Perspectives on Patient-Reported Outcome Data After Treatment Discontinuation in Cancer Clinical Trials.

OBJECTIVES: Patient-reported outcome (PRO) data are critical in understanding treatments from the patient perspective in cancer clinical trials. The potential benefits and methodological approaches to the collection of PRO data after treatment discontinuation (eg, because of progressive disease or unacceptable drug toxicity) are less clear. The purpose of this article is to describe the Food and Drug Administration's Oncology Center of Excellence and the Critical Path Institute cosponsored 2-hour virtual roundtable, held in 2020, to discuss this specific issue. METHODS: We summarize key points from this discussion with 16 stakeholders representing academia, clinical practice, patients, international regulatory agencies, health technology assessment bodies/payers, industry, and PRO instrument development. RESULTS: Stakeholders recognized that any PRO data collection after treatment discontinuation should have clearly defined objectives to ensure that data can be analyzed and reported. CONCLUSIONS: Data collection after discontinuation without a justification for its use wastes patients' time and effort and is unethical.

Ethical Considerations for the Inclusion of Patient-Reported Outcomes in Clinical Research: The PRO Ethics Guidelines.

Importance: Patient-reported outcomes (PROs) can inform health care decisions, regulatory decisions, and health care policy. They also can be used for audit/benchmarking and monitoring symptoms to provide timely care tailored to individual needs. However, several ethical issues have been raised in relation to PRO use. Objective: To develop international, consensus-based, PRO-specific ethical guidelines for clinical research. Evidence Review: The PRO ethics guidelines were developed following the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network's guideline development framework. This included a systematic review of the ethical implications of PROs in clinical research. The databases MEDLINE (Ovid), Embase, AMED, and CINAHL were searched from inception until March 2020. The keywords patient reported outcome* and ethic* were used to search the databases. Two reviewers independently conducted title and abstract screening before full-text screening to determine eligibility. The review was supplemented by the SPIRIT-PRO Extension recommendations for trial protocol. Subsequently, a 2-round international Delphi process (n = 96 participants; May and August 2021) and a consensus meeting (n = 25 international participants; October 2021) were held. Prior to voting, consensus meeting participants were provided with a summary of the Delphi process results and information on whether the items aligned with existing ethical guidance. Findings: Twenty-three items were considered in the first round of the Delphi process: 6 relevant candidate items from the systematic review and 17 additional items drawn from the SPIRIT-PRO Extension. Ninety-six international participants voted on the relevant importance of each item for inclusion in ethical guidelines and 12 additional items were recommended for inclusion in round 2 of the Delphi (35 items in total). Fourteen items were recommended for inclusion at the consensus meeting (n = 25 participants). The final wording of the PRO ethical guidelines was agreed on by consensus meeting participants with input from 6 additional individuals. Included items focused on PRO-specific ethical issues relating to research rationale, objectives, eligibility requirements, PRO concepts and domains, PRO assessment schedules, sample size, PRO data monitoring, barriers to PRO completion, participant acceptability and burden, administration of PRO questionnaires for participants who are unable to self-report PRO data, input on PRO strategy by patient partners or members of the public, avoiding missing data, and dissemination plans. Conclusions and Relevance: The PRO ethics guidelines provide recommendations for ethical issues that should be addressed in PRO clinical research. Addressing ethical issues of PRO clinical research has the potential to ensure high-quality PRO data while minimizing participant risk, burden, and harm and protecting participant and researcher welfare.

Advancing digital health applications: priorities for innovation in real-world evidence generation.

In 2019, Germany passed the Digital Healthcare Act, which, among other things, created a "Fast-Track" regulatory and reimbursement pathway for digital health applications in the German market. The pathway explicitly provides for flexibility in how researchers can present evidence for new digital products, including the use of real-world data and real-world evidence. Against this backdrop, the Digital Medicine Society and the Health Innovation Hub of the German Federal Ministry of Health convened a set of roundtable discussions to bring together international experts in evidence generation for digital medicine products. This Viewpoint highlights findings from these discussions with the aims of (1) accelerating and stimulating innovative approaches to digital medical product evaluation, and (2) promoting international harmonisation of best evidentiary practices. Advancing these topics and fostering international agreement on evaluation approaches will be vital to the safe, effective, and evidence-based deployment and acceptance of digital health applications globally.

Understanding Use of Real-World Data and Real-World Evidence to Support Regulatory Decisions on Medical Product Effectiveness.

RWE has potential to provide efficient and relevant information on the effectiveness of medical products, complementing the data generated in clinical trials; however, how RWE can support regulatory decision-making is unclear, potentially limiting its use. The objective of this study was to identify and characterize instances where RWE was included in the evidence package to support the effectiveness of a medical product regulated by U.S. Food and Drug Administration. A retrospective landscape analysis was conducted to identify instances where RWE was submitted to support effectiveness through targeted review of white and gray literature and publicly available FDA reviews of medical products. Trained evaluators examined FDA reviews to determine if and how RWE contributed to regulatory decision-making regarding effectiveness. Evaluators identified 34 instances of RWE submitted between 1954 and 2020, where 26% of instances were for oncology, 18% for hematology, and 12% for neurology. Over 50% of the products were indicated for use in rare disease or pediatric populations. 82% of products where RWE was submitted received an orphan designation. RWE was included in the product label in 59% of instances. Stated reasons indicating why submitted RWE did not significantly contribute to regulatory decision-making included lack of pre-specification of study design and analysis as well as data reliability and relevancy concerns. While there is historical use of RWE to support medical product effectiveness for oncology and rare diseases, potential exists to leverage the strengths of RWE to support other therapeutic areas and capture outcomes that are most relevant to patients.

State variation in effects of state social distancing policies on COVID-19 cases.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) sickened over 20 million residents in the United States (US) by January 2021. Our objective was to describe state variation in the effect of initial social distancing policies and non-essential business (NEB) closure on infection rates early in 2020. METHODS: We used an interrupted time series study design to estimate the total effect of all state social distancing orders, including NEB closure, shelter-in-place, and stay-at-home orders, on cumulative COVID-19 cases for each state. Data included the daily number of COVID-19 cases and deaths for all 50 states and Washington, DC from the New York Times database (January 21 to May 7, 2020). We predicted cumulative daily cases and deaths using a generalized linear model with a negative binomial distribution and a log link for two models. RESULTS: Social distancing was associated with a 15.4% daily reduction (Relative Risk = 0.846; Confidence Interval [CI] = 0.832, 0.859) in COVID-19 cases. After 3 weeks, social distancing prevented nearly 33 million cases nationwide, with about half (16.5 million) of those prevented cases among residents of the Mid-Atlantic census division (New York, New Jersey, Pennsylvania). Eleven states prevented more than 10,000 cases per 100,000 residents within 3 weeks. CONCLUSIONS: The effect of social distancing on the infection rate of COVID-19 in the US varied substantially across states, and effects were largest in states with highest community spread.

Correction to: Comparing Associations of State Reopening Strategies with COVID-19 Burden.

In the original version of this paper, an author was misidentified. The corrected author listing appears here, and has been updated in the online version.

