In Europe, Article 13.1 of the European Food Safety Authority’s (EFSA) EC Regulation on nutrition and health claims contains some 4637 entries that manufacturers can use to make certain claims based on vitamin and mineral content.1
The volume of generic claims and increased competition is driving manufacturers and marketers to develop more unique selling propositions (USPs) to use in marketing efforts, which has led to a significant growth in the number of nutraceutical trials.
In this article, Sonia Cobain, Senior Statistician at Quanticate, discusses the challenges of nutraceutical trial design and offers guidance for optimising the process.
Challenges of nutraceutical trial design
Although there is some inevitable crossover, the nutraceutical and pharmaceutical testing processes are distinct in several key areas, and the former presents a number of unique challenges for researchers.
Nutraceuticals is an evolving market and many companies in the sector are unfamiliar with clinical trials. The reason for this is manifold:
- there’s less incentive, as broader claims about an ingredient may already exist
- borrowing data and claims from other already completed research is possible if a product’s active ingredients or composition is the same
- food and ingredients manufacturers often have no or very low budget dedicated to trials.
The final point in this list poses a further challenge beyond getting a study off the ground. The health effects of nutraceuticals are often minimal compared with pharmaceuticals and more easily affected by the heterogeneity of subjects, environmental factors and lifestyle factors such as eating, smoking, exercise habit, etc.
To counter this and to create a viable study, larger sample sizes than would normally be required in a drug trial are needed; however, this may not be achievable if there are budget constraints in place.
It’s also very difficult to pick an end-point and establish what claims sponsors want to make in a nutraceutical trial, and there is often a need to do a pilot study to gain insight into desired end results, creating additional cost.
It’s also the case that nutraceutical trials are harder to recruit for and have higher drop-out rates than pharmaceutical counterparts.
Counterintuitively, the demands on participants are often higher in nutraceutical trials as they must often maintain a healthy lifestyle and record more related information. Whereas the challenges for nutraceutical studies are plentiful and complex, they can all be managed with a well-planned and effective trial design.
Picking an end-point
It is imperative that sponsors pick a claim that they want to evidence before commencing a full trial. It is often the case that a pilot study is needed to understand the effects of an ingredient and what the potential claims may be.
If the desired end-point is to state that a product has preventive qualities, a significant amount of data is required and the trial will have to run for a longer period.
If a claim relates to heart disease, for example, researchers would have to follow the subjects for many years to see whether more heart disease develops in the control group. This again creates additional cost.
Often, a surrogate marker is used, but it must be suitable, researchers must have confidence in it and other people will need to acknowledge it as an appropriate surrogate. Instead of claiming that a product “lowers the risk of strokes or heart attacks,” the surrogate claim is that a product “reduces levels of bad cholesterol associated with the increased risk of strokes and heart attacks.”
The selected end-point will influence how the study is designed. Blinded studies are always preferred when the desired claim is to that a product has a preventive quality — as it helps to prevent participants from altering their lifestyle and biasing the results. Participants knowingly taking a placebo may also be less committed to the study than those taking the active substance.
Uncontrolled, controlled, open and blinded
Whether a trial will be controlled or uncontrolled, open or blinded is likely to be determined by the type of product, the desired end-point or, perhaps, logistical and budgetary constraints.
Whenever possible, trials should include a comparator group. The nutraceutical will ideally be compared against a placebo, but standard care or even a well understood medication could be used.
People often change their behaviour when it is being monitored for a trial; so, without a comparator group, it’s impossible to know whether changes observed in people taking the nutraceutical are derived from the product or some other factor.
As with pharmaceutical trials, a double-blinded trial is the gold standard and should be used whenever possible. If the end-point is subjective, it is especially important to blind; if lifestyle choices are likely to influence the end-point, it is also vital to blind, as the knowledge of whether the subjects are taking the active component will change their behaviour and so bias the result.
If it is not possible to design a suitable placebo, then an open label approach would be required. This is to be avoided when possible because if a participant knows whether they are taking the active product or placebo it will change their behaviour.
Compliance with the study protocol is likely to be poorer in the placebo group, and participants are more likely to withdraw from the study because they have no incentive to continue. They are also not likely to perceive any improvement in symptoms if they know they are taking placebo, whereas participants who know they are receiving the active product may perceive an improvement whether there is one or not. This introduces bias and makes any results less reliable.
In many cases, lifestyle choices have a bigger influence on a nutraceutical than a drug and a more significant impact on the outcome of the trial. Participants that improve their diet and exercise behaviours are likely to lose more weight … irrelevant of the nutraceutical they may or may not be taking in a trial.
For this reason, it is imperative that the study design acknowledges lifestyle variables and ensures that these are effectively recorded and factored into the final statistical analysis.
Selection of participant inclusion and exclusion criteria is vital here as an effect of the nutraceutical in the selected subjects needs to be achievable and evidenced in the trial. Sponsors will often need to set stricter inclusion and exclusion criteria than they would for a pharmaceutical trial, considering the impact they expect lifestyle factors to have on potential efficacy.
As with a pharmaceutical study, participants need to start off with symptoms severe enough that an improvement can be seen; there would be little point in conducting a trial to prove the cholesterol-lowering effect of a drug in a population that already has low cholesterol.
Although selection criteria need to be strict, the study and subsequent data need to be as generable as possible, and the results need to give enough confidence to show that a nutraceutical has an effect … not just in the study participants but in a wider population.
A careful balance needs to be achieved so that the study population is homogenous enough to see a result, but not so homogenous that the results are not generalisable to a wider population.
Running the trial from different centres ensures sponsors can capture more diverse demographic and environmental issues and that the subsequent data is more reliable. CROs are well versed in trial setup and would have to advise and explain the importance of control groups and blinding to sponsors if they plan to make rigorous marketing claims.
The nutra/pharma crossover
One area in which nutraceutical trials are advantaged is in the interpretation of data; the same tried and tested mechanisms used in the pharmaceutical sector can be used for nutraceutical trial data analysis.
Clinical research organisations (CRO) that have been operating in the pharma sector for many years have qualified procedures in place for appropriate recruitment, logistics, sample and data handling, and use qualified statisticians for protocol planning and data analysis.
All of this is essential for a successful trial. CROs are also familiar with implementing the quality management systems that are important in terms of meeting authority standards. These systems are transferable to food regulatory body requirements.
Final thought
Nutraceutical trials offer a unique set of challenges compared with pharmaceutical counterparts; however, the guiding principles of robust design, effective data capture and expert data analysis ring true in both industries.
The upshot is that nutraceutical trial sponsors are well-placed to rely on the existing expertise on offer through multidisciplinary CROs that have comprehensive processes and statistical knowledge in place.
Reference
1. www.efsa.europa.eu/en/topics/topic/article13.