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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 [Cl], 3.44 to 5.92) for bisphosphonate use and nonhealingfemoral 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. [ABSTRACT FROM AUTHOR]

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 ofmarketing 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 clopidogrelassociated 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. [ABSTRACT FROM AUTHOR]

The article focuses on a conceptual model to evaluate the cost-effectiveness of cancer navigation programs such as the one used by the Patient Navigation Research Program (PNRP), a multicenter study supported by the National Cancer Institute in the U.S. It states that navigation programs improve access to healthcare but their efficiency, efficacy of cancer diagnostic and therapeutic services remain unclear. PNRP examines navigation programs that reduce time to deliver a quality cancer care.

The article discusses research which was conducted to review the mortality and venous thrombembolism (VTE) risks associated with administration of erythropoiesis-stimulating agent (ESA) for treating chemotherapy-associated anemia in patients with nonmyeloid malignancies. The data used included a published overview from the Cochrane Collaboration, MEDLINE and EMBASE databases, the web site of the U.S. Food and Drug Administration and ESA manufacturers and safety advisories. The selection used for review was phase 3 trials comparing ESAs with placebo or standard of care for anemia treatment in cancer patients. Research found that ESA administration to cancer patients is associated with increased risks of VTE and mortality.

The article reports on a study which evaluated serious adverse drug reaction (ADR) descriptions in the U.S. Food and Drug Administration (FDA) and Research on Adverse Drug events And Reports (RADAR) databases. The comprehensiveness of notifications sent out by drug manufacturers and the RADAR researchers was also studied. Results indicated that the proactive safety activities of the RADAR researchers are more comprehensive than those performed by drug companies and the FDA.

Summary: More than half of all serious adverse reactions are identified 7 or more years after a drug receives approval from the US Food and Drug Administration (FDA). In 2002, 9 months after the intravenous bisphosphonate zoledronic acid received regulatory approval for marketing, the FDA received reports of nine patients with cancer, who were treated with zoledronic acid, who unexpectedly developed osteonecrosis of the jaw. During the next 2 years, three oral surgeons described 104 patients with cancer with osteonecrosis of the jaw in the medical literature and identified intravenous bisphosphonate therapy as being common to the care of these patients. In subspecialty medical, radiology, and dental journals, case reports and case series described clinical features of osteonecrosis of the jaw in patients with cancer who were treated with bisphosphonates. Manufacturer-sponsored epidemiological studies reported the first estimates of the incidence of this toxic effect, ranging from 0·1% to 1·8%. By contrast, independent epidemiological efforts from clinicians and the International Myeloma Foundation reported incidence estimates between 5% and 10%. Between 2003 and 2005, warnings about the risks of bisphosphonate-associated osteonecrosis were disseminated by national regulatory agencies, the manufacturers of bisphosphonates, and the International Myeloma Foundation. From 2006, independent clinical recommendations for diagnosis, prevention, and treatment of this toxic effect have been disseminated by manufacturers, national regulatory authorities, the International Myeloma Foundation, and medical specialty organisations. Furthermore, independent efforts by pharmaceutical manufacturers, dental and medical professionals, a non-profit organisation (the International Myeloma Foundation), patients, and regulatory authorities has led to the rapid identification and dissemination of safety information for this serious adverse reaction. Better coordination of safety-related pharmacovigilance initiatives is now needed. [Copyright &y& Elsevier]

