Impact of Hypomethylating Agent Use on Hospital and Emergency Room Visits, and Predictors of Early Discontinuation in Patients With Higher-Risk Myelodysplastic Syndromes.

BACKGROUND: Previous analyses using the SEER-Medicare database have reported substantial underutilization of hypomethylating agents (HMAs) among patients with higher-risk myelodysplastic syndromes (MDS), and an association between poor HMA persistence and high economic burden. We aimed to compare rates of hospitalizations and emergency room (ER) visits among patients with higher-risk MDS according to use or non-use of HMA therapy, and to explore factors associated with early discontinuation of HMA therapy. PATIENTS AND METHODS: We used the 2010-2016 SEER-Medicare database to identify patients aged ≥66 years with a new diagnosis of refractory anemia with excess blasts (RAEB; a surrogate for higher-risk MDS) between 2011 and 2015. New hospitalizations and ER visits during the 12 months following MDS diagnosis were determined. Treatment discontinuation was defined as stopping HMA therapy before 4 cycles. RESULTS: Overall, 664 (55.8%) patients were HMA users and 526 (44.2%) non-users. Non-users had more hospitalizations (mean 0.47 vs. 0.30, P < .001) and ER visits (mean 0.69 vs. 0.41, P = .005) per month than HMA users. Among HMA users, 193 (29.1%) discontinued HMA therapy before 4 cycles, and 91 (47.2%) of these after 1 cycle. Older age and poor performance status were associated with higher risk of HMA discontinuation. CONCLUSION: An increased rate of hospitalizations and ER visits occurred in HMA non-users vs. HMA users. Approximately one-third of patients discontinued HMA therapy early. Predictors of discontinuation included older age and poor performance status. Novel approaches are needed to improve utilization and persistence with HMA therapy and associated outcomes, particularly among these higher-risk groups.

Treatment patterns and burden of myelosuppression for patients with small cell lung cancer: A SEER-medicare study.

PURPOSE: To depict the treatment journey for patients with small cell lung cancer (SCLC) and evaluate health care resource utilization (HCRU) associated with myelosuppression, a complication induced by chemotherapy or chemotherapy plus radiation therapy. PATIENTS AND METHODS: This was a descriptive, retrospective study of patients with SCLC aged ≥65 years, identified from linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data curated between January 2012 and December 2015. Treatment types (chemotherapy, radiation therapy, surgery) were classified as first, second, or third line, depending on the temporal sequence in which regimens were prescribed. For each year, the proportions of patients completing 4- or 6-cycle chemotherapy regimens, with hospital admissions associated with myelosuppression, or who used granulocyte colony-stimulating factors (G-CSFs), blood/platelet transfusions, or erythropoiesis-stimulating agents (ESAs), were calculated. RESULTS: Chemotherapy was administered as initial treatment in 7,807/11,907 (65.6%) patients whose treatment journey was recorded. Approximately one-third (n = 3,985) subsequently received radiation therapy. In total, 5,791 (57.8%) patients completed the guideline-recommended 4-6 cycles of chemotherapy. Among all chemotherapy-treated patients, 10,370 (74.3%) experienced ≥1 inpatient admission associated with myelosuppression (anemia, 7,366 [52.8%]; neutropenia, 4,642 [33.3%]; thrombocytopenia, 2,375 [17.0%]; pancytopenia, 1,983 [14.2%]). Supportive care interventions included G-CSF (6,756 [48.4%] patients), ESAs (1,534 [11.0%]), and transfusions (3,674 [26.3%]). CONCLUSION: Chemotherapy remains a cornerstone of care for patients with SCLC. Slightly over half of patients completed the recommended number of cycles, underscoring the frailty of patients and aggressiveness of SCLC. HCRU associated with myelosuppression was prominent, suggesting a substantial burden on older patients with SCLC.

Assessing the transition from intravenous to subcutaneous delivery of rituximab: Benefits for payers, health care professionals, and patients with lymphoma.

