Background.

In 2006, nephrologists in Denmark unexpectedly identified chronic kidney disease (CKD) patients with a new syndrome, nephrogenic systemic fibrosis (NSF). Subsequently, 1603 NSF patients were reported to the Food and Drug Administration. Sixty hospitals in the USA account for 93% of these cases, and two hospitals in Denmark account for 4% of these reports. We review Denmark’s identification and subsequent rapid eradication of NSF.

Methods.

NSF reports from clinicians, the Danish Medicines Agency (DMA) and gadolinium-based contrast agents (GBCAs) manufacturers were reviewed (2002–11).

Results.

In 1994, the DMA approved a non-ionic linear GBCA, gadodiamide (0.1 mmol/kg), for magnetic resonance imagings (MRIs), with a renal insufficiency contraindication. In 1996, 0.3 mmol/kg dosing received DMA approval. In 1998, the DMA removed renal contraindications. In 1997 and 2002, radiologists at Skejby Hospital and Herlev Hospital, respectively, began performing gadodiamide-enhanced magnetic resonance angiography scans (0.3 mmol/kg) of CKD patients. In 2005, Herlev clinicians requested assistance in evaluating etiological causes of NSF occurring among 10 CKD patients who had developed NSF. This investigation, focusing on infectious agents, was inconclusive. In 2006, Herlev clinicians reported that of 108 CKD patients who had received gadodiamide-enhanced MRI, 20 had developed probable NSF. Herlev radiologists voluntarily discontinued administering gadodiamide to all patients and no new NSF cases at Herlev Hospital developed subsequently. After meeting with Herlev radiologists, Skejby radiologists also discontinued administering gadodiamide to all patients. In 2007, the European Medicines Agency and the DMA contraindicated gadodiamide administration to CKD patients. In 2008, in response to these advisories, radiologists at the other 36 Danish hospitals discontinued administering gadodiamide to all patients, following on practices adopted at Skejby and Herlev Hospitals. In 2009, clinicians at Skejby Hospital reported that a look-back survey identified 33 CKD patients with NSF developing after undergoing GBCA-enhanced MRIs between 1999 and 2007. In 2010, an independent review, commissioned by the Minister of Health, concluded that the DMA had erred in rescinding gadodiamide’s renal insufficiency contraindication in 1998 and that this error was a key factor in the development of NSF in Denmark. In 2011, three NSF cases associated with macrocyclic GBCA-associated NSF and three NSF patients with Stages 3 and 4 CKD disease from Skejby Hospital were reported.

Conclusion.

A confluence of factors led to the development and eradication of NSF in Denmark.

Purpose

To report on the use of pharmaceutical patient assistance programs (PAPs) in the outpatient pharmacy at the largest tertiary cancer center in the United States.

Methods

We conducted a retrospective (July 1, 2006–Dec 31,2007) cross-sectional analysis of outpatient pharmacy, medical, and cancer registry records at the cancer center. The cancer center identified 104 medications available through PAPs. Study-eligible patients received at least one of these medications, either as a PAP case patient or as a PAP control non-user. Binary logit regression models predicted PAP use, and descriptive statistics compared PAP user and non-user medication fills.

Results

Of 25,552 cancer patients at who received an outpatient medication during the study period, 1,929 met study criteria (n=950 PAP users, 979 PAP non-users). In comparison to controls, PAP users were more likely to be uninsured (odds ratio (OR)=4.60, 95% confidence interval (CI): 2.118, 9.970), indigent (OR=16.95, 95% CI: 6.845, 41.960), and < 65 years old (OR=2.31, 95% CI: 1.517, 3.509). Of the most frequently dispensed medications to PAP users from PAPs (n=5,271), 88% (n=4,936) were for supportive care (e.g., nausea/vomiting). PAPs provided 35% (n=842) of the most common anticancer agents administered to PAP users (n=1,296), accounting for a monthly mean of $55,000 in pharmaceutical expenditures.

Conclusions

In the cancer center’s outpatient pharmacy, PAPs provided financial support for about a third of the most commonly used therapies, primarily for supportive care indications, for a small percentage of eligible cancer patients.

Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy (TMA). Studies report that the majority of TTP patients present with a deficiency of ADAMTS13 activity. In a database of TMA patients in Japan identified between 1998 and 2008, 186 patients with first onset of acquired idiopathic (ai) ADAMTS13-deficient TTP (ADAMTS13 activity <5%) were diagnosed. The median age of onset of TTP in this group of patients was 54 years, 54.8% were female, 75.8% had renal involvement, 79.0% had neurologic symptoms, and 97.8% had detectable inhibitors to ADAMTS13 activity. Younger patients were less likely to present with renal or neurologic dysfunction (p<0.01), while older patients were more likely to die during the TTP hospitalization (p<0.05). Findings from this cohort in Japan differ from those reported previously from the United States, Europe, and Korea with respect to age at onset (two decades younger in the other cohort) and gender composition (60% to 100% female in the other cohort). We conclude that in one of the largest cohorts of ai-TTP with severe deficiency of ADAMTS13 activity reported to date, demographic characteristics differ in Japanese patients relative to those reported from a large Caucasian registry from Western societies. Additional studies exploring these findings are needed.

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.

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.

Objectives

An emerging issue in the proxy literature is whether specifying different proxy viewpoints contributes to different health-related quality of life (HRQL) assessments, and if so, how might each perspective be informative in medical decision making. The aims of this study were to determine if informal caregiver assessments of patients with prostate cancer differed when prompted from both the patient perspective (proxy-patient) and their own viewpoint (proxy-proxy), and to identify factors associated with differences in proxy perspectives (ie, the intraproxy gap).

Research Design and Methods

Using a cross-sectional design, prostate cancer patients and their informal caregivers were recruited from urology clinics in the Jesse Brown Veterans Affairs Healthcare System in Chicago. Dyads assessed HRQL using the EQ-5D visual analog scale (VAS) and EORTC QLQ-C30.

Results

Of 87 dyads, most caregivers were female (83%) and were spouses/partners (58%). Mean difference scores between proxy-patient and proxy-proxy perspectives were statistically significant for QLQ-C30 physical and emotional functioning, and VAS (all P < 0.05), with the proxy-patient perspective closer to patient self-report. Emotional functioning had the largest difference, mean 6.0 (SD 12.8), an effect size = 0.47. Factors weakly correlated with the intraproxy gap included relationship (spouse) and proxy gender for role functioning, and health literacy (limited/functional) for physical functioning (all P < 0.05, 0.20 < r < 0.35).

Conclusions

Meaningful differences between proxy-patient and proxy-proxy perspectives on mental health were consistent with a conceptual framework for understanding proxy perspectives. Prompting different proxy viewpoints on patient health could help clinicians identify patients who may benefit from clinical intervention.

Objectives

We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).

Background

The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).

Methods

Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.

Results

Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.

Conclusions

Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.

Purpose

US veterans have been shown to be a vulnerable population with high cancer rates, and cancer care quality in Veterans Affairs (VA) hospitals is the focus of a congressionally mandated review. We examined rates of surgery and chemotherapy use among veterans with colon cancer at VA and non-VA facilities in California to gain insight into factors associated with quality of cancer care.

Methods

A retrospective cohort of incident colon cancer patients from the California Cancer Registry, who were ≥ 66 years old and eligible to use VA and Medicare between 1999 and 2001, were observed for 6 months after diagnosis.

Results

Among 601 veterans with colon cancer, 72% were initially diagnosed and treated in non-VA facilities. Among veterans with stage I to III cancer, those diagnosed and initially treated in VA facilities experienced similar colectomy rates as those at non-VA facilities. Stage III patients diagnosed and initially treated in VA versus non-VA facilities had similar odds of receiving adjuvant chemotherapy. In both settings, older patients had lower odds of receiving chemotherapy than their younger counterparts even when race and comorbidity were considered (age 76 to 85 years: odds ratio [OR] = 0.18; 95% CI, 0.07 to 0.46; age ≥ 86 years: OR = 0.17; 95% CI, 0.04 to 0.73).