Background: Between 1988 and 1998, antibody-associated pure red-cell aplasia was reported in three patients who had undergone treatment with recombinant human erythropoietin (epoetin). Between 1998 and 2000, 13 such cases were reported from France — 12 in patients who had received the Eprex formulation of epoetin alfa and 1 in a patient who had received Neorecormon (a formulation of epoetin beta); both are products that are marketed outside the United States. Methods: We obtained reports of epoetin-associated pure red-cell aplasia from the Food and Drug Administration and from the manufacturers of Eprex, Epogen (another formulation of epoetin alfa), and Neorecormon. The numbers of case reports and estimates of exposure-adjusted incidence were analyzed according to the product, the cause of anemia, the route of administration, the country in which pure red-cell aplasia was identified, and the date on which pure red-cell aplasia was reported. Results: Between January 1998 and April 2004, 175 cases of epoetin-associated pure red-cell aplasia were reported for Eprex, 11 cases for Neorecormon, and 5 cases for Epogen. Over half these cases had occurred in France, Canada, the United Kingdom, and Spain. Between 2001 and 2003, the estimated exposure-adjusted incidence was 18 cases per 100,000 patient-years for the Eprex formulation without human serum albumin, 6 per 100,000 patient-years for the Eprex formulation with human serum albumin, 1 case per 100,000 patient-years for Neorecormon, and 0.2 case per 100,000 patient-years for Epogen. After procedures were adopted to ensure appropriate storage, handling, and administration of Eprex to patients with chronic kidney disease, the exposure-adjusted incidence decreased by 83 percent worldwide. Conclusions: After the peak incidence of Eprex-associated pure red-cell aplasia was reached in 2001, interventions designed in response to drug-monitoring programs worldwide resulted in a reduction of more than 80 percent in the incidence of pure red-cell aplasia due to Eprex. N Engl J Med 2004;351:1403-8. [ABSTRACT FROM AUTHOR]

To improve the care of older adults with cancer, the traditional approach to clinical trial design needs to be reconsidered. Older adults are underrepresented in clinical trials with limited or no information on geriatric-specific factors, such as cognition or comorbidities. To address this knowledge gap and increase relevance of therapeutic clinical trial results to the real-life population, integration of aspects relevant to older adults is needed in oncology clinical trials. Geriatric assessment (GA) is a multidimensional tool comprising validated measures assessing specific health domains that are more frequently affected in older adults, including aspects related to physical function, comorbidity, medication use (polypharmacy), cognitive and psychological status, social support, and nutritional status. There are several mechanisms for incorporating either the full GA or specific GA measures into oncology therapeutic clinical trials to contribute to the overarching goal of the trial. Mechanisms include utilizing GA measures to better characterize the trial population, define trial eligibility, allocate treatment receipt within the context of the trial, develop predictive models for treatment outcomes, guide supportive care strategies, personalize care delivery, and assess longitudinal changes in GA domains. The objective of this manuscript is to review how GA measures can contribute to the overall goal of a clinical trial, to provide a framework to guide the selection and integration of GA measures into clinical trial design, and ultimately enable accrual of older adults to clinical trials by facilitating the design of trials tailored to older adults treated in clinical practice., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The population of older adults with cancer in the United States is rapidly increasing, which will have a substantial impact on the oncology and public health workforces across the cancer continuum, from prevention to end of life. Unfortunately, inequities in existing social structures that cause increased psychosocial stressors have led to disparities in the incidence of cancer and the morbidity and mortality of cancer for individuals from marginalized backgrounds. It is imperative that older adults, especially those from historically marginalized backgrounds, be adequately represented in all stages of cancer research to address health inequities. Continued efforts and progress toward achieving social justice and health equity require a deeper commitment to and better understanding of the impact of social determinants of health within the cancer domain. Undoubtedly, a more holistic and integrated view that extends beyond the biologic and genetic factors of health must be adopted for health entities to recognize the critical role of environmental, behavioral, and social determinants in cancer health disparities. Against this backdrop, this paper uses a life course approach to present a multifactorial framework for understanding and addressing cancer disparities in an effort to advance social justice and health equity for racially and ethnically diverse older adults.

Competing Interests: Reginald D. Tucker-SeeleyLeadership: American Board of Internal Medicine FoundationNo other potential conflicts of interest were reported.

This Chapter provides an introduction and overview of the U.S. FDA REMS program and applicable regulatory aspects. Topics covered include the 2015 Draft Guidance, organization structure and functions, a discussion on pharmacovigilance and adverse event reports, and a discussion of the applicability of REMS in oncology.

Funded by the 21 st Century Cures Act, The Beau Biden Cancer Moonshot Initiative is broad, deep, integrative, and intended to expediently address cancer's most vexing problems. Launched in 2015, it is an effort to accelerate the pace of cancer research with a focus on breaking down silos through cross-pollination of research, recruitment of multidisciplinary clinical and basic science research teams, sharing of complex scientific databases, and the creation of public-private research partnerships. This audacious approach to cancer treatment is intended to alleviate the current burden of cancer within countries and across borders. At its core is the rapid development of safe drug therapies across different disciplines through the employment of genomics, targeted proteomics with predictive analytics, and other emerging drug therapies. It will use expansive patient registries and increase early access to clinical trials. The initiative is cocooned in forward-thinking drug policies that consider the specific needs of all oncology stakeholder groups both nationally and internationally.

