Safety and efficacy of an artificial intelligence-enabled decision tool for treatment decisions in neovascular age-related macular degeneration and an exploration of clinical pathway integration and implementation: protocol for a multi-methods validation study.

INTRODUCTION: Neovascular age-related macular degeneration (nAMD) management is one of the largest single-disease contributors to hospital outpatient appointments. Partial automation of nAMD treatment decisions could reduce demands on clinician time. Established artificial intelligence (AI)-enabled retinal imaging analysis tools, could be applied to this use-case, but are not yet validated for it. A primary qualitative investigation of stakeholder perceptions of such an AI-enabled decision tool is also absent. This multi-methods study aims to establish the safety and efficacy of an AI-enabled decision tool for nAMD treatment decisions and understand where on the clinical pathway it could sit and what factors are likely to influence its implementation. METHODS AND ANALYSIS: Single-centre retrospective imaging and clinical data will be collected from nAMD clinic visits at a National Health Service (NHS) teaching hospital ophthalmology service, including judgements of nAMD disease stability or activity made in real-world consultant-led-care. Dataset size will be set by a power calculation using the first 127 randomly sampled eligible clinic visits. An AI-enabled retinal segmentation tool and a rule-based decision tree will independently analyse imaging data to report nAMD stability or activity for each of these clinic visits. Independently, an external reading centre will receive both clinical and imaging data to generate an enhanced reference standard for each clinic visit. The non-inferiority of the relative negative predictive value of AI-enabled reports on disease activity relative to consultant-led-care judgements will then be tested. In parallel, approximately 40 semi-structured interviews will be conducted with key nAMD service stakeholders, including patients. Transcripts will be coded using a theoretical framework and thematic analysis will follow. ETHICS AND DISSEMINATION: NHS Research Ethics Committee and UK Health Research Authority approvals are in place (21/NW/0138). Informed consent is planned for interview participants only. Written and oral dissemination is planned to public, clinical, academic and commercial stakeholders.

C-reactive protein concentrations are higher in dogs with stage IV chronic kidney disease treated with intermittent hemodialysis.

In chronic kidney disease dogs, the inflammatory process increases C-reactive protein concentrations. This study aimed to determine C-reactive protein serum concentrations in stage IV chronic kidney disease dogs treated with intermittent hemodialysis. A prospective cohort study was conducted with 23 dogs allocated into three groups: control group (CG, n = 7), intermittent hemodialysis group (IHG, n = 8) and clinical treatment group (CTG, n = 8), both comprised of stage IV chronic kidney disease dogs. One blood sample from CG (initial evaluation) and two samples from IHG and CTG (first- and last-moment) were obtained to determine C-reactive protein concentration, total leukocytes, platelets, erythrocytes, total plasma protein, serum albumin, urea, creatinine, and phosphorus. C-reactive protein was higher in IHG compared to CG in the first- and last-moments (p <0.001) and compared to CTG in the first-moment (p = 0.0406). C-reactive protein presented moderate positive correlation with leukocytes (r = 0.5479; p = 0.01), and moderate negative correlation with albumin (r = - 0.5974; p = 0.006) and red blood cells (r = - 0.5878, p = 0.01). A high correlation coefficient was observed in the tests' evaluation (CI = 0.59-0.78; r = 0.70; P<0.0001). In conclusion, both assays used in this study to measure C-reactive protein have provided safe and reliable quantification of the results. Additionally, despite IHG dogs presented an active inflammatory profile, intermittent hemodialysis has proven to be beneficial, leading to a clinical improvement in life quality of patients, and thus being recommended for stage IV CKD dogs when performed by trained professionals.

A prospective, multi-center, randomized comparison of iron isomaltoside 1000 versus iron sucrose in patients with iron deficiency anemia; the FERWON-IDA trial.

