A systematic review and meta-analysis of risks and benefits with breast reduction in the public healthcare system: priorities for further research.

BACKGROUND: There is no consensus for when publicly funded breast reduction is indicated and recommendations in guidelines vary greatly, indicating a lack of evidence and unequal access. The primary aim of this review was to examine risks and benefits of breast reduction to treat breast hypertrophy. Secondary aims were to examine how the studies defined breast hypertrophy and indications for a breast reduction. METHODS: A systematic literature search was conducted in PubMed, MEDLINE All, Embase, the Cochrane Library, and PsycInfo. The included articles were critically appraised, and certainty of evidence was assessed using the GRADE approach. Meta-analyses were performed when possible. RESULTS: Fifteen articles were included; eight reporting findings from four randomised controlled trials, three non-randomised controlled studies, three case series, and one qualitative study. Most studies had serious study limitations and problems with directness. Few of the studies defined breast hypertrophy. The studies showed significantly improved health-related quality of life and sexuality-related outcomes in patients who had undergone breast reduction compared with controls, as well as reduced depressive symptoms, levels of anxiety and pain. Most effect sizes exceeded the reported minimal important difference for the scale. Certainty of evidence for the outcomes above is low (GRADE ⊕ ⊕). Although four studies reported significantly improved physical function, the effect is uncertain (very low certainty of evidence, GRADE ⊕). None of the included studies reported data regarding work ability or sick leave. Three case series reported a 30-day mortality of zero. Reported major complications after breast reduction ranged from 2.4 to 14% and minor complications from 2.4 to 69%. CONCLUSION: There is a lack of high-quality studies evaluating the results of breast reduction. A breast reduction may have positive psychological and physical effects for women, but it is unclear which women benefit the most and which women should be offered a breast reduction in the public healthcare system. Several priorities for further research have been identified. PRE-REGISTRATION: The study is based on a Health Technology Assessment report, pre-registered and then published on the website of The Regional HTA Centre of Region Västra Götaland, Sweden.

Assessment of Early Response to Neoadjuvant Systemic Therapy in Triple-Negative Breast Cancer Using Amide Proton Transfer-weighted Chemical Exchange Saturation Transfer MRI: A Pilot Study.

Purpose To determine if amide proton transfer-weighted chemical exchange saturation transfer (APTW CEST) MRI is useful in the early assessment of treatment response in persons with triple-negative breast cancer (TNBC). Materials and Methods In this prospective study, a total of 51 participants (mean age, 51 years [range, 26-79 years]) with TNBC were included who underwent APTW CEST MRI with 0.9- and 2.0-µT saturation power performed at baseline, after two cycles (C2), and after four cycles (C4) of neoadjuvant systemic therapy (NAST). Imaging was performed between January 31, 2019, and November 11, 2019, and was a part of a clinical trial (registry number NCT02744053). CEST MR images were analyzed using two methods-magnetic transfer ratio asymmetry (MTRasym) and Lorentzian line shape fitting. The APTW CEST signals at baseline, C2, and C4 were compared for 51 participants to evaluate the saturation power levels and analysis methods. The APTW CEST signals and their changes during NAST were then compared for the 26 participants with pathology reports for treatment response assessment. Results A significant APTW CEST signal decrease was observed during NAST when acquisition at 0.9-µT saturation power was paired with Lorentzian line shape fitting analysis and when the acquisition at 2.0 µT was paired with MTRasym analysis. Using 0.9-µT saturation power and Lorentzian line shape fitting, the APTW CEST signal at C2 was significantly different from baseline in participants with pathologic complete response (pCR) (3.19% vs 2.43%; P = .03) but not with non-pCR (2.76% vs 2.50%; P > .05). The APTW CEST signal change was not significant between pCR and non-pCR at all time points. Conclusion Quantitative APTW CEST MRI depended on optimizing acquisition saturation powers and analysis methods. APTW CEST MRI monitored treatment effects but did not differentiate participants with TNBC who had pCR from those with non-pCR. © RSNA, 2021 Clinical trial registration no. NCT02744053 Supplemental material is available for this article. Keywords Molecular Imaging-Cancer, Molecular Imaging-Clinical Translation, MR-Imaging, Breast, Technical Aspects, Tumor Response, Technology Assessment.

Stance-Control Knee-Ankle-Foot Orthoses for People With Knee Instability: A Health Technology Assessment.

