Impact of a Value-based Formulary on Medication Utilization, Health Services Utilization, and Expenditures.

BACKGROUND: Value-based benefit design has been suggested as an effective approach to managing the high cost of pharmaceuticals in health insurance markets. Premera Blue Cross, a large regional health plan, implemented a value-based formulary (VBF) for pharmaceuticals in 2010 that explicitly used cost-effectiveness analysis (CEA) to inform medication copayments. OBJECTIVE OF THE STUDY: The objective of the study was to determine the impact of the VBF. DESIGN: Interrupted time series of employer-sponsored plans from 2006 to 2013. SUBJECTS: Intervention group: 5235 beneficiaries exposed to the VBF. CONTROL GROUP: 11,171 beneficiaries in plans without any changes in pharmacy benefits. INTERVENTION: The VBF-assigned medications with lower value (estimated by CEA) to higher copayment tiers and assigned medications with higher value to lower copayment tiers. MEASURES: Primary outcome was medication expenditures from member, health plan, and member plus health plan perspectives. Secondary outcomes were medication utilization, emergency department visits, hospitalizations, office visits, and nonmedication expenditures. RESULTS: In the intervention group after VBF implementation, member medication expenditures increased by $2 per member per month (PMPM) [95% confidence interval (CI), $1-$3] or 9%, whereas health plan medication expenditures decreased by $10 PMPM (CI, $18-$2) or 16%, resulting in a net decrease of $8 PMPM (CI, $15-$2) or 10%, which translates to a net savings of $1.1 million. Utilization of medications moved into lower copayment tiers increased by 1.95 days' supply (CI, 1.29-2.62) or 17%. Total medication utilization, health services utilization, and nonmedication expenditures did not change. CONCLUSIONS: Cost-sharing informed by CEA reduced overall medication expenditures without negatively impacting medication utilization, health services utilization, or nonmedication expenditures.

Decision Making on Medical Innovations in a Changing Health Care Environment: Insights from Accountable Care Organizations and Payers on Personalized Medicine and Other Technologies.

BACKGROUND: New payment and care organization approaches, such as those of accountable care organizations (ACOs), are reshaping accountability and shifting risk, as well as decision making, from payers to providers, within the Triple Aim context of health reform. The Triple Aim calls for improving experience of care, improving health of populations, and reducing health care costs. OBJECTIVES: To understand how the transition to the ACO model impacts decision making on adoption and use of innovative technologies in the era of accelerating scientific advancement of personalized medicine and other innovations. METHODS: We interviewed representatives from 10 private payers and 6 provider institutions involved in implementing the ACO model (i.e., ACOs) to understand changes, challenges, and facilitators of decision making on medical innovations, including personalized medicine. We used the framework approach of qualitative research for study design and thematic analysis. RESULTS: We found that representatives from the participating payer companies and ACOs perceive similar challenges to ACOs' decision making in terms of achieving a balance between the components of the Triple Aim-improving care experience, improving population health, and reducing costs. The challenges include the prevalence of cost over care quality considerations in ACOs' decisions and ACOs' insufficient analytical and technology assessment capacity to evaluate complex innovations such as personalized medicine. Decision-making facilitators included increased competition across ACOs and patients' interest in personalized medicine. CONCLUSIONS: As new payment models evolve, payers, ACOs, and other stakeholders should address challenges and leverage opportunities to arm ACOs with robust, consistent, rigorous, and transparent approaches to decision making on medical innovations.

Drug use and spending under a formulary informed by cost-effectiveness.

