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1.  Regulatory and clinical considerations for biosimilar oncology drugs 
The Lancet. Oncology  2014;15(13):e594-e605.
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 healthcare 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.
doi:10.1016/S1470-2045(14)70365-1
PMCID: PMC4404762  PMID: 25456378
2.  Systematic Review: The Association and Impact of Financial Conflicts of Interest in Basic Science Research 
Archives of internal medicine  2010;170(16):1490-1498.
Background
No prior study has evaluated financial relationships of investigators with pharmaceutical manufacturers for basic science. An example of the importance and impact of such relationships is in the evaluation of erythropoietin receptors’(EpoRs) effects on cancer cell lines, since studies have reported increased mortality when cancer patients receive erythropoiesis stimulating agents (ESAs).
Purpose
To assess the disclosed association that exist between pharmaceutical industry support and EpoRs effects on solid cancer cell lines.
Data Sources
MEDLINE and EMBASE (1988- July 2008) and two EpoR conferences sponsored by the National Institutes of Health.
Study Selection
All publications investigating EpoRs that met inclusion criteria were identified and included.
Data Extraction
Data were extracted on detection of EpoRs, presence of erythropoietin-induced signaling events, presence of erythropoietin-induced changes in cellular function, nature of qualitative conclusions, and sources of funding for all 74 studies.
Data Synthesis
In comparison to studies of academic investigators with no disclosed funding support from ESA manufacturers (n=64), the studies from academic investigators with funding support from ESA manufacturers (n= 7) and the laboratories directed by investigators employed by ESA manufacturers (n=3) were both less likely to identify: EpoR presence on solid tumor cells; erythropoietin-induced signaling events; erythropoietin-induced changes in cellular function; and less likely to conclude that their research had identified potentially harmful effects of erythropoietin on cancer cells. Additionally, presentations from industry-based investigator teams at NIH conferences were less likely to report EpoRs on cancer cell lines, downstream effects of erythropoietin, and cell proliferation and migration effects following EpoR administration.
Conclusion
Financial conflicts of interest impact the outcomes and presentation of basic science research data as well as publications.
doi:10.1001/archinternmed.2010.309
PMCID: PMC4138541  PMID: 20837837
3.  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
4.  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
5.  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
6.  Financial burden experienced by patients undergoing treatment for malignant gliomas 
Neuro-Oncology Practice  2014;1(2):71-76.
Background
Patients undergoing treatment for malignant gliomas (MGs) can encounter medical costs beyond what their insurance covers. The magnitude and type of costs experienced by patients are unknown. The purpose of this study was to have patients or their families report on the medical costs incurred during the patients MG treatment.
Methods
Patients with MG were eligible if they were within 6 months of diagnosis or tumor recurrence. Patients had to be ≥18 years of age, fluent in English, and not aphasic. Weekly logbooks were issued to patients for recording associated costs for ∼6 months or until tumor progression. “Out-of-pocket” (OOP) costs included medical and nonmedical expenses that were not reimbursed by insurance. Direct medical costs included hospital and physician bills. Direct nonmedical costs included transportation, parking, and other related items. Indirect medical costs included lost wages. Costs were analyzed to provide mean and medians with range of expenses.
Results
Forty-three patients provided cost data for a median of 12 weeks. There were 25 men and 18 women with a median age of 57 years (range, 24y–73y); 79% were married, and 49% reported annual income >$75 000. Health insurance coverage was preferred provider organizations for 58% of patients, and median deductible was $1 500. Median monthly OOP cost was $1 342 (mean, $2 451; range, $333.41–$17 267.16). The highest OOP median costs were medication copayments ($710; range, $0–13 611.20), transportation ($327; range, $0–$1 927), and hospital bill copayments ($403; range, $0–$4 000). Median lost wages were $7 500, and median lost days of work were 12.8.
Conclusions
OOP costs for MG patients can be significant and comprise direct and indirect costs across several areas. Informing patients about expected costs could limit additional duress and allow financial support systems to be implemented.
doi:10.1093/nop/npu002
PMCID: PMC4371162  PMID: 26034619
financial burden; glioma; medical costs
8.  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
9.  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
10.  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
11.  Cardiac risks associated with antibiotics: azithromycin and levofloxacin 
Expert opinion on drug safety  2014;14(2):295-303.
Introduction
Azithromycin and levofloxacin have been shown to be efficacious in treating infections. The adverse drug events associated with azithromycin and levofloxacin were considered rare. However, the US FDA released warnings regarding the possible risk of QT prolongation with azithromycin and levofloxacin.
Areas covered
Case reports/case series, observational studies and clinical trials assessing cardiovascular risks associated with azithromycin and levofloxacin were critically reviewed, including 15 case reports/series, 5 observational studies and 5 clinical trials that investigated the cardiac risks associated azithromycin and levofloxacin.
