Changes in Erythropoiesis Stimulating Agent Use Under a Risk Evaluation and Mitigation Strategy (REMS) Program.

FDA on April 13 ended the risk evaluation and mitigation strategy (REMS) program for erythropoiesis-stimulating agents (ESAs), a decision that caught some longtime users of the program off-guard. At Ministry Saint Michael’s Hospital, part of Ascension in Stevens Point, Wisconsin, a nurse’s inability to look up a new prescriber’s registration information at the REMS program’s website was the first hint of change. “That’s when we noticed that the REMS program was no longer active,” said Brook DesRivieres, director of pharmacy at the 50-bed hospital. Known officially as the ESA APPRISE Oncology Program, the REMS program was approved in 2010 by FDA for two epoetin alfa products—Amgen’s Epogen and Janssen’s Procrit—and Amgen’s darbepoetin alfa product, Aranesp. The REMS plan was created to ensure that the benefits of the products exceed their risks when used as an alternative to red blood cell transfusion in cancer patients with anemia resulting from myelosuppressive therapy. The specific risks named in the REMS program were shortened overall survival time and an increased likelihood of tumor progression or recurrence in patients with cancer.

Purpose: Programs referred to as Risk Evaluation and Mitigation Strategies (REMS) have been implemented to assess the risk with drug and biologic therapies. Prescriber assessment of risks awareness with a medication can be done through third party web-based surveys in which the resultant data are analyzed in aggregate form to assess if the communication and education surrounding the REMS is meeting its goal. The purpose of this study is to provide prescriber data and outcome of the infliximab (IFX) REMS program at the 18-month assessment time period. Methods: The FDA may now require manufacturers like Centocor Ortho Biotech Inc. to implement a REMS (a strategy to manage a known or potential serious risk associated with a drug or biologic), if they determine that a REMS is necessary to ensure that the benefits of the drug or biological product outweigh the risks of the medication. The IFX REMS was required with the following goals outlined in the approved REMS: To communicate and mitigate the risks associated with IFX by: 1. Alerting and warning health care providers (HCPs) about cases of unrecognized histoplasmosis (Histo) and other invasive fungal infections associated with Tumor Necrosis Factor (TNF) blockers; and 2. Educating patients about the serious risks associated with IFX therapy. An individual medication's REMS program is unique to the product and may include one or more of the elements listed in the table below. Assessments of the REMS have time tables and at minimum must be submitted to FDA at 18 months, 3 years, and 7 years after approval of the strategy, with additional assessments as required by the FDA. Results: The IFX REMS includes a medication guide, communication plan and a timetable for assessments (18 months, 3 years and 7 years). The implementation of the IFX REMS communication plan consisting of a Dear Health Care Professional Letter (DHCPL) and Serious Infection Guide disseminated to >13,800 adult and pediatric gastroenterologists (GEs) combined and >356,000 other HCPs, including infusion centers has been executed. Medication Guides are included in each dispensed vial of IFX. Data presented will include the prescriber assessment findings for 415 IFX prescribers (gastroenterology subspecialty, n=211). Risk survey data indicate that nearly all prescribers surveyed were aware of re-activation of TB (97% [GEs n=211, 98%]) and of the development of Histo and other invasive fungal infections (91% [GEs n=96, 90%]) when questioned as to possible risks associated with taking IFX. Conclusion: REMS is an important tool that can be used by the FDA, HCPs and the pharmaceutical industry to improve medication safety and access to efficacious treatment options. The IFX 18-month assessment data indicate the IFX REMS is meeting its goals. Disclosure: JR McGowen: Employee, Centocor Ortho Biotech Services; L Brajdic: Employee, Centocor Ortho Biotech Services; B Sarokhan: Employee, Centocor Ortho Biotech Services; S Patel: Employee, Centocor Ortho Biotech Services. This research was supported by an industry grant from This study was sponsored by Centocor Ortho Biotech Services, LLC.Table: Elements of REMS

