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

EFSA BIOHAZ Panel (EFSA Panel on Biologicial Hazards), 2013. Scientific Opinion on the public health hazards to be covered by inspection of meat (solipeds)

A risk ranking process identified Trichinella spp. as the most relevant biological hazard in the context of meat inspection of domestic solipeds. Without a full and reliable soliped traceability system, it is considered that either testing all slaughtered solipeds for Trichinella spp., or inactivation meat treatments (heat or irradiation) should be used to maintain the current level of safety. With regard to general aspects of current meat inspection practices, the use of manual techniques during current post-mortem soliped meat inspection may increase microbial cross-contamination, and is considered to have a detrimental effect on the microbiological status of soliped carcass meat. Therefore, the use of visual-only inspection is suggested for “non-suspect” solipeds. For chemical hazards, phenylbutazone and cadmium were ranked as being of high potential concern. Monitoring programmes for chemical hazards should be more flexible and based on the risk of occurrence, taking into account Food Chain Information (FCI), covering the specific on-farm environmental conditions and individual animal treatments, and the ranking of chemical substances, which should be regularly updated and include new hazards. Sampling, testing and intervention protocols for chemical hazards should be better integrated and should focus particularly on cadmium, phenylbutazone and priority “essential substances” approved for treatment of equine animals. Implementation and enforcement of a more robust and reliable identification system throughout the European Union is needed to improve traceability of domestic solipeds. Meat inspection is recognised as a valuable tool for surveillance and monitoring of animal health and welfare conditions. If visual only post-mortem inspection is implemented for routine slaughter, a reduction in the detection of strangles and mild cases of rhodococcosis would occur. However, this was considered unlikely to affect the overall surveillance of both diseases. Improvement of FCI and traceability were considered as not having a negative effect on animal health and welfare surveillance

Annual report 1996

SIGLEAvailable from British Library Document Supply Centre-DSC:1143.26375(1996) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

CMR International Agenda for 2001

SIGLEAvailable from British Library Document Supply Centre-DSC:3287.27465(2001) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

The impact of economic and political factors on pharmaceutical innovation

Lecture held in London (GB), 14 Jul 1998Available from British Library Document Supply Centre-DSC:3287.27465(1998) / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo

Healthcare policy in the twenty-first century The outlook for innovation

Annual lecture presented at the Royal College of Physicians, London, on June 27, 2000Available from British Library Document Supply Centre-DSC:3287.27465(2000) / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo

Current strategies and future prospects in pharmaceutical outsourcing

SIGLEAvailable from British Library Document Supply Centre-DSC:99/40655 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN)

BACKGROUND:Bevacizumab (Avastin(®), Roche), which is used in cancer therapy, is the 'parent' molecule from which ranibizumab (Lucentis(®), Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5-10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs.OBJECTIVE:To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD.DESIGN:Multicentre, factorial randomised controlled trial with within-trial cost-utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed.SETTING:Twenty-three ophthalmology departments in NHS hospitals.PARTICIPANTS:Patients ??50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) ??25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter >?6000?µm, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required.INTERVENTIONS:Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5?mg or bevacizumab 1.25?mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated.MAIN OUTCOME MEASURES:The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes.RESULTS:Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [-1.37 letters, 95% confidence interval (CI) -3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1.63 letters, 95% CI -4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p?=?0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p?=?0.004). Odds of developing new GA during the trial were similar by drug [odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p?=?0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p?=?0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p?=?0.05). Continuous ranibizumab cost £3.5M per QALY compared with continuous bevacizumab; continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses.CONCLUSIONS:Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at £20,000 per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment