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1.  Rituximab and biosimilars – equivalence and reciprocity 
Biosimilars  2013;2013(3):19-25.
Cancer is a debilitating disease affecting millions of people daily. Over the years, cancer treatment has advanced in leaps and bounds. Antibodies are important breakthrough therapeutic agents for cancer. These agents, proteins produced by B lymphocytes of the immune system in response to antigens, bind to receptors on cell surfaces so that the antigen–antibody complexes can be recognized and destroyed by phagocytes. While each B cell synthesizes only one kind of antibody, an entire population of different types of B cells and their respective antibodies are produced in response to various antigens to which the organism had been exposed. However, to be useful clinically, substantial amounts of a single antibody must be generated from a single ancestral B cell. These antibodies produced by a specific population of B cells are the monoclonal antibodies that have become the cornerstone of treatment for cancer and many immunologic illnesses. The purpose of this report is to provide an overview of the clinical development of biosimilars in clinical oncology, focusing on rituximab and like biosimilars.
doi:10.2147/BS.S20681
PMCID: PMC4017581  PMID: 24829884
rituximab; cancer treatment; biosimilars
2.  Underreporting of Hemorrhagic and Thrombotic Complications of Pharmaceuticals to the U.S. Food and Drug Administration: Empirical Findings for Warfarin, Clopidogrel, Ticlopidine, and Thalidomide from the Southern Network on Adverse Reactions (SONAR) 
The U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS), familiarly known as “MedWatch,” is the nation's primary tool for postmarket pharmaceutical safety surveillance. This system relies on adverse events voluntarily reported by health care providers and consumers either directly to the FDA or to drug manufacturers, which are required to prepare and forward the information to the agency. Little is known about how frequently adverse events are reported. Previous estimates range from 1 to 31% depending on the event, drug, and time period. We used published incidence studies to calculate reporting rates for hemorrhage, emergency hospitalization, and venous thromboembolism (VTE) associated with four drugs. We estimated annual reporting rates of 1.07% for 33,171 emergency hospitalizations of patients older than 65 years associated with warfarin, 0.9% for 13,363 hospitalizations of clopidogrel and ticlopidine, and 1.02% for an estimated 67,200 hemorrhage cases associated with warfarin. We also estimated a 9-year reporting rate of 2.3% for VTE associated with thalidomide. The incidence of these hematologic adverse drug events is high and reporting rates are low, and near the lower boundary of the 1 to 15% range seen for other events.
doi:10.1055/s-0032-1328890
PMCID: PMC3947536  PMID: 23086541
U.S. Food and Drug Administration; adverse drug events; hemorrhage; venous thromboembolism; warfarin; thalidomide; clopidogrel; ticlopidine
3.  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.
doi:10.1055/s-0032-1328884
PMCID: PMC3947540  PMID: 23111861
darbepoetin; epoetin; erythropoiesis-stimulating agents; peginesatide
4.  Thromboprophylaxis Guidelines in Cancer with a Primary Focus on Ambulatory Patients Receiving Chemotherapy: A Review from the Southern Network on Adverse Reactions (SONAR) 
Patients with cancer are at increased risk for venous thromboembolism (VTE). Factors related to cancer type, site, stage, duration, and extent of disease contribute to the oncology patient’s risk of VTE. Patient-specific factors such as history of prior VTE and comorbidity are also contributory. The role of treatment-related factors, including chemotherapy regimen, has been a focus of recent investigation because most cases of VTE in the oncology setting occur in ambulatory patients. Thus, an emerging area of clinical research is primary VTE prophylaxis in the ambulatory cancer setting. Clinical guidelines currently recommend primary thromboprophylaxis in cancer patients who are undergoing surgery, who are hospitalized, and who are in a specific subset of high-risk ambulatory cancer patients. Validated risk stratification tools are essential for identification of patients who are at high risk of thrombosis. Emerging data from recently published clinical trials, as well as ongoing studies, are likely to advance our understanding of the potential utility of antithrombotic agents for primary prophylaxis in ambulatory patients with cancer and may influence future clinical guideline recommendations.
doi:10.1055/s-0032-1328893
PMCID: PMC4017864  PMID: 23111863
anticoagulants; chemotherapy; cancer; venous thromboembolism; thromboprophylaxis
5.  Unintended Consequences of Health Information Technology: Evidence From Veterans Affairs Colorectal Cancer Oncology Watch Intervention 
Journal of Clinical Oncology  2012;30(32):3947-3952.
Purpose
We evaluated the Colorectal Cancer (CRC) Oncology Watch intervention, a clinical reminder implemented in Veterans Integrated Service Network 7 (including eight hospitals) to improve CRC screening rates in 2008.
Patients and Methods
Veterans Affairs (VA) administrative data were used to construct four cross-sectional groups of veterans at average risk, age 50 to 64 years; one group was created for each of the following years: 2006, 2007, 2009, and 2010. We applied hospital fixed effects for estimation, using a difference-in-differences model in which the eight hospitals served as the intervention sites, and the other 121 hospitals served as controls, with 2006 to 2007 as the preintervention period and 2009 to 2010 as the postintervention period.
Results
The sample included 4,352,082 veteran-years in the 4 years. The adherence rates were 37.6%, 31.6%, 34.4%, and 33.2% in the intervention sites in 2006, 2007, 2009, and 2010, respectively, and the corresponding rates in the controls were 31.0%, 30.3%, 32.3%, and 30.9%. Regression analysis showed that among those eligible for screening, the intervention was associated with a 2.2–percentage point decrease in likelihood of adherence (P < .001). Additional analyses showed that the intervention was associated with a 5.6–percentage point decrease in likelihood of screening colonoscopy among the adherent, but with increased total colonoscopies (all indicators) of 3.6 per 100 veterans age 50 to 64 years.
Conclusion
The intervention had little impact on CRC screening rates for the studied population. This absence of favorable impact may have been caused by an unintentional shift of limited VA colonoscopy capacity from average-risk screening to higher-risk screening and to CRC surveillance, or by physician fatigue resulting from the large number of clinical reminders implemented in the VA.
doi:10.1200/JCO.2011.39.7448
PMCID: PMC3488268  PMID: 23045582
6.  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.
doi:10.1055/s-0032-1328894
PMCID: PMC3804561  PMID: 23111862
thrombotic thrombocytopenic purpura; ticlopidine; clopidogrel; prasugrel; adverse event
7.  Colony-Stimulating Factors for Febrile Neutropenia during Cancer Therapy 
The New England journal of medicine  2013;368(12):1131-1139.
A 55-year-old, previously healthy woman received a diagnosis of diffuse large-B-cell lymphoma after the evaluation of an enlarged left axillary lymph node obtained on biopsy. She had been asymptomatic except for the presence of enlarged axillary lymph nodes, which she had found while bathing. She was referred to an oncologist, who performed a staging evaluation. A complete blood count and test results for liver and renal function and serum lactate dehydrogenase were normal. Positron-emission tomography and computed tomography (PET–CT) identified enlarged lymph nodes with abnormal uptake in the left axilla, mediastinum, and retroperitoneum. Results on bone marrow biopsy were normal. The patient’s oncologist recommends treatment with six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (CHOP-R) at 21-day intervals. Is the administration of prophylactic granulocyte colony-stimulating factor (G-CSF) with the first cycle of chemotherapy indicated?
doi:10.1056/NEJMct1210890
PMCID: PMC3947590  PMID: 23514290
8.  Cost-Effectiveness Comparison of Response Strategies to a Large-Scale Anthrax Attack on the Chicago Metropolitan Area: Impact of Timing and Surge Capacity 
Rapid public health response to a large-scale anthrax attack would reduce overall morbidity and mortality. However, there is uncertainty about the optimal cost-effective response strategy based on timing of intervention, public health resources, and critical care facilities. We conducted a decision analytic study to compare response strategies to a theoretical large-scale anthrax attack on the Chicago metropolitan area beginning either Day 2 or Day 5 after the attack. These strategies correspond to the policy options set forth by the Anthrax Modeling Working Group for population-wide responses to a large-scale anthrax attack: (1) postattack antibiotic prophylaxis, (2) postattack antibiotic prophylaxis and vaccination, (3) preattack vaccination with postattack antibiotic prophylaxis, and (4) preattack vaccination with postattack antibiotic prophylaxis and vaccination. Outcomes were measured in costs, lives saved, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). We estimated that postattack antibiotic prophylaxis of all 1,390,000 anthrax-exposed people beginning on Day 2 after attack would result in 205,835 infected victims, 35,049 fulminant victims, and 28,612 deaths. Only 6,437 (18.5%) of the fulminant victims could be saved with the existing critical care facilities in the Chicago metropolitan area. Mortality would increase to 69,136 if the response strategy began on Day 5. Including postattack vaccination with antibiotic prophylaxis of all exposed people reduces mortality and is cost-effective for both Day 2 (ICER=$182/QALY) and Day 5 (ICER=$1,088/QALY) response strategies. Increasing ICU bed availability significantly reduces mortality for all response strategies. We conclude that postattack antibiotic prophylaxis and vaccination of all exposed people is the optimal cost-effective response strategy for a large-scale anthrax attack. Our findings support the US government's plan to provide antibiotic prophylaxis and vaccination for all exposed people within 48 hours of the recognition of a large-scale anthrax attack. Future policies should consider expanding critical care capacity to allow for the rescue of more victims.
