Treatment switching in cancer trials: Issues and proposals

Objectives: Treatment switching occurs when patients in a randomized clinical trial switch from the treatment initially assigned to them to another treatment, typically from the control to experimental treatment. This study discusses the issues this raises and possible approaches to addressing them in trials of cancer drugs. Methods: Stakeholders from around the world were invited to a 1.5-day Workshop in Adelaide, Australia. This study attempts to capture the key points from the discussion and the perspectives of the various stakeholder groups, but is not a formal consensus statement. Results: Treatment switching raises challenging ethical issues with arguments for and against allowing it. It is increasingly common in cancer drug trials and presents challenges for the interpretation of results by regulators, clinicians, patients, and payers. Proposals are offered for good practice in the design, management, and analysis of trials and wider development programs for cancer drugs in which treatment switching has occurred or is likely to. Recommendations are also offered for further action to improve understanding of the importance and challenges of treatment switching and to promote agreement between key stakeholders on guidelines and other steps to address these challenges. Conclusions: The handling of treatment switching in trials is of concern to all stakeholders. On the basis of the discussions at the Adelaide International Workshop, there would appear to be common ground on approaches to addressing treatment switching in cancer trials and scope for the development of formal guidelines to inform the work of regulators, payers, industry, trial designers and other stakeholders

Impact of CTLA-4 checkpoint antibodies on ligand binding and Transendocytosis

Anti-CTLA-4 antibodies have pioneered the field of tumour immunotherapy. However, despite impressive clinical response data, the mechanism by which anti-CTLA-4 antibodies work is still controversial. Two major checkpoint antibodies (ipilimumab and tremelimumab) have been trialled clinically. Both have high affinity binding to CTLA-4 and occupy the ligand binding site, however recently it has been suggested that in some settings such antibodies may not block ligand-CTLA-4 interactions. Here we evaluated blocking capabilities of these antibodies in a variety of settings using both soluble and cell bound target proteins. We found that when ligands (CD80 or CD86) were expressed on cells, soluble CTLA-4-Ig bound in line with affinity expectations and that this interaction was effectively disrupted by both ipilimumab and tremelimumab antibodies. Similarly, cellular CTLA-4 binding to soluble ligands was comparably prevented. We further tested the ability of these antibodies to block transendocytosis, whereby CTLA-4 captures ligands from target cells during a cognate cell-cell interaction. Once again ipilimumab and tremelimumab were similar in preventing removal of ligand by transendocytosis. Furthermore, even once transendocytosis was ongoing and cell contact was fully established, the addition of these antibodies could prevent further ligand transfer. Together these data indicate that the above checkpoint inhibitors performed in-line with predictions based on affinity and binding site data and are capable of blocking CTLA-4-ligand interactions in a wide range of settings tested

In Vivo Assessment of Arsenic Bioavailability in Rice and Its Significance for Human Health Risk Assessment

BACKGROUND: Millions of people worldwide consume arsenic-contaminated rice; however, little is known about the uptake and bioavailability of arsenic species after arsenic-contaminated rice ingestion. OBJECTIVES: In this study, we assessed arsenic speciation in greenhouse-grown and supermarket-bought rice, and determined arsenic bioavailability in cooked rice using an in vivo swine model. RESULTS: In supermarket-bought rice, arsenic was present entirely in the inorganic form compared to greenhouse-grown rice (using irrigation water contaminated with sodium arsenate), where most (~ 86%) arsenic was present as dimethylarsinic acid (organic arsenic). Because of the low absolute bioavailability of dimethylarsinic acid and the high proportion of dimethylarsinic acid in greenhouse-grown rice, only 33 ± 3% (mean ± SD) of the total rice-bound arsenic was bioavailable. Conversely, in supermarket-bought rice cooked in water contaminated with sodium arsenate, arsenic was present entirely in the inorganic form, and bioavailability was high (89 ± 9%). CONCLUSIONS: These results indicate that arsenic bioavailability in rice is highly dependent on arsenic speciation, which in turn can vary depending on rice cultivar, arsenic in irrigation water, and the presence and nature of arsenic speciation in cooking water. Arsenic speciation and bioavailability are therefore critical parameters for reducing uncertainties when estimating exposure from the consumption of rice grown and cooked using arsenic-contaminated water

