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An association between the use of contraceptives containing exogenous estrogen compounds and subsequent diagnosis for malignant melanoma (MM) has been suspected for decades. This is, in part, due to the finding that estrogen stimulates melanogenesis1 and the observation that the incidence of MM is greater in women vs. men before the age of 50, but lower than men after the age of 502, corresponding with the average age of menopause when estrogen levels dramatically decrease. Prior studies assessing the relationship between the incidence of MM and exposure to exogenous estrogen provide conflicting results3-6. This article is protected by copyright. All rights reserved.

Global introspection is considered an unreliable method for attribution of causality of serious adverse events (SAEs), yet remains widely used for cancer drug clinical trials. Here, we compare structured case abstraction (SCA) to the routine method for detecting, evaluating, and reporting ADEs during cancer drug clinical trials to an Institutional Review Board (IRB). We obtained all SAE reports (2001-2008) received by one IRB for six clinical trials involving bevacizumab or oxaliplatin for treatment of gastrointestinal cancers. We compared the routine IRB SAE method to SCA for adverse event detection and causality attribution. Of 205 adverse events, 182 events (75%) were not reported; of these, 6 (20%) of 30 SAEs requiring an IRB report were unreported. For the 10 item Naranjo score, the amount of information useful for causality attribution was higher with SCA than the routine method (6.0 vs. 2.4 items, P

In 1998, a multidisciplinary team of investigators initiated the Research on Adverse Drug events And Reports (RADAR) project, a post-marketing surveillance effort that systematically investigates and disseminates information describing serious and previously unrecognized serious adverse drug and device reactions (sADRs).Herein, we describe the findings, dissemination efforts, and lessons learned from the first decade of the RADAR project.After identifying serious and unexpected clinical events suitable for further investigation, RADAR collaborators derived case information from physician queries, published and unpublished clinical trials, case reports, US FDA databases and manufacturer sales figures.All major RADAR publications from 1998 to the present are included in this analysis.For each RADAR publication, data were abstracted on data source, correlative basic science findings, dissemination and resultant safety information.RADAR investigators reported 43 serious ADRs. Data sources included case reports (17 sADRs), registries (5 sADRs), referral centers (8 sADRs) and clinical trial reports (13 sADRs). Correlative basic science findings were reported for ten sADRs. Thirty-seven sADRS were described as published case reports (5 sADRs) or published case-series (32 sADRs). Related safety information was disseminated as warnings or boxed warnings in the package insert (17 sADRs) and/or 'Dear Healthcare Professional' letters (14 sADRs).An independent National Institutes of Health-funded post-marketing surveillance programme can supplement existing regulatory and pharmaceutical manufacturer-supported drug safety initiatives.

Purpose: To determine whether acute kidney injury (AKI) is identified within the US Food and Drug Administration’s Adverse Events and Reporting System (FDA AERS) as an adverse event resulting from bisphosphonate (BP) use in cancer therapy. Methods: A search of the FDA AERS records from January 1998 through June 2009 was performed; search terms were “renal problems” and all drug names for BPs. The search resulted in 2,091 reports. We analyzed for signals of disproportional association by calculating the proportional reporting ratio for zoledronic acid (ZOL) and pamidronate. Literature review of BP-associated renal injury within the cancer setting was conducted. Results: Four hundred eighty cases of BP-associated acute kidney injury (AKI) were identified in patients with cancer. Two hundred ninety-eight patients (56%) were female; mean age was 66 10 years. Multiple myeloma (n 220, 46%), breast cancer (n 98, 20%), and prostate cancer (n 24, 5%) were identified. Agents included ZOL (n 411, 87.5%), pamidronate (n 8, 17%), and alendronate (n 36, 2%). Outcomes included hospitalization (n 304, 63.3%) and death (n 68, 14%). The proportional reporting ratio for ZOL was 1.22 (95% CI, 1.13 to 1.32) and for pamidronate was 1.55 (95% CI, 1.25 to 1.65), reflecting a nonsignificant safety signal for both drugs. Conclusion: AKI was identified in BP cancer clinical trials, although a safety signal for BPs and AKI within the FDA AERS was not detected. Our findings may be attributed, in part, to clinicians who believe that AKI occurs infrequently; ascribe the AKI to underlying premorbid disease, therapy, or cancer progression; or consider that AKI is a known adverse drug reaction of BPs and thus under-report AKI to the AERS.

Background: In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts. Methods: We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012). Results: The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [CI], 3.44 to 5.92) for bisphosphonate use and nonhealing femoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures. Conclusions: Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing.

Summary Background Tumour necrosis factor-α inhibitors (TNFαIs) are used for treatment of inflammatory disorders. There is evidence linking these agents with occurrence of malignancies. For four out of five TNFαIs the Food and Drug Administration (FDA) label states, ‘melanoma has been reported in patients treated with these agents’. Objectives To determine whether a statistically significant association exists between administration of TNFαIs and development of malignant melanoma. Methods We searched the FDA Adverse Event Reporting System (FAERS) database for terms related to melanoma and TNFαIs for detection of safety signals. We also searched a large urban academic electronic medical record (EMR) database for which we calculated the relative risk (RR) of melanoma in subjects exposed to TNFαIs vs. nonexposed subjects. Results There were 972 reports of melanoma associated with a TNFαI identified in the FAERS database, with 69 reports among individuals using more than one TNFαI. A safety signal was detected for infliximab, golimumab, etanercept and adalimumab, but not certolizumab pegol. For TNFαIs as a class of drugs, a safety signal was detectable in the FAERS database, and RR was significant in the EMR database. For the EMR cohort, 6045 patients were exposed to TNFαIs and 35 cases of melanoma were detected. Significance for RR was detected for adalimumab (RR 1·8, P = 0·02) and etanercept (RR 2·35, P = 0·0004 < 0·001). Conclusions We identified a significant association between exposure to TNFαIs and malignant melanoma in two different analyses. Our findings add to existing evidence linking these agents with the occurrence of malignant melanoma. Additional investigations are required to explore this association further along with the risk of melanoma with TNFαI therapy.

