Extent and nature of duplication in PROSPERO using COVID-19-related registrations: a retrospective investigation and survey.

OBJECTIVES: During COVID-19, the International Prospective Register of Systematic Reviews (PROSPERO) experienced a surge in registrations for COVID-19-related systematic reviews, and duplication of research questions became apparent. Duplication can waste funding, time and research effort and make policy making more difficult.This project explored the extent of and reasons for duplication of COVID-19-related systematic review registrations in PROSPERO during the pandemic. DESIGN: Retrospective analysis of COVID-19-related registrations in PROSPERO, and a qualitative survey. SETTING: PROSPERO was searched for registrations related to four COVID-19 research areas: epidemiology, rehabilitation, transmission and treatments. METHODS: Records identified were compared using Population, Intervention/Exposure, Comparator, Outcome, Study Design (PICOS) elements of PROSPERO registration forms. Registrations with similar or identical PICOS were evaluated further as 'duplicates'.Authors of 'duplicate' registrations were invited to complete a survey asking whether they searched PROSPERO prior to registration, identified similar reviews and, if so, why they continued with their review. RESULTS: 1054 COVID-19 reviews were registered between March 2020 and January 2021, of which 138 were submitted when at least one similar protocol was already registered in PROSPERO. Duplication was greatest in reviews of COVID-19 treatments; for example, there were 14 similar reviews evaluating the efficacy of hydroxychloroquine.From 138 authors invited to take part in the survey, we received 41 responses. Most respondents said that they identified similar reviews when they searched PROSPERO prior to registration. Main reasons given for 'duplication' were differences in PICOS or planned analyses (n=13), poor quality of previous registrations (n=2) and the need to update evidence (n=3). CONCLUSIONS: This research highlights that registration of similar and duplicate systematic reviews related to COVID-19 in PROSPERO occurred frequently. Awareness of research waste is required, and initial checking for similar reviews should be embedded within good review practice.

Appraising the Costs of Genomic Testing for Histology-Independent Technologies: An Illustrative Example for NTRK Fusions.

OBJECTIVES: Histology-independent (HI) technologies are authorized for patients with advanced or metastatic cancer if they express a particular biomarker regardless of its position in the body. Although this represents an important advancement in cancer treatment, genomic testing to identify eligible individuals for HI technologies will require substantial investment and impact their cost-effectiveness. Estimating these costs is complicated by several issues, which affect not only the overall cost of testing but also the distribution of testing costs across tumor types. METHODS: Key issues that should be considered when evaluating the cost of genomic testing to identify those eligible for HI technologies are discussed. These issues are explored in illustrative analyses where costs of genomic testing for NTRK fusions in England for recently approved HI technologies are estimated. RESULTS: The prevalence of mutation, testing strategy adopted, and current testing provision affect the cost of identifying eligible patients. The illustrative analysis estimated the cost of RNA-based next-generation sequencing to identify 1 individual with an NTRK fusion ranged between £377 and £282 258. To improve cost-effectiveness, testing costs could be shared across multiple technologies. An estimated additional ∼4000 patients would need to be treated with other HI therapies for testing in patients with advanced or metastatic cancer to be cost-effective. CONCLUSIONS: The cost of testing to identify individuals eligible for HI technologies affect the drug's cost-effectiveness. The cost of testing across tumor types varies owing to heterogeneity in the mutation's prevalence and current testing provision. The cost-effectiveness of HI technologies may be improved if testing costs could be shared across multiple agents.

Coenzyme Q10 to manage chronic heart failure with a reduced ejection fraction: a systematic review and economic evaluation.