Objective: To review and summarize reports of tendon rupture associated with each fluoroquinolone (FQ) currently marketed in the United States (US), as reported to the FDA's Adverse Event Reporting System (FAERS)., Methods: FAERS data were reviewed for reports of tendon rupture associated with each FQ from their respective approval date through September 2012. Disproportional reporting signal detection was estimated using empirical Bayes geometric mean (EBGM) with 95% confidence intervals (CI)., Results: There were 2495 FAERs reports of tendon rupture associated with currently approved FQs. Most FAERS reports were associated with levofloxacin (n = 1555) followed by ciprofloxacin (n = 606) and moxifloxacin (n = 230). Signal detection results for FQs were as follows: levofloxacin (EBGM = 55.2, 95% CI = 52.3 - 58.0), ciprofloxacin (EBGM = 20.0, 95% CI = 18.2 - 21.6), moxifloxacin (EBGM = 13.3, 95% CI = 11.7 - 15.1), norfloxacin (EBGM = 9.6, 95% CI = 6.5 - 13.5), ofloxacin (EBGM = 8.2, 95%CI = 6.3 - 10.2) and gemifloxacin (EBGM = 1.9, 95% CI = 0.7 - 4.5). The mean age of affected individuals was 59.6 ± 5.1 years. Corticosteroids were administered concomitantly with FQs in 21.2% of cases., Conclusion: As noted in boxed warnings, FQ use is associated with increased tendon rupture risk. Risk factors for FQ associated tendon rupture include use in the elderly, and in patients with concomitant corticosteroids. Further monitoring may be needed due to antibiotic overuse and marketing of newer FQs.

Objectives: To summarize reports of anaphylaxis associated with gadolinium-based contrast agents (GBCAs) reported to the Food and Drug Administrations Adverse Event Reporting System (FAERS), examine the safety signals of anaphylaxis from GBCAs, and perform a literature review of relevant case reports., Methods: FAERS (1/1988-8/2012) was searched using groups of preferred event terms for anaphylaxis combined with all drug names for GBCAs Signal detection involved determination of proportional reporting ratios (PRRs) and empirical Bayes geometric means (EBGM). Published case reports were identified through a Medline search (1/1988-7/2013)., Results: There were 614 GBCA FAERS reports of anaphylaxis, resulting in a safety signal (PRR = 6.2, 95% confidence interval (CI) = 5.7 - 6.7; EBGM = 5.1 CI = 5.6 - 6.6). Among GBCAs, 43% were associated with gadopentetate dimeglumine (PRR = 4.9, CI = 4.3 - 5.5; EBGM = 4.8, CI = 4.3 - 5.4), 29% with gadobenate dimeglumine (PRR = 17.5, CI = 15.2 - 20.2; EBGM = 17.1, CI = 14.6 - 19.8) , and 17% with gadoteridol (PRR = 5.7, CI = 4.7 - 6.8; EBGM = 5.6, CI = 4.6 - 56.7). There were 14 anaphylaxis case reports in the literature., Conclusions: GBCAs used as medical imaging agents, can cause life-threatening or fatal anaphylaxis. There were differences in disproportionality of reporting between between agents. Although differences in numbers of reports of anaphylaxis reflect relative utilization rates of the various agents, disproportionality analyses (PRR, EBGM) disclose significant safety signals of anaphylaxis associated with most GBCAs.

