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Background: Gene and RNA therapies have potential to transform the treatment of rare inherited diseases, but there are concerns about the evidence supporting their use and high costs., Objective: We analyze the evidence supporting Food and Drug Administration (FDA) approval of gene and RNA therapies for rare inherited diseases and discuss implications for clinical practice and policy., Methods: We conducted a qualitative analysis of FDA documents outlining the basis of approval for gene and RNA therapies approved for rare inherited diseases between 2016 and 2023. For each drug, we gathered five characteristics of the evidence supporting FDA approval (no phase 3 trial, nonrandomized, no clinical endpoint, lack of demonstrated benefit, and significant protocol deviation) and four characteristics of the FDA approval process (prior rejection or complete response, negative committee vote, discrepancy between label and trial population, and boxed warning). The main outcome was the number of drugs with each characteristic., Results: Between 2016 and 2023, 19 gene and RNA therapies received FDA approval to treat rare inherited diseases. The most common limitations in the evidence supporting approval of these drugs were nonrandomized studies (8/19, 42%), no clinical endpoint (7/19, 37%), lack of demonstrated benefit or inconsistent results (4/19, 21%), and no phase 3 trial (4/19, 21%). Half (3/6) of accelerated approvals and 57% (5/9) of drugs with breakthrough designation had nonrandomized trials, and gene therapies with one-time dosing were overrepresented (5/7, 71%) among the drugs with nonrandomized trials. Five of six accelerated approvals (83%) and five of nine pediatric drugs (56%), most of which were indicated for Duchenne muscular dystrophy, had no clinical endpoint. Four of nine (44%) pediatric drugs and four of six (67%) accelerated approvals failed to demonstrate benefit compared with none of the nonpediatric drugs and none of the traditional approvals. Five drugs, which all had different indications and represented a mix of RNA and gene therapies, did not have any of these evidence characteristics. Among drugs that received prior rejections or negative committee opinions, all four had nonrandomized trials and lacked a clinical endpoint, and 75% (3/4) lacked demonstrated benefit. Five of nine (56%) pediatric drugs were indicated for broader age groups according to the drug label compared with the trial populations. Of the three drugs with boxed warnings, two had pediatric indications and nonrandomized studies, and one had no phase 3 trial., Conclusions: Issues related to trial design, outcome, and data integrity in the evidence supporting FDA approval of rare inherited disease gene and RNA therapies raise questions about whether this evidence is adequate to inform prescribing decisions. Gene and RNA therapies with accelerated approval and pediatric indications were overrepresented among drugs lacking clinical endpoints or demonstrated benefit and should be the focus of efforts to reduce uncertainty in the evidence., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Venture capital (VC) firms fund biopharmaceutical research and development (R&D) while incurring substantial financial risk. VC firms seek to invest in clinical areas with the greatest potential for financial return. Using a combination of data for clinical trials and VC investment deals between January 2014 and March 2024, we found that approximately 75% of VC investments were allocated to clinical trials studying small-molecule drugs compared to biologics or gene therapies, without substantial changes over the study period. Most of VC firms' investment in biopharmaceutical R&D was concentrated in phase 1 and phase 2 clinical trials. This trend has increased in recent years, with phase 1 trials accounting for nearly half of total deals and capital investments in 2023. VC investments were concentrated in several therapeutic areas, including cancer., Competing Interests: Conflicts of interest Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Aim: To assess the cost-effectiveness of a digital diabetes prevention programme (d-DPP) compared with a diabetes prevention programme (DPP) for preventing type 2 diabetes (T2D) in individuals with prediabetes in the United States., Methods: A Markov cohort model was constructed, simulating a 10-year period starting at the age of 45 years, with a societal and healthcare sector perspective. The effectiveness of the d-DPP intervention was evaluated using a meta-analysis, with that of the DPP as the comparator. The initial cycle represented the treatment period, and transition probabilities for the post-treatment period were derived from a long-term lifestyle intervention meta-analysis. The onset of T2D complications was estimated using microsimulation. Quality-adjusted life years (QALYs) were calculated based on health utility measured by short form (SF)-12 scores, and a willingness-to-pay threshold of $100 000 per QALY gained was applied., Results: The d-DPP intervention resulted in cost savings of $3,672 from a societal perspective and $2,990 from a healthcare sector perspective and a gain of 0.08 QALYs compared with the DPP. The dropout rate was identified as a significant factor influencing the results. Probabilistic sensitivity analysis showed that the d-DPP intervention was preferred in 85.8% in the societal perspective and 85.2% in the healthcare sector perspective., Conclusions: The d-DPP is a cost-effective alternative to in-person lifestyle interventions for preventing the development of T2D among individuals with prediabetes in the United States., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Prediabetes is a highly prevalent condition that heralds an increased risk of progression to type 2 diabetes, along with associated microvascular and macrovascular complications. The Diabetes Prevention Program (DPP) is an established effective intervention for diabetes prevention. However, participation in this 12-month lifestyle change program has historically been low. Digital DPPs have emerged as a scalable alternative, accessible asynchronously and recognized by the Centers for Disease Control and Prevention (CDC). Yet, most digital programs still incorporate human coaching, potentially limiting scalability. Furthermore, existing effectiveness results of digital DPPs are primarily derived from per protocol, longitudinal non-randomized studies, or comparisons to control groups that do not represent the standard of care DPP. The potential of an AI-powered DPP as an alternative to the DPP is yet to be investigated. We propose a randomized controlled trial (RCT) to directly compare these two approaches., Methods: This open-label, multicenter, non-inferiority RCT will compare the effectiveness of a fully automated AI-powered digital DPP (ai-DPP) with a standard of care human coach-based DPP (h-DPP). A total of 368 participants with elevated body mass index (BMI) and prediabetes will be randomized equally to the ai-DPP (smartphone app and Bluetooth-enabled body weight scale) or h-DPP (referral to a CDC recognized DPP). The primary endpoint, assessed at 12 months, is the achievement of the CDC's benchmark for type 2 diabetes risk reduction, defined as any of the following: at least 5% weight loss, at least 4% weight loss and at least 150 min per week on average of physical activity, or at least a 0.2-point reduction in hemoglobin A1C. Physical activity will be objectively measured using serial actigraphy at baseline and at 1-month intervals throughout the trial. Secondary endpoints, evaluated at 6 and 12 months, will include changes in A1C, weight, physical activity measures, program engagement, and cost-effectiveness. Participants include adults aged 18-75 years with laboratory confirmed prediabetes, a BMI of ≥ 25 kg/m 2 (≥ 23 kg/m 2 for Asians), English proficiency, and smartphone users. This U.S. study is conducted at Johns Hopkins Medicine in Baltimore, MD, and Reading Hospital (Tower Health) in Reading, PA., Discussion: Prediabetes is a significant public health issue, necessitating scalable interventions for the millions affected. Our pragmatic clinical trial is unique in directly comparing a fully automated AI-powered approach without direct human coach interaction. If proven effective, it could be a scalable, cost-effective strategy. This trial will offer vital insights into both AI and human coach-based behavioral change strategies in real-world clinical settings., Trial Registration: ClinicalTrials.gov NCT05056376. Registered on September 24, 2021, https://clinicaltrials.gov/study/NCT05056376., (© 2024. The Author(s).)

