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Background: The number of healthcare interventions described as ‘personalised medicine’ (PM) is increasing rapidly. As healthcare systems struggle to decide whether to fund PM innovations, it is unclear what models for financing and reimbursement are appropriate to apply in this context. Objective: To review financing and reimbursement models for PM, summarise their key characteristics, and describe whether they can influence the development and uptake of PM. Methods: A literature review was conducted in Medline, Embase, Web of Science, and Econlit to identify studies published in English between 2009 and 2021, and reviews published before 2009. Grey literature was identified through Google Scholar, Google and subject-specific webpages. Articles that described financing and reimbursement of PM, and financing of non-PM were included. Data were extracted and synthesised narratively to report on the models, as well as facilitators, incentives, barriers and disincentives that could influence PM development and uptake. Results: One hundred and fifty-three papers were included. Research and development of PM was financed through both public and private sources and reimbursed largely through traditional models such as single fees, Diagnosis-Related Groups, and bundled payments. Financial-based reimbursement, including rebates and price-volume agreements, was mainly applied to targeted therapies. Performance-based reimbursement was identified mainly for gene and targeted therapies, and some companion diagnostics. Gene therapy manufacturers offered outcome-based rebates for treatment failure for interventions including Luxturna®, Kymriah®, Yescarta®, Zynteglo®, Zolgensma® and Strimvelis®, and coverage with evidence development for Kymriah® and Yescarta®. Targeted testing with OncotypeDX® was granted value-based reimbursement through initial coverage with evidence development. The main barriers and disincentives to PM financing and reimbursement were the lack of strong links between stakeholders and the lack of demonstrable benefit and value of PM. Conclusions: Public-private financing agreements and performance-based reimbursement models could help facilitate the development and uptake of PM interventions with proven clinical benefit.

Objective The objective of this study was to develop guidance contributing to improved consistency and quality in economic evaluations of personalised medicine (PM), given current ambiguity about how to measure the value of PM as well as considerable variation in the methodology and reporting in economic evaluations of PM. Methods A targeted literature review of methodological papers was performed for an overview of modelling challenges in PM. Expert interviews were held to discuss best modelling practice. A systematic literature review of economic evaluations of PM was conducted to gain insight into current modelling practice. The findings were synthesised and used to develop a set of draft recommendations. The draft recommendations were discussed at a stakeholder workshop and subsequently finalised. Results Twenty-two methodological papers were identified. Some argued that the challenges in modelling PM can be addressed within existing methodological frameworks, others disagreed. Eighteen experts were interviewed. They believed large uncertainty to be a key concern. Out of 195 economic evaluations of PM identified, 56% addressed none of the identified modelling challenges. A set of 23 recommendations was developed. Eight recommendations focus on the modelling of test-treatment pathways. The use of non-randomised controlled trial data is discouraged but several recommendations are provided in case randomised controlled trial data are unavailable. The parameterisation of structural uncertainty is recommended. Other recommendations consider perspective and discounting; premature survival data; additional value elements; patient and clinician compliance; and managed entry agreements. Conclusions This study provides a comprehensive list of recommendations to modellers of PM and to evaluators and reviewers of PM models. Supplementary Information The online version contains supplementary material available at 10.1007/s40273-021-01010-z.

Objectives: Precision oncology is generating vast amounts of multiomic data to improve human health and accelerate research. Existing clinical study designs and attendant data are unable to provide comparative evidence for economic evaluations. This lack of evidence can cause inconsistent and inappropriate reimbursement. Our study defines a core data set to facilitate economic evaluations of precision oncology. Methods: We conducted a literature review of economic evaluations of next-generation sequencing technologies, a common application of precision oncology, published between 2005 and 2018 and indexed in PubMed (MEDLINE). Based on this review, we developed a preliminary core data set for informal expert feedback. We then used a modified-Delphi approach with individuals involved in implementation and evaluation of precision medicine, including 2 survey rounds followed by a final voting conference to refine the data set. Results: Two authors determined that variation in published data elements was reached after abstraction of 20 economic evaluations. Expert consultation refined the data set to 83 unique data elements, and a multidisciplinary sample of 46 experts participated in the modified-Delphi process. A total of 68 elements (81%) were selected as required, spanning demographics and clinical characteristics, genomic data, cancer treatment, health and quality of life outcomes, and resource use. Conclusions: Cost-effectiveness analyses will fail to reflect the real-world impacts of precision oncology without data to accurately characterize patient care trajectories and outcomes. Data collection in accordance with the proposed core data set will promote standardization and enable the generation of decision-grade evidence to inform reimbursement.

