Patient Characteristics Associated With Using Transcatheter Left Atrial Appendage Occlusion Versus Oral Anticoagulants for Atrial Fibrillation.

BACKGROUND: Transcatheter left atrial appendage occlusion (LAAO) is an alternative to oral anticoagulants (OACs) for stroke prevention in patients with atrial fibrillation, but the predictors of LAAO use in routine care are unclear. We aimed to assess the utilization trends of LAAO and compare the change in characteristics of LAAO users versus OACs since its marketing. METHODS: Using the US Medicare claims database (March 15, 2015, to December 31, 2020), we identified patients with atrial fibrillation, ≥65 years, and CHA2DS2-VASc score ≥2 (men) or ≥3 (women), with either first implantation of an LAAO device or initiation of OACs, including apixaban, dabigatran, rivaroxaban, edoxaban, or warfarin. Patient characteristics, measured 365 days before the first LAAO or OAC use date, were compared using logistic regression. RESULTS: There were 30 058 LAAO recipients (mean age, 77.74 years; female, 42.1%) and 792 600 OAC initiators (mean age, 78.48; female, 53.3%). In 2020, patients had higher odds of initiating LAAO use than in 2015 (0.52 versus 9.32%; adjusted odds ratio [aOR], 13.64 [95% CI, 12.56-14.81]). Old age (ie, >85 versus 65-75 years; aOR, 0.84 [95% CI, 0.80-0.88]), female sex (aOR, 0.74 [95% CI, 0.71-0.76]), Black race (aOR, 0.63 [95% CI, 0.58-0.68]) versus White race, and Medicaid eligibility (aOR, 0.61 [95% CI, 0.58-0.64]) were associated with lower odds of receiving LAAO. Among clinical characteristics, frailty, cancer, fractures, and venous thromboembolism were associated with lower odds of LAAO use, while history of intracranial and extracranial bleeding, coagulopathy, and falls were associated with higher odds of receiving LAAO. CONCLUSIONS: Among patients with atrial fibrillation receiving stroke-preventive therapy, LAAO use increased rapidly from 2015 to 2020 and was positively associated with the risk factors for OAC complications but negatively associated with old age, advanced frailty, and cancer. Black race and female sex were associated with a lower likelihood of receiving LAAO.

Use of Efficiency Frontiers to Align Prices and Clinical Benefits of Biologic Therapies for Plaque Psoriasis.

Importance: The US lacks a systematic approach for aligning drug prices with clinical benefit, and traditional cost-effectiveness analysis (CEA) faces political obstacles. The efficiency frontier (EF) method offers policymakers an alternative approach. Objective: To assess how the EF approach could align prices and clinical benefits of biologic medications for plaque psoriasis and estimate price reductions in the US vs 4 peer countries: Australia, Canada, France, and Germany. Design and Setting: This health economic evaluation used the EF approach to compare the prices and clinical benefits of 11 biologics and 2 biosimilars for plaque psoriasis in the US, Australia, Canada, France, and Germany. Data were collected from February to March 2023 and analyzed from March to June 2023. Main Outcome Measures: EFs were constructed based on each biologic's efficacy, measured using the Psoriasis Area and Severity Index (PASI) 90 response rate, and annual treatment cost as of January 2023; US costs were net of estimated manufacturer rebates. Prices based on the EF were compared with traditional CEA-based prices calculated by the Institute for Clinical and Economic Review at a threshold of $150 000 per quality-adjusted life-year gained. Results: Among 13 biologics, PASI 90 response rates ranged from 17.9% (etanercept) to 71.6% (risankizumab); US net annual treatment costs ranged from $1664 (infliximab-dyyb) to $79 277 (risankizumab). The median (IQR) net annual treatment cost was higher in the US ($34 965 [$20 493-$48 942]) than prerebate costs in Australia ($9179 [$6691-$12 688]), Canada ($15 556 [$13 017-$16 112]), France ($9478 [$6637-$11 678]), and Germany ($13 829 [$13 231-$15 837]). The US EF included infliximab-dyyb (PASI 90: 57.4%; annual cost: $1664), ixekizumab (PASI 90: 70.8%; annual cost: $33 004), and risankizumab (PASI 90: 71.6%; annual cost: $79 277). US prices for psoriasis biologics would need to be reduced by a median (IQR) of 71% (31%-95%) to align with those estimated using the EF; the same approach would yield smaller price reductions in Canada (41% [6%-57%]), Australia (36% [0%-65%]), France (19% [0%-67%]), and Germany (11% [8%-26%]). Except for risankizumab, the EF-based prices were lower than the prices based on traditional CEA. Conclusions and Relevance: This economic evaluation showed that for plaque psoriasis biologics, using an EF approach to negotiate prices could lead to substantial price reductions and better align prices with clinical benefits. US policymakers might consider using EFs to achieve prices commensurate with comparative clinical benefits, particularly for drug classes with multiple therapeutic alternatives for which differences can be adequately summarized by a single outcome measurement.