Background: Prostate cancer disproportionately affects low-income and minority men. This study evaluates the impact of a patient navigation intervention on timeliness of diagnostic resolution and treatment initiation among veterans with an abnormal prostate cancer screen., Methods: Participants were enrolled between 2006 and 2010. The intervention involved a social worker and lay health worker navigation team that assisted patients in overcoming barriers to care. For navigated (n = 245) versus control (n = 245) participants, we evaluated rates of diagnostic resolution and treatment and adjusted for race, age, and Gleason score., Results: Of 490 participants, 68% were African American, 47% were ≥ 65 years old, and 35% had cancer. Among those with an abnormal screen, navigation did not have a significant effect on time to diagnostic resolution compared to controls (median days of 97 versus 111; adj. HR 1.17, 95% CI, 0.96-1.43, p = 0.12). On analysis of the period beyond 80 days, navigated men reached resolution faster than controls (median of 151 days versus 190 days; adj. HR 1.41, 95% CI, 1.07-1.86, p = 0.01). Among those with cancer, navigation did not have a significant effect on time to treatment initiation compared to controls (median of 93 days versus 87 days; adj. HR 1.15, 95% CI, 0.82-1.62, p = 0.41)., Conclusion: Our navigation program did not significantly impact the overall time to resolution or treatment for men with prostate cancer compared to controls. The utility of navigation programs may extend beyond targeted navigation times, however, and future studies focusing on other outcomes measures are therefore needed.

Introduction: 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)., Objective: Herein, we describe the findings, dissemination efforts, and lessons learned from the first decade of the RADAR project., Methods: 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., Study Selection: All major RADAR publications from 1998 to the present are included in this analysis., Data Extraction: For each RADAR publication, data were abstracted on data source, correlative basic science findings, dissemination and resultant safety information., Results: 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)., Conclusion: 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 the relationship between boxed warnings issuance by the US Food and Drug Administration (FDA) and the proportional reporting rates of the associated adverse drug reactions (ADRs) to the FDA's Adverse Event Reporting System (FAERS) for multiple myeloma (MM) drugs., Methods: We compiled a list of all FDA approved MM drugs and identified their associated ADR boxed warnings, through FDA's website and physician desk reference. Drugs that were issued boxed warnings after their market launch were included in the analysis, i.e., melphalan, thalidomide, vincristine, carmustine and doxorubicin. For each drug/ADR boxed warning combination, we retrieved all reported cases from the FAERS and calculated their Empiric Bayes Geometric Means (EBGMs), in pre- and post-boxed warning periods. Chi-square tests were performed to compare serious adverse drug events before and after boxed warnings for all drug/ADR combinations., Results: A total of 10 drug/ADR boxed warning combinations were identified, of which EBGM signals increased for six combinations after a boxed warning was issued. Reports of serious adverse drug events also increased significantly (p < 0.05)., Conclusion: Boxed warnings were associated with increased FAERS reporting, indicating increased awareness of ADRs for MM drugs. Proactive pharmacovigilance programs, such as the FDA's Mini-Sentinel Project, may improve timeliness of detection of rare ADRs.

Individuals with type II diabetes have an increased risk of cancer diagnosis (relative risk [RR]=1.12-2.50) and mortality (RR=1.4) compared to normoglycemic individuals. Biologic mechanisms, including mitogenic effects of insulin, hyperglycemia, and increased oxidative stress, as well as behavioral factors (eg, difficulty managing the comorbidity) may explain the elevated risk. To investigate the effects of the comorbidity on disease management, the authors compared diabetes education utilization in individuals with diabetes-cancer co-morbidity to utilization by individuals with diabetes in the absence of cancer. The effect of diabetes education on outcomes was further assessed in the subset of individuals with diabetes-cancer comorbidity. Administrative claims data were used for this analysis. The study population included individuals >60 years of age and members of both commercial and Medicare Advantage health plans from a private national database of payer data, but excluded Medicare fee for service and Medicaid patients. Most of these individuals were eligible to receive reimbursement for diabetes education. Diabetes education utilization was identified using procedure codes. Outcomes were assessed for a 3-year time period. There was little difference in diabetes education utilization between individuals with diabetes in the absence of cancer (3.8% utilization) and those with diabetes-cancer comorbidity (3.5% utilization). Individuals who receive diabetes education are more likely to have multiple HbA1c tests per year, fewer emergency department visits, fewer hospital admissions, and lower care-associated costs (except for outpatient and pharmacy averages). When diabetes coexists with cancer, management of diabetes often lags, making diabetes education an imperative.

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.