Background One of the functions of the reformed Cancer Drugs Fund in England is as a managed access fund, providing conditional funding for cancer drugs where there is uncertainty in the economic case, and where that uncertainty can be addressed by data collection during two years’ use in the NHS. Our study characterises likely sources of such uncertainty, through a review of recent NICE Technology Appraisals. Methods Discussions of uncertainty in NICE Appraisal Committees were extracted from published Single Technology Appraisals of cancer drugs, 2014–2016, and categorised inductively. The location of the comments within the structured Appraisal document was used as a proxy for the degree of concern shown by the Committee. Results Twenty-nine appraisals were analysed, of which 23 (79%) were recommended for funding. Six main sources of uncertainty were identified. Immaturity of survival data, and issues relating to comparators, were common sources of uncertainty regardless of degree of concern. Uncertainties relating to quality of life, and the patient population in the trial, were discussed frequently but rarely occurred in the more uncertain appraisals. Concerns with trial design, and cost uncertainty, were less common, but a high proportion contributed to the most uncertain appraisals. Funding decisions were not driven by uncertainty in the evidence base, but by the expected cost per QALY relative to acceptance thresholds, and the resultant level of uncertainty in the decision. Conclusions The reformed CDF is an improvement on its predecessor. However the main types of uncertainty seen in recent cancer appraisals will not readily be resolved solely by 2 years’ RWD collection in the reformed CDF; where there are no ongoing trials to provide longer-term data, randomised trials rather than RWD may be needed to fully resolve questions of relative efficacy. Other types of uncertainty, and concerns with generalisability, may be more amenable to the RWD approach, and it is these that we expect to be the focus of data collection arrangements in the reformed CDF.

Background A multi-disciplinary approach to promote engagement, inform decision-making and support clinicians and patients is increasingly advocated to realise the potential of genome-scale sequencing in the clinic for patient benefit. Here we describe the results of establishing a genomic medicine multi-disciplinary team (GM-MDT) for case selection, processing, interpretation and return of results. Methods We report a consecutive case series of 132 patients (involving 10 medical specialties with 43.2% cases having a neurological disorder) undergoing exome sequencing over a 10-month period following the establishment of the GM-MDT in a UK NHS tertiary referral hospital. The costs of running the MDT are also reported. Results In total 76 cases underwent exome sequencing following triage by the GM-MDT with a clinically reportable molecular diagnosis in 24 (31.6%). GM-MDT composition, operation and rationale for whether to proceed to sequencing are described, together with the health economics (cost per case for the GM-MDT was £399.61), the utility and informativeness of exome sequencing for molecular diagnosis in a range of traits, the impact of choice of sequencing strategy on molecular diagnostic rates and challenge of defining pathogenic variants. In 5 cases (6.6%), an alternative clinical diagnosis was indicated by sequencing results. Examples were also found where findings from initial genetic testing were reconsidered in the light of exome sequencing including TP63 and PRKAG2 (detection of a partial exon deletion and a mosaic missense pathogenic variant respectively); together with tissue-specific mosaicism involving a cytogenetic abnormality following a normal prenatal array comparative genomic hybridization. Conclusions This consecutive case series describes the results and experience of a multidisciplinary team format that was found to promote engagement across specialties and facilitate return of results to the responsible clinicians. Electronic supplementary material The online version of this article (10.1186/s13073-019-0651-9) contains supplementary material, which is available to authorized users.

Background Recruitment into surgical RCTs can be threatened if new interventions available outside the trial compete with those being evaluated. Adapting the trial to include the new intervention may overcome this issue, yet this is not often done in surgery. This paper describes the challenges, rationale and methods for adapting an RCT to include a new intervention. Methods The By‐Band study was designed in the UK in 2009–2010 to compare the effectiveness of laparoscopic adjustable gastric band and Roux‐en‐Y gastric bypass for severe obesity. It contained a pilot phase to establish whether recruitment was possible, and the grant proposal specified that an adaptation to include sleeve gastrectomy would be considered if practice changed and recruitment was successful. Information on changing obesity surgery practice, updated evidence and expert opinion about trial design were used to inform the adaptation. Results The pilot phase recruited over 13 months in 2013–2014 and randomized 80 patients (79 anticipated). During this time, major changes in obesity practice in the UK were observed, with gastric band reducing from 32·6 to 15·8 per cent and sleeve gastrectomy increasing from 9·0 to 28·1 per cent. The evidence base had not changed markedly. The British Obesity and Metabolic Surgery Society and study oversight committees supported an adaptation to include sleeve gastrectomy, and a proposal to do so was approved by the funder. Conclusion Adaptation of a two‐group surgical RCT can allow evaluation of a third procedure and maintain relevance of the RCT to practice. It also optimizes the use of existing trial infrastructure to answer an additional important research question. Registration number: ISRCTN00786323 (http://www.isrctn.com/)., Something to consider