Iron deficiency anemia (IDA) is prevalent, and intravenous iron, especially if given in a single dose, may result in better adherence compared with oral iron. The present trial (FERWON-IDA) is part of the FERWON program with iron isomaltoside 1000/ferric derisomaltose (IIM), evaluating safety and efficacy of high dose IIM in IDA patients of mixed etiologies. This was a randomized, open-label, comparative, multi-center trial conducted in the USA. The IDA patients were randomized 2:1 to a single dose of 1000 mg IIM, or iron sucrose (IS) administered as 200 mg intravenous injections, up to five times. The co-primary endpoints were adjudicated serious or severe hypersensitivity reactions, and change in hemoglobin from baseline to week eight. A total of 1512 patients were enrolled. The frequency of patients with serious or severe hypersensitivity reactions was 0.3% (95% confidence interval: 0.06;0.88) vs 0.4% (0.05;1.45) in the IIM and IS group, respectively. The co-primary safety objective was met, and no risk difference was observed between groups. The co-primary efficacy endpoint of non-inferiority in hemoglobin change was met, and IIM led to a significantly more rapid hematological response in the first two weeks. The frequency of cardiovascular events was 0.8% and 1.2% in the IIM and IS group, respectively (P = .570). The frequency of hypophosphatemia was low in both groups. Iron isomaltoside administered as 1000 mg resulted in a more rapid and more pronounced hematological response, compared with IS, which required multiple visits. The safety profile was similar with a low frequency of hypersensitivity reactions and cardiovascular events.

Accumulation Of Chronic Conditions At The Time Of Death Increased In Ontario From 1994 To 2013.

With falling mortality rates for several diseases, patients are living longer with complex multimorbidities. We explored the burden of multimorbidity at the time of death, how it varies by socioeconomic status, and trends over time in Ontario, Canada. We calculated the proportions of decedents with varying degrees of multimorbidity and types of conditions at death, and we analyzed the trend from 1994 to 2013 in the number of conditions at the time of death. The prevalence of multimorbidity at death increased from 79.6 percent in 1994 to 95.3 percent in 2013. An upward trend in the number of conditions per person at death was observed for all chronic conditions except chronic coronary syndrome, congestive heart failure, and stroke. Chronic respiratory diseases and diabetes were disproportionately represented in low-income and deprived neighborhoods. The trend toward greater multimorbidity burden over time and the existence of steep socioeconomic gradients underscore the importance of integrated health care planning for preventing and managing multiple complex conditions.

Hypocalcaemia in patients with metastatic bone disease treated with denosumab.

BACKGROUND: This analysis was performed to further characterise treatment-emergent hypocalcaemia in patients with bone metastases receiving denosumab. METHODS: Laboratory abnormalities and adverse events of hypocalcaemia in patients with metastatic bone disease were analysed using data from three identically designed phase 3 trials of subcutaneous denosumab 120 mg (n = 2841) versus intravenous zoledronic acid 4 mg (n = 2836). RESULTS: The overall incidence of laboratory events of hypocalcaemia grade ⩾ 2 was higher with denosumab (12.4%) than with zoledronic acid (5.3%). Hypocalcaemia events were primarily grade 2 in severity and usually occurred within the first 6 months of treatment. Patients who reported taking calcium and/or vitamin D supplements had a lower incidence of hypocalcaemia. Prostate cancer or small-cell lung cancer, reduced creatinine clearance and higher baseline bone turnover markers of urinary N-telopeptide of type I collagen (uNTx; > 50 versus ⩽ 50 nmol/mmol) and bone-specific alkaline phosphatase (BSAP; > 20.77 µg/L [median] versus ⩽ 20.77 µg/L) values were important risk factors for developing hypocalcaemia. The risk associated with increased baseline BSAP levels was greater among patients who had > 2 bone metastases at baseline versus those with ⩽ 2 bone metastases at baseline. CONCLUSION: Hypocalcaemia was more frequent with denosumab versus zoledronic acid, consistent with denosumab's greater antiresorptive effect. Low serum calcium levels and potential vitamin D deficiency should be corrected before initiating treatment with a potent osteoclast inhibitor, and corrected serum calcium levels should be monitored during treatment. Adequate calcium and vitamin D intake appears to substantially reduce the risk of hypocalcaemia.

Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors.

PURPOSE: Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma. METHODS: Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening. RESULTS: Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68-0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72-1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66-1.00), pain worsening (HR, 0.83; 95 % CI, 0.71-0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61-0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %). CONCLUSIONS: Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis.

Multispecialty physician networks in Ontario.

