrinology, Department of Child Health, Wales School of Medicine, Cardiff University

6. Professor Steve Halligan, Professor of Gastrointestinal Radiology, University College Hospital, London

7. Professor Angela Harden, Professor of Community and Family Health, Institute for Health and Human Development, University of East London

8. Dr Martin J Landray, Reader in Epidemiology, Honorary Consultant Physician, Clinical Trial Service Unit, University of Oxford

9. Dr Joanne Lord, Reader, Health Economics Research Group, Brunel University

10. Professor Stephen Morris, Professor of Health Economics, University College London, Research Department of Epidemiology and Public Health, University College London

11. Professor Dion Morton, Professor of Surgery, Academic Department of Surgery, University of Birmingham

12. Professor Gail Mountain, Professor of Health Services Research, Rehabilitation and Assistive Technologies Group, University of Sheffield

13. Professor Irwin Nazareth, Professor of Primary Care and Head of Department, Department of Primary Care and Population Sciences, University College London

14. Professor E Andrea Nelson, Professor of Wound Healing and Director of Research, School of Healthcare, University of Leeds

15. Professor John David Norrie, Chair in Clinical Trials and Biostatistics, Robertson Centre for Biostatistics, University of Glasgow

16. Dr Rafael Perera, Lecturer in Medical Statisitics, Department of Primary Health Care, University of Oxford

17. Professor Barney Reeves, Professorial Research Fellow in Health Services Research, Department of Clinical Science, University of Bristol

18. Professor Peter Tyrer, Professor of Community Psychiatry, Centre for Mental Health, Imperial College London

19. Professor Martin Underwood, Professor of Primary Care Research, Warwick Medical School, University of Warwick

20. Professor Caroline Watkins, Professor of Stroke and Older People’s Care, Chair of UK Forum for Stroke Training, Stroke Practice Research Unit, University of Central Lancashire

21. Dr Duncan Young, Senior Clinical Lecturer and Consultant, Nuffield Department of Anaesthetics, University of Oxford

1. Dr Tom Foulks, Medical Research Council

2. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

HTA Clinical Evaluation and Trials Board

1. Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick and Professor of Rehabilitation, Nuffield Department of Orthopaedic, Rheumatology and Musculoskeletal Sciences, University of Oxford

2. Professor of the Psychology of Health Care, Leeds Institute of Health Sciences, University of Leeds

3. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

1. Professor Keith Abrams, Professor of Medical Statistics, Department of Health Sciences, University of Leicester

2. Professor Martin Bland, Professor of Health Statistics, Department of Health Sciences, University of York

3. Professor Jane Blazeby, Professor of Surgery and Consultant Upper GI Surgeon, Department of Social Medicine, University of Bristol

4. Professor Julia M Brown, Director, Clinical Trials Research Unit, University of Leeds

5. Professor Alistair Burns, Professor of Old Age Psychiatry, Psychiatry Research Group, School of Community-Based Medicine, The University of Manchester & National Clinical Director for Dementia, Department of Health

6. Dr Jennifer Burr, Director, Centre for Healthcare Randomised trials (CHART), University of Aberdeen

7. Professor Linda Davies, Professor of Health Economics, Health Sciences Research Group, University of Manchester

8. Professor Simon Gilbody, Prof of Psych Medicine and Health Services Research, Department of Health Sciences, University of York

9. Professor Steven Goodacre, Professor and Consultant in Emergency Medicine, School of Health and Related Research, University of Sheffield

10. Professor Dyfrig Hughes, Professor of Pharmacoeconomics, Centre for Economics and Policy in Health, Institute of Medical and Social Care Research, Bangor University

11. Professor Paul Jones, Professor of Respiratory Medicine, Department of Cardiac and Vascular Science, St George‘s Hospital Medical School, University of London

12. Professor Khalid Khan, Professor of Women’s Health and Clinical Epidemiology, Barts and the London School of Medicine, Queen Mary, University of London

13. Professor Richard J McManus, Professor of Primary Care Cardiovascular Research, Primary Care Clinical Sciences Building, University of Birmingham

14. Professor Helen Rodgers, Professor of Stroke Care, Institute for Ageing and Health, Newcastle University

15. Professor Ken Stein, Professor of Public Health, Peninsula Technology Assessment Group, Peninsula College of Medicine and Dentistry, Universities of Exeter and Plymouth