Progressive multifocal leucoencephalopathy (PML) is a serious and usually fatal CNS infection caused by JC polyoma virus. CD4+ and CD8+ T lymphopenia, resulting from HIV infection, chemotherapy, or immunosuppressive therapy, are the primary risk factors. The immune modulatory monoclonal antibodies rituximab, natalizumab, and efalizumab have received regulatory approval in the USA and Europe for treatment of non-Hodgkin lymphoma, rheumatoid arthritis, and chronic lymphocytic leukaemia (Europe only); multiple sclerosis and Crohn's disease; and psoriasis, respectively. Efalizumab and natalizumab administration is associated with CD4+ T lymphopenia and altered trafficking of T lymphocytes into the CNS, and rituximab leads to prolonged B-lymphocyte depletion. Unexpected cases of PML developing in people who receive these drugs have been reported, with many of the affected individuals dying from this disease. Herein, we review clinical findings, pathology, epidemiology, basic science, and risk-management issues associated with PML infection developing after treatment with these monoclonal antibodies.

Gemtuzumab ozogamicin (GO) was approved for marketing in 2000 by the United States Food and Drug Administration (FDA) for older patients with relapsed acute myeloid leukemia (AML). Four months later, 14 phase II clinical trial participants who received novel GO-containing combination chemotherapy regimens developed an unexpected hepatic toxicity termed sinusoidal obstructive syndrome (SOS) or hepatic veno-occlusive disease (VOD). Investigators associated with the Research on Adverse Drug Events and Reports (RADAR) project reviewed safety reports for GO included in reports of clinical trials and observational studies, interim reports from an FDA mandated Prospective Observational Registry, and the Food and Drug Administration's Adverse Event Reporting System. Medline searches provided incidence estimates of GO-associated SOS and comparative rates of SOS without GO. SOS is characterized by hyperbilirubinemia, painful hepatomegaly, ascites, and sudden weight gain developing at a median of 10 days following GO administration for patients who did not undergo an allogeneic SCT procedure and 13 days following an allogeneic SCT for patients who had previously received GO. Among adult AML patients who received GO in clinical trials, SOS incidence was 3% at doses < or =6 mg/m(2) if administered as monotherapy or in combination with non-hepatotoxic agents versus 28% if administered with thioguanine and 15% when administered as monotherapy at a dose of 9 mg/m(2). Observational studies identified SOS rates between 15% and 40% if an SCT is performed within 3 months of GO administration. The FDA mandated Prospective Observational Registry of patients who receive care at 60 medical centers has identified GO-associated SOS rates of 14% if an SCT is performed and 9% otherwise. Caution is advised when administering GO in routine clinical practice, particularly if administered with other hepatotoxic agents, at doses and schedules more intensive than those approved by the FDA, or within 3 months of a SCT procedure.

Rasburicase, a recombinant urate oxidase, is used to rapidly metabolize uric acid in patients with hyperuricaemia. Rasburicase is an immunogenic therapeutic protein, which has been shown to elicit antibody response in 64 % of healthy volunteers within 1-6 weeks after the initial course, with persistent antibodies for over 1 year. Drug labelling indicates that anaphylaxis rarely occurs (in1 % of patients) after a single course of therapy with rasburicase, but there are no data available on the incidence of anaphylaxis in patients receiving a subsequent rasburicase course.The objective of this study was to determine the incidence of anaphylaxis after multiple treatment courses of rasburicase.A retrospective chart review was performed on 97 consecutively treated patients who received repeated courses of rasburicase for hyperuricaemia.None of the 97 patients who were reviewed experienced anaphylaxis during the first rasburicase course; however, six patients (6.2 %) experienced anaphylaxis during a subsequent rasburicase treatment course (p = 0.03).Anaphylaxis after a second course of rasburicase appears to occur more frequently than described in the US Food and Drug Administration-approved package insert for initial treatment courses. Given the serious nature of anaphylactic events, caution is advised when administering repeated courses of rasburicase.

OBJECTIVES We undertook the review of all available cases of hypersensitivity reactions after placement of a drug-eluting stent (DES) and classified potential causes. BACKGROUND Six months after the approval of the first DES, the Food and Drug Administration (FDA) reported 50 hypersensitivity reactions after stent placement but later concluded these were due to concomitantly prescribed medications such as clopidogrel. Nevertheless, the FDA continued to receive reports of hypersensitivity. METHODS Reports available from April 2003 through December 2004 for hypersensitivity-like reactions associated with the sirolimus-eluting stent (CYPHER, Cordis Corp., Miami Lakes, Florida) and paclitaxel-eluting stent (TAXUS, Boston Scientific Corp., Natick, Massachusetts) were reviewed. Sources of reports included the FDA's adverse-device-event database, the published literature, and investigators from the Research on Adverse Drug/Device events And Reports (RADAR) project. Causality was assessed using standardized World Health Organization criteria. RESULTS Of 5,783 reports identified for the DES in the FDA database, 262 unique events included hypersensitivity symptoms. Of these reports, 2 were certainly and 39 unlikely caused by clopidogrel and 1 was certainly, 9 probably, and 13 unlikely caused by the DES. From all sources, we identified 17 distinct cases that were probably or certainly caused by the stent, of which 9 had symptoms that lasted longer than four weeks. Four autopsies confirmed intrastent eosinophilic inflammation, thrombosis, and lack of intimal healing. CONCLUSIONS The FDA reports and autopsy findings suggest that DES may be a cause of systemic and intrastent hypersensitivity reactions that, in some cases, have been associated with late thrombosis and death.

In 2002, investigators from France reported 13 patients in whom pure red cell aplasia developed during treatment with recombinant human erythropoietin (epoetin). We reviewed 208 cases of this syndrome reported worldwide. Adverse event reports describing suspected and confirmed cases of epoetin-associated PRCA in websites maintained by the manufacturers and distributors of epoetin products and other publicly available sources were reviewed. Cases were reported from countries in Europe, North America, Asia, Australia and the United States (US). For >95% of the cases, EPREX had been administered subcutaneous to persons with chronic kidney disease (CKD) and anemia for a mean of nine months prior to diagnosis of PRCA. For 80% of persons with the syndrome, reversal of antibody production and recovery of reticulocytes occurred with discontinuation of epoetin and treatment with immunosuppressive agents. Patients with anemia of CKD who developed neutralizing anti-erythropoietin antibodies and pure red cell aplasia during treatment with epoetin have been identified in a number of countries. In non-US countries, switching renal dialysis patients from subcutaneous to intravenous administration of epoetin alpha and improved handling of the drug appear to have been successful strategies for reducing the occurrence of this toxicity. The decrease in cases occurred coincident with these varied changes, although it is difficult to prove causality. PRCA is a rare, but important side effect of epoetin therapy.

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), to discuss methods of prevention, and to promote reporting of ADRs to the FDA's medWatch program (800-FDA-1088). If you have reported an interesting preventable ADR to medWatch, please consider sharing the account with our readers.

