Demissie Alemayehu

Applications of ROC Analysis in Medical Research: Recent Developments and Future Directions

With the growing focus on comparative effectiveness research and personalized medicine, receiver-operating characteristic analysis can continue to play an important role in health care decision making. Specific applications of receiver-operating characteristic analysis include predictive model assessment and validation, biomarker diagnostics, responder analysis in patient-reported outcomes, and comparison of alternative treatment options. The authors present a survey of the potential applications of the method and briefly review several relevant extensions. Given the level of attention paid to biomarker validation, personalized medicine and comparative effectiveness research, it is highly likely that the receiver-operating characteristic analysis will remain an important visual and analytic tool for medical research and evidence-based medicine in the foreseeable future.

Revisiting issues, drawbacks and opportunities with observational studies in comparative effectiveness research

RATIONALE Despite their inherently pervasive limitations, data from observational studies are increasingly relied upon by health care decision makers to fill critical information gaps created by lack of evidence from randomized controlled trials. AIM AND OBJECTIVE The aim and objective of this article was to revisit the major issues associated with observational studies from secondary data sources. METHOD The method of this article was canvass of the literature. RESULTS Sources of bias are highlighted and steps intended to minimize bias are summarized. CONCLUSION Efforts should be made to improve causal inference of treatment effects from observational studies found in secondary data sources. Extra care and caution should be exercised in the interpretation and reporting of results from these studies.

Big Data: transforming drug development and health policy decision making

The explosion of data sources, accompanied by the evolution of technology and analytical techniques, has created considerable challenges and opportunities for drug development and healthcare resource utilization. We present a systematic overview these phenomena, and suggest measures to be taken for effective integration of the new developments in the traditional medical research paradigm and health policy decision making. Special attention is paid to pertinent issues in emerging areas, including rare disease drug development, personalized medicine, Comparative Effectiveness Research, and privacy and confidentiality concerns.

Improving Conduct and Feasibility of Clinical Trials to Evaluate Antibacterial Drugs to Treat Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Recommendations of the Clinical Trials Transformation Initiative Antibacterial Drug Development Project Team

BACKGROUND The etiology of hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) is often multidrug-resistant infections. The evaluation of new antibacterial drugs for efficacy in this population is important, as many antibacterial drugs have demonstrated limitations when studied in this population. HABP/VABP trials are expensive and challenging to conduct due to protocol complexity and low patient enrollment, among other factors. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development by streamlining HABP/VABP clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. METHODS In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with HABP/VABP protocol complexity. The Project Team developed potential solutions to streamline HABP/VABP trials using a Quality by Design approach. RESULTS CTTI recommendations focus on 4 key areas to improve HABP/VABP trials: informed consent processes/practices, protocol design, choice of an institutional review board (IRB), and trial outcomes. Informed consent processes should include legally authorized representatives. Protocol design decisions should focus on eligibility criteria, prestudy antibacterial therapy considerations, use of new diagnostics, and sample size. CTTI recommends that sponsors use a central IRB and discuss trial endpoints with regulators, including defining a clinical failure and evaluating the impact of concomitant antibacterial drugs. CONCLUSIONS Streamlining HABP/VABP trials by addressing key protocol elements can improve trial startup and patient recruitment/retention, reduce trial complexity and costs, and ensure patient safety while advancing antibacterial drug development.

Assessing exchangeability in indirect and mixed treatment comparisons

In comparative effectiveness research (CER), investigators often resort to methods of indirect and mixed treatment comparisons, due to the unavailability of head-to-head compara- tive data from randomized clinical trials for competing treatment options. However, implicit in the available indirect comparison techniques is an assumption of exchangeability, which in practice cannot be conclusively verified. This paper discusses the implications of violations of this assumption, and describes approaches to evaluate its validity and steps that may be taken to minimize the impact on conclusions drawn from such studies.

Considerations for the design and conduct of a pharmacovigilance study involving mass drug administration in a resource-constrained setting.

By most estimates, about one billion people worldwide are affected by neglected tropical diseases (NTDs). These diseases are found primarily in developing countries, and those affected are generally marginalized sectors of the population that may not have access to safe water, good hygiene, or adequate medicines. NTDs cause major health problems, and often lead to permanent disability of the victims. Consequently, the social and economic impact of these diseases is massive [1]. With the growing recognition of the deleterious effects of the NTDs, several initiatives are now underway at national and international levels to tackle the problem with the aim of controlling or eliminating them. The drive to contain or eliminate the diseases has further been highlighted in numerous papers [1]–[10], through persistent advocacy of the World Health Organization (WHO) and other institutions [11]–[13], and by funding from government, private, and corporate grants. An approach that has received wide acceptance in recent years is an integrated strategy that involves mass administration of combination treatments [4], [9]–[15]. This is particularly the case when two or more of the NTDs share a common method of management. The initial emphasis of this approach has been on the seven NTDs: the three soil-transmitted helminthiases (caused by whipworm, hookworm, and roundworm), schistosomiasis, lymphatic filariasis (LF), trachoma, and onchocerciasis. The integrated approach typically involves coordinated use of therapy according to established guidelines, leveraging disease-control activities within the national health system, and active involvement of the community. When the strategy comprises mass drug administration (MDA), the whole endemic population is normally targeted for treatment. Given the proven efficacy of the individual drugs, an essential facet of the integrated programs is assessment of the safety of the combination therapy in the target population. Accordingly, there is a growing list of studies that have been conducted to evaluate the safety of co-administration of drugs [16]–[19]. Although there is an obvious appreciation of the need to conduct studies to establish the safety of combination drugs in MDA, there has been no public discussion on what guidance may be needed to help researchers in these resource-constrained areas to design, conduct, and analyze such studies. The objective of this policy platform is, therefore, to initiate discussion on this topic, with particular reference to data handling, safety assessment, and other aspects of pharmacovigilance that should be considered to protect the well-being of the target population. Examples will be provided from two studies. The first study [16] was performed in Zanzibar (the “Zanzibar study”) and examined co-administration of ivermectin, albendazole, and praziquantel in children and adults. The second illustrative study pertains to a triple co-administration of azithromycin, ivermectin, and albendazole for the treatment of trachoma and LF (the “trachoma/LF study”). At the time of preparation of this manuscript, preliminary pharmacokinetic (PK) studies for the latter have been reported [15],[17]. While the scope of the this policy platform is the conduct and reporting of MDA studies, it may be worthwhile to note the main features that distinguish such studies from conventional clinical trials for efficacy. In the last section, some relevant aspects of the two types are discussed, with emphasis on compliance requirements and subject inclusion and exclusion criteria.

Vaccines: A review of immune‐based interventions to prevent and treat disease

The enormous gains made in public health during the 20th century, through the prevention and treatment of infectious disease, have contributed to dramatic improvements in the quality and length of the human lifespan. Continued advances in medicine are dependent on addressing several challenges including the increase in existing and new resistance to antibiotics, the decrease in productivity of the research and development (R&D) ecosystem, uncertain regulatory pathways, and an economic environment that rewards innovation for developing therapeutics that involve long cycle times from idea to a product. In this article, we consider important issues pertaining to the development of vaccines with particular emphasis on preclinical requirements, optimal dose selection, design, execution, and reporting of clinical trials for regulatory submission, planning and implementation of post‐approval life‐cycle programs, and emerging themes in therapeutic vaccines.

Tests for Normality Based on Entropy Divergences

The normal distribution is among the most useful distributions in statistical applications. Accordingly, testing for normality is of fundamental importance in many fields including biopharmaceutical research. A generally powerful test for normality is the Shapiro-Wilk test, which can be derived based on estimated entropy divergence. Another well-known test for normality based on entropy divergence was proposed by Vasicek (1976) which has inspired the development of many goodness-of-fit tests for other important distributions. Despite extensive research on the subject, there still exists considerable confusion concerning the fundamental characteristics of Vasicek’s test. This article presents a unified derivation of both the Shapiro-Wilk test and Vasicek’s test based on estimated entropy divergence and clarifies some existing confusion. A comparative study of power performance for these two well-known tests for normality is presented with respect to a wide range of alternatives.

Evaluation of Reporting Bias in Postmarketing Risk Assessment Based on Spontaneous Reporting Systems

Databases of spontaneously reported cases of adverse drug reactions play a significant role in the safety monitoring of marketed medicinal products. However, the inherent limitations of such data render the interpretation of results fairly difficult. One major issue is the bias introduced by under-reporting or differential reporting of events. Despite considerable progress in the development of analytical tools for spontaneously reported data, the issue of reporting bias has not been effectively addressed in the literature. This article discusses the problem of handling reporting bias, considers the plausibility of adapting techniques from other areas of application and suggests directions for future research. While the problems associated with spontaneous reporting data are complex and multifaceted, it is concluded that judicious and careful use of rigorous statistical techniques to assess bias can help enhance the reliability of research on the relative toxicity of marketed products.

A New Paradigm for Deriving and Analyzing Number Needed to Treat

ABSTRACT The inverse of the risk difference, commonly referred to as the number needed to treat (NNT) has been recently proposed as a useful measure for comparing two treatments. Since its introduction, the method has been used widely to establish comparative treatment benefits, and has also been the subject of extensive discussions among statisticians. In this paper, we examine the assumptions behind the original definition of NNT, and introduce a new formulation of the method based on a random walk model. Using stopping times, we develop a paradigm for NNT that avoids some of the conceptual and inferential difficulties and pitfalls associated with the previous work on NNT. Simulation results are provided to illustrate the bias introduced by using alternative formulations of NNT, and several open problems are suggested for future research.