The ongoing debate about the definition of clinical trials intensifies as new guidelines classify physiological studies examining the effects of diet or exercise as clinical trials. Researchers argue that this broad definition imposes undue burdens and hinders exploratory research that is crucial for understanding human physiology. Proponents believe that the stringent standards enhance research safety and integrity. This dispute underscores the need for nuanced guidelines that differentiate between exploratory studies and genuine clinical trials to ensure scientific progress and integrity.
In recent years, a change in the categorisation of some scientific studies involving humans has sparked considerable debate in the scientific community. Traditionally, clinical trials have been specifically defined as studies that test the effectiveness and safety of health-related treatments such as drugs or surgery.
However, guidelines from the International Committee of Medical Journal Editors (ICMJE) have broadened this definition to include any research that assigns people to a health-related intervention to observe health-related outcomes. This broad definition now unexpectedly encompasses physiological studies, such as those examining how diet or exercise affects healthy individuals, classifying them as clinical trials.
“Classifying these exploratory studies as clinical trials imposes a significant administrative burden, but more importantly, restricts research projects to investigating predictable outcomes. This is wrong since exploratory research is and should be unpredictable, making this requirement problematic,” Erik A. Richter, the lead author of a recent letter in Cell Metabolism, points out.
Explore unknowns about how the human body functions
Erik A. Richter is a Professor at the The August Krogh Section for Molecular Physiology at the Department of Nutrition, Exercise and Sports at University of Copenhagen, and his sentiment is echoed by many researchers, especially those focused on studying human physiology. They argue that this misclassification could hinder the progress of exploratory research, which is crucial for understanding how the human body works under various conditions.
Supporters of the ICMJE guidelines argue that a broad definition ensures that all studies involving people adhere to high ethical standards, thereby enhancing the quality and safety of the research.
“There is no doubt that this is intended for pharmaceutical companies conducting trials to ensure that they state the primary outcome they aim for. They might also have one or more secondary outcomes. They cannot change these when reporting their findings. This is sensible, since they usually hypothesise that the drug will achieve specific effects, and that is what they pursue.”
According to Erik A. Richter, clinical trials are really designed for testing a medication on people who have a specific health condition.
“But if people are healthy, and you are just carrying out an exercise or dietary intervention, such as testing the effects of running on endurance or of changes in diet, I do not consider this a clinical trial, but that is required now.”
Generating hypotheses rather than being driven by them
Erik A. Richter points out that the experiments conducted currently are much more hypothesis generating compared with previously, so the ICMJE guidelines are not appropriate for current exploratory experiments. The guidelines belong to a different era.
“Specifically, when we do experimental studies with largely unknown outcomes, having to define primary and secondary outcomes is somewhat frustrating. When the time to publish comes, reviewers will look back at the primary outcome. If it has not been achieved or perhaps even not addressed because other much more interesting observations have been discovered, the results cannot be published.”
So even though the ICMJE guidelines might have made sense in the past, the type of studies carried out today would not have been possible.
“Our tools are now so broad that we can discover things we never imagined. That is also the intention. It is more to generate hypotheses rather than being driven by them.”
However, many journals have started requiring preregistration, meaning that the researchers must preregister the experiment in the clinical trial system before starting and need to define the primary and secondary outcomes.
“We register our studies with the appropriate ethics committee and have done so for years without issues. But nowadays, when we submit to a reputable journal for publishing, they say that they follow the ICMJE guidelines and ask for our clinical registration. When I say we do not have it, they respond that, unfortunately, they cannot consider our work.”
Might delay breakthroughs
According to Erik A. Richter and colleagues, the requirement to define specific outcomes at the study’s outset can restrict such research, which thrives on the freedom to follow where the initial findings lead.
“A study might begin by exploring how a new type of exercise affects heart rate, only to unveil unforeseen insights into stress or anxiety. Nevertheless, under stringent guidelines, any findings not preregistered risk being overlooked and are difficult to report, depriving us of potentially crucial knowledge.”
The debate also touches on the future of research. The broad classification could potentially slow the pace of scientific discovery in physiology if researchers are deterred by the stringent requirements intended for clinical trials testing the effectiveness and safety of health-related treatments.
“There is a risk that fewer studies will explore fundamental questions about human health, which could limit understanding of vital health issues and delay breakthroughs in health-related treatments.”
Replace health with disease
As a response, Erik A. Richter and 95 international supporters advocate for a more flexible approach.
“We suggest adopting the European Union’s narrower definition of clinical trials, which clearly distinguishes between clinical trials and physiological studies. Alternatively, modifying the ICMJE guidelines to replace ‘health outcomes’ with ‘disease outcomes’ would ensure that clinical trials explicitly focus on treatments for diseases rather than general health interventions among healthy individuals.”
This ongoing debate highlights the need for journal editors and regulatory bodies to engage more with the research community to develop practical guidelines that respect the nuances of different types of research.
“A more tailored approach, involving a case-by-case determination of what constitutes a clinical trial, could ensure that valuable exploratory research continues alongside traditional clinical trials. This flexibility is key to maintaining the integrity and progress of scientific research, ultimately leading to deeper understanding of human health and more effective health-related treatments,” Erik A. Richter concludes.
“Exploratory physiological experiments are not clinical trials” has been published in Cell Metabolism. Several authors received funding from the Novo Nordisk Foundation through their affiliations with the Department of Nutrition, Exercise and Sports and the Novo Nordisk Foundation Center for Basic Metabolic Research, both at the University of Copenhagen.
