Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada.

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%-40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. IMPLICATIONS FOR PRACTICE: We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing "rebate traps" where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

Relationships Between Social/Emotional Support and Quality of Life, Depression and Disability in Patients With Chronic Obstructive Pulmonary Disease: An Analysis Based on Propensity Score Matching.

BACKGROUND: Patients with chronic obstructive pulmonary diseases (COPD) suffer from impaired Health-Related Quality of Life (HRQoL). Having an adequate social/emotional support may improve the quality of life of COPD patients. OBJECTIVE: To study the relationships between social/emotional support and HRQoL, depression and disability among patients with COPD. METHODS: We applied a propensity score model using data from a large U.S. population-based health survey to match COPD patients who reported rarely/never receiving social/emotional support with those who received that support. Social/emotional support and all dependent variables were dichotomized into yes/no responses. For HRQoL domains, number of days of poor physical or mental health and activity limitations, "yes" indicated ≥14 unhealthy days in the last 30 days. McNemar's test was used to compare the matched groups. RESULTS: Social/emotional support was rarely/never received by 37% of responders. Standardized differences between matched groups, after propensity score matching, were less than 10% indicating successful matching. COPD patients who rarely/never receive social/emotional support were more likely to report: depression (n = 321 pairs, odds ratio (OR) = 2.2, 95% confidence interval (CI): 1.56-3.14, p < .001), ≥14 poor mental HRQoL days (n = 310 pairs, OR = 3.12, 95% CI: 2.1-4.73, p < .001) and ≥14 poor physical HRQoL days (n = 307 pairs, OR = 1.5, 95% CI: 1.06-2.13, p = .02). There were no significant differences in general health, disability, or activity limitations. CONCLUSION: Among COPD patients, lower levels of social/emotional support are associated with depression and deterioration of mental and physical HRQoL. The importance of social/emotional support should be emphasized by policy makers, healthcare providers, and family members, to improve functioning among COPD patients.

The impact of a theory-based web-intervention on the intention to use prescription drugs for non-medical purposes among college students: a randomized controlled trial.

The non-medical use of prescription drugs (NMUPD) among college students is escalating at an alarming rate. A limited number of studies have utilized a theoretical framework to influence this behavior. To utilize the reasoned-action approach theory to design and evaluate a web-based intervention to influence students' attitudes, perceived norms (PNs), perceived behavioral control (PBC) and intentions toward NMUPD. Using a two-group post-test only controlled trial, students were randomized to view either a general health website or a web-based intervention focused on NMUPD. The intervention was presented in multiple sections to address each component of the reasoned-action approach. Subsequently, respondents completed a web-survey. Independent t-tests were used to compare responses between the two groups. Of 391 respondents, 112 (28.9%) students indicated previous NMUPD. The intervention group had significantly (P = 0.04) more negative attitudes toward NMUPD. No significant differences were found in PNs (P = 0.11), PBC (P = 0.68) or intentions to NMUPD (P = 0.97). The intervention was successful in changing attitudes toward NMUPD. Targeting the intervention toward college students regardless of previous experiences of NMUPD might have led to insufficiency of the intervention to influence intentions. Additional research is needed to improve the intervention dissemination and utilization.

Dietary Intake Among Opioid- and Alcohol-Using Pregnant Women.

BACKGROUND: Substance abuse in nonpregnant adults has been associated with increased intake in calories and decreased intake of nutrient-dense foods; however, studies examining dietary intake in opioid-using and alcohol-using pregnant women are lacking. OBJECTIVE: The objective of this study was to evaluate dietary intake in opioid-using pregnant women with or without concurrent light-to-moderate alcohol use as compared to abstaining controls. METHODS: This prospective birth cohort included 102 pregnant women classified into four study groups: controls (n = 27), medication-assisted treatment (MAT; n = 26), alcohol (ALC; n = 22), and concurrent use of both substances (MAT + ALC; n = 27). Percentage differences in macro- and micronutrient intake were estimated from the food frequency questionnaire and compared among the study groups. Proportions of participants with intakes below the estimated average requirements (EAR) based on diet and diet with supplements were estimated. RESULTS: Three exposed groups had lower prevalence of multivitamin use in periconceptional period (11.5-31.8%) than controls (44.4%). Unadjusted mean energy intake was significantly higher in the MAT + ALC group compared to controls, while micronutrient intake per 1000 kcal was the highest in the control group for almost all of the micronutrients analyzed. After adjustment for energy intake and sociodemographic characteristics, MAT group had lower estimated dietary intake of iron (-15.0%, p = 0.04) and folate (-16.8%, p = 0.04) compared to controls. A high proportion of participants in all study groups had dietary intake below the EAR for vitamin E, iron, and folate. CONCLUSION: Results highlight the need for targeted dietary interventions for opioid-using pregnant women.

