Dennis W. Raisch

Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project

Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.

Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia

CONTEXT The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs. OBJECTIVE To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer. DATA SOURCES A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008). STUDY SELECTION Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer. DATA EXTRACTION Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE. DATA SYNTHESIS Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20). CONCLUSIONS Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.

A Review of Quantitative Risk–Benefit Methodologies for Assessing Drug Safety and Efficacy—Report of the ISPOR Risk–Benefit Management Working Group

OBJECTIVE Although regulatory authorities evaluate the risks and benefits of any new drug therapy during the new drug-approval process, quantitative risk-benefit assessment (RBA) is not typically performed, nor is it presented in a consistent and integrated framework when it is used. Our purpose is to identify and describe published quantitative RBA methods for pharmaceuticals. METHODS Using MEDLINE and other Internet-based search engines, a systematic literature review was performed to identify quantitative methodologies for RBA. These distinct RBA approaches were summarized to highlight the implications of their differences for the pharmaceutical industry and regulatory agencies. RESULTS Theoretical models, parameters, and key features were reviewed and compared for the 12 quantitative RBA methods identified in the literature, including the Quantitative Framework for Risk and Benefit Assessment, benefit-less-risk analysis, the quality-adjusted time without symptoms and toxicity, number needed to treat (NNT), and number needed to harm and their relative-value-adjusted versions, minimum clinical efficacy, incremental net health benefit, the risk-benefit plane (RBP), the probabilistic simulation method, multicriteria decision analysis (MCDA), the risk-benefit contour (RBC), and the stated preference method (SPM). Whereas some approaches (e.g., NNT) rely on subjective weighting schemes or nonstatistical assessments, other methods (e.g., RBP, MCDA, RBC, and SPM) assess joint distributions of benefit and risk. CONCLUSIONS Several quantitative RBA methods are available that could be used to help lessen concern over subjective drug assessments and to help guide authorities toward more objective and transparent decision-making. When evaluating a new drug therapy, we recommend the use of multiple RBA approaches across different therapeutic indications and treatment populations in order to bound the risk-benefit profile.

Epoetin-associated pure red cell aplasia: past, present, and future considerations.

BACKGROUND: Since 1988, millions of patients have received epoetin products intravenously (IV) and subcutaneously. In 1998, epoetin‐associated pure red cell aplasia (PRCA) was first reported and causation was attributed to formulations without human serum albumin (HSA), subcutaneous administration, and uncoated rubber stoppers.

Pharmacovigilance and reporting oversight in US FDA fast- track process: bisphosphonates and osteonecrosis of the jaw

More than half of all serious adverse reactions are identified 7 or more years after a drug receives approval from the US Food and Drug Administration (FDA). In 2002, 9 months after the intravenous bisphosphonate zoledronic acid received regulatory approval for marketing, the FDA received reports of nine patients with cancer, who were treated with zoledronic acid, who unexpectedly developed osteonecrosis of the jaw. During the next 2 years, three oral surgeons described 104 patients with cancer with osteonecrosis of the jaw in the medical literature and identified intravenous bisphosphonate therapy as being common to the care of these patients. In subspecialty medical, radiology, and dental journals, case reports and case series described clinical features of osteonecrosis of the jaw in patients with cancer who were treated with bisphosphonates. Manufacturer-sponsored epidemiological studies reported the first estimates of the incidence of this toxic effect, ranging from 0.1% to 1.8%. By contrast, independent epidemiological efforts from clinicians and the International Myeloma Foundation reported incidence estimates between 5% and 10%. Between 2003 and 2005, warnings about the risks of bisphosphonate-associated osteonecrosis were disseminated by national regulatory agencies, the manufacturers of bisphosphonates, and the International Myeloma Foundation. From 2006, independent clinical recommendations for diagnosis, prevention, and treatment of this toxic effect have been disseminated by manufacturers, national regulatory authorities, the International Myeloma Foundation, and medical specialty organisations. Furthermore, independent efforts by pharmaceutical manufacturers, dental and medical professionals, a non-profit organisation (the International Myeloma Foundation), patients, and regulatory authorities has led to the rapid identification and dissemination of safety information for this serious adverse reaction. Better coordination of safety-related pharmacovigilance initiatives is now needed.