Background: Knee instability can arise from various causes and conditions such as neuromuscular disease, central nervous system conditions, and trauma. For people with knee instability, knee orthosis devices are prescribed to help with standing, walking, and performing tasks. We conducted a health technology assessment of stance-control knee-ankle-foot orthoses (SCKAFOs) for people with knee instability, which included an evaluation of the effectiveness, safety, and budget impact of publicly funding SCKAFOs, as well as patient preferences and values. Methods: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Risk of Bias in Nonrandomized Studies (RoBANS) tool and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and also analyzed the budget impact of publicly funding SCKAFOs in people with knee instabilities in Ontario. We did not conduct a primary economic evaluation as there was limited comparative clinical evidence to inform an economic model. Our reference case budget impact analysis was done from the perspective of the Ontario Ministry of Health; it compared the total costs of a basic mechanical SCKAFO and locked KAFO (LKAFO) for people with knee instability. We also performed scenario analyses varying the following parameters: the price of all classes of SCKAFO (mechanical, electronic, and microprocessor), and the uptake of SCKAFO. To contextualize the potential value of SCKAFO, we spoke with people with knee instability. Results: We included four studies in the clinical evidence review. We are uncertain if SCKAFOs improve walking ability, energy consumption, or activities of daily living compared with LKAFOs (GRADE: Very low). Our economic evidence review identified one costing analysis that suggested that the costs of orthotic devices such as LKAFOs and SCKAFOs are highly variable according to the cost of materials, professional time, and customization required by the individual patient. The budget impact of publicly funding mechanical SCKAFOs in Ontario over the next 5 years (at a full device cost of $10,784) ranged from an additional $0.50 million in year 1 (at an uptake rate of 30% in the target population [429 eligible people]) to $0.83 million in year 5 (at an uptake rate of 50%), with a total budget impact of $3.34 million over 5 years. We found that the greatest increase in budget impact in the scenario analysis came from the microprocessor SCKAFO device, which had an additional cost of $10.07 million in year 1, increasing to $16.78 million in year 5. When we decreased the cost of a mechanical SCKAFO device (to $7,384), this reduced the 5-year budget impact to $0.89 million (vs. $3.34 million in the reference case). The people with knee instability with whom we spoke reported that they preferred a device that would provide a more typical gait, but starting with this type of device would be easier than switching from an existing LKAFO. Conclusions: We are uncertain if SCKAFOs improve walking ability, reduce energy consumption, or improve activities of daily living compared with LKAFOs. We estimate that the additional cost to provide public funding for a mechanical SCKAFO in people with knee instability would range from about $0.50 million in year 1 to $0.83 million in year 5, yielding a total budget impact of $3.34 million over 5 years. Depending on the class of SCKAFO and the uptake rate for the device, the budget impact may vary. People who met the criteria for the use of a SCKAFO did have a strong preference for it over an LKAFO.

Enhanced Visualization Methods for First Transurethral Resection of Bladder Tumour in Suspected Non-muscle-invasive Bladder Cancer: A Health Technology Assessment.

Background: Bladder cancer begins in the innermost lining of the bladder wall and, on histological examination, is classified as one of two types: non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer. Transurethral resection of bladder tumour (TURBT) is the standard treatment for people with NMIBC, but the high rate of cancer recurrence after first TURBT is a challenge that physicians and patients face. Tumours seen during follow-up may have been missed or incompletely resected during first TURBT. TURBT is conventionally performed using white light to see the tumours. However, small papillary or flat tumours may be missed with the use of white light alone. With the emergence of new technologies to improve visualization during TURBT, better diagnostic and patient outcomes may be expected. We conducted a health technology assessment of two enhanced visualization methods, both as an adjunct to white light to guide first TURBT for people with suspected NMIBC-hexaminolevulinate hydrochloride (HAL), a solution that is instilled into the bladder to make tumours fluoresce under blue-violet light, and narrow band imaging (NBI), a technology that filters light into wavelengths that can be absorbed by hemoglobin in the tumours, making them appear darker. Our assessment included an evaluation of effectiveness, safety, cost-effectiveness, and the budget impact of publicly funding these new technologies to improve patient outcomes following first TURBT. The use of NBI in diagnostic cystoscopy was out of scope for this health technology assessment. Methods: We performed a systematic literature search of the clinical evidence from inception to April 15, 2020. We searched for randomized controlled trials (RCTs) that compared the outcomes of first TURBT with the use of HAL or NBI, both as an adjunct to white light, with the outcomes of first TURBT using white light alone, or studies that made such comparison between HAL and NBI. We conducted pairwise meta-analyses using a fixed effects model where head-to-head comparisons were available. In the absence of any published RCT for comparison between HAL and NBI, we indirectly compared the two technologies through indirect treatment comparison (ITC) analysis. We assessed the risk of bias of each included study using the Cochrane risk-of-bias tool. We assessed the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and conducted a cost-utility analysis with a 15-year time horizon from a public payer perspective. We also analyzed the budget impact of publicly funding HAL and NBI as an adjunct to white light in people undergoing their first TURBT for suspected non-muscle-invasive bladder cancer in Ontario. Results: In the clinical evidence review, we identified 8 RCTs that used HAL or NBI as an adjunct to white light during first TURBT. Pairwise meta-analysis of HAL studies showed that HAL-guided TURBT as an adjunct to white light significantly reduces recurrence rate at 12 months compared with TURBT using white light alone (risk ratio 0.70, 95% confidence interval [CI] 0.51-0.95) (GRADE: Moderate). Five-year recurrence-free survival was significantly higher when HAL was used as an adjunct to white light than when white light was used alone (GRADE: Moderate). There was little to no difference in the tumour progression rate (GRADE: Moderate).Meta-analysis of NBI studies did not show a significant difference between NBI-guided TURBT as an adjunct to white light and TURBT using white light alone in reducing the rate of recurrence at 12 months (risk ratio 0.94, 95% CI 0.75-1.19) (GRADE: Moderate). No evidence on the effect on recurrence-free survival or tumour progression rate was identified for NBI-guided TURBT. The indirect estimate from the network analysis showed a trend toward a lower rate of recurrence after HAL-guided TURBT than after NBI-guided TURBT but the difference was not statistically significant (risk ratio 0.76, 95% CI 0.51-1.11) (GRADE: Low). Studies showed that use of HAL or NBI during TURBT was generally safe.The incremental cost-effectiveness ratio of HAL-guided TURBT compared with NBI-guided TURBT, both as an adjunct to white light, is $12,618 per quality-adjusted life-year (QALY) gained. Compared with TURBT using white light alone and using adjunct NBI, the probability of HAL-guided TURBT being cost-effective is 69.1% at a willingness-to-pay value of $50,000 per QALY gained and 74.6% at a willingness-to-pay of $100,000 per QALY gained. The annual budget impact of publicly funding HAL-guided TURBT in Ontario over the next 5 years ranges from an additional $0.6 million in year 1 to $2.5 million in year 5. Conclusions: First TURBT guided by HAL as an adjunct to white light likely reduces the rate of recurrence at 12 months and increases 5-year recurrence-free survival when compared with first TURBT using white light alone. There is likely little to no difference in the tumour progression rate. First TURBT guided by NBI as an adjunct to white light likely results in little to no difference in the rate of recurrence at 12 months when compared with first TURBT using white light alone. Based on an indirect comparison, there may be little to no difference in cancer recurrence rate between HAL-guided and NBI-guided first TURBT. Use of HAL or NBI during first TURBT is generally safe. For people undergoing their first TURBT for suspected non-muscle-invasive bladder cancer, using HAL as an adjunct to white light is likely to be cost-effective compared with using white light alone or with using NBI as an adjunct to white light. We estimate that publicly funding HAL as an adjunct to white light to guide first TURBT for people in Ontario with suspected NMIBC would result in additional costs of between $0.6 million and $2.5 million per year over the next 5 years.

