Fractional Exhaled Nitric Oxide Testing for the Diagnosis and Management of Asthma: a Health Technology Assessment.

Asthma is a common respiratory disease characterized by airflow obstruction caused by inflammation and narrowing of the airways. Nitric oxide is a gas that is present at low levels in the lungs, but that is elevated in the presence of airway inflammation. Fractional exhaled nitric oxide (FeNO) testing may help in the diagnosis and management of asthma by measuring the amount of nitric oxide in the breath. We conducted a health technology assessment of FeNO testing for the diagnosis and management of asthma in children and adults, which included an evaluation of the accuracy, effectiveness, cost-effectiveness, the budget impact of publicly funding FeNO testing, and patient preferences and values. We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Quality Assessment of Diagnostic Accuracy Studies tool, version 2 (QUADAS-2) and of each systematic review using the Risk of Bias Assessment Tool for Systematic Reviews (ROBIS). We evaluated 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 cost-utility analyses with a 20-year time horizon from a public payer perspective. We also analyzed the budget impact of publicly funding FeNO testing in children and adults in Ontario. To contextualize the potential value of FeNO testing, we spoke with people with asthma and their care partners. We included 48 primary studies assessing the diagnostic accuracy of FeNO testing and 2 reviews evaluating the effectiveness of FeNO testing for asthma management in the clinical evidence review. The use of FeNO testing for the diagnosis of asthma reported variable (~30% to 90%) sensitivities (GRADE: Very low) and consistently high (~70% to 100%) specificities (GRADE: Low) in children and adults. FeNO testing for asthma management likely reduced exacerbations in children (GRADE: Moderate) and adults (GRADE: Moderate), lowered oral corticosteroid use in children (GRADE: Moderate), and slightly improved lung function in a mixed population (GRADE: Moderate), but little to no improvement was seen in other outcomes. We found that, for asthma diagnosis, FeNO testing in addition to standard testing is cost-effective in children, with an incremental cost-effectiveness ratio (ICER) of $6,192 per quality-adjusted life-year (QALY) gained. FeNO testing is not cost-effective for asthma diagnosis in adults except when a higher FeNO cut-off is applied. For asthma management, the ICER of FeNO testing compared with standard care alone is $103,893 per QALY gained in children and $200,135 per QALY gained in adults. Publicly funding FeNO testing as an adjunct to standard testing for asthma diagnosis over the next 5 years would cost about $0.10 million to $0.22 million for children and $1.19 million to $1.61 million for adults over the next 5 years, and for asthma management would cost about $22.37 million for children and $195.99 million for adults over the next 5 years. Participants were unaware if they had experience with FeNO testing because of its similarity to other types of asthma testing, but they reported valuing the potential of FeNO testing to provide more information about their condition as well as aid in the diagnosis and management. Barriers to access include lack of awareness and the limited availability of FeNO testing across the province. We found that FeNO testing had good diagnostic specificity (i.e., low false positive rate), supporting its use as an adjunct to standard testing to help rule-in an asthma diagnosis in both children and adults. FeNO testing to monitor and manage asthma likely resulted in a reduction in the number of people who experienced exacerbations and used oral corticosteroids, but may make little to no difference in improving other health outcomes. FeNO testing is likely cost-effective as an additional test to support the diagnosis of asthma in children, as well as in adults when a higher FeNO cut-off is applied, but is likely not cost-effective as an additional test to monitor and manage asthma in both children and adults. We estimate that publicly funding FeNO testing as an adjunct to standard testing for asthma diagnosis in Ontario would result in additional costs of $0.10 million to $0.22 million for children and $1.19 million to $1.61 million for adults over the next 5 years. For monitoring and managing asthma, FeNO testing would result in additional costs of $22.37 million for children and $195.99 million for adults over the next 5 years. People we spoke with were unaware if they had experience with FeNO testing because of its similarity to other types of asthma testing, but they reported valuing the potential of FeNO testing to provide more information about their condition as well as aid in the diagnosis and management of asthma.

