Current and Future Use of HEOR Data in Healthcare Decision-Making in the United States and in Emerging Markets

Background

Health economics and outcomes research (HEOR) is a growing field that provides important information for making healthcare coverage and access decisions. However, there is no standard process for incorporating HEOR into the decision-making process, and the current use of HEOR by healthcare payers remains unknown.

Objectives

To examine how HEOR data are being used by healthcare payers, including managed care organizations today, and how the use of such data is expected to change in the future in relation to access and reimbursement decision-making.

Methods

The Managed Care Survey (MCS) and the Pharmacy & Therapeutics (P&T) Committee Survey (PTS) were distributed to decision makers in the United States. A total of 72 managed care decision makers responded to the MCS and 30 P&T Committee members responded to the PTS from US healthcare organizations that cover from tens of thousands to millions of lives. The goal of these surveys was to understand the current use of HEOR data, perceived barriers and limitations in the use of HEOR, and the expectations for future use, and how these and other factors affect formulary decisions. An international perspective was gained by modifying the MCS based on feedback received at a European conference, and a pilot version was given to individuals in emerging markets across Asia, Latin America, and the Middle East and Africa.

Results

The majority of US respondents to the MCS (74%; N = 53) and to the PTS (77%; N = 23) indicate that HEOR is currently being used in their decision-making process; but the majority of respondents to the MCS (66%; N = 48) also state that quality assessment is limited (quality assessment was not addressed in the PTS). In addition, the majority of respondents to the MCS (82%; N = 59) expect the use of HEOR to increase in the future. Safety and efficacy were reported in the PTS to be the most important factors in the P&T Committee decision-making process, followed by head-to-head comparisons, and cost. The current use of HEOR in Asia, Latin America, and the Middle East and Africa varied widely across respondents.

Conclusion

This study provides an important benchmark of HEOR use in the United States before the implementation of healthcare reform. Between the years 2010 and 2011, HEOR data were used to varying extents across global regions, but their use in the future is likely to increase in relation to access and reimbursement decisions.With increasing access and utilization of healthcare, resources become more restricted, and prioritization in healthcare becomes unavoidable. Health economics and outcomes research (HEOR) is a discipline that is used to complement traditional clinical development information (ie, efficacy, safety, quality) to guide decision makers regarding patient access to specific drugs and services. HEOR has advanced considerably in methodology and in quantity over the past several decades. HEOR can provide data to help healthcare payers determine if treatments work in the populations they serve, and how much of the drug or treatment cost should be reimbursed by the healthcare system.As a key part of the request for comparative effectiveness evidence, the increased use of HEOR data can be expected in future decision-making processes.1,2 In addition, a greater emphasis has recently been placed on positioning the patient at the center of healthcare decisions. Outcomes research plays an increasingly important role in this, because it can provide data on specific populations and treatment combinations that are used. Understanding how these data are used in decision-making in the United States and globally can direct future efforts in this area.Currently, several global reimbursement agencies formally ask for HEOR information for their standard assessment process, including the National Institute for Health and Clinical Excellence in the United Kingdom, some of the Spanish health technology assessment (HTA) agencies, the Korean Health Insurance Review Agency, and the Health Intervention and Technology Assessment Program in Thailand.3–5 However, health-care payers in the United States do not currently have a standardized process for requesting or for using HEOR data. In the United States, HEOR data may come primarily from pharmaceutical companies via the Academy of Managed Care Pharmacy (AMCP) dossier format. Consequently, the pharmaceutical industry invests heavily in HEOR studies alongside clinical trials and continues to collect clinical, humanistic, and economic real-world data throughout the life cycle of a therapy.3 Discussions between healthcare payers and academic health economists suggest a need for this information by decision makers, but there is a lack of standardization regarding how such information is integrated into the current processes for drug (and other technology) evaluations.6,7Therefore, it remains unclear how healthcare payers in the United States currently use HEOR, and whether the use of such evidence will change in the future. The objective of this article is to describe the current and expected future use of HEOR data by healthcare payers, and to examine how pharmaceutical drug and manufacturer attributes are used in the decision-making process. This article summarizes the results of 2 surveys administered to individuals in formulary and reimbursement decision-making positions in the United States, as well as an adaptation of one of these surveys and workshops performed in other parts of the world.     