Comparing Associations of State Reopening Strategies with COVID-19 Burden.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) infected over 5 million United States (US) residents resulting in more than 180,000 deaths by August 2020. To mitigate transmission, most states ordered shelter-in-place orders in March and reopening strategies varied. OBJECTIVE: To estimate excess COVID-19 cases and deaths after reopening compared with trends prior to reopening for two groups of states: (1) states with an evidence-based reopening strategy, defined as reopening indoor dining after implementing a statewide mask mandate, and (2) states reopening indoor dining rooms before implementing a statewide mask mandate. DESIGN: Interrupted time series quasi-experimental study design applied to publicly available secondary data. PARTICIPANTS: Fifty United States and the District of Columbia. INTERVENTIONS: Reopening indoor dining rooms before or after implementing a statewide mask mandate. MAIN MEASURES: Outcomes included daily cumulative COVID-19 cases and deaths for each state. KEY RESULTS: On average, the number of excess cases per 100,000 residents in states reopening without masks is ten times the number in states reopening with masks after 8 weeks (643.1 cases; 95% confidence interval (CI) = 406.9, 879.2 and 62.9 cases; CI = 12.6, 113.1, respectively). Excess cases after 6 weeks could have been reduced by 90% from 576,371 to 63,062 and excess deaths reduced by 80% from 22,851 to 4858 had states implemented mask mandates prior to reopening. Over 50,000 excess deaths were prevented within 6 weeks in 13 states that implemented mask mandates prior to reopening. CONCLUSIONS: Additional mitigation measures such as mask use counteract the potential growth in COVID-19 cases and deaths due to reopening businesses. This study contributes to the growing evidence that mask usage is essential for mitigating community transmission of COVID-19. States should delay further reopening until mask mandates are fully implemented, and enforcement by local businesses will be critical for preventing potential future closures.

Characterizing and assessing antiemetic underuse in patients initiating highly emetogenic chemotherapy.

BACKGROUND: Patients initiating highly emetic chemotherapy (HEC) are at a 90% risk of chemotherapy-induced nausea and vomiting (CINV). Despite guideline-concordant antiemetic prescribing preventing CINV in up to 80% of patients, studies suggest that guideline-concordant antiemetic regimen use by patients initiating HEC is sub-optimal. However, these studies have been limited to single-site or single-cancer type with limited generalizability. The objective of this study was to describe antiemetic fill regimens and to assess predictors of underuse in the USA. METHODS: Our study population was adult patients under the age of 65 with cancer initiating intravenous HEC between 2013 and 2015 with employer-sponsored insurance in the IBM Watson/Truven MarketScan Commercial Claims database (N = 31,923). Descriptive statistics were used to explain antiemetic prescribing patterns, including antiemetic underuse. Modified Poisson regression was used to identify factors associated with antiemetic underuse. RESULTS: Among individuals initiating HEC, 49% underused guideline-concordant antiemetics. Most classified as under-using lacked an NK1 fill. While dexamethasone and 5HT3A uptake was over 80%, olanzapine use was minimal. Having lower generosity for prescription and medical benefits (paying more versus less than 20% out-of-pocket) increased the underuse risk by 3% and 4% (RR,1.03; 95% CI,1.01-1.05; P = 0.01 and RR,1.04; CI, 1.00-1.09; P = 0.03), respectively. Additionally, compared to receiving chemotherapy in the physician office setting, patients were at a 28% (RR, 1.28; 95% CI, 1.25-1.30; P < 0.0001) higher underuse risk in the outpatient hospital setting. CONCLUSION: Antiemetic underuse is high in patients initiating HEC, potentially leading to avoidable CINV events. We found that insurance generosity has a minimal effect on antiemetic guideline concordance in this population, suggesting discordance may be the result of site of care as well as gaps in provider knowledge or accountability.

Value-based arrangements may be more prevalent than assumed.

OBJECTIVES: To better understand the prevalence of US value-based payment arrangements (VBAs), their characteristics, and the factors that facilitate their success or act as barriers to their implementation. STUDY DESIGN: Surveys were administered to a convenience sample of subject matter experts who were senior representatives from payer organizations and biopharmaceutical manufacturers. These data were supplemented with qualitative interviews in a subsample of survey respondents. METHODS: Descriptive statistics, including percentages for categorical values and mean (SD) and median (interquartile range) for continuous variables, were assessed for quantitative questions. Trained reviewers collated responses to free-text survey questions and the qualitative interviews to identify themes. RESULTS: Of the 25 respondents, 1 manufacturer and 4 payers reported not having explored or negotiated any VBAs. Subsequently, questionnaire results from 11 biopharmaceutical manufacturers and 9 payers who had experience with VBAs were analyzed. More than 70% of VBAs implemented between 2014 and 2017 were not publicly disclosed. Furthermore, although consideration of VBAs as a coverage and payment tool is increasing, VBA implementation is relatively low, with manufacturers and payers reporting that approximately 33% and 60% of early dialogues translate into signed VBA contracts, respectively. Respondents' reasoning for VBA negotiation process breakdowns generally differed by sector and reflected each sector's respective priorities. CONCLUSIONS: This study reveals that the majority of VBAs are not publicly disclosed, which could underestimate their true prevalence and impact. Given the effort required to implement a VBA, future arrangements would likely benefit from a framework or other evaluative tool to help assess VBA pursuit desirability and guide the negotiation and implementation process.

