Manuscript Submission

This chapter presents an overview of the process of manuscript submission. It also presents a summary of the basic format of a scientific paper, highlighting the important content of each section. The chapter discusses the following topics: (i) starting a manuscript submission; (ii) presenting the scientific data; (iii) writing a draft for journal review; (iv) choosing where to submit the research; and (v) what to expect after submitting a manuscript. In the course of the discussion, it also examines the current publication landscape, from open access versus subscription journals, with a trend of bias toward publication of more positive studies than negative ones.

The Business of Clinical Research

This chapter presents a series of important topics that should be considered and evaluated before conducting a clinical trial in which there is a collaboration between industry and academia. It discusses important topics such as the project budget and sources of funding. Additionally, this chapter highlights the advantages of the academia-industry partnership, potential conflicts of interest, and, in the advent of a conflict of interest, strategies to minimize its effects. Intellectual property, indemnifications, publication, and other specific issues are also presented as key elements in a clinical trial agreement. A clinical case is used to exemplify and discuss the practical aspects of this challenging negotiation.

Survival Analysis

This chapter focuses on basic principles of survival analysis for the clinical investigator. Survival analysis is a specific type of standardized statistical analysis that focuses on assessing the time elapsed since the exposure/intervention to the occurrence of an event. Important concepts such as median survival time, cumulative probability of survival at specific time points by using Kaplan-Meier estimators, and the use of the use of log rank (Mantel–Cox) to compare survival functions are discussed. This chapter also discusses the concept of censoring, which happens when the event occurs outside the pre-specified time window, and how to develop hazard functions when there are several interrelated factors that can contribute to the increase or decrease of survival probability.

Study Population

Chapter 3 discusses the decision-making process of choosing the study population. This is critical given that any study’s main goal is to make inferences that go beyond the individuals under study and can be used to explain the phenomenon in the broader population with shared characteristics or conditions. In this chapter, the definition of the target population is discussed—i.e. the portion of the general population from which a researcher wants to draw robust conclusions or inferences. The sampling process according to the study phase is also summarized, focusing on phase II and III clinical trials, as phase I trials are especially designed to assess safety, while phase IV trials are open-label studies, usually assessing post-marketing safety. The internal and external validity of a study is also discussed, as well as sampling methods, both probabilistic (simple random, systematic, stratified, cluster, or multistage sampling) and non-probabilistic (convenience, consecutive, and snowball sampling).

Selection of the Research Question

Selecting a research question is the first step of any research project. This chapter discusses how to formulate a specific research question from a variety of scientific interests. The reader will learn that a good research question needs to consider several aspects, such as feasibility, innovation, and significance, and that merging all these aspects into one research question may be challenging. This chapter reviews the importance of generating a strong research question using the PICOT format: population (P), intervention (I), control (C), outcomes (O), and time (T). This chapter also discusses the selection of appropriate outcome variables—surrogates or clinical endpoints, based on the types of questions or study phase. The final goal of this chapter is to refine the researcher’s general idea into the process of shaping a strong research question that will be feasible, important, ethical, and answerable.

Adaptive Trials and Interim Analysis

This chapter discusses the important aspect of changing trial aspects, including analyzing data, before formal completion of a trial. Interim analysis (or analyses before trial is finished) should be planned and described in the study protocol, before starting the trial, to ensure the potential penalties for doing such analyses do not invalidate trial results and/or satisfy ethical requirements. The chapter discusses reasons and methods to perform interim analysis. Based on the results from interim analysis, some adjustments in the trial should be required, including early termination. Although the main goal of adaptive design is to increase the success of clinical development, making the studies more efficient and more likely to demonstrate the effect of a treatment, the investigator needs to be careful when using these methods as they can also introduce other potential biases in the study.

Other Issues in Statistics II

This chapter focuses on two important concepts: subgroup analysis and meta-analysis. Subgroup analysis is especially concerned about variability and how treatment effects can differ due to specific characteristics of the population. Important issues, however, arise when planning for subgroup analysis, such as dealing with false positives and methods for dealing with multiple statistical comparisons. The chapter also points out that the analysis of data from subgroups of patients with certain baseline characteristics is typically insufficient to change general clinical practice. The second section of this chapter focuses on meta-analysis, which is a method of pooling data from several studies in order to quantify the overall effect of an intervention or exposure, and thus potentially change clinical practice. This section discusses data search and synthesis, quantification of heterogeneity, choice of fixed or random model, as well as sensitivity analysis.

Basic Study Designs

This chapter on basic study designs provides an overview of the most common design methodologies used in interventional studies. The chapter discusses both the advantages and limitations of parallel group designs (placebo or active control comparison trial, factorial design), repeated measures design (cross-over or between-subjects design), and quasi-experimental designs. It provides examples and discusses designs that are used in specific settings (for example, rare diseases, phases of dug development, and interventions in real life, including large simple trials, N-of-1). The chapter ends with a case study that illustrates the in-depth application of the available options into practice.

Basics of Clinical Research

Chapter 1 explores the history, ethical issues, and importance of regulations in clinical research. The history of clinical research is long and fascinating, starting from dietary therapy, such as legumes and lemons, and advancing to modern-day drugs and regulations. Advances in medical treatments today have been achieved because of the application of knowledge gained from experiments conducted hundreds of years ago. The rules and regulations were required to address unethical issues and the misuse of the clinical research. The chapter asserts that the development of clinical research regulations may still be under development in terms of optimizing safety and the use of future drugs and medical devices.

Assessing Risk and Adverse Events

This chapter provides an overview of safety assessment in clinical trials, including challenges for designing and reporting studies measuring safety. Adverse events are undesirable, unfavorable, harmful, and unexpected effects resulting from a normal dosage of drug, medication, therapy, or any other intervention such as surgery. Monitoring of adverse events is critical to the patient’s safety (i.e., human subject’s protection) and data integrity in clinical trials. Moreover, this chapter reviews the regulatory aspects related to adverse events in clinical trials. Finally it presents a case discussion in which an unexpected adverse effect is detected and investigators need to determine whether this event is or is not related to the intervention and define a plan of action.