Intratumor mapping of intracellular water lifetime: metabolic images of breast cancer?

Shutter‐speed pharmacokinetic analysis of dynamic‐contrast‐enhanced (DCE)‐MRI data allows evaluation of equilibrium inter‐compartmental water interchange kinetics. The process measured here – transcytolemmal water exchange – is characterized by the mean intracellular water molecule lifetime (τ_i). The τ_i biomarker is a true intensive property not accessible by any formulation of the tracer pharmacokinetic paradigm, which inherently assumes it is effectively zero when applied to DCE‐MRI. We present population‐averaged in vivo human breast whole tumor τ_i changes induced by therapy, along with those of other pharmacokinetic parameters. In responding patients, the DCE parameters change significantly after only one neoadjuvant chemotherapy cycle: while K^trans (measuring mostly contrast agent (CA) extravasation) and k_ep (CA intravasation rate constant) decrease, τ_i increases. However, high‐resolution, (1 mm)², parametric maps exhibit significant intratumor heterogeneity, which is lost by averaging. A typical 400 ms τ_i value means a trans‐membrane water cycling flux of 10¹³ H₂O molecules s^?1/cell for a 12 µm diameter cell. Analyses of intratumor variations (and therapy‐induced changes) of τ_i in combination with concomitant changes of v_e (extracellular volume fraction) indicate that the former are dominated by alterations of the equilibrium cell membrane water permeability coefficient, P_W, not of cell size. These can be interpreted in light of literature results showing that τ_i changes are dominated by a P_W(active) component that reciprocally reflects the membrane driving P‐type ATPase ion pump turnover. For mammalian cells, this is the Na⁺,K⁺‐ATPase pump. These results promise the potential to discriminate metabolic and microenvironmental states of regions within tumors in vivo, and their changes with therapy. © 2014 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.     

Scaffold mesh size affects the osteoblastic differentiation of seeded marrow stromal cells cultured in a flow perfusion bioreactor

In this study, we cultured marrow stromal cells on titanium fiber meshes in a flow perfusion bioreactor and examined the effect of altering scaffold mesh size on cell behavior in an effort to develop a bone tissue construct composed of a scaffold, osteogenic cells, and extracellular matrix. Scaffolds of differing mesh size, that is, distance between fibers, were created by altering the diameter of the mesh fibers (20 or 40 microm) while maintaining a constant porosity. These scaffolds had a porosity of 80% and mesh sizes of 65 microm (20-microm fibers) or 119 microm (40-microm fibers). Cell/scaffold constructs were grown in static culture or under flow for up to 16 days and assayed for osteoblastic differentiation. Cellularity was higher at early time points and Ca2+ deposition was higher at later time points for flow constructs over static controls. The 20-microm mesh had reduced cellularity in static culture. Under flow conditions, mass transport limitations are mitigated allowing uniform cell growth throughout the scaffold, and there was no difference in cellularity between mesh types. There was greater alkaline phosphatase (ALP) activity, osteopontin levels, and calcium under flow at 8 days for the 40-microm mesh compared to the 20-microm mesh. However, by day 16, the trend was reversed, suggesting the time course of differentiation was dependent on scaffold mesh size under flow conditions. However, this dependence was not linear with respect to time; larger mesh size was conducive to early osteoblast differentiation while smaller mesh size was conducive to later differentiation and matrix deposition.     

Mineralized matrix deposition by marrow stromal osteoblasts in 3D perfusion culture increases with increasing fluid shear forces

In this study we report on direct involvement of fluid shear stresses on the osteoblastic differentiation of marrow stromal cells. Rat bone marrow stromal cells were seeded in 3D porous titanium fiber mesh scaffolds and cultured for 16 days in a flow perfusion bioreactor with perfusing culture media of different viscosities while maintaining the fluid flow rate constant. This methodology allowed exposure of the cultured cells to increasing levels of mechanical stimulation, in the form of fluid shear stress, whereas chemotransport conditions for nutrient delivery and waste removal remained essentially constant. Under similar chemotransport for the cultured cells in the 3D porous scaffolds, increasing fluid shear forces led to increased mineral deposition, suggesting that the mechanical stimulation provided by fluid shear forces in 3D flow perfusion culture can indeed enhance the expression of the osteoblastic phenotype. Increased fluid shear forces also resulted in the generation of a better spatially distributed extracellular matrix inside the porosity of the 3D titanium fiber mesh scaffolds. The combined effect of fluid shear forces on the mineralized extracellular matrix production and distribution emphasizes the importance of mechanosensation on osteoblastic cell function in a 3D environment.     

