Charles L. Bennett

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.

Purpose: Serious adverse drug event (sADE) reporting to Institutional Review Boards (IRB) is essential to ensure pharmaceutical safety. However, the quality of these reports has not been studied. Safety reports are especially important for cancer drugs that receive accelerated Food and Drug Administration approval, like imatinib, as preapproval experience with these drugs is limited. We evaluated the quality, accuracy, and completeness of sADE reports submitted to an IRB. Experimental Design: sADE reports submitted to an IRB from 14 clinical trials with imatinib were reviewed. Structured case report forms, containing detailed clinical data fields and a validated causality assessment instrument, were developed. Two forms were generated for each ADE, the first populated with data abstracted from the IRB reports, and the second populated with data from the corresponding clinical record. Completeness and causality assessments were evaluated for each of the two sources, and then compared. Accuracy (concordance between sources) was also assessed. Results: Of 115 sADEs reported for 177 cancer patients to the IRB, overall completeness of adverse event descriptions was 2.4-fold greater for structured case report forms populated with information from the clinical record versus the corresponding forms from IRB reports (95.0% versus 40.3%, P < 0.05). Information supporting causality assessments was recorded 3.5-fold more often in primary data sources versus IRB adverse event descriptions (93% versus 26%, P < 0.05). Some key clinical information was discrepant between the two sources. Conclusions: The use of structured syndrome-specific case report forms could enhance the quality of reporting to IRBs, thereby improving the safety of pharmaceuticals administered to cancer patients.

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.

There has been a dramatic sea change in the use of erythropoiesis‐stimulating agents (ESAs) for anemic persons with chronic kidney disease (CKD) or cancer patients undergoing chemotherapy. An important area that has not been addressed previously is a CKD patient who also has a malignancy. Clinical guidelines exist that outline recommended treatments for each disease, but the intersection of the two disease processes presents difficult decisions for patients and physicians. Herein, we review the background underlying recent revisions in clinical alerts and guidelines for ESAs, and provide guidance for treating anemia among CKD patients who are receiving no therapy, chemotherapy with curative intent, or chemotherapy with palliative intent. The guiding principle is that comprehensive assessment of risks and benefits in the relevant clinical setting is imperative.

BACKGROUND. Few studies have examined the costs of supportive care for radiochemotherapy‐induced mucosits/pharyngitis among patients with head and neck cancer (HNC) or lung cancers despite the documented negative clinical impact of these complications. METHODS. The authors identified a retrospective cohort of patients with HNC or nonsmall lung cancer (NSCLC) who had received radiochemotherapy at 1 of 3 Chicago hospitals (a Veterans Administration hospital, a county hospital, or a tertiary care hospital). Charts were reviewed for the presence/absence of severe mucositis/pharyngitis and the medical resources that were used. Resource estimates were converted into cost units obtained from standard sources (hospital bills, Medicare physician fee schedule, Red Book). Estimates of resources used and direct medical costs were compared for patients who did and patients who did not develop severe mucositis/pharyngitis. RESULTS. Severe mucositis/pharyngitis occurred in 70.1% of 99 patients with HNC and in 37.5% of 40 patients with NSCLC during radiochemotherapy. The total median medical costs per patient were $39,313 for patients with mucositis/pharyngitis and $20,798 for patients without mucositis/pharyngitis (P = .007). Extended inpatient hospitalization accounted for $12,600 of the increased medical costs (median 14 days [$19,600] with severe mucositis/pharyngitis vs 5 days [$7000] without; P = .017). For patients who had HNC with mucositis/pharyngitis, incremental inpatient hospitalization costs were $14,000, and total medical costs were $17,244. For patients who had NSCLC with mucositis/pharyngitis, these costs were $11,200 and $25,000, respectively. CONCLUSIONS. In the current study, the medical costs among the patients with HNC and NSCLC who received radiochemotherapy were greater for those who developed severe mucositis/pharyngitis than for those who did not. Cancer 2008. © 2008 American Cancer Society.

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

Purpose: Colorectal cancer (CRC) screening is the most underused evidence-based cancer screening test in the United States. Few studies have reported the cost-effectiveness of CRC screening promotional efforts. In a recent randomized controlled trial, a patient-directed intervention for average-risk patients who had been referred for screening colonoscopy led to a 12% increase in CRC screening rates. The objective of this secondary analysis is to assess the cost-effectiveness of this intervention. Patients and Methods: Patients in the intervention arm received a customized mailed brochure that included a reminder to schedule a screening colonoscopy and general information about CRC, the importance of CRC screening, and how to prepare for the procedure. The end point was completion of screening colonoscopy. The costs and incremental cost-effectiveness ratio of this patient-directed intervention were derived. Sensitivity analyses were based on varying the costs of labor and supplies. Results: Rates of CRC screening for the intervention (n = 386 patients) versus control (n = 395) arms were 71% and 59%, respectively (P = .001). The total cost of the intervention was $1,927 and the incremental cost-effectiveness ratio was $43 per additional patient screened ($38 to $47 in a sensitivity analysis). Conclusion: An intervention based on mailing a customized brochure to patients who were referred for a screening colonoscopy improved CRC screening rates at a university-based general medicine clinic. This intervention was comparable in effectiveness and cost-effectiveness to a similar recently reported low-intensity patient-directed CRC screening intervention, and markedly more affordable and cost-effective than a previously reported physician-directed CRC screening promotion intervention.