The Impact of Pharmaceutical Services in Community and Ambulatory Care Settings: Evidence and Recommendations for Future Research

OBJECTIVE: TO review and evaluate research on pharmaceutical services in community and ambulatory care pharmacy settings, specifically study designs and patient outcome measures, and to provide recommendations to improve future research on pharmaceutical services in community and ambulatory care pharmacy settings. DATA SOURCE: English-language articles were identified by searching MEDLINE (1966-December 1998) and International Pharmaceutical Abstracts (1970-December 1998), using a combination of search terms: pharmacist services, pharmacist interventions, community pharmacy, ambulatory care, primary care, and patient outcomes. Relevant studies were selected based on article abstracts. DATA EXTRACTION: From each relevant study, we extracted the study objectives, sample size, study period, study design, major tasks performed by pharmacists, and economic, clinical, and humanistic outcomes (ECHO). Results were tabulated separately for research on community pharmacy and ambulatory care pharmacy settings. RESULTS: We identified 95 relevant studies. Of these, 21 studies were conducted in community pharmacy settings and 74 in ambulatory care settings. Ten community pharmacy studies used prospective, single group, pretest/posttest, or posttest only designs; seven used prospective two or more group comparison designs; and four used randomized, controlled designs. Nine studies on community pharmacies measured clinical outcomes, two measured humanistic outcomes, and five measured economic outcomes. Four studies measured both clinical and humanistic outcomes and one measured humanistic and economic outcomes. No study measured all three ECHO variables. Twenty-three studies in ambulatory care settings used prospective or retrospective, single group, pretest/posttest or posttest only designs; 21 used prospective or retrospective two-or-more group comparison designs; and 30 used randomized, controlled designs. Thirty-six measured clinical outcomes, five measured humanistic outcomes, and 15 measured economic outcomes. Fifteen studies measured clinical and economic outcomes and three measured clinical and humanistic outcomes. CONCLUSIONS: Only 21 of 95 selected studies were conducted in community pharmacy settings and measured the impact of pharmaceutical services on patient outcomes. Few studies employed adequate research designs to control threats to internal and external validity. In order to obtain a comprehensive and accurate picture of the impact of pharmaceutical services on patient outcomes, an attempt must be made to measure all three ECHO variables while employing adequate research design.

Clopidogrel-Associated TTP: An Update of Pharmacovigilance Efforts Conducted by Independent Researchers, Pharmaceutical Suppliers, and the Food and Drug Administration

Background and Purpose— Since the 1999 identification of clopidogrel-associated thrombotic thrombocytopenic purpura (TTP) through independent active surveillance, subsequent cases have been identified by pharmaceutical suppliers of clopidogrel and the Food and Drug Administration (FDA). For cases of clopidogrel-associated TTP reported between 1998 to 2002, we evaluated the quality and timeliness of data from 3 reporting systems-independent active surveillance (n=13), pharmaceutical suppliers (n=24), and the FDA (n=13)—and identified prognostic factors associated with mortality. Methods— This study assessed the completeness of information on TTP diagnosis, treatment response, and causality from the 3 reporting systems. In addition, predictors of mortality were identified through classification tree analysis. Results— Completeness, timeliness, and certainty of diagnosis were best for cases obtained by active surveillance, intermediate for cases reported to the pharmaceutical supplier, and poorest for cases reported directly to the FDA. Clopidogrel had been used for ≤2 weeks by 65%. The survival rate for patients with clopidogrel-associated TTP was 71.2%. Receipt of therapeutic plasma exchange within 3 days of onset of TTP increased the likelihood of survival (100% versus 27.3%, P <0.001). Conclusions— Compared with reports submitted by suppliers or the FDA, reports obtained through active surveillance provided timelier and more complete information. Clopidogrel-associated TTP often occurs within 2 weeks of drug initiation, occasionally relapses, and has a high mortality if not treated promptly.

Impact of computerized prescriber order entry on the incidence of adverse drug events in pediatric inpatients.