Development and validation of multivariable machine learning algorithms to predict risk of cancer in symptomatic patients referred urgently from primary care: a diagnostic accuracy study

Objectives To develop and validate tests to assess the risk of any cancer for patients referred to the NHS Urgent Suspected Cancer (2-week wait, 2WW) clinical pathways. Setting Primary and secondary care, one participating regional centre. Participants Retrospective analysis of data from 371 799 consecutive 2WW referrals in the Leeds region from 2011 to 2019. The development cohort was composed of 224 669 consecutive patients with an urgent suspected cancer referral in Leeds between January 2011 and December 2016. The diagnostic algorithms developed were then externally validated on a similar consecutive sample of 147 130 patients (between January 2017 and December 2019). All such patients over the age of 18 with a minimum set of blood counts and biochemistry measurements available were included in the cohort. Primary and secondary outcome measures sensitivity, specificity, negative predictive value, positive predictive value, Receiver Operating Characteristic (ROC) curve Area Under Curve (AUC), calibration curves Results We present results for two clinical use-cases. In use-case 1, the algorithms identify 20% of patients who do not have cancer and may not need an urgent 2WW referral. In use-case 2, they identify 90% of cancer cases with a high probability of cancer that could be prioritised for review. Conclusions Combining a panel of widely available blood markers produces effective blood tests for cancer for NHS 2WW patients. The tests are affordable, and can be deployed rapidly to any NHS pathology laboratory with no additional hardware requirements

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

The interaction of aminoacridines with DNA

129 leaves : ill., offprintsThesis (Ph.D.) -- University of Adelaide, Dept. of Zoology, 197

Interaction between Phenytoin, 5-(p-Hydroxyphenyl)-5- Phenyihydantoin and Vaiproate in the Rat

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Prices for innovative pharmaceutical products that provide health gain: A comparison between Australia and the United States

AbstractObjectivesPricing polices used in many countries are often viewed in the United States as a mechanism of price constraint. Support for this contention has arisen from pricing studies which demonstrate that the United States pays higher prices for many pharmaceutical products. No study to date, however, has examined the prices paid for pharmaceuticals that provide significant health gain, which might be expected to be lower where price constraints were operating. This study aimed to examine prices paid by federal government programs and agencies in Australia and the United States for pharmaceutical products that provide significant health gain.MethodsProducts identified by the US Food and Drug Administration and the Canadian Patented Medicines Prices Review Board as likely to confer significant health gains between 1999 and 2004 were identified. Australian and USfederal government prices ($US) and US average manufacturer prices (AMP), which do not include discounts or rebates, during the second quarter of 2006 were compared.ResultsOf 22 products for which comparisons were possible, Australian prices were higher than the US Federal Supply Schedule (FSS) prices for 14 (64%) products. When compared with AMP, Australian prices were higher for eight of the 22 products. Overall, Australian prices were higher on average by 4.2% when compared with the FSS and lower by 14.4% when compared with the AMP.ConclusionThese results suggest that Australian prices for medicines representing significant advances in therapy are similar to those paid under key US programs despite fundamental differences in policy contexts

Ensuring the safety of new medications and devices: are naltrexone implants safe? (editorial)

It is concerning that the recent research on naltrexone implants in Australia has not followed usual scientific processes. In particular, naltrexone implants have not been subject to the usual rigorous scrutiny required for new drug products seeking registration in this country. Nevertheless, they are available through the TGA Special Access Scheme; there is no requirement for TGA approval for access to unapproved goods in Australia for Category A patients under this Scheme, and no apparent requirement for collection of efficacy or safety data. Supporters of the naltrexone implant have argued that heroin injectors meet the criteria for Category A patients under the Scheme as “persons who are seriously ill with a condition from which death is reasonably likely to occur within a matter of months, or from which premature death is reasonably likely to occur in the absence of early treatment”