Ontario Health (Quality) 《-》

Measurement of exhaled nitric oxide concentration in asthma: a systematic review and economic evaluation of NIOX MINO, NIOX VERO and NObreath.

Harnan SE ，Tappenden P ，Essat M ，Gomersall T ，Minton J ，Wong R ，Pavord I ，Everard M ，Lawson R ... -  《-》

Supplemental Screening as an Adjunct to Mammography for Breast Cancer Screening in People With Dense Breasts: A Health Technology Assessment.

Screening with mammography aims to detect breast cancer before clinical symptoms appear. Among people with dense breasts, some cancers may be missed using mammography alone. The addition of supplemental imaging as an adjunct to screening mammography has been suggested to detect breast cancers missed on mammography, potentially reducing the number of deaths associated with the disease. We conducted a health technology assessment of supplemental screening with contrast-enhanced mammography, ultrasound, digital breast tomosynthesis (DBT), or magnetic resonance imaging (MRI) as an adjunct to mammography for people with dense breasts, which included an evaluation of effectiveness, harms, cost-effectiveness, the budget impact of publicly funding supplemental screening, the preferences and values of patients and health care providers, and ethical issues. We performed a systematic literature search of the clinical evidence published from January 2015 to October 2021. We assessed the risk of bias of each included study using the Cochrane Risk of Bias or RoBANS tools, 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 review and conducted cost-effectiveness analyses with a lifetime horizon from a public payer perspective. We also analyzed the budget impact of publicly funding supplemental screening as an adjunct to mammography for people with dense breasts in Ontario. To contextualize the potential value of supplemental screening for dense breasts, we spoke with people with dense breasts who had undergone supplemental screening; performed a rapid review of the qualitative literature; and conducted an ethical analysis of supplemental screening as an adjunct to mammography. We included eight primary studies in the clinical evidence review. No studies evaluated contrast-enhanced mammography. Nonrandomized and randomized evidence (GRADE: Very low to Moderate) suggests that mammography plus ultrasound was more sensitive and less specific, and detected more cancers compared to mammography alone. Fewer interval cancers occurred after mammography plus ultrasound (GRADE: Very low to Low), but recall rates were nearly double that of mammography alone (GRADE: Very low to Moderate). Evidence of Low to Very low quality suggested that compared with supplemental DBT, supplemental ultrasound was more sensitive, detected more cancers, and led to more recalls. Among people with extremely dense breasts, fewer interval cancers occurred after mammography plus supplemental MRI compared to mammography alone (GRADE: High). Supplemental MRI after negative mammography was highly accurate in people with extremely dense breasts and heterogeneously dense breasts in nonrandomized and randomized studies (GRADE: Very Low and Moderate). In people with extremely dense breasts, MRI after negative mammography detected 16.5 cancers per 1,000 screens (GRADE: Moderate), and up to 9.5% of all people screened were recalled (GRADE: Moderate). Contrast-related adverse events were infrequent (GRADE: Moderate). No study reported psychological impacts, breast cancer-specific mortality, or overall mortality.We included nine studies in the economic evidence, but none of the study findings was directly applicable to the Ontario context. Our lifetime cost-effectiveness analyses showed that supplemental screening with ultrasound, MRI, or DBT found more screen-detected cancers, decreased the number of interval cancers, had small gains in life-years or quality-adjusted life-years (QALYs), and was associated with savings in cancer management costs. However, supplemental screening also increased imaging costs and the number of false-positive cases. Compared to mammography alone, the incremental cost-effectiveness ratios (ICERs) for supplemental screening with handheld ultrasound, MRI, or DBT for people with dense breasts were $119,943, $314,170, and $212,707 per QALY gained, respectively. The ICERs for people with extremely dense breasts were $83,529, $101,813, and $142,730 per QALY gained, respectively. In sensitivity analyses, the diagnostic test sensitivity of mammography alone and of mammography plus supplemental screening had the greatest effect on ICER estimates. The total budget impact of publicly funding supplemental screening with handheld ultrasound, MRI, or DBT for people with dense breasts over the next 5 years is estimated at $15 million, $41 million, or $33 million, respectively. The corresponding total budget impact for people with extremely dense breasts is $4 million, $10 million, or $9 million.We engaged directly with 70 people via interviews and an online survey. The participants provided diverse perspectives on broad access to supplemental screening for people with dense breasts in Ontario. Themes discussed