Multi-gene Pharmacogenomic Testing That Includes Decision-Support Tools to Guide Medication Selection for Major Depression: A Health Technology Assessment.

Background: Major depression is a substantial public health concern that can affect personal relationships, reduce people's ability to go to school or work, and lead to social isolation. Multi-gene pharmacogenomic testing that includes decision-support tools can help predict which depression medications and dosages are most likely to result in a strong response to treatment or to have the lowest risk of adverse events on the basis of people's genes.We conducted a health technology assessment of multi-gene pharmacogenomic testing that includes decision-support tools for people with major depression. Our assessment evaluated effectiveness, safety, cost-effectiveness, the budget impact of publicly funding multi-gene pharmacogenomic testing, and patient preferences and values. Methods: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane Risk of Bias Tool and the Risk of Bias Assessment Tool for Nonrandomized studies (RoBANS) and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria.We performed a systematic literature search of the economic evidence to review published cost-effectiveness studies on multi-gene pharmacogenomic testing that includes a decision-support tool in people with major depression. We developed a state-transition model and conducted a probabilistic analysis to determine the incremental cost of multi-gene pharmacogenomic testing versus treatment as usual per quality-adjusted life-year (QALY) gained for people with major depression who had inadequate response to one or more antidepressant medications. In the reference case (with GeneSight-guided care), we considered a 1-year time horizon with an Ontario Ministry of Health perspective. We also estimated the 5-year budget impact of publicly funding multi-gene pharmacogenomic testing for people with major depression in Ontario.To contextualize the potential value of multi-gene pharmacogenomic testing that includes decision-support tools, we spoke with people who have major depression and their families. Results: We included 14 studies in the clinical evidence review that evaluated six multi-gene pharmacogenomic tests. Although all tests included decision-support tools, they otherwise differed greatly, as did study design, populations included in studies, and outcomes reported. Little or no improvement was observed on change in HAM-D17 depression score compared with treatment as usual for any test evaluated (GRADE: Low-Very Low). GeneSight- and NeuroIDgenetix-guided medication selection led to statistically significant improvements in response (GRADE: Low-Very Low) and remission (GRADE: Low-Very Low), while treatment guided by CNSdose led to significant improvement in remission rates (GRADE: Low), but the study did not report on response. Results were inconsistent and uncertain for the impact of Neuropharmagen, and no significant improvement was observed for Genecept or another unspecified test for either response or remission (GRADE: Low-Very Low). Neuropharmagen may reduce adverse events and CNSDose may reduce intolerability to medication, while no difference was observed in adverse events with GeneSight, Genecept, or another unspecified test (GRADE: Moderate-Very Low). No studies reported data on suicide, treatment adherence, relapse, recovery, or recurrence of depression symptoms.Our review included four model-based economic studies and found that multi-gene pharmacogenomic testing was associated with greater effectiveness and cost savings than treatment as usual, over long-term (i.e., 3-,5-year and lifetime) time horizons. Since none of the included studies was fully applicable to the Ontario health care system, we conducted a primary economic evaluation.Our reference case analysis over the 1-year time horizon found that multi-gene pharmacogenomic testing (with GeneSight) was associated with additional QALYs (0.03, 95% credible interval [CrI]: 0.005; 0.072) and additional costs ($1,906, 95% Crl: $688; $3,360). An incremental cost-effectiveness ratio was $60,564 per QALY gained. The probability of the intervention being cost-effective (vs. treatment as usual) was 36.8% at a willingness-to-pay amount of $50,000 per QALY (i.e., moderately likely not to be cost-effective), rising to 70.7% at a willingness-to-pay amount of $100,000 per QALY (i.e., moderately likely to be cost-effective). Evidence informing economic modeling of the reference case with GeneSight and other multi-gene pharmacogenomic tests was of low to very low quality, implying considerable uncertainty or low confidence in the effectiveness estimates. The price of the test, efficacy of the intervention on remission, time horizon, and analytic perspective were major determinants of the cost-effectiveness results. If the test price were assumed to be $2,162 (compared with $2,500 in the reference case), the intervention would be cost-effective at a willingness-to-pay amount of $50,000 per QALY; moreover, if the price decreased to $595, the intervention would be cost saving (or dominant) compared with treatment as usual.At an increasing uptake of 1% per year and a test price of $2,500, the annual budget impact of publicly funding multi-gene pharmacogenomic testing in Ontario over the next 5 years ranged from an additional $3.5 million in year 1 (at uptake of 1%) to $16.8 million in year 5. The 5-year budget impact was estimated at about $52 million.People with major depression and caregivers generally supported multi-gene pharmacogenomic testing because they believed it could provide guidance that fit their values. They hoped such guidance would speed symptom relief, would reduce side effects and help inform their medication choices. Some patients expressed concerns over maintaining confidentiality of test results and the possibility that physicians would sacrifice patient-centred care to follow pharmacogenomic guidance. Conclusions: Multi-gene pharmacogenomic testing that includes decision-support tools to guide medication selection for depression varies widely. Differences between individual tests must be considered, as clinical utility observed with one test might not apply to other tests. Overall, effectiveness was inconsistent among the six multi-gene pharmacogenomic tests we identified. Multi-gene pharmacogenomic tests may result in little or no difference in improvement in depression scores compared with treatment as usual, but some tests may improve response to treatment or remission from depression. The impact on adverse events is uncertain. The evidence, however, is uncertain, and therefore our confidence that these observed effects reflect the true effects is low to very low.For the management of major depression in people who had inadequate response to at least one medication, some multi-gene pharmacogenomic tests that include decision support tools are associated with additional costs and QALYs over the 1-year time horizon, and maybe be cost-effective at the willingness-to-pay amount of $100,000 per QALY. Publicly funding multi-gene pharmacogenomic testing in Ontario would result in additional annual costs of between $3.5 million and $16.8 million, with a total budget impact of about $52 million over the next 5 years.People with major depression and caregivers generally supported multi-gene pharmacogenomic testing because they believed it could provide guidance that fit their values. They hoped such guidance would speed symptom relief, would reduce side and help inform their medication choices. Some patients expressed concerns over maintaining confidentiality of test results and the possibility that physicians would sacrifice patient-centred care to follow pharmacogenomic guidance.

