Discriminatory Properties of Quality-Adjusted Life Year Based Cost-Effectiveness Analyses for Patients With Disabilities: A Duchenne Muscular Dystrophy Case Study.

OBJECTIVES: Quality-adjusted life years (QALYs) have been challenged as a measure of benefit for people with disabilities, particularly for those in low-utility health states or with irreversible disability. This study examined the impact of a QALY-based assessment on the price for a hypothetical treatment for Duchenne muscular dystrophy (DMD), a progressive, genetic neuromuscular disease. METHODS: A previously published, 5-state model, which analyzed treatments for early ambulatory (EA) DMD patients, was replicated, validated, and adapted to include early nonambulatory (ENA) DMD patients. The model was used to assess a QALY-based threshold price (maximum cost-effective price) for a hypothetical treatment for 13-year-old ENA and 5-year-old EA patients (initial health states with lower and higher utility, respectively). All inputs were replicated including willingness-to-pay thresholds of $50 000 to $200 000/QALY. RESULTS: In contrast to EA patients, ENA patients had a 98% modeled decline in QALY-based threshold price at a willingness-to-pay of $150 000/QALY or higher, despite equal treatment benefit (delayed progression/death). At $100 000/QALY or lower, net nontreatment costs exceeded health benefits, implying any treatment for ENA patients would not be considered cost-effective, even at $0 price, including an indefinite pause in disease progression. CONCLUSIONS: For certain severe, disabling conditions, traditional approaches are likely to conclude that treatments are not cost-effective at any price once a patient progresses to a disabled health state with low utility value. These findings elucidate theoretical/ethical concerns regarding potential discriminatory properties of traditional QALY assessments for people with disabilities, particularly those who have lost ambulation or have other physical limitations.

Patient-centeredness and psychometric properties of the Defense and Veterans Pain Rating Scale 2.0 (DVPRS).

OBJECTIVE: This study aims to assess the patient-centeredness and psychometric properties of the Defense and Veterans Pain Rating Scale 2.0 (DVPRS) as a patient-reported outcome measure (PROM) for pain assessment in a military population. DESIGN: A critical evaluation of the DVPRS was conducted, considering its fit-for-purpose as a PROM and its patient-centeredness using the National Health Council's Rubric to Capture the Patient Voice. SETTING: The study focused on the use of the DVPRS within the Department of Defense (DoD) and Veterans Health Administration (VA) healthcare settings. SUBJECTS: The DVPRS was evaluated based on published studies and information provided by measure developers. The assessment included content validity, reliability, construct validity, and ability to detect change. Patient-centeredness and patient engagement were assessed across multiple domains. METHODS: Two independent reviewers assessed the DVPRS using a tool/checklist/questionnaire, and any rating discrepancies were resolved through consensus. The assessment included an evaluation of psychometric properties and patient-centeredness based on established criteria. RESULTS: The DVPRS lacked sufficient evidence of content validity, with no patient involvement in its development. Construct validity was not assessed adequately, and confirmatory factor analysis was not performed. Patient-centeredness and patient engagement were also limited, with only a few domains showing meaningful evidence of patient partnership. CONCLUSIONS: The DVPRS as a PROM for pain assessment in the military population falls short in terms of content validity, construct validity, and patient-centeredness. It requires further development and validation, including meaningful patient engagement, to meet current standards and best practices for PROMs.

Developing Patient-Centered Real-World Evidence: Emerging Methods Recommendations From a Consensus Process.