Subcutaneous (SC) administration of rituximab provides an opportunity for reduced patient treatment burden and increased healthcare efficiencies as an alternative to intravenous (IV) rituximab. There is minimal evidence comparing costs associated with SC and IV rituximab in a US setting. This research assessed the impact of transitioning patients from IV to SC rituximab for treatment of non-Hodgkin's lymphoma (NHL) from the US payer, provider, and patient perspective. We developed a model to estimate cost differences for transitioning 20% of a patient cohort from IV to SC rituximab. We included patients with incident diffuse large B-cell lymphoma, incident and recurrent follicular lymphoma, and incident and recurrent chronic lymphocytic leukemia. In the model, each patient received the same number of doses and that there was no difference in discontinuation between cohorts due to non-inferior efficacy and a similar safety profile. Model inputs were collected from published literature and publicly available data. Scenario analyses tested the impact of availability of low-cost biosimilars. In the base case (1,000,000 covered lives), we estimated a total of 157 patients, with 769 total drug administrations. A transition of 20% of patients from IV to SC was projected to generate $153,000 in payer savings, increase provider capacity by 270 hours, and free 470 hours of patient time. Scenario analyses suggest SC administration will be cost saving for payers even with a market where biosimilars approach 50% market share. A 20% transition to SC rituximab in a single cohort of patients has the potential to generate significant US health system value in the form of payer savings, increased practice capacity, and patient time.

Real-world use and outcomes of hypomethylating agent therapy in higher-risk myelodysplastic syndromes: why are we not achieving the promise of clinical trials?

Myelodysplastic syndromes are hematological malignancies characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Hypomethylating agents (HMAs), azacitidine and decitabine, are standard of care therapy for higher-risk myelodysplastic syndromes. However, outcomes reported for real-world studies fall short of those achieved in clinical trials. We conducted a targeted literature review exploring real-world utilization, persistence and outcomes with intravenous and subcutaneous HMA therapies to better understand barriers to achieving optimal outcomes in clinical practice. The potential benefits of oral HMA therapy were also explored. Underutilization and poor persistence with HMA therapy are associated with suboptimal outcomes, highlighting the need for approaches to improve utilization and persistence, so that patients achieve the optimum benefit from HMA therapy.

Lay abstract Myelodysplastic syndromes (MDS) are bone marrow disorders affecting the production of blood cells. In some patients, MDS can progress to acute myeloid leukemia (AML), an aggressive blood cancer with poor prognosis. Patients with higher-risk MDS are often treated with a type of chemotherapy called hypomethylating agents (HMAs). Studies conducted in real-world clinical practice have shown HMAs to be less effective than has been found in clinical trials. We reviewed available studies exploring real-world utilization, persistence and outcomes with current HMA therapies to better understand any barriers to patients achieving the best outcomes. Two important factors were found to be the underuse of HMAs and poor persistence with HMA therapy, highlighting the need for approaches to improve HMA utilization and persistence.

Patient-Focused Drug Development: A New Direction for Collaboration.

CONTEXT: Patient-Focused Drug Development (PFDD) is a new initiative from the Food and Drug Administration (FDA) intended to bring patient perspectives into an earlier stage of product development. The goal is that patients will be able to provide context for benefit-risk assessments and input to review divisions, and also aid in the development of new assessment tools, study endpoints, and risk communications. This paper provides a summary on what is known to date about FDA's PFDD initiative and describes implications for patients, researchers, payers, and the biopharmaceutical industry. It also provides a roadmap for stakeholders to consider in defining their role in and in shaping PFDD's direction, and for expanding PFDD principles to conditions beyond the current 20 under FDA consideration. METHODS: A search was conducted of the peer-reviewed and gray literature using PubMed and Google. This included laws, FDA guidance documents, the peer-reviewed literature, and FDA presentations for content relevant to the search term "patient-focused drug development." FINDINGS: Currently, FDA activities within PFDD are limited to gaining patient insights through 20 disease-specific meetings. However, many stakeholders see the initiative much more generally as representing a broad shift toward patient centeredness in biopharmaceutical product development. CONCLUSIONS: Depending upon the trajectory taken and whether or not all PFDD aims are eventually addressed, the initiative has the potential to change product development in fundamental ways. Further research should explore how patient input on disease manifestation and treatment options is best ascertained from patients and documented before initiating and during drug development.

The hypothetical migraine drug comparative effectiveness study: a payer's recommendations for obtaining more useful results.

This article explores issues of concern to payers evaluating the hypothetical comparative effectiveness case study of two fictitious migraine treatments in this month's Health Affairs. The case study presents the seemingly paradoxical situation in which randomized controlled trials produce one result, and real-world observational comparative effectiveness research produces another. For the payer making coverage decisions, this scenario raises three major themes related to interpretation and communication. First, there is a need for a well-considered set of criteria that weigh evidence across comparative effectiveness studies to determine whether enough evidence exists to communicate or enact new health care policies. Second, emphasis should be placed on studies that are published or presented in peer-reviewed settings. Third, access to raw comparative effectiveness research data would enable payers to more deeply explore research interests relevant to their particular constituencies. Payers' involvement in comparative effectiveness research should be encouraged, not discouraged, to advance our understanding of what works best and for whom.

Greater adherence to diabetes drugs is linked to less hospital use and could save nearly $5 billion annually.

Improving adherence to medication offers the possibility of both reducing costs and improving care for patients with chronic illness. We examined a national sample of diabetes patients from 2005 to 2008 and found that improved adherence to diabetes medications was associated with 13 percent lower odds of subsequent hospitalizations or emergency department visits. Similarly, losing adherence was associated with 15 percent higher odds of these outcomes. Based on these and other effects, we project that improved adherence to diabetes medication could avert 699,000 emergency department visits and 341,000 hospitalizations annually, for a saving of $4.7 billion. Eliminating the loss of adherence (which occurred in one out of every four patients in our sample) would lead to another $3.6 billion in savings, for a combined potential savings of $8.3 billion. These benefits were particularly pronounced among poor and minority patients. Our analysis suggests that improved adherence among patients with diabetes should be a key goal for the health care system and policy makers. Strategies might include reducing copayments for certain medications or providing feedback about adherence to patients and providers through electronic health records.

Integrating scientific and real-world evidence within and beyond the drug development process.

Newly developed healthcare treatments face a complex environment with many stakeholders who can accelerate or decelerate adoption, most notably the healthcare system payers. Understanding and integrating their needs earlier in clinical development will ensure a smoother transition from bench to bedside. This paper describes a new approach to shaping a more effective complementary process of 'value' evidence generation both in and outside the clinical drug development process. We propose that biopharmaceutical companies consider bringing new solutions to market by marshaling cross-functional approaches to what we term an evidence-definition phase, evidence-generation phase and evidence-translation phase to drug and technology research and development. The organization of ongoing discovery, evaluation and translation with a 'real- world' perspective should provide a more streamlined approach to ensure both regulatory and eventual marketplace success.

Comparative effectiveness research and personalized medicine: catalyzing or colliding?

Comparative effectiveness research (CER) is generating intense attention as interest grows in finding new and better drug technology assessment processes. The federal government is supporting the expansion of CER through funding made available in the American Recovery and Reinvestment Act of 2009 (ARRA) and by establishing the Patient-Centered Outcomes Research Institute through the Patient Protection and Affordable Care Act of 2010. At the same time, personalized medicine is generating debate about its place in clinical medicine, and so, naturally, how CER can or cannot play a role in personalized medicine is part of these debates. At the heart of the debate around the role of CER in personalized medicine is the nature of personalized medicine and how it fits within contemporary clinical research concepts. We maintain in this article that CER can serve to catalyze personalized medicine, but we recognize that, for this to happen, researchers will need to embrace new data sources and new analytic approaches. We also recognize that drug technology assessment processes will have to undergo necessary adaptations to accommodate CER as configured for personalized medicine, and that clinicians will need to be educated appropriately and provided access to decision-support systems through health information technology to use the information coming from this research. To illustrate our argument, we describe two ongoing CER studies funded and managed in the private sector evaluating personalized medicine interventions that have important clinical and financial implications. One of the studies investigates the clinical and financial effects of pharmacogenomic testing for warfarin as prescribed in conditions of typical practice settings. The other study is also set in community practice settings and compares cardiovascular outcomes of patients receiving clopidogrel who are extensive metabolizer phenotypes for the cytochrome P450 2C19 hepatic isoenzyme with all patients receiving prasugrel.