DPYD Genotyping in Patients Who Have Planned Cancer Treatment With Fluoropyrimidines: A Health Technology Assessment.

Background: Fluoropyrimidine drugs (such as 5-fluorouracil and capecitabine) are used to treat different types of cancer. However, these drugs may cause severe toxicity in about 10% to 40% of patients. A deficiency in the dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by the DPYD gene, increases the risk of severe toxicity. DPYD genotyping aims to identify variants that lead to DPD deficiency and may help to identify people who are at higher risk of developing severe toxicity, allowing their treatment to be modified before it begins. Recommendations for fluoropyrimidine treatment modification are available for four DPYD variants, which are the focus of this review: DPYD∗2A, DPYD∗13, c.2846A>T, and c.1236G>A. We conducted a health technology assessment of DPYD genotyping for patients who have planned cancer treatment with fluoropyrimidines, which included an evaluation of clinical validity, clinical utility, the effectiveness of treatment with a reduced fluoropyrimidine dose, cost-effectiveness, the budget impact of publicly funding DPYD genotyping, and patient preferences and values. Methods: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included systematic review and primary study using the Risk of Bias in Systematic Reviews (ROBIS) tool and the Newcastle-Ottawa Scale, respectively, and we assessed the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature review and conducted cost-effectiveness and cost-utility analyses with a half-year time horizon from a public payer perspective. We also analyzed the budget impact of publicly funding pre-treatment DPYD genotyping in patients with planned fluoropyrimidine treatment in Ontario. To contextualize the potential value of DPYD testing, we spoke with people who had planned cancer treatment with fluoropyrimidines. Results: We included 29 observational studies in the clinical evidence review, 25 of which compared the risk of severe toxicity in carriers of a DPYD variant treated with a standard fluoropyrimidine dose with the risk in wild-type patients (i.e., non-carriers of the variants under assessment). Heterozygous carriers of a DPYD variant treated with a standard fluoropyrimidine dose may have a higher risk of severe toxicity, dose reduction, treatment discontinuation, and hospitalization compared to wild-type patients (GRADE: Low). Six studies evaluated the risk of severe toxicity in DPYD carriers treated with a genotype-guided reduced fluoropyrimidine dose versus the risk in wild-type patients; one study also included a second comparator group of DPYD carriers treated with a standard dose. The evidence was uncertain, because the results of most of these studies were imprecise (GRADE: Very low). The length of hospital stay was shorter in DPYD carriers treated with a reduced dose than in DPYD carriers treated with a standard dose, but the evidence was uncertain (GRADE: Very low). One study assessed the effectiveness of a genotype-guided reduced fluoropyrimidine dose in DPYD∗2A carriers versus wild-type patients, but the results were imprecise (GRADE: Very low).We found two cost-minimization analyses that compared the costs of the DPYD genotyping strategy with usual care (no testing) in the economic literature review. Both studies found that DPYD genotyping was cost-saving compared to usual care. Our primary economic evaluation, a cost-utility analysis, found that DPYD genotyping might be slightly more effective (incremental quality-adjusted life years of 0.0011) and less costly than usual care (a savings of $144.88 per patient), with some uncertainty. The probability of DPYD genotyping being cost-effective compared to usual care was 91% and 96% at the commonly used willingness-to-pay values of $50,000 and $100,000 per quality-adjusted life-year gained, respectively. Assuming a slow uptake, we estimated that publicly funding pre-treatment DPYD genotyping in Ontario would lead to a savings of $714,963 over the next 5 years.The participants we spoke to had been diagnosed with cancer and treated with fluoropyrimidines. They reported on the negative side effects of their treatment, which affected their day-to-day activities, employment, and mental health. Participants viewed DPYD testing as a beneficial addition to their treatment journey; they noted the importance of having all available information possible so they could make informed decisions to avoid adverse reactions. Barriers to DPYD testing include lack of awareness of the test and the fact that the test is being offered in only one hospital in Ontario. Conclusions: Studies found that carriers of a DPYD variant who were treated with a standard fluoropyrimidine dose may have a higher risk of severe toxicity than wild-type patients treated with a standard dose. DPYD genotyping led to fluoropyrimidine treatment modifications. It is uncertain whether genotype-guided dose reduction in heterozygous DPYD carriers resulted in a risk of severe toxicity comparable to that of wild-type patients. It is also uncertain if the reduced dose resulted in a lower risk of severe toxicity compared to DPYD carriers treated with a standard dose. It is also uncertain whether the treatment effectiveness of a reduced dose in carriers was comparable to the effectiveness of a standard dose in wild-type patients.For patients with planned cancer treatment with fluoropyrimidines, DPYD genotyping is likely cost-effective compared to usual care. We estimate that publicly funding DPYD genotyping in Ontario may be cost-saving, with an estimated total of $714,963 over the next 5 years, provided that the implementation, service delivery, and program coordination costs do not exceed this amount.For people treated with fluoropyrimidines, cancer and treatment side effects had a substantial negative effect on their quality of life and mental health. Most saw the value of DPYD testing as a way of reducing the risk of serious adverse events. Barriers to receipt of DPYD genotyping included lack of awareness and limited access to DPYD testing.