Rapid public health response to a large-scale anthrax attack would reduce overall morbidity and mortality, but what is the optimal cost-effective response strategy for timing of intervention, public health resources, and critical care facilities? Using a hypothetical large-scale anthrax attack on the Chicago metropolitan area, this study compared response strategies that would begin either 2 days or 5 days after the attack and would consist of administering prophylaxis and vaccine in various combinations. The findings support the government's plan to provide antibiotic prophylaxis and vaccination for all exposed people within 48 hours of the recognition of a large-scale anthrax attack.
doi:10.1089/bsp.2011.0105
PMCID: PMC3440066  PMID: 22845046
9.  Mind the gap: Racial differences in breast cancer incidence and biologic phenotype, but not stage, among low-income women participating in a government-funded screening program 
Background
Breast cancer mortality rates in South Carolina (SC) are 40% higher among African-American (AA) than European-American (EA) women. Proposed reasons include race-associated variations in care and/or tumor characteristics, which may be subject to income effects. We evaluated race-associated differences in tumor biologic phenotype and stage among low-income participants in a government-funded screening program.
Methods
Best Chance Network (BCN) data were linked with the SC Central Cancer Registry. Characteristics of breast cancers diagnosed in BCN participants aged 47–64 years during 1996–2006 were abstracted. Race-specific case proportions and incidence rates based on estrogen receptor (ER) status and histologic grade were estimated.
Results
Among 33,880 low-income women accessing BCN services, repeat breast cancer screening utilization was poor, especially among EAs. Proportionally, stage at diagnosis did not differ by race (607 cancers, 53% among AAs), with about 40% advanced stage. Compared to EAs, invasive tumors in AAs were 67% more likely (proportions) to be of poor-prognosis phenotype (both ER-negative and high-grade); this was more a result of the 46% lesser AA incidence (rates) of better-prognosis (ER+ lower-grade) cancer than the 32% greater incidence of poor-prognosis disease (p-values <0.01). When compared to the general SC population, racial disparities in poor prognostic features within the BCN population were attenuated; this was due to more frequent adverse tumor features in EAs rather than improvements for AAs.
Conclusion
Among low-income women in SC, closing the breast cancer racial and income mortality gaps will require improved early diagnosis, addressing causes of racial differences in tumor biology, and improved care for cancers of poor-prognosis biology.
doi:10.1007/s10549-012-2305-0
PMCID: PMC3660400  PMID: 23239148
Breast cancer; Health disparities; Racial disparities; Low-income population; Cancer screening; Rates and proportions
10.  Linking Drugs to Obscure Illnesses: Lessons from Pure Red Cell Aplasia, Nephrogenic Systemic Fibrosis, and Reye’s Syndrome. A Report From the Southern Network on Adverse Reactions (SONAR) 
Journal of General Internal Medicine  2012;27(12):1697-1703.
Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye’s syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States’ NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.
doi:10.1007/s11606-012-2098-1
PMCID: PMC3509314  PMID: 22692632
pure red cell aplasia; nephrogenic systemic fibrosis; Reye’s syndrome
11.  A Tale of Two Citizens: A State Attorney General and a Hematologist Facilitate Translation of Research Into US Food and Drug Administration Actions—A SONAR Report 
Journal of Oncology Practice  2012;8(6):e158-e167.