Purpose: To describe the clinical findings, occurrence rates, causality evidence, and dissemination media for serious cancer drug–associated adverse drug reactions (ADRs) reported in the postmarketing setting. Methods: ADRs were termed serious if they resulted in death or severe organ failure. ADR information for oncology drugs from package insert (PI) revisions, so-called Dear Doctor letters, and journal articles was evaluated to identify serious ADRs reported from 2000 to 2002. Timing and content of information disseminated was assessed. Results: Twenty-five serious ADRs associated with 22 oncology drugs were identified after approval. Approximately half of these serious ADRs are associated with drugs approved before 1995. ADRs were described in articles in medical journals (17 ADRs), PI revisions (18 ADRs), and Dear Doctor letters (12 ADRs). PI revisions occurred less than 1 year after peer-reviewed publication for four ADRs. These revisions often differed for similar ADRs that occurred with drugs of the same class. Five of the seven ADRs lacking PI changes occurred with off-label use, for which PI change is not recommended by US Food and Drug Administration (FDA) policy. No cancer drug was withdrawn from the market during the observation period. Conclusion: Our findings demonstrate that serious ADRs may be discovered as long as 36 years after a drug receives FDA approval. This suggests a need for continued vigilance and efficient strategies for dissemination of information about ADRs associated with cancer drugs.

e14072 Background: Romidepsin (R) is indicated for cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma. Hypomagnesemia (HM) is common in these patients and is also listed in the Full Prescribing Information (FPI) for R. Moreover, since cardiac arrhythmias are associated with HM, patients exposed to R may be at higher risk. This study assessed whether HM was causally related to R exposure and to what extent magnesium (M) supplementation was undertaken in those with HM. Methods: We searched a large, U.S. patient data repository to detect all patients (aged 20-94 years) exposed to R (10/2010-01/2017). For these patients, serum M, as well as M supplementation data, was collected. Baseline M was assessed at initial R exposure, and HM was defined as either, a decline in M to < 1.8 mg/dL after R exposure or, in those with baseline M < 1.8 mg/dL, a decline in M by ≥0.1 mg/dL after R exposure. For each patient with HM after R exposure, the validated Naranjo Adverse Drug Reaction Probability Scale (NADRPS) was used to determine the probability that HM was caused by R. Results: Of 51 R-exposed CTCL (or other lymphoma) patients, 25 (49.0%) had HM. Of these 25, NADRPS scores yielded: 1 doubtful, 16 possible, 8 probable and 0 definite. Additionally, 24 of 25 patients with HM had documentation for presence or absence of M supplementation: 9 (37.5%) had supplementation with M agents considered to be bioavailable, 12 (50%) received M agents considered to have low bioavailability, and 3 (12.5%) had no M supplementation. Conclusions: In this study population, 25 of 51 (49.0%) patients had HM after R exposure, which appears to nearly double the percentage of patients described in the FPI. Moreover, 8 of 25 (32%) patients with HM had causality attributed to R exposure. In addition, 15 of 24 (63%) patients with HM received M supplementation with agents considered to have low bioavailability or received no M supplementation. These findings support the need for ongoing monitoring of R-exposed patients with low M, as well as the importance of repleting M with agents considered to be adequately bioavailable. Also, given that HM appears to be more frequent in this study population compared to pre-marketing data in the FPI, further studies are warranted.

To compare and contrast three databases, that is, The International Centre for Nephrogenic Systemic Fibrosis Registry (ICNSFR), the Food and Drug Administration Adverse Event Reporting System (FAERS) and a legal data set, through pharmacovigilance and to evaluate international nephrogenic systemic fibrosis (NSF) safety efforts.The Research on Adverse Drug events And Reports methodology was used for assessment-the FAERS (through June 2009), ICNSFR and the legal data set (January 2002 to December 2010). Safety information was obtained from the European Medicines Agency, the Danish Medicine Agency and the Food and Drug Administration.The FAERS encompassed the largest number (n = 1395) of NSF reports. The ICNSFR contained the most complete (n = 335, 100%) histopathological data. A total of 382 individual biopsy-proven, product-specific NSF cases were analysed from the legal data set. 76.2% (291/382) identified exposure to gadodiamide, of which 67.7% (197/291) were unconfounded. Additionally, 40.1% (153/382) of cases involved gadopentetate dimeglumine, of which 48.4% (74/153) were unconfounded, while gadoversetamide was identified in 7.3% (28/382) of which 28.6% (8/28) were unconfounded. Some cases involved gadobenate dimeglumine or gadoteridol, 5.8% (22/382), all of which were confounded. The mean number of exposures to gadolinium-based contrast agents (GBCAs) was gadodiamide (3), gadopentetate dimeglumine (5) and gadoversetamide (2). Of the 279 unconfounded cases, all involved a linear-structured GBCA. 205 (73.5%) were a non-ionic GBCA while 74 (26.5%) were an ionic GBCA.Clinical and legal databases exhibit unique characteristics that prove complementary in safety evaluations. Use of the legal data set allowed the identification of the most commonly implicated GBCA.This article is the first to demonstrate explicitly the utility of a legal data set to pharmacovigilance research.