Gene and RNA therapies are promising treatments for many rare diseases. Pediatric populations that could benefit from these drugs are overrepresented among state Medicaid programs. Using Medicaid State Drug Utilization Data, we examined Medicaid spending and utilization of rare disease gene and RNA therapies. Between 2017 and 2022, the number of available gene and RNA therapies increased from 3 to 13, yearly Medicaid spending increased from $148.3 million to $879.7 million, and the number of yearly treatments (a proxy for number of patients) increased from 327 to 1638. Nearly all spending was attributed to spinal muscular atrophy (SMA) and Duchenne muscular dystrophy drugs. States participating in Medicaid pooled purchasing initiatives had 39% higher treatments per 100 000 enrollees with no differences in spending. Compared to states without a carve-out, states that carved SMA drugs out of managed Medicaid contracts had higher utilization (54%). Spending among carve-out states varied according to managed care enrollment, being higher for those with <80% of enrollees in managed care as compared with those with ≥80% of enrollees in managed care. This suggests that multi-state purchasing initiatives and managed care carve-outs can help increase access to gene and RNA therapies among Medicaid beneficiaries, but it is unclear if these strategies are effective at managing spending., Competing Interests: Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials. Ms. Odouard was previously employed as a consultant at life sciences and health care consulting firms Blue Matter Consulting and Health Technology Analysts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Background: The 2022 Inflation Reduction Act authorizes Medicare to negotiate the prices of 10 drugs in 2026 and additional drugs thereafter. Understanding the sociodemographic and spending characteristics of beneficiaries taking these specific drugs could be important describing the impact of the legislation., Objective: To describe sociodemographic and spending characteristics of Medicare beneficiaries who use the 10 prescription drugs ("negotiated drugs") that will face Medicare drug price negotiations in 2026., Methods: A 20% sample of Medicare Part D beneficiaries from 2020 (n = 10,224,642) was used. Sociodemographic and spending characteristics were descriptively reported for beneficiaries taking the negotiated drugs, including subgroups by low-income subsidy (LIS) status and by drug, and for Part D beneficiaries not taking negotiated drugs., Results: Part D beneficiaries taking a negotiated drug compared with Part D beneficiaries not taking a negotiated drug overall had similar sociodemographic characteristics, more comorbidities (3.9 vs 2.2) and higher mean [median] Medicare ($33,882 [$18,251] vs $12,366 [$3,429]) and out-of-pocket (OOP) spending ($813 [$307] vs $441 [$160]). There was variation in characteristics by LIS status. The mean age was highest among non-LIS beneficiaries taking a negotiated drug compared with LIS beneficiaries taking a negotiated drug and beneficiaries not taking a negotiated drug (76.2 vs 69.9 vs 71.4). Among beneficiaries using negotiated drugs, a higher percentage of LIS beneficiaries compared with non-LIS was female (59.7% vs 48.0%), was Black (20.9% vs 6.6%), and resided in lower-income areas (39.1% vs 20.3%). Mean [median] annual Part D OOP spending for negotiated drugs was $115 [$59] for beneficiaries with LIS and $1,475 [$1,204] for beneficiaries without LIS. There were also differences depending on which negotiated drug was used. Drugs for cancer and blood clots had the highest proportions of White users, whereas type 2 diabetes and heart failure drugs had the highest proportions of Black users and beneficiaries residing in lower-income areas. Annual Part D OOP costs were lowest for sitagliptin (LIS: $104 [$60], non-LIS: $1,391 [$1,153]) and highest for ibrutinib (LIS: $649 [$649], non-LIS: $6,449 [$6,867]). Among non-LIS beneficiaries, 24% (22% to 76%) had more than $2,000 in OOP costs., Conclusions: Inflation Reduction Act OOP spending caps and LIS expansion will lower prescription drug costs for beneficiaries with OOP costs exceeding $2,000 who are mostly White and live in higher-income areas, insulin users who are disproportionately Black with multiple chronic conditions, and beneficiaries with low incomes. However, these provisions will not impact the 76% of non-LIS beneficiaries using negotiated drugs who have OOP costs that are still substantial but below $2,000. Negotiations could reduce OOP costs through reduced coinsurance payments for this group, which is older and has more chronic conditions compared with beneficiaries not taking negotiated drugs. Part D plan design, spending, and utilization changes should be monitored after negotiation to determine if further solutions are needed to lower OOP costs for this group.