The authors reviewed FDA and manufacturer responses to a citizen petition filed to address thalidomide safety issues and concluded that new approaches addressing off-label safety are needed.
Purpose:
Pharmaceutical safety is a public health issue. In 2005, the Connecticut Attorney General (AG) raised concerns over adverse drug reactions in off-label settings, noting that thalidomide was approved to treat a rare illness, but more than 90% of its use was off label. A hematologist had reported thalidomide with doxorubicin or dexamethasone was associated with venous thromboembolism (VTE) rates of 25%. We review US Food and Drug Administration (FDA) and manufacturer responses to a citizen petition filed to address these thalidomide safety issues.
Methods:
Case study.
Results:
The AG petitioned the FDA requesting thalidomide-related safety actions. Coincidentally, the manufacturer submitted a supplemental New Drug Approval (sNDA), requesting approval to treat multiple myeloma with thalidomide-dexamethasone. FDA safety officers reviewed the petition and the literature and noted that VTE risks with thalidomide were not appropriately addressed in the existing package insert. In the sNDA application, the manufacturer reported thalidomide-associated toxicities for multiple myeloma were primarily somnolence and neurotoxicity, and a proposed package insert did not focus on VTE risks. In October, the FDA informed the Oncology Drug Division that VTE risks with thalidomide were poorly addressed in the existing label. After reviewing this memorandum, an Oncology Drug Division reviewer informed the manufacturer that approval of the sNDA would be delayed until several thalidomide-associated VTE safety actions, including revisions of the package insert, were implemented. The manufacturer and FDA agreed on these actions, and the sNDA was approved.
Conclusion:
New approaches addressing off-label safety are needed. The conditions that facilitated the successful response to this citizen petition are uncommon.
doi:10.1200/JOP.2011.000504
PMCID: PMC3500490  PMID: 23598851
13.  Gadolinium-induced nephrogenic systemic fibrosis: the rise and fall of an iatrogenic disease 
Clinical Kidney Journal  2012;5(1):82-88.
Background.
In 2006, nephrologists in Denmark unexpectedly identified chronic kidney disease (CKD) patients with a new syndrome, nephrogenic systemic fibrosis (NSF). Subsequently, 1603 NSF patients were reported to the Food and Drug Administration. Sixty hospitals in the USA account for 93% of these cases, and two hospitals in Denmark account for 4% of these reports. We review Denmark’s identification and subsequent rapid eradication of NSF.
Methods.
NSF reports from clinicians, the Danish Medicines Agency (DMA) and gadolinium-based contrast agents (GBCAs) manufacturers were reviewed (2002–11).
Results.
In 1994, the DMA approved a non-ionic linear GBCA, gadodiamide (0.1 mmol/kg), for magnetic resonance imagings (MRIs), with a renal insufficiency contraindication. In 1996, 0.3 mmol/kg dosing received DMA approval. In 1998, the DMA removed renal contraindications. In 1997 and 2002, radiologists at Skejby Hospital and Herlev Hospital, respectively, began performing gadodiamide-enhanced magnetic resonance angiography scans (0.3 mmol/kg) of CKD patients. In 2005, Herlev clinicians requested assistance in evaluating etiological causes of NSF occurring among 10 CKD patients who had developed NSF. This investigation, focusing on infectious agents, was inconclusive. In 2006, Herlev clinicians reported that of 108 CKD patients who had received gadodiamide-enhanced MRI, 20 had developed probable NSF. Herlev radiologists voluntarily discontinued administering gadodiamide to all patients and no new NSF cases at Herlev Hospital developed subsequently. After meeting with Herlev radiologists, Skejby radiologists also discontinued administering gadodiamide to all patients. In 2007, the European Medicines Agency and the DMA contraindicated gadodiamide administration to CKD patients. In 2008, in response to these advisories, radiologists at the other 36 Danish hospitals discontinued administering gadodiamide to all patients, following on practices adopted at Skejby and Herlev Hospitals. In 2009, clinicians at Skejby Hospital reported that a look-back survey identified 33 CKD patients with NSF developing after undergoing GBCA-enhanced MRIs between 1999 and 2007. In 2010, an independent review, commissioned by the Minister of Health, concluded that the DMA had erred in rescinding gadodiamide’s renal insufficiency contraindication in 1998 and that this error was a key factor in the development of NSF in Denmark. In 2011, three NSF cases associated with macrocyclic GBCA-associated NSF and three NSF patients with Stages 3 and 4 CKD disease from Skejby Hospital were reported.