OBJECTIVES: The Joint ISPOR-ISPE Special Task Force on Real-World Evidence included patient/stakeholder engagement as a recommended good procedural practice when designing, conducting, and disseminating real-world evidence (RWE). However, there are no guidelines describing how patient experience data (PED) can be applied when designing real-world data (RWD) studies. This article describes development of consensus recommendations to guide researchers in applying PED to develop patient-centered RWE. METHODS: A multidisciplinary advisory board, identified through recommendations of collaborators, was established to guide development of recommendations. Semistructured interviews were conducted to identify how experienced RWD researchers (n = 15) would apply PED when designing a hypothetical RWD study. Transcripts were analyzed and emerging themes developed into preliminary methods recommendations. An eDelphi survey (n = 26) was conducted to refine/develop consensus on the draft recommendations. RESULTS: We identified 13 recommendations for incorporating PED throughout the design, conduct, and translation of RWE. The recommendations encompass themes related to the development of a patient-centered research question, designing a study, disseminating RWE, and general considerations. For example, consider how patient input can inform population/subgroups, comparators, and study period. Researchers can leverage existing information describing PED and may be able to apply those insights to studies relying on traditional RWD sources and/or patient registries. CONCLUSIONS: Applying these emerging recommendations may improve the patient centricity of RWE through improved relevance of RWE to patient communities of interest and foster greater multidisciplinary participation and transparency in RWD research. As researchers gather experience by applying the methods recommendations, further refinement of these consensus recommendations may lead to "best practices."

Peer Review and Transparency in Evidence-Source Selection in Value and Health Technology Assessment.

OBJECTIVES: Value and health technology assessment (V/HTA) is often used in clinical, access, and reimbursement decisions. V/HTA data-source selection may not be transparent, which is a necessary element for stakeholder understanding and trust and for fostering accountability among decision makers. Peer review is considered one mechanism for judging data trustworthiness. Our objective was (1) to use publicly available documentation of V/HTA methods to identify requirements for inclusion of peer-reviewed evidence sources, (2) to compare and contrast US and non-US approaches, and (3) to assess evidence sources used in published V/HTA reports. METHODS: Publicly available methods documentation from 11 V/HTA organizations in North America and Europe were manually searched and abstracted for descriptions of requirements and recommendations regarding search strategy and evidence-source selection. The bibliographies of a subset of V/HTA reports published in 2018 were manually abstracted for evidence-source types used in each. RESULTS: Heterogeneity in evidence-source retrieval and selection was observed across all V/HTA organizations, with more pronounced differences between US and non-US organizations. Not all documentation of organizations' methods address the evidence-source selection processes (7 of 11), and few explicitly reference peer-reviewed sources (3 of 11). Documentation of the evidence-source selection strategy was inconsistent across reports (6 of 13), and the level of detail provided varied across organizations. Some information on evidence-source selection was often included in confidential documentation and was not publicly available. CONCLUSIONS: Disparities exist among V/HTA organizations in requirements and guidance regarding evidence-source selection. Standardization of evidence-source selection strategies and documentation could help improve V/HTA transparency and has implications for decision making based on report findings.

Defining Patient Engagement in Research: Results of a Systematic Review and Analysis: Report of the ISPOR Patient-Centered Special Interest Group.

OBJECTIVES: Lack of clarity on the definition of "patient engagement" has been highlighted as a barrier to fully implementing patient engagement in research. This study identified themes within existing definitions related to patient engagement and proposes a consensus definition of "patient engagement in research." METHODS: A systematic review was conducted to identify definitions of patient engagement and related terms in published literature (2006-2018). Definitions were extracted and qualitatively analyzed to identify themes and characteristics. A multistakeholder approach, including academia, industry, and patient representation, was taken at all stages. A proposed definition is offered based on a synthesis of the findings. RESULTS: Of 1821 abstracts identified and screened for eligibility, 317 were selected for full-text review. Of these, 169 articles met inclusion criteria, from which 244 distinct definitions were extracted for analysis. The most frequently defined terms were: "patient-centered" (30.5%), "patient engagement" (15.5%), and "patient participation" (13.4%). The majority of definitions were specific to the healthcare delivery setting (70.5%); 11.9% were specific to research. Among the definitions of "patient engagement," the most common themes were "active process," "patient involvement," and "patient as participant." In the research setting, the top themes were "patient as partner," "patient involvement," and "active process"; these did not appear in the top 3 themes of nonresearch definitions. CONCLUSION: Distinct themes are associated with the term "patient engagement" and with engagement in the "research" setting. Based on an analysis of existing literature and review by patient, industry, and academic stakeholders, we propose a scalable consensus definition of "patient engagement in research."