Potential Medicare and Medicaid Savings on Anti-CD20 Therapy for Multiple Sclerosis.

This cross-sectional study compares price data for ocrelizumab and rituximab to estimate the savings to Medicare and Medicaid if rituximab were used in the treatment of multiple sclerosis instead of the higher-priced ocrelizumab.

Federal Funding For Discovery And Development Of Costly HIV Drugs Was Far More Than Previously Estimated.

In July 2012, tenofovir disoproxil fumarate-emtricitabine (TDF-FTC, brand name Truvada) was approved by the Food and Drug Administration (FDA) to prevent HIV infection. To estimate the extent of the US government's direct financial contribution to the discovery and development of Truvada, we identified National Institutes of Health awards using FDA documents, peer-reviewed literature, patent records, court filings, and other publicly available materials. We classified seventy-three federal government awards to eleven researchers as being directly linked to the development and clinical testing of Truvada for prevention therapy, through which the US government spent an estimated $143 million. The substantial public funding raises questions about the high price charged by the drug's manufacturer, which reduced its affordability and limited its accessibility as HIV preventive therapy.

US public investment in development of mRNA covid-19 vaccines: retrospective cohort study.

OBJECTIVE: To estimate US public investment in the development of mRNA covid-19 vaccines. DESIGN: Retrospective cohort study. SETTING: Publicly funded science from January 1985 to March 2022. DATA SOURCES: National Institutes of Health (NIH) Report Portfolio Online Reporting Tool Expenditures and Results (RePORTER) and other public databases. Government funded grants were scored as directly, indirectly, or not likely related to four key innovations underlying mRNA covid-19 vaccines-lipid nanoparticle, mRNA synthesis or modification, prefusion spike protein structure, and mRNA vaccine biotechnology-on the basis of principal investigator, project title, and abstract. MAIN OUTCOME MEASURE: Direct public investment in research and vaccine development, stratified by the rationale, government funding agency, and pre-pandemic (1985-2019) versus pandemic (1 January 2020 to 31 March 2022). RESULTS: 34 NIH funded research grants that were directly related to mRNA covid-19 vaccines were identified. These grants combined with other identified US government grants and contracts totaled $31.9bn (£26.3bn; €29.7bn), of which $337m was invested pre-pandemic. Pre-pandemic, the NIH invested $116m (35%) in basic and translational science related to mRNA vaccine technology, and the Biomedical Advanced Research and Development Authority (BARDA) ($148m; 44%) and the Department of Defense ($72m; 21%) invested in vaccine development. After the pandemic started, $29.2bn (92%) of US public funds purchased vaccines, $2.2bn (7%) supported clinical trials, and $108m (<1%) supported manufacturing plus basic and translational science. CONCLUSIONS: The US government invested at least $31.9bn to develop, produce, and purchase mRNA covid-19 vaccines, including sizeable investments in the three decades before the pandemic through March 2022. These public investments translated into millions of lives saved and were crucial in developing the mRNA vaccine technology that also has the potential to tackle future pandemics and to treat diseases beyond covid-19. To maximize overall health impact, policy makers should ensure equitable global access to publicly funded health technologies.

