1. Is the ingredient safe and how has safety been verified?
Safety is obviously the first consideration for any ingredient. But the level of science supporting safety claims can vary greatly.
- Has the safety data been published in a peer-reviewed toxicology journal?
- Is the ingredient GRAS approved for foods as well as supplements?
- Has the ingredient manufacturer received a “no objection” letter from the FDA on its GRAS submission?
Has the package of safety data been reviewed by other leading government regulatory agencies, such as Health Canada and EFSA (EU)? Verify the regulatory position by requesting and reviewing regulatory letters from government institutions.
2. Has the mechanism of action been elucidated, defined and published?
Understanding how an immune health ingredient works in the body is critical to evaluating its efficacy. Is it understood how the ingredient affects the immune system at the cellular level? How is the ingredient taken up or absorbed by the body? Mechanism of action research should be conducted independently and repeatedly and, of course, peer reviewed. It is also important that studies are conducted in a manner that demonstrate the ingredient’s mechanism of action as measured by its effect on the innate or acquired immune system. Research models that don’t match mechanism with desired outcomes are meaningless.
3. Is the ingredient an immune stimulator or an immune modulator?
There are a number of terms to describe immune-enhancing ingredients: boosters, stimulators, enhancers, primers and modulators. What does these terms mean from a scientific standpoint? Immune boosters temporarily stimulate the immune system and create an artificial and unnatural state that may damage the body if taken too long. Immune modulating ingredients prime the body’s natural immune mechanisms to respond to a challenge and maintain the balance of the immune system and can be taken year-round.
4. What is the quality and quantity of the clinical research?
Look at the number of studies conducted, whether they were peer-review published and the quality of the studies. When reviewing the entire body of research, look for consistent outcomes from multiple studies. Peer-reviewed, double-blinded, placebo-controlled clinical studies are the gold standard, but other forms of human clinical study can be valid and provide support of efficacy. In vitro (test tube studies) may be interesting but insufficient to demonstrate clinical efficacy. Preclinical studies may demonstrate interesting health benefits, but are not directly applicable to humans.
5. Was the research conducted with the specific ingredient or borrowed from other products?
The regulatory position that research supporting the safety and efficacy of probiotics must be strain-specific has implications for other immune-enhancing ingredients. It is critical to ask whether the research was conducted with the specific ingredient that the study allegedly supports. Borrowed science is junk science. The specific biological strain or chemical structure matters as has been demonstrated repeatedly with, for example, vitamin E tocopherols and various carotenoid sources.
6. How was each clinical study designed?
Study design is critical to eliminating unintentional bias on the part of researchers to study subjects. When evaluating study results, it is important to understand and weigh the merits of single blind, open label, double blind, and crossover study designs. All are valid study designs; however, a double-blind study is considered to be the best. A crossover design is equally good as it eliminates data variations owing to the particular physical make up of each treatment group.
7. What kind of outcomes were employed in the study?
Because of the complexity of immunology, the two major forms of outcomes that are of scientific and regulatory interest are biomarker outcomes and physical health outcomes (an observable physical health benefit such as reduced sneezing, reduced downtime – missed work – etc.) Many outcomes can be misinterpreted or are surrogates for the clinical endpoint. The outcome used in a human clinical study must have a demonstrable positive benefit for humans. Selection of outcomes is not always a clear-cut process. Recently, the Institute of Medicine developed a position paper on establishing a biomarker evaluation process. The IOM recommended a three-step process that includes analytical validation of biomarkers, qualification that the evidence-based role of selected biomarkers has been confirmed with clinical endpoints and that a strong decision process on the evidence and specific context for the use of a biomarker as a surrogate endpoint exists. These recommendations are a step in the right direction, but need to have some flexibility.
8. Is the ingredient well characterized?
It is absolutely critical that the health benefit activity can be attributed to known component(s). Is its molecular structure well defined? Characterization allows for measurement and standardization, which is required for establishing dosage, consistency in manufacturing and stability and shelf-life testing. Identifying the active component is necessary for determining the desired health effect and having confidence that one batch of the product does not differ from another in terms of efficacy or stability. The danger of a poorly characterized ingredient is one does not know the other components and whether they may be harmful.
9. How is dosage determined?
Does the ingredient’s dose-response data support the recommended daily dose? A demonstration of dose response is the best indicator of optimum or effective dosage.
10. What are the formulation characteristics?
No matter how safe or effective the ingredient, it is essential that it can be formulated into foods and beverages. Can the ingredient withstand the heat, pH, pressure required in the manufacturing process? Many ingredients break down and lose their potency.