Background Brentuximab vedotin (BV) is a novel antibody drug conjugate consisting of an anti- CD30 IgG1 antibody, cAC10, linked to monomethylauristatin E, a potent inhibitor of microtubule polymerization. It is approved for treatment of relapsed classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) in the US (FDA; 8/2011) and Europe (EMA; 10/2012). Peripheral neuropathy was the most frequent treatment-related adverse event (AE) in phase II trials, and the most common Grade 3 or higher toxicity apart from cytopenias. Although abdominal pain has been observed in up to 25% of all patients, pancreatitis is a previously unrecognized AE. We now report 8 cases of BV-associated pancreatitis, 2 of them fatal. Methods Following a grade 5 AE from pancreatitis in a patient receiving single-agent BV on an ongoing clinical trial ([NCT01476410][1]), collaborating investigators examined their collective cases of pancreatitis associated with BV. Lymphoma specialists at other centers were solicited for additional events. IRB or Ethics Committee approval as required was obtained in all cases. AE's reported to the FDA Adverse Event Report Systems (FAERS) from 6/2011-7/2013 were also examined. Data was collected and analyzed through the Research on Adverse Drug Events and Reports Project. Immunohistochemical staining with the anti-CD30 antibody BER-H2 (DAKO) was performed on residual normal pancreas from one of the fatal cases and normal control pancreas. Results Eight cases of BV-associated pancreatitis were identified by collaborators, and one additional report with limited information was listed in FAERS. Demographic, treatment and AE information for the eight complete cases is detailed in [Table 1][2]. In all cases, BV was administered as a single agent. In seven cases, the dosing was 1.8 mg/kg every 21 days with a maximum of 180 mg; in one case, BV was administered weekly at 1.2 mg/kg (days 1,8,15, q 28). Two patients were retreated with BV after resolution of pancreatitis; one had no further evidence of pancreatitis and proceeded to a stem cell transplant, whereas the other patient, having recovered from Grade 4 pancreatitis, experienced a second episode (Grade 3). All patients demonstrated clinical evidence of pancreatitis as manifested by severe abdominal pain and nausea. In addition, all patients had biochemical and radiologic evidence of pancreatitis. Notably, no patient had an antecedent history of excess alcohol use or radiologic evidence of biliary pathology. Two patients developed progressive and fatal multiorgan dysfunction as a consequence of acute pancreatitis. An autopsy performed on one of the two fatalities showed evidence of acute necrotizing pancreatitis as the cause of death; diffuse pancreatic parenchymal necrosis and fat necrosis were seen but no cholelithiasis. Although the anti-CD30 antibody BER-H2 was previously reported to stain normal pancreas (BLOOD 1989 74:1678), routine immunohistochemical staining for CD30 on both the patient pancreas and normal pancreas controls were negative. View this table: Table 1 BV-associated pancreatitis (n = 8) Conclusion This is the first series describing pancreatitis as a rare, but serious and potentially fatal toxicity related to BV. Pancreatitis has been previously reported with other microtubule inhibitors such as taxanes and vinca alkaloids, but the mechanism, as with BV, remains unclear. Genetic factors that predispose to both acute and chronic pancreatitis have been reported and may underlie a susceptibility to this uncommon complication of treatment with BV. Clinicians prescribing BV should evaluate patients who present with abdominal pain for pancreatitis, and should consider pre-treatment biochemical assessments with serum lipase and/or amylase. Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Evens: Seattle Genetics : Consultancy, Honoraria. Fenske: Seattle Genetics: Consultancy. Hamlin: Seattle Genetics : Consultancy, Honoraria. Coiffier: Millennium Pharmaceuticals : Consultancy. Engert: Millennium Pharmaceuticals : Consultancy. Moskowitz: Seattle Genetics : Research Funding. Ghosh: Millennium Pharmaceuticals : Membership on an entity’s Board of Directors or advisory committees. Petrich: Seattle Genetics : Consultancy, Honoraria, Research Funding. Gordon: Seattle Genetics : Research Funding. Winter: Seattle Genetics : Research Funding. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01476410&atom=%2Fbloodjournal%2F122%2F21%2F4380.atom [2]: #T1

The widespread use of bisphosphonates for osteoporosis is estimated to have reduced hip fracture rates by as much as 30%1. As more patients have used these drugs for longer durations, it has also been noted that a small number of patients have developed atypical femoral fractures, which were sometimes associated with delayed healing. Negative media attention regarding these rare events has, in one Australian report, resulted in a voluntary decline in bisphosphonate use sufficient to cause a projected seventy additional hip fractures and fourteen deaths in that country alone2. Although an absolute cause-and-effect relationship between atypical femoral fractures and bisphosphonates has not been established, the probability that these events represent rare adverse drug reactions has resulted in safety notifications and requirements for drug label warnings in the United States, Canada, and Australia3-5. In addition, the literature suggests that the incidence of atypical fractures increases with increasing duration of therapy6. It is also possible that lack of awareness and underreporting may mask the true frequency of these fractures7. In their very ambitious article, Edwards et al. attempt not only to come closer to establishing the actual incidence …

The phosphodiesterase 5 (PDE5)-selective inhibitors sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) are frequently prescribed for treatment of erectile dysfunction (ED). 1 These medications have implications for men with prostate cancer who undergo treatment with radical prostatectomy or radiation therapy (brachytherapy or external beam radiation), as these treatments are associated with an increased risk for ED. Instances of nonarteritic ischemic optic neuropathy (NAION) and permanent vision loss following ingestion of PDE5-selective inhibitors have been reported.2 – 4 Investigators affiliated with the Research on Adverse Drug Events and Reports (RADAR), an established pharmacovigilance program, reviewed the literature as well as US Food and Drug Administration (FDA) reports to determine the frequency and clinical characteristics of PDE5selective inhibitor-associated NAION and permanent vision loss in men with ED. Reports and associated toxicities We reviewed case descriptions of PDE5-selective inhibitor-associated optic neuropathy events reported to the FDA between 1998 and 2004 or in the peer-reviewed literature between 1998 and 2005. Thirty-nine cases of optic neuropathy in sildenafil- or tadalafil-treated patients were identified as case reports (n = 18) or in FDA databases (n = 21). Affected men were similar in age (median, 62 years), and 90% of the cases were reported among men who had ingested PDE5-selective inhibitors and suffered permanent vision loss. Importantly, the quality of the case reports in the FDA database is suboptimal given that they often lack important information on duration of PDE5-selective inhibitor use, time since ingestion of the most recent dose, identification of affected eye, fundoscopic examination findings, and response to de-challenge. A plausible explanation as to cause-and-effect relative to PDE5-selective inhibitor therapy and NAION does not exist.

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.