Avoiding Opportunity Cost Neglect in Cost-Effectiveness Analysis for Health Technology Assessment.

Despite being a fundamental tenet of economic analysis there is a lack of clarity regarding the relevance of opportunity costs to cost-effectiveness analysis for health technology assessment. We argue that this is due, in part, to the importance of the decision context in understanding the nature of opportunity costs. Taking the example of the National Institute of Health and Care Excellence (NICE) on behalf of the National Health Service (NHS) in England and Wales, we explore the implications of existing discrepancies between policy thresholds and emerging empirical evidence of health opportunity costs. In particular, we consider analysts communicating the results of cost-effectiveness analysis, and recommend that analysts provide analysis according to both the policy threshold and the latest empirical evidence until the discrepancies are better understood or resolved. A number of conceptually related, but distinct, issues are discussed and clarified.

A prognostic model, including quantitative fetal fibronectin, to predict preterm labour: the QUIDS meta-analysis and prospective cohort study.

BACKGROUND: The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly hospital admissions. Measurement of fetal fibronectin in vaginal fluid is a biochemical test that can indicate impending preterm birth. OBJECTIVES: To develop an externally validated prognostic model using quantitative fetal fibronectin concentration, in combination with clinical risk factors, for the prediction of spontaneous preterm birth and to assess its cost-effectiveness. DESIGN: The study comprised (1) a qualitative study to establish the decisional needs of pregnant women and their caregivers, (2) an individual participant data meta-analysis of existing studies to develop a prognostic model for spontaneous preterm birth within 7 days in women with symptoms of preterm labour based on quantitative fetal fibronectin and clinical risk factors, (3) external validation of the prognostic model in a prospective cohort study across 26 UK centres, (4) a model-based economic evaluation comparing the prognostic model with qualitative fetal fibronectin, and quantitative fetal fibronectin with cervical length measurement, in terms of cost per QALY gained and (5) a qualitative assessment of the acceptability of quantitative fetal fibronectin. DATA SOURCES/SETTING: The model was developed using data from five European prospective cohort studies of quantitative fetal fibronectin. The UK prospective cohort study was carried out across 26 UK centres. PARTICIPANTS: Pregnant women at 22+0-34+6 weeks' gestation with signs and symptoms of preterm labour. HEALTH TECHNOLOGY BEING ASSESSED: Quantitative fetal fibronectin. MAIN OUTCOME MEASURES: Spontaneous preterm birth within 7 days. RESULTS: The individual participant data meta-analysis included 1783 women and 139 events of spontaneous preterm birth within 7 days (event rate 7.8%). The prognostic model that was developed included quantitative fetal fibronectin, smoking, ethnicity, nulliparity and multiple pregnancy. The model was externally validated in a cohort of 2837 women, with 83 events of spontaneous preterm birth within 7 days (event rate 2.93%), an area under the curve of 0.89 (95% confidence interval 0.84 to 0.93), a calibration slope of 1.22 and a Nagelkerke R 2 of 0.34. The economic analysis found that the prognostic model was cost-effective compared with using qualitative fetal fibronectin at a threshold for hospital admission and treatment of ≥ 2% risk of preterm birth within 7 days. LIMITATIONS: The outcome proportion (spontaneous preterm birth within 7 days of test) was 2.9% in the validation study. This is in line with other studies, but having slightly fewer than 100 events is a limitation in model validation. CONCLUSIONS: A prognostic model that included quantitative fetal fibronectin and clinical risk factors showed excellent performance in the prediction of spontaneous preterm birth within 7 days of test, was cost-effective and can be used to inform a decision support tool to help guide management decisions for women with threatened preterm labour. FUTURE WORK: The prognostic model will be embedded in electronic maternity records and a mobile telephone application, enabling ongoing data collection for further refinement and validation of the model. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015027590 and Current Controlled Trials ISRCTN41598423. 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. 25, No. 52. See the NIHR Journals Library website for further project information.

Do Advanced Therapies Have a Future in the Low- and Middle-Income Countries - The Case of Bulgaria, Romania, and Poland.