BACKGROUND: The National Academy of Medicine has called for value-based drug formularies to address health plan prescription drug spending while maintaining access to high-value medicines. Thirty employer-sponsored plans implemented a "Value-Based Formulary-essentials" (VBF-e) program that uses cost-effectiveness evidence to inform cost-sharing and coverage exclusion. OBJECTIVE: To evaluate if the VBF-e was associated with changes in medication use and patient out-of-pocket spending and health plan spending on prescription drugs and other health care. METHODS: This was a cohort study using a difference-in-differences design from 2015 through 2019 with 1 year of follow-up after VBF-e implementation at Premera Blue Cross, the largest nonprofit health plan in the Pacific Northwest. The VBF-e exposure group was composed of all individuals aged younger than 65 years and enrolled at least 12 months prior to their employer group's VBF-e implementation date. The contemporaneous control group was composed of propensity score-matched individuals with the same inclusion criteria but their employer group that did not implement VBF-e. We prespecified the following outcomes: days of medication on hand overall and by VBF-e tier (high-value generic, brand, and specialty drugs were in tiers 1 to 3, respectively, and low-value drugs were in tier 4 or excluded from coverage); prescription drug spending; and other health care use (emergency department visits, hospital days, and outpatient visits). RESULTS: Comparing 12,111 exposed (mean age = 36.0; 49.8% female sex) participants with 24,222 control participants (mean age = 34.7; 49.6% female sex), VBF-e reduced use of low-value drugs by 0.3 days per member per month (PMPM) (95% CI = -0.5 to -0.1; 17% decrease) for tier 4 drugs and 0.4 days PMPM (95% CI = -0.5 to -0.4; 83% decrease) for excluded drugs. High-value specialty drug use increased by 0.1 days PMPM (95% CI = 0.0-0.1; 123% increase). Health plan spending decreased by $14 PMPM (95% CI = -26 to -4) and member out-of-pocket spending increased by $1 PMPM (95% CI = 1-2). Other health care use did not change significantly. CONCLUSIONS: An exclusion formulary informed by cost-effectiveness evidence reduced low-value drug use, increased high-value specialty drug use, reduced health plan spending, and increased member out-of-pocket spending without increasing acute care use. DISCLOSURES: This research was supported by a grant from the Patrick and Catherine Weldon Donaghue Medical Research Foundation's Greater Value Portfolio Program. Study Registration Number: NCT04904055.

ICER's Version of HTA Is Positioned to Guide U.S. Health Care Reform.

DISCLOSURES: No funding supported the writing of this letter. The author is an unpaid member of the ICER Methods Advisory Committee and has participated in discussions at ICER meetings and meetings of the New England Comparative Effectiveness Advisory Council (CEPAC).

Augmenting Cost-Effectiveness Analysis Will Not Improve Affordability.

DISCLOSURES: No outside funding contributed to this article. The authors are employed by Premera Blue Cross and have nothing to disclose.

Evolution of the AMCP Format for Formulary Submissions.

DISCLOSURES: No funding was required for this project. The authors are or have been members of the Format Executive Committee.

Effects of low-level light therapy on hepatic antioxidant defense in acute and chronic diabetic rats.

Diabetes causes oxidative stress in the liver and other tissues prone to complications. Photobiomodulation by near infrared light (670 nm) has been shown to accelerate diabetic wound healing, improve recovery from oxidative injury in the kidney, and attenuate degeneration in retina and optic nerve. The present study tested the hypothesis that 670 nm photobiomodulation, a low-level light therapy, would attenuate oxidative stress and enhance the antioxidant protection system in the liver of a model of type I diabetes. Male Wistar rats were made diabetic with streptozotocin (50 mg/kg, ip) then exposed to 670 nm light (9 J/cm(2)) once per day for 18 days (acute) or 14 weeks (chronic). Livers were harvested, flash frozen, and then assayed for markers of oxidative stress. Light treatment was ineffective as an antioxidant therapy in chronic diabetes, but light treatment for 18 days in acutely diabetic rats resulted in the normalization of hepatic glutathione reductase and superoxide dismutase activities and a significant increase in glutathione peroxidase and glutathione-S transferase activities. The results of this study suggest that 670 nm photobiomodulation may reduce, at least in part, acute hepatic oxidative stress by enhancing the antioxidant defense system in the diabetic rat model.

Attenuation of TCDD-induced oxidative stress by 670 nm photobiomodulation in developmental chicken kidney.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a potent developmental teratogen inducing oxidative stress and sublethal changes in multiple organs, provokes developmental renal injuries. In this study, we investigated TCDD-induced biochemical changes and the therapeutic efficacy of photobiomodulation (670 nm; 4 J/cm(2)) on oxidative stress in chicken kidneys during development. Eggs were injected once prior to incubation with TCDD (2 pg/g or 200 pg/g) or sunflower oil vehicle control. Half of the eggs in each dose group were then treated with red light once per day through embryonic day 20 (E20). Upon hatching at E21, the kidneys were collected and assayed for glutathione peroxidase, glutathione reductase, catalase, superoxide dimutase, and glutathione-S-transferase activities, as well as reduced glutathione and ATP levels, and lipid peroxidation. TCDD exposure alone suppressed the activity of the antioxidant enzymes, increased lipid peroxidation, and depleted available ATP. The biochemical indicators of oxidative and energy stress in the kidney were reversed by daily phototherapy, restoring ATP and glutathione contents and increasing antioxidant enzyme activities to control levels. Photobiomodulation also normalized the level of lipid peroxidation increased by TCDD exposure. The results of this study suggest that 670 nm photobiomodulation may be useful as a noninvasive treatment for renal injury resulting from chemically induced cellular oxidative and energy stress.