BACKGROUND: Large multispecialty physician group practices, with a central role for primary care practitioners, have been shown to achieve high-quality, low-cost care for patients with chronic disease. We assessed the extent to which informal multispecialty physician networks in Ontario could be identified by using health administrative data to exploit natural linkages among patients, physicians, and hospitals based on existing patient flow. METHODS: We linked each Ontario resident to his or her usual provider of primary care over the period from fiscal year 2008/2009 to fiscal year 2010/2011. We linked each specialist to the hospital where he or she performed the most inpatient services. We linked each primary care physician to the hospital where most of his or her ambulatory patients were admitted for non-maternal medical care. Each resident was then linked to the same hospital as his or her usual provider of primary care. We computed "loyalty" as the proportion of care to network residents provided by physicians and hospitals within their network. Smaller clusters were aggregated to create networks based on a minimum population size, distance, and loyalty. Networks were not constrained geographically. RESULTS: We identified 78 multispecialty physician networks, comprising 12,410 primary care physicians, 14,687 specialists, and 175 acute care hospitals serving a total of 12,917,178 people. Median network size was 134,723 residents, 125 primary care physicians, and 143 specialists. Virtually all eligible residents were linked to a usual provider of primary care and to a network. Most specialists (93.5%) and primary care physicians (98.2%) were linked to a hospital. Median network physician loyalty was 68.4% for all physician visits and 81.1% for primary care visits. Median non-maternal admission loyalty was 67.4%. Urban networks had lower loyalties and were less self-contained but had more health care resources. INTERPRETATION: We demonstrated the feasibility of identifying informal multispecialty physician networks in Ontario on the basis of patterns of health care-seeking behaviour. Networks were reasonably self-contained, in that individual residents received most of their care from providers within their respective networks. Formal constitution of networks could foster accountability for efficient, integrated care through care management tools and quality improvement, the ideas behind "accountable care organizations."

Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.

PURPOSE: This study compared denosumab, a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand antibody, with zoledronic acid (ZA) for delaying or preventing skeletal-related events (SRE) in patients with advanced cancer and bone metastases (excluding breast and prostate) or myeloma. PATIENTS AND METHODS: Eligible patients were randomly assigned in a double-blind, double-dummy design to receive monthly subcutaneous denosumab 120 mg (n = 886) or intravenous ZA 4 mg (dose adjusted for renal impairment; n = 890). Daily supplemental calcium and vitamin D were strongly recommended. The primary end point was time to first on-study SRE (pathologic fracture, radiation or surgery to bone, or spinal cord compression). RESULTS: Denosumab was noninferior to ZA in delaying time to first on-study SRE (hazard ratio, 0.84; 95% CI, 0.71 to 0.98; P = .0007). Although directionally favorable, denosumab was not statistically superior to ZA in delaying time to first on-study SRE (P = .03 unadjusted; P = .06 adjusted for multiplicity) or time to first-and-subsequent (multiple) SRE (rate ratio, 0.90; 95% CI, 0.77 to 1.04; P = .14). Overall survival and disease progression were similar between groups. Hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred at similarly low rates in both groups. Acute-phase reactions after the first dose occurred more frequently with ZA, as did renal adverse events and elevations in serum creatinine based on National Cancer Institute Common Toxicity Criteria for Adverse Events grading. CONCLUSION: Denosumab was noninferior (trending to superiority) to ZA in preventing or delaying first on-study SRE in patients with advanced cancer metastatic to bone or myeloma. Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.

Deconstructing cancer: what makes a good-quality news story?

OBJECTIVE: To describe an in-depth analysis of the content and quality of stories about new cancer interventions in Australian media. DESIGN AND SETTING: Search of the Media Doctor Australia media-monitoring website for stories about newly reported cancer interventions, including drugs, diagnostic tests, surgery and complementary therapies, that had been collected from June 2004 to June 2009 and rated for quality using a validated rating instrument. A mixed-methods approach was used to analyse data and story content. Data from the website on stories about other new health interventions and procedures were compared. MAIN OUTCOME MEASURES: Differences in quality scores between cancer-related news stories ("cancer stories") and other stories, and between types of media outlet; differences in how cancer was reported in terms of cancer type, morbidity, mortality, and in the use of hyperbole and emotive language. RESULTS: 272 unique cancer stories were critically reviewed by Media Doctor Australia. Cancer stories had significantly higher scores for quality than other stories (F=7.1; df=1; P=0.008). Most cancer stories concerned disease affecting the breast or prostate gland, with breast cancer appearing to be over-represented as a topic relative to its incidence. Pairwise comparisons showed statistically significant superiority for broadsheet newspaper stories over online stories (F=12.7; df=1; P<0.001) and television stories (F=10.7; df=1; P=0.001). Descriptions of morbidity and mortality were variable and often confusing in terms of numbers, time periods and locations. Literary devices including hyperbole and emotive language were used extensively, mostly by the researchers. CONCLUSIONS: While reporting of cancer in the general media is of low quality, many of the poorer aspects of content are directly attributable to the researchers. Researchers and journals need to do more to ensure that a higher standard of information about cancer is presented to the media.