Generic oncology drugs: are they all safe?

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.

Assessing the Quality of Economic Evaluations of FDA Novel Drug Approvals: A Systematic Review.

OBJECTIVE: To systematically review and assess the quality of the novel drugs' economic evaluation literature in print during the drugs' early commercial availability following US regulatory approval. DATA SOURCES: MEDLINE and the United Kingdom National Health Service Economic Evaluation Database were searched from 1946 through December 2011 for economic evaluations of the 50 novel drugs approved by the FDA in 2008 and 2009. STUDY SELECTION AND DATA EXTRACTION: The inclusion criteria were English-language, peer-reviewed, original economic evaluations (cost-utility, cost-effectiveness, cost-minimization, and cost-benefit analyses). We extracted and analyzed data from 36 articles considering 19 of the 50 drugs. Two reviewers assessed each publication's quality using the Quality of Health Economic Studies (QHES) instrument and summarized study quality on a 100-point scale. DATA SYNTHESIS: Study quality had a mean of 70.0 ± 16.2 QHES points. The only study characteristics associated with QHES score (with P < 0.05) were having used modeling or advanced statistics, 75.1 versus 61.9 without; using quality-adjusted life years as an outcome, 75.9 versus 64.7 without; and cost-utility versus cost-minimization analysis, 75.9 versus 58.7. Studies most often satisfied quality aspects about stating study design choices and least often satisfied aspects about justifying design choices. CONCLUSION: The reviewed literature considered a minority of the 2008-2009 novel drugs and had mixed study quality. Cost-effectiveness stakeholders might benefit from efforts to improve the quality and quantity of literature examining novel drugs. Editors and reviewers may support quality improvement by stringently imposing economic evaluation guidelines about justifying study design choices.

Improving the effectiveness of pharmacist-assisted tobacco cessation: a study of participant- and pharmacy-specific differences in quit rates.

BACKGROUND: The New Mexico Pharmaceutical Care Foundation provided a pharmacist-assisted tobacco cessation program from 2004 to 2010. In evaluating the program, discrepant 6-month quit rates were observed between pharmacies. OBJECTIVE: To identify participant- and pharmacy-specific factors associated with improved quit rates. METHODS: To supplement data regarding participant characteristics and quit rates, semistructured interviews of 7 participating pharmacists were conducted. Multivariate logistic regression quantified associations between successful abstinence at 6 months and participant characteristics and pharmacy-specific factors. RESULTS: Quit rates by pharmacy ranged from 1.1% to 59.4% (mean = 19.1%). There were 1235 participants enrolled at 7 pharmacies, and because of missing participant data, 883 were included in the quantitative analysis. Three pharmacy-specific characteristics distinguished 6-month success rates: number and duration of follow-ups and format of counseling sessions. Participants followed up at least 3 times were more likely to quit at 6 months than those contacted once or twice (odds ratio [OR] =4.9; 95% CI = 1.6-15.0). Compared with follow-ups of <15 minutes, longer durations of follow-ups were associated with higher success rates: 15 to 30 minutes, OR = 7.2, 95% CI = 3.7-14.3); >30 minutes, OR = 10.0, 95% CI = 3.5-28.9. Participants who attended group sessions were more likely to quit at 6 months than those who attended individual sessions: OR = 8.2; 95% CI = 2.8-23.9. Most pharmacists (88%) noted that participants' high or low commitment to quit was associated with success or failure, respectively. Several pharmacists (43%) noted difficulties with follow-up associated with participants' relapse. Time constraints were an obstacle noted by 70% of pharmacists. CONCLUSIONS: Pharmacy-specific factors, including counseling format and program intensity, affected success.

Regulatory and clinical considerations for biosimilar oncology drugs.

Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents-molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs-provide opportunities both to improve health-care access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns.

Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project.