Payer perspectives on pharmacogenomics testing and drug development.

A series of questions about hypothetical drugs and pharmacogenomic tests was posed to a panel of representatives from the health plan, government and employer sectors in order to elicit suggestions for input on data or study design considerations important for coverage determination. The panel suggested seven areas for drug developers to strongly consider. These areas were to include comparative information on new tests versus usual care, assess the negative predictive value of new tests, measure and report on cost offsets, balance relative risk improvement with absolute risk, consider the policy implications of the products or tests, report percentage responders in addition to group mean improvements, and to include specific pharmacogenomic information in US FDA approved labels. The panel was generally enthusiastic about the promise of the field to improve drug selection or dosing.

The effect of three-tier formulary adoption on medication continuation and spending among elderly retirees.

OBJECTIVE: To assess the effect of three-tier formulary adoption on medication continuation and spending among elderly members of retiree health plans. DATA SOURCES: Pharmacy claims and enrollment data on elderly members of four retiree plans that adopted a three-tier formulary over the period July 1999 through December 2002 and two comparison plans that maintained a two-tier formulary during this period. STUDY DESIGN: We used a quasi-experimental design to compare the experience of enrollees in intervention and comparison plans. We used propensity score methods to match intervention and comparison users of each drug class and plan. We estimated repeated measures regression models for each class/plan combination for medication continuation and monthly plan, enrollee, and total spending. We estimated logit models of the probability of nonpersistent use, medication discontinuation, and medication changes. DATA COLLECTION/EXTRACTION METHODS: We used pharmacy claims to create person-level drug utilization and spending files for the year before and year after three-tier adoption. PRINCIPAL FINDINGS: Three-tier formulary adoption resulted in shifting of costs from plan to enrollee, with relatively small effects on medication continuation. Although implementation had little effect on continuation on average, a small minority of patients were more likely to have gaps in use and discontinue use relative to comparison patients. CONCLUSIONS: Moderate cost sharing increases from three-tier formulary adoption had little effect on medication continuation among elderly enrolled in retiree health plans with relatively generous drug coverage.

Trends in medication treatment for ADHD.

OBJECTIVE: This study examines demographic trends in the use of medications to treat ADHD in adult and pediatric populations. METHOD: Using pharmacy claims data for a large population of commercially insured Americans, the study measures ADHD treatment prevalence and drug use from 2000 to 2005. RESULTS: In 2005, 4.4% of children (ages 0 to 19) and 0.8% of adults (ages 20 and older) used ADHD medications. Treatment rates were higher in boys (6.1%) than in girls (2.6%), but the rates for men and women were approximately equal (0.8%). During the period of the study, treatment prevalence increased rapidly (11.8% per year) for the population as a whole. Treatment rates grew more rapidly for adults than for children, more rapidly for women than for men, and more rapidly for girls than for boys. CONCLUSION: Improved identification of ADHD in adult and female patients has contributed to rapid growth in ADHD medication use.

Impact of medication adherence on hospitalization risk and healthcare cost.

OBJECTIVE: The objective of this study was to evaluate the impact of medication adherence on healthcare utilization and cost for 4 chronic conditions that are major drivers of drug spending: diabetes, hypertension, hypercholesterolemia, and congestive heart failure. RESEARCH DESIGN: The authors conducted a retrospective cohort observation of patients who were continuously enrolled in medical and prescription benefit plans from June 1997 through May 1999. Patients were identified for disease-specific analysis based on claims for outpatient, emergency room, or inpatient services during the first 12 months of the study. Using an integrated analysis of administrative claims data, medical and drug utilization were measured during the 12-month period after patient identification. Medication adherence was defined by days' supply of maintenance medications for each condition. PATIENTS: The study consisted of a population-based sample of 137,277 patients under age 65. MEASURES: Disease-related and all-cause medical costs, drug costs, and hospitalization risk were measured. Using regression analysis, these measures were modeled at varying levels of medication adherence. RESULTS: For diabetes and hypercholesterolemia, a high level of medication adherence was associated with lower disease-related medical costs. For these conditions, higher medication costs were more than offset by medical cost reductions, producing a net reduction in overall healthcare costs. For diabetes, hypercholesterolemia, and hypertension, cost offsets were observed for all-cause medical costs at high levels of medication adherence. For all 4 conditions, hospitalization rates were significantly lower for patients with high medication adherence. CONCLUSIONS: For some chronic conditions, increased drug utilization can provide a net economic return when it is driven by improved adherence with guidelines-based therapy.