Background and objective: The antiretroviral nevirapine can cause severe hepatotoxicity when used ‘off-label’ for preventing mother-to-child HIV transmission (PMTCT), newborn post-exposure prophylaxis and for pre- and post-exposure prophylaxis among non-HIV-infected individuals. We describe the incidence of hepatotoxicity with short-versus long-course nevirapine-containing regimens in these groups. Methods: We reviewed hepatotoxicity cases among non-HIV-infected individuals and HIV-infected pregnant women and their offspring receiving short- (≤4 days) versus long-course (≥5 days) nevirapine prophylaxis. Sources included adverse event reports from pharmaceutical manufacturers and the US FDA, reports from peer-reviewed journals/scientific meetings and the Research on Adverse Drug events And Reports (RADAR) project. Hepatotoxicity was scored using the AIDS Clinical Trial Group criteria. Results: Toxicity data for 8216 patients treated with nevirapine-containing regimens were reviewed. Among 402 non-HIV-infected individuals receiving short- (n = 251) or long-course (n = 151) nevirapine, rates of grade 1–2 hepatotoxicity were 1.99% versus 5.30%, respectively, and rates of grade 3–4 hepatotoxicity were 0.00% versus 13.25%, respectively (p < 0.001 for both comparisons). Among 4740 HIV-infected pregnant women receiving short- (n = 3031) versus long-course (n=1709) nevirapine, rates of grade 1–2 hepatotoxicity were 0.62% and 7.04%, respectively, and rates of grade 3–4 hepatotoxicity were 0.23% versus 4.39%, respectively (p< 0.001 for both comparisons). The rates of grade 3–4 hepatotoxicity among 3074 neonates of nevirapine-exposed HIV-infected pregnant women were 0.8% for those receiving short-course (n = 2801) versus 1.1 % for those receiving long-course (n=273) therapy (p < 0.72). Conclusions: Therapy duration appears to significantly predict nevirapine hepatotoxicity. Short-course nevirapine for HIV prophylaxis is associated with fewer hepatotoxic reactions for non-HIV-infected individuals or pregnant HIV-infected women and their offspring, but administration of prophylactic nevirapine for ≥2 weeks appears to be associated with high rates of hepatotoxicity among non-HIV-infected individuals and HIV-infected pregnant mothers. When full highly active antiretroviral therapy (HAART) regimens are not available, single-dose nevirapine plus short-course nucleoside reverse transcriptase inhibitors to decrease the development of HIV viral resistance is an essential therapeutic option for PMTCT and these data support the safety of single-dose nevirapine in this setting.

Aromatase inhibitors (AIs) prevent the conversion of adrenal androgens into estrogens by the enzyme aromatase and thus impede the majority of estrogen production in peri- and postmenopausal women. By lowering estrogen levels, AIs inhibit tumor progression. Unlike other hormonal therapies, AIs produce no clinically relevant suppression of cortisol or aldosterone. Additionally, several large randomized trials comparing AIs with tamoxifen as first-line treatment of metastatic breast cancer have demonstrated similar or slightly superior clinical efficacy. Because of these attributes, AIs have become a widely popular breast cancer treatment in postmenopausal women. Recent instances of increased fracture risk have been reported among perimenopausal women using AI treatment. The use of AIs in perimenopausal women can decrease estrogen levels by approximately 90%, leading to the onset of premature menopause, increased bone turnover, and accelerated bone loss.1 The effects of AI-induced estrogen loss are less severe among pre- and postmenopausal women. Because estrogen is vital for maintaining bone health, perimenopausal women with breast cancer, like their menopausal counterparts, have demonstrated an increased risk of fractures while using AIs. In this article, investigators affiliated with RADAR (Research on Adverse Drug events And Reports), an established pharmacovigilance program, reviewed clinical trial reports and one observational study to determine the frequency and clinical characteristics of AI-associated fractures in menopausal women with breast cancer.

Granulocyte-colony stimulating factor (G-CSF) is widely administered to donors who provide peripheral blood stem cells (PBSC) for individuals who undergo hematopoietic stem cell transplants. Questions have been raised about the safety of G-CSF in this setting. Herein, the Research on Adverse Drug Events and Reports (RADAR) project investigators reviewed the literature on G-CSF-associated adverse events in healthy individuals or persons with chronic neutropenia or cancer. Toxicities identified included bone pain and rare instances of splenic rupture, allergic reactions, flares of underlying autoimmune disorders, lung injury and vascular events. Among healthy individuals, four patients developed splenic rupture shortly after G-CSF administration and three patients developed acute myeloid leukemia 1 to 5 years after G-CSF administration. Registry studies identified no increased risks of malignancy among healthy individuals who received G-CSF before PBSC harvesting. However, more than 2000 donors would have to be followed for 10 years to detect a 10-fold increase in leukemia risk. Our review identifies bone pain as the most common toxicity of G-CSF administration. There are questions about a causal relationship between G-CSF administration and acute leukemia, but more long-term safety data from database registries are needed to adequately evaluate such a relationship.

Pharmaceuticals used to treat hematologic malignancies can lead to unexpected adverse events that involve a wide range of organ systems and physiological processes. The National Cancer Institute and National Heart Lung and Blood Institute-funded Research on Adverse Drug Events and Reports (RADAR) project-a collaboration of the Robert H. Lurie Comprehensive Cancer Center, the Department of Veterans Affairs, the Northwestern University Feinberg School of Medicine, and numerous academic institutions-identifies and evaluates unexpected adverse drug reactions associated with drugs used to treat malignant disorders. This article reviews the features of the safety program maintained by the U.S. Food and Drug Administration and the RADAR program.

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) and granulocyte colony-stimulating factor (G-CSF) promote haematopoietic progenitor cell maturation. We reviewed the findings for healthy volunteers/donors who developed haematological malignancies following PEG-rHuMGDF or G-CSF administration. Information was reviewed for three of 538 volunteers who received PEG-rHuMGDF in clinical trials and two of 200 donors who underwent G-CSF mobilised stem cell harvesting procedures for sibling stem cell transplants. Mantle cell, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia were diagnosed 1-5 years after PEG-rHuMGDF exposure among three volunteers. For one patient, thrombocytopenia due to autoantibodies to PEG-rHuMGDF developed shortly after PEG-rHuMGDF administration and persisted until chemotherapy was administered. All three achieved complete remission, although one patient relapsed. Acute myeloid leukaemia was diagnosed 4 and 5 years after G-CSF mobilisation in two donors who underwent peripheral blood stem cell donation for sibling allogeneic haematopoietic stem cell transplantation. Following intensive chemotherapy, one died from acute leukaemia and the second is in complete remission. Controversy exists over the appropriateness of administering haematopoietic growth factors to healthy individuals. While a causal relationship with haematological malignancies cannot be demonstrated, long-term follow-up among healthy individuals who receive haematopoietic growth factors is needed.

BACKGROUND Gemcitabine is a commonly used chemotherapeutic agent structurally and pharmacologically similar to cytarabine. Recently, instances of severe gemcitabine-associated lung injury have been reported. Herein, investigators affiliated with the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program evaluated clinical characteristics of gemcitabine-associated severe acute lung injury from clinical trial reports, medical literature case reports, and spontaneous reports to the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). METHODS Clinical data were obtained by reviewing adverse event case reports for gemcitabine-associated lung injury as reported in the medical literature and in the FDA AERS database. Upper limit estimates of ADE rate were derived from review of published clinical trials reporting gemcitabine-associated lung injury rates of 10% or higher. RESULTS A total of 178 reports of gencitabine-associated lung injury were identified; in AERS, there were 55 cases from clinical trials and 92 spontaneous reports. A comprehensive search revealed 31 medical literature reports. Clinical features of gemcitabine-associated lung injury included dyspnea, fever, pulmonary infiltrate, and cough with recognition of toxicity occurring after a median duration of 48 (range, 1-529) days after initiation of gemcitabine. The taxanes, docetaxel and paclitaxel, were frequently reported as coadministered therapies. Eleven Phase II or Phase III clinical trials with 317 patients identified gemcitabine-associated lung injury rates of greater than 10%, with the highest rates (22% and 42%) being observed in Phase III clinical trials where Hodgkin disease patients were treated with a regimen that included gemcitabine and bleomycin. CONCLUSIONS High rates of gemcitabine-associated severe lung injury were observed when gemcitabine was combined with other therapies known to also cause lung injury. Physicians should have a high index of suspicion for this toxicity and report the relevant clinical findings to the FDA's AERS. Cancer 2006. © 2006 American Cancer Society.