Continuity of Medication Management among Adults with Schizophrenia and Comorbid Cardiometabolic Conditions.

OBJECTIVES: Adults with schizophrenia and cardiometabolic conditions may be good candidates for co-management by primary care prescribers and specialists. Associated risks for discontinuity in medication management have not been well-studied. This study examines whether medication adherence, inpatient admissions, and emergency department (ED) visits vary by the number and types of prescribers seen by adults with schizophrenia and cardiometabolic conditions. METHODS: This study used a retrospective cohort of 4,223 adult Medicaid enrollees with schizophrenia and hypertension, hyperlipidemia, and/or diabetes from three states in 2009-2010. Logistic regression models were run on outcome variables reflecting medication adherence, ED utilization, and inpatient admissions as a function of the number and types of prescribers. KEY FINDINGS: Increases in number of psychiatric specialists were associated with better antipsychotic adherence, but decreasing statin adherence. Increases in number of psychiatric specialists were also associated with a higher probability of inpatient admission and ED visits, while increases in number of primary care prescribers were associated with increases in the probability of ED visits. CONCLUSION: Greater antipsychotic adherence for adults receiving prescriptions from multiple psychiatric specialists was counteracted by lower statin adherence and greater risk of ED and inpatient utilization. This may help inform optimal care models for these complex individuals.

Incidence of and Risk Factors for Severe Adverse Events in Elderly Patients Taking Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers after an Acute Myocardial Infarction.

STUDY OBJECTIVE: To assess the incidence of and risk factors associated with severe adverse events in elderly patients who used angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) after an acute myocardial infarction (AMI). DESIGN: Retrospective cohort study. DATA SOURCES: Centers for Medicare & Medicaid Services Chronic Conditions Data Warehouse (Medicare service claims database), American Community Survey of the U.S. Census Bureau, and Multum Lexicon Drug database. PATIENTS: A total of 101,588 eligible Medicare fee-for-service beneficiaries 66 years or older, who were hospitalized for AMI between January 1, 2008, and December 31, 2009, and used ACEIs or ARBs within 30 days after discharge. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were hospitalizations for acute renal failure (ARF) and hyperkalemia. The secondary outcome was discontinuation or suspension of ACEI/ARB therapy after a visit to a health care provider. The primary risk factors of interest were age, sex, race/ethnicity, and chronic kidney disease (CKD). Cumulative incidence curves and multivariable Fine-Gray proportional hazards models with 95% confidence intervals (CIs) were used with death as a competing risk in both intention-to-treat (ITT) and as-treated (AT) analyses. In the study cohort, 2.8% experienced ARF, 0.5% experienced hyperkalemia, and 63.7% discontinued ACEI/ARB therapy within 1 year after hospital discharge. Approximately half of the incidence of ARF and hyperkalemia occurred within 6 months after hospital discharge, but the cumulative incidence increased after 6 months. Patients older than 85 years had a higher rate of ARF (ITT hazard ratio [HR] 1.15, 95% CI 1.04-1.28) and hyperkalemia (ITT HR 1.33, 95% CI 1.05-1.68) compared with those aged 65-74 years. Patients with baseline CKD had higher rates of ARF (ITT HR 1.61, 95% CI 1.42-1.82), hyperkalemia (ITT HR 1.41, 95% CI 1.11-1.77), and ACEI/ARB therapy discontinuation or suspension (ITT HR 1.05, 95% CI 1.02-1.09). CONCLUSION: We found a low incidence of ARF and hyperkalemia in elderly patients treated with ACEIs or ARBs after AMI hospitalization. However, a high rate of treatment discontinuation might prevent a higher rate of occurrence of these events. Long-term careful monitoring of severe adverse events and timely discontinuation of ACEIs or ARBs among elderly patients with advancing age and CKD after an AMI is warranted in clinical practice.