Macitentan: Endothelin receptor antagonist

The Food and Drug Administration Amendments Act of 2007 gave the FDA the authority to require drug sponsors to submit a risk evaluation and mitigation strategies (REMS) program for those medicines with serious risks such that failure to effectively manage these risks would tip the benefit-risk balance. As of August 8, 2013, the 34 distinct individual and shared REMS programs that have specific elements to assure safe use (ETASU) were reviewed to ascertain the types of risks managed, the goals of the REMS, and the tools that were employed targeting prescribers, health care facilities, pharmacists, and particular conditions for safe use. Most REMS (65%) have a combination of risk mitigation and educational goals, but 4 REMS programs (12%) have exclusively educational goals. Preventing fetotoxicity (25%) is the most common risk managed by REMS with ETASU. Seventy-nine percent of ETASU REMS employ prescriber-based tools that include performing laboratory testing (eg, pregnancy, hepatic enzymes) or monitoring (eg, ophthalmologic examinations, documenting vaccination). The goals of REMS programs should focus on measurable behaviors that directly reduce risk. The tools that are employed should create the appropriate conditions for safe use. With the number of programs and the plethora of tools applied, serious consideration should be given to better integration of risk management into health care and pharmacy systems that are best equipped to manage such risks.

The erythropoiesis-stimulating agents (ESAs) epoetin alfa (EA) and darbepoetin alfa (DA) have comparable efficacy in treating chemotherapy-induced anaemia (CIA). Therapy choice depends on many factors, including cost. Previous estimates of ESA cost differences have been derived from claims data. These data lack clinical variables, such as baseline haemoglobin (Hb) level, which are likely to influence choice of ESA, dosing and costs. We estimated cost differences between DA and EA in patients with cancer receiving chemotherapy, using a propensity-score matched analysis of baseline patient characteristics with and without Hb values to assess the effect of this clinical variable on ESA cost estimates. Data were extracted from electronic medical records in two US databases between January 2004 and December 2006. The study sample included 6743 patients receiving chemotherapy, with one or more visits during the study period, who received an ESA during a chemotherapy episode. Episodes of chemotherapy care were constructed using a 90-day gap in administration to identify the start and end. Patients receiving both DA and EA during their initial chemotherapy episode or with missing data were excluded, representing 42% of patients with CIA receiving an ESA. Drug costs were calculated from the cumulative dose multiplied by 106% of the average sales price (ASP) for DA or EA. Two propensity-score matches were conducted: first using variables available in administrative billing claims systems, then adding the baseline Hb test result. Regression-adjusted cost differences were estimated with and without baseline Hb, using generalized linear models. Using baseline Hb levels resulted in a better match of the baseline characteristics for the EA and DA treatment groups than the original sample or the matched sample without Hb variables. Mean ESA costs (year 2007 values) for the original sample were $US4171 for EA and $US3811 for DA (mean difference $US360; p < 0.001, standard error [SE] $US99). With propensity-score matching without Hb variables, mean estimated costs were $US3836 for EA and $US3599 for DA (mean difference $US237; p = 0.053, SE $US123). With propensity-score match including Hb variables, mean costs were $US3965 for EA and $US3536 for DA (mean difference $US429; p = 0.001, SE $US125). Cost differences in sensitivity analyses ranged between $US102 (p = 0.201) and $US261 (p = 0.003). Addition of baseline Hb level as a variable in propensity score and ESA cost models affects ESA treatment cost estimates in patients with cancer receiving chemotherapy. Cost comparisons based on observational data should use analytical methods that account for differences in clinical variables between treatment groups.