Real-world evidence to support regulatory decision-making for medicines: Considerations for external control arms.

Randomized clinical trials (RCTs) are the gold standard in producing clinical evidence of efficacy and safety of medical interventions. More recently, a new paradigm is emerging-specifically within the context of preauthorization regulatory decision-making-for some novel uses of real-world evidence (RWE) from a variety of real-world data (RWD) sources to answer certain clinical questions. Traditionally reserved for rare diseases and other special circumstances, external controls (eg, historical controls) are recognized as a possible type of control arm for single-arm trials. However, creating and analyzing an external control arm using RWD can be challenging since design and analytics may not fully control for all systematic differences (biases). Nonetheless, certain biases can be attenuated using appropriate design and analytical approaches. The main objective of this paper is to improve the scientific rigor in the generation of external control arms using RWD. Here we (a) discuss the rationale and regulatory circumstances appropriate for external control arms, (b) define different types of external control arms, and (c) describe study design elements and approaches to mitigate certain biases in external control arms. This manuscript received endorsement from the International Society for Pharmacoepidemiology (ISPE).

Receipt of Treatment for Depression Following Traumatic Brain Injury.

OBJECTIVE: Lack of evidence for efficacy and safety of treatment and limited clinical guidance have increased potential for undertreatment of depression following traumatic brain injury (TBI). METHODS: We conducted a retrospective cohort study among individuals newly diagnosed with depression from 2008 to 2014 to assess the impact of TBI on receipt of treatment for incident depression using administrative claims data. We created inverse probability of treatment-weighted populations to evaluate the impact of TBI on time to receipt of antidepressants or psychotherapy following new depression diagnosis during 24 months post-TBI or matched index date (non-TBI cohort). RESULTS: Of 10 428 individuals with incident depression in the TBI cohort, 44.7% received 1 or more antidepressants and 20.0% received 1 or more psychotherapy visits. Of 10 463 in the non-TBI cohort, 41.2% received 1 or more antidepressants and 17.6% received 1 or more psychotherapy visits. TBI was associated with longer time to receipt of antidepressants compared with the non-TBI cohort (average 39.6 days longer than the average 126.2 days in the non-TBI cohort; 95% confidence interval [CI], 24.6-54.7). Longer time to psychotherapy was also observed among individuals with TBI at 6 months post-TBI (average 17.1 days longer than the average 47.9 days in the non-TBI cohort; 95% CI, 4.2-30.0), although this association was not significant at 12 and 24 months post-TBI. CONCLUSIONS: This study raises concerns about the management of depression following TBI.

Engaging hepatitis C infected patients in cost-effectiveness analyses: A literature review.

Cost-effectiveness analyses (CEAs) of hepatitis C virus (HCV) treatment strategies have become common, but few appear to include patient engagement or the patient perspective. The objectives of the current study were to (1) identify published HCV CEA studies that include patient input and (2) derive insights on patient-informed variable and outcome selection to build a framework for future economic analyses of HCV. A literature search was conducted using SCOPUS, EMBASE, and PubMed from January 1, 2012 to May 28, 2017. Terms sought included a combination of "incremental cost-effectiveness ratio" OR "economic evaluation" OR "cost effectiveness analysis" OR "cost utility analysis" OR "budget impact analysis" OR "cost benefit analysis" AND "hepatitis C". A total of 1,040 articles were identified in the search and seven articles were selected for further evaluation after abstracts and the full text of eligible articles were screened. One economic evaluation used direct patient engagement to account for patient preferences in the final model. The study endpoints identified included a variety of clinical, social, psychological, and economic outcomes. Costs primarily focused on productivity loss, missed work, out-of-pocket treatment costs, and indirect costs to family or friends supporting the patient. Conclusion: To date, the inclusion of the patient voice through patient engagement as part of methods in cost-effectiveness research in existing published studies has been limited. Future CEA studies should consider how patient engagement may impact economic models and their implementation into practice. (Hepatology 2018;67:774-781).