in the interviews included self-advocacy, patient-doctor partnership, preventive care, and a shared preference for broad access to screening modalities that are clinically effective in detecting breast cancer in people with dense breasts.We included 10 studies in the qualitative evidence rapid review. Thematic synthesis of these reports yielded three analytical themes: coming to know and understand breast density, which included introductions to and making sense of breast density; experiences of vulnerability, which influenced or were influenced by understandings and misunderstandings of breast density and responses to breast density; and choosing supplemental screening, which was influenced by knowledge and perception of the risks and benefits of supplemental screening, and the availability of resources.The ethics review determined that the main harms of supplemental screening for people with dense breasts are false-positives and overdiagnosis, both of which lead to unnecessary and burdensome health care treatments. Screening programs raise inherent tensions between individual- and population-level interests; they may yield population-level benefit, but are statistically of very little benefit to individuals. Entrenched cultural beliefs about the value of breast cancer screening, combined with uncertainty about the effects of supplemental screening on some outcomes and the discomfort of many health care providers in discussing screening options for people with dense breasts suggest that it may be difficult to ensure that patients can provide informed consent to engage in supplemental screening. Funding supplemental screening for people with dense breasts may lead to improved equity in the effectiveness of identifying cancers in people with dense breasts (compared to mammography alone), but it is not clear whether it would lead to equity in terms of improved survival and decreased morbidity. Supplemental screening with ultrasound, DBT, or MRI as an adjunct to mammography detected more cancers and increased the number of recalls and biopsies, including false-positive results. Fewer interval cancers tended to occur after supplemental screening compared to mammography alone. It is unclear whether supplemental screening as an adjunct to mammography would reduce breast cancer-related or overall mortality among people with dense breasts.Supplemental screening with ultrasound, DBT, or MRI as an adjunct to mammography in people aged 50 to 74 years improved cancer detection but increased costs. Depending on the type of imaging modality, publicly funding supplemental screening in Ontario over the next 5 years would require additional total costs between $15 million and $41 million for people with dense breasts, and between $4 million and $10 million for people with extremely dense breasts.The people we engaged with directly valued the potential clinical benefits of supplemental screening and emphasized that patient education and equitable access should be a requirement for implementation in Ontario. Our review of the qualitative literature found that the concept of breast density is poorly understood, both by people with dense breasts and by some general practitioners. People with dense breasts who receive routine mammography (especially those who receive health care in their nonpreferred language or are perceived to have lower economic status or health literacy) and their general practitioners may not have the awareness or knowledge to make informed decisions about supplemental screening. Some people with dense breasts experienced emotional distress from barriers to accessing supplemental screening, and many wanted to engage in supplemental screening, even when educated about its potential harms, including false-positives and overdiagnosis.Given an overall lack of robust evidence about morbidity and mortality associated with supplemental screening for people with dense breasts, it is not possible to determine whether funding supplemental screening for dense breasts delivers on the ethical duties to maximize benefits and minimize harms for populations and individuals. It is likely that existing inequities in access to breast screening and cancer treatment will persist, even if supplemental screening for dense breasts is funded. Continued efforts to address these inequities by removing barriers to screening might mitigate this concern. It will be important to identify and minimize sources of uncertainty related to benefits and risks of supplemental screening for dense breasts to optimize the capacity for everyone involved to live up to their ethical obligations. Some of these may be resolved with further evidence related to the outcomes of supplemental screening for dense breasts.

Ontario Health (Quality) 《-》

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

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. 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. 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. 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.

Ontario Health (Quality) 《-》

Intrathecal Drug Delivery Systems for Cancer Pain: A Health Technology Assessment.

