Simulations to Evaluate HIV Vaccine Trial Designs

Many HIV vaccine trials have been proposed to evaluate susceptibility of individuals. However, vac cines may also affect an epidemic's course at the population level by altering the infectiousness of vaccinated individuals who become infected. A vac cine trial design that does not estimate both suscep tibility and infectiousness might reject a proposed vaccine that is capable of halting the HIV epidemic. We describe a vaccine trial design called the Retro spective Partner Trial (RPT), which can quantify vaccine effects on both susceptibility and infectious ness. We describe HIVSIM, a simulation environ ment that generates simulated populations and al lows for empirical evaluation of the statistical power of the RPT. HIVSIM explicitly models a number of factors which influence transmission and preva lence, and which have proven difficult to model us ing standard models. These factors include the infec tion stage of infected individuals, partnership selec tion, the duration of partnerships and concurrence, and transmission of HIV. The simulation analysis indicates that the RPT design has substantially greater statistical power for identifying vaccines which, in spite of exhibiting poor protection against infection, are nonetheless capable of halting the HIV epidemic by substantially reducing the infectious ness of vaccinated individuals who become infected.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68501/2/10.1177_003754979807100403.pd

Preclinical Assessment of HIV Vaccines and Microbicides by Repeated Low-Dose Virus Challenges

BACKGROUND: Trials in macaque models play an essential role in the evaluation of biomedical interventions that aim to prevent HIV infection, such as vaccines, microbicides, and systemic chemoprophylaxis. These trials are usually conducted with very high virus challenge doses that result in infection with certainty. However, these high challenge doses do not realistically reflect the low probability of HIV transmission in humans, and thus may rule out preventive interventions that could protect against “real life” exposures. The belief that experiments involving realistically low challenge doses require large numbers of animals has so far prevented the development of alternatives to using high challenge doses. METHODS AND FINDINGS: Using statistical power analysis, we investigate how many animals would be needed to conduct preclinical trials using low virus challenge doses. We show that experimental designs in which animals are repeatedly challenged with low doses do not require unfeasibly large numbers of animals to assess vaccine or microbicide success. CONCLUSION: Preclinical trials using repeated low-dose challenges represent a promising alternative approach to identify potential preventive interventions

Efficient Principally Stratified Treatment Effect Estimation in Crossover Studies with Absorbent Binary Endpoints

Suppose one wishes to estimate the effect of a binary treatment on a binary endpoint conditional on a post-randomization quantity in a counterfactual world in which all subjects received treatment. It is generally difficult to identify this parameter without strong, untestable assumptions. It has been shown that identifiability assumptions become much weaker under a crossover design in which subjects not receiving treatment are later given treatment. Under the assumption that the post-treatment biomarker observed in these crossover subjects is the same as would have been observed had they received treatment at the start of the study, one can identify the treatment effect with only mild additional assumptions. This remains true if the endpoint is absorbent, i.e. an endpoint such as death or HIV infection such that the post-crossover treatment biomarker is not meaningful if the endpoint has already occurred. In this work, we review identifiability results for a parameter of the distribution of the data observed under a crossover design with the principally stratified treatment effect of interest. We describe situations in which these assumptions would be falsifiable, and show that these assumptions are not otherwise falsifiable. We then provide a targeted minimum loss-based estimator for the setting that makes no assumptions on the distribution that generated the data. When the semiparametric efficiency bound is well defined, for which the primary condition is that the biomarker is discrete-valued, this estimator is efficient among all regular and asymptotically linear estimators. We also present a version of this estimator for situations in which the biomarker is continuous. Implications to closeout designs for vaccine trials are discussed

Randomised trials at the level of the individual

In global health research, short-term, small-scale clinical trials with fixed, two-arm trial designs that generally do not allow for major changes throughout the trial are the most common study design. Building on the introductory paper of this Series, this paper discusses data-driven approaches to clinical trial research across several adaptive trial designs, as well as the master protocol framework that can help to harmonise clinical trial research efforts in global health research. We provide a general framework for more efficient trial research, and we discuss the importance of considering different study designs in the planning stage with statistical simulations. We conclude this second Series paper by discussing the methodological and operational complexity of adaptive trial designs and master protocols and the current funding challenges that could limit uptake of these approaches in global health research

Simulations for designing and interpreting intervention trials in infectious diseases.

BACKGROUND: Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods. DISCUSSION: Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects. CONCLUSION: Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials

Simulations for designing and interpreting intervention trials in infectious diseases.

BACKGROUND: Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods. DISCUSSION: Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects. CONCLUSION: Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials

Leveraging Contact Network Structure in the Design of Cluster Randomized Trials

Background: In settings like the Ebola epidemic, where proof-of-principle trials have succeeded but questions remain about the effectiveness of different possible modes of implementation, it may be useful to develop trials that not only generate information about intervention effects but also themselves provide public health benefit. Cluster randomized trials are of particular value for infectious disease prevention research by virtue of their ability to capture both direct and indirect effects of intervention; the latter of which depends heavily on the nature of contact networks within and across clusters. By leveraging information about these networks – in particular the degree of connection across randomized units – we propose a novel class of connectivity-informed cluster trial designs that aim both to improve public health impact (speed of control l epidemics) while preserving the ability to detect intervention effects. Methods: We consider cluster randomized trials with staggered enrollment, in each of which the order of enrollment is based on the total number of ties (contacts) from individuals within a cluster to individuals in other clusters. These designs can accommodate connectivity based either on the total number of inter-cluster connections at baseline or on connections only to untreated clusters, and include options analogous both to traditional Parallel and Stepped Wedge designs. We further allow for control clusters to be “held-back” from re-randomization for some period. We investigate the performance of these designs in terms of epidemic control (time to end of epidemic and cumulative incidence) and power to detect vaccine effect by simulating vaccination trials during an SEIR-type epidemic outbreak using a network-structured agent-based model. Results: In our simulations, connectivity-informed designs lead to lower peak infectiousness than comparable traditional study designs and a 20% reduction in cumulative incidence, but have little impact on epidemic length. Power to detect differences in incidence across clusters is reduced in all connectivity-informed designs. However the inclusion of even a brief “holdback” restores most of the power lost in comparison to a traditional Stepped Wedge approach. Conclusions: Incorporating information about cluster connectivity in design of cluster randomized trials can increase their public health impact, especially in acute outbreak settings. Using this information helps control outbreaks – by minimizing the number of cross-cluster infections – with modest cost in power to detect an effective intervention