Statistical Communications in Infectious Diseases

Published by De Gruyter

Volume 11 Issue 1 - Special Issue: HIV Prevention Efficacy Trial Designs of the Future, Special Issue Editor: Holly Janes, PhD, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center and Department of Biostatistics, University of Washington

January 2019

Issue of Statistical Communications in Infectious Diseases

Contents
Journal Overview

Articles

July 18, 2019

Designing the Next Generation of HIV Prevention Efficacy Trials: Synopsis of a 2018 Symposium

Holly Janes, Deborah Donnell, Martha Nason

Article number: 20190004

Abstract

A one-day symposium was held in Seattle, Washington on November 5, 2018, including a broad array of stakeholders in the HIV prevention community. The topic of discussion was the challenge of designing future HIV prevention efficacy trials, given the multiplicity and speed of changes in the field in recent years, the development and rollout of effective prevention tools, and the resultant complexity in designing trials to evaluate new HIV prevention products. The goal was to identify potential statistical trial design approaches worthy of further investigation, as well as gaps in understanding and logical next steps. We overview the themes that emerged from the presentations, panels, and floor discussions, and outline initial next steps in further exploring design options.

July 6, 2019

Current and Future Challenges in Trial Design for Pre-Exposure Prophylaxis in HIV Prevention

Deborah Donnell

Article number: 20190008

Abstract

Success in establishing efficacy of antiretroviral drugs to prevent acquisition of HIV infection has fundamentally changed the trial design considerations for future experimental drugs. Current trials of potential new antiretroviral agents for pre-exposure prophylaxis are using active control designs – where all trial participants receive an active antiretroviral drug. Current trials of other experimental approaches, such as vaccines and monoclonal antibodies, permit use of the proven prevention agent FTC/TDF for all trial participants. In the future, if even more effective prevention methods are approved, active control designs would anticipate very few infection events and not provide statistically robust evidence. A potential alternative is to conduct placebo randomized trials limited to participants for whom current prevention tools are not acceptable.

July 27, 2019

Ongoing Vaccine and Monoclonal Antibody HIV Prevention Efficacy Trials and Considerations for Sequel Efficacy Trial Designs

Peter B. Gilbert

Article number: 20190003

Abstract

Four randomized placebo-controlled efficacy trials of a candidate vaccine or passively infused monoclonal antibody for prevention of HIV-1 infection are underway (HVTN 702 in South African men and women; HVTN 705 in sub-Saharan African women; HVTN 703/HPTN 081 in sub-Saharan African women; HVTN 704/HPTN 085 in U.S., Peruvian, Brazilian, and Swiss men or transgender persons who have sex with men). Several challenges are posed to the optimal design of the sequel efficacy trials, including: (1) how to account for the evolving mosaic of effective prevention interventions that may be part of the trial design or standard of prevention; (2) how to define viable and optimal sequel trial designs depending on the primary efficacy results and secondary “correlates of protection” results of each of the ongoing trials; and (3) how to define the primary objective of sequel efficacy trials if HIV-1 incidence is expected to be very low in all study arms such that a standard trial design has a steep opportunity cost. After summarizing the ongoing trials, I discuss statistical science considerations for sequel efficacy trial designs, both generally and specifically to each trial listed above. One conclusion is that the results of “correlates of protection” analyses, which ascertain how different host immunological markers and HIV-1 viral features impact HIV-1 risk and prevention efficacy, have an important influence on sequel trial design. This influence is especially relevant for the monoclonal antibody trials because of the focused pre-trial hypothesis that potency and coverage of serum neutralization constitutes a surrogate endpoint for HIV-1 infection. Another conclusion is that while assessing prevention efficacy against a counterfactual placebo group is fraught with risks for bias, such analysis is nonetheless important and study designs coupled with analysis methods should be developed to optimize such inferences. I draw a parallel with non-inferiority designs, which are fraught with risks given the necessity of making unverifiable assumptions for interpreting results, but nevertheless have been accepted when a superiority design is not possible and a rigorous/conservative non-inferiority margin is used. In a similar way, counterfactual placebo group efficacy analysis should use rigorous/conservative inference techniques that formally build in a rigorous/conservative margin to potential biases that could occur due to departures from unverifiable assumptions. Because reliability of this approach would require new techniques for verifying that the study cohort experienced substantial exposure to HIV-1, currently it may be appropriate as a secondary objective but not as a primary objective.

June 22, 2019

The Modern Randomized Clinical Trial: Is it Time to Sharpen a Blunt Instrument?

Janet Turk Wittes

Article number: 20190005

Abstract

In spite of the obvious differences in the diseases under study, designs of trials of prevention of HIV and cardiovascular disease share some common features. A trial of prevention should identify a population at risk for the disease; it should have a clearly defined, clinically important, outcome; it should be large enough to have sufficient power to detect an effect of public health importance; and participants should be followed long enough for the effect of the intervention to become manifest (but the trial should not take so long as to render the intervention no longer of interest). Many cardiovascular prevention studies have been large, simple, randomized trials leading to easily interpretable results. This paper urges that designers of trials of HIV prevention should consider mimicking the strategies used in cardiovascular disease prevention trials: focus on a clear inferential path to the question being asked while limiting unnecessary data collection, auditing, and complexity. Finally, showing benefit in a trial is only the first step in reducing the burden of disease: aggressive, effective efforts at educating the population at risk so they will implement the intervention is essential to improvement in public health.

Open Access July 12, 2019

The Connection between the Averted Infections Ratio and the Rate Ratio in Active-control Trials of Pre-exposure Prophylaxis Agents

David T. Dunn, David V. Glidden

Article number: 20190006

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Abstract

The design and analysis of active-control trials to evaluate experimental HIV pre-exposure prophylaxis (PrEP) agents pose serious statistical challenges. We recently proposed a new outcome measure, the averted infections ratio (AIR) – the proportion of infections that would be averted by using the experimental agent rather than the control agent (compared to no intervention). The main aim of the current paper is to examine the mathematical connection between AIR and the HIV incidence rate ratio, the standard outcome measure. We also consider the sample size implications of the choice of primary outcome measure and explore the connection between effectiveness and efficacy under a simplified model of adherence.

July 12, 2019

Regulatory Perspectives for Streamlining HIV Prevention Trials

Jeffrey Scott Murray

Article number: 20190002

Abstract

Designing and conducting active-controlled trials of HIV pre-exposure prophylaxis (PrEP) therapeutics are becoming challenging due to inconsistency of adherence across trials and the need for increasingly larger trials to assess efficacy. In the United States (US), trials evaluating oral contraceptives (OC) use the Pearl Index to assess efficacy in single-arm trials. This article explores the possibility of using an index (“HIV Incidence Index”) analogous to the Pearl Index to assess preventive efficacy in active-controlled HIV prevention trials in sexually-acquired HIV. One proposal for constructing an HIV Incidence Index is to use the incidence of sexually transmitted infections (STIs) during a trial to serve as a marker for HIV risk behavior and to estimate what the HIV seroconversion rate would have been had the participants not been on efficacious PrEP. In addition, a consensus of expert opinion will be needed to define clinically acceptable HIV seroconversion rates for populations at risk of HIV-infection receiving active PrEP.

August 6, 2019

Advancing Novel PrEP Products – Alternatives to Non-Inferiority

David V Glidden

Article number: 20190011

Abstract

With the scale-up of HIV pre-exposure prophylaxis (PrEP) with tenofovir (TDF) with or without emtricitabine (FTC), we have entered an era of highly effective HIV prevention with a growing pipeline of potential products to be studied. These studies are likely to be randomized trials with an oral TDF/FTC control arm. These studies require comparison of incident infections and can be time and resource intensive. Conventional approaches for design and analysis active controlled trial can lead to very large sample sizes. We demonstrate the important of assumptions about background infections for interpreting trial results and suggest alternative criteria for demonstrating the efficacy and effectiveness of potential PrEP agents.

July 18, 2019

Designing & Conducting Trials to Reliably Evaluate HIV Prevention Interventions

Thomas R. Fleming, Victor DeGruttola, Deborah Donnell

Article number: 20190001

Abstract

While much has been achieved, much remains to be accomplished in the science of preventing the spread of HIV infection. Clinical trials that are properly designed, conducted and analyzed are of integral importance in the pursuit of reliable insights about HIV prevention. As we build on previous scientific breakthroughs, there will be an increasing need for clinical trials to be designed to efficiently achieve insights without compromising their reliability and generalizability. Key design features should continue to include: (1) the use of randomization and evidence-based controls, (2) specifying the use of intention-to-treat analyses to preserve the integrity of randomization and to increase interpretability of results, (3) obtaining direct assessments of effects on clinical endpoints such as the risk of HIV infection, (4) using either superiority designs or non-inferiority designs with rigorous non-inferiority margins, and (5) enhancing generalizability through the choice of a relative risk rather than risk difference metric. When interventions have complementary and potentially synergistic effects, factorial designs should be considered to increase efficiency as well as to obtain clinically important insights about interaction and the contribution of component interventions to the efficacy and safety of combination regimens. Key trial conduct issues include timely enrollment of participants at high HIV risk recruited from populations with high viral burden, obtaining ‘best real-world achievable’ levels of adherence to the interventions being assessed and ensuring high levels of retention. High quality of trial conduct occurs through active rather than passive monitoring, using pre-specified targeted levels of performance with defined methods to achieve those targets. During trial conduct, active monitoring of the performance standards not only holds the trial leaders accountable but also can assist in the development and implementation of creative alternative approaches to increase the quality of trial conduct. Designing, conducting and analyzing HIV prevention trials with the quality needed to obtain reliable insights is an ethical as well as scientific imperative.