Background:Anemia of chronic kidney disease is associated with adverse outcomes and a reduced quality of life. Erythropoiesis-stimulating agents (ESAs) have improved anemia management, and 2 agents are available in Canada, epoetin alfa (EPO) and darbepoetin alfa (DA). EPO and DA are considered equally effective in achieving target hemoglobin (Hb), but it is not clear whether there is a cost difference. There have been few head-to-head comparisons; most published studies are observational switch studies.Objective:To compare the cost of DA and EPO and to determine the dose conversion ratio over a 12-month period.Design:Randomized controlled trial.Setting:Canadian outpatient hemodialysis center.Patients:Eligible patients were adult hemodialysis patients requiring ESA therapy.Measurements:The primary outcome was ESA cost (Can$) per patient over 12 months. Secondary outcomes included the dose conversion ratio, deviation from target ranges in anemia indices, iron dose and cost, and time and number of dose changes.Methods:An open-label randomized controlled trial of intravenous (IV) DA versus EPO was conducted in 50 hemodialysis patients. Participants underwent a minimum 6-week run-in phase followed by a 12-month active study phase. ESA and iron were dosed using a study algorithm.Results:The median cost was $4179 (interquartile range [IQR]: $2416-$5955) for EPO and $2303 (IQR: $1178-$4219) for DA with a difference of $1876 (P = .02). The dose conversion ratio was 280:1 (95% confidence interval [CI]: 197-362:1) at the end of the run-in phase, 360:1 (95% CI: 262-457:1) at the 3-month point of the active phase, and 382:1 (95% CI: 235-529:1) at the 6-month point of the active phase. There were no significant differences between the 2 groups in weekly iron dose, Hb, serum ferritin, or transferrin saturation. The number of dose changes and the time to Hb stability were similar.Limitations:Results may not be generalizable to hemodialysis units without algorithm-based anemia management, with subcutaneous ESA administration, or to the nondialysis chronic kidney disease population. The effective conversion ratio between EPO and DA is known to increase at higher doses; the Hb targets used in the study were slightly higher than those recommended today so it is possible that the doses used were also higher. Because of this, the cost savings estimated for DA could differ somewhat from the savings realizable in current practice.Conclusions:In this study of hemodialysis patients with comparable anemia management, IV DA cost $1876 less per year per patient than IV EPO. The dose conversion ratio was greater than 350:1 by the 3-month point.Trial registration:ClinicalTrials.gov (NCT02817555).

Successful Implementation of a Chimeric Antigen Receptor T-Cell Risk Evaluation and Mitigation Strategies (REMS) Program