Cell salvage for minimising perioperative allogeneic blood transfusion.

BACKGROUND: Concerns regarding the safety of transfused blood have prompted reconsideration of the use of allogeneic (from an unrelated donor) red blood cell (RBC) transfusion, and a range of techniques to minimise transfusion requirements. OBJECTIVES: To examine the evidence for the efficacy of cell salvage in reducing allogeneic blood transfusion and the evidence for any effect on clinical outcomes. SEARCH STRATEGY: We identified studies by searching CENTRAL (The Cochrane Library 2009, Issue 2), MEDLINE (1950 to June 2009), EMBASE (1980 to June 2009), the internet (to August 2009) and bibliographies of published articles. SELECTION CRITERIA: Randomised controlled trials with a concurrent control group in which adult patients, scheduled for non-urgent surgery, were randomised to cell salvage (autotransfusion) or to a control group who did not receive the intervention. DATA COLLECTION AND ANALYSIS: Data were independently extracted and the risk of bias assessed. Relative risks (RR) and weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Data were pooled using a random-effects model. The primary outcomes were the number of patients exposed to allogeneic red cell transfusion and the amount of blood transfused. Other clinical outcomes are detailed in the review. MAIN RESULTS: A total of 75 trials were included. Overall, the use of cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 38% (RR 0.62; 95% CI 0.55 to 0.70). The absolute reduction in risk (ARR) of receiving an allogeneic RBC transfusion was 21% (95% CI 15% to 26%). In orthopaedic procedures the RR of exposure to RBC transfusion was 0.46 (95% CI 0.37 to 0.57) compared to 0.77 (95% CI 0.69 to 0.86) for cardiac procedures. The use of cell salvage resulted in an average saving of 0.68 units of allogeneic RBC per patient (WMD -0.68; 95% CI -0.88 to -0.49). Cell salvage did not appear to impact adversely on clinical outcomes. AUTHORS' CONCLUSIONS: The results suggest cell salvage is efficacious in reducing the need for allogeneic red cell transfusion in adult elective cardiac and orthopaedic surgery. The use of cell salvage did not appear to impact adversely on clinical outcomes. However, the methodological quality of trials was poor. As the trials were unblinded and lacked adequate concealment of treatment allocation, transfusion practices may have been influenced by knowledge of the patients' treatment status potentially biasing the results in favour of cell salvage.

Cell salvage for minimising perioperative allogeneic blood transfusion.

BACKGROUND: Concerns regarding the safety of transfused blood, have prompted reconsideration of the use of allogeneic (blood from an unrelated donor) red blood cell (RBC) transfusion, and a range of techniques to minimise transfusion requirements. OBJECTIVES: To examine the evidence for the efficacy of cell salvage in reducing allogeneic blood transfusion and the evidence for any effect on clinical outcomes. SEARCH STRATEGY: We identified studies by searching CENTRAL (The Cochrane Library 2009, Issue 2), MEDLINE (1950 to June 2009), EMBASE (1980 to June 2009), the Internet (to August 2009) and bibliographies of published articles. SELECTION CRITERIA: Randomised controlled trials with a concurrent control group in which adult patients, scheduled for non-urgent surgery, were randomised to cell salvage (autotransfusion), or to a control group, who did not receive the intervention. DATA COLLECTION AND ANALYSIS: Data were independently extracted and the risk of bias assessed. Relative risks (RR) and weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Data were pooled using a random effects model. The primary outcomes were the number of patients exposed to allogeneic red cell transfusion, and the amount of blood transfused. Other clinical outcomes are detailed in the review. MAIN RESULTS: A total of 75 trials were included. Overall, the use of cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 38% (RR=0.62: 95% CI 0.55 to 0.70). The absolute reduction in risk (ARR) of receiving an allogeneic RBC transfusion was 21% (95% CI 15% to 26%). In orthopaedic procedures the RR of exposure to RBC transfusion was 0.46 (95% CI 0.37 to 0.57) compared to 0.77 (95% CI 0.69 to 0.86) for cardiac procedures. The use of cell salvage resulted in an average saving of 0.68 units of allogeneic RBC per patient (WMD=-0.68; 95% CI -0.88 to -0.49). Cell salvage did not appear to impact adversely on clinical outcomes. AUTHORS' CONCLUSIONS: The results suggest cell salvage is efficacious in reducing the need for allogeneic red cell transfusion in adult elective cardiac and orthopaedic surgery. The use of cell salvage did not appear to impact adversely on clinical outcomes. However, the methodological quality of trials was poor. As the trials were unblinded and lacked adequate concealment of treatment allocation, transfusion practices may have been influenced by knowledge of the patients' treatment status potentially biasing the results in favour of cell salvage.

Pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials of darbepoetin alfa in the treatment of patients with chemotherapy-induced anemia.

PURPOSE: Although numerous clinical trials have demonstrated the efficacy and tolerability of erythropoiesis-stimulating agents (ESAs) in patients with chemotherapy-induced anemia (CIA), results of some recent trials and one meta-analysis have suggested that ESAs may negatively impact survival and/or disease control in patients with cancer. METHODS: To assess the benefits and risks of ESAs in CIA, we conducted a pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials in 2,122 patients with CIA receiving darbepoetin alfa (DA; n = 1,200) or placebo (n = 912). RESULTS: DA did not increase mortality (hazard ratio = 0.97; 95% CI, 0.85 to 1.1) and had no effect on progression-free survival (hazard ratio = 0.93; 95% CI, 0.84 to 1.04) and disease progression (hazard ratio = 0.92; 95% CI, 0.82 to 1.03), but, as expected, increased the risk for thromboembolic events (hazard ratio = 1.57; 95% CI, 1.10 to 2.26). Overall and progression-free survival were not affected by baseline hemoglobin and seemed better in patients who achieved hemoglobin more than 12 or more than 13 g/dL. Transfusions and rates of hemoglobin increase (> 1 g/dL in 14 days; > 2 g/dL in 28 days) owing to transfusions were associated with an increased risk for death and disease progression in both treatment groups; in the absence of transfusions, rates of hemoglobin increase did not appear to increase the risk for adverse outcomes. Compared with placebo, DA significantly reduced the risk of receiving one or more transfusion. CONCLUSION: There seemed to be no association between DA and risk of death or disease progression in this meta-analysis of individual patient data from DA studies conducted in CIA, the approved indication for ESAs in oncology.

Media reporting of health interventions: signs of improvement, but major problems persist.

BACKGROUND: Studies have persistently shown deficiencies in medical reporting by the mainstream media. We have been monitoring the accuracy and comprehensiveness of medical news reporting in Australia since mid 2004. This analysis of more than 1200 stories in the Australian media compares different types of media outlets and examines reporting trends over time. METHODS AND FINDINGS: Between March 2004 and June 2008 1230 news stories were rated on a national medical news monitoring web site, Media Doctor Australia. These covered a variety of health interventions ranging from drugs, diagnostic tests and surgery to dietary and complementary therapies. Each story was independently assessed by two reviewers using ten criteria. Scores were expressed as percentages of total assessable items deemed satisfactory according to a coding guide. Analysis of variance was used to compare mean scores and Fishers exact test to compare proportions. Trends over time were analysed using un-weighted linear regression analysis. Broadsheet newspapers had the highest average satisfactory scores: 58% (95% CI 56-60%), compared with tabloid newspapers and online news outlets, 48% (95% CI 44-52) and 48% (95% CI 46-50) respectively. The lowest scores were assigned to stories broadcast by human interest/current affairs television programmes (average score 33% (95% CI 28-38)). While there was a non- significant increase in average scores for all outlets, a significant improvement was seen in the online news media: a rise of 5.1% (95%CI 1.32, 8.97; P 0.009). Statistically significant improvements were seen in coverage of the potential harms of interventions, the availability of treatment or diagnostic options, and accurate quantification of benefits. CONCLUSION: Although the overall quality of medical reporting in the general media remains poor, this study showed modest improvements in some areas. However, the most striking finding was the continuing very poor coverage of health news by commercial current affairs television programs.