Melatonin as a principal component of red light therapy.

Melatonin is well recognized for its role as a potent antioxidant and is directly implicated in the free radical theory of aging [1] [Reiter RJ, Pablos MI, Agapito TT, Guerrero JM. Melatonin in the context of the free radical theory of aging. Ann N Y Acad Sci 1996;786:362-78]. Moreover, melatonin has been shown to retard age-related increases in lipid peroxidation and oxidative damage [2] [Okatani Y, Wakatsuki A, Reiter RJ. Melatonin protects hepatic mitochondrial respiratory chain activity in senescence-accelerated mice. J Pineal Res 2002;32:143-8] and to act directly upon the immune system [3] [Poon AM, Liu ZM, Pang CS, Brown GM, Pang SF. Evidence for a direct action of melatonin on the immune system. Biol Signals 1994;3:107-17]. This report focuses on characterizing documented functions of melatonin in the context of red light therapy and proposes that melatonin is a potential mediator of red light's therapeutic effects, a hypothesis that is as yet untested. Red light therapy (670 nm, 4J/cm(2)) has been shown to restore glutathione redox balance upon toxicological insult and enhance both cytochrome c oxidase and energy production, all of which may be affected by melatonin. The red light treatment has also been successfully implemented in the clinical setting for its effectiveness in reducing both the number of incidences and severity of oral mucositis resulting in part from the chemotherapy and/or radiation administered prior to bone marrow transplants. Moreover, red light therapy improves wound healing and is being further tested for its ability to ameliorate toxicant-induced retinal and visual cortical neuron damage. Researchers in the growing field of light therapy may be in a position to draw from and collaborate with melatonin researchers to better characterize this alternative treatment.

Impact of a value-based formulary in three chronic disease cohorts.

OBJECTIVES: Value-based insurance design has been suggested as an effective approach to ensure access to highvalue medications in health insurance markets. Premera Blue Cross, a large regional health plan, implemented a value-based formulary (VBF) for pharmaceuticals in 2010 that explicitly used cost-effectiveness analysis to inform medication co-payments. This study assesses the impact of a VBF on adherence and patient and health plan expenditures on 3 chronic disease states: diabetes, hypertension, and hyperlipidemia. STUDY DESIGN: Interrupted time series design of employer-sponsored plans from 2006 to 2013. Beneficiaries exposed to the VBF formed the intervention group, and beneficiaries in similar plans without any changes in pharmacy benefits formed the control group. METHODS: We measured medication expenditures from member, health plan, and member-plus-health plan (overall) perspectives and medication adherence as proportion of days covered. We conducted an exploratory analysis of medication utilization classifying medications according to whether co-payments moved up or down in the year following VBF implementation. RESULTS: For the diabetes cohort, there was a statistically significant reduction in member and overall expenditures of $5 per member per month (PMPM) and $9 PMPM, respectively. For the hypertension cohort, there was a statistically significant reduction in member expenditures of $4 PMPM and an increase in health plan expenditures of $3 PMPM. There were no statistically significant effects on hyperlipidemia cohort expenditures or on medication adherence in any of the 3 disease cohorts. Exploratory analyses suggest that patients in the diabetes and hyperlipidemia cohorts were switching to higher-value medications. CONCLUSIONS: A VBF can ensure access to high-value medications while maintaining affordability.

Application of economic analyses in U.S. managed care formulary decisions: a private payer's experience.