Introduction: The significant therapeutic potential of the advanced therapies (ATs) has predetermined the increased interests in their development mainly in the context of rare diseases most of which are genetically determined. However, there are still many challenges in front of the health insurance funds related to the cost-effectiveness and budget impact issues of these therapies. Our aim was to review and analyze the potential of low- and middle-income countries for health technology assessment (HTA) of advanced therapies focusing on Bulgaria, Romania and Poland as reference countries. A literature review of the existing good practices related to HTA of advanced therapies across the world and comparison with the national reality were performed. A list of challenges and issues from the point of view of the payer institution of all analyzed countries was performed. Pilot recommendations on how to overcome the barriers were created based on the existing practices and the potential of the national system. Discussion: 15 out of 80 articles identified in PubMed were found as applicable to the study scope as most of them were published in the period 2019-2021. Undoubtedly, the main challenges correspond to the high treatment costs, the uncertainty in clinical effectiveness, and poor HTA methodological approaches applicable for ATs worldwide. The issues identified for low and middle-income countries are similar having as well the lack of enough qualified health economists for the purposes of assessment and appraisal of HTA dossiers of the advanced therapies, lack of adequate existing separate financial programs for those therapies, and not preparedness of the health system and the society as a whole for such therapies. Conclusions: Despite the difficulties and challenges, the advanced therapies can be defined as a futuristic therapy for which great discoveries are yet to come. Therefore, each country should consider the implementation of reliable and nationally oriented programs for HTA and adequate financial coverage of these therapies.

Controversy Over Using Quality-Adjusted Life-Years In Cost-Effectiveness Analyses: A Systematic Literature Review.

Researchers and policy makers in the US are exploring the implementation of health technology assessment and value-based pricing to negotiate drug prices and limit spending. Objections made to the quality-adjusted life-year (QALY), the most frequently used health economic outcome for such assessments, are a barrier to the adoption of these tools. This literature review identifies and addresses the range of criticisms made against QALYs. Methods-based criticisms require attention from stakeholders to address well-known shortcomings of the QALY and ensure consistency. Ethical criticisms, however, do not apply only to the QALY and require political decisions about societal values. Understanding and overcoming criticisms of the QALY to enable its use as part of health technology assessment and value-based pricing will be crucial as US policy makers seek to address high drug costs and health care spending.

Therapist-supported online remote behavioural intervention for tics in children and adolescents in England (ORBIT): a multicentre, parallel group, single-blind, randomised controlled trial.

BACKGROUND: Exposure and Response Prevention (ERP) is a form of behavioural therapy for tics; however, its effectiveness remains uncertain. We aimed to evaluate the effectiveness of internet-delivered, therapist-supported, and parent-assisted ERP for treatment of tics in children and young people with Tourette syndrome or chronic tic disorder. METHODS: This multicentre, parallel group, single-blind, randomised controlled trial was conducted across two study sites in England. Participants were recruited via 16 patient identification centres, two study sites in England (Nottingham and London), or online self-referral. Eligible participants were aged 9-17 years, had Tourette syndrome or chronic tic disorder, had not received behavioural therapy for tics in the past 12 months or were about to start, and had a Yale Global Tic Severity Scale (YGTSS) Total Tic Severity Score (TTSS) of more than 15 or more than 10 if they had only motor or vocal tics. Patients were excluded if they had started or stopped medication for tics within the past 2 months; had current alcohol or substance dependence, psychosis, suicidality, anorexia nervosa, or suspected moderate to severe intellectual disability; or presented an immediate risk to self or others; or the parent or carer was unable to speak, read, or write in English. Eligible patients were randomly assigned (1:1) by masked outcome assessors to receive 10 weeks of online, remotely delivered, therapist-supported ERP or psychoeducation (active control). Outcome assessors, statisticians, health economists, the trial manager, and the chief investigator were masked to group allocation. Patients were not directly informed of their allocation, but this could be established from the content once treatment commenced and the patients were not, therefore, considered masked to treatment. The primary outcome was YGTSS-TTSS 3 months after randomisation, and analysis was done in all randomised patients for whom data were available for each timepoint and outcome. Safety analysis was by intention to treat. Longer term follow-up is ongoing. This trial is registered with ISRCTN (ISRCTN70758207) and ClinicalTrials.gov (NCT03483493). FINDINGS: Between May 8, 2018, and Sept 30, 2019, we assessed 445 candidates for inclusion in the study. 221 potential participants were excluded (90 did not meet inclusion criteria, 84 declined to participate, and 47 unable to contact family). 224 participants were enrolled and randomly assigned to ERP (n=112) or psychoeducation (n=112). The enrolled patients were mostly male (n=177; 79%) and of White ethnicity (n=195; 87%). 11 patients were lost to follow-up 3 months after randomisation in the ERP group, compared with 12 patients in the psychoeducation group. Mean YGTSS-TTSS at 3 months after randomisation was 23·9 (SD 8·2) in the ERP group and 26·8 (7·3) in the psychoeducation group. The mean total decrease in YGTSS-TTSS at 3 months was 4·5 (16%, SD 1·1) in the ERP group versus 1·6 (6%, 1·0) in the psychoeducation group. The estimated mean difference in YGTSS-TTSS change between the groups adjusted for baseline and site was -2·29 points (95% CI -3·86 to -0·71) in favour of ERP, with an effect size of -0·31 (95% CI -0·52 to -0·10). Two serious adverse events occurred (one collapse and one tic attack), both in the psychoeducation group, neither of which were related to study treatment. INTERPRETATION: ERP is an effective behavioural therapy for tics. Remotely delivered, online ERP with minimal therapist contact time represents an efficient public mental health approach to improve access to behavioural therapy for tics in children and adolescents. FUNDING: National Institute for Health Research and Health and Technology Assessment.