In April 2009, the FDA retracted a warning asserting that ceftriaxone and intravenous calcium products should not be coadministered to any patient to prevent precipitation events leading to end-organ damage. Following that announcement, we sought to evaluate if the retraction was justified. A search of the FDA Adverse Event Reporting System was conducted to identify any ceftriaxone-calcium interactions that resulted in serious adverse drug events. Ceftazidime-calcium was used as a comparator agent. One hundred four events with ceftriaxone-calcium and 99 events with ceftazidime-calcium were identified. Adverse drug events were recorded according to the listed description of drug involvement (primary or secondary suspect) and were interpreted as probable, possible, unlikely, or unrelated. For ceftriaxone-calcium-related adverse events, 7.7% and 20.2% of the events were classified as probable and possible for embolism, respectively. Ceftazidime-calcium resulted in fewer probable embolic events (4%) but more possible embolic events (30.3%). Among cases that considered ceftriaxone or ceftazidime and calcium as the primary or secondary drug, one case was classified as a probable embolic event. That patient received ceftriaxone-calcium and died, although an attribution of causality was not possible. Our analysis suggests a lack of support for the occurrence of ceftriaxone-calcium precipitation events in adults. The results of the current analysis reinforce the revised FDA recommendations suggesting that patients >28 days old may receive ceftriaxone and calcium sequentially and provide a transparent and reproducible methodology for such evaluations.

Anemia is a widely prevalent complication among cancer patients. At the time of diagnosis, 30% to 40% of patients with non-Hodgkin lymphoma or Hodgkin lymphoma and up to 70% of patients with multiple myeloma are anemic; rates are higher among persons with myelodysplastic syndromes. Among patients with solid cancers or lymphomas, up to half develop anemia following chemotherapy. For almost 2 decades, erythropoiesis-stimulating agents (ESAs) were the primary treatment for cancer-related anemia. However, reassessments of benefits and risks of ESAs for cancer-associated anemia have occurred internationally. We reviewed guidelines and notifications from regulatory agencies and manufacturers, reimbursement policies, and utilization for ESAs in the cancer and chronic kidney disease settings within the United States, Europe, and Canada. In 2008 the US Food and Drug Administration (FDA) restricted ESAs from cancer patients seeking cure. Reimbursement is limited to hemoglobin levels < 10 g/dL. In the United States, ESA usage increased 340% between 2001 and 2006, and decreased 60% since 2007. The European Medicines Agency (EMEA) recommended that ESA benefits do not outweigh risks. In Europe between 2001 and 2006, ESA use increased 51%; since 2006, use decreased by 10%. In 2009, Canadian manufacturers recommended usage based on patient preferences. In Canada in 2007, approximately 20% of anemic cancer patients received ESAs, a 20% increase since 2004. In contrast to Europe, where ESA use has increased over time, reassessments of ESA-associated safety concerns in the United States have resulted in marked decrements in ESA use among cancer patients.

Racial disparities in HIV-care include the disproportionate impact of HIV/AIDS on African Americans. We conducted a retrospective review of 1,855 cases at 78 hospitals in nine cities to evaluate racial variations in inpatient care for AIDS-related Pneumocystis pneumonia (PCP) shortly after the introduction of highly active anti-retroviral therapies. While inpatient HIV-related PCP mortality was comparable between Whites and Hispanics (p=0.94), African Americans were less likely than Whites to die in-hospital (AOR 0.69, 95% CI 0.48, 0.99) and more likely to receive timely anti-PCP medications (AOR 1.67, 95% CI 1.21, 2.30) and timely corticosteroids (AOR 1.46, 95% CI 1.17, 1.82). Findings were compared with those from our study involving 1,547 patients at 82 hospitals in five cities over the first decade of the AIDS epidemic. In contrast to the first study, in the second decade African Americans were more likely to receive timely and appropriate therapy for HIV-related PCP, and resultantly were more likely to survive the hospitalization.

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.

