A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints

There is growing interest in integrated Phase I/II oncology clinical trials involving molecularly targeted agents (MTA). One of the main challenges of these trials are nontrivial dose–efficacy relationships and administration of MTAs in combination with other agents. While some designs were recently proposed for such Phase I/II trials, the majority of them consider the case of binary toxicity and efficacy endpoints only. At the same time, a continuous efficacy endpoint can carry more information about the agent's mechanism of action, but corresponding designs have received very limited attention in the literature. In this work, an extension of a recently developed information‐theoretic design for the case of a continuous efficacy endpoint is proposed. The design transforms the continuous outcome using the logistic transformation and uses an information–theoretic argument to govern selection during the trial. The performance of the design is investigated in settings of single‐agent and dual‐agent trials. It is found that the novel design leads to substantial improvements in operating characteristics compared to a model‐based alternative under scenarios with nonmonotonic dose/combination–efficacy relationships. The robustness of the design to missing/delayed efficacy responses and to the correlation in toxicity and efficacy endpoints is also investigated.     

An optimal Bayesian predictive probability design for phase II clinical trials with simple and complicated endpoints

Most existing phase II clinical trial designs focus on conventional chemotherapy with binary tumor response as the endpoint. The advent of novel therapies, such as molecularly targeted agents and immunotherapy, has made the endpoint of phase II trials more complicated, often involving ordinal, nested, and coprimary endpoints. We propose a simple and flexible Bayesian optimal phase II predictive probability (OPP) design that handles binary and complex endpoints in a unified way. The Dirichlet-multinomial model is employed to accommodate different types of endpoints. At each interim, given the observed interim data, we calculate the Bayesian predictive probability of success, should the trial continue to the maximum planned sample size, and use it to make the go/no-go decision. The OPP design controls the type I error rate, maximizes power or minimizes the expected sample size, and is easy to implement, because the go/no-go decision boundaries can be enumerated and included in the protocol before the onset of the trial. Simulation studies show that the OPP design has satisfactory operating characteristics.     

Application of the spiral plating method to study antimicrobial action

The spiral gradient endpoint (SGE), a developement method for determination of minimum inhibitory concentration (MIC), was compared to a standard agar dilution method (SAD). Three antimicrobials, benzyl-penicillin, ampicillin and gentamicin, were tested against a laboratory collection of 14 streptococci and r_s values were, depending on inoculum tested, 0.93−0.84, 0.97−0.89 and 0.86−0.73, respectively, for each antibiotic. Using a membrane transfer technique, the spiral plater was further evaluated as a method for determination of interaction between an aminoglycoside and 2 β-lactams. The effect of gentamicin at fixed concentrations of 2 and 8 mg.l⁻¹ on determination of MIC and minimum bactericidal concentration (MBC) for benzylpenicillin and ampicilin was determined. Synergy between gentamicin and the 2 β-lactams corresponded to previously published data in that, marked synergy required a degree of susceptibility by the streptococci to gentamicin (MIC<3 mg·l⁻¹) and a degree of insuscpetibility to the β-lactams.     

Correct and logical inference on efficacy in subgroups and their mixture for binary outcomes

Targeted therapies are becoming more common. In targeted therapy development, suppose its companion diagnostic test divides patients into a marker‐positive subgroup and its complementary marker‐negative subgroup. To find the right patient population for the therapy to target, inference on efficacy in the marker‐positive and marker‐negative subgroups as well as efficacy in the overall mixture population are all of interest. Depending on the type of clinical endpoints, inference on mixture population can be nontrivial and commonly used efficacy measures may not be suitable for a mixture population. Correlations among estimates of efficacy in the marker‐positive, marker‐negative, and overall mixture population play a crucial role in using an earlier phase study to inform on the design of a confirmatory study (e.g., determination of sample size). This article first shows that when the clinical endpoint is binary (such as respond or not), odds ratio is inappropriate as an efficacy measure in this setting, but relative response (RR) is appropriate. We show a safe way of calculating estimated correlations is to consider mixing subgroup response probabilities within each treatment arm first, and then derive the joint distribution of RR estimates. We also show, if one calculates RR within each subgroup first, how wrong the correlations can be if the Delta method derivation fails to take randomness of estimating the mixing coefficient into account.     

