Advantages, Disadvantages, and Future Trends on the Use of Design of Experiments in Cross-Over Trials in Nutritional Clinical Investigation

Introduction

Human clinical trials are often designed to assess the effectiveness of an intervention or treatment on human health. Typically, these trials are used to test the efficacy of different therapeutic options in medicine, pharmacology or nutrition. However, in the last decades the use of such trials is increasingly common for the investigation of the effect of other types of habits and interventions on human health, as may be the case with nutrition baseline research. In addition to basic research, one of the most common purposes for conducting nutrition trials is to demonstrate the beneficial effects of a specific food component in order to use this information in the in food labeling. Food products that are labeled with messages related to the promotion of human health are marketed at a price 30–50% higher than their counterparts that cannot use these health claims, and in some cases can reach even more (Miranda et al., 2018). In order to obtain authorization for the use of one of these health claims, it is usually necessary to present a meta-analysis demonstrating the beneficial effects of the food on human health. As an example, in the European Union it is compulsory to include human trials to obtain authorization for the use of health claims in marketing food products (European Food Safety Authority, EFSA, 2011). Following this obligation imposed by the European Union, the number of nutrition-related clinical trials published worldwide increased significantly. As it can be seen in Figure 1, clinical trials related to human nutrition showed gradual growth between 2000 and 2010, which accelerated substantially from that date onwards for both cross-clinical trials and for other types of clinical trials.

Figure 1.

Total clinical trials and crossover trials related to human nutrition published from 2000 to 2018 (source: ISI web of knowledge^®). Search criteria: total clinical trials were search by “clinical trial” in the field “title” and “nutrition” in the field “topic”. Crossover trials were search by “crossover trial” in the field “title” and “nutrition” in the field “topic”.

Randomized clinical trials are considered the “gold standard” to evaluate therapeutic effectiveness due to its ability to avoid or minimize bias associated with imbalance in potentially confounding variables (Leonard, Lafrenaye & Goffaux, 2012). The most employed randomized clinical trials are the so-called parallel-group trial or design (Harris & Raynor, 2017), in which subjects are randomized to a unique intervention or control group during the entire trial, that occur simultaneously in time. Identical dependent outcome variables are measured in all groups included in the trial, with outcomes compared between groups, or between subjects, with the aim to determine the intervention effectiveness. In contrast, in a so-called crossover design, all subjects receive all levels of the independent variable at some point in the study, but subjects do not receive all levels at the same time (Figure 2). To determine intervention effectiveness, dependent outcome variables are measured for the two levels of the intervention and afterwards, then they are compared within the same subject (Harris & Raynor, 2017).

Figure 2.

Basic (2x2) crossover trial design