Impact of 3-tier formularies on drug treatment of attention-deficit/hyperactivity disorder in children.

BACKGROUND: Expenditures for medications used to treat attention-deficit/hyperactivity disorder (ADHD) in children have increased rapidly. Many employers and health plans have adopted 3-tier formularies in an attempt to control costs for these and other drugs. OBJECTIVE: To assess the effect of copayment increases associated with 3-tier formulary adoption on use and spending patterns for ADHD medications for children. DESIGN AND SETTING: Observational study using quasi-experimental design to compare effects on ADHD medication use and spending for children enrolled as dependents in an employer-sponsored plan that made major changes to its pharmacy benefit design and a comparison group of children covered by the same insurer. The plan simultaneously moved from a 1-tier (same copayment required for all drugs) to a 3-tier formulary and implemented an across-the-board copayment increase. The plan later moved 3 drugs from tier 3 to tier 2. PARTICIPANTS: An intervention group of 20 326 and a comparison group of 15 776 children aged 18 years and younger. MAIN OUTCOME MEASURES: Monthly probability of using an ADHD medication; plan, enrollee, and total ADHD medication spending; and medication continuation. RESULTS: A 3-tier formulary implementation resulted in a 17% decrease in the monthly probability of using medication (P<.001), a 20% decrease in expected total medication expenditures, and a substantial shifting of costs from the plan to families (P<.001). Intervention group children using medications in the pre-period were more likely to change to a medication in a different tier after 3-tier adoption, relative to the comparison group (P = .08). The subsequent tier changes resulted in increased plan spending (P<.001) and decreased patient spending (P = .003) for users but no differences in continuation. CONCLUSIONS: The copayment increases associated with 3-tier formulary implementation by 1 employer resulted in lower total ADHD medication spending, sizeable increases in out-of-pocket expenditures for families of children with ADHD, and a significant decrease in the probability of using these medications.

The effect of incentive-based formularies on prescription-drug utilization and spending.

BACKGROUND: Many employers and health plans have adopted incentive-based formularies in an attempt to control prescription-drug costs. METHODS: We used claims data to compare the utilization of and spending on drugs in two employer-sponsored health plans that implemented changes in formulary administration with those in comparison groups of enrollees covered by the same insurers. One plan simultaneously switched from a one-tier to a three-tier formulary and increased all enrollee copayments for medications. The second switched from a two-tier to a three-tier formulary, changing only the copayments for tier-3 drugs. We examined the utilization of angiotensin-converting-enzyme (ACE) inhibitors, proton-pump inhibitors, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). RESULTS: Enrollees covered by the employer that implemented more dramatic changes experienced slower growth than the comparison group in the probability of the use of a drug and a major shift in spending from the plan to the enrollee. Among the enrollees who were initially taking tier-3 statins, more enrollees in the intervention group than in the comparison group switched to tier-1 or tier-2 medications (49 percent vs. 17 percent, P<0.001) or stopped taking statins entirely (21 percent vs. 11 percent, P=0.04). Patterns were similar for ACE inhibitors and proton-pump inhibitors. The enrollees covered by the employer that implemented more moderate changes were more likely than the comparison enrollees to switch to tier-1 or tier-2 medications but not to stop taking a given class of medications altogether. CONCLUSIONS: Different changes in formulary administration may have dramatically different effects on utilization and spending and may in some instances lead enrollees to discontinue therapy. The associated changes in copayments can substantially alter out-of-pocket spending by enrollees, the continuation of the use of medications, and possibly the quality of care.