Assessing plasma pharmacokinetics of cholesterol following oral coadministration with a novel vegetable stanol mixture to fasting rats

The purpose of this project was to assess the plasma pharmacokinetics of [(3)H]cholesterol following coadministration of a novel vegetable stanol mixture composed of sitostanol and campestanol (FCP-3P4) to fasting rats. Following an overnight fast (12-16 h) and 48 h post-surgery, adult male Sprague Dawley rats were divided into six treatment groups and received a single-dose oral gavage at 0700 h of either: [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (5 mg/kg) + [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (12.5 mg/kg) + [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (25 mg/kg) + [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (50 mg/kg) + [(3)H]cholesterol (25 microCi/mL), or FCP-3P4 (100 mg/kg) + [(3)H]cholesterol (25 microCi/mL). Intralipid (10%) was the vehicle used to solubilize and coadminister [(3)H]cholesterol and FCP-3P4. Liquid chromatography-mass spectrometry analysis confirmed minimal cholesterol and vegetable stanol content within 10% Intralipid. Analysis of plasma pharmacokinetics was initiated by sampling 0.5 mL of blood prior to and 0.25, 0.5 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24, 28, 32, and 48 h post-oral gavage. Plasma samples were obtained by centrifugation of the blood samples and analyzed for [(3)H]cholesterol radioactivity. Pharmacokinetics analysis was performed by standard noncompartmental methods using statistical moment theory. Thin-layer chromatography was used to confirm that the majority of radioactivity measured in plasma was cholesterol (in the form of esterified or unesterified cholesterol). Greater than 90% of the radioactivity measured in all plasma samples was cholesterol-associated (in the form of either esterified or unesterified cholesterol). The coadministration of FCP-3P4 significantly decreased the area under the curve of [(3)H]cholesterol concentration versus time from 0 to 48 h (AUC(0-48h)) and maximum concentration (C(max)) in a dose-dependent manner. However, coadministration of FCP-3P4 at 25, 50, and 100 mg/kg resulted in a significant increase in apparent total body clearance (CL/F, where F is the bioavailability constant), apparent volume of distribution (V(d)/F), and oral absorption rate constant (k(a)) of [(3)H]cholesterol compared with controls. These findings suggest that the novel vegetable stanol mixture, FCP-3P4, modifies the plasma pharmacokinetics of [(3)H]cholesterol in fasting rats on oral coadministration.     

Flow perfusion culture induces the osteoblastic differentiation of marrow stroma cell-scaffold constructs in the absence of dexamethasone

Flow perfusion culture of scaffold/cell constructs has been shown to enhance the osteoblastic differentiation of rat bone marrow stroma cells (MSCs) over static culture in the presence of osteogenic supplements including dexamethasone. Although dexamethasone is known to be a powerful induction agent of osteoblast differentiation in MSC, we hypothesied that the mechanical shear force caused by fluid flow in a flow perfusion bioreactor would be sufficient to induce osteoblast differentiation in the absence of dexamethasone. In this study, we examined the ability of MSCs seeded on titanium fiber mesh scaffolds to differentiate into osteoblasts in a flow perfusion bioreactor in both the presence and absence of dexamethasone. Scaffold/cell constructs were cultured for 8 or 16 days and osteoblastic differentiation was determined by analyzing the constructs for cellularity, alkaline phosphatase activity, and calcium content as well as media samples for osteopontin. For scaffold/cell constructs cultured under flow perfusion, there was greater scaffold cellularity, alkaline phosphatase activity, osteopontin secretion, and calcium deposition compared with static controls, even in the absence of dexamethasone. When dexamethasone was present in the cell culture medium under flow perfusion conditions, there was further enhancement of osteogenic differentiation as evidenced by lower scaffold cellularity, greater osteopontin secretion, and greater calcium deposition. These results suggest that flow perfusion culture alone induces osteogenic differentiation of rat MSCs and that there is a synergistic effect of enhanced osteogenic differentiation when both dexamethasone and flow perfusion culture are used.