Objectives: To assess the cost-effectiveness of trastuzumab deruxtecan compared with trastuzumab emtansine as second-line therapy for patients with human epidermal growth factor receptor 2 positive metastatic breast cancer from a US healthcare sector perspective., Methods: A 3-state partitioned survival model was developed to estimate the cost-effectiveness of trastuzumab deruxtecan compared with trastuzumab emtansine. For both treatments, modeled patients were administered treatment intravenously every 3 weeks indefinitely or until disease progression. Transition parameters were principally derived from the updated DESTINY-Breast03 phase III randomized clinical trial. Costs include drug costs extracted from Centers for Medicare and Medicaid Services average sales price and administrative, adverse event, and third-line therapy costs derived from published literature, measured in 2022 US dollars. Health utilities for health states and disutilities for adverse events were sourced from published literature. Effects were measured in quality-adjusted life years (QALYs). We conducted both probabilistic sensitivity analysis and comprehensive scenario analysis to test model assumptions and robustness, while utilizing a lifetime horizon., Results: In our base-case analysis, total costs for trastuzumab deruxtecan were $1 266 945, compared with $820 082 for trastuzumab emtansine. Total QALYs for trastuzumab deruxtecan were 5.09, compared with 3.15 for trastuzumab emtansine. The base-case incremental cost-effectiveness ratio was $230 285/QALY. Probabilistic sensitivity analysis indicated that trastuzumab deruxtecan had an 11.1% probability of being cost-effective at a $100 000 per QALY willingness-to-pay threshold., Conclusions: Despite the higher efficacy of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer, our findings raise concern regarding its value at current prices., Competing Interests: Author Disclosures Links to the individual disclosure forms provided by the authors are available here., (Copyright © 2023 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved.)