Continuity of medication management in Medicaid patients with chronic comorbid conditions: An examination by mental health status.

OBJECTIVE: Patients with serious mental illness (SMI) often have comorbid cardiometabolic conditions (CMCs) that may increase the number of prescribers involved in treatment. This study examined whether patients with SMI (depression and schizophrenia) and comorbid CMCs experience greater discontinuity of prescribing than patients with CMCs alone. METHODS: 2009 Medicaid data were used to compare number and types of prescribers (primary care, cardiometabolic, psychiatric, other) in individuals with 1-3 CMCs (diabetes, hypertension, dyslipidemia) alone (n=76.451); with CMC and schizophrenia (n=6507); and with CMC and depression (n=23.510) and the degree of prescribing within a provider's area of specialty. RESULTS: 44%, 61%, and 71% of individuals with CMCs only, with CMCs and schizophrenia, and with CMCs and depression had medications from these classes prescribed by 5 or more providers respectively. >35% of patients with CMCs alone or CMCs and schizophrenia had prescriptions provided by 3 or more PCP providers, which increased to 49.1% for patients with CMCs and depression. In the schizophrenia cohort, 29% of antipsychotics were PCP-prescribed while psychiatrists prescribed 10%, 9%, and 9% of antihypertensive, antihyperlipidemic, and antidiabetic medications respectively. CONCLUSIONS: The presence of SMI increases the number of prescribers treating individuals with CMCs. The impact of this fragmentation in medication management on health outcomes is unknown.

Prescription Drug Utilization and Reimbursement Increased Following State Medicaid Expansion in 2014.

BACKGROUND: The Affordable Care Act (ACA) expanded health care and medication insurance coverage through Medicaid expansion in select states. Expansion has the potential to increase the availability of health services to patients, including prescription medications. However, limited studies have examined how expansion affected prescription drug utilization and reimbursement. OBJECTIVE: To compare prescription drug utilization (number of prescriptions filled) and reimbursement trends between states that did and did not expand Medicaid coverage in 2014, while accounting for known effects of expansion on Medicaid enrollment. METHODS: We conducted a comparative interrupted time series using retrospective Medicaid state drug utilization data from 2011 to 2014. After inclusion/exclusion criteria, 8 states that expanded Medicaid in 2014 and 10 states that did not expand Medicaid were studied. Primary outcomes were changes in quarterly prescription drug utilization and quarterly total prescription drug reimbursement before and after expansion. To account for increases in enrollment in expansion states, secondary outcomes were per-member-per-quarter (PMPQ) utilization and reimbursement before and after expansion. RESULTS: Expansion states experienced a 1.4 million prescriptions per quarter and $163 million per quarter increase in utilization and reimbursement above the change in rates observed in nonexpansion states after expansion (P < 0.001). Specifically, 1 year after ACA implementation, expansion states used 17.0% more prescriptions and spent 36.1% more in reimbursement than the quarter preceding expansion. Expansion and nonexpansion states experienced significant drops in PMPQ prescriptions immediately after expansion (P < 0.001), but PMPQ prescriptions and reimbursement trends increased by the end of the postexpansion period in expansion states (P < 0.029 and P < 0.001, respectively). CONCLUSIONS: Study results suggest that Medicaid expansion offers vulnerable patients who were previously uninsured increased access to health care resources, specifically prescription drugs. Although this hypothesis would benefit from further testing, it aligns with previous studies that have shown that Medicaid expansion has led to increased access to coverage and care. While enrollment contributes to the increase in prescription utilization and reimbursement, the drop in PMPQ utilization suggests that the patients entering the program are healthier than existing patients. This shows that risk pooling is working. However, the increase in PMPQ reimbursement suggests that new enrollment may not be the only factor driving reimbursement changes. Factors such as changes in product mix, risk pool composition, and drug pricing and their effects on total and per-member reimbursement should be evaluated in future studies. DISCLOSURES: No outside funding supported this study. Mahendraratnam is currently a Worldwide Health Economics and Outcomes Research Pre-doctoral Fellow at Bristol-Myers Squibb and previously provided advisory services to public and private sector clients while employed at Avalere Health, an Inovalon Company, as well as completed an internship at Genentech, a member of the Roche Group. Farley and Dusetzina have no conflicts of interest to report. Preliminary results of this study were presented at the 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 21st Annual Meeting in Washington, DC, on May 21-25, 2016, and the 2016 AcademyHealth Annual Research Meeting (ARM) in Boston, Massachusetts, on June 26-28, 2016. Study concept and design were contributed by Farley, Mahendraratnam, and Dusetzina. Mahendraratnam, Farley, and Dusetzina collected the data, and data interpretation was performed by all the authors. The manuscript was written by Mahendraratnam, Farley, and Dusetzina and revised by Farley, Dusetzina, and Mahendraratnam.