Conclusion.
A confluence of factors led to the development and eradication of NSF in Denmark.
doi:10.1093/ckj/sfr172
PMCID: PMC3341839  PMID: 22833806
chronic kidney disease; gadodiamide; gadolinium; magnetic resonance angiography; nephrogenic systemic fibrosis
14.  Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989–2008) 
Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.
doi:10.1038/ki.2008.613
PMCID: PMC3500614  PMID: 19180126
drug-associated TTP; epidemiology; ADAMTS13
15.  Gadolinium–associated nephrogenic systemic fibrosis 
Community oncology  2008;5(6):325-326.
The authors explain why physicians should refrain from ordering MRIs for patients with renal dysfunction unless the test is essential to provide diagnostic information. A possibly class-wide toxicity from the contrast agent gadolinium has been reported.
PMCID: PMC2777717  PMID: 19920874
16.  Quality of Reporting of Serious Adverse Drug Events to an Institutional Review Board 
Clinical Cancer Research  2009;15(11):3850-3855.
Purpose
Serious adverse drug event (sADE) reporting to Institutional Review Boards (IRB) is essential to ensure pharmaceutical safety. However, the quality of these reports has not been studied. Safety reports are especially important for cancer drugs that receive accelerated Food and Drug Administration approval, like imatinib, as preapproval experience with these drugs is limited. We evaluated the quality, accuracy, and completeness of sADE reports submitted to an IRB.
Experimental Design
sADE reports submitted to an IRB from 14 clinical trials with imatinib were reviewed. Structured case report forms, containing detailed clinical data fields and a validated causality assessment instrument, were developed. Two forms were generated for each ADE, the first populated with data abstracted from the IRB reports, and the second populated with data from the corresponding clinical record. Completeness and causality assessments were evaluated for each of the two sources, and then compared. Accuracy (concordance between sources) was also assessed.
Results
Of 115 sADEs reported for 177 cancer patients to the IRB, overall completeness of adverse event descriptions was 2.4-fold greater for structured case report forms populated with information from the clinical record versus the corresponding forms from IRB reports (95.0% versus 40.3%, P < 0.05). Information supporting causality assessments was recorded 3.5-fold more often in primary data sources versus IRB adverse event descriptions (93% versus 26%, P < 0.05). Some key clinical information was discrepant between the two sources.
Conclusions
The use of structured syndrome-specific case report forms could enhance the quality of reporting to IRBs, thereby improving the safety of pharmaceuticals administered to cancer patients.
doi:10.1158/1078-0432.CCR-08-1811
PMCID: PMC3296235  PMID: 19458059
17.  Intersecting Guidelines: Administering Erythropoiesis-Stimulating Agents to Chronic Kidney Disease Patients with Cancer 
Seminars in Dialysis  2008;22(1):1-4.
There has been a dramatic sea change in the use of erythropoiesis-stimulating agents (ESAs) for anemic persons with chronic kidney disease (CKD) or cancer patients undergoing chemotherapy. An important area that has not been addressed previously is a CKD patient who also has a malignancy. Clinical guidelines exist that outline recommended treatments for each disease, but the intersection of the two disease processes presents difficult decisions for patients and physicians. Herein, we review the background underlying recent revisions in clinical alerts and guidelines for ESAs, and provide guidance for treating anemia among CKD patients who are receiving no therapy, chemotherapy with curative intent, or chemotherapy with palliative intent. The guiding principle is that comprehensive assessment of risks and benefits in the relevant clinical setting is imperative.
doi:10.1111/j.1525-139X.2008.00524.x
PMCID: PMC3296236  PMID: 19175532
18.  Amiodarone-Associated Optic Neuropathy: A Critical Review 
The American Journal of Medicine  2012;125(5):447-453.