Policy Points Little attention to date has been directed at examining how the long-term services and supports (LTSS) environmental context affects the health and well-being of older adults with disabilities. We develop a conceptual framework identifying environmental domains that contribute to LTSS use, care quality, and care experiences. We find the LTSS environment is highly associated with person-reported care experiences, but the direction of the relationship varies by domain; increased neighborhood social and economic deprivation are highly associated with experiencing adverse consequences due to unmet need, whereas availability and generosity of the health care and social services delivery environment are inversely associated with participation restrictions in valued activities. Policies targeting local and state-level LTSS-relevant environmental characteristics stand to improve the health and well-being of older adults with disabilities, particularly as it relates to adverse consequences due to unmet need and participation restrictions., Context: Long-term services and supports (LTSS) in the United States are characterized by their patchwork and unequal nature. The lack of generalizable person-reported information on LTSS care experiences connected to place of community residence has obscured our understanding of inequities and factors that may attenuate them., Methods: We advance a conceptual framework of LTSS-relevant environmental domains, drawing on newly available data linkages from the 2015 National Health and Aging Trends Study to connect person-reported care experiences with public use spatial data. We assess relationships between LTSS-relevant environmental characteristic domains and person-reported care adverse consequences due to unmet need, participation restrictions, and subjective well-being for 2,411 older adults with disabilities and for key population subgroups by race, dementia, and Medicaid enrollment status., Findings: We find the LTSS environment is highly associated with person-reported care experiences, but the direction of the relationship varies by domain. Measures of neighborhood social and economic deprivation (e.g., poverty, public assistance, social cohesion) are highly associated with experiencing adverse consequences due to unmet care needs. Measures of the health care and social services delivery environment (e.g., Medicaid Home and Community-Based Service Generosity, managed LTSS [MLTSS] presence, average direct care worker wage, availability of paid family leave) are inversely associated with experiencing participation restrictions in valued activities. Select measures of the built and natural environment (e.g., housing affordability) are associated with participation restrictions and lower subjective well-being. Observed relationships between measures of LTSS-relevant environmental characteristics and care experiences were generally held in directionality but were attenuated for key subpopulations., Conclusions: We present a framework and analyses describing the variable relationships between LTSS-relevant environmental factors and person-reported care experiences. LTSS-relevant environmental characteristics are differentially relevant to the care experiences of older adults with disabilities. Greater attention should be devoted to strengthening state- and community-based policies and practices that support aging in place., (© 2023 Milbank Memorial Fund.)

Objectives: To assess the cost-effectiveness of a digital Diabetes Prevention Program (dDPP) in preventing type 2 diabetes mellitus among prediabetic patients from a health system perspective over a 10-year time horizon., Methods: A Markov cohort model was constructed to assess the cost-effectiveness of dDPP compared to a small group education (SGE) intervention. Transition probabilities for the first year of the model were derived from two clinical trials on dDPP. Transition probabilities for longer-term effects were derived from meta-analyses on lifestyle and Diabetes Prevention Program interventions. Cost and health utilities were derived from published literature. Partial completion of interventions was incorporated to provide a robust prediction of a real-world deployment. Parameter uncertainties were assessed using univariate and probabilistic sensitivity analyses. Cost-effectiveness was measured by an incremental cost-effectiveness ratio (ICER) between dDPP and SGE from a health system perspective over a 10-year time horizon., Results: The dDPP dominated the SGE at the $50,000, $100,000, and $150,000 willingness-to-pay thresholds per quality-adjusted life years (QALYs). The base case analysis at the $100,000 willingness-to-pay threshold (WTP) revealed a dominated ICER, with the SGE costing $1332 more and accruing an average of 0.04 fewer QALYs. Probabilistic sensitivity analysis showed that the dDPP was preferred in 64.4% of simulations across the $100,000 WTP thresholds., Conclusions: The findings comparing a dDPP to an SGE suggest that a dDPP can be cost-effective for patients with a high risk of developing type 2 diabetes.

