Jean Hamilton

Background: Breast cancer is the most commonly diagnosed cancer in women in England. Breast cancer and chemotherapy treatment can impact upon patients’ quality of life and survival. Tumour profiling tests can help to identify whether patients will benefit from chemotherapy. Objectives: To evaluate the effectiveness and cost-effectiveness of four tumour profiling tests (Oncotype DX, Prosigna, EPclin and MammaPrint), compared with current decision-making (no testing), to guide use of adjuvant chemotherapy in people with hormone-receptor positive, human epidermal growth factor receptor 2 negative, early-stage breast cancer with one to three positive lymph nodes. Methods and data sources: A systematic review identified studies via a literature search in April 2023 and from our previous review. The economic analysis included a review of existing models and development of an independent model. Results: Fifty-five articles were included, 42 for prognostic and predictive ability and 13 for impact on chemotherapy decisions. All four tests showed prognostic ability for determining risk of relapse. The RxPONDER randomised controlled trial of Oncotype DX indicated no chemotherapy benefit in post-menopausal lymph node-positive patients with a recurrence score of 0–25, but a statistically significant benefit in pre-menopausal patients with a recurrence score of 0–25. An older randomised controlled trial reanalysis (Southwest Oncology Group-8814) indicated lower relative chemotherapy benefit with lower recurrence score, with statistically significant interactions between recurrence score and chemotherapy benefit in some but not all analyses. There was no clear evidence of prediction of relative chemotherapy benefit for Prosigna, EPclin or MammaPrint. Decision impact studies in lymph node-positive populations in the United Kingdom and Europe were only available for Oncotype DX, and they reported a reduction of 12–75% in chemotherapy recommendations following testing. Based on the list prices of the tests and downstream treatments, the independent model suggests the following: Oncotype DX: This test dominates current decision-making in post-menopausal lymph node-positive women, provided an assumption of predictive benefit holds, but the test is dominated if this assumption does not hold. The test is dominated by current decision-making in pre-menopausal lymph node-positive women. Prosigna: The probabilistic incremental cost-effectiveness ratio for Prosigna versus current decision-making in post-menopausal lymph node-positive women is £39,357 per quality-adjusted life-year gained. EPclin: The probabilistic incremental cost-effectiveness ratio for EPclin versus current decision-making in post-menopausal lymph node-positive women is £4113 per quality-adjusted life-year gained. MammaPrint: Within clinical high-risk pre-/post-menopausal lymph node-positive women, MammaPrint is dominated by current decision-making. Limitations: There are limited data on the prediction of chemotherapy benefit; evidence for Oncotype DX may support a predictive benefit, but this is uncertain. Decision impact studies in a lymph node-positive population were available only for Oncotype DX. The economic model relies on an assumption of predictive benefit for Oncotype DX, and broader assumptions around the way that Prosigna, MammaPrint and EPclin test results would affect chemotherapy decisions. Conclusions: All four tests provide prognostic information on the risk of relapse. The evidence on prediction of relative chemotherapy benefit is weaker and mostly limited to Oncotype DX. The economic analyses indicate that Oncotype DX and EPclin may have favourable cost-effectiveness profiles in post-menopausal lymph node-positive subgroups, although this is uncertain. Study registration: This study is registered as PROSPERO CRD42023425638. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR135822) and is published in full in Health Technology Assessment; Vol. 29, No. 49. See the NIHR Funding and Awards website for further award information.

Background: To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of ceftazidime-avibactam in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England. Methods: The health benefit of ceftazidime-avibactam was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients’ mortality risks and health-related quality of life. Patient-level costs and health-related quality of life of ceftazidime-avibactam under various usage scenarios compared with alternative management strategies in the high-value clinical scenarios were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population in quality-adjusted life-years using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for ceftazidime-avibactam. Results: The clinical effectiveness of ceftazidime-avibactam relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. In the base case, ceftazidime-avibactam was associated with a statistically significantly higher susceptibility relative to colistin (odds ratio 7.24, 95% credible interval 2.58 to 20.94). The remainder of the treatments were associated with lower susceptibility than colistin (odds ratio < 1). The results were sensitive to the definition of resistance and the studies included in the analysis. In the base case, patient-level benefit of ceftazidime-avibactam was between 0.08 and 0.16 quality-adjusted life-years, depending on the site of infection and the usage scenario. There was a high degree of uncertainty surrounding the benefits of ceftazidime-avibactam across all subgroups, and the results were sensitive to assumptions in the meta-analysis used to estimate susceptibility. There was substantial uncertainty in the number of infections that are suitable for treatment with ceftazidime-avibactam, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time, and rates of emergence of resistance. The population-level benefit varied substantially across the scenarios, from 531 to 2342 quality-adjusted life-years over 20 years. Conclusion: This work has provided quantitative estimates of the value of ceftazidime-avibactam within its areas of expected usage within the NHS. Limitations: Given existing evidence, the estimates of the value of ceftazidime-avibactam are highly uncertain. Future work: Future evaluations of antimicrobials would benefit from improvements to NHS data linkages, research to support appropriate synthesis of susceptibility studies, and application of routine data and decision modelling to assess enablement value. Study registration: No registration of this study was undertaken. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Policy Research Programme (NIHR award ref: NIHR135592), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 28, No. 73. See the NIHR Funding and Awards website for further award information.

Background: To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of cefiderocol in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform the National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England. Methods: The health benefit of cefiderocol was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients’ mortality risks and health-related quality of life. The clinical effectiveness of cefiderocol relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. Patient-level costs and health outcomes of cefiderocol under various usage scenarios compared with alternative management strategies were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population values using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for cefiderocol. Results: Among Enterobacterales isolates with the metallo-beta-lactamase resistance mechanism, the base-case network meta-analysis found that cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.32, 95% credible intervals 0.04 to 2.47), but the result was not statistically significant. The other treatments were also associated with lower susceptibility than colistin, but the results were not statistically significant. In the metallo-beta-lactamase Pseudomonas aeruginosa base-case network meta-analysis, cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.44, 95% credible intervals 0.03 to 3.94), but the result was not statistically significant. The other treatments were associated with no susceptibility. In the base case, patient-level benefit of cefiderocol was between 0.02 and 0.15 quality-adjusted life-years, depending on the site of infection, the pathogen and the usage scenario. There was a high degree of uncertainty surrounding the benefits of cefiderocol across all subgroups. There was substantial uncertainty in the number of infections that are suitable for treatment with cefiderocol, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time and rates of emergence of resistance. The population-level benefits varied substantially across the base-case scenarios, from 896 to 3559 quality-adjusted life-years over 20 years. Conclusion: This work has provided quantitative estimates of the value of cefiderocol within its areas of expected usage within the NHS. Limitations: Given existing evidence, the estimates of the value of cefiderocol are highly uncertain. Future work: Future evaluations of antimicrobials would benefit from improvements to NHS data linkages; research to support appropriate synthesis of susceptibility studies; and application of routine data and decision modelling to assess enablement value. Study registration: No registration of this study was undertaken. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Policy Research Programme (NIHR award ref: NIHR135591), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in Health Technology Assessment; Vol. 28, No. 28. See the NIHR Funding and Awards website for further award information.

Background: Pharmacological prophylaxis to prevent venous thromboembolism is currently recommended for women assessed as being at high risk of venous thromboembolism during pregnancy or in the 6 weeks after delivery (the puerperium). The decision to provide thromboprophylaxis involves weighing the benefits, harms and costs, which vary according to the individual’s venous thromboembolism risk. It is unclear whether the United Kingdom’s current risk stratification approach could be improved by further research. Objectives: To quantify the current decision uncertainty associated with selecting women who are pregnant or in the puerperium for thromboprophylaxis and to estimate the value of one or more potential future studies that would reduce that uncertainty, while being feasible and acceptable to patients and clinicians. Methods: A decision-analytic model was developed which was informed by a systematic review of risk assessment models to predict venous thromboembolism in women who are pregnant or in the puerperium. Expected value of perfect information analysis was used to determine which factors are associated with high decision uncertainty and should be the target of future research. To find out whether future studies would be acceptable and feasible, we held workshops with women who have experienced a blood clot or have been offered blood-thinning drugs and surveyed healthcare professionals. Expected value of sample information analysis was used to estimate the value of potential future research studies. Results: The systematic review included 17 studies, comprising 19 unique externally validated risk assessment models and 1 internally validated model. Estimates of sensitivity and specificity were highly variable ranging from 0% to 100% and 5% to 100%, respectively. Most studies had unclear or high risk of bias and applicability concerns. The decision analysis found that there is substantial decision uncertainty regarding the use of risk assessment models to select high-risk women for antepartum prophylaxis and obese postpartum women for postpartum prophylaxis. The main source of decision uncertainty was uncertainty around the effectiveness of thromboprophylaxis for preventing venous thromboembolism in women who are pregnant or in the puerperium. We found that a randomised controlled trial of thromboprophylaxis in obese postpartum women is likely to have substantial value and is more likely to be acceptable and feasible than a trial recruiting women who have had a previous venous thromboembolism. In unselected postpartum women and women following caesarean section, the poor performance of risk assessment models meant that offering prophylaxis based on these models had less favourable cost effectiveness with lower decision uncertainty. Limitations: The performance of the risk assessment model for obese postpartum women has not been externally validated. Conclusions: Future research should focus on estimating the efficacy of pharmacological thromboprophylaxis in pregnancy and the puerperium, and clinical trials would be more acceptable in women who have not had a previous venous thromboembolism. Study registration: This study is registered as PROSPERO CRD42020221094. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR131021) and is published in full in Health Technology Assessment; Vol. 28, No. 9. See the NIHR Funding and Awards website for further award information.

Objectives To assess the comparative accuracy of risk assessment models (RAMs) to identify women during pregnancy and the early postnatal period who are at increased risk of venous thromboembolism (VTE). Design Systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data sources MEDLINE, Embase, Cochrane Library and two research registers were searched until February 2021. Eligibility criteria All validation studies that examined the accuracy of a multivariable RAM (or scoring system) for predicting the risk of developing VTE in women who are pregnant or in the puerperium (within 6 weeks post-delivery). Data extraction and synthesis Two authors independently selected and extracted data. Risk of bias was appraised using PROBAST (Prediction model Risk Of Bias ASsessment Tool). Data were synthesised without meta-analysis. Results Seventeen studies, comprising 19 externally validated RAMs and 1 internally validated model, met the inclusion criteria. The most widely evaluated RAMs were the Royal College of Obstetricians and Gynaecologists guidelines (six studies), American College of Obstetricians and Gynecologists guidelines (two studies), Swedish Society of Obstetrics and Gynecology guidelines (two studies) and the Lyon score (two studies). In general, estimates of sensitivity and specificity were highly variable with sensitivity estimates ranging from 0% to 100% for RAMs that were applied to antepartum women to predict antepartum or postpartum VTE and 0% to 100% for RAMs applied postpartum to predict postpartum VTE. Specificity estimates were similarly diverse ranging from 28% to 98% and 5% to 100%, respectively. Conclusions Available data suggest that external validation studies have weak designs and limited generalisability, so estimates of prognostic accuracy are very uncertain. PROSPERO registration number CRD42020221094.

Background: The term ‘medically unexplained symptoms’ is used to cover a wide range of persistent bodily complaints for which adequate examination and appropriate investigations do not reveal sufficiently explanatory structural or other specified pathologies. A wide range of interventions may be delivered to patients presenting with medically unexplained symptoms in primary care. Many of these therapies aim to change the behaviours of the individual who may have worsening symptoms.Objectives: An evidence synthesis to determine the clinical effectiveness and cost-effectiveness of behavioural modification interventions for medically unexplained symptoms delivered in primary care settings was undertaken. Barriers to and facilitators of the effectiveness and acceptability of these interventions from the perspective of patients and service providers were evaluated through qualitative review and realist synthesis.Data sources: Full search strategies were developed to identify relevant literature. Eleven electronic sources were searched. Eligibility criteria – for the review of clinical effectiveness, randomised controlled trials were sought. For the qualitative review, UK studies of any design were included. For the cost-effectiveness review, papers were restricted to UK studies reporting outcomes as quality-adjusted life-year gains. Clinical searches were conducted in November 2015 and December 2015, qualitative searches were conducted in July 2016 and economic searches were conducted in August 2016. The databases searched included MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE. Updated searches were conducted in February 2019 and March 2019.Participants: Adult participants meeting the criteria for medically unexplained symptoms, including somatoform disorders, chronic unexplained pain and functional somatic syndromes.Interventions: Behavioural interventions were categorised into types. These included psychotherapies, exercise-based interventions, multimodal therapies (consisting of more than one intervention type), relaxation/stretching/social support/emotional support, guided self-help and general practitioner interventions, such as reattribution.Evidence synthesis: a network meta-analysis was conducted to allow a simultaneous comparison of all evaluated interventions in a single coherent analysis. Separate network meta-analyses were performed at three time points: end of treatment, short-term follow-up (< 6 months since the end of treatment) and long-term follow-up (≥ 6 months after the end of treatment). Outcomes included physical and psychological symptoms, physical functioning and impact of the illness on daily activities.Economic evaluation: within-trial estimates of cost-effectiveness were generated for the subset of studies where utility values (or quality-adjusted life-years) were reported or where these could be estimated by mapping from Short Form questionnaire-36 items or Short Form questionnaire-12 items outcomes.Results: Fifty-nine studies involving 9077 patients were included in the clinical effectiveness review. There was a large degree of heterogeneity both between and within intervention types, and the networks were sparse across all outcomes. At the end of treatment, behavioural interventions showed some beneficial effects when compared with usual care, in particular for improvement of specific physical symptoms [(1) pain: high-intensity cognitive–behavioural therapy (CBTHI) standardised mean difference (SMD) 0.54 [95% credible interval (CrI) 0.28 to 0.84], multimodal SMD 0.52 (95% CrI 0.19 to 0.89); and (2) fatigue: low-intensity cognitive–behavioural therapy (CBTLI) SMD 0.72 (95% CrI 0.27 to 1.21), relaxation/stretching/social support/emotional support SMD 0.87 (95% CrI 0.20 to 1.55), graded activity SMD 0.51 (95% CrI 0.14 to 0.93), multimodal SMD 0.52 (95% CrI 0.14 to 0.92)] and psychological outcomes [(1) anxiety CBTHI SMD 0.52 (95% CrI 0.06 to 0.96); (2) depression CBTHI SMD 0.80 (95% CrI 0.26 to 1.38); and (3) emotional distress other psychotherapy SMD 0.58 (95% CrI 0.05 to 1.13), relaxation/stretching/social support/emotional support SMD 0.66 (95% CrI 0.18 to 1.28) and sport/exercise SMD 0.49 (95% CrI 0.03 to 1.01)]. At short-term follow-up, behavioural interventions showed some beneficial effects for specific physical symptoms [(1) pain: CBTHI SMD 0.73 (95% CrI 0.10 to 1.39); (2) fatigue: CBTLI SMD 0.62 (95% CrI 0.11 to 1.14), relaxation/stretching/social support/emotional support SMD 0.51 (95% CrI 0.06 to 1.00)] and psychological outcomes [(1) anxiety: CBTHI SMD 0.74 (95% CrI 0.14 to 1.34); (2) depression: CBTHI SMD 0.93 (95% CrI 0.37 to 1.52); and (3) emotional distress: relaxation/stretching/social support/emotional support SMD 0.82 (95% CrI 0.02 to 1.65), multimodal SMD 0.43 (95% CrI 0.04 to 0.91)]. For physical functioning, only multimodal therapy showed beneficial effects: end-of-treatment SMD 0.33 (95% CrI 0.09 to 0.59); and short-term follow-up SMD 0.78 (95% CrI 0.23 to 1.40). For impact on daily activities, CBTHI was the only behavioural intervention to show beneficial effects [end-of-treatment SMD 1.30 (95% CrI 0.59 to 2.00); and short-term follow-up SMD 2.25 (95% CrI 1.34 to 3.16)]. Few effects remained at long-term follow-up. General practitioner interventions showed no significant beneficial effects for any outcome. No intervention group showed conclusive beneficial effects for measures of symptom load (somatisation). A large degree of heterogeneity was found across individual studies in the assessment of cost-effectiveness. Several studies suggested that the interventions produce fewer quality-adjusted life-years than usual care. For those interventions that generated quality-adjusted life-year gains, the mid-point incremental cost-effectiveness ratios (ICERs) ranged from £1397 to £129,267, but, where the mid-point ICER fell below £30,000, the exploratory assessment of uncertainty suggested that it may be above £30,000.Limitations: Sparse networks meant that it was not possible to conduct a metaregression to explain between-study differences in effects. Results were not consistent within intervention type, and there were considerable differences in characteristics between studies of the same type. There were moderate to high levels of statistical heterogeneity. Separate analyses were conducted for three time points and, therefore, analyses are not repeated-measures analyses and do not account for correlations between time points.Conclusions: Behavioural interventions showed some beneficial effects for specific medically unexplained symptoms, but no one behavioural intervention was effective across all medically unexplained symptoms. There was little evidence that these interventions are effective for measures of symptom load (somatisation). General practitioner-led interventions were not shown to be effective. Considerable heterogeneity in interventions, populations and sparse networks mean that results should be interpreted with caution. The relationship between patient and service provider is perceived to play a key role in facilitating a successful intervention. Future research should focus on testing the therapeutic effects of the general practitioner–patient relationship within trials of behavioural interventions, and explaining the observed between-study differences in effects within the same intervention type (e.g. with more detailed reporting of defined mechanisms of the interventions under study).Study registration: This study is registered as PROSPERO CRD42015025520.Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 46. See the NIHR Journals Library website for further project information.

Background: Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture.Objectives: The objectives were to evaluate the clinical effectiveness, safety and cost-effectiveness of non-bisphosphonates {denosumab [Prolia^®; Amgen Inc., Thousand Oaks, CA, USA], raloxifene [Evista^®; Daiichi Sankyo Company, Ltd, Tokyo, Japan], romosozumab [Evenity^®; Union Chimique Belge (UCB) S.A. (Brussels, Belgium) and Amgen Inc.] and teriparatide [Forsteo^®; Eli Lilly and Company, Indianapolis, IN, USA]}, compared with each other, bisphosphonates or no treatment, for the prevention of fragility fracture.Data sources: For the clinical effectiveness review, nine electronic databases (including MEDLINE, EMBASE and the World Health Organization International Clinical Trials Registry Platform) were searched up to July 2018.Review methods: A systematic review and network meta-analysis of fracture and femoral neck bone mineral density were conducted. A review of published economic analyses was undertaken and a model previously used to evaluate bisphosphonates was adapted. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years for a simulated cohort of patients with heterogeneous characteristics. This was done for each non-bisphosphonate treatment, a strategy of no treatment, and the five bisphosphonate treatments previously evaluated. The model was populated with effectiveness evidence from the systematic review and network meta-analysis. All other parameters were estimated from published sources. An NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture^®(QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX^®(web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net monetary benefit was estimated using non-parametric regression. A probabilistic sensitivity analysis and scenario analyses were used to assess uncertainty.Results: Fifty-two randomised controlled trials of non-bisphosphonates were included in the clinical effectiveness systematic review and an additional 51 randomised controlled trials of bisphosphonates were included in the network meta-analysis. All treatments had beneficial effects compared with placebo for vertebral, non-vertebral and hip fractures, with hazard ratios varying from 0.23 to 0.94, depending on treatment and fracture type. The effects on vertebral fractures and the percentage change in bone mineral density were statistically significant for all treatments. The rate of serious adverse events varied across trials (0–33%), with most between-group differences not being statistically significant for comparisons with placebo/no active treatment, non-bisphosphonates or bisphosphonates. The incremental cost-effectiveness ratios were > £20,000 per quality-adjusted life-year for all non-bisphosphonate interventions compared with no treatment across the range of QFracture and FRAX scores expected in the population eligible for fracture risk assessment. The incremental cost-effectiveness ratio for denosumab may fall below £30,000 per quality-adjusted life-year at very high levels of risk or for high-risk patients with specific characteristics. Raloxifene was dominated by no treatment (resulted in fewer quality-adjusted life-years) in most risk categories.Limitations: The incremental cost-effectiveness ratios are uncertain for very high-risk patients.Conclusions: Non-bisphosphonates are effective in preventing fragility fractures, but the incremental cost-effectiveness ratios are generally greater than the commonly applied threshold of £20,000–30,000 per quality-adjusted life-year.Study registration: This study is registered as PROSPERO CRD42018107651.Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 29. See the NIHR Journals Library website for further project information.

Background: Medullary thyroid cancer (MTC) is a rare form of cancer that affects patients’ health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq^®; Ipsen, Paris, France) and vandetanib (Caprelsa^®; Sanofi Genzyme, Cambridge, MA, USA) are currently the treatment modality of choice for treating unresectable progressive and symptomatic MTC.Objectives: (1) To evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. (2) To estimate the incremental cost-effectiveness of cabozantinib and vandetanib versus each other and best supportive care. (3) To identify key areas for primary research. (4) To estimate the overall cost of these treatments in England.Data sources: Peer-reviewed publications (searched from inception to November 2016), European Public Assessment Reports and manufacturers’ submissions.Review methods: A systematic review [including a network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. The economic analysis included a review of existing analyses and the development of a de novo model.Results: The systematic review identified two placebo-controlled trials. The Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial evaluated the efficacy and safety of cabozantinib in patients with unresectable locally advanced, metastatic and progressive MTC. The ZETA trial evaluated the efficacy and safety of vandetanib in patients with unresectable locally advanced or metastatic MTC. Both drugs significantly improved progression-free survival (PFS) more than the placebo (p < 0.001). The NMA suggested that, within the symptomatic and progressive MTC population, the effects on PFS were similar (vandetanib vs. cabozantinib: hazard ratio 1.14, 95% credible interval 0.41 to 3.09). Neither trial demonstrated a significant overall survival benefit for cabozantinib or vandetanib versus placebo, although data from ZETA were subject to potential confounding. Both cabozantinib and vandetanib demonstrated significantly better objective response rates and calcitonin (CTN) and carcinoembryonic antigen (CEA) response rates than placebo. Both cabozantinib and vandetanib produced frequent adverse events, often leading to dose interruption or reduction. The assessment group model indicates that, within the EU-label population (symptomatic and progressive MTC), the incremental cost-effectiveness ratios (ICERs) for cabozantinib and vandetanib are > £138,000 per quality-adjusted life-year (QALY) gained. Within the restricted EU-label population (symptomatic and progressive MTC with CEA/CTN doubling times of ≤ 24 months), the ICER for vandetanib is expected to be > £66,000 per QALY gained. The maximum annual budget impact within the symptomatic and progressive population is estimated to be ≈£2.35M for cabozantinib and ≈£5.53M for vandetanib. The costs of vandetanib in the restricted EU-label population are expected to be lower.Limitations: The intention-to-treat populations of the EXAM and ZETA trials are notably different. The analyses of ZETA subgroups may be subject to confounding as a result of differences in baseline characteristics and open-label vandetanib use. Attempts to statistically adjust for treatment switching were unsuccessful. No HRQoL evidence was identified for the MTC population.Conclusions: The identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs for cabozantinib and vandetanib are > £138,000 per QALY gained. Within the restricted EU-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained.Future research priorities: (1) Primary research assessing the long-term effectiveness of cabozantinib and vandetanib within relevant subgroups. (2) Reanalyses of the ZETA trial to investigate the impact of adjusting for open-label vandetanib use using appropriate statistical methods. (3) Studies assessing the impact of MTC on HRQoL.Study registration: This study is registered as PROSPERO CRD42016050403.Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Rheumatoid arthritis (RA) is a chronic, debilitating disease associated with reduced quality of life and substantial costs. It is unclear which tests and assessment tools allow the best assessment of prognosis in people with early RA and whether or not variables predict the response of patients to different drug treatments. Objective: To systematically review evidence on the use of selected tests and assessment tools in patients with early RA (1) in the evaluation of a prognosis (review 1) and (2) as predictive markers of treatment response (review 2). Data sources: Electronic databases (e.g. MEDLINE, EMBASE, The Cochrane Library, Web of Science Conference Proceedings; searched to September 2016), registers, key websites, hand-searching of reference lists of included studies and key systematic reviews and contact with experts. Study selection: Review 1 – primary studies on the development, external validation and impact of clinical prediction models for selected outcomes in adult early RA patients. Review 2 – primary studies on the interaction between selected baseline covariates and treatment (conventional and biological disease-modifying antirheumatic drugs) on salient outcomes in adult early RA patients. Results: Review 1 – 22 model development studies and one combined model development/external validation study reporting 39 clinical prediction models were included. Five external validation studies evaluating eight clinical prediction models for radiographic joint damage were also included. c -statistics from internal validation ranged from 0.63 to 0.87 for radiographic progression (different definitions, six studies) and 0.78 to 0.82 for the Health Assessment Questionnaire (HAQ). Predictive performance in external validations varied considerably. Three models [(1) Active controlled Study of Patients receiving Infliximab for the treatment of Rheumatoid arthritis of Early onset (ASPIRE) C-reactive protein (ASPIRE CRP), (2) ASPIRE erythrocyte sedimentation rate (ASPIRE ESR) and (3) Behandelings Strategie (BeSt)] were externally validated using the same outcome definition in more than one population. Results of the random-effects meta-analysis suggested substantial uncertainty in the expected predictive performance of models in a new sample of patients. Review 2 – 12 studies were identified. Covariates examined included anti-citrullinated protein/peptide anti-body (ACPA) status, smoking status, erosions, rheumatoid factor status, C-reactive protein level, erythrocyte sedimentation rate, swollen joint count (SJC), body mass index and vascularity of synovium on power Doppler ultrasound (PDUS). Outcomes examined included erosions/radiographic progression, disease activity, physical function and Disease Activity Score-28 remission. There was statistical evidence to suggest that ACPA status, SJC and PDUS status at baseline may be treatment effect modifiers, but not necessarily that they are prognostic of response for all treatments. Most of the results were subject to considerable uncertainty and were not statistically significant. Limitations: The meta-analysis in review 1 was limited by the availability of only a small number of external validation studies. Studies rarely investigated the interaction between predictors and treatment. Suggested research priorities: Collaborative research (including the use of individual participant data) is needed to further develop and externally validate the clinical prediction models. The clinical prediction models should be validated with respect to individual treatments. Future assessments of treatment by covariate interactions should follow good statistical practice. Conclusions: Review 1 – uncertainty remains over the optimal prediction model(s) for use in clinical practice. Review 2 – in general, there was insufficient evidence that the effect of treatment depended on baseline characteristics. Study registration: This study is registered as PROSPERO CRD42016042402. Funding: The National Institute for Health Research Health Technology Assessment programme.