BACKGROUND: Chronic heart failure is a debilitating condition that accounts for an annual NHS spend of £2.3B. Low levels of endogenous coenzyme Q10 may exacerbate chronic heart failure. Coenzyme Q10 supplements might improve symptoms and slow progression. As statins are thought to block the production of coenzyme Q10, supplementation might be particularly beneficial for patients taking statins. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of coenzyme Q10 in managing chronic heart failure with a reduced ejection fraction. METHODS: A systematic review that included randomised trials comparing coenzyme Q10 plus standard care with standard care alone in chronic heart failure. Trials restricted to chronic heart failure with a preserved ejection fraction were excluded. Databases including MEDLINE, EMBASE and CENTRAL were searched up to March 2020. Risk of bias was assessed using the Cochrane Risk of Bias tool (version 5.2). A planned individual participant data meta-analysis was not possible and meta-analyses were mostly based on aggregate data from publications. Potential effect modification was examined using meta-regression. A Markov model used treatment effects from the meta-analysis and baseline mortality and hospitalisation from an observational UK cohort. Costs were evaluated from an NHS and Personal Social Services perspective and expressed in Great British pounds at a 2019/20 price base. Outcomes were expressed in quality-adjusted life-years. Both costs and outcomes were discounted at a 3.5% annual rate. RESULTS: A total of 26 trials, comprising 2250 participants, were included in the systematic review. Many trials were reported poorly and were rated as having a high or unclear risk of bias in at least one domain. Meta-analysis suggested a possible benefit of coenzyme Q10 on all-cause mortality (seven trials, 1371 participants; relative risk 0.68, 95% confidence interval 0.45 to 1.03). The results for short-term functional outcomes were more modest or unclear. There was no indication of increased adverse events with coenzyme Q10. Meta-regression found no evidence of treatment interaction with statins. The base-case cost-effectiveness analysis produced incremental costs of £4878, incremental quality-adjusted life-years of 1.34 and an incremental cost-effectiveness ratio of £3650. Probabilistic sensitivity analyses showed that at thresholds of £20,000 and £30,000 per quality-adjusted life-year coenzyme Q10 had a high probability (95.2% and 95.8%, respectively) of being more cost-effective than standard care alone. Scenario analyses in which the population and other model assumptions were varied all found coenzyme Q10 to be cost-effective. The expected value of perfect information suggested that a new trial could be valuable. LIMITATIONS: For most outcomes, data were available from few trials and different trials contributed to different outcomes. There were concerns about risk of bias and whether or not the results from included trials were applicable to a typical UK population. A lack of individual participant data meant that planned detailed analyses of effect modifiers were not possible. CONCLUSIONS: Available evidence suggested that, if prescribed, coenzyme Q10 has the potential to be clinically effective and cost-effective for heart failure with a reduced ejection fraction. However, given important concerns about risk of bias, plausibility of effect sizes and applicability of the evidence base, establishing whether or not coenzyme Q10 is genuinely effective in a typical UK population is important, particularly as coenzyme Q10 has not been subject to the scrutiny of drug-licensing processes. Stronger evidence is needed before considering its prescription in the NHS. FUTURE WORK: A new independent, well-designed clinical trial of coenzyme Q10 in a typical UK heart failure with a reduced ejection fraction population may be warranted. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018106189. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 4. See the NIHR Journals Library website for further project information.

People living with chronic heart failure suffer from shortness of breath, ankle swelling, tiredness, frequent stays in hospital and reduced quality of life and have shorter lives. The NHS spends over £2 billion each year managing chronic heart failure. Coenzyme Q10 is a vitamin-like substance made by the body that helps cells produce energy. Low levels of coenzyme Q10 in heart muscle may lead to, or exacerbate, chronic heart failure. Taking coenzyme Q10 supplements might improve symptoms or slow deterioration. To the best of our knowledge, we found all randomised clinical trials of coenzyme Q10 in patients with the type of chronic heart failure caused by muscle weakness (i.e. heart failure with reduced ejection fraction, where the heart's pumping function is weaker than normal). We asked the research groups responsible for these trials to provide the patient data that they had collected in their trials. Most research groups did not share their data and so we mainly used information from published trial reports. This limited our planned analyses. We found that taking coenzyme Q10 alongside usual treatment for heart failure with reduced ejection fraction potentially reduced deaths by approximately one-third and reduced readmission to hospital by around 40%. However, these results were uncertain. Side effects were not increased. We had some concerns about how reliable the data were, and it is not clear how well the results apply to UK patients. We also worked out what the benefits and costs to the NHS would be if coenzyme Q10 became available on prescription for patients with heart failure with reduced ejection fraction. Our model found that prescription could be worthwhile; however, a new trial is needed first to make sure that coenzyme Q10 improves outcomes for patients. A new trial would be particularly important because coenzyme Q10 has not been assessed in the same way as prescribed medicines. A new trial could make sure that there is better evidence about whether or not prescribing would be a good use of NHS resources.

Exploring Heterogeneity in Histology-Independent Technologies and the Implications for Cost-Effectiveness.

BACKGROUND: The National Institute for Health and Care Excellence and a number of international health technology assessment agencies have recently undertaken appraisals of histology-independent technologies (HITs). A strong and untested assumption inherent in the submissions included identical clinical response across all tumour histologies, including new histologies unrepresented in the trial. Challenging this assumption and exploring the potential for heterogeneity has the potential to impact upon cost-effectiveness. METHOD: Using published response data for a HIT, a Bayesian hierarchical model (BHM) was used to identify heterogeneity in response and to estimate the probability of response for each histology included in single-arm studies, which informed the submission for the HIT, larotrectinib. The probability of response for a new histology was estimated. Results were inputted into a simplified response-based economic model using hypothetical parameters. Histology-independent and histology-specific incremental cost-effectiveness ratios accounting for heterogeneity were generated. RESULTS: The results of the BHM show considerable heterogeneity in response rates across histologies. The predicted probability of response estimated by the BHM is 60.9% (95% credible interval 16.0; 91.8%), lower than the naively pooled probability of 74.5%. A mean response probability of 56.9% (0.2; 99.9%) is predicted for an unrepresented histology. Based on the economic analysis, the probability of the hypothetical HIT being cost-effective under the assumption of identical response is 78%. Allowing for heterogeneity, the probability of various approval decisions being cost-effective ranges from 93% to 11%. CONCLUSIONS: Central to the challenge of reimbursement of HITs is the potential for heterogeneity. This study illustrates how heterogeneity in clinical effectiveness can result in highly variable and uncertain estimates of cost-effectiveness. This analysis can help improve understanding of the consequences of histology-independent versus histology-specific decisions.