July 12, 2019

Crossover and Repeated Randomization in Event Driven Trials for HIV Prevention: Addressing the Impact of Heterogeneity in Risk in the Trial Design

Clara P. Domínguez Islas, Elizabeth R. Brown

Article number: 20190009

Abstract

The availability of effective Pre-Exposure Prophylaxis (PrEP) for HIV introduces new challenges for testing novel on-demand, user-controlled HIV prevention products, including lower placebo arm incidence and increased between-participant variability in HIV risk. In this paper, we discuss how low HIV incidence may result in longer trials in which the variability in participants' risk may impact the estimate of risk reduction. We introduce a measure of per-exposure efficacy that may be more relevant than the population level reduction in incidence for on demand products and explore alternatives to the parallel arm design that could target better this parameter of interest: the crossover and the re-randomization designs. We propose three different ways in which crossover and re-randomization of intervention assignments could be implemented in event-driven trials. We evaluate the performance of these designs through a simulation study, finding that they allow for better estimation and higher power than the traditional event-driven parallel arm design. We conclude by discussing future work, practical challenges and ethical considerations that need to be addressed to take these designs closer to implementation.

July 6, 2019

Tomorrow’s HIV Prevention Trials of Vaccines and Antibodies

Dean Follmann

Article number: 20190007

Abstract

Effective HIV prevention has the potential to change the landscape of HIV prevention trials. Low infection rates will make superiority studies necessarily large while non-inferiority trials will need some evidence that a counterfactual placebo group had a meaningful HIV infection rate in order to provide evidence of effective interventions. This paper explores these challenges in the context of immune related interventions of mAbs and vaccines. We discuss the issue of effect modification in the presence of PrEP, where subjects on PrEP may have less of a benefit of a mAb or (vaccine) than subjects off PrEP. We also discuss different methods of placebo infection rate imputation. We estimate infection risk as a function of mAb level (or vaccine induced immune response) in the mAb (or vaccine) arm and then extrapolate this infection risk to zero mAbs as a proxy for the placebo infection rate. Important aspects are the use of triangulation or multiple methods to impute the placebo infection rate, concern about extrapolation if few mAbs are close to zero, and the use of currently available data with placebo groups to rigorously evaluate the accuracy of imputation methods. We also discuss use of historical controls and some generalizations of the idea of (DMurray, J. 2019. “Regulatory Perspectives for Streamlining HIV Prevention Trials.” Statistical Communications in Infectious Diseases .) to use rectal gonorrhea rates to impute HIV infection rate. Generalizations include regression adjustment to calibrate for potential differences in baseline covariates for ongoing vs historical studies and the use of the gonorrhea, HIV relationship in a contemporaneous observational study. Examples of recent and ongoing trials of malaria chemoprophylaxis and HPV vaccines, where extremely effect prevention methods are available, are provided.

About this journal

Objective
The mission of Statistical Communications in Infectious Diseases is to serve as the primary vehicle for the communication and education of statistical thinking in infectious disease research and policy.

The infectious diseases community faces many difficult challenges. These include: (1) coping with continuing high-impact diseases such as HIV, malaria, TB, and flu; (2) dealing with infectious disease outbreaks such as Ebola, pandemic avian influenza, or SARS; and (3) preparing for the inevitable emergence of diseases that are unknown or are recognized but will reemerge in a more threatening form (e.g., antibiotic resistant [nightmare] bacteria or superbugs). Research in infectious diseases is also challenged by funding limitations, politics, and ethical dilemmas.

Increasingly complex data is also creating new challenges to the design and analysis of research studies. Enhanced statistical expertise is essential to address these challenges and to develop and evaluate medical and public health responses to potential outbreaks and epidemics.

Statistical Communications in Infectious Diseases (SCID) publishes significant research on the application of statistical ideas to problems arising from studies of infectious diseases. SCID takes a broad perspective on the role of statistics in infectious disease research including application, policy, education and theory. SCID fosters much-needed communication among statisticians on the best approaches to evolving complex infectious disease data, and is a venue for statisticians to enter a dialogue with other scientists and policy makers on the strengths and limitations of policies and methods for design, monitoring, analysis, and reporting of infectious disease research studies.

SCID goes beyond the application of statistical methods to data arising from infectious disease studies or new statistical strategies. SCID serves as a sounding board to discuss policy issues, as well as to accomplish the following goals: (1) engage and raise the quality of the discussions of important issues in the public and scientific press; (2) ensure that optimal scientific tools are utilized in infectious disease research; (3) improve the training and practice of the next generation of professionals involved in infectious diseases research through educational articles; (4) raise the profile of quantitative science in infectious disease research by demonstrating its value in decision making and public health.

Topics

How heavily should the public invest in research or implementation of different prevention modalities?
What is necessary to achieve control of epidemics (for example, do we require a vaccine to control the spread of HIV or what procedures are required to halt the spread of Ebola)?
How can statisticians help with grass roots epidemic control efforts?
How can we optimally evaluate the benefits vs. harms vs. costs of competing interventions?
How can we best characterize the trade-offs between civil liberties and public safety?
How should we adjust the traditionally required level of evidence to address areas of unmet medical need?
How do we revise our traditional approaches to the design, monitoring, analyses, and reporting of infectious disease studies to improve medical practice and public health?

Article formats
Original research articles, book reviews