Variation in Use of Lung Cancer Targeted Therapies Across State Medicaid Programs, 2020-2021.

Importance: Targeted therapies for EGFR (OMIM 131550)- and ALK (OMIM 105590)-altered metastatic non-small cell lung cancer (NSCLC) substantially improve outcomes for some patients. However, use of these therapies is lower among Medicaid patients, and access to oncology care varies across state Medicaid programs. Evidence is lacking on how use of targeted therapies for metastatic NSCLC varies across state Medicaid programs. Objectives: To characterize state-level variation in the use of targeted therapies among Medicaid patients with metastatic NSCLC and to describe factors associated with this variation. Design, Setting, and Participants: This cross-sectional study used publicly available data from the Medicaid Drug Utilization Database from 2020 and 2021 and peer-reviewed data on NSCLC incidence, the prevalence of EGFR and ALK alterations, and expected treatment durations to estimate expected use of targeted therapies for EGFR- and ALK-altered NSCLC in 33 states. Exposures: State-specific Medicaid programs and state policies and characteristics. Main Outcomes and Measures: The primary outcome was the estimated proportion of person-time of Medicaid patients with EGFR- or ALK-altered NSCLC associated with receipt of targeted therapy in each state Medicaid program. Nested linear regression models examined associations between the observed variation and state policies and characteristics. Results: There were an estimated 3461 person-years in which EGFR- and ALK-targeted therapies were indicated in 2020 and 2021. During these years, only 2281 person-years of EGFR- and ALK-targeted therapies were dispensed to Medicaid patients, suggesting that an estimated 66% of Medicaid patients with EGFR- and ALK-altered metastatic disease received indicated targeted therapies across all states. Rates of targeted therapy use ranged from 18% in Arkansas to 113% in Massachusetts; 30 of 33 states (91%) had lower rates of targeted therapy use than expected. The observed variation across state Medicaid programs was associated with Medicaid policies, the density of oncologists, and state gross domestic product per capita. Conclusions and Relevance: This study suggests that rates of targeted therapy use among Medicaid patients with EGFR- and ALK-altered NSCLC were lower than expected and varied across state Medicaid programs. State policies and characteristics were associated with the observed variation, indicating where interventions could improve access to treatment and outcomes for patients with NSCLC.

Variations in Use of Diabetes Drugs With Cardiovascular Benefits Among Medicaid Patients.

Importance: Cardiovascular death remains the leading cause of mortality in patients with type 2 diabetes (T2D). A better understanding of the current use and adoption of glucose-lowering drugs with cardiovascular benefit can inform state policies to ensure their appropriate use in patients with T2D. Objective: To characterize the use of glucose-lowering agents with known cardiovascular benefit over time and across states. Design, Setting, and Participants: This cross-sectional pharmacoepidemiological study of Medicaid prescription rates of glucose-lowering agents with known cardiovascular benefit vs those with less well-established cardiovascular benefit was conducted between 2014 and 2019. In 50 states and the District of Columbia, the study focused on nonmetformin, noninsulin glucose-lowering drugs divided into 3 cohorts: (1) sodium-glucose cotransporter 2 (SGLT2) inhibitors, (2) glucagon-like peptide 1 (GLP1) receptor agonists, and (3) all other classes of glucose-lowering drugs. Data were analyzed from January 2014 to December 2019. Main Outcomes and Measures: Number of days supplied of each cohort, use ratios between the aggregated days supplied of glucose-lowering agents with known cardiovascular benefit vs those with less well-established cardiovascular benefit, and the mean change in use ratios per quarter. Results: Across the 50 states and the District of Columbia, the use ratio of glucose-lowering agents with known cardiovascular benefit ranged from 1.58 to 0.14 (mean [SD], 0.48 [0.27]) in 2019. A lower use ratio was seen in states with a higher prevalence of diabetes (ß = -0.049; 95% CI, -0.086 to -0.012; P = .01), a larger total population (ß = -0.013; 95% CI, -0.023 to -0.003; P = .01), a greater number of Medicaid enrollees (ß = -0.054; 95% CI, -0.096 to -0.014; P = .01), a greater proportion of people enrolled in Medicaid (ß = -0.018; 95% CI, -0.030 to -0.007; P = .002), and a greater proportion of Medicaid patients enrolled in managed care organizations (ß = -0.0032; 95% CI, -0.0051 to -0.0013; P = .002). Higher Medicaid expenditures per enrollee (ß = 0.047; 95% CI, 0.007 to 0.089; P = .03) were associated with a higher use ratio of these agents. The relative use of glucose-lowering agents with known cardiovascular benefit by Medicaid enrollees increased 7.4% per year from 2014 to 2019, with wide variations across state Medicaid programs. Conclusions and Relevance: In this cross-sectional study, glucose-lowering agents with cardiovascular benefit increased in use during the study period, but also demonstrated considerable variation among states in their relative use. Medicaid programs should try to clarify which factors may be contributing to relative underuse of these potentially life-saving drugs.