Study Objective: We evaluated US Food and Drug Administration labels for drugs approved under the accelerated approval pathway and whether these labels contained in sufficient information regarding their accelerated approval., Design: Retrospective, observational, cohort study., Data Source: Label information for drugs with an accelerated approved indication were ascertained from two online platforms: Drugs@FDA and FDA Drug Label Repository., Intervention: Drugs with indications receiving accelerated approval after January 1, 1992, but had not received full approval by December 31, 2020., Measurements: Outcomes include whether the drug label indicated the use of the accelerated approval pathway, identified the specific surrogate marker(s) that supported it, or described the clinical outcomes being evaluated in post-approval commitment trials., Results: 253 clinical indications corresponding to 146 drugs received accelerated approval. We identified a total of 110 accelerated approval indications across 62 drugs that had not received full approval by December 31, 2020. A total of 13% of labels for accelerated approved indications lacked sufficient information that approval was via the accelerated approval or based on surrogate outcome measures: 7% did not mention accelerated approval but described surrogate markers, 4% did not mention accelerated approval nor describe surrogate markers, and 2% mentioned accelerated approval but did not describe surrogate markers. No label described the clinical outcomes being evaluated in post-approval commitment trials., Conclusion: Labels for accelerated approved clinical indications that do not yet have full approval should be revised to include the information required in the FDA guidance to help guide clinical decision-making., (© 2023 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

Background: Given patient preferences, the choice of delivery modality for vaccines against SARS-CoV-2 has the potential to significantly impact both health and economic consequences of an outbreak of COVID-19. This study models the projected health and economic impact of an oral COVID-19 vaccine in the United States during an outbreak occurring between December 1, 2021 and February 16, 2022.  METHODS: A cost-of-illness economic decision analysis model is utilized to assess both the health and economic impact of an oral vaccine delivery platform compared with the status quo deployment of existing intramuscular vaccines against COVID-19. Health impact is assessed in terms of predicted cases, deaths, hospitalization days, intensive care unit admission days, and mechanical ventilation days averted. Health system economic impact is assessed based on the cost-of-illness averted derived from the average daily costs of medical care, stratified by severity. Productivity loss due to premature death is estimated based on regulatory analysis guidelines proposed by the U.S. Department of Health and Human Services.  RESULTS: Based upon preference data, we estimate that the availability of an oral COVID-19 vaccine would increase vaccine uptake from 214 million people to 232 million people. This higher vaccination rate was estimated to result in 2,497,087 fewer infections, 25,709 fewer deaths, 1,365,497 fewer hospitalization days, 186,714 fewer Intensive Care Unit (ICU) days, and 80,814 fewer patient days requiring mechanical ventilation (MV) compared with the status quo. From a health systems perspective, this translates into $3.3 billion in health sector costs averted. An additional $139-$450 billion could have been averted in productivity loss due to a reduction in premature deaths., Conclusions: Vaccine delivery modalities that are aligned with patient preferences have the ability to increase vaccination uptake and reduce both the health and economic impact of an outbreak of COVID-19. We estimate that the total economic impact of productivity loss and health systems cost-of-illness averted from an oral vaccine could range from 0.6%-2.9% of 2021 U.S, Gross Domestic Product (GDP)., (© 2022. The Author(s).)

Background: Well-functioning competitive markets are key to controlling generic drug prices. This is important since over 90% of all drugs sold in the US are generics. Recently, there have been examples of large price increases in the generic market., Methods: This paper examines price trajectories for generic drugs using a group-based trajectory modelling approach (GBTM). We fit the model using quarterly price information in the IBM MarketScan claims database for the past decade., Results: We identify three dominant price trajectories for this period: rapid increase trajectories, slow decline and rapid decline. Most generic drugs show a slow or a rapid decline in price trajectories. However, around 17% of all generic drugs show rapid price increase trajectories., Conclusions: As Congress is exploring an excise tax on drugs whose list price increases faster than the rate of inflation, we discuss what drugs would be most likely to be affected by this law., (© 2022. The Author(s).)

Background: The U.S. Food and Drug Administration provides accelerated approval to drugs on the basis of surrogate end points deemed to be "reasonably likely" to predict clinical benefit. To receive full approval, drugs must complete a confirmatory trial. Although most accelerated approved drugs ultimately receive full approval, others remain on the market without full approval for many years, and some are withdrawn before full approval is granted. Until confirmatory trials are completed and full approval is granted, there is uncertainty surrounding each drug's clinical benefits., Objective: To estimate fee-for-service Medicare payments on accelerated approved drugs without full approvals., Design: Cross-sectional analysis., Setting: Fee-for-service Medicare Part B and Part D drug claims in 2019., Participants: Beneficiaries enrolled in Medicare Part B and Part D plans., Measurements: Medicare spending for drugs treating accelerated approved indications without full approval, beneficiary spending, and drug characteristics., Results: In 2019, 45 drugs associated with 69 accelerated approved indications lacked full approval. Of those, the fee-for-service Medicare program spent $1.2 billion on 36 drugs across 55 indications. Medicare beneficiaries had $209 million in out-of-pocket spending on these drugs. Oncology drugs represented 82% of these indications and 72% of the Medicare spending. Extrapolating to Medicare Advantage, total Medicare spending on these drugs in 2019 was $1.8 billion., Limitations: The study drugs may have clinical benefit and may come to receive full approval after this analysis. The algorithm used to identify accelerated approved indications is novel. Generalizability to other years is unclear., Conclusion: In 2019, fee-for-service Medicare spent $1.2 billion on accelerated approved drugs without full approval. Medicare should adjust incentives to encourage sponsors to complete confirmatory trials as soon as possible., Primary Funding Source: Laura and John Arnold Foundation.