Continuous erythropoiesis receptor activator (CERA) is a newer, longer acting ESA which might be preferred to other ESAs (epoetin or darbepoetin) based on its lower frequency of administration. Different dosing requirements and molecular characteristics of CERA compared with other ESAs may lead to different health outcomes (mortality, cardiovascular events, quality of life) in people with anaemia and chronic kidney disease (CKD). To assess benefits and harms of CERA compared with other epoetins (darbepoetin alfa and epoetin alfa or beta) or placebo/no treatment or CERA with differing strategy of administration for anaemia in individuals with CKD. We searched the Cochrane Kidney and Transplant Specialised Register to 13 June 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. We included randomised controlled trials (RCTs) of at least three months' duration, comparing CERA with a different ESA (darbepoetin alfa or epoetin alfa or beta) or placebo or standard care or versus CERA with different strategies for administration in people with any stage of CKD. Data were extracted by two independent investigators. We summarised patient-centred outcomes (all-cause and cardiovascular mortality, major adverse cardiovascular events, red cell blood transfusion, iron therapy, cancer, hypertension, seizures, dialysis vascular access thrombosis, drug injection-related events, hyperkalaemia and health-related quality of life and haemoglobin levels) using random effects meta-analysis. Treatment estimates were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean differences or standardized mean difference with 95% CI for continuous outcomes. We included 27 studies involving 5410 adults with CKD. Seven studies (1273 participants) involved people not requiring dialysis, 19 studies (4209 participants) involved people treated with dialysis and one study (71 participants) evaluated treatment in recipients of a kidney transplant. Treatment was given for 24 weeks on average. No data were available for children with CKD. Studies were generally at high or unclear risk of bias from allocation concealment and blinding of outcomes. Only two studies masked participants and investigators to treatment allocation. One study compared CERA with placebo, nine studies CERA with epoetin alfa or beta, nine studies CERA with darbepoetin alfa, and two studies compared CERA with epoetin alfa or beta and darbepoetin alfa. Three studies assessed the effects of differing frequencies of CERA administration and five assessed differing CERA doses.There was low certainty evidence that CERA had little or no effects on mortality (RR 1.07, 95% CI 0.73 to 1.57; RR 1.11, 95% CI 0.75 to 1.65), major adverse cardiovascular events (RR 5.09, 95% CI 0.25 to 105.23; RR 5.56, 95% CI 0.99 to 31.30), hypertension (RR 1.01, 95% CI 0.75 to 1.37; RR 1.00, 95% CI 0.79 to 1.28), need for blood transfusion (RR 1.02, 95% CI 0.72 to 1.46; RR 0.94, 95% CI 0.55 to 1.61), or additional iron therapy (RR 1.03, 95% CI 0.91 to 1.15; RR 0.99, 95% CI 0.95 to 1.03) compared to epoetin alfa/beta or darbepoetin alfa respectively. There was insufficient evidence to compare the effect of CERA to placebo on clinical outcomes. Only one low quality study reported that CERA compared to placebo might lead to little or no difference in the risk of major cardiovascular events (RR 2.97, 95% CI 0.31 to 28.18) and hypertension ((RR 0.73, 95% CI 0.35 to 1.52). There was low certainty evidence that different doses (higher versus lower) or frequency (twice versus once monthly) of CERA administration had little or no different effect on all-cause mortality (RR 3.95, 95% CI 0.17 to 91.61; RR 0.97, 95% CI 0.56 to 1.66), hypertension (RR 0.45, 95% CI 0.08 to 2.52; RR 0.85, 95% CI 0.60 to 1.21), and blood cell transfusions (RR 4.16, 95% CI 0.89 to 19.53; RR 0.91, 95% CI 0.51 to 1.62). No studies reported comparative treatment effects of different ESAs on health-related quality of life. There is low certainty evidence that CERA has little or no effects on patient-centred outcomes compared with placebo, epoetin alfa or beta or darbepoetin alfa for adults with CKD. The effects of CERA among children who have CKD have not studied in RCTs.

e19067 Background: The median survival for pts with LR-MDS is estimated to be 5–10 years. ESAs are utilized as first-line treatment for anemia in LR-MDS; however, real-world treatment patterns, clinical outcomes, and HCRU for pts with LR-MDS who reinitiated ESAs following previous discontinuation are not well-established. Methods: This was a retrospective study of pts with LR-MDS in a network of US community health systems who initiated ESAs as first-line therapy between January 1, 2016 and June 30, 2019 and were followed through June 30, 2021. Pts were required to have discontinued (had a ≥ 3-week gap between treatment with epoetin alfa, or a ≥ 6-week gap between treatment with darbepoetin alfa) and subsequently reinitiated ESA therapy at least once during follow-up. Outcomes included failure to achieve transfusion independence (TI), progression to acute myeloid leukemia (AML), overall survival (OS), number and type of health system visits, and medication use. TI was defined per IWG 2006 criteria in the subset of pts who had received ≥ 1 transfusion in the 8 weeks prior to ESA initiation. Results: There were 108 pts with confirmed LR-MDS who initiated ESA-based therapy. Pts had a median age of 79 years at diagnosis (interquartile range [IQR] 73–85), were predominantly male (58%), White (97%), and overweight or obese (52%). The median follow-up period was 17.0 months (IQR 7.2–34.7). The most used ESA was darbepoetin alfa (60%), followed by epoetin alfa (38%) and epoetin alfa-epbx (2%). Of the 33 pts who received a baseline transfusion, 52% did not achieve TI; 53% and 43% failed to achieve TI at 6 and 12 months, respectively. The majority of pts were repeatedly treated with ESAs (n = 61, 56%). Among these patients, 2% progressed to AML and 48% died during follow-up; median OS was 45 months. The median number of health system visits per patient-month was 3.2 (IQR 0.6–4.9); 89%, 62%, and 72% of pts had ≥ 1 outpatient, emergency department, or inpatient visit respectively, with median length of hospitalization of 12 days (IQR 4.8–27.8). Most pts (54%) received an antibiotic at least once during follow-up; overall, use of immunosuppressive therapy (2%) or iron chelation (3%) was rare. Conclusions: In this real-world study of community practice in the USA, reinitiation of ESA treatment after prior discontinuation in LR-MDS was prevalent. In these pts, poor clinical outcomes and frequent health system visits were observed. This study highlights the need to consider alternative treatment options for pts with LR-MDS.