BACKGROUND: Promoting use of pharmaco-economic models by formulary reviewers is a goal of the Academy of Managed Care Pharmacy (AMCP) Format for Formulary Submissions, but relatively few decision makers use such models, and many doubt that they provide meaningful input. OBJECTIVE: To demonstrate how sophisticated disease-based pharmaco-economic models can aid formulary decision makers when long-term outcomes data are lacking. METHODS: The Center for Outcomes Research (CORE) Diabetes Model (CDM), a published, validated Markov pharmaco-economic model that projects clinical and economic endpoints, was used to model the cost-effectiveness of exenatide, a new injectable antidiabetic agent that enhances glucose-dependent insulin secretion, in a standard cohort of type 2 diabetes patients (mean body mass index [BMI] = 27.5 3 kg/m2), compared with a modified obese cohort (mean BMI = 35 3 kg/m2) that was otherwise demographically identical at baseline to the standard cohort. The standard cohort was assumed to maintain baseline weight during treatment, and the modified obese cohort was assumed to experience weight loss of approximately 9% (mean = 3 kg/m2), with corresponding improvements in blood pressure, low density lipoprotein cholesterol, and triglycerides. We selected a 30-year time horizon because it was the time interval during which the CDM predicted most of the subjects would have died, and the costs obtained thus reasonably projected lifetime total direct medical costs for these cohorts. While treatment options certainly will change over a 30-year period, our goal was to estimate the incremental effect of exenatide over other available therapies. RESULTS: The model predicted reduced long-term treatment costs in obese patients, driven by an 11% decrease in cardiovascular disease burden and derived from the presumed weight loss. The incremental cost-effectiveness ratio (ICER) for adding exenatide over 3 years was 35,000 dollars/quality-adjusted life-year (QALY). Using a 30-year horizon, ICER values were 13,000 dollars/QALY versus insulin, 32,000 dollars versus generic glyburide, and 16,000 dollars versus no additional treatment. Exenatide dominated pioglitazone. By comparison, the 30-year ICER for exenatide versus insulin in the nonobese cohort was 33,000 dollars. These results were presented to the pharmacy and therapeutics (P&T) committee and influenced its decision to add exenatide to the drug formulary. While our modeling assumed certain patient characteristics (e.g., obesity, need of further A1c reduction at baseline, motivation to lose weight), the P&T committee imposed only a step-therapy requirement to try either metformin or a sulfonylurea before trying exenatide and did adopt a nonspecific requirement for physician reauthorization of refills before the fourth pharmacy claim for exenatide. CONCLUSIONS: Disease-based pharmaco-economic models may help third party payers project costs and be particularly useful when only data from short-term clinical trials are available. In the present case, the pharmacy staff of a health plan used a pharmaco-economic model for drug treatment of type 2 diabetes provided by the manufacturer as part of the AMCP Format dossier process to project cost outcomes for exenatide, adjunct injectable therapy for patients taking metformin and/or sulfonylurea. The P&T committee approved the drug for inclusion in the drug formulary based in part on the results of the pharmaco-economic model produced from the cost inputs entered into the model by the health plan pharmacists.

Effects of low-carbohydrate diet and Pycnogenol treatment on retinal antioxidant enzymes in normal and diabetic rats.

Because chronic hyperglycemia of uncontrolled diabetes mellitus may lead to increased reactive oxygen species and decreased enzymatic antioxidant defenses responsible for pathological processes in diabetic retinopathy, this study examined the hypothesis that a low-carbohydrate, high-fat diet, either alone or in combination with Pinus maritima can reduce hyperglycemia, restoring a more balanced, oxidative condition. Normal and streptozotocininduced diabetic rats were fed either a regular or low-carbohydrate diet for 30 or 90 d. In addition, normal and diabetic rats on the chronic (90-d) low-carbohydrate diet were treated with daily intraperitoneal Pinus maritima doses (10 mg/kg) for 14 consecutive days. Retinas were fractionated to assay activities of glutathione peroxidase, glutathione reductase, and gamma-glutamyl transferase. After 30 d, the low-carbohydrate diet reduced glycemic parameters and normalized aspartate aminotransferase activity in diabetic animals, suggesting less organ damage. No differences were observed between males and females in any measured glycemic parameters. Whereas all diabetic control animals developed cataracts bilaterally, no treated diabetic animals developed cataracts. There were no deleterious effects on retinal antioxidant defenses with either a 30-d or chronic low-carbohydrate diet. When diet was combined with Pinus maritima treatment, both retinal glutathione peroxidase and glutathione reductase activities increased, suggesting that a low-carbohydrate diet plus Pinus maritima may be an effective antioxidant and antihyperglycemic therapy, reducing the risk of diabetic retinopathy and cataract formation.

Effects of antioxidant treatment on normal and diabetic rat retinal enzyme activities.

Diabetes mellitus is characterized by hyperglycemia and, in chronic disease, by microvascular pathologies, especially in the kidney, peripheral nerve, and eye. Although hyperglycemia can be controlled with insulin and/or antihyperglycemic medications, diabetic retinopathy continues to be the leading cause of blindness in the United States. Because increased oxidative stress may be a cause of retinopathy, this study examined the hypothesis that administration of exogenous antioxidants can restore a more balanced oxidative condition. Normal and 30-day streptozotocin-induced diabetic Sprague-Dawley rats received daily intraperitoneal doses (10 mg/kg) of beta-carotene, alpha-lipoic, and Pycnogenol individually or in combinations for 14 days, after which retinae were dissected and fractionated for the assay of activities of glutathione reductase, glutathione peroxidase, gamma-glutamyl transferase, and superoxide dismutase. In normal rats, treatment with antioxidant combinations led to a decrease in gamma-glutamyl transferase activity; beta-carotene plus pycnogenol treatment decreased the activity of both glutathione-related enzymes. Decreased retinal gamma-glutamyl transferase activity of diabetic rats was normalized by the administration of pycnogenol alone or in combination with beta-carotene. In diabetic rats, retinal glutathione reductase activity increased after treatment with beta-carotene alone or with pycnogenol. Treatment with pycnogenol and alpha-lipoic acid alone or in combination decreased the activity of glutathione peroxidase, while this activity was increased after treatment with a combination of all antioxidants. Elevated activity of superoxide dismutase in diabetic retina was normalized by treatment with alpha-lipoic acid and with pycnogenol and beta-carotene in combination, but not with all three together. Antioxidants can access the retina and, once there, can alter antioxidant enzyme activities. In both normal and diabetic rats, combinations of antioxidants have different effects on retinal antioxidant enzyme activities than do individual antioxidants.

Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells.

We investigated whether altering Warburg metabolism (aerobic glycolysis) by treatment with the metabolic agent dichloroacetate (DCA) could increase the X-ray-induced cell killing of the radiation-resistant human non-small-cell lung cancer (NSCLC) cell lines A549 and H1299. Treatment with 50mM DCA decreased lactate production and glucose consumption in both A549 and H1299, clear indications of attenuated aerobic glycolysis. In addition, we found that DCA treatment also slowed cell growth, increased population-doubling time, and altered cell cycle distribution. Furthermore, we report that treatment with 50mM DCA significantly increased single and fractionated X-ray-induced cell killing of A549 and H1299 cells. Assay of DNA double-strand break repair by neutral comet assays demonstrated that DCA inhibited both the fast and the slow kinetics of X-ray-induced DSB repair in both A549 and H1299 NSCL cancer cells. Taken together the data suggest a correlation between an attenuated aerobic glycolysis and enhanced cytotoxicity and radiation-induced cell killing in radiation-resistant NSCLC cells.

Design, implementation, and first-year outcomes of a value-based drug formulary.

BACKGROUND: Value-based insurance design attempts to align drug copayment tier with value rather than cost. Previous implementations of value-based insurance design have lowered copayments for drugs indicated for select "high value" conditions and have found modest improvements in medication adherence. However, these implementations have generally not resulted in cost savings to the health plan, suggesting a need for increased copayments for "low value" drugs. Further, previous implementations have assigned equal copayment reductions to all drugs within a therapeutic area without assessing the value of individual drugs. Aligning the individual drug's copayment to its specific value may yield greater clinical and economic benefits. In 2010, Premera Blue Cross, a large not-for-profit health plan in the Pacific Northwest, implemented a value-based drug formulary (VBF) that explicitly uses cost-effectiveness analyses after safety and efficacy reviews to estimate the value of each individual drug. Concurrently, Premera increased copayments for existing tiers. OBJECTIVE: To describe and evaluate the design, implementation, and first-year outcomes of the VBF. METHODS: We compared observed pharmacy cost per member per month in the year following the VBF implementation with 2 comparator groups: (1) observed pharmacy costs in the year prior to implementation, and (2) expected costs if no changes were made to the pharmacy benefits. Expected costs were generated by applying autoregressive integrated moving averages to pharmacy costs over the previous 36 months. We used an interrupted time series analysis to assess drug use and adherence among individuals with diabetes, hypertension, or dyslipidemia compared with a group of members in plans that did not implement a VBF.  RESULTS: Pharmacy costs decreased by 3% compared with the 12 months prior and 11% compared with expected costs. There was no significant decline in medication use or adherence to treatments for patients with diabetes, hypertension, or dyslipidemia. CONCLUSIONS: The VBF and copayment changes enabled pharmacy plan cost savings without negatively affecting utilization in key disease states.

Inclusion of a competency-based curriculum in medical pharmacology.

Medical education programs have emphasized the acquisition of basic scientific knowledge and practical skills in well-defined subject areas using lecture and role modeling as the principle means of instruction. The need to address changes in the practice environment, the recognition that alternative instructional models may be desirable in some cases, and the fact that instruction in the traditional subject areas does not prepare students for all aspects of medical practice have driven recent curricular changes at many schools. Indiana University School of Medicine, with multiple instructional sites distributed throughout the state, has adopted a school-wide plan that specifies desired educational outcomes and provides an instrument for rating student achievement. In this report we describe the implementation of new media and pedagogical methods in a two-semester medical pharmacology course with the goal of fostering and assessing competency in the nine areas outlined in this educational plan. The general conclusion is that these changes not only furthered the broader educational goals of the competency-based curriculum, but also may exert a positive influence on student learning of discipline-specific material.