Importantly, companies are investing in clinical trials to support claims on their products. “Nutrasource has seen continued interest in immune health over the past several years, with a predominant interest in cold symptom prevention, effect on allergen response, reduction in recurrent urinary tract infections and gastrointestinal inflammation, barrier function and most recently interest in microbes and their role in host defence,” William Rowe, President, CEO and Co-Founder of NutraSource Diagnostics Inc., told us.
Najla Guthrie, President/CEO of KGK Synergize Inc., has seen similar increasing interest. “This seems to be associated with the increase in ingredients and finished products entering the market as well as the regulatory requirements for having sound science behind products ensuring the safety of the consumer,” she said.
Demand is related to sports nutrition and stress, and their effects on the immune response, noted Guthrie, with there has also been a “large volume of trials” looking to better understand the effects pre-and probiotics on immune support and immune health.
However, investigating immune health is challenging and CROs need to assess if a product/protocol would have to go under an Investigational New Drug application if it crosses the line into a disease risk reduction or disease intervention, said DeAnn Liska, senior director of nutrition and scientific affairs at Biofortis-Merieux NutriSciences
“We believe this issue has impacted the amount of immunity trials we have been approached to evaluate and conduct,” said Liska.
Clearly define the desired claims before you start…
The current regulatory requirements allow only healthy populations to be studied for structure function claims, said Guthris, which poses unique challenges when you consider immune health. “Perhaps the most significant is the fact that, healthy people do not present consistently with the “indication/symptom” that one is interested in investigating and the resulting fluctuation can be a confounder contributing to non-significant results,” she said.
It is important for a dietary supplement marketer to be clearly define any implied and direct marketing and/or health claims in order to properly design a clinical trial for ‘immune support’, explained Rowe.
Choosing the population is also critical, said Guthrie.
“In designing immune studies in healthy populations understanding the components of the immune system that may respond to movement is necessary. Age, nutritional status, sex, ethnicity, physical fitness and sleep deprivation can affect the flexibility of the immune system. Understanding the components of the immune system and recognising the external events impacting immune movement is critical in building a study design to measure the impact of dietary supplements. In choosing populations for immune studies identifying situations where medically healthy populations become vulnerable to immune change is required,” she said.
Modulation of the immune system by supplementing with dietary supplements require the consideration of several factors, said Guthrie. Nutrients, unlike drugs, target all cells and tissues and work in complex networks, and they may also take longer to produce an effect that would translate into biological and statistical significance. “This concept lends very well to the fact that the immune system does not function in an autonomous manner but respond to signals from other organ systems.
“While the randomized double-blind placebo-controlled design is the only design that provides a robust causal relationship between investigational dietary supplement, the outcome and the claim and satisfies the requirements of regulatory bodies, working with medically healthy individuals within this design requires fore thought and knowledge of the various immune iterations that may be elicited. Acute and brief stressor models as well as acute exercise models are well suited to studying the effects of immune support ingredients in healthy populations.”
But what exactly are you measuring? “Selection of biomarkers for immune support studies will vary based on the specific claim, indication and population under study,” said Rowe. “When selecting biomarkers, consideration must be given to the heterogeneous nature of the inflammatory response, the ease of sampling especially as it relates to the population under study, (particularly in the case of studies in children) and the acceptance of the biomarker in relation to the indication. Sampling time also requires consideration during protocol design; more specifically, there needs to be an understanding of the appropriate timing of sample collection for the biomarker of interest relative to the appearance/presence of symptomology.
“It is important to understand that studying biomarkers alone may be insufficient to substantiate a claim for supporting, maintaining or conferring an immune health benefit. There are a number of biomarkers that may be considered, such as, cytokines (interleukins), T cell response, phagocyte activity, natural killer cell activity, immunoglobulin levels, changes in gut microbiota and changes in intestinal epithelium structure. However, biomarkers provide information on mechanism of action rather than outcome and should be studied in parallel with physiological effect or a clinical outcome,” he said.
At the end of the day, a dietary supplement marketer is looking to make claims, which are supported by a specific and measurable benefit or effect that is relevant to structure and function.
“Structure function claims for immune products in the US and Europe are limited to straight claims that describe efficacy. Namely, ‘supports or maintains immune function’,” said Guthrie. “Qualifying the claim by introducing a mechanism of action is a possibility.
“Both agencies are convinced that consumers interpret ‘boosts’ and ‘strengthens’ immune function as implying taking the product will reduce the risk of contracting a disease such as cold or flu. However, the terms ‘supports’ and ‘maintains’ immune function are innocuous claims that consumers don’t assume means reduced risks; instead both agencies agree that the consumer likely looks at ‘maintenance’ claims as promises to help them stay at their current level of immune function. The mechanism of action on markers is accepted to support maintenance claims, provided those markers are relevant.
“In Canada, Health Canada allows for making ‘Improvement in immune function’ claims which demonstrate a health benefit. Further more ‘risk reduction’ and ‘prevention’ claims are allowed without having to market the supplement as a drug. Corroborating evidence based on an improvement in a clinical outcome may also be required.”