A recent U.S. Food and Drug Administration (FDA) alert has raised further concerns about potential adverse effects of erythropoiesis-stimulating agents (ESAs) in anemic cancer patients who are not receiving chemotherapy [1]. The warning was issued following interim analysis of an investigator-led phase III trial of 989 patients with head and neck cancers randomized to receive darbepoetin alfa (Aranesp; Amgen, Thousand Oaks, CA) or placebo (Danish Head and Neck Cancer Group [DAHANCA] 10 study, http://www. dahanca.dk). The enrolled patients were anemic but were not receiving chemotherapy. The trial data showed that darbepoetin alfa was associated with a higher mortality than with placebo (hazard ratio, 1.25; confidence interval [CI], 1.04–1.51) and, furthermore, darbepoetin alfa did not reduce the need for blood transfusion [2]. Hard on the heels of the darbepoetin alfa alert, Roche announced that it had temporarily suspended recruitment into its phase II dose-finding study with Continuous Erythropoietin Receptor Activator (CERA) in anemic patients with advanced nonsmall lung cell cancer (NSCLC) receiving chemotherapy [3]. Very recently, an unplanned safety analysis resulted in closure of a randomized placebo-controlled trial of epoetin alfa in NSCLC patients with disease-related anemia [4]. This analysis suggested poorer overall survival in patients with NSCLC treated with erythropoietin (Epo) [4]. Anemia in cancer patients has a multifactorial etiology. Anemia may develop secondary to impaired production of Epo or a blunted response of erythroid precursors to Epo [5]. Anemia may be exacerbated by chronic blood loss from tumor sites or be secondary to chemotherapy and radiotherapy. Debilitating fatigue, if it is secondary to anemia, can be managed by blood transfusions or ESAs to improve the quality of life (QOL) for anemic cancer patients. Interestingly, the effect of Epo therapy on QOL as a prospective outcome is not entirely consistent [6, 7]. Darbepoetin alfa is a hyperglycosylated Epo analog with an extended serum half-life [8] compared with available recombinant human Epos (epoetin alfa [Procrit, Ortho Biotech, Bridgewater, NJ; Epogen, Amgen; or Eprex, Janssen-Cilag Ltd, High Wycombe, U.K.] and epoetin beta [NeoRecormon, Roche, Basel, Switzerland]). CERA incorporates methoxy-polyethylene glycol polymers, which increase its mass to 60 kDa, twice that of Epo, and substantially prolong its half-life to about 135 hours. Darbepoetin alfa and CERA therefore have the therapeutic advantage of requiring less frequent administration for anemia management. Previous reports have suggested that ESA therapy may be harmful to some groups of cancer patients. Henke and colleagues [9] described the outcome of epoetin beta treatment in a randomized trial of 351 anemic head and neck cancer patients undergoing radiotherapy. The therapeutic goal was normalization of hemoglobin to 14 g/dl in men and 13 g/dl in women. Unexpectedly, locoregional progression-free survival was worse in the Epo treatment arm compared with placebo. In the same year, another random-

White paper on designing a risk evaluation and mitigation strategies (REMS) system to optimize the balance of patient access, medication safety, and impact on the health care system