Patient-Reported Outcomes in Orphan Drug Labels Approved by the US Food and Drug Administration.

OBJECTIVES: In recent years, there has been increasing recognition of the need to assess treatment benefit from the patient's perspective. The extent of patient-reported outcome (PRO) data included in labeling for rare disease treatment is largely unknown. The objective of this study was to review trends over time for PRO-based labeling granted by the US Food and Drug Administration (FDA) for orphan drugs. STUDY DESIGN: Review of FDA package inserts. METHODS: Products included in this analysis were all new molecular entities (NMEs) and biologic license applications (BLAs) with orphan designations approved by the FDA from 2002 through 2017. For identified products, package inserts were reviewed to determine the number and type of PRO claim(s) granted, endpoint status, and PRO measure named. Two trends were analyzed: (1) over all years 2002 to 2017 and (2) 2002 to 2017 stratified into 3 periods (before draft FDA PRO guidance [2006], between draft and final guidance release, and after final guidance [2009] release. RESULTS: A total of 156 NMEs and BLAs with orphan designations were approved between 2002 and 2017. Of these, 13 products (8.3%) had PRO-based labeling, and 7 of 13 were symptom-related. The percent of orphan drugs approved with PRO-based labeling between 2002 and 2005, 2006 and 2008, and 2009 and 2017 was 0, 10.5, and 9.9, respectively. CONCLUSIONS: In FDA-approved labeling for orphan therapies, PRO measures used as primary and secondary endpoints increased after draft FDA PRO guidance release but remained relatively low thereafter. It is important to understand barriers to PRO measure use to ensure that treatments capture perspectives of patients with rare diseases.

Future of Patients in Healthcare Evaluation: The Patient-Informed Reference Case.

The "Reference Case" was developed to facilitate comparability among published cost-effectiveness analyses intended to contribute to decisions about the broad allocation of healthcare resources. Although the societal perspective is recommended for Reference Case analyses, empirical estimations rarely adequately represent the patient perspective, and more often, healthcare system or payer perspectives are used. In this commentary, we discuss the evolution of the Reference Case over the past 20 years and how it now needs to further evolve. This should begin with a patient-informed societal perspective. A realignment of the societal perspective to better include patient perspectives in CEA creates a conduit for patient inclusion. Engaging patients to both derive patient-informed value elements and prioritize value elements using stated preference methods will lead to patient inclusion in the societal perspective and a patient-informed Reference Case analysis.

An Algorithm to Characterize a Dementia Population by Disease Subtype.

PURPOSE: Identification of Alzheimer disease and related dementias (ADRD) subtypes is important for pharmacologic treatment and care planning, yet inaccuracies in dementia diagnoses make ADRD subtypes hard to identify and characterize. The objectives of this study were to (1) develop a method to categorize ADRD cases by subtype and (2) characterize and compare the ADRD subtype populations by demographic and other characteristics. METHODS: We identified cases of ADRD occurring during 2008 to 2014 from the OptumLabs Database using diagnosis codes and antidementia medication fills. We developed a categorization algorithm that made use of temporal sequencing of diagnoses and provider type. RESULTS: We identified 36,838 individuals with ADRD. After application of our algorithm, the largest proportion of cases were nonspecific dementia (41.2%), followed by individuals with antidementia medication but no ADRD diagnosis (15.6%). Individuals with Alzheimer disease formed 10.2% of cases. Individuals with vascular dementia had the greatest burden of comorbid disease. Initial documentation of dementia occurred primarily in the office setting (35.1%). DISCUSSION: Our algorithm identified 6 dementia subtypes and three additional categories representing unique diagnostic patterns in the data. Differences and similarities between groups provided support for the approach and offered unique insight into ADRD subtype characteristics.