Conclusion

In California, older veterans with colon cancer used both VA and non-VA facilities for cancer treatment, and odds of receiving cancer-directed surgery and chemotherapy were similar in both systems. Among stage III patients, older age lowered odds of receiving adjuvant chemotherapy in both systems. Further studies should continue to explore potential health system effects on quality of colon cancer care across the United States.

Purpose

Colorectal cancer (CRC) screening remains underutilized in the United States. Prior studies reporting the cost effectiveness of randomized interventions to improve CRC screening have not been replicated in the setting of small physician practices. We recently conducted a randomized trial evaluating an academic detailing intervention in 264 small practices in geographically diverse New York City communities. The objective of this secondary analysis is to assess the cost effectiveness of this intervention.

Methods

A total of 264 physician offices were randomly assigned to usual care or to a series of visits from trained physician educators. CRC screening rates were measured at baseline and 12 months. The intervention costs were measured and the incremental cost-effectiveness ratio (ICER) was derived. Sensitivity analyses were based on varying cost and effectiveness estimates.

Results

Academic detailing was associated with a 7% increase in CRC screening with colonoscopy. The total intervention cost was $147,865, and the ICER was $21,124 per percentage point increase in CRC screening rate. Sensitivity analyses that varied the costs of the intervention and the average medical practice size were associated with ICERs ranging from $13,631 to $36,109 per percentage point increase in CRC screening rates.

Conclusion

A comprehensive, multicomponent academic detailing intervention conducted in small practices in metropolitan New York was clinically effective in improving CRC screening rates, but was not cost effective.

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.

Background

In recent decades, extensive resources have been invested to develop cellular, molecular and genomic technologies with clinical applications that span the continuum of cancer care.

Methods

In December 2006, the National Cancer Institute sponsored the first workshop to uniquely examine the state of health services research on cancer-related cellular, molecular and genomic technologies and identify challenges and priorities for expanding the evidence base on their effectiveness in routine care.

Results

This article summarizes the workshop outcomes, which included development of a comprehensive research agenda that incorporates health and safety endpoints, utilization patterns, patient and provider preferences, quality of care and access, disparities, economics and decision modeling, trends in cancer outcomes, and health-related quality of life among target populations.

Conclusions

Ultimately, the successful adoption of useful technologies will depend on understanding and influencing the patient, provider, health care system and societal factors that contribute to their uptake and effectiveness in ‘real-world’ settings.

Background:

Drug- and device-associated hypersensitivity reactions are serious toxicities that can result in respiratory failure or acute cardiac ischemic events, or even severe hypersensitivity syndromes such as Stevens–Johnson syndrome. These toxicities are usually poorly described in the “black box” warnings section of the product labels.

Methods:

Adverse event reports contained in databases maintained by the Project on Medical Research on Adverse Drug Events and Reports (Med-RADAR), product labels, safety advisories disseminated by pharmaceutical manufacturers, the Food and Drug Administration (FDA), and the Centers for Disease Control and Prevention (CDC) were reviewed.

Results:

Adverse event reports identified three health care workers who developed nevirapine-associated Stevens–Johnson syndrome following occupational exposure to HIV-infected blood or blood products; four persons with localized hypersensitivity and fatal cardiac events associated with rapamycin- or paclitaxel-coated coronary artery stent placements; and six persons with breast cancer who developed severe or fatal anaphylaxis after receiving adjuvant chemotherapy with Cremophor-EL containing paclitaxel. Safety advisories from the FDA, CDC, and the relevant pharmaceutical manufacturers were ambiguous in their description in “black box” warning sections of package inserts describing these serious and potentially fatal toxicities.

Conclusion:

Improvements are needed in pharmacovigilance and subsequent dissemination of safety advisories for drug/device-associated hypersensitivity reactions.

The authors explain why physicians should refrain from ordering MRIs for patients with renal dysfunction unless the test is essential to provide diagnostic information. A possibly class-wide toxicity from the contrast agent gadolinium has been reported.

Background

The evaluation of research output, such as estimation of the proportion of treatment successes, is of ethical, scientific, and public importance but has rarely been evaluated systematically. We assessed how often experimental cancer treatments that undergo testing in randomized clinical trials (RCTs) result in discovery of successful new interventions.

Methods

We extracted data from all completed (published and unpublished) phase 3 RCTs conducted by the National Cancer Institute cooperative groups since their inception in 1955. Therapeutic successes were determined by (1) assessing the proportion of statistically significant trials favoring new or standard treatments, (2) determining the proportion of the trials in which new treatments were considered superior to standard treatments according to the original researchers, and (3) quantitatively synthesizing data for main clinical outcomes (overall and event-free survival).

Results

Data from 624 trials (781 randomized comparisons) involving 216 451 patients were analyzed. In all, 30% of trials had statistically significant results, of which new interventions were superior to established treatments in 80% of trials. The original researchers judged that the risk-benefit profile favored new treatments in 41% of comparisons (316 of 766). Hazard ratios for overall and event-free survival, available for 614 comparisons, were 0.95 (99% confidence interval [CI], 0.93-0.98) and 0.90 (99% CI, 0.87- 0.93), respectively, slightly favoring new treatments. Breakthrough interventions were discovered in 15% of trials.

Conclusions

Approximately 25% to 50% of new cancer treatments that reach the stage of assessment in RCTs will prove successful. The pattern of successes has become more stable over time. The results are consistent with the hypothesis that the ethical principle of equipoise defines limits of discoverability in clinical research and ultimately drives therapeutic advances in clinical medicine.

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.

BACKGROUND

Since 1988, millions of patients have received epoetin products intravenously (IV) and subcutaneously. In 1998, epoetin-associated pure red cell aplasia (PRCA) was first reported and causation was attributed to formulations without human serum albumin (HSA), subcutaneous administration, and uncoated rubber stoppers.

STUDY DESIGN AND METHODS

Data on erythropoietin (EPO)-associated PRCA were obtained from the Food and Drug Administration (FDA), regulatory authorities in other countries, and the manufacturers of epoetin alfa, epoetin beta, and darbepoetin. The data included information on numbers of PRCA cases and estimated exposure-adjusted incidence rates by EPO product, anemia etiology, administration route, country of PRCA identification, and date reported.

RESULTS

In 1999, academicians in Paris identified 12 EPO-treated patients with antibody-mediated PRCA; 11 of these patients were on hemodialysis and had received subcutaneous Eprex (Johnson & Johnson). In 2002, authorities in Europe, Australia, Singapore, and Canada mandated Eprex by IV route to hemodialysis patients, and the relevant manufacturers added Teflon coating to prefilled syringes of Eprex; PRCA cases subsequently decreased by 90 percent. By 2003, 180 Eprex-associated PRCA cases were identified in Europe, Canada, Australia, and Asia, despite improvements in handling. Since 2002, FDA safety databases include information on 59 new cases of antibody-associated PRCA, primarily associated with subcutaneous epoetin alfa and darbepoetin that does not contain HSA.

CONCLUSION

Independent actions by regulatory authorities, manufacturers, and academic researchers identified significant numbers of PRCA cases between 1998 and 2003 and characterized the probable etiology. Today, antibody-mediated PRCA is an infrequent class toxicity occurring among some hemodialysis patients on EPOs.

The authors reviewed FDA and manufacturer responses to a citizen petition filed to address thalidomide safety issues and concluded that new approaches addressing off-label safety are needed.

Purpose:

Pharmaceutical safety is a public health issue. In 2005, the Connecticut Attorney General (AG) raised concerns over adverse drug reactions in off-label settings, noting that thalidomide was approved to treat a rare illness, but more than 90% of its use was off label. A hematologist had reported thalidomide with doxorubicin or dexamethasone was associated with venous thromboembolism (VTE) rates of 25%. We review US Food and Drug Administration (FDA) and manufacturer responses to a citizen petition filed to address these thalidomide safety issues.

Methods:

Case study.

Results:

The AG petitioned the FDA requesting thalidomide-related safety actions. Coincidentally, the manufacturer submitted a supplemental New Drug Approval (sNDA), requesting approval to treat multiple myeloma with thalidomide-dexamethasone. FDA safety officers reviewed the petition and the literature and noted that VTE risks with thalidomide were not appropriately addressed in the existing package insert. In the sNDA application, the manufacturer reported thalidomide-associated toxicities for multiple myeloma were primarily somnolence and neurotoxicity, and a proposed package insert did not focus on VTE risks. In October, the FDA informed the Oncology Drug Division that VTE risks with thalidomide were poorly addressed in the existing label. After reviewing this memorandum, an Oncology Drug Division reviewer informed the manufacturer that approval of the sNDA would be delayed until several thalidomide-associated VTE safety actions, including revisions of the package insert, were implemented. The manufacturer and FDA agreed on these actions, and the sNDA was approved.

Conclusion:

New approaches addressing off-label safety are needed. The conditions that facilitated the successful response to this citizen petition are uncommon.

BACKGROUND

Adverse events resulting from medication error are a serious concern. Patients' literacy and their ability to understand medication information are increasingly seen as a safety issue.

OBJECTIVE

To examine whether adult patients receiving primary care services at a public hospital clinic were able to correctly interpret commonly used prescription medication warning labels.

DESIGN

In-person structured interviews with literacy assessment.

SETTING

Public hospital, primary care clinic.

PARTICIPANTS

A total of 251 adult patients waiting for an appointment at the Louisiana State University Health Sciences Center in Shreveport (LSUHSC-S) Primary Care Clinic.

MEASUREMENTS

Correct interpretation, as determined by expert panel review of patients' verbatim responses, for each of 8 commonly used prescription medication warning labels.

RESULTS

Approximately one-third of patients (n=74) were reading at or below the 6th-grade level (low literacy). Patient comprehension of warning labels was associated with one's literacy level. Multistep instructions proved difficult for patients across all literacy levels. After controlling for relevant potential confounding variables, patients with low literacy were 3.4 times less likely to interpret prescription medication warning labels correctly (95% confidence interval: 2.3 to 4.9).

CONCLUSIONS

Patients with low literacy had difficulty understanding prescription medication warning labels. Patients of all literacy levels had better understanding of warning labels that contained single-step versus multiple-step instructions. Warning labels should be developed with consumer participation, especially with lower literate populations, to ensure comprehension of short, concise messages created with familiar words and recognizable icons.

Background

This study was designed to evaluate if erythropoietin (EPO) is effective in the treatment of cancer related anemia, and if its effect remains unchanged when data are analyzed according to various clinical and methodological characteristics of the studies. We also wanted to demonstrate that cumulative meta-analysis (CMA) can be used to resolve uncertainty regarding clinical questions.

Methods

Systematic Review (SR) of the published literature on the role of EPO in cancer-related anemia. A cumulative meta-analysis (CMA) using a conservative approach was performed to determine the point in time when uncertainty about the effect of EPO on transfusion-related outcomes could be considered resolved. Participants: Patients included in randomized studies that compared EPO versus no therapy or placebo. Main outcome measures: Number of patients requiring transfusions.

Results

Nineteen trials were included. The pooled results indicated a significant effect of EPO in reducing the number of patients requiring transfusions [odds ratio (OR) = 0.41; 95%CI: 0.33 to 0.5; p < 0.00001;relative risk (RR) = 0.61; 95% CI: 0.54 to 0.68]. The results remain unchanged after the sensitivity analyses were performed according to the various clinical and methodological characteristics of the studies. The heterogeneity was less pronounced when OR was used instead of RR as the measure of the summary point estimate. Analysis according to OR was not heterogeneous, but the pooled RR was highly heterogeneous. A stepwise metaregression analysis did point to the possibility that treatment effect could have been exaggerated by inadequacy in allocation concealment and that larger treatment effects are seen at hb level > 11.5 g/dl. We identified 1995 as the point in time when a statistically significant effect of EPO was demonstrated and after which we considered that uncertainty about EPO efficacy was resolved.

Conclusion

EPO is effective in the treatment of anemia in cancer patients. This could have already been known in 1995 if a CMA had been performed at that time.

Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.

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.