ContextIn 1998, a multidisciplinary team of investigators initiated RADAR (Research on Adverse Drug events And Reports), a clinically based postmarketing surveillance program that systematically investigates and disseminates information describing serious and previously unrecognized adverse drug and device reactions (ADRs).ObjectiveTo describe the structure, operations, and preliminary findings from the RADAR project and related dissemination efforts by pharmaceutical suppliers and the US Food and Drug Administration (FDA).DesignAfter identifying a serious and unexpected clinical event suitable for further investigation, RADAR collaborators postulated clinical hypotheses and derived case series and incidence estimates from physician queries, published and unpublished clinical trials, published case reports, FDA databases, and manufacturer sales figures.ResultsRADAR investigators identified 16 types of serious ADRs among 1699 patients, of whom 169 (10%) died as a result of the reaction. Initial cases were identified by 7 RADAR investigators, 4 collaborating physicians, 2 attorneys, and by reviewing 3 published reports. Additional sources included queries of occupational health programs and medical directors of interventional cardiology laboratories (3 types of ADRs), published manuscripts and clinical trials (11 types of ADRs), review of medical records at a RADAR site (2 types of ADRs), unpublished clinical trial reports (3 types of ADRs), and reports from attorneys, family members, or patients (4 types of ADRs). Incidence estimates, ranging from 0.4% to 33%, were derived from 5 clinical trial reports, 2 physician queries, and 2 observational databases. Laboratory support for hypotheses included identification of 3 neutralizing antibodies and 3 histopathological findings. ADR reports were disseminated as 8 revised package inserts, 7 “dear doctor” letters, and 9 peer-reviewed articles.ConclusionA new, clinically based, hypothesis-driven approach to postmarketing surveillance may supplement existing regulatory surveillance systems and improve patient safety.

Since its introduction in 1988, recombinant human erythropoietin (epoetin) has been standard treatment for patients with anemia due to chronic kidney disease. From 1998 to 2004, nearly 200 epoetin-treated persons with chronic kidney disease developed antibodies to epoetin, resulting in pure red cell aplasia (PRCA). The majority of these patients received Eprex, an epoetin alfa product marketed exclusively outside the United States. Herein, we report on the long-term outcome of these individuals. For 170 chronic kidney disease patients who developed epoetin-associated PRCA and had 3 months or more follow-up information available, case reports from the Food and Drug Administration and epoetin manufacturers were reviewed for information on clinical characteristics of the patients, immunosuppressive treatments, epoetin responsiveness, and hematologic recovery. Overall, 64% of the PRCA patients received immunosuppressive therapy, including 19 who also underwent a renal transplantation. Thirty-seven percent experienced a hematologic recovery, with higher hematologic recovery rates among PRCA patients who received immunosuppressive therapy (57% vs 2%, P < .001). Among 34 patients who received epoetin after the onset of PRCA, 56% regained epoetin responsiveness. The highest rates of epoetin responsiveness were observed among persons whose antierythropoietin antibodies were undetectable when epoetin was administered (89%). Among chronic kidney disease patients with epoetin-associated PRCA, epoetin discontinuation and immunosuppressive therapy or renal transplantation is necessary for hematologic recovery. Reinitiation of epoetin therapy among individuals could be considered if antierythropoietin antibodies are undetectable.

6559 Background: RADAR is the only independent academic pharmacovigilance organization funded exclusively by peer-reviewed grants. We describe the role of high quality case reports in the detection of drug safety signals. Methods: RADAR has identified 11 cancer-related adverse drug reactions (ADRs). Initial reports for small numbers of cases were obtained from our own institution, NU, (4 ADRs) or from referral centers (7 ADRs). Clinicians at these centers voluntarily provided brief case reports to RADAR, who submitted detailed case reports to the FDA/manufacturer. Clinicians were promised that patient/provider data would be kept confidential and that these data would be submitted as peer-reviewed manuscripts. Results: See Table. Conclusions: RADAR was successful at signal generation and amplification because it focused on quality, not quantity of case reports. Pharmacovigilance efforts that allow clinicians to complete brief forms, maintain confidentiality of patient and provider, and result in submission of collaborative manuscripts may improve early detection of drug safety signals initiatives in oncology. [Table: see text] No significant financial relationships to disclose.