The Value of Vedolizumab as Rescue Therapy in Moderate-Severe Crohn's Disease Patients with Adalimumab Non-response in the USA.

BACKGROUND AND AIMS: In May 2014, vedolizumab was approved by the Food and Drug Administration for the treatment of moderate-to-severe Crohn's disease. In clinical practice it is typically used in patients who are primary or secondary non-responders to adalimumab [Humira]. We aim to estimate the incremental benefits and costs of using vedolizumab as rescue therapy for adalimumab non-responders. METHODS: A Markov model was used to simulate the clinical course of Crohn's disease in a hypothetical cohort of 10,000 patients over a 12-month period. The treatment strategies evaluated were adalimumab only [with and without dose intensification] and adalimumab and vedolizumab [with and without adalimumab dose intensification]. The base case strategy was adalimumab only with 25% of non-responders undergoing dose intensification. Our primary outcomes were changes in costs and quality of life measures over the analytical horizon. RESULTS: In a 1-year period, initiating vedolizumab as rescue therapy in adalimumab non-responders reduces the average total cost per patient by 10%, and increases the average amount of time spent in remission or mild disease by up to 2 months. CONCLUSIONS: Treating on-label adalimumab non-responders with vedolizumab can, in the short term, significantly improves the quality of life of Crohn's disease patients that do not respond to adalimumab.

Who has used internal company documents for biomedical and public health research and where did they find them?

OBJECTIVE: To describe the sources of internal company documents used in public health and healthcare research. METHODS: We searched PubMed and Embase for articles using internal company documents to address a research question about a health-related topic. Our primary interest was where authors obtained internal company documents for their research. We also extracted information on type of company, type of research question, type of internal documents, and funding source. RESULTS: Our searches identified 9,305 citations of which 357 were eligible. Scanning of reference lists and consultation with colleagues identified 4 additional articles, resulting in 361 included articles. Most articles examined internal tobacco company documents (325/361; 90%). Articles using documents from pharmaceutical companies (20/361; 6%) were the next most common. Tobacco articles used documents from repositories; pharmaceutical documents were from a range of sources. Most included articles relied upon internal company documents obtained through litigation (350/361; 97%). The research questions posed were primarily about company strategies to promote or position the company and its products (326/361; 90%). Most articles (346/361; 96%) used information from miscellaneous documents such as memos or letters, or from unspecified types of documents. When explicit information about study funding was provided (290/361 articles), the most common source was the US-based National Cancer Institute. We developed an alternative and more sensitive search targeted at identifying additional research articles using internal pharmaceutical company documents, but the search retrieved an impractical number of citations for review. CONCLUSIONS: Internal company documents provide an excellent source of information on health topics (e.g., corporate behavior, study data) exemplified by articles based on tobacco industry documents. Pharmaceutical and other industry documents appear to have been less used for research, indicating a need for funding for this type of research and well-indexed and curated repositories to provide researchers with ready access to the documents.