Use of Extrapolation in New Drug Approvals by the US Food and Drug Administration.

Importance: The US Food and Drug Administration (FDA)-approved indications can be factors in prescribing practices and insurance coverage, yet the frequency with which the extrapolation of clinical characteristics from pivotal trial data to the final approved indication occurs is not well understood. Objectives: To evaluate the frequency of extrapolation beyond pivotal trial data into approved indications in relation to disease severity, disease subtype, and concomitant medication use. Design, Setting, and Participants: In a cross-sectional study, the characteristics of patients in pivotal trials of 105 novel drug approvals from 2015 to 2017 were identified and compared with the FDA-approved indications for the drugs. Main sources analyzed included FDA reviews, published material describing the pivotal trials, and the original drug labeling. The study was conducted from July 4, 2019, to June 1, 2021. Exposures: Clinical characteristics of pivotal trials used in FDA approval. Main Outcomes and Measures: Main outcomes included the nature and frequency of extrapolation from study populations to the final indications. Extrapolation was defined as the granting of an indication for use in a broader population than was included in the pivotal trials on the basis of disease severity, disease subtype, or concomitant medication use. Results: Among the 105 novel FDA drug approvals studied, 23 extrapolations of trial population characteristics to the approved indication were identified in 21 drugs (20%): 12 times (29%) in 2015, 3 times (15%) in 2016, and 6 times (14%) in 2017. Extrapolation of trial findings to patients with greater disease severity was most common (n = 14 drugs), followed by differences in disease subtype (n = 6) and concomitant medication use (n = 3). Conclusions and Relevance: The findings of this study suggest that extrapolation from pivotal trial data to FDA-approved indications is common. Although extrapolations may be grounded in reasonable clinical predictions, they can limit the generalizability of such indications to specific prescribing decisions; these findings suggest a greater need for close postapproval monitoring to determine whether new safety issues arise, or effectiveness differs from expectations when these medications are used in broader real-world populations.

Discovery and Development of Pregabalin (Lyrica): The Role of Public Funding.

BACKGROUND AND OBJECTIVES: Pregabalin (Lyrica), a widely used drug that has generated billions in revenue as a treatment for diabetic neuropathy and other conditions, was originally discovered in an academic medical center, largely supported by public funding. We aimed to define the extent of direct federal public funding that contributed to various stages of pregabalin's development prior to US Food and Drug Administration (FDA) approval. METHODS: We identified key research, scientists, and organizations involved in the development of pregabalin from its discovery through FDA approval. Using key terms (e.g., its indications and mechanism of action), we searched PubMed for relevant publications and determined whether each publication was based on federal public funding using the NIH RePORTER. For each award prior to the drug's FDA approval, we scored its potential relatedness to pregabalin's development based on its title, investigator, and organization, and then examined descriptions of the most relevant awards to aid in defining these relationships. The budgets for all related awards were converted to 2020 dollars. RESULTS: Pregabalin was discovered largely on the basis of publicly funded research at Northwestern University; in 1990, it was licensed to Parke-Davis, which further developed it through its FDA approval in 2004. Most key terms were related to the drug and drug target (n = 5) and organizations involved (n = 5), followed by patent-listed inventors (n = 3). These key terms linked 6,438 core project awards and we identified 37 NIH awards related to pregabalin's development: 9 awards through 1990 ($3.3 million) and 28 from 1991 through 2004 ($10.5 million). CONCLUSION: Like that of many other widely sold medications, the development of pregabalin relied on public sector as well as industry contributions to its discovery, with relevant NIH awards totaling $13.8 million during its preapproval development.