Although amiodarone is the most commonly prescribed antiarrhythmic drug, its use is limited by serious toxicities, including optic neuropathy. Current reports of amiodarone associated optic neuropathy identified from the Food and Drug Administration's Adverse Event Reporting System (FDA-AERS) and published case reports were reviewed. A total of 296 reports were identified: 214 from AERS, 59 from published case reports, and 23 from adverse events reports for patients enrolled in clinical trials. Mean duration of amiodarone therapy before vision loss was 9 months (range 1-84 months). Insidious onset of amiodarone associated optic neuropathy (44%) was the most common presentation, and nearly one-third were asymptomatic. Optic disc edema was present in 85% of cases. Following drug cessation, 58% had improved visual acuity, 21% were unchanged, and 21% had further decreased visual acuity. Legal blindness (< 20/200) was noted in at least one eye in 20% of cases. Close ophthalmologic surveillance of patients during the tenure of amiodarone administration is warranted.
doi:10.1016/j.amjmed.2011.09.020
PMCID: PMC3322295  PMID: 22385784
amiodarone; vision loss; optic neuropathy
19.  Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura 
Objectives
We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).
Background
The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).
Methods
Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.
Results
Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.
Conclusions
Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.
doi:10.1016/j.jacc.2007.04.093
PMCID: PMC3167088  PMID: 17868804
21.  Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs? 
Journal of Clinical Oncology  2009;27(26):4398-4405.
Purpose
Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials.
Methods
We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995.
Results
Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non–orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non–orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval.
Conclusion
AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.
doi:10.1200/JCO.2008.21.1961
PMCID: PMC2744277  PMID: 19636013
22.  Cancer patients’ use of pharmaceutical patient assistance programs in the outpatient pharmacy at a large tertiary cancer center 
Community oncology  2012;8(6):279-286.
Purpose
To report on the use of pharmaceutical patient assistance programs (PAPs) in the outpatient pharmacy at the largest tertiary cancer center in the United States.
Methods
We conducted a retrospective (July 1, 2006–Dec 31,2007) cross-sectional analysis of outpatient pharmacy, medical, and cancer registry records at the cancer center. The cancer center identified 104 medications available through PAPs. Study-eligible patients received at least one of these medications, either as a PAP case patient or as a PAP control non-user. Binary logit regression models predicted PAP use, and descriptive statistics compared PAP user and non-user medication fills.
Results
Of 25,552 cancer patients at who received an outpatient medication during the study period, 1,929 met study criteria (n=950 PAP users, 979 PAP non-users). In comparison to controls, PAP users were more likely to be uninsured (odds ratio (OR)=4.60, 95% confidence interval (CI): 2.118, 9.970), indigent (OR=16.95, 95% CI: 6.845, 41.960), and < 65 years old (OR=2.31, 95% CI: 1.517, 3.509). Of the most frequently dispensed medications to PAP users from PAPs (n=5,271), 88% (n=4,936) were for supportive care (e.g., nausea/vomiting). PAPs provided 35% (n=842) of the most common anticancer agents administered to PAP users (n=1,296), accounting for a monthly mean of $55,000 in pharmaceutical expenditures.
Conclusions
In the cancer center’s outpatient pharmacy, PAPs provided financial support for about a third of the most commonly used therapies, primarily for supportive care indications, for a small percentage of eligible cancer patients.
doi:10.1016/S1548-5315(12)70023-2
PMCID: PMC3413301  PMID: 22879815
cancer; supportive care; medication assistance; anticancer agents; outpatient pharmacy
23.  Acquired Idiopathic ADAMTS13 Activity Deficient Thrombotic Thrombocytopenic Purpura in a Population from Japan 
PLoS ONE  2012;7(3):e33029.
Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy (TMA). Studies report that the majority of TTP patients present with a deficiency of ADAMTS13 activity. In a database of TMA patients in Japan identified between 1998 and 2008, 186 patients with first onset of acquired idiopathic (ai) ADAMTS13-deficient TTP (ADAMTS13 activity <5%) were diagnosed. The median age of onset of TTP in this group of patients was 54 years, 54.8% were female, 75.8% had renal involvement, 79.0% had neurologic symptoms, and 97.8% had detectable inhibitors to ADAMTS13 activity. Younger patients were less likely to present with renal or neurologic dysfunction (p<0.01), while older patients were more likely to die during the TTP hospitalization (p<0.05). Findings from this cohort in Japan differ from those reported previously from the United States, Europe, and Korea with respect to age at onset (two decades younger in the other cohort) and gender composition (60% to 100% female in the other cohort). We conclude that in one of the largest cohorts of ai-TTP with severe deficiency of ADAMTS13 activity reported to date, demographic characteristics differ in Japanese patients relative to those reported from a large Caucasian registry from Western societies. Additional studies exploring these findings are needed.