BACKGROUND: Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate that was approved in 2011 for the treatment of patients with anaplastic large cell and Hodgkin lymphomas. The product label indicates that 3 patients who were treated with BV developed progressive multifocal leukoencephalopathy (PML), a frequently fatal JC virus-induced central nervous system infection. Prior immunosuppressive therapy and compromised immune systems were postulated risk factors. In the current study, the authors reported 5 patients who developed BV-associated PML, including 2 immunocompetent patients. METHODS: Case information was obtained from clinicians (4 patients) or a US Food and Drug Administration database (1 patient). RESULTS: All 5 patients had lymphoid malignancies. Two patients with cutaneous T-cell lymphomas had not previously received chemotherapy. PML developed after a median of 3 BV doses (range, 2 doses-6 doses) and within a median of 7 weeks after BV initiation (range, 3 weeks-34 weeks). Presenting findings included aphasia, dysarthria, confusion, hemiparesis, and gait dysfunction; JC virus in the cerebrospinal fluid (2 patients) or central nervous system biopsy (3 patients); and brain magnetic resonance imaging scans with white matter abnormalities (5 patients). Four patients died at a median of 8 weeks (range, 6 weeks-16 weeks) after PML diagnosis. The sole survivor developed immune reconstitution inflammatory syndrome. CONCLUSIONS: PML can develop after a few BV doses and within weeks of BV initiation. Clinicians should be aware of this syndrome, particularly when neurologic changes develop after the initiation of BV treatment. The decision to administer BV to patients with indolent cutaneous lymphomas should be based on consideration of risk-benefit profiles and of alternative options.

Life-threatening dermatologic adverse events in oncology.

The incidences of life-threatening toxicities such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are inconsistently reported. The potential association of anticancer agents with SJS or TEN has not been systematically investigated. We searched the literature (Ovid: 1950 to June 2013 and PubMed: 1948 to June 2013) using terms for SJS/TEN and anticancer therapies. Primary case reports, case series, and clinical trials were included. In addition, MedWatch, the Food and Drug Administration Adverse Event Reporting System (FAERS), was searched (1968 to August 2012) for SJS/TEN reports associated with anticancer therapies. Proportional reporting ratios (PRR>2, N>3), empirical Bayes geometric mean (EBGM>2, N>3), and lower 95% confidence interval (EBGM0.05>2) were used as thresholds to constitute a signal of association between SJS/TEN and anticancer drugs. There were 46 SJS and 37 TEN cases associated with 18 and 22 anticancer drugs in the literature, respectively. Among cases in the FAERS, significant signals were associated with SJS for bendamustine and with TEN for bendamustine, busulfan, chlorambucil, fludarabine, lomustine, and procarbazine. Several drugs reported in the published literature to be associated with SJS/TEN were not found to have significant signals in FAERS. Proactive pharmacovigilance to detect and define safety signals serves to aid oncology practitioners in the recognition of possible, yet uncommon, serious, and/or life-threatening skin reactions.

Pediatric nephrogenic systemic fibrosis is rarely reported: a RADAR report.

BACKGROUND: Nephrogenic systemic fibrosis is a fibrosing disorder associated with exposure to gadolinium-based contrast agents in people with severely compromised renal function. OBJECTIVE: The purpose of this study was to determine the reported number of cases of nephrogenic systemic fibrosis in children using three distinct publicly available data sources. MATERIALS AND METHODS: We conducted systematic searches of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), the International Center for Nephrogenic Systemic Fibrosis Research (ICNSFR) registry and published literature from January 1997 through September 2012. We contacted authors of individual published cases to obtain follow-up data. Data sets were cross-referenced to eliminate duplicate reporting. RESULTS: We identified 23 children with nephrogenic systemic fibrosis. Seventeen had documented exposure to gadolinium-based contrast agents. Six children had been reported in both the FAERS and the literature, four in the FAERS and the ICNSFR registry and five in all three data sources. CONCLUSION: Nephrogenic systemic fibrosis has been rarely reported in children. Although rules related to confidentiality limit the ability to reconcile reports, active pharmaco-vigilance using RADAR (Research on Adverse Drug events And Reports) methodology helped in establishing the number of individual pediatric cases within the three major data sources.

The effect of oxandrolone on the healing of chronic pressure ulcers in persons with spinal cord injury: a randomized trial.