16. Professor Jonathan Sterne, Professor of Medical Statistics and Epidemiology, Department of Social Medicine, University of Bristol

17. Mr Andy Vail, Senior Lecturer, Health Sciences Research Group, University of Manchester

18. Professor Clare Wilkinson, Professor of General Practice and Director of Research North Wales Clinical School, Department of Primary Care and Public Health, Cardiff University

19. Dr Ian B Wilkinson, Senior Lecturer and Honorary Consultant, Clinical Pharmacology Unit, Department of Medicine, University of Cambridge

1. Ms Kate Law, Director of Clinical Trials, Cancer Research UK

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

Diagnostic Technologies and Screening Panel

1. Scientific Director of the Centre for Magnetic Resonance Investigations and YCR Professor of Radiology, Hull Royal Infirmary

2. Professor Judith E Adams, Consultant Radiologist, Manchester Royal Infirmary, Central Manchester & Manchester Children’s University Hospitals NHS Trust, and Professor of Diagnostic Radiology, University of Manchester

3. Mr Angus S Arunkalaivanan, Honorary Senior Lecturer, University of Birmingham and Consultant Urogynaecologist and Obstetrician, City Hospital, Birmingham

4. Dr Diana Baralle, Consultant and Senior Lecturer in Clinical Genetics, University of Southampton

5. Dr Stephanie Dancer, Consultant Microbiologist, Hairmyres Hospital, East Kilbride

6. Dr Diane Eccles, Professor of Cancer Genetics, Wessex Clinical Genetics Service, Princess Anne Hospital

7. Dr Trevor Friedman, Consultant Liason Psychiatrist, Brandon Unit, Leicester General Hospital

8. Dr Ron Gray, Consultant, National Perinatal Epidemiology Unit, Institute of Health Sciences, University of Oxford

9. Professor Paul D Griffiths, Professor of Radiology, Academic Unit of Radiology, University of Sheffield

10. Mr Martin Hooper, Public contributor

11. Professor Anthony Robert Kendrick, Associate Dean for Clinical Research and Professor of Primary Medical Care, University of Southampton

12. Dr Nicola Lennard, Senior Medical Officer, MHRA

13. Dr Anne Mackie, Director of Programmes, UK National Screening Committee, London

14. Mr David Mathew, Public contributor

15. Dr Michael Millar, Consultant Senior Lecturer in Microbiology, Department of Pathology & Microbiology, Barts and The London NHS Trust, Royal London Hospital

16. Mrs Una Rennard, Public contributor

17. Dr Stuart Smellie, Consultant in Clinical Pathology, Bishop Auckland General Hospital

18. Ms Jane Smith, Consultant Ultrasound Practitioner, Leeds Teaching Hospital NHS Trust, Leeds

19. Dr Allison Streetly, Programme Director, NHS Sickle Cell and Thalassaemia Screening Programme, King’s College School of Medicine

20. Dr Matthew Thompson, Senior Clinical Scientist and GP, Department of Primary Health Care, University of Oxford

21. Dr Alan J Williams, Consultant Physician, General and Respiratory Medicine, The Royal Bournemouth Hospital

1. Dr Tim Elliott, Team Leader, Cancer Screening, Department of Health

2. Dr Joanna Jenkinson, Board Secretary, Neurosciences and Mental Health Board (NMHB), Medical Research Council

3. Professor Julietta Patrick, Director, NHS Cancer Screening Programme, Sheffield

4. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

5. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

6. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Disease Prevention Panel

1. Professor of Epidemiology, University of Warwick Medical School, Coventry

2. Dr Robert Cook, Clinical Programmes Director, Bazian Ltd, London

3. Dr Colin Greaves, Senior Research Fellow, Peninsula Medical School (Primary Care)

4. Mr Michael Head, Public contributor

5. Professor Cathy Jackson, Professor of Primary Care Medicine, Bute Medical School, University of St Andrews

6. Dr Russell Jago, Senior Lecturer in Exercise, Nutrition and Health, Centre for Sport, Exercise and Health, University of Bristol

7. Dr Julie Mytton, Consultant in Child Public Health, NHS Bristol

8. Professor Irwin Nazareth, Professor of Primary Care and Director, Department of Primary Care and Population Sciences, University College London

9. Dr Richard Richards, Assistant Director of Public Health, Derbyshire County Primary Care Trust

10. Professor Ian Roberts, Professor of Epidemiology and Public Health, London School of Hygiene & Tropical Medicine

11. Dr Kenneth Robertson, Consultant Paediatrician, Royal Hospital for Sick Children, Glasgow

12. Dr Catherine Swann, Associate Director, Centre for Public Health Excellence, NICE

13. Mrs Jean Thurston, Public contributor

14. Professor David Weller, Head, School of Clinical Science and Community Health, University of Edinburgh

1. Ms Christine McGuire, Research & Development, Department of Health

2. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

External Devices and Physical Therapies Panel

1. Consultant Physician North Bristol NHS Trust

2. Reader in Wound Healing and Director of Research, University of Leeds

3. Professor Bipin Bhakta, Charterhouse Professor in Rehabilitation Medicine, University of Leeds

4. Mrs Penny Calder, Public contributor

5. Dr Dawn Carnes, Senior Research Fellow, Barts and the London School of Medicine and Dentistry

6. Dr Emma Clark, Clinician Scientist Fellow & Cons. Rheumatologist, University of Bristol

7. Mrs Anthea De Barton-Watson, Public contributor

8. Professor Nadine Foster, Professor of Musculoskeletal Health in Primary Care Arthritis Research, Keele University

9. Dr Shaheen Hamdy, Clinical Senior Lecturer and Consultant Physician, University of Manchester

10. Professor Christine Norton, Professor of Clinical Nursing Innovation, Bucks New University and Imperial College Healthcare NHS Trust

11. Dr Lorraine Pinnigton, Associate Professor in Rehabilitation, University of Nottingham

12. Dr Kate Radford, Senior Lecturer (Research), University of Central Lancashire

13. Mr Jim Reece, Public contributor

14. Professor Maria Stokes, Professor of Neuromusculoskeletal Rehabilitation, University of Southampton

15. Dr Pippa Tyrrell, Senior Lecturer/Consultant, Salford Royal Foundation Hospitals’ Trust and University of Manchester

16. Dr Nefyn Williams, Clinical Senior Lecturer, Cardiff University

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Interventional Procedures Panel

1. Professor of Vascular Surgery, University of Sheffield

2. Consultant Colorectal Surgeon, Bristol Royal Infirmary

3. Mrs Isabel Boyer, Public contributor

4. Mr Sankaran Chandra Sekharan, Consultant Surgeon, Breast Surgery, Colchester Hospital University NHS Foundation Trust

5. Professor Nicholas Clarke, Consultant Orthopaedic Surgeon, Southampton University Hospitals NHS Trust

6. Ms Leonie Cooke, Public contributor

7. Mr Seumas Eckford, Consultant in Obstetrics & Gynaecology, North Devon District Hospital

8. Professor Sam Eljamel, Consultant Neurosurgeon, Ninewells Hospital and Medical School, Dundee

9. Dr Adele Fielding, Senior Lecturer and Honorary Consultant in Haematology, University College London Medical School

10. Dr Matthew Hatton, Consultant in Clinical Oncology, Sheffield Teaching Hospital Foundation Trust

11. Dr John Holden, General Practitioner, Garswood Surgery, Wigan

12. Dr Fiona Lecky, Senior Lecturer/Honorary Consultant in Emergency Medicine, University of Manchester/Salford Royal Hospitals NHS Foundation Trust