Pain is a common and very distressing symptom for adults and children with cancer. Compared with other routes of delivery, infusing pain medication directly into the intrathecal space around the spinal cord may reduce the incidence of systemic side effects and allow for more rapid and effective pain relief. We conducted a health technology assessment of intrathecal drug delivery systems (IDDSs) for adults and children with cancer pain, which included an evaluation of effectiveness, safety, cost-effectiveness, the budget impact of publicly funding IDDSs, patient preferences and values, and ethical considerations. We performed a systematic literature search of the clinical evidence to retrieve systematic reviews, and we selected and reported results from 2 recent reviews that were relevant to our research questions. We complemented the chosen systematic reviews with a literature search to identify primary studies published after December 2020. We used the Risk of Bias in Systematic Reviews (ROBIS) tool to assess the risk of bias of each included systematic review. 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-effectiveness analysis comparing IDDSs with standard care (i.e., non-IDDS methods of pain management) from a public payer perspective. We also analyzed the budget impact of publicly funding IDDSs in Ontario. To contextualize the potential value of IDDSs, we spoke with patients with cancer pain and with caregivers of patients with cancer pain. We explored ethical considerations from a review of published literature on the use of IDDSs for the management of cancer pain in adults and children as well as a review of the other components of this health technology assessment to identify ethical considerations relevant to the Ontario context. We included 2 systematic reviews (1 on adults and 1 on children) in the clinical evidence review. In adults with cancer pain who have a life expectancy greater than 6 months, intrathecal drug delivery was associated with a significant reduction in pain intensity compared with before implantation up to a 1-year follow-up (GRADE: Moderate to Low). Improved pain management appeared to be maintained beyond a 4-week follow-up. IDDSs likely decrease the use of systemic opioids (GRADE: Moderate to Low). They may also improve health-related quality of life (GRADE: Low), functional outcomes (GRADE: Low), and survival (GRADE: Low to Very low). In children with cancer pain, IDDSs may reduce pain intensity, improve functional outcomes, and improve survival, but the evidence is very uncertain (all GRADEs: Very low). IDDS implantation carries certain rare risks related to mechanical errors, drug-related side effects, and surgical complications. There are inherent limitations in conducting research in patients with refractory cancer pain; therefore, it is unlikely that higher-quality evidence will emerge in the next few years. Our primary economic evaluation found that IDDSs are more effective and more costly than standard care. The incremental cost-effectiveness ratio of IDDSs compared with standard care is $57,314 per quality-adjusted life-year (QALY) gained. The probability of IDDSs being cost-effective versus standard care is 43.46% at a willingness-to-pay of $50,000 per QALY gained and 72.54% at a willingness-to-pay of $100,000 per QALY gained. Publicly funding IDDSs in Ontario would cost an additional $0.27 million per year, for a total of $1.34 million over the next 5 years. The patients with cancer pain and caregivers with whom we spoke described the debilitating nature of cancer pain and the difficulty of finding effective pain management options. Patients with experience of an IDDS spoke of its effectiveness and its positive impact on their quality of life and mental health. Implementing IDDSs for patients with cancer pain raises several ethical and equity considerations related to the experiences and management of cancer pain, how limitations in evidence may entail uncertainties in clinical and health system decision-making, as well as clinical, geographic, and health system access barriers. Intrathecal drug delivery likely reduces pain intensity and decreases the use of systemic opioids in adults with cancer pain who have a life expectancy greater than 6 months. It may also improve health-related quality of life, functional outcomes, and survival, although the evidence for survival is very uncertain. The clinical evidence in children with cancer pain is very uncertain. IDDS implantation is reasonably safe. Intrathecal drug delivery is more effective and more costly than standard care. We estimate that funding IDDSs in Ontario will result in additional costs of $0.27 million per year, for a total of $1.34 million over the next 5 years. Considerations related to funding and implementing IDDSs for patients with cancer pain in Ontario will require explicit and focused attention to considerations of equity and access in the diagnosis and management of cancer pain and in the use, clinical uptake, and delivery of IDDS pain management.

Ontario Health 《-》