Emerging Good Practices for Transforming Value Assessment: Patients' Voices, Patients' Values.

BACKGROUND: Patient engagement is a transformative strategy for improving value assessment. US value framework developers have increased engagement activities, but more needs to be learned about how to best achieve meaningful patient engagement in value assessment. The objective was to glean good practices in patient engagement emerging from patient community experiences, to be used in value assessment. METHODS: The National Health Council Value Workgroup conducted a survey and held a focus group with its member advocacy organizations to gather experiences with value framework developers and views on emerging good practices. RESULTS: Ten of 13 organizations completed the survey; reporting 13 interactions with four framework developers. Most rated experiences as "good" to "very good." Emerging good practices included (1) engage early; (2) engage a range of patients; (3) leverage patient-provided information, data resources, and outreach mechanisms; (4) be transparent; and (5) appreciate and accommodate resource constraints. Twelve of 13 organizations participated in the focus group, and this produced 30 emerging good practices in four areas: (1) timing; (2) methodology and data; (3) partnering; and (4) characterizing engagement. DISCUSSION: Patient engagement was limited in early development of value frameworks but has increased in the past few years. Patient groups report positive experiences that can serve as emerging good practices. These groups also reported experienced challenges in their interactions and recommended good practices to mitigate those challenges. CONCLUSIONS/RECOMMENDATIONS: The growing pool of patient engagement experiences can be translated into good practices to advance a patient-centered, value-driven health care ecosystem. Lessons learned from these early experiences can help establish recommend emerging good practices that can eventually result in best practices and standards in the field.

Patient-Reported Outcome Measures in the Food and Drug Administration Pilot Compendium: Meeting Today's Standards for Patient Engagement in Development?

BACKGROUND: In 2016, the Food and Drug Administration (FDA) released a Pilot Clinical Outcome Assessment Compendium (COA Compendium) intended to foster patient-focused drug development (PFDD). However, it is unclear whether patient perspectives were solicited during development or validation of the included patient-reported outcome (PRO) measures. OBJECTIVE: To examine the pedigree of a sample of measures included in the COA Compendium. METHODS: PROs included in chapters 1 or 2 of the COA Compendium were extracted and three reviewers independently searched PubMed and Google to identify information on measure pedigree. Data on method and stage of measure development where patient engagement took place were documented. RESULTS: Among the 26 evaluated PRO measures, we were unable to identify information on development or validation on nearly half the sample (n = 12). Among the remaining 14 measures, 5 did not include any evidence of patient engagement; 2 engaged patients during concept elicitation only; 1 engaged patients during psychometric validation only; and 6 engaged patients during both concept elicitation and cognitive interviewing. Measures either previously qualified or submitted for qualification were more likely to include patient engagement. CONCLUSIONS: For the FDA Pilot COA Compendium to fulfill its purpose of fostering PFDD, it needs fine-tuning to reflect today's standards, improving transparency and facilitating clear identification of included measures so that the level of patient engagement, among other factors, can be properly assessed. Suggested improvements include identifying clinical trials that correspond to the COA Compendium's use in drug development; more clearly identifying which measure is referred to; and including only those measures that already qualified or undergoing qualification.

Increased Health Care Utilization in Dementia Subtypes Before Diagnosis.

INTRODUCTION: Prior studies have reported higher health care utilization (HCU) leading up to diagnosis of the Alzheimer disease and related dementia (ADRD), but none have assessed variation in HCU by ADRD subtype or examined disease-specific HCU. The objectives of this study were to identify ADRD subtypes and: (1) characterize all-cause and (2) disease-specific HCU during the 3 years preceding diagnosis, and (3) determine if HCU varied by ADRD subtype. METHODS: We used data from the OptumLabs Data Warehouse 2008 to 2014 to identify ADRD subtypes (total N=36,838) using an algorithm based on temporal sequencing of diagnoses and provider type. Annual counts of all-cause and disease-specific HCU in each of the 3 years preceding ADRD diagnosis were regressed on ADRD subtypes with mild cognitive impairment (MCI) as the reference group, year, and other variables. RESULTS: HCU increased over time, was highest in the outpatient setting, and varied by ADRD subtype. Compared with MCI, highest HCU was observed in vascular and nonspecific dementia. Compared with MCI, most subtypes had elevated disease-specific HCU. DISCUSSION: Variation in HCU by ADRD subtype points to different pathways to diagnosis and patterns of use.