Erythropoiesis-stimulating agents (ESAs), indicated for treating some patients with chemotherapy-induced anemia (CIA), may increase the risk of tumor progression and mortality. FDA required a Risk Evaluation and Mitigation Strategy (REMS) to mitigate these risks. We assessed REMS impact on ESA administration and red blood cell (RBC) transfusion as surrogate metrics for REMS effectiveness. Retrospective cohort study including data from January 1, 2006 to December 31, 2018 for beneficiaries ≥65 years enrolled in Centers for Medicare & Medicaid Services (CMS) Medicare Parts A/B with a cancer diagnosis; patients with other indications for ESA use were excluded. Study time was divided into five periods demarcated by issuance of CMS National Coverage Determination (NCD) (Pre-NCD, Pre-REMS) and REMS milestones (Grace Period, REMS, post-REMS). Study outcomes were monthly proportion of chemotherapy episodes (CTEs) with concomitant ESA administration, with post-CTE ESA administration, and with RBC transfusions. Of 1 778 855 beneficiaries treated with CT, 308742 received concomitant ESA for CIA. The proportion of CTEs with concomitant and post-CTE ESA administration decreased Pre-REMS (9.0 percentage points [pp] and 3.5 pp, respectively). There were no significant post-REMS changes in the proportion of CTEs with concomitant (0.0 pp) and post-CTE ESA administration (0.1 pp). Fluctuation in RBC transfusions was <4 pp throughout the study period. Medicare beneficiaries showed a substantive decrease in ESA administration after NCD, with minimal impact by the REMS and its removal. Small changes in RBC transfusion over the study period were likely due to a national secular trend.

The present meta-analysis was undertaken to (1) assess erythroid response rates in myelodysplastic syndromes (MDS) patients treated with epoetin alfa as a monotherapy, (2) gain further insights into predictors of response rates, and (3) compare the erythroid response rates observed with epoetin alfa and darbepoetin alfa. A systematic review of studies from 1990 to 2006 in MDS patients treated with epoetin alfa or darbepoetin alfa was performed and yielded 30 studies evaluating a total of 1,314 patients (epoetin alfa: 22 studies, 925 patients; darbepoetin alfa: eight studies, 389 patients). Pooled estimates of erythroid response rates, stratified by the International Working Group criteria (IWGc) and treatment group, were calculated using random-effects meta-analysis methods. Univariate meta-regression analyses were further conducted to identify study characteristics associated with erythroid response rate. The pooled estimate of erythroid response rate was significantly higher for epoetin alfa IWGc studies (57.6%) as compared to non-IWGc studies (31.6%; p < 0.001). Study factors predictive of higher response rate in the epoetin alfa IWGc studies included higher proportion of patients with RA/RARS (p < 0.001), lower mean baseline serum erythropoietin level (p = 0.007), and fixed dosing regimen (p < 0.001). There was no significant difference in the pooled erythroid response rates between the two agents (epoetin alfa: 57.6% vs. darbepoetin alfa: 59.4%; p = 0.828). The current study reported significantly higher erythroid response rates predominantly in the more recent studies that primarily utilized IWGc to define response. With the use of standardized patient selection and response evaluation methods, epoetin alfa and darbepoetin alfa yielded comparable erythroid response rates in MDS patients.

Anemia is a frequent complication of chronic kidney disease (CKD) due to the inability of the kidneys to release sufficient erythropoietin to regulate the production of red blood cells. Administration of erythropoiesis-stimulating agents (ESAs) is highly effective in correcting anemia of CKD. The ESAs currently approved in Italy are epoetin alfa, epoetin beta, epoetin theta, darbepoetin alfa, CERA and biosimilars epoetin alfa and epoetin zeta. All the ESAs are effective in correcting renal anemia and increasing hemoglobin levels, but the choice of which to use should also take into account their pharmacokinetics and pharmacodynamics, their administration route, and economic issues. However, regarding the optimal use of ESAs an issue that remains controversial is the most appropriate dose conversion between epoetin alfa and darbepoetin alfa. In fact clinical experience demonstrates that the dose relationship between epoetin alfa and darbepoetin alfa is non proportional across the dosing spectrum. In this review is presented an update on the latest available evidence in the treatment of anemia in CKD patients, with particular reference to the definition of the correct conversion ratio EPO:DARB.

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