The Research on Adverse Drug Events and Reports project (RADAR) is one of only a few independent pharmacovigilance programs funded entirely by peer-reviewed grants. It is the only such program that focuses on serious adverse drug reactions (sADRs) related to hematology and oncology. RADAR leverages the resources of a comprehensive cancer center, an academic hematology/oncology program, and a global network of physicians. Since its inception in 1998, RADAR has identified 33 unique sADRs. Information about these sADRs are traditionally disseminated in peer-reviewed manuscripts (21 sADRs), warnings or black box warnings in FDA-approved package inserts or manufacturer warnings (12 sADRs), or Dear Doctor letters (8 sADRs). In the absence of formal collaborations between the FDA, drug manufacturers, and independent pharmacovigilance programs, RADAR has expanded its dissemination efforts to non-traditional strategies, such as face-to-face meetings with drug manufacturers (22 sADRs), which lead to further actions by regulatory agencies and stakeholders (Table). These actions have included revised clinical guidelines from NCCN, ASCO, ASH, and the American College of Radiology, FDA advisory hearings focusing on safety, the first ever drug safety focused citizen’s petition filed by a state attorney general, and safety statements from the Centers for Disease Control and Prevention. Moving forward, RADAR is developing novel strategies for dissemination by partnering with Consumer Reports, the internet-based Medpedia Project, and monthly safety columns published in Community Oncology and Oncology News International. Table. Hematology-related sADRs identified by RADAR and novel dissemination efforts. Drug sADR Peer-reviewed Publications (Year) FDA or Manufacturer Warnings (Year) Face-to-face meeting with drug manufacturer Actions by Regulatory Agencies or Stakeholders Ticlopidine Thrombotic Thrombocytopenic purpura Ann Intern Med (1998); Lancet (1998); Arch Intern Med (1999); JAMA (1999) Dear Doctor letter (1998); Boxed Warning (1999) Yes Drug sales diminished to minimal level due to safety concerns (even though generic drug); FDA presentation Clopidogrel Thrombotic thrombocytopenic purpura NEJM (2000); Transplantation (2002); Stroke (2004) Warnings (2000, 2006) Yes Patient message in direct-to-consumer advertisements Epoetin/darbepoetin Venous thromboembolism; mortality JAMA (2008) FDA Alerts (2006, 2007), Black box warning (2007) Yes FDA hearing; CMS policy change; EMEA guidelines change; NCCN guidelines change Epoetin Pure red-cell aplasia NEJM (2004); Blood (2005) Boxed warning (2002); Dear Doctor letter (2005) Yes Manufacturer changes; Canada Health; EMEA statements; FDA presentation Thalidomide/lenalidomide Venous thromboembolism JAMA (2006) Black box warning(2006) Yes Citizen’s petition by attorney general of Connecticut (upheld) Gemtuzumab Sinusoidal obstructive syndrome Leukemia Research (2006) Boxed warning (2001) Yes FDA-mandated postmarketing registry Rituximab Progressive multifocal leuko-encephalopathy ASH (2007); ASCO (2008) Black box warning (2006) Yes Under consideration G-CSF/GM-CSF Acute myeloid leukemia; myelodisplatic syndrome JNCI (2007) None Yes Reconsideration of G-CSF administration to pediatric donors in Japan PEG-rHuMGDF Lymphoproliferative disorder British J of Haematology (2006) None No Drug development discontinued because of safety concerns Zoledronate Osteonecrosis of the jaw Lancet Oncology (2008) Dear Doctor letter (2004) Yes Guidelines from radiology, dentistry, hematology, oncology Nevirapine Stevens-Johnson syndrome; hepatotoxicity J Acquir Immune Defic Syndr (2004) Boxed warning (1998); Warning (1999); Dear Doctor letters (2000, 2004) Yes Drug no longer. used for post-needle stick exposure to HIV by healthcare workers

Background: The accelerated approval (AA) regulation (21CFR314.510 Subpart H) is granted by the Food and Drug Administration (FDA) when drugs for serious medical illnesses are shown to be an improvement over available therapy. AA provides an option to use surrogate outcomes considered likely to predict clinical benefit. AA was initially developed to hasten access to HIV drugs, then, in 1995, AA was extended to cancer indications. Sponsors receiving AA are required to confirm clinical benefit (termed subpart H trials). Policy makers have several raised concerns: AA is no longer relevant today as the approval bar via this mechanism has been raised too high; many drugs that received AA did not complete subpart H trials; and some drugs approved by AA were subsequently found to be unsafe or ineffective. Methods: Using publicly available databases, we compared safety, efficacy, clinical development times, and subpart H completion rates for FDA-approved new molecular entities (NMEs) for hematologic and solid tumor cancers from 1995–2008. Results: 37% of all oncology NMEs received AA versus regular approval (64% during 1995–2003 and 33% during 2004–2008). Twenty oncology NMEs received FDA approval for hematologic malignancies (lymphomas, leukemias, Kaposi’s sarcoma, and myelodysplastic syndromes), accounting for 34% of regular approvals and 53% of AAs for oncology NMEs. Compared to NMEs approved for solid tumors, NMEs approved for hematologic malignancies were more likely to involve Orphan Drug indications (95% vs. 32%); to have shorter development times, defined as the interval between investigational new drug filing and marketing approval, (median 5.6 vs. 7.8 years); and to be approved based on phase II studies (65% vs. 29%). Prior to 2004, development times were similar for solid tumor and hematologic malignancy NMEs. Since 2004, development times have decreased by more than 2 years for hematologic malignancy NMEs, but not for solid tumor NMEs. 50% of NMEs approved for hematologic malignancies versus 71% of NMEs for solid tumor diagnoses are included in first-line cancer regimens in current National Comprehensive Cancer Network guidelines. Drugs approved for solid tumor and hematologic indications have similar safety profiles and efficacy; respectively, 30% and 38% carried black box warnings at initial approval, and 15% and 10% had black box warnings added post-approval. Studies confirming efficacy were completed for 89% of NMEs receiving AA for solid tumor indications versus 30% for NMEs receiving AA for hematologic malignancy indications. Concern that sponsors are not completing subpart H commitments has led the FDA to move from basing AA on final results of single-arm phase II trials to interim results of phase III trials. Conclusions: AAs for hematologic malignancy indications are less likely to complete Subpart H commitments. In the current era, development times for NMEs are shorter for hematologic malignancy versus solid tumor indications, principally related to the approval based on Phase II versus Phase III studies. Establishing a global policy that AA approval for cancer drugs should be based on interim results of phase III analyses rather than on final analyses of phase II trials may hamper development of novel therapies for hematologic malignancies. Solide tumor indications Hematologic malignancy indications 1995–2003 (n=21) 2004–2008 (n=10) 1995–2003 (n=11) 2004–2008 (n=9) Drugs receivving AA (%) 29 30 64 33 Orphan drugs (%) 24 40 100 78 Of AAs, Subpart H completion (%) 100 66 27 0 Approval based on phase II trial (%) 33 0 73 78 Median development time (years) 8.4 7.8 8.8 5.2

6635 Background: ESAs were approved in 1989 and 1993 for treatment of anemia associated with chronic kidney disease (CKD) or chemotherapy-associated anemia, respectively. Since then, clinicians hav...