Mortality and Associated Morbidities Following Traumatic Brain Injury in Older Medicare Statin Users.

OBJECTIVE: To assess the relationship between posttraumatic brain injury statin use and (1) mortality and (2) the incidence of associated morbidities, including stroke, depression, and Alzheimer's disease and related dementias following injury. SETTING AND PARTICIPANTS: Nested cohort of all Medicare beneficiaries 65 years of age and older who survived a traumatic brain injury (TBI) hospitalization during 2006 through 2010. The final sample comprised 100 515 beneficiaries. DESIGN: Retrospective cohort study of older Medicare beneficiaries. Relative risks (RR) and 95% confidence interval (CI) were obtained using discrete time analysis and generalized estimating equations. MEASURES: The exposure of interest included monthly atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin use. Outcomes of interest included mortality, stroke, depression, and Alzheimer's disease and related dementias. RESULTS: Statin use of any kind was associated with decreased mortality following TBI hospitalization discharge. Any statin use was also associated with a decrease in any stroke (RR, 0.86; 95% confidence intervals (CI), 0.81-0.91), depression (RR, 0.85; 95% CI, 0.79-0.90), and Alzheimer's disease and related dementias (RR, 0.77; 95% CI, 0.73-0.81). CONCLUSION: These findings provide valuable information for clinicians treating older adults with TBI as clinicians can consider, when appropriate, atorvastatin and simvastatin to older adults with TBI in order to decrease mortality and associated morbidities.

PEER-REVIEWED JOURNAL EDITORS' VIEWS ON REAL-WORLD EVIDENCE.

OBJECTIVES: Peer-review publication is a critical step to the translation and dissemination of research results into clinical practice guidelines, health technology assessment (HTA) and payment policies, and clinical care. The objective of this study was to examine current views of journal editors regarding: (i) The value of real-world evidence (RWE) and how it compares with other types of studies; (ii) Education and/or resources journal editors provide to their peer reviewers or perceive as needed for authors, reviewers, and editors related to RWE. METHODS: Journal editors' views on the value of RWE and editorial procedures for RWE manuscripts were obtained through telephone interviews, a survey, and in-person, roundtable discussion. RESULTS: In total, seventy-nine journals were approached, resulting in fifteen telephone interviews, seventeen survey responses and eight roundtable participants. RWE was considered valuable by all interviewed editors (n = 15). Characteristics of high-quality RWE manuscripts included: novelty/relevance, rigorous methodology, and alignment of data to research question. Editors experience challenges finding peer reviewers; however, these challenges persist across all study designs. Journals generally do not provide guidance, assistance, or training for reviewers, including for RWE studies. Health policy/health services research (HSR) editors were more likely than specialty or general medicine editors to participate in this study, potentially indicating that HSR researchers are more comfortable/interested in RWE. CONCLUSIONS: Editors report favorable views of RWE studies provided studies examine important questions and are methodologically rigorous. Improving peer-review processes across all study designs, has the potential to improve the evidence base for decision making, including HTA.

Value to Whom? The Patient Voice in the Value Discussion.