BACKGROUND: Anabolic steroids have been reported to improve wound healing. OBJECTIVE: To determine whether oxandrolone increases the percentage of target pressure ulcers (TPUs) that heal compared with placebo and whether healed ulcers remain closed 8 weeks after treatment. DESIGN: Parallel-group, placebo-controlled, randomized trial conducted from 1 August 2005 to 30 November 2008. Patients, clinical care providers, study personnel, and statisticians were blinded to treatment assignment. (ClinicalTrials.gov: NCT00101361). SETTING: 16 inpatient spinal cord injury (SCI) services at Veterans Affairs medical centers. PATIENTS: 1900 prescreened, 779 screened, and 212 randomly assigned inpatients with SCI and stage III or IV TPUs. INTERVENTION: Oxandrolone, 20 mg/d (n = 108), or placebo (n = 104) until the TPU healed or 24 weeks. MEASUREMENTS: The primary outcome was healed TPUs. The secondary outcome was the percentage of TPUs that remained healed at 8-week follow-up. RESULTS: 24.1% (95% CI, 16.0% to 32.1%) of TPUs in oxandrolone recipients and 29.8% (CI, 21.0% to 38.6%) in placebo recipients healed (difference, -5.7 percentage points [CI, -17.5 to 6.8 percentage points]; P = 0.40). At 8-week follow-up, 16.7% (CI, 9.6% to 23.7%) of oxandrolone recipients and 15.4% (CI, 8.5% to 22.3%) of placebo recipients retained a healed TPU (difference, 1.3 percentage points [CI, -8.8 to 11.2 percentage points]; P = 0.70). No serious adverse events were related to oxandrolone. Liver enzyme levels were elevated in 32.4% (CI, 23.6% to 41.2%) of oxandrolone recipients and 2.9% (CI, 0.0% to 6.1%) of placebo recipients (P < 0.001). LIMITATIONS: Selection of severe wounds may have reduced treatment response. Approximately one third of patients did not complete the study in the treatment and placebo groups. The study was terminated after a futility analysis showed a low probability of detecting a significant difference between the groups. CONCLUSION: Oxandrolone showed no benefit over placebo for improving healing or the percentage of TPUs that remained closed after 8 weeks of treatment. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

The feasibility and cost of neonatal screening for prenatal alcohol exposure by measuring phosphatidylethanol in dried blood spots.

BACKGROUND: Accurate confirmation of prenatal alcohol exposure (PAE) is required as a diagnostic criterion for the majority of children adversely affected by PAE who do not manifest the physical features associated with fetal alcohol syndrome. A number of ethanol biomarkers have been used to assess PAE, often with suboptimal results. The purpose of this study was to evaluate the feasibility and cost of PAE screening in newborns by measuring phosphatidylethanol (PEth) in dried blood spot (DBS) cards. METHODS: The feasibility of collecting an additional DBS card during routine newborn screening and the background prevalence of PAE were evaluated in a de-identified sample of newborn children delivered at the University of New Mexico Hospital. Electronic orders to collect DBS cards from newborns who continue to bleed after the routine newborn screen, glucose, or hematocrit testing were initiated for all infants delivered during a 4-week time frame. Specimens were sent to a contract laboratory for PEth analysis by liquid chromatography-tandem mass spectrometry. A cost analysis was conducted to compare the cost of PAE screening by PEth in DBS versus PEth in conventional blood specimens and by meconium fatty acid ethyl esters. RESULTS: From 230 collected cards, 201 (87.4%) had at least 1 full blood spot (amount sufficient for PEth analysis), and 6.5% had PEth >20 ng/ml indicative of potential PAE in late pregnancy. PAE screening by PEth in DBS is logistically simpler and less expensive compared with 2 other screening approaches. CONCLUSIONS: These results indicate that screening for PAE in DBS cards is a feasible procedure and that a majority of infants have enough blood after the routine heel prick to fill an additional card. Moreover, screening by PEth analysis from DBS cards is cost-efficient. The acceptability of such screening by parents and corresponding ethical issues remain to be investigated.

Use of number needed to treat in cost-effectiveness analyses.