OBJECTIVES. This study was conducted to determine the impact of a computerized physician order entry system with substantial decision support on the incidence and types of adverse drug events in hospitalized children. METHODS. A prospective methodology was used for the collection of adverse drug events and potential adverse drug events from all patients admitted to the pediatric intensive care and general pediatric units over a 6-month period. Data from a previous adverse drug event study of the same patient care units before computerized physician order entry implementation were used for comparison purposes. RESULTS. Data for 1197 admissions before the introduction of computerized physician order entry were compared with 1210 admissions collected after computerized physician order entry implementation. After computerized physician order entry implementation, it was observed that the number of preventable adverse drug events (46 vs 26) and potential adverse drug events (94 vs 35) was reduced. Reductions in overall errors, dispensing errors, and drug-choice errors were associated with computerized physician order entry. There were reductions in significant events, as well as those events rated as serious or life threatening, after the implementation of computerized physician order entry. Some types of adverse drug events continued to persist, specifically underdosing of analgesics. There were no differences in length of stay or patient disposition between preventable adverse drug events and potential adverse drug events in either study period. CONCLUSIONS. This study demonstrated that a computerized physician order entry system with substantive decision support was associated with a reduction in both adverse drug events and potential adverse drug events in the inpatient pediatric population. Additional system refinements will be necessary to affect remaining adverse drug events. Preventable events did not predict excess length of stay and instead may represent a sign, rather than a cause, of more complicated illness.

Depression predicts all-cause mortality: Epidemiological evaluation from the ACCORD HRQL substudy

OBJECTIVE Depression affects up to 20–25% of adults with type 2 diabetes and may increase all-cause mortality, but few well-designed studies have examined the effects of depression on the full range of cardiovascular disease outcomes in type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 2,053 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Health-Related Quality of Life substudy completed the Patient Health Questionnaire (PHQ)-9 measure of depression symptoms at baseline and 12, 36, and 48 months. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) (95% CI) for the time-varying impact of depression on protocol-defined clinical outcomes with and without adjustment for demographic, trial-related, clinical, and behavioral variables. RESULTS In fully adjusted models, depression was not significantly related to the ACCORD primary composite outcome (cardiovascular death, nonfatal heart attack, or stroke) (HR 1.53 [95% CI 0.85–2.73]) or to the ACCORD microvascular composite outcome (0.93 [0.53–1.62]), but all-cause mortality was significantly increased both in those with PHQ-assessed probable major depression (2.24 [1.24–4.06]) and PHQ score of ≥10 (1.84 [1.17–2.89]). The effect of depression on all-cause mortality was not related to previous cardiovascular events or to assignment to intensive or standard glycemia control. Probable major depression (by PHQ-9) had a borderline impact on the ACCORD macrovascular end point (1.42 [0.99–2.04]). CONCLUSIONS Depression increases the risk of all-cause mortality and may increase the risk of macrovascular events among adults with type 2 diabetes at high risk for cardiovascular events.

Comparison of Anticancer Drug Coverage Decisions in the United States and United Kingdom: Does the Evidence Support the Rhetoric?

PURPOSE In contrast to the United States, several European countries have health technology assessment programs for drugs, many of which assess cost effectiveness. Coverage decisions that consider cost effectiveness may lead to restrictions in access. METHODS For a purposive sample of five decision-making bodies, we analyzed US and United Kingdom coverage decisions on all anticancer drugs approved by the US Food and Drug Administration (FDA) from 2004 to 2008. Data sources for the timing and outcome of licensing and coverage decisions included published and unpublished documentation, Web sites, and personal communication. RESULTS The FDA approved 59 anticancer drugs over the study period, of which 46 were also approved by the European Medicines Agency. In the United States, 100% of drugs were covered, mostly without restriction. However, the United Kingdom bodies made positive coverage decisions for less than half of licensed drugs (National Institute for Health and Clinical Excellence [NICE]: 39%; Scottish Medicines Consortium [SMC]: 43%). Whereas the Centers for Medicare and Medicaid Services (CMS) and the Department of Veterans Affairs (VA) covered all 59 drugs from the FDA license date, delays were evident for some Regence Group decisions that were informed by cost effectiveness (median, 0 days; semi-interquartile range [SIQR], 122 days; n = 22). Relative to the European Medicines Agency license date, median time to coverage was 783 days (SIQR, 170 days) for NICE and 231 days (SIQR, 129 days) for the SMC. CONCLUSION Anticancer drug coverage decisions that consider cost effectiveness are associated with greater restrictions and slower time to coverage. However, this approach may represent an explicit alternative to rationing achieved through the use of patient copayments.