Purpose: We conducted a systematic literature review to summarize the current health economic evidence for whole-exome sequencing (WES) and whole-genome sequencing (WGS).Methods: Relevant studies were identified in the EMBASE, MEDLINE, Cochrane Library, EconLit and University of York Centre for Reviews and Dissemination databases from January 2005 to July 2016. Publications were included in the review if they were economic evaluations, cost studies, or outcome studies.Results: Thirty-six studies met our inclusion criteria. These publications investigated the use of WES and WGS in a variety of genetic conditions in clinical practice, the most common being neurological or neurodevelopmental disorders. Study sample size varied from a single child to 2,000 patients. Cost estimates for a single test ranged from $555 to $5,169 for WES and from $1,906 to $24,810 for WGS. Few cost analyses presented data transparently and many publications did not state which components were included in cost estimates.Conclusion: The current health economic evidence base to support the more widespread use of WES and WGS in clinical practice is very limited. Studies that carefully evaluate the costs, effectiveness, and cost-effectiveness of these tests are urgently needed to support their translation into clinical practice.

Background: In an environment of limited healthcare resources, it is crucial for healthcare systems who provide blood transfusion to have accurate and comprehensive information on the costs of transfusion, incorporating not only the costs of blood products, but also their administration. Unfortunately, in many countries accurate costs for administering blood are not available. Our study aimed to generate comprehensive estimates of the costs of administering transfusions for the UK National Health Service. Study Design and Methods: A detailed micro-costing study was used to cost two key inputs into transfusion: transfusion laboratory and nursing inputs. For each input, data collection forms were developed to capture staff time, equipment and consumables associated with each step in the transfusion process. Costing results were combined with costs of blood product wastage to calculate the cost per unit transfused, separately for different blood products. Data were collected in 2014/15 British pounds, and converted to US dollars. Results: 438 data collection forms were completed by 74 staff. The cost of administering blood was $71 (£49) per unit for red blood cells, $84 (£58) for platelets, $55 (£38) for fresh frozen plasma and $72 (£49) for cryoprecipitate. Conclusions: Blood administration costs add substantially to the costs of the blood products themselves. These are frequently incurred costs; applying estimates to the blood components supplied to UK hospitals in 2015, the annual cost of blood administration, excluding blood products, exceeds $175 (£120) million. These results provide more accurate estimates of the total costs of transfusion than those previously available.

AIM: Genomic interventions could enable improved disease stratification and individually tailored therapies. However, they have had a limited impact on clinical practice to date due to a lack of evidence, particularly economic evidence. This is partly because health economists are yet to reach consensus on whether existing methods are sufficient to evaluate genomic technologies. As different approaches may produce conflicting adoption decisions, clarification is urgently required. This article summarizes the methodological issues associated with conducting economic evaluations of genomic interventions. MATERIALS and METHODS: A structured literature review was conducted to identify references that considered the methodological challenges faced when conducting economic evaluations of genomic interventions. RESULTS: Methodological challenges related to the analytical approach included the choice of comparator, perspective and timeframe. Challenges in costing centered around the need to collect a broad range of costs, frequently, in a data-limited environment. Measuring outcomes is problematic as standard measures have limited applicability, however, alternative metrics (e.g., personal utility) are underdeveloped and alternative approaches (e.g., cost-benefit analysis) underused. Effectiveness data quality is weak and challenging to incorporate into standard economic analyses, while little is known about patient and clinician behavior in this context. Comprehensive value of information analyses are likely to be helpful. CONCLUSION: Economic evaluations of genomic technologies present a particular challenge for health economists. New methods may be required to resolve these issues, but the evidence to justify alternative approaches is yet to be produced. This should be the focus of future work in this field.