Background: School-based programmes, including hearing screening, provide essential preventive services for rural children. However, minimal evidence on screening methodologies, loss to follow-up, and scarcity of specialists for subsequent care compound rural health disparities. We hypothesised telemedicine specialty referral would improve time to follow-up for school hearing screening compared with standard primary care referral., Methods: In this cluster-randomised controlled trial conducted in 15 rural Alaskan communities, USA, we randomised communities to telemedicine specialty referral (intervention) or standard primary care referral (control) for school hearing screening. All children (K-12; aged 4-21 years) enrolled in Bering Straight School District were eligible. Community randomisation occurred within four strata using location and school size. Participants were masked to group allocation until screening day, and assessors were masked throughout data collection. Screening occurred annually, and children who screened positive for possible hearing loss or ear disease were monitored for 9 months from the screening date for follow-up. Primary outcome was the time to follow-up after a positive hearing screen; analysis was by intention to treat. The trial was registered with ClinicalTrials.gov, NCT03309553., Findings: We recruited participants between Oct 10, 2017, and March 28, 2019. 15 communities were randomised: eight (750 children) to telemedicine referral and seven (731 children) to primary care referral. 790 (53·3%) of 1481 children screened positive in at least one study year: 391 (52∤1%) in the telemedicine referral communities and 399 (50∤4%) in the primary care referral communities. Of children referred, 268 (68·5%) in the telemedicine referral communities and 128 (32·1%) in primary care referral communities received follow-up within 9 months. Among children who received follow-up, mean time to follow-up was 41·5 days (SD 55·7) in the telemedicine referral communities and 92·0 days (75·8) in the primary care referral communities (adjusted event-time ratio 17·6 [95% CI 6·8-45·3] for all referred children). There were no adverse events., Interpretation: Telemedicine specialty referral significantly improved the time to follow-up after hearing screening in Alaska. Telemedicine might apply to other preventive school-based services to improve access to specialty care for rural children., Funding: Patient-Centered Outcomes Research Institute., Competing Interests: Declaration of interests SKR has received payment for telehealth lectures by the American Academy of Audiology and Audiology Today. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Climate impacts are rarely considered in health impact and economic assessments of public health programs. This study estimates the greenhouse gas (GHG) emissions averted by a novel oral SARS-CoV-2 (COVID-19) vaccine compared with four existing intramuscular vaccines: AstraZeneca's COVISHIELD®, Pfizer/BioNTech's COMIRNATY®, Moderna's mRNA-1273, and Johnson & Johnson's Ad26.COV2.S COVID-19 vaccine., Methods: We estimated GHG emissions averted for five vaccine modalities across nine countries. GHG emissions averted were derived from differences in cold chain logistics, production of vaccine supplies, and medical waste disposal. Countryspecific data including population coverage and electricity production mix were included in GHG emissions calculations. Results are presented in averted GHG per vaccine course and country level based on modeled vaccination demand., Findings: Per course, an oral vaccine is estimated to avert between 0.007 and 0.024 kgCO 2 e compared with Johnson & Johnson, 0.013 to 0.048 kgCO 2 e compared with AstraZeneca, 0.23 to 0.108 kgCO 2 e compared with Moderna, and 0.134 to 0.466 kgCO 2 e compared with Pfizer/BioNTech. The total GHG averted varied across countries based upon predicted demand, mix of electrical production, and vaccination strategy with the largest emissions reductions projected for India and the United States., Interpretation: Our results demonstrate large potential GHG emissions reductions from the use of oral vs. intramuscular vaccines for mass COVID-19 vaccination programs. Up to 82.25 million kgCO 2 e could be averted from utilization of an oral vaccine in the United States alone, which is equivalent to eliminating 17,700 automobiles from the road for one year., Funding: Funding was provided by Vaxart, Inc. Vaxart, Inc. is currently developing an oral COVID-19 vaccine, the characteristics of which were utilized to define the thermostable oral vaccine discussed in this study. Apart from providing data on the characteristics of the oral vaccine under development, the funders had no influence over the study design, methods, statistical analyses, results, framing of results, decision to submit the manuscript for publication, or choice of journal., Competing Interests: The authors received funding for this study from Vaxart, Inc. Vaxart, Inc. is currently developing an oral COVID-19 vaccine, the characteristics of which were utilized to define the thermostable oral vaccine discussed in this study. Apart from providing data on the characteristics of the oral vaccine under development, the funders had no influence over the study design, methods, statistical analyses, results, framing of results, decision to submit the manuscript for publication, or choice of journal., (© 2022 The Authors.)