Uncertainty in Impact and Externality Assessments - Implications for Decision-Making (13 pp)

Goal, Scope and Background Many disciplines, amongst them LCIA, environmental impact and external cost assessments, are often faced with evaluating trade-offs between two or more alternative options in terms of a range of incommensurable indicators. Using process modeling and valuation, these indicators are quantified at mid- or endpoint levels. Recent discussion amongst LCA experts showed that because of the mutually exclusive aspects of uncertainty and relevance, the midpoint/endpoint debate is controversial and difficult to reconcile. This article is aimed at a more quantitative analysis of mid- and endpoint impacts, and the implications of uncertainty for decision-making. Methods The consequences for decision-making of uncertainties of endpoints are analysed quantitatively for the example of ExternE results, by employing statistical hypothesis testing. The Analytic Hierarchy Process (AHP) is then used to demonstrate the use of multi-criteria techniques at midpoint levels. Results and Discussion Statistical hypothesis testing at the endpoint level shows that for the ExternE example, probabilities of mistakenly favouring one alternative over another when they are in reality indistinguishable can be as high as 80%. Therefore, the best estimate of external cost is inadequate for most policy making purposes. Indicators at midpoint levels are more certain, but since they are only \proxy attributes\, they carry a hidden uncertainty in their relevance. Conclusion If endpoint information is too uncertain to allow a decision to be made with reasonable confidence, then the assessment can be carried out in midpoint terms. However, midpoint indicators are generally further removed from people's experience, and less relevant to the question that people actually want to solve. Nevertheless, if this ultimate question is unanswerable (within the certainty required by the decision-maker), a decision can be made on the basis of stakeholders' subjective judgments about the more certain midpoint levels. The crucial point is that these judgments are able to intuitively incorporate many aspects that impact modeling and valuation has trouble quantifying, such as perceived risk, distribution of burdens and benefits, equity, ethical, moral, religious and political beliefs and principles, immediacy and reversibility of potential impacts, voluntariness, controllability and familiarity of exposure, or perceived incompleteness of human knowledge.     

A short-duration dark adaptation protocol for assessment of age-related maculopathy

Dark adaptometry may be a useful diagnostic test and clinical trial endpoint for age-related maculopathy (ARM) because impaired night vision is a hallmark of early ARM. A novel dark adaptometer, the AdaptDx, was evaluated for the detection of ARM. The AdaptDx incorporates a 20-minute protocol optimized for the detection of ARM. ARM patients (N = 17) exhibited substantial dark adaptation impairment compared with normal adults (N = 17). The diagnostic sensitivity was 88% and the specificity was 100%. The diagnostic test characteristics of the AdaptDx are similar to previously reported studies using 60- to 120-minute protocols.     

Midpoints versus endpoints: The sacrifices and benefits

On May 25–26, 2000 in Brighton (England), the third in a series of international workshops was held under the umbrella of UNEP addressing issues in Life Cycle Impact Assessment (LCIA). The workshop provided a forum for experts to discuss midpoint vs. endpoint modeling. Midpoints are considered to be links in the cause-effect chain (environmental mechanism) of an impact category, prior to the endpoints, at which characterization factors or indicators can be derived to reflect the relative importance of emissions or extractions. Common examples of midpoint characterization factors include ozone depletion potentials, global warming potentials, and photochemical ozone (smog) creation potentials. Recently, however, some methodologies have adopted characterization factors at an endpoint level in the cause-effect chain for all categories of impact (e.g., human health impacts in terms of disability adjusted life years for carcinogenicity, climate change, ozone depletion, photochemical ozone creation; or impacts in terms of changes in biodiversity, etc.). The topics addressed at this workshop included the implications of midpoint versus endpoint indicators with respect to uncertainty (parameter, model and scenario), transparency and the ability to subsequently resolve trade-offs across impact categories using weighting techniques. The workshop closed with a consensus that both midpoint and endpoint methodologies provide useful information to the decision maker, prompting the call for tools that include both in a consistent framework.