Going beyond probability of success: Opportunities for statisticians to influence quantitative decision-making at the portfolio level.

The pharmaceutical industry is plagued with long, costly development and high risk. Therefore, a company's effective management and optimisation of a portfolio of projects is critical for success. Project metrics such as the probability of success enable modelling of a company's pipeline accounting for the high uncertainty inherent within the industry.

Replenishing the pipeline: A quantitative approach to optimising the sourcing of new projects.

Large pharmaceutical companies maintain a portfolio of assets, some of which are projects under development while others are on the market and generating revenue. The budget allocated to R&D may not always be sufficient to fund all the available projects for development. Much attention has been paid to the selection of optimal subsets of available projects to fit within the available budget.

Quantifying the Benefits of Digital Biomarkers and Technology-Based Study Endpoints in Clinical Trials: Project Moneyball.

Introduction: Digital biomarkers have significant potential to transform drug development, but only a few have contributed meaningfully to bring new treatments to market. There are uncertainties in how they will generate quantifiable benefits in clinical trial performance and ultimately to the chances of phase 3 success. Here we have proposed a statistical framework and ran a proof-of-concept model with hypothetical digital biomarkers and visualized them in a familiar manner to study power calculation.

Do strict decision criteria hamper productivity in the pharmaceutical industry?

The discouragingly high rates of attrition in drug development, and in particular in Phase 2, warrant a closer look at the decision criteria applied for investment in the next phase (Phase 3). We have in this article evaluated Stop/Go criteria after Phase 2, based on a model encompassing both Phase 2 and 3, as well as the eventual outcome on the market. The results indicate that the value of a drug project is often maximized if rather liberal decision criteria are applied.

Selection bias, investment decisions and treatment effect distributions.

When making decisions regarding the investment and design for a Phase 3 programme in the development of a new drug, the results from preceding Phase 2 trials are an important source of information. However, only projects in which the Phase 2 results show promising treatment effects will typically be considered for a Phase 3 investment decision. This implies that, for those projects where Phase 3 is pursued, the underlying Phase 2 estimates are subject to selection bias.

A modelling framework for improved design and decision-making in drug development.

The development of a new drug is an extremely high-risk enterprise. The attrition rates of development projects and the average costs for each launched product are daunting, and the completion of a development program requires a very long time horizon. These facts imply that there are huge potential gains, should one be able to improve efficiency and enhance decision-making capabilities.

Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis.

One hallmark of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is infiltration of leukocytes into the CNS, where chemokines and their receptors play a major mediatory role. CX3CR1 is a chemokine receptor involved in leukocyte adhesion and migration and hence a mediator of immune defense reactions. The role of CX3CR1 in MS and EAE pathogenesis however remains to be fully assessed.

Modelling and simulation in the pharmaceutical industry--some reflections.

Modelling and simulation (M&S) is increasingly being applied in (clinical) drug development. It provides an opportune area for the community of pharmaceutical statisticians to pursue. In this article, we highlight useful principles behind the application of M&S.

A novel approach to data processing of the QT interval response in the conscious telemetered beagle dog.

Introduction: Drug-induced QT interval prolongation may lead to ventricular arrhythmias. The aim of the study was to optimize QT interval data processing to quantify drug-induced QT interval prolongation in the telemetry instrumented conscious dog model.

Methods: The test substances cisapride, dofetilide, haloperidol, and terfenadine and corresponding vehicles were given to male and female beagle dogs during two consecutive 90-min intravenous infusions.

Avoidance response of sediment living amphipods to zinc pyrithione as a measure of sediment toxicity.

An avoidance test was developed using non-cultured individuals of the sediment dwelling amphipod Monoporeia affinis. As test substance we used zinc pyrithione, an antifouling agent and a common shampoo ingredient. The toxicity to Daphnia and fish is well known but sediment toxicity of this very hydrophobic compound is less known.

Pharmacokinetic-pharmacodynamic modeling of drug-induced effect on the QT interval in conscious telemetered dogs.

Introduction: To assure drug safety, the investigation of the relationship between plasma concentration and drug-induced prolongation of the QT interval of the ECG is a challenge in drug discovery. For this purpose, dofetilide was utilized to demonstrate the benefits of characterizing the complete time course of concentrations and effect in conscious beagle dogs in the assessment of drug safety.

Method: On two separate occasions, four male and two female beagle dogs were given vehicle or the test substance, dofetilide (0.

Benefits of combining the sexes when evaluating data from toxicological studies.

In the assessment of the safety of a new drug, a large battery of toxicological studies is performed. In toxicological studies it is common practice to analyse the data from the sexes separately. We argue that this is not best practice and that much is to be gained from combining data from both sexes when evaluating studies.

Dynamics of lipids and polychlorinated biphenyls in a Baltic amphipod (Monoporeia affinis): a field study.

Processes such as accumulation and elimination, which control tissue concentration of polychlorinated biphenyls (PCBs), were examined over time in an in situ study of the amphipod Monoporeia affinis. These processes were studied with respect to individual PCB congeners, percentage lipid and composition, and body weight. A secondary objective was to examine the impact of seasonal variability in percentage lipids and lipid composition on PCB concentration in two coexisting Baltic amphipods, M.

Aspects of design and statistical analysis in the Comet assay.

Some aspects of the statistical design and analysis of the Comet (single cell gel electrophoresis) assay have been evaluated by means of a simulation study. The tail length and tail moment were selected for the quantification of DNA migration. Results from the simulation study showed that the choice of measure to summarize the cells on each slide is extremely important in order to facilitate an efficient analysis.