doi:10.1371/journal.pone.0033029
PMCID: PMC3299727  PMID: 22427934
24.  Proxy Assessment of Health-Related Quality of Life in African American and White Respondents With Prostate Cancer 
Medical care  2009;47(2):176-183.
Objectives
An emerging issue in the proxy literature is whether specifying different proxy viewpoints contributes to different health-related quality of life (HRQL) assessments, and if so, how might each perspective be informative in medical decision making. The aims of this study were to determine if informal caregiver assessments of patients with prostate cancer differed when prompted from both the patient perspective (proxy-patient) and their own viewpoint (proxy-proxy), and to identify factors associated with differences in proxy perspectives (ie, the intraproxy gap).
Research Design and Methods
Using a cross-sectional design, prostate cancer patients and their informal caregivers were recruited from urology clinics in the Jesse Brown Veterans Affairs Healthcare System in Chicago. Dyads assessed HRQL using the EQ-5D visual analog scale (VAS) and EORTC QLQ-C30.
Results
Of 87 dyads, most caregivers were female (83%) and were spouses/partners (58%). Mean difference scores between proxy-patient and proxy-proxy perspectives were statistically significant for QLQ-C30 physical and emotional functioning, and VAS (all P < 0.05), with the proxy-patient perspective closer to patient self-report. Emotional functioning had the largest difference, mean 6.0 (SD 12.8), an effect size = 0.47. Factors weakly correlated with the intraproxy gap included relationship (spouse) and proxy gender for role functioning, and health literacy (limited/functional) for physical functioning (all P < 0.05, 0.20 < r < 0.35).
Conclusions
Meaningful differences between proxy-patient and proxy-proxy perspectives on mental health were consistent with a conceptual framework for understanding proxy perspectives. Prompting different proxy viewpoints on patient health could help clinicians identify patients who may benefit from clinical intervention.
doi:10.1097/MLR.0b013e31818475f4
PMCID: PMC3215256  PMID: 19169118
quality of life; proxy; prostate cancer; Veterans
25.  Surgery and Adjuvant Chemotherapy Use Among Veterans With Colon Cancer: Insights From a California Study 
Journal of Clinical Oncology  2010;28(15):2571-2576.
Purpose
US veterans have been shown to be a vulnerable population with high cancer rates, and cancer care quality in Veterans Affairs (VA) hospitals is the focus of a congressionally mandated review. We examined rates of surgery and chemotherapy use among veterans with colon cancer at VA and non-VA facilities in California to gain insight into factors associated with quality of cancer care.
Methods
A retrospective cohort of incident colon cancer patients from the California Cancer Registry, who were ≥ 66 years old and eligible to use VA and Medicare between 1999 and 2001, were observed for 6 months after diagnosis.
Results
Among 601 veterans with colon cancer, 72% were initially diagnosed and treated in non-VA facilities. Among veterans with stage I to III cancer, those diagnosed and initially treated in VA facilities experienced similar colectomy rates as those at non-VA facilities. Stage III patients diagnosed and initially treated in VA versus non-VA facilities had similar odds of receiving adjuvant chemotherapy. In both settings, older patients had lower odds of receiving chemotherapy than their younger counterparts even when race and comorbidity were considered (age 76 to 85 years: odds ratio [OR] = 0.18; 95% CI, 0.07 to 0.46; age ≥ 86 years: OR = 0.17; 95% CI, 0.04 to 0.73).
Conclusion
In California, older veterans with colon cancer used both VA and non-VA facilities for cancer treatment, and odds of receiving cancer-directed surgery and chemotherapy were similar in both systems. Among stage III patients, older age lowered odds of receiving adjuvant chemotherapy in both systems. Further studies should continue to explore potential health system effects on quality of colon cancer care across the United States.
doi:10.1200/JCO.2009.23.5200
PMCID: PMC2881731  PMID: 20406940

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