We regularly field inquiries from nutrition companies about conducting clinical studies of various sizes, from pilot scale to small trials and large clinical studies. We applaud their initiative. However, for many, our advice is to take a few steps back down the investigative path.
 
Clinical research should be approached with discretion. In our current regulatory environment, nutrition products, especially foods, may be better for you than the FDA allows companies to say. For example, we know that a wide range of phytocompounds behave as antioxidants. Our knowledge of this chemistry is beyond dispute. However, the FDA has not established nutrient antioxidant guidelines for most of them, and discourages even modest antioxidant label claims. This places a risk on claims that it is not prudent to accept. Similar risks exist across a range of potential benefits which research attributes to food sources.
 
So what is a company to do? How does a company approach advanced research? What objectives and expectations should it set?
 
Define Your Objectives
What is the purpose of testing? Are you trying to establish screening metrics for product development? Develop parameters for quality control and/or specification sheets? Or do you want to build a research foundation for more advanced uses, such as patents or label claims? These objectives are fundamental to decisions about how far you should take your investigation.
 
Define Product Characteristics
The first step is to understand the nature of your product. This, by itself, can be a challenging process. For an ingredient like cocoa extract, for example, you might focus on quantifying concentration of cocoa flavanols. This investigation can lead to a range of tests—from more general measures (e.g., total flavanols), to more specific (e.g., unique levels of monomers, dimmers, trimers of proanthocyanidins), etc.
 
Testing of a complex matrix, whether in ingredient formulations or finished products, can add an extra dimension, as a company may want to establish additional parameters, such as other primary compound groups, or individual compounds. There are also other complementary in vitro tests, such as the ORAC panel, which can further inform about product characteristics and point toward mechanisms of action and potential in vivo outcomes.
 
This stage of investigation resides largely in the area of analytical chemistry, and brings much needed clarity to the nature and potential of a product. By itself, it can provide meaningful information for internal R&D, product specifications, and QC/QA protocols. It can also form a directional foundation for further investigation.
 
Pre-Clinical Biological Testing
We can make an important, and useful, transition from in vitro chemistry tests to a live biological environment through the use of cell-based and enzymatic assays. These assays can provide meaningful data on a wide range of investigative fronts, including cytotoxicity, bioavailability of active agents, cell permeability and uptake.
 
They can also provide a first glimpse at potential mechanisms of action in a biological environment. There are robust commercial cell-based assays that employ respected markers for oxidative damage, inflammation, cellular glucose regulation, mitochondrial and telomere damage, and certain cancers.
 
Investigators may have a wide choice of markers, depending upon objectives. For example, pre-clinical inflammatory markers include TNF-alpha, C-reactive protein, NFkB, LOX enzymes, COX enzymes, and interleukins.
 
If clinical investigation were a long-distance relay race, then pre-clinical biological testing is the first baton pass. It forms the first connection between chemical characterization and potential biological significance, and offers initial data that helps inform more advanced investigation.
 
Animal Model Testing
Many companies reject the idea of animal testing because of their own or their customers’ ethical concerns. (It should also be noted that many animal models do not require the sacrifice of the animals used.) However, animal testing can be a part of the bedrock of health research that offers advanced investigation at an affordable cost.
 
Animal model studies offer, at least, the following: 1) help define and clarify potential mechanisms of action, toxicity, and therapeutic targets; 2) provide guidance for more precise and efficient human clinical protocols; and 3) mitigate the risk of human clinical studies.
 
Animal studies have the advantage of providing diverse investigative range: including obesity, metabolism, respiratory, cardiovascular, immune system, and cancer models. They provide value guidance for the development of efficient and successful human clinical protocols.
 
Human Clinical Studies
After extensive consideration, you have decided to perform a clinical study. If you have already conducted pre-clinical and/or animal model work, then you will have data that helps inform and direct the development of a strong clinical protocol. What comes next?
 
First, we establish the objective of the study. Do you seek data about bioavailability, retention time, or efficacy? Are you principally concerned with safety data? Answers to these questions will provide the primary framework for the study.
 
Second, we identify key outcomes, target metrics, and variables. This is a phase in which previous investigative data helps refine protocol development. Here, also, it is valuable to have a familiarity with the research literature that is relevant to your investigative objectives. It can provide valuable guidance about the design of a successful protocol. For example, what might the published literature tell us about the pharmacokinetics, the relevance of specific inflammation markers, detection limits, or confounding variables related to the study of tea catechins and cardiovascular health?
 
Third, we build a study design that is attentive to patient safