Adalimumab for Treating Moderate-to-Severe Hidradenitis Suppurativa: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of adalimumab (AbbVie) to submit evidence on the clinical effectiveness and cost effectiveness of adalimumab for the treatment of moderate-to-severe hidradenitis suppurativa (HS). The appraisal assessed adalimumab as monotherapy in adult patients with an inadequate response to conventional systemic HS therapy. The School of Health and Related Research Technology Appraisal Group was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical effectiveness and cost effectiveness of the technology based on the company’s submission to NICE. The evidence was mainly derived from three randomised controlled trials comparing adalimumab with placebo in adults with moderate-to-severe HS. The clinical-effectiveness review found that significantly more patients achieved a clinical response in the adalimumab groups than in the control groups but that the treatment effect varied between trials and there was uncertainty regarding its impact on a range of other relevant outcomes as well as long-term efficacy. The company’s submitted Markov model assessed the incremental cost effectiveness of adalimumab versus standard care for the treatment of HS from the perspective of the UK NHS and Personal Social Services (PSS) over a lifetime horizon. The original submitted model, including a patient access scheme (PAS), suggested that the incremental cost-effectiveness ratio (ICER) for adalimumab versus standard care was expected to be £16,162 per quality-adjusted life-year (QALY) gained. Following a critique of the model, the ERG’s preferred base case, which corrected programming errors and structural problems surrounding discontinuation rules and incorporated a lower unit cost for HS surgery, resulted in a probabilistic ICER of £29,725 per QALY gained. Based on additional analyses undertaken by the company and the ERG following the publication of the appraisal consultation document (ACD), the Appraisal Committee concluded that the maximum possible ICER for adalimumab compared with supportive care was between £28,500 and £33,200 per QALY gained but was likely to be lower. The Appraisal Committee recommended adalimumab (with the PAS) for the treatment of active moderate-to-severe HS in adults whose disease has not responded to conventional systemic therapy

The clinical effectiveness and cost-effectiveness of abatacept, adalimumab, etanercept and tocilizumab for treating juvenile idiopathic arthritis: a systematic review and economic evaluation

Background: Juvenile idiopathic arthritis (JIA) is characterised by joint pain, swelling and limitation of movement caused by inflammation. Subsequent joint damage can lead to disability and growth restriction. Treatment commonly includes disease modifying anti-rheumatic drugs (DMARD) such as methotrexate. Clinical practice now favours newer drugs termed biologic DMARDs where indicated.Objective: To assess the clinical and cost-effectiveness of four biologic DMARDs (etanercept, abatacept, adalimumab and tocilizumab - with or without methotrexate where indicated) for the treatment of JIA (systemic or oligoarticular JIA excluded).Data sources: Electronic bibliographic databases including MEDLINE, EMBASE, The Cochrane Library and DARE were searched for published studies from inception to May 2015 for English language articles. Bibliographies of related papers, systematic reviews and company submissions were screened and experts were contacted to identify additional evidence.Review methods: Systematic reviews of clinical-effectiveness, health-related quality of life and cost-effectiveness were undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. A cost-utility decision analytic model was developed to compare estimated cost-effectiveness of biologic DMARDs versus methotrexate. The base case time horizon was 30 years and the model took a National Health Service (NHS) perspective, with costs and benefits discounted at 3.5%.Results: Four placebo-controlled RCTs met the inclusion criteria for the clinical-effectiveness review (one RCT evaluating each biologic DMARD). Only one RCT included UK participants. Participants had to achieve an American College of Rheumatology Pediatric (ACR Pedi) 30 response to open-label lead-in treatment in order to be randomised. An exploratory adjusted indirect comparison suggests that the four biologic DMARDs are similar with fewer disease flares and greater proportions with ACR Pedi 50 and 70 responses among participants randomised to continued biologic DMARD. However, confidence intervals were wide, the number of trials was low and there was clinical heterogeneity between trials. Open-label extensions of the trials showed that generally ACR responses remained constant or even increased after the double-blind phase. The proportions of adverse events and serious adverse events were generally similar between treatment and placebo groups. Four economic evaluations of biologic DMARDs for patients with JIA were identified but all had limitations. Two quality of life studies were included, one of which informed the cost-utility model. The incremental cost-effectiveness ratio (ICER) for adalimumab, etanercept and tocilizumab versus methotrexate was £38,127, £32,526 and £38,656 per QALY, respectively. The ICER for abatacept versus methotrexate as a second line biologic was £39,536 per QALY.Limitations: The model does not incorporate the natural history of JIA in terms of long-term disease progression, as the current evidence is limited. There are no head-to-head trials of biologic DMARDs and clinical evidence for specific JIA subtypes is limited.Conclusions: Biologic DMARDs are superior to placebo (with methotrexate where permitted) in children with (predominantly) polyarticular course JIA, and an insufficient response to previous treatment. Randomised comparisons of biologic DMARDs with long-term efficacy and safety follow- are needed to establish comparative effectiveness. RCTs for JIA subtypes where evidence is lacking are also required.Funding: The National Institute for Health Research Health Technology Assessment programme. <br/

Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people: systematic review and economic evaluation

Background: Psoriasis is a chronic inflammatory disease that predominantly affects the skin. Adalimumab (HUMIRA®, AbbVie, Maidenhead, UK), etanercept (Enbrel®, Pfizer, New York, NY, USA) and ustekinumab (STELARA®, Janssen Biotech, Inc., Titusville, NJ, USA) are the three biological treatments currently licensed for psoriasis in children. Objective: To determine the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and ustekinumab within their respective licensed indications for the treatment of plaque psoriasis in children and young people. Data sources: Searches of the literature and regulatory sources, contact with European psoriasis registries, company submissions and clinical study reports from manufacturers, and previous National Institute for Health and Care Excellence (NICE) technology appraisal documentation. Review methods: Included studies were summarised and subjected to detailed critical appraisal. A network meta-analysis incorporating adult data was developed to connect the effectiveness data in children and young people and populate a de novo decision-analytic model. The model estimated the cost-effectiveness of adalimumab, etanercept and ustekinumab compared with each other and with either methotrexate or best supportive care (BSC), depending on the position of the intervention in the management pathway. Results: Of the 2386 non-duplicate records identified, nine studies (one randomised controlled trial for each drug plus six observational studies) were included in the review of clinical effectiveness and safety. Etanercept and ustekinumab resulted in significantly greater improvements in psoriasis symptoms than placebo at 12 weeks’ follow-up. The magnitude and persistence of the effects beyond 12 weeks is less certain. Adalimumab resulted in significantly greater improvements in psoriasis symptoms than methotrexate for some but not all measures at 16 weeks. Quality-of-life benefits were inconsistent across different measures. There was limited evidence of excess short-term adverse events; however, the possibility of rare events cannot be excluded. The majority of the incremental cost-effectiveness ratios for the use of biologics in children and young people exceeded NICE’s usual threshold for cost-effectiveness and were reduced significantly only when combined assumptions that align with those made in the management of psoriasis in adults were adopted. Limitations: The clinical evidence base for short- and long-term outcomes was limited in terms of total participant numbers, length of follow-up and the absence of young children. Conclusions: The paucity of clinical and economic evidence to inform the cost-effectiveness of biological treatments in children and young people imposed a number of strong assumptions and uncertainties. Health-related quality-of-life (HRQoL) gains associated with treatment and the number of hospitalisations in children and young people are areas of considerable uncertainty. The findings suggest that biological treatments may not be cost-effective for the management of psoriasis in children and young people at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year, unless a number of strong assumptions about HRQoL and the costs of BSC are combined. Registry data on biological treatments would help determine safety, patterns of treatment switching, impact on comorbidities and long-term withdrawal rates. Further research is also needed into the resource use and costs associated with BSC. Adequately powered randomised controlled trials (including comparisons against placebo) could substantially reduce the uncertainty surrounding the effectiveness of biological treatments in biologic-experienced populations of children and young people, particularly in younger children. Such trials should establish the impact of biological therapies on HRQoL in this population, ideally by collecting direct estimates of EuroQol-5 Dimensions for Youth (EQ-5D-Y) utilities. Study registration: This study is registered as PROSPERO CRD42016039494. Funding: The National Institute for Health Research Health Technology Assessment programme

A systematic review and economic evaluation of adalimumab and dexamethasone for treating non-infectious intermediate, posterior or panuveitis in adults

Background: Non-infectious intermediate uveitis, posterior uveitis and panuveitis are a heterogeneous group of inflammatory eye disorders. Management includes local and systemic corticosteroids, immunosuppressants and biologic drugs. Objectives: To evaluate clinical and cost-effectiveness of subcutaneous adalimumab and dexamethasone intravitreal implant in adults with non-infectious intermediate, posterior or panuveitis. Methods: Nine electronic databases were searched to June 2016. A Markov model was developed to assess cost-effectiveness of dexamethasone and adalimumab, each compared with current practice, from an NHS and PSS perspective over a lifetime horizon, parameterised with published evidence. Costs and benefits were discounted at 3.5%. Substantial sensitivity analyses were undertaken. Results: Two studies (VISUAL I, active uveitis; and VISUAL II, inactive uveitis) compared adalimumab against placebo, plus limited standard care in both arms. Time to treatment failure (reduced visual acuity, intraocular inflammation, new vascular lesions) was longer for adalimumab than placebo, with hazard ratio 0.50 (95% CI 0.36 to 0.70, p<0.001) in VISUAL I and 0.57 (0.39 to 0.84, p=0.004) in VISUAL II. Adalimumab provided significantly greater improvement in VFQ-25 composite score in VISUAL I (mean difference, 4.20; p=0.010) but not VISUAL II (mean difference, 2.12; p=0.16). Some systemic adverse effects occurred more frequently with adalimumab than placebo. One study (HURON, active uveitis) compared single 0.7mg dexamethasone implant against sham, plus limited standard care in both arms. Dexamethasone provided significant benefits over sham at 8 and 26 weeks in percentage of patients with vitreous haze score zero (p<0.014); mean BCVA improvement (p≤0.002); and percentage of patients with ≥5-point improvement in VFQ-25 (p<0.05). Raised intraocular pressure and cataracts occurred more frequently with dexamethasone than sham. The incremental cost-effectiveness ratio (ICER) of one dexamethasone implant in one eye for a combination of patients with unilateral and bilateral uveitis, compared with limited current practice as per the HURON trial, is estimated as £19,509 per quality-adjusted life year (QALY) gained. The ICER of adalimumab for patients with mainly bilateral uveitis, compared with limited current practice as per the VISUAL trials, is estimated as £94,523 and £317,547 per QALY gained in active and inactive uveitis respectively. Sensitivity analyses suggest rate of blindness has the biggest impact upon model results. The interventions may be more cost-effective in populations where there is a greater risk of blindness. Limitations: The clinical trials did not fully reflect clinical practice. Thirteen studies of clinically-relevant comparator treatments were identified; however, network meta-analysis was not feasible. The model results are highly uncertain due to the limited evidence base. Conclusions: Two RCTs of systemic adalimumab and one RCT of unilateral, single dexamethasone implant showed significant benefits over placebo or sham. The ICERs for adalimumab are estimated to be above generally accepted thresholds for cost-effectiveness. The cost-effectiveness of dexamethasone is estimated to fall below standard thresholds. However there is substantial uncertainty around the model assumptions. Future work: Primary research should compare dexamethasone and adalimumab with current treatments over the long term, and in important subgroups, and consider how short-term improvements relate to long-term effects on vision. Study registration: PROSPERO CRD42016041799 Funding details: NIHR HTA Programm

Epidemiologie der Myelodysplastischen Syndrome

Ziel des Forschungsvorhabens ist die Beschreibung der Epidemiologie und der Patientenpopulation der Myelodysplastischen Syndrome zur Verwendung der Angaben im Nutzendossier in der Indikation Myelodysplastische Syndrome. Die Ergebnisse der Prävalenz und Inzidenz können als Ausgangspunkt für die Berechnung der Patienten in der Zielpopulation verwendet werden. Primäres Forschungsziel ist die Beschreibung der 5-Jahres-Prävalenz, 1-Jahres Prävalenz und der jährlichen Inzidenz der Myelodysplastischen Syndrome im Zeitraum 2015/16-2019/20 (bei Datenverfügbarkeit wird der Zeitraum 2016-2020 gewählt). Sekundäres Forschungziel ist die Beschreibung der Charakteristika von Patienten mit Myelodysplastischen Syndromenen (Alter, Geschlecht, Bundesland des Wohnortes) im Zeitraum 2015/16-2019/20 (bei Datenverfügbarkeit wird der Zeitraum 2016-2020 gewählt)