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The National Institute for Health and Care Excellence (NICE), as part of the institute’s single technology appraisal (STA) process, invited the company that makes obinutuzumab (Roche Products Limited) to submit evidence of the clinical and cost effectiveness of the drug in combination with chemotherapy, with or without obinutuzumab as maintenance therapy for adult patients with untreated, advanced follicular lymphoma (FL) in the UK. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company’s submission, the ERG review, and NICE’s subsequent decisions. The clinical evidence was derived from two phase III, company-sponsored, randomised, open-label studies. Most evidence on obinutuzumab was based on the GALLIUM trial that compared obinutuzumab in combination with chemotherapy as induction followed by obinutuzumab maintenance monotherapy with rituximab in combination with chemotherapy as induction followed by rituximab maintenance monotherapy in previously untreated patients with FL (grades 1–3a). Long-term clinical evidence was based on the PRIMA trial, studying the benefit of two years of rituximab maintenance after first-line treatment in patients with FL. The cost-effectiveness evidence submitted by the company relied on a partitioned survival cost-utility model, implemented in Microsoft® Excel. The base-case incremental cost-effectiveness ratio (ICER) presented in the company submission was

BACKGROUND: We assessed the accuracy and clinical effectiveness of high-sensitivity cardiac troponin (hs-cTn) assays for early rule-out of non-ST-segment elevation myocardial infarction (NSTEMI) in adults presenting with acute chest pain. METHODS: Sixteen databases were searched to September 2019. Review methods followed published guidelines. The bivariate model was used to estimate summary sensitivity and specificity with 95% confidence intervals for meta-analyses involving 4 or more studies, otherwise random-effects logistic regression was used. RESULTS: Thirty-seven studies (124 publications) were included in the review. The hs-cTn test strategies evaluated in the included studies were defined by the combination of 4 factors (assay, number of tests, timing of tests, and threshold concentration or change in concentration between tests). Clinical opinion indicated a minimum acceptable sensitivity of 97%. A single test at presentation using a threshold at or near the assay limit of detection could reliably rule-out NSTEMI for a range of hs-cTn assays. Serial testing strategies, which include an immediate rule-out step, increased the proportion ruled out without loss of sensitivity. Finally, serial testing strategies without an immediate rule-out step had excellent sensitivity and specificity, but at the expense of the option for immediate patient discharge. CONCLUSION: Test strategies that comprise an initial rule-out step, based on low hs-cTn concentrations at presentation and a minimum symptom duration, and a second step for those not ruled-out that incorporates a small absolute change in hs-cTn at 1, 2, or 3 hours, produce the highest rule-out rates with a very low risk of missed NSTEMI. PROSPERO REGISTRATION: CRD42019154716.

Objective: To assess the clinical effectiveness of weekly delivery of low dose, high frequency therapeutic ultrasound in conjunction with standard care for hard to heal venous leg ulcers. Design: Multicentre, pragmatic, two arm randomised controlled trial. Setting: Community and district nurse led services, community leg ulcer clinics, and hospital outpatient leg ulcer clinics in 12 urban and rural settings (11 in the United Kingdom and one in the Republic of Ireland). Participants: 337 patients with at least one venous leg ulcer of >6 months' duration or >5 cm2 area and an ankle brachial pressure index of ≥0.8. Interventions: Weekly administration of low dose, high frequency ultrasound therapy (0.5 W/cm2, 1 MHz, pulsed pattern of 1:4) for up to 12 weeks plus standard care compared with standard care alone. Main outcome measures: Primary outcome was time to healing of the largest eligible leg ulcer. Secondary outcomes were proportion of patients healed by 12 months, percentage and absolute change in ulcer size, proportion of time participants were ulcer-free, health related quality of life, and adverse events. Results: The two groups showed no significant difference in the time to healing of the reference leg ulcer (log rank test, P=0.61). After adjustment for baseline ulcer area, baseline ulcer duration, use of compression bandaging, and study centre, there was still no evidence of a difference in time to healing (hazard ratio 0.99 (95% confidence interval 0.70 to 1.40), P=0.97). The median time to healing of the reference leg ulcer was inestimable. There was no significant difference between groups in the proportion of participants with all ulcers healed by 12 months (72/168 in ultrasound group v 78/169 in standard care group, P=0.39 for Fisher's exact test) nor in the change in ulcer size at four weeks by treatment group (model estimate 0.05 (95% CI -0.09 to 0.19)). There was no difference in time to complete healing of all ulcers (log rank test, P=0.61), with median time to healing of 328 days (95% CI 235 to inestimable) with standard care and 365 days (224 days to inestimable) with ultrasound. There was no evidence of a difference in rates of recurrence of healed ulcers (17/31 with ultrasound v 14/ 31 with standard care, P=0.68 for Fisher's exact test). There was no difference between the two groups in health related quality of life, both for the physical component score (model estimate 0.69 (-1.79 to 3.08)) and the mental component score (model estimate -0.93 (-3.30 to 1.44)), but there were significantly more adverse events in the ultrasound group (model estimate 0.30 (0.01 to 0.60)). There was a significant relation between time to ulcer healing and baseline ulcer area (hazard ratio 0.64 (0.55 to 0.75)) and baseline ulcer duration (hazard ratio 0.59 (0.50 to 0.71)), with larger and older ulcers taking longer to heal. In addition, those centres with high recruitment rates had the highest healing rates. Conclusions: Low dose, high frequency ultrasound administered weekly for 12 weeks during dressing changes in addition to standard care did not increase ulcer healing rates, affect quality of life, or reduce ulcer recurrence. Trial registration ISRCTN21175670 and National Research Register N0484162339.

Objectives: To compare the clinical effectiveness and cost-effectiveness of larval therapy with a standard debridement technique (hydrogel). Design: A pragmatic, three-arm, randomised controlled trial with an economic evaluation. Setting: Community nursing services, community leg ulcer clinics and hospital outpatient leg ulcer clinics. A range of urban and rural settings. Participants: Patients with venous or mixed venous/arterial ulcers (minimum ankle brachial pressure index of 0.6) where a minimum of 25% of ulcer area was covered by slough and/or necrotic material. Interventions: Loose larval therapy and bagged larval therapy compared with hydrogel. Main outcome measures: The primary end point was complete healing of the largest eligible ulcer. The primary outcome was time to complete healing of the reference ulcer. Secondary outcomes were: time to debridement, cost of treatments, health-related quality of life (including ulcer-related pain), bacterial load, presence of methicillin-resistant Staphylococcus oureus and staff and patient attitudes to and beliefs about larval therapy. Results: Between July 2004 and May 2007 the trial recruited 267 people aged 20-94 years at trial entry. There were more female (n = 158) than male (n = 109) participants and most ulcers were classified by the nurse as having an area greater than 5 cm(2). The time to healing for the three treatment arms was compared using the log rank test. The difference in time to healing in the three treatments was not statistically significant at the 5% level. Adjustment was then made for stratification and prespecified prognostic factors (centre, baseline ulcer area, ulcer duration and type of ulcer) using a Cox proportional hazards model. No difference was found in healing rates between the loose and bagged larvae groups. Results for larvae (loose and bagged pooled) compared with hydrogel showed no evidence of a difference in time to healing. When the same analytical steps were used to investigate time to debridement, larvae-treated ulcers debrided significantly more rapidly than hydrogel-treated ulcers; however, the difference in time to debridement between loose and bagged larvae was not significant. The adjusted analysis reported the hazard of debriding at any time for those in loose and bagged larvae groups as approximately twice that of the hydrogel group. No differences in health-related quality of life or bacteriology were observed between trial arms. Larval therapy was associated with significantly more ulcer-related pain than hydrogel. Our base-case economic evaluation showed large decision uncertainty associated with the cost-effectiveness of larval therapy compared with hydrogel, suggesting that larval therapy and hydrogel therapy have similar costs and effects in the treatment of sloughy and/or necrotic leg ulcers. Conclusions: Larval therapy significantly reduced the time to debridement of sloughy and/or necrotic, chronic venous and mixed venous/arterial leg ulcers, compared with hydrogel; however, larval therapy did not significantly increase the rate of healing of the ulcers. It was impossible to distinguish between larval therapy and hydrogel in terms of cost-effectiveness. Future research should investigate the association of debridement and healing and the value of debridement as a clinical outcome for patients and clinicians. To inform decision-makers' selection of debriding agents where debridement is the treatment goal, decision analytic modelling of all alternative debridement treatments is required.