Modelling approaches for histology-independent cancer drugs to inform NICE appraisals: a systematic review and decision-framework.

BACKGROUND: The first histology-independent marketing authorisation in Europe was granted in 2019. This was the first time that a cancer treatment was approved based on a common biomarker rather than the location in the body at which the tumour originated. This research aims to explore the implications for National Institute for Health and Care Excellence appraisals. METHODS: Targeted reviews were undertaken to determine the type of evidence that is likely to be available at the point of marketing authorisation and the analyses required to support National Institute for Health and Care Excellence appraisals. Several challenges were identified concerning the design and conduct of trials for histology-independent products, the greater levels of heterogeneity within the licensed population and the use of surrogate end points. We identified approaches to address these challenges by reviewing key statistical literature that focuses on the design and analysis of histology-independent trials and by undertaking a systematic review to evaluate the use of response end points as surrogate outcomes for survival end points. We developed a decision framework to help to inform approval and research policies for histology-independent products. The framework explored the uncertainties and risks associated with different approval policies, including the role of further data collection, pricing schemes and stratified decision-making. RESULTS: We found that the potential for heterogeneity in treatment effects, across tumour types or other characteristics, is likely to be a central issue for National Institute for Health and Care Excellence appraisals. Bayesian hierarchical methods may serve as a useful vehicle to assess the level of heterogeneity across tumours and to estimate the pooled treatment effects for each tumour, which can inform whether or not the assumption of homogeneity is reasonable. Our review suggests that response end points may not be reliable surrogates for survival end points. However, a surrogate-based modelling approach, which captures all relevant uncertainty, may be preferable to the use of immature survival data. Several additional sources of heterogeneity were identified as presenting potential challenges to National Institute for Health and Care Excellence appraisal, including the cost of testing, baseline risk, quality of life and routine management costs. We concluded that a range of alternative approaches will be required to address different sources of heterogeneity to support National Institute for Health and Care Excellence appraisals. An exemplar case study was developed to illustrate the nature of the assessments that may be required. CONCLUSIONS: Adequately designed and analysed basket studies that assess the homogeneity of outcomes and allow borrowing of information across baskets, where appropriate, are recommended. Where there is evidence of heterogeneity in treatment effects and estimates of cost-effectiveness, consideration should be given to optimised recommendations. Routine presentation of the scale of the consequences of heterogeneity and decision uncertainty may provide an important additional approach to the assessments specified in the current National Institute for Health and Care Excellence methods guide. FURTHER RESEARCH: Further exploration of Bayesian hierarchical methods could help to inform decision-makers on whether or not there is sufficient evidence of homogeneity to support pooled analyses. Further research is also required to determine the appropriate basis for apportioning genomic testing costs where there are multiple targets and to address the challenges of uncontrolled Phase II studies, including the role and use of surrogate end points. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 76. See the NIHR Journals Library website for further project information.

In May 2017, the US Food and Drug Administration granted the first approval for a cancer treatment based on a common biomarker rather than the location in the body at which the tumour originated (the tumour site); that is, a site-agnostic or 'histology-independent' indication was granted. Research from the National Institute for Health and Care Excellence suggests that there are approximately 20 technologies currently in development for histology-independent indications. The first marketing authorisation was granted in Europe in 2019. Histology-independent treatments have the potential to have important effects in patient populations for whom there are currently limited or no available treatment options. However, it is also important to ensure that the use of these treatments in the NHS is supported by systematic and robust assessments of clinical evidence (i.e. how well the medicine or treatment works) and economic evidence (i.e. the medicine's value for money). These assessments are undertaken by the National Institute for Health and Care Excellence, usually for treatments targeting specific tumours sites. However, a histology-independent marketing authorisation would probably include many tumour sites and it is not possible for the National Institute for Health and Care Excellence to conduct a separate assessment for each tumour site for which the treatment could be beneficial. As a result, the National Institute for Health and Care Excellence needs to consider how these products can be appropriately assessed without creating unnecessary delays in patient access. This research explores the extent to which the National Institute for Health and Care Excellence's existing approaches for assessing clinical and economic value can be applied to histology-independent indications, and any changes that might be required. We explore the nature and amount of evidence that is typically available at the point of initial marketing authorisation and develop recommendations to establish the evidence and analyses required to help inform the National Institute for Health and Care Excellence's decisions. We use case studies to highlight possible challenges and to explore ways that these challenges might be addressed. This research will help to inform future National Institute for Health and Care Excellence policy on how to appraise cancer drugs with histology-independent indications. It will also inform the development of guidance for those developing these treatments to help their understanding of the clinical effectiveness and cost-effectiveness assessments that will be required to inform the National Institute for Health and Care Excellence's appraisals.