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy.

BACKGROUND: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. METHODS: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. FINDINGS: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86-1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91-1·32; p=0·21). INTERPRETATION: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. FUNDING: UK Medical Research Council and Health Technology Assessment Programme.

The Effects of 3D Immersion Technology (3Scape) on Mental Health in Outpatients From a Short-Term Assessment, Rehabilitation, and Treatment Program: Feasibility Protocol for a Randomized Controlled Trial.

BACKGROUND: Mental health conditions are prevalent among Canadians and are a leading cause of disability. Each year, 1 in 5 Canadians experiences a mental health issue. A total of 5% of people aged ≥65 years perceive their mental health as fair or poor, and 6.3% of them have mood disorders. Regarding older adults with cognitive impairments such as dementia, up to 40%-50% of them experience depression at some point. We believe that older adults can benefit significantly from information and telecommunication technologies as a strategy for improving mental health conditions such as depression and anxiety, while simultaneously improving their quality of life. 3Scape Systems Inc is an Alberta-based private company that has produced a series of specialized 3D videos designed to simulate real-life events and engage individuals living with mental health disorders and cognitive impairments such as dementia. OBJECTIVE: This study aims to explore the trial design and effects of 3Scape videos on older adults' symptoms of depression and anxiety and the efficacy of this technology in improving the quality of life of patients attending the Short-Term Assessment, Rehabilitation, and Treatment Psychiatry Day Hospital program at Glenrose Rehabilitation Hospital and to provide data to estimate the parameters required to design a definitive randomized controlled trial. METHODS: The trial will use a randomized controlled design comprising 15 intervention participants and 15 control group participants. The participants will be adults aged ≥65 years who are cognitively intact or have minimal cognitive impairment (ie, Montreal Cognitive Assessment score ≥18), and are clients of the Short-Term Assessment, Rehabilitation, and Treatment Psychiatry Day Hospital program at Glenrose Rehabilitation Hospital. This study's primary outcome variables are related to clients' depressive and anxiety symptoms and their quality of life. The control group will receive the standard of care (ie, the Short-Term Assessment, Rehabilitation, and Treatment Psychiatry Day Hospital program at Glenrose Rehabilitation Hospital). The intervention group will receive the same standard of care as the control group and will use 3Scape Systems videos for therapeutic activities. RESULTS: Our study is currently on hold because of the COVID-19 pandemic. The recruitment process is expected to resume by November 2021, and the primary impact analysis is expected to be conducted by February 2022. CONCLUSIONS: This study will provide valuable information such as the measurement of comparative intervention effects, perception of older adults and mental health therapists about the 3Scape Systems, the associated costs of treatment, and product costs. This will contribute to the evidence planning process, which will be crucial for the future adoption of 3Scape Systems. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 93685907; https://www.isrctn.com/ISRCTN93685907. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/25017.

Changing face of healthcare: digital therapeutics in the management of diabetes.

Diagnosis, prevention, management and treatment of acute and chronic medical conditions have improved with technological advancements in terms of scalability, efficacy, access, and personalized approach. Digital therapeutic applications (DTx) (Blue Star, Diabeo System, Livongo Diabetes Program, Tidepool etc.,) use web-based applications/cloud platforms to provide evidence-based, personalized, rapid point of care management of chronic, behavior-modifiable conditions, including diabetes mellitus (DM). DTx has improved patient compliance, therapeutic success and economic outcomes in DM management by enabling active patient engagement, lifestyle change, comprehensive medical care, and periodic monitoring of glycemic status. Addressing concerns along DTx data vulnerability, comparative efficacy with conventional treatments, ability to accommodate diverse population needs, and resolving ambiguous regulatory policies and reimbursement guidelines are critical for increasing access to DTx, and overcoming availability, accessibility, and affordability issues in the existing resource limited healthcare environment. In this commentary the authors explore the potential, prospects, and challenges of DTx in the management of Diabetes Mellitus.

Comprehensive review of statistical methods for analysing patient-reported outcomes (PROs) used as primary outcomes in randomised controlled trials (RCTs) published by the UK's Health Technology Assessment (HTA) journal (1997-2020).

OBJECTIVES: To identify how frequently patient-reported outcomes (PROs) are used as primary and/or secondary outcomes in randomised controlled trials (RCTs) and to summarise what statistical methods are used for the analysis of PROs. DESIGN: Comprehensive review. SETTING: RCTs funded and published by the United Kingdom's (UK) National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme. DATA SOURCES AND ELIGIBILITY: HTA reports of RCTs published between January 1997 and December 2020 were reviewed. DATA EXTRACTION: Information relating to PRO use and analysis methods was extracted. PRIMARY AND SECONDARY OUTCOME MEASURES: The frequency of using PROs as primary and/or secondary outcomes; statistical methods that were used for the analysis of PROs as primary outcomes. RESULTS: In this review, 37.6% (114/303) of trials used PROs as primary outcomes, and 82.8% (251/303) of trials used PROs as secondary outcomes from 303 NIHR HTA reports of RCTs. In the 114 RCTs where the PRO was the primary outcome, the most used PRO was the Short-Form 36 (8/114); the most popular methods for multivariable analysis were linear mixed model (45/114), linear regression (29/114) and analysis of covariance (13/114); logistic regression was applied for binary and ordinal outcomes in 14/114 trials; and the repeated measures analysis was used in 39/114 trials. CONCLUSION: The majority of trials used PROs as primary and/or secondary outcomes. Conventional methods such as linear regression are widely used, despite the potential violation of their assumptions. In recent years, there is an increasing trend of using complex models (eg, with mixed effects). Statistical methods developed to address these violations when analysing PROs, such as beta-binomial regression, are not routinely used in practice. Future research will focus on evaluating available statistical methods for the analysis of PROs.