Objectives: To assess the cost-effectiveness of systemic treatments for metastatic castration-sensitive prostate cancer from the US healthcare sector perspective with a lifetime horizon., Methods: We built a partitioned survival model based on a network meta-analysis of 7 clinical trials with 7287 patients aged 36 to 94 years between 2004 and 2018 to predict patient health trajectories by treatment. We tested parameter uncertainties with probabilistic sensitivity analyses. We estimated drug acquisition costs using the Federal Supply Schedule and adopted generic drug prices when available. We measured cost-effectiveness by an incremental cost-effectiveness ratio (ICER)., Results: The mean costs were approximately $392 000 with androgen deprivation therapy (ADT) alone and approximately $415 000, $464 000, $597 000, and $959 000 with docetaxel, abiraterone acetate, enzalutamide, and apalutamide, added to ADT, respectively. The mean quality-adjusted life-years (QALYs) were 3.38 with ADT alone and 3.92, 4.76, 3.92, and 5.01 with docetaxel, abiraterone acetate, enzalutamide, and apalutamide, added to ADT, respectively. As add-on therapy to ADT, docetaxel had an ICER of $42 069 per QALY over ADT alone; abiraterone acetate had an ICER of $58 814 per QALY over docetaxel; apalutamide had an ICER of $1 979 676 per QALY over abiraterone acetate; enzalutamide was dominated. At a willingness to pay below $50 000 per QALY, docetaxel plus ADT is likely the most cost-effective treatment; at any willingness to pay between $50 000 and $200 000 per QALY, abiraterone acetate plus ADT is likely the most cost-effective treatment., Conclusions: These findings underscore the value of abiraterone acetate plus ADT given its relative cost-effectiveness to other systemic treatments for metastatic castration-sensitive prostate cancer., (Copyright © 2021 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Despite prescribing declines between 2011 and 2019, opioid morbidity and mortality in the United States continued to rise during this period. We estimated the relationship between opioid prescribing, opioid use disorder (OUD) and fatal opioid overdose in the United States., Design: Dynamic Markov model., Setting: United States, using data from the National Survey on Drug Use and Health, Centers for Disease Control and Prevention, National Health and Nutrition Examination Survey and National Epidemiologic Survey on Alcohol and Related Conditions III., Participants: Simulated US individuals 12+ years of age from the general population or with prescription opioid medical use, prescription opioid non-medical use, illicit opioid (e.g. heroin, illicit fentanyl) use, prescription OUD, illicit OUD with a history of prior prescription opioid non-medical use or non-fatal or fatal opioid overdose., Measurements: Active OUD cases and fatal prescription opioid overdoses., Findings: Between 2010 and 2019, opioid prescribing declined 42.5%. Although fatal opioid overdoses increased by 103.2%, these reductions in opioid prescribing averted an estimated 9600 [95% uncertainty interval (UI) = 7205, 15 478] deaths starting in 2011 relative to continued prescribing at 2010 levels-and are projected to avert another 50 918 (95% UI = 38 829, 79 795) overdose deaths between 2020 and 2029. The median time from initial opioid prescription to fatal opioid overdose was 5.2 years. Of the 2.4 million (95% UI = 2.2 million, 2.7 million) individuals in the United States with estimated active OUD in 2019, 65% (95% UI = 59%, 71%) were attributable to initial opioid use occurring prior to 2011, whereas 14% (95% UI = 12%, 17%) were attributable to initial opioid use occurring between 2017 and 2019. The impact, by 2029, of additional reductions in prescribing initiated in 2020 would be more than three times greater than that of similar reductions initiated in 2025., Conclusions: Observed reductions in opioid prescribing volume in the United States from 2010 to 2019 appear to have saved approximately 9600 lives by 2019 and are anticipated to avert more than 50 000 fatal overdoses by 2029., (© 2021 Society for the Study of Addiction.)