Pursuing Value-Based Prices for Drugs: A Comprehensive Comparison of State Prescription Drug-Pricing Boards.

Policy Points In the absence of federal action on rising prescription drug costs, we reviewed the details of five states that have enacted prescription drug-pricing boards seeking to lower drug prices based on products' value. Within these states, six such boards are currently authorized; they have similarities but vary in terms of structure, authority, scope, and leverage. As of June 2021, only one of the boards in our sample has conducted pricing reviews; legislators in other states can learn from the successes and challenges of existing boards. Prescription drug-pricing boards represent a novel and promising way to curb state spending and pay for value in prescription drugs but face legal and political barriers in implementation. CONTEXT: Rising prescription drug costs are consuming a growing proportion of state and private budgets. In response, lawmakers have experimented with a variety of policies to contain spending and achieve value in prescription drugs. As part of this series of reforms, some state legislatures have recently authorized prescription drug-pricing boards to address the high prices of brand-name prescription drugs and assess the value of those drugs. METHODS: We identified state prescription drug-pricing boards in the United States, defined as any agency authorized by a state legislature to review specific drugs and pursue value-based drug prices. To describe the characteristics of the boards, we obtained public records of authorizing legislation, guidance documents, and board meeting minutes. We compared the boards' powers and responsibilities and analyzed completed pricing reviews. FINDINGS: Six state drug-pricing boards in five states met our definition; their design varied substantially. Two of the boards (New York Medicaid and Massachusetts) have authority over drug rebates paid by state Medicaid programs, one (New York Drug Accountability Board) has jurisdiction over state-regulated commercial insurance, and another three (Maine, Maryland, and New Hampshire) oversee non-Medicaid, state-funded insurance. Three boards are authorized to require manufacturers to confidentially submit information related to the pricing and clinical effectiveness of reviewed drugs to inform value determinations. Only one board (New York Medicaid) had completed pricing reviews as of June 3, 2021. CONCLUSIONS: Boards' structure, scope, and statutory leverages to compel manufacturers to negotiate lower net costs are key factors that influence whether and to what extent boards can achieve cost savings for states. Though legal constraints may limit the effective reach of prescription drug-pricing boards, these agencies can enable states to address rising prescription drug costs, in part by virtue of their very existence. To overcome practical limitations, states seeking to implement similar policies can build on the experiences and designs of current boards.

Characteristics of Clinical Trials Launched Early in the COVID-19 Pandemic in the US and in France.

Based on hierarchical classification and logistic regression of early US and French COVID-19 clinical trials we show that despite the registration of a large number of trials, only a minority had characteristics usually associated with providing robust and relevant evidence.

Public funding for transformative drugs: the case of sofosbuvir.

The approval of sofosbuvir (Sovaldi) in 2013 transformed chronic hepatitis C virus (HCV) care, but its high cost was criticized in part because of reports of substantial public involvement in its development. We developed a methodology to assess the public's contribution through the National Institutes of Health (NIH) in developing sofosbuvir. Using key terms from the timeline of sofosbuvir, we identified articles in PubMed; linked them to federal funding using the NIH RePORTER; reviewed the title, organization, and investigator of each resulting award for relatedness; and converted related awards to 2018 US dollars. Of 6043 unique awards, we identified 29 that were directly (US$7.7 million) and 110 that were indirectly (US$53.2 million) related awards made to major academic institutions and companies engaged in the development of the drug. These findings indicate that public funding had a key role in developing sofosbuvir, with an estimated US$60.9 million provided in NIH funding.