13. Dr Nadim Malik, Consultant Cardiologist/Honorary Lecturer, University of Manchester

14. Mr Hisham Mehanna, Consultant & Honorary Associate Professor, University Hospitals Coventry & Warwickshire NHS Trust

15. Dr Jane Montgomery, Consultant in Anaesthetics and Critical Care, South Devon Healthcare NHS Foundation Trust

16. Professor Jon Moss, Consultant Interventional Radiologist, North Glasgow Hospitals University NHS Trust

17. Dr Simon Padley, Consultant Radiologist, Chelsea & Westminster Hospital

18. Dr Ashish Paul, Medical Director, Bedfordshire PCT

19. Dr Sarah Purdy, Consultant Senior Lecturer, University of Bristol

20. Dr Matthew Wilson, Consultant Anaesthetist, Sheffield Teaching Hospitals NHS Foundation Trust

21. Professor Yit Chiun Yang, Consultant Ophthalmologist, Royal Wolverhampton Hospitals NHS Trust

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Pharmaceuticals Panel

1. Professor in Child Health, University of Nottingham

2. Senior Lecturer in Clinical Pharmacology, University of East Anglia

3. Dr Martin Ashton-Key, Medical Advisor, National Commissioning Group, NHS London

4. Dr Peter Elton, Director of Public Health, Bury Primary Care Trust

5. Dr Ben Goldacre, Research Fellow, Division of Psychological Medicine and Psychiatry, King’s College London

6. Dr James Gray, Consultant Microbiologist, Department of Microbiology, Birmingham Children’s Hospital NHS Foundation Trust

7. Dr Jurjees Hasan, Consultant in Medical Oncology, The Christie, Manchester

8. Dr Carl Heneghan, Deputy Director Centre for Evidence-Based Medicine and Clinical Lecturer, Department of Primary Health Care, University of Oxford

9. Dr Dyfrig Hughes, Reader in Pharmacoeconomics and Deputy Director, Centre for Economics and Policy in Health, IMSCaR, Bangor University

10. Dr Maria Kouimtzi, Pharmacy and Informatics Director, Global Clinical Solutions, Wiley-Blackwell

11. Professor Femi Oyebode, Consultant Psychiatrist and Head of Department, University of Birmingham

12. Dr Andrew Prentice, Senior Lecturer and Consultant Obstetrician and Gynaecologist, The Rosie Hospital, University of Cambridge

13. Ms Amanda Roberts, Public contributor

14. Dr Gillian Shepherd, Director, Health and Clinical Excellence, Merck Serono Ltd

15. Mrs Katrina Simister, Assistant Director New Medicines, National Prescribing Centre, Liverpool

16. Professor Donald Singer, Professor of Clinical Pharmacology and Therapeutics, Clinical Sciences Research Institute, CSB, University of Warwick Medical School

17. Mr David Symes, Public contributor

18. Dr Arnold Zermansky, General Practitioner, Senior Research Fellow, Pharmacy Practice and Medicines Management Group, Leeds University

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Mr Simon Reeve, Head of Clinical and Cost-Effectiveness, Medicines, Pharmacy and Industry Group, Department of Health

3. Dr Heike Weber, Programme Manager, Medical Research Council

4. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

5. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Psychological and Community Therapies Panel

1. Professor of Psychiatry, University of Warwick, Coventry

2. Consultant & University Lecturer in Psychiatry, University of Cambridge

3. Professor Jane Barlow, Professor of Public Health in the Early Years, Health Sciences Research Institute, Warwick Medical School

4. Dr Sabyasachi Bhaumik, Consultant Psychiatrist, Leicestershire Partnership NHS Trust

5. Mrs Val Carlill, Public contributor

6. Dr Steve Cunningham, Consultant Respiratory Paediatrician, Lothian Health Board

7. Dr Anne Hesketh, Senior Clinical Lecturer in Speech and Language Therapy, University of Manchester

8. Dr Peter Langdon, Senior Clinical Lecturer, School of Medicine, Health Policy and Practice, University of East Anglia

9. Dr Yann Lefeuvre, GP Partner, Burrage Road Surgery, London

10. Dr Jeremy J Murphy, Consultant Physician and Cardiologist, County Durham and Darlington Foundation Trust

11. Dr Richard Neal, Clinical Senior Lecturer in General Practice, Cardiff University

12. Mr John Needham, Public contributor

13. Ms Mary Nettle, Mental Health User Consultant

14. Professor John Potter, Professor of Ageing and Stroke Medicine, University of East Anglia

15. Dr Greta Rait, Senior Clinical Lecturer and General Practitioner, University College London

16. Dr Paul Ramchandani, Senior Research Fellow/Cons. Child Psychiatrist, University of Oxford

17. Dr Karen Roberts, Nurse/Consultant, Dunston Hill Hospital, Tyne and Wear

18. Dr Karim Saad, Consultant in Old Age Psychiatry, Coventry and Warwickshire Partnership Trust

19. Dr Lesley Stockton, Lecturer, School of Health Sciences, University of Liverpool

20. Dr Simon Wright, GP Partner, Walkden Medical Centre, Manchester

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health