Current FDA and pharmaceutical industry drug safety efforts rely on statistical review of large databases populated with voluntary reports of sADRs. These data are limited by low rates of complete reporting and high rates of underreporting. Improved post-marketing drug surveillance efforts are needed to improve patient safety. The RADAR project is an academic pharmacovigilance program that focuses on small numbers of thoroughly researched cases of sADRs. In the last decade, RADAR has utilized the resources of a comprehensive cancer center and a global network of collaborators to evaluate and disseminate information on sADRs, many of which are related to hematology. Between 1998 and 2007, RADAR investigated and reported 16 hematology-associated sADRs. RADAR disseminated information on over half of the sADRs within 2 years of FDA approval, compared to half of all new sADRs documented in the Physician’s Desk Reference within 7 years of FDA approval. RADAR’s novel pharmacovigilance methods identified previously undetected sADRs based on small numbers of completely described reports. The RADAR project’s experience shows that private sector programs that utilize small yet comprehensive datasets can significantly contribute to pharmacovigilance networks in hematology. As the FDA develops public-private networks to evaluate safety concerns associated with new drugs, focused independent efforts can assume increasing importance to address unmet needs. Summary of 16 hematology-associated sADRs reported by RADAR since 1998. Drug (FDA approval) sADR (# of reports) Clinical Setting (yr) Data Source Time to detection (yrs) FDA/Company alert PEG-rHuMGDF(unapproved) ITP (13) Healthy volunteers (2001) Phase I trials Preclinical detection NA PEG-rHuMGDF(unapproved) Lymphomas (3) Healthy volunteers (2003) Case reports Preclinical detection NA Ticlopidine (1991) TTP (13) CVA pts (1998) Case reports

19591 Background: Serious adverse drug reactions (sADRs) such as venous thromboembolism resulting from cancer pharmaceutical use are underappreciated and often misattributed to the cancer diagnosis, rather than the therapy. The Research on Adverse Drug events And Reports (RADAR) group evaluated factors associated with identification of serious cancer-related sADRs (i.e. an adverse drug reaction that results in death or severe organ failure). Methods: Information on sources of clinical information, incidence, setting, and time from FDA approval to initial identification was obtained for sADRs that resulted in death or severe organ failure. Most of the ADRs are described as Black Box warnings or in “Dear Doctor” letters. Results: Summarized in table . Conclusion: Clinical trial safety reports from off-label settings facilitate identification of common (>3% rate) cancer associated sADRs. Case reports and observational databases from on-label settings facilitate detection of rare cancer-associated sADRs ( No significant financial relationships to disclose. [Table: see text]

2552 Background: Cancer patients are at increased risk for VTE as compared to the general population, making VTE as a sADR difficult to detect in the oncology setting. In 2004, two phase III trials identified higher mortality rates among epo-treated cancer patients who were receiving chemotherapy in “off-label” settings- with these studies identifying higher VTE rates in the treatment arms. We reviewed data on epo/darb-associated VTE in the oncology setting. Methods: Data sources were meta-analyses and the FDA’s MedWatch database. Results: Since 1996, only 259 VTE reports (darb: n=30, epo: n=229) of VTE in the setting of chemotherapy and epo/darb were reported to MedWatch. Meta-analyses findings are tabulated below: Conclusions: In 2004, package inserts for Epo/Darb were revised, identifying increased risks of VTE with these agents in the oncology setting. Identification of this adverse drug reaction thirteen years after Epo received FDA approval for this indication (and had been prescribed to > 500,000 cancer patients) illustrates difficulties inherent with current pharmacovigilance efforts. [Table: see text] No significant financial relationships to disclose.

6519 Background: Two years after zoledronate, received FDA approval, four dental professionals treated 107 cases of osteonecrosis of the jaw (ONJ). We review the timeline and source for initial recognition of ONJ and the comprehensiveness of dissemination of information on this adverse drug event. Methods: Data sources included primary case series from dental professionals; published case reports, clinical trials, and cases reported to the manufacturers or the FDA. Exposure adjusted incidence rates estimates were derived from manufacturer sponsored and investigator initiated review of claims data from large cancer centers. Safety notifications were disseminated by the manufacturers, regulatory authorities, and academic investigators. Results: Between 2001 and 2003, 107 patients with ONJ received care from dental professionals. In late 2003, and 2004 peer-reviewed case series were published. By 2006, safety databases maintained by the FDA, the manufacturer, and the RADAR project included information on 2,270, 1,178, and 368 cases of ONJ, respectively. In 2004 and 2005, incidence estimates of 0.8 and 22 ONJ cases per 1,000 person-years of intravenous bisphosphonate therapy were reported by the manufacturer and academic investigators. From 2003 to 2006, safety information from manufacturers, national regulatory authorities, case series, and clinical guidelines were disseminated. Conclusions: Recognition and reporting of ONJ occurred two years after FDA approval of zoledronate, dissemination of safety information occurred in the third year, and publications were disseminated from year three to year five. The life-cycle for identification and information dissemination for this serious adverse drug reaction was short and comprehensive. [Table: see text] [Table: see text]

A new approach to pharmacovigilance developed by doctors in Chicago can identify adverse drug reactions up to six years before the Food and Drug Administration or monitoring programmes run by the drug industry, researchers say ( Archives of Internal Medicine 2007;167:1041-9 doi: 10.1001/archinte.167.10.1041). The scheme, the research on adverse drug events and reports (RADAR) project, was developed by Charles Bennett and colleagues at the Northwestern University Feinberg School of Medicine, in Chicago, and launched in 1998. Dr Bennett told the BMJ that other pharmacovigilance programmes are based on epidemiology and databases. The RADAR approach is based on considering whether there is a theoretical reason why a drug might have an adverse side …

The Food and Drug Administration (FDA) and pharmaceutical manufacturers conduct most postmarketing pharmaceutical safety investigations. These efforts are frequently based on data mining of databases. In 1998, investigators initiated the Research on Adverse Drug events And Reports (RADAR) project to investigate reports of serious adverse drug reactions (ADRs) and prospectively obtain information on these cases. We compare safety efforts for evaluating serious ADRs conducted by the FDA and pharmaceutical manufacturers vs the RADAR project.We evaluated the completeness of serious ADR descriptions in the FDA and RADAR databases and the comprehensiveness of notifications disseminated by pharmaceutical manufacturers and the RADAR investigators. A serious ADR was defined as an event that led to death or required intensive therapies to reverse.The RADAR investigators evaluated 16 serious ADRs. Compared with descriptions of these ADRs in FDA databases (2296 reports), reports in RADAR databases (472 reports) had a 2-fold higher rate of including information on history and physical examination (92% vs 45%; P.001) and a 9-fold higher rate of including basic science findings (34% vs 4%; P = .08). Safety notifications were disseminated earlier by pharmaceutical suppliers (2 vs 4 years after approval, respectively), although notifications were less likely to include information on incidence (46% vs 93%; P = .02), outcomes (8% vs 100%; P.001), treatment or prophylaxis (25% vs 93%; P.001), or references (8% vs 80%; P.001).Proactive safety efforts conducted by the RADAR investigators are more comprehensive than those conducted by the FDA and pharmaceutical manufacturers, but dissemination of related safety notifications is less timely.