Early cost estimating model for new bioabsorbable orthopedic implant candidates: A theoretical study.

An early health technology assessment (HTA) study was performed to assess the need for developing a new bioabsorbable implant for the treatment of specific orthopedic injuries. The Anterior Cruciate Ligament Reconstruction (ACLR) procedure was selected based on the need and potential impact of bioabsorbable implants in the treatment of ACL injuries. The economic model considers the possible health events after an ACLR (failures and other complications such as stiffness and pain). A decision tree approach was used, and several sensitivity analyses were performed using a Monte Carlo simulation. A cost estimating model was applied comparatively for currently available metal and bioabsorbable implants against a potential new bioabsorbable implant with improved performance. A reduction in stiffness and pain symptoms were considered as targets for these new implants performance, with reduced inflammation resulting from the use of materials with appropriate biological and mechanical properties. The current study estimates that, under the assumptions made, the introduction of a new bioabsorbable implant in ACLR surgeries may generate yearly cost savings. The model estimates positive cost-benefits of the new implant when it reduces the probability of failure by more than 30%, or reduces at least 14% the probability of complications of an inflammatory nature. The development of a new bioabsorbable orthopedic implant for ACLR is encouraged by this study identifying the need for new bioabsorbable implants with improved biological and mechanical performance. The results of this early HTA have made it possible to anticipate design needs and objectives for the research and development of new orthopedic bioabsorbable implants.

Considering potential solutions for limitations and challenges in the health economic evaluation of gene therapies.

INTRODUCTION: The limited evidence in the clinical trials of gene therapies (GTs) posed substantial challenges for a reliable health technology assessment (HTA). This paper provides insights into the relationship between the background of diseases and the health economics assessment of GTs.Areas covered: The impacts of differentiated severity and unmet needs of genetic diseases, on the economic analysis of GTs, were discussed.Expert opinion: GTs offer a potential cure or significant clinical improvement, while limitations in clinical evidence constitute major obstacles for a robust assessment of clinical effectiveness and economic outcomes. This uncertainty may be balanced by the severity of the targeted condition and the associated unmet needs, thus leading to a relatively higher acceptance for GTs. Overtime, HTA agencies will become more demanding on comprehensive evidence of long-term effectiveness. With a growing number of GTs on the horizon, to what extent the unmet needs of previously devastating diseases will be fulfilled remain unclear. Nonetheless, comparative studies, either with a historical control group or existing treatments, will be necessary to demonstrate the additional benefits associated with GTs.

Identification and selection of health technologies for assessment by agencies in support of reimbursement decisions in Latin America.

OBJECTIVE: There is no health system that has the resources to evaluate all technologies. The presence of a clear process to prioritize health technologies for assessment by health technology assessment (HTA) agencies is a good practice principle recognized at the international level. The objective of Health Technology Assessment International's 2020 Latin American Policy Forum (LatamPF) was to explore how to improve the way HTA agencies in Latin America identify and prioritize technologies for assessment. METHODS: This paper is based on a background document, a survey, and the deliberations of the members of the LatamPF (forty-six participants from eleven countries) using a design thinking methodology. RESULTS: Participants agreed that a lack of clear prioritization mechanisms results in HTA processes and decisions that are perceived to be of low transparency and overly exposed to political or interest group pressures. The LatamPF identified barriers and recommended actions to improve HTA prioritization mechanisms in Latin America. The criteria identified as the most important to be taken into consideration by HTA agencies in the region when prioritizing a technology for assessment were: the burden of illness, the potential clinical benefit, the alignment with national health priorities, the potential impact on equity, a lack of treatment alternatives for patients, and the potential economic impact. CONCLUSIONS: Forum participants agreed that the establishment of transparent prioritization processes is a key element for all health systems. Improvements in these processes will strengthen HTA and provide greater legitimacy to decision making.

Description of the use of multicriteria to support pricing and reimbursement decisions by European health technology assessment bodies.

BACKGROUND: Heterogeneity in drug access throughout Europe may be influenced by differences in drug-assessment strategies. The EUnetHTA's assessment core model (EUnetHTA-core) and the EVIDEM's multicriteria framework are reference methodologies in this context, the latter including a wider compromise between non-contextual and contextual criteria. Compliance of 37 European Health Technology Assessment bodies (HTAb) with EUnetHTA-core has been reported, but the use of EVIDEM by this HTAb is still unknown. METHODS: To describe the uptake and use of multicriteria approaches to evaluate drug value by European HTAb using EVIDEM as reference framework, a multicriteria framework was obtained based on EVIDEM model. The criteria used for drug appraisal by HTAb was extracted from the EUnetHTA report, and completed through search of websites, publications and HTAb reports. Use of EVIDEM assessment model in 37 European HTAb has been described semi-quantitatively and summarized using an alignment heatmap. RESULTS: Aligned, medium or misaligned profiles were seen for 24,3%, 51,4% and 24,3% of HTAb when matching to EVIDEM dimensions and criteria was considered. HTAb with explicit responsibilities in providing specific advice on reimbursement showed more aligned profiles on contextual and non-contextual dimensions. CONCLUSIONS: EUnetHTA's core model is limited in assessing medicines while EVIDEM's framework provides contextual dimension used by some HTAb in Europe that can be escalated to other agencies. Most of the 37 European HTAb have room to broaden their contextual assessment tools, especially when social and medical perception of need requires to be explicit to support payer's decision on reimbursement.