Purpose: To compare the efficacy and safety of ranibizumab and bevacizumab intravitreal injections to treat neovascular age-related macular degeneration (nAMD). Design: Multicenter, noninferiority factorial trial with equal allocation to groups. The noninferiority limit was 3.5 letters. This trial is registered (ISRCTN92166560). Participants: People >50 years of age with untreated nAMD in the study eye who read

OBJECTIVES: To assess the value of the cervical smear test to women, taking account of the positive and negative aspects of the cervical screening service. DESIGN: A postal survey. SETTING: Tayside Health Board region of Scotland. PARTICIPANTS: A sample of 2000 women aged 20-59. MAIN OUTCOME MEASURES: Maximum willingness to pay (WTP) for a cervical smear test. RESULTS: Women were prepared to pay 50.20 British pounds per smear on a 3-yearly basis. Willingness to pay was positively related to income, but unrelated to age and whether or not the respondent had previously had a smear. CONCLUSIONS: Previous studies have estimated the cost per screen or cost per life year saved by cervical screening. This study used the economic instrument of WTP to take account of other potential (dis)benefits to women. The value women place on having a smear was more than the cost to the National Health Service (NHS) of providing the service. The output of a WTP study is potentially useful at the policy level. Future work should explore both the value of alternative approaches to cervical screening, and the value of competing health care interventions.

Background Slow and cumbersome laboratory diagnostics for Mycobacterium tuberculosis complex (MTBC) risk delayed treatment and poor patient outcomes. Whole-genome sequencing (WGS) could potentially provide a rapid and comprehensive diagnostic solution. In this prospective study, we compare real-time WGS with routine MTBC diagnostic workflows. Methods We compared sequencing mycobacteria from all newly positive liquid cultures with routine laboratory diagnostic workflows across eight laboratories in Europe and North America for diagnostic accuracy, processing times, and cost between Sept 6, 2013, and April 14, 2014. We sequenced specimens once using local Illumina MiSeq platforms and processed data centrally using a semi-automated bioinformatics pipeline. We identified species or complex using gene presence or absence, predicted drug susceptibilities from resistance-conferring mutations identified from reference-mapped MTBC genomes, and calculated genetic distance to previously sequenced UK MTBC isolates to detect outbreaks. WGS data processing and analysis was done by staff masked to routine reference laboratory and clinical results. We also did a microcosting analysis to assess the financial viability of WGS-based diagnostics. Findings Compared with routine results, WGS predicted species with 93% (95% CI 90–96; 322 of 345 specimens; 356 mycobacteria specimens submitted) accuracy and drug susceptibility also with 93% (91–95; 628 of 672 specimens; 168 MTBC specimens identified) accuracy, with one sequencing attempt. WGS linked 15 (16% [95% CI 10–26]) of 91 UK patients to an outbreak. WGS diagnosed a case of multidrug-resistant tuberculosis before routine diagnosis was completed and discovered a new multidrug-resistant tuberculosis cluster. Full WGS diagnostics could be generated in a median of 9 days (IQR 6–10), a median of 21 days (IQR 14–32) faster than final reference laboratory reports were produced (median of 31 days [IQR 21–44]), at a cost of £481 per culture-positive specimen, whereas routine diagnosis costs £518, equating to a WGS-based diagnosis cost that is 7% cheaper annually than are present diagnostic workflows. Interpretation We have shown that WGS has a scalable, rapid turnaround, and is a financially feasible method for full MTBC diagnostics. Continued improvements to mycobacterial processing, bioinformatics, and analysis will improve the accuracy, speed, and scope of WGS-based diagnosis. Funding National Institute for Health Research, Department of Health, Wellcome Trust, British Colombia Centre for Disease Control Foundation for Population and Public Health, Department of Clinical Microbiology, Trinity College Dublin.

We aim to establish whether it is ever appropriate to conduct cost-minimisation analysis (CMA) rather than cost-effectiveness analysis.We perform a literature review to examine how the use of CMA has changed since Briggs and O'Brien announced its death in 2001. Examples of simulated and trial data are presented: firstly to illustrate the advantages and disadvantages of CMA in the context of non-inferiority trials and those finding no significant difference in efficacy and secondly to assess whether CMA gives biased results.We show that CMA is still used and will bias measures of uncertainty, causing overestimation or underestimation of the value of information and the probability that treatment is cost-effective. Although bias will be negligible for non-inferiority studies comparing treatments that differ enormously in cost, it is generally necessary to collect and analyse data on costs and efficacy (including utilities) to assess this bias. Cost-effectiveness analysis (including evaluation of the joint distribution of costs and benefits) is almost always required to avoid biased estimation of uncertainty. The remit of CMA in trial-based economic evaluation is therefore even narrower than previously thought, suggesting that CMA is not only dead but should also be buried. Copyright © 2011 John Wiley and Sons, Ltd.