An analysis of news media coverage of complementary and alternative medicine.

BACKGROUND: To examine the accuracy and adequacy of lay media news stories about complementary and alternative medicines and therapies. METHODOLOGY/PRINCIPAL FINDINGS: A descriptive analysis of news stories about complementary and alternative medicine (CAM) in the Australian media using a national medical news monitoring website, mediadoctor.org.au. Each story was rated against 10 criteria by two individuals. Consensus scores of 222 news articles reporting therapeutic claims about complementary medicines posted on mediadoctor.org.au between 1 January 2004 and 1 September 2007 were calculated. The overall rating score for 222 CAM articles was 50% (95% CI 47% to 53%). There was a statistically significant (F = 3.68, p = 0.006) difference in cumulative mean scores according to type of therapy: biologically based practices (54%, 95% CI 50% to 58%); manipulative body based practices (46%, 95% CI 39% to 54%), whole medical systems (45%, 95% CI 32% to 58%), mind body medicine (41%, 95% CI 31% to 50%) and energy medicine (33%, 95% CI 11% to 55%). There was a statistically significant difference in cumulative mean scores (F = 3.72, p = 0.0001) according to the clinical outcome of interest with stories about cancer treatments (62%, 95% CI 54% to 70%) scoring highest and stories about treatments for children's behavioural and mental health concerns scoring lowest (31%, 95% CI 19% to 43%). Significant differences were also found in scores between media outlets. CONCLUSIONS/SIGNIFICANCE: There is substantial variability in news reporting practices about CAM. Overall, although they may be improving, the scores remain generally low. It appears that much of the information the public receives about CAM is inaccurate or incomplete.

Australian pharmaceutical policy: price control, equity, and drug innovation in Australia.

This paper outlines the increasing salience of drug "innovation" in the debate for reform of Australia's pharmaceutical policy, particularly change to Australia's price control mechanisms. The pharmaceutical industry has consistently criticised the central role of price control in Australia's pharmaceutical regulatory regime as an impediment to drug innovation and industry growth. Despite ambivalent or contrary evidence on the impact of price control on drug innovation, this criticism, and the appeals for reform it supports, appear to be increasingly influential in directing pharmaceutical policy. This is particularly evident in the implementation of the Australia/United States Free Trade Agreement, which has led to a weakening of the historical process of evidence-based reference pricing in Australia. Should drug innovation come to dominate Australian pharmaceutical policy, there is the potential to precipitate a devaluing of the current public orientation of regulation and diminish equitable access to affordable pharmaceuticals. The manner in which trade policy has effectively undermined a publicly funded pharmaceutical benefits scheme has clear implications for many countries that maintain such programmes.

Guidelines and recommendations for the management of anaemia in patients with lymphoid malignancies.

Patients with lymphoid malignancies frequently require repetitive and intensive anticancer treatments to induce and maintain disease remission. Anaemia (haemoglobin [Hb] <12 g/dL) is a common and debilitating problem associated with both the malignancy itself and its treatment burden. Anaemia negatively impacts on all aspects of patient quality of life (QOL) and treatment outcomes and survival, particularly in this disease setting. Widely acknowledged goals of anaemia treatment include Hb correction to approximately 12 g/dL, reduction in transfusion requirements and optimisation of patient QOL. Since the introduction of recombinant human erythropoietic therapy, transfusion (once the only anaemia treatment option available) is now primarily reserved for non-responders or those with severe or life-threatening anaemia. Data from randomised, double-blind, placebo-controlled studies, and large, non-randomised, open-label, community-based studies, along with almost 15 years of practical experience, support the assertion that epoetin alfa administered at a dosage of 150-300 U/kg three times weekly or 40,000-60,000U once weekly, both of which are US FDA-approved dose administration schedules, can effectively and safely achieve anaemia treatment goals for the majority of patients with lymphoid malignancies. Data and practical experience collected over the last 5 years on another erythropoietic agent with a slightly longer half-life but lower binding affinity, darbepoetin alfa, show that this agent when administered according to the FDA-approved dose administration schedules (2.25-4.5 microg/kg once weekly or 500microg once every 3 weeks) or according to a commonly-administered dose in clinical practice (3.0-5.0 microg/kg once every 2 weeks) can also effectively and safely correct anaemia, reduce transfusion requirements and improve QOL in many patients with lymphoid malignancies. One comparative head-to-head trial suggested that epoetin alfa might be superior to darbepoetin alfa in anaemic cancer patients receiving chemotherapy with respect to timing and magnitude of Hb correction, although further study is necessary, especially concerning optimal dose administration. Alternative dose administration schedules, such as epoetin alfa 80,000U every 2 weeks from initiation or 80,000U every 3 weeks following initiation with once weekly administration and darbepoetin alfa 4.5 microg/kg every 3 weeks following initiation with once weekly administration, are being actively investigated with the goal of increased flexibility for patients and healthcare providers. The treatment of anaemia in patients with lymphoid malignancies is an important part of overall disease management, as evidenced by continuous investigation of existing erythropoietic agents and new agents. Although treatment guidelines issued by organisations such as the National Comprehensive Cancer Network (NCCN) and American Society of Hematology (ASH)/American Society of Clinical Oncology (ASCO) suggest intervention with erythropoietic therapy when Hb falls below 10-11 g/dL or based on clinical symptoms, data suggest that anaemia is vastly under-recognised and under-treated. Clearly, an update on the definition, identification and optimal management of anaemia in patients with lymphoid malignancies is warranted.

Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy.

PURPOSE: To evaluate the safety and efficacy of intravenous (IV) sodium ferric gluconate complex (FG), oral ferrous sulfate, or no iron to increase hemoglobin (Hb) in anemic cancer patients receiving chemotherapy and epoetin alfa. PATIENTS AND METHODS: In this open-label, multicenter trial, 187 patients with chemotherapy-related anemia (Hb <11 g/dl; serum ferritin > or =100 ng/ml or transferrin saturation > or =15%) scheduled to receive chemotherapy and epoetin alfa (40,000 U subcutaneously weekly) were randomized to 8 weeks of 125 mg of IV FG weekly, 325 mg of oral ferrous sulfate three times daily, or no iron. The primary outcome was a change in Hb from baseline to endpoint, first whole-blood or red blood cell transfusion, or study withdrawal. RESULTS: One hundred twenty-nine patients were evaluable for efficacy (FG, n = 41; oral iron, n = 44; no iron, n = 44). Mean increase in Hb was 2.4 g/dl (95% confidence interval [CI], 2.1-2.7) for FG (p = .0092 vs. oral iron; p = .0044 vs. no iron), 1.6 g/dl (95% CI, 1.1-2.1) for oral iron (p =.7695 vs. no iron), and 1.5 g/dl (95% CI, 1.1-1.9) for no iron. Hb response (increase > or =2 g/dl) was 73% for FG (p = .0099 vs. oral iron; p = .0029 vs. no iron), 46% for oral iron (p = .6687 vs. no iron), and 41% for no iron. FG was well tolerated. CONCLUSION: For cancer patients with chemotherapy-related anemia receiving epoetin alfa, FG produces a significantly greater increase in Hb and Hb response compared with oral iron or no iron, supporting more aggressive treatment with IV iron supplementation for these patients.

Epoetin alfa treatment for patients with chemotherapy-induced anemia.

Anemia (hemoglobin [Hb] < 12 g/dL) is a frequent and debilitating complication in the treatment of cancer. The negative effects of anemia include impairment of organ systems, disruption of important aspects of patient quality of life, and potential interference with completion and outcomes of cancer chemotherapy. Guidelines issued by the National Comprehensive Cancer Network and the American Society of Hematology/American Society of Clinical Oncology jointly suggest that anemia in patients with cancer be managed by restoring Hb levels to approximately 12 g/dL, thereby minimizing transfusion requirements and resolving clinical symptoms associated with anemia. Recombinant human erythropoietin (epoetin alfa) administered 150 U/kg 3 times weekly or 40,000 U once weekly has been shown in randomized, double-blind, placebo-controlled trials and large, open-label, nonrandomized, community-based studies to effectively and safely correct anemia in patients with cancer undergoing chemotherapy. Several clinical trials support that treatment with epoetin alfa results in quality of life benefits that significantly correlate with Hb increases. Areas currently being investigated with epoetin alfa in the chemotherapy setting include the following: extended dosing regimens beyond the Food and Drug Administration-approved 3-times-weekly and once-weekly dosing regimens, early intervention for mild anemia, effects on treatment outcomes and survival, and optimal administration of concurrent iron supplementation.