The U.S. has the tools to end the HIV epidemic, but progress has stagnated. A major gap in U.S. efforts to address HIV is the under-utilization of medications that can virtually eliminate acquisition of the virus, known as pre-exposure prophylaxis (PrEP). This document proposes a financing and delivery system to unlock broad access to PrEP for those most vulnerable to HIV acquisition and bring an end to the HIV epidemic.

Antiretroviral pre-exposure prophylaxis (PrEP) is protective against HIV. Low utilization rates amongst HIV vulnerable populations are due in part to the high cost of PrEP. Generic PrEP offers the potential to improve health at significantly reduced costs. In this study, we examine early utilization patterns and prices for generic PrEP. We discuss the opportunities and challenges for generic PrEP to improve health among HIV vulnerable populations.

BACKGROUND: Genetic therapies are a promising treatment for children born with spinal muscular atrophy (SMA); however, their high price tags can evoke coverage restrictions. OBJECTIVE: To assess variation in coverage guidelines across fee-for-service state Medicaid programs for 2 novel genetic therapies, nusinersen and onasemnogene abeparvovec, that treat SMA. We also assessed the association of these coverage guidelines with use of the 2 genetic therapies. METHODS: We evaluated fee-for-service Medicaid coverage policies for nusinersen and onasemnogene abeparvovec from publicly available websites for the period February 2020-March 2020. We then documented areas of agreement and disagreement across 4 key coverage domains. We used 2018 and 2019 state Medicaid drug utilization data to calculate the use of nusinersen across Medicaid programs and assessed that use against the restrictiveness of the coverage guidelines. RESULTS: We identified 19 state Medicaid coverage guidelines for nusinersen. Most states agreed on diagnostics requirements; however, there were disagreements based on ventilator status. We identified 17 state Medicaid coverage guidelines for onasemnogene abeparvovec. There was more discordance in these coverage guidelines compared with nusinersen, notably in domains of SMN2 gene count and ventilator status. When comparing utilization of nusinersen with coverage restrictions, we found that the more restrictive states had considerably lower utilization of nusinersen. CONCLUSIONS: There was significant variation across fee-for-service Medicaid coverage policies for nusinersen and onasemnogene abeparvovec. Although states can impose individual coverage guidelines for each drug, we presented policy options that could reduce variation and potentially decrease the cost burden of these drugs. DISCLOSURES: This study was funded by Arnold Ventures. The authors have no conflicts of interest to disclose.

Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) in the setting of aspirin-exacerbated respiratory disease (AERD) is a disease that is difficult to treat and prone to recurrence. Dupilumab is a promising treatment for these patients, but its cost-effectiveness has not yet been compared with aspirin (acetylsalicyclic acid, or ASA) desensitization, a known and effective treatment. We aimed to compare the cost-effectiveness of ASA desensitization with dupilumab therapy for the treatment of CRSwNP in AERD., Methods: Analyses of cost-effectiveness, as measured in quality-adjusted life years (QALYs), and cost-utility, as measured in number of required revision endoscopic sinus surgeries (ESSs), were conducted., Results: ASA desensitization after ESS was cost-effective and dominated appropriate medical management. Adding salvage dupilumab was also cost-effective (incremental cost-effectiveness ratio [ICER] $135,517.33), and upfront dupilumab therapy was not cost-effective in any scenario (ICER $273,181.32). The cost-utility analysis demonstrated that, over a 10-year period per patient, appropriate medical management after ESS cost $54,125.31 and resulted in 2.25 revision ESSs, ASA desensitization after ESS cost $53,775.15 and resulted in 2.02 revision ESSs, ASA desensitization with salvage dupilumab cost $121,176.25 and resulted in 1.68 revision ESSs, and upfront dupilumab cost $185,950.34 and resulted in 1.51 revision ESSs., Conclusion: Dupilumab for the treatment of severe CRSwNP was found to be cost-effective as salvage therapy under the willingness-to-pay threshold of $150,000. Further analysis highlighted that the cost-effectiveness of dupilumab was most sensitive to drug price and expected gains in quality of life. This suggests that additional investigation into improving patient population selection and tailoring treatment algorithms may improve the cost-effectiveness of dupilumab in specific scenarios., (© 2021 ARS-AAOA, LLC.)

Competing Interests: The authors declare no conflicts of interest.