Expert opinion
Results are discordant. Two retrospective studies utilizing large databases demonstrated an increased risk of cardiovascular death with azithromycin, when azithromycin was compared with amoxicillin. Two other retrospective studies found no difference in cardiovascular death associated with azithromycin and other antibiotics. For levofloxacin, the increased risk of cardiovascular death was only found in one retrospective study. Therefore, the risks and benefits of antibacterial therapies should be considered when making prescription decisions. This study should not preclude clinicians from avoiding azithromycin and levofloxacin. If a patient has an indication to receive an antibiotic and if azithromycin or levofloxacin is needed, it may be used, but the potential risks must be understood.
doi:10.1517/14740338.2015.989210
PMCID: PMC4404501  PMID: 25494485
adverse drug reactions; antibiotics; azithromycin; cardiac death; cardiovascular risks; drug safety; infections; levofloxacin; review
12.  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
13.  Improving Mammography Screening Among the Medically Underserved 
ABSTRACT
BACKGROUND
We evaluated the effectiveness and cost-effectiveness of alternative interventions designed to promote mammography in safety-net settings.
METHODS
A three-arm, quasi-experimental evaluation was conducted among eight federally qualified health clinics in predominately rural Louisiana. Mammography screening efforts included: 1) enhanced care, 2) health literacy-informed education of patients, and 3) education plus nurse support. Outcomes included mammography screening completion within 6 months and incremental cost-effectiveness.
RESULTS
Overall, 1,181 female patients ages 40 and over who were eligible for routine mammography were recruited. Baseline screening rates were < 10 %. Post intervention screening rates were 55.7 % with enhanced care, 51.8 % with health literacy-informed education and 65.8 % with education and nurse support. After adjusting for race, marital status, self-efficacy and literacy, patients receiving health-literacy informed education were not more likely to complete mammographic screening than those receiving enhanced care; those additionally receiving nurse support were 1.37-fold more likely to complete mammographic screening than those receiving the brief education (95 % Confidence Interval 1.08–1.74, p = 0.01). The incremental cost per additional women screened was $2,457 for literacy-informed education with nurse support over literacy-informed education alone.
CONCLUSIONS
Mammography rates were increased substantially over existing baseline rates in all three arms with the educational initiative, with nurse support and follow-up being the most effective option. However, it is not likely to be cost-effective or affordable in resource-limited clinics.
doi:10.1007/s11606-013-2743-3
PMCID: PMC3965756  PMID: 24366401
cancer screening; mammography; community clinics; health literacy; underserved populations
14.  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
15.  STEC:O111-HUS complicated by acute encephalopathy in a young girl was successfully treated with a set of hemodiafiltration, steroid pulse, and soluble thrombomodulin under plasma exchange 
Clinical Case Reports  2015;3(4):208-212.
Key Clinical Message
We report a 14-year-old girl, who developed shigatoxin-producing E. coli (STEC)-HUS complicated by encephalopathy. She was successfully treated with hemodiafiltration, high-dose methylprednisolone pulse therapy, and soluble recombinant thrombomodulin under plasma exchange. von Willebrand factor multimers analysis provides potential insights into how the administered therapies might facilitate successful treatment of STEC-HUS.
doi:10.1002/ccr3.196
PMCID: PMC4405303  PMID: 25914810
Encephalopathy; Escherichia coli O111; hemolytic uremic syndrome; plasma exchange; recombinant soluble thrombomodulin; von Willebrand factor
16.  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
17.  Strategies to Improve Repeat Fecal Occult Blood Testing Cancer Screening 
Background
A comparative effectiveness intervention by this team improved initial fecal occult blood testing (FOBT) rates from 3% to 53% among community clinic patients. The purpose of this study was to evaluate the effectiveness and costs associated with a literacy-informed intervention on repeat FOBT testing.
Methods
Between 2008 and 2011, a three-arm quasi-experiential comparative effectiveness evaluation was conducted in 8 community clinics in Louisiana. Clinics were randomly assigned to receive: enhanced care, a screening recommendation and FOBT kit annually; a brief educational intervention where patients additionally received a literacy appropriate pamphlet and simplified FOBT instructions; or nurse support where a nurse manager provided the education and followed up with phone support. In year 2 all materials were mailed. The study consisted of 461 patients, ages 50–85, with a negative initial FOBT.
Results
Repeat FOBT rates were 38% enhanced care, 33% education, and 59% with nurse support (p=0.017). After adjusting for age, race, gender, and literacy, patients receiving nurse support were 1.46 times more likely to complete repeat FOBT screening than those receiving education (95% CI 1.14–1.06, p=0.002) and 1.45 times more likely than those in enhanced care but this was not significant (95% CI 0.93–2.26 p=0.10). The incremental cost per additional person screened was $2,450 for nurse over enhanced care.
Conclusion
A mailed pamphlet and FOBT with simplified instructions did not improve annual screening.
Impact
Telephone outreach by a nurse manager was effective in improving rates of repeat FOBT yet this may be too costly for community clinics.
doi:10.1158/1055-9965.EPI-13-0795
PMCID: PMC3894742  PMID: 24192009
Health Literacy; Colon Cancer Screening; Annual screening; Cost effectiveness; Federally Qualified Health Centers
19.  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
20.  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
21.  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
22.  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
25.  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

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