BACKGROUND: Professional societies and other organizations have recently taken a visible role trying to define treatment value via value frameworks and assessments, providing payer or provider recommendations, and potentially impacting patient access. Patient perspectives routinely differ from those of other stakeholders. Yet, it is not always apparent that patients were engaged in value framework development or assessment. OBJECTIVES: To describe the development and content of the National Health Council's (NHC's) Rubric, a tool that includes criteria for evaluation of value frameworks specifically with regard to patient-centeredness and meaningful patient engagement. METHODS: The NHC held a multistakeholder, invitational roundtable in Washington, DC, in 2016. Participants reviewed existing patient-engagement rubrics, discussed experiences with value frameworks, debated and thematically grouped hallmark patient-centeredness characteristics, and developed illustrative examples of the characteristics. These materials were organized into the rubric, and subsequently vetted via multistakeholder peer review. RESULTS: The resulting rubric describes six domains of patient-centered value frameworks: partnership, transparency, inclusiveness, diversity, outcomes, and data sources. Each domain includes specific examples illustrating how patient engagement and patient-centeredness can be operationalized in value framework processes. CONCLUSIONS: The NHC multistakeholder roundtable's recommendations are captured in the NHC's Rubric to assess value framework and model patient-centeredness and patient engagement. The Rubric is a tool that will be refined over time on the basis of feedback from patient, patient group, framework developer, and other stakeholder-use experiences.

Patient-Reported Outcome and Observer-Reported Outcome Assessment in Rare Disease Clinical Trials: An ISPOR COA Emerging Good Practices Task Force Report.

BACKGROUND: Rare diseases (RDs) affect a small number of people within a population. About 5000 to 8000 distinct RDs have been identified, with an estimated 6% to 8% of people worldwide suffering from an RD. Approximately 75% of RDs affect children. Frequently, these conditions are heterogeneous; many are progressive. Regulatory incentives have increased orphan drug designations and approvals. OBJECTIVE: To develop emerging good practices for RD outcomes research addressing the challenges inherent in identifying, selecting, developing, adapting, and implementing patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments for use in RD clinical trials. GOOD PRACTICES FOR OUTCOMES RESEARCH: This report outlines the challenges and potential solutions in determining clinical outcomes for RD trials. It follows the US Food and Drug Administration Roadmap to Patient-Focused Outcome Measurement in Clinical Trials. The Roadmap consists of three columns: 1) Understanding the Disease or Condition, 2) Conceptualizing Treatment Benefit, and 3) Selecting/Developing the Outcome Measure. Challenges in column 1 include factors such as incomplete natural history data and heterogeneity of disease presentation and patient experience. Solutions include using several information sources, for example, clinical experts and patient advocacy groups, to construct the condition's natural history and understand treatment patterns. Challenges in column 2 include understanding and measuring treatment benefit from the patient's perspective, especially given challenges in defining the context of use such as variations in age or disease severity/progression. Solutions include focusing on common symptoms across patient subgroups, identifying short-term outcomes, and using multiple types of COA instruments to measure the same constructs. Challenges in column 3 center around the small patient population and heterogeneity of the condition or study sample. Few disease-specific instruments for RDs exist. Strategies include adapting existing instruments developed for a similar condition or that contain symptoms of importance to the RD patient population, or using a generic instrument validated for the context of use. CONCLUSIONS: This report provides state-of-the-art solutions to patient-reported outcome (PRO) and observer-reported outcome (ObsRO) assessments challenges in clinical trials of patients with RDs. These recommended solutions are both pragmatic and creative and posed with clear recognition of the global regulatory context used in RD clinical development programs.

The Impact of Coverage Restrictions on Antipsychotic Utilization Among Low-Income Medicare Part D Enrollees.

Prior research demonstrates substantial access problems associated with utilization management and formulary exclusions for antipsychotics in Medicaid, but the use and impact of coverage restrictions for these medications in Medicare Part D remains unknown. We assess the effect of coverage restrictions on antipsychotic utilization in Part D by exploiting a unique natural experiment in which low-income beneficiaries are randomly assigned to prescription drug plans with varying levels of formulary generosity. Despite considerable variation in use of coverage restrictions across Part D plans, we find no evidence that these restrictions significantly deter utilization or reduce access to antipsychotics for low-income beneficiaries.