OBJECTIVE: To review the use of number needed to treat (NNT) and/or number needed to harm (NNH) values to determine their relevance in helping clinicians evaluate cost-effectiveness analyses (CEAs). DATA SOURCES: PubMed and EconLit were searched from 1966 to September 2012. STUDY SELECTION AND DATA EXTRACTION: Reviews, editorials, non-English-language articles, and articles that did not report NNT/NNH or cost-effectiveness ratios were excluded. CEA studies reporting cost per life-year gained, per quality-adjusted life-year (QALY), or other cost per effectiveness measure were included. Full texts of all included articles were reviewed for study information, including type of journal, impact factor of the journal, focus of study, data source, publication year, how NNT/NNH values were reported, and outcome measures. DATA SYNTHESIS: A total of 188 studies were initially identified, with 69 meeting our inclusion criteria. Most were published in clinician-practice-focused journals (78.3%) while 5.8% were in policy-focused journals, and 15.9% in health-economics-focused journals. The majority (72.4%) of the articles were published in high-impact journals (impact factor >3.0). Many articles focused on either disease treatment (40.5%) or disease prevention (40.5%). Forty-eight percent reported NNT as a part of the CEA ratio per event. Most (53.6%) articles used data from literature reviews, while 24.6% used data from randomized clinical trials, and 20.3% used data from observational studies. In addition, 10% of the studies implemented modeling to perform CEA. CONCLUSIONS: CEA studies sometimes include NNT ratios. Although it has several limitations, clinicians often use NNT for decision-making, so including NNT information alongside CEA findings may help clinicians better understand and apply CEA results. Further research is needed to assess how NNT/NNH might meaningfully be incorporated into CEA publications.

Medication adherence assessment in a clinical trial with centralized follow-up and direct-to-patient drug shipments.

BACKGROUND: Assessment of adherence to study medications is a common challenge in clinical research. Counting unused study medication is the predominant method by which adherence is assessed in outpatient clinical trials but it has limitations that include questionable validity and burdens on research personnel. PURPOSE: To compare capsule counts, patient questionnaire responses, and plasma drug levels as methods of determining adherence in a clinical trial that had 2056 participants and used centralized drug distribution and patient follow-up. METHODS: Capsule counts from study medication bottles returned by participants and responses to questions regarding adherence during quarterly telephone interviews were averaged and compared. Both measures were compared to plasma drug levels obtained at the 3-month study visit of patients in the treatment group. Counts and questionnaire responses were converted to adherence rates (doses taken divided by days elapsed) and were categorized by stringent (≥85.7%) and liberal (≥71.4%) definitions. We calculated the prevalence-adjusted bias-adjusted kappa to assess agreement between the two measures. RESULTS: Using a pre-paid mailer, participants returned 76.0% of study medication bottles to the central pharmacy. Both capsule counts and questionnaire responses were available for 65.8% of participants and were used to assess adherence. Capsule counts identified more patients who were under-adherent (18.8% by the stringent definition and 7.5% by the liberal definition) than self-reports did (10.4% by the stringent definition and 2.1% by the liberal definition). The prevalence-adjusted bias-adjusted kappa was 0.58 (stringent) and 0.83 (liberal), indicating fair and very good agreement, respectively. Both measures were also in agreement with plasma drug levels determined at the 3-month visit (capsule counts: p = 0.005 for the stringent and p = 0.003 for the liberal definition; questionnaire: p = 0.002 for both adherence definitions). LIMITATIONS: Inconsistent bottle returns and incomplete notations of medication start and stop dates resulted in missing data but exploratory missing data analyses showed no reason to believe that the missing data resulted in systematic bias. CONCLUSIONS: Depending upon the definition of adherence, there was fair to very good agreement between questionnaire results and capsule counts among returned study bottles, confirmed by plasma drug levels. We conclude that a self-report of medication adherence is potentially comparable to capsule counts as a method of assessing adherence in a clinical trial, if a relatively low adherence threshold is acceptable, but adherence should be confirmed by other measures if a high adherence threshold is required.

A review of safety, efficacy, and utilization of erythropoietin, darbepoetin, and peginesatide for patients with cancer or chronic kidney disease: a report from the Southern Network on Adverse Reactions (SONAR).

The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin prevent transfusions among chemotherapy-associated anemia patients. Clinical trials, meta-analyses, and guidelines identify mortality, tumor progression, and venous thromboembolism (VTE) risks with ESA administration in this setting. Product labels advise against administering ESAs with potentially curative chemotherapy (United States) or to conduct risk-benefit assessments (Europe/Canada). Since 2007, fewer chemotherapy-associated anemia patients in the United States and Europe receive ESAs. ESAs and the erythropoietin receptor agonist peginesatide prevent transfusions among chronic kidney disease (CKD) patients; clinical trials, guidelines, and meta-analyses demonstrate myocardial infarction, stroke, VTE, or mortality risks with ESAs targeting high hemoglobin levels. U.S. labels recommend administering ESAs or peginesatide at doses sufficient to prevent transfusions among dialysis CKD patients. For dialysis CKD patients, Canadian and European labels recommend targeting hemoglobin levels of 10 to 12 g/dL and 11 to 12 g/dL, respectively, with ESAs. ESA utilization for dialysis CKD patients has decreased in the United States.

Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: a 20-year review from the Southern Network on Adverse Reactions (SONAR).

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

Baseline comparison of three health utility measures and the feeling thermometer among participants in the Action to Control Cardiovascular Risk in Diabetes trial.

BACKGROUND: Health utility (HU) measures are used as overall measures of quality of life and to determine quality adjusted life years (QALYs) in economic analyses. We compared baseline values of three HUs including Short Form 6 Dimensions (SF-6D), and Health Utilities Index, Mark II and Mark III (HUI2 and HUI3) and the feeling thermometer (FT) among type 2 diabetes participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. We assessed relationships between HU and FT values and patient demographics and clinical variables. METHODS: ACCORD was a randomized clinical trial to test if intensive controls of glucose, blood pressure and lipids can reduce the risk of major cardiovascular disease (CVD) events in type 2 diabetes patients with high risk of CVD. The health-related quality of life (HRQOL) sub-study includes 2,053 randomly selected participants. Interclass correlations (ICCs) and agreement between measures by quartile were used to evaluate relationships between HU's and the FT. Multivariable regression models specified relationships between patient variables and each HU and the FT. RESULTS: The ICCs were 0.245 for FT/SF-6D, 0.313 for HUI3/SF-6D, 0.437 for HUI2/SF-6D, 0.338 for FT/HUI2, 0.337 for FT/HUI3 and 0.751 for HUI2/HUI3 (P < 0.001 for all). Common classification by quartile was found for the majority (62%) of values between HUI2 and HUI3, which was significantly (P < 0.001) higher than between other HUs and the FT: SF-6D/HUI3 = 40.8%, SF-6D/HUI2 = 40.9%, FT/HUI3 = 35.0%, FT/HUI2 = 34.9%, and FT/SF-6D = 31.9%. Common classification was higher between SF-6D/HUI2 and SF-6D/HUI3 (P < 0.001) than between FT/SF-6D, FT/HUI2, and FT/HUI3. The mean difference in HU values per patient ranged from -0.024 ± 0.225 for SF-6D/ HUI3 to -0.124 ± 0.133 for SF-6D/HUI2. Regression models were significant; clinical and demographic variables explained 6.1% (SF-6D) to 7.7% (HUI3) of the variance in HUs. CONCLUSIONS: The agreements between the different HUs were poor except for the two HUI measures; therefore HU values derived different measures may not be comparable. The FT had low agreement with HUs. The relationships between HUs and demographic and clinical measures demonstrate how severity of diabetes and other clinical and demographic factors are associated with HUs and FT measures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00000620.

Comparisons of Food and Drug Administration and European Medicines Agency risk management implementation for recent pharmaceutical approvals: report of the International Society for Pharmacoeconomics and outcomes research risk benefit management working group.

OBJECTIVE: 1) To compare the Food and Drug Administration's (FDA's) Risk Evaluation and Mitigation Strategies (REMS) and European Medicines Agency's (EMA's) Risk Management Plan (RMP) guidances and 2) to compare REMS and RMPs for specific chemical entities and biological products. METHODS: FDA, EMA, and pharmaceutical company Web sites were consulted for details pertaining to REMS and RMPs. REMS requirements include medication guides, communication plans, elements to ensure safe use, implementation systems, and specified assessment intervals. RMP requirements are increased pharmacovigilance and risk minimization activities. We compared these requirements for drugs requiring both REMS and RMPs. RESULTS: We identified 95 drugs on FDA's REMS list as of March 2010. Of these, there were 29 drugs (11 biologics and 18 new chemical entities) with EMA RMPs. REMS and RMPs are similar in objectives, with comparable toolkits. Both allow flexibility in product-specific actions, recognizing adverse effects of potential concern. Of the 29 drugs reviewed, REMS requirements not included in RMPs were patient medication guides (100% of the drugs), provider communication plans (38%), and routine monitoring of REMS (66%). RMP requirements not included in REMS were specific adverse event reporting (45% of the drugs), prospective registry studies (34%), prospective epidemiology studies (24%), additional trial data (28%), and Summary of Product Characteristics contraindications (76%). CONCLUSIONS: Both REMS and RMPs provide positive guidance for identification, monitoring, and minimization of risk to patient safety. Currently, neither agency provides specific guidance on how risk should be related to benefit either qualitatively or quantitatively.