Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk

Human and rabbit plasma contain a cholesteryl ester transfer protein (CETP) that promotes net mass transfers of cholesteryl esters from high density lipoproteins (HDL) to other plasma lipoprotein fractions. As predicted, inhibition of CETP in both humans and rabbits increases the concentration of cholesterol in the potentially protective HDL fraction, while decreasing it in potentially proatherogenic non-HDL fractions. Inhibition of CETP in rabbits also inhibits the development of diet-induced atherosclerosis. However, use of the CETP inhibitor torcetrapib in humans did not reduce atheroma in three imaging trials and caused an excess of deaths and cardiovascular events in a large clinical outcome trial. The precise explanation for the harm caused by torcetrapib is unknown but may relate to documented, potentially harmful effects unrelated to inhibition of CETP. More recently, a trial using the weak CETP inhibitor dalcetrapib, which raises HDL levels less effectively than torcetrapib and does not lower non-HDL lipoprotein levels, was terminated early for reasons of futility. There was no evidence that dalcetrapib caused harm in that trial. Despite these setbacks, the hypothesis that CETP inhibitors will be antiatherogenic in humans is still being tested in studies with anacetrapib and evacetrapib, two CETP inhibitors that are much more potent than dalcetrapib and that do not share the off-target adverse effects of torcetrapib.     

Chromatin-modifying agents in anti-cancer therapy

Epigenetic alterations are involved in every step of carcinogenesis. The development of chromatin-modifying agents (CMAs) has provided the ability to fight cancer by reversing these alterations. Currently, four CMAs have been approved for cancer treatment; two DNA demethylating agents and two deacetylase inhibitors. A number of promising CMAs are undergoing clinical trials in several cancer types. Moreover, already approved CMAs are still under clinical investigation to improve their efficacy and to extend their use to a broader panel of cancers. Combinatorial treatments with CMAs are already considered a promising strategy to improve clinical benefits and to limit side effects. The real mechanisms by which these CMAs allow the improvement and remission of patients are still obscure. A deeper analysis of the molecular features expressed by responding patients should be performed to reveal this information. In this review, we focus on clinical trials with CMAs, discussing the success and the pitfalls of this new class of anti-cancer drugs.     

Ethics, ambiguity aversion, and the review of complex translational clinical trials

Clinical trials of novel agents often present several layers of ethical challenge. Because time and resources for ethical and safety review are limited, how investigators, IRBs, and regulators allocate attention to a trial's various safety dimensions itself represents a critical ethical question. In what follows, I use the example of a Parkinson's disease gene transfer trial to show how risks involving unknown probabilities or outcomes (ambiguity), might sometimes draw attention away from risks that involve known probabilities or outcomes. This potentially undermines the goal of 'systematic and nonarbitrary analysis of risk' during ethical review. To counteract the possible effects of such attention biases, I propose that reviewers develop 'cognitive aids' like lists and, where appropriate, set aside time to discuss non-ambiguous risks. I also propose further research for addressing and understanding how attention allocation, emotion, and ambiguity influence ethical decision-making.     

Bayesian optimal design for phase II screening trials

Summary .   Most phase II screening designs available in the literature consider one treatment at a time. Each study is considered in isolation. We propose a more systematic decision-making approach to the phase II screening process. The sequential design allows for more efficiency and greater learning about treatments. The approach incorporates a Bayesian hierarchical model that allows combining information across several related studies in a formal way and improves estimation in small data sets by borrowing strength from other treatments. The design incorporates a utility function that includes sampling costs and possible future payoff. Computer simulations show that this method has high probability of discarding treatments with low success rates and moving treatments with high success rates to phase III trial.     

A comparison of methods for adaptive treatment selection

Traditionally drug development is generally divided into three phases which have different aims and objectives. Recently so-called adaptive seamless designs that allow combination of the objectives of different development phases into a single trial have gained much interest. Adaptive trials combining treatment selection typical for Phase II and confirmation of efficacy as in Phase III are referred to as adaptive seamless Phase II/III designs and are considered in this paper. We compared four methods for adaptive treatment selection, namely the classical Dunnett test, an adaptive version of the Dunnett test based on the conditional error approach, the combination test approach, and an approach within the classical group-sequential framework. The latter two approaches have only recently been published. In a simulation study we found that no one method dominates the others in terms of power apart from the adaptive Dunnett test that dominates the classical Dunnett by construction. Furthermore, scenarios under which one approach outperforms others are described.     

Stratified or Multicentre Analysis with Extended Mantel–Haenszel Statistics

Since its introduction in 1959 the ability of the classical Mantel-Haenszel (M–H) procedure for combining the odds ratios of a set of I 2 × 2 tables has led to its use also in stratified or multicentre type clinical trials. A familiar application is the M–H logrank test in survival analysis. An extension of the M–H procedure covering the case of 2 × K contingency tables (MANTEL , 1963) with ordered levels retains the essential property of pooling the results of I homogeneous tables (i.e. in absence of qualitative interactions). The assignment of some score for the K columns of a table is essential for the use of the method (in comparing 2 treatments). Some possibilities of score assignment are discussed: for clinical outcome variables such as the degree of severity of a disease, pain and so on, the score is at hand in a natural way. A less well-known type of scoring consists in ranking the observations of a continuous variable, leading to cell sizes of 1 or 0. In this case, however, if equidistant ranking was used, the E–M–H procedure appears as an extension of Wilcoxon's rank sum test and represents a powerful non-parametric approach in stratified or multicentre type designs with non normally distributed outcome variables. The results of some Monte-Carlo simulations for 2 possible equidistant ranking procedures are presented, which indicate only a moderate gain in power as compared to Wilcoxon's rank sum test under the common situation of centre effects not exceeding treatment effects. Use of the E–M–H pro?edure is also recommended as a simple method to overcome the potential bias due to unequally distributed prognostic factors among treatment groups.     

Seed quality effects in bulb onions (Allium cepa L.)

The nature and persistence of seed quality effects produced by a range of seed production treatments was investigated in the autumn-sown onion crop. Genotypically equivalent seed lots raised in different glasshouses within the same year were found to germinate at significantly different rates. The seed lot which emerged earlier produced larger seedlings and this difference in size persisted throughout the growing period. In a comparison between the effects of hand crossing and self-pollination techniques the hand crossing method produced a much lower total seed yield but heavier seeds and larger plants. The induced effects persisted throughout the year but were not significant in the mature bulb characters. The implications of these results upon the control of seed production for plant breeding and genetical experiments is discussed.