Background: Cost-related medication non-adherence may be influenced by patients' perceived importance of their medications., Objectives: This exploratory pilot study addresses three related but distinct questions: Do patients perceive different levels of importance among their medications? What factors influence perceptions of medication importance? Is perceived importance associated with perceived worth of medications, and does expense impact on that association?, Methods: Study participants included individuals aged >or=60 years who were taking three or more prescription drugs. Semi-structured, in-person interviews were conducted to measure how patients rated their medications in terms of importance, expense and worth. Factors that influenced medication importance were identified using qualitative analysis. Ordinal logistic regression analyses were employed to examine the association between perceived importance and perceived worth of medications, and the impact of expense on that association., Results: For 143 prescription drugs reported by 20 participants, the weighted mean rating of medication importance was 8.2 (SD 1.04) on a scale from 0 (not important at all) to 10 (most important). Patients considered 38% of these medications to be expensive. The weighted mean rating of worth was 8.4 (SD 1.46) on a scale from 0 (not worth it at all) to 10 (most worth). Three major factors influenced medication importance: drug-related (characteristics, indications, effects and alternatives); patient-related (knowledge, attitudes and health); and external (the media, healthcare and family caregivers, and peers). Regression analyses showed an association between perceived importance and perceived worth for inexpensive medications (odds ratio [OR] 2.23; p = 0.002) and an even greater association between perceived importance and perceived worth for expensive medications (OR 4.29; p < 0.001)., Discussion: This study provides preliminary evidence that elderly patients perceive different levels of importance for their medications based on factors beyond clinical efficacy. Their perception of importance influences how they perceive their medications' worth, especially for medications of high costs. Understanding how patients perceive medication importance may help in the development of interventions to reduce cost-related non-adherence.

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.

Patients aged 65 years and older represent 12% of the US population yet account for approximately 56% of cancer cases and 69% of all cancer mortalities. The overall cost of cancer in 2005 was $209.9 billion--$74 billion for direct medical costs and $118.4 billion for indirect mortality costs. This paper considers the direct, indirect, and out-of-pocket expenditures incurred by cancer patients > or = 50 years of age. Several major empirical studies on supportive care for older patients and cancer-related costs were reviewed. Insurance coverage, hematologic malignancies, squamous cell carcinoma of the head and neck, and cancers of the breast, prostate, colorectum, and lung were evaluated. Major sources of direct medical expenditures covered by third-party insurers for patients aged 65 years and older include extended length of hospital stay, home health assistance following hospital discharge, adjuvant prescription medications, lower-risk treatment (for prostate cancer), and advent of new pharmaceuticals (for colorectal cancer). The mean total direct medical cost for breast cancer is $35,164, and the cumulative cost for prostate cancer is $42,570. Emerging targeted cancer drug costs range from $20,000 to $50,000 annually per patient. Additional clinical trials and cost-effective treatments are needed for older patients to ameliorate the disproportionate economic burden among older individuals with cancer. Additional research about cancer costs may also lead to reforms in cancer care reimbursement, and therefore provide access to affordable health care for older patients.

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.

Purpose: Colorectal cancer screening is underused, particularly in the Veterans Affairs (VA) population. In a randomized controlled trial, a health care provider-directed intervention that offered quarterly feedback to physicians on their patients' colorectal cancer screening rates led to a 9% increase in colorectal cancer screening rates among veterans. The objective of this secondary analysis was to assess the cost effectiveness of the colorectal cancer screening promotion intervention., Methods: Providers in the intervention arm attended an educational workshop on colorectal cancer screening and received confidential feedback on individual and group-specific colorectal cancer screening rates. The primary end point was completion of colorectal cancer screening tests. Sensitivity analyses investigated cost-effectiveness estimates varying the data collection methods, costs of labor and technology, and the effectiveness of the intervention., Results: Rates of colorectal cancer screening for the intervention versus control arms were 41.3% v 32.4%, respectively (P < .05). The incremental cost-effectiveness ratio was dollar 978 per additional veteran screened based on feedback reports generated from manual review of records. However, if feedback reports could be generated from information technology systems, sensitivity analyses indicate that the cost-effectiveness estimate would decrease to dollar 196 per additional veteran screened., Conclusion: An intervention based on quarterly feedback reports to physicians improved colorectal cancer screening rates at a VA medical center. This intervention would be cost effective if relevant data could be generated by existing information technology systems. Our findings may have broad applicability because a 2005 Medicare initiative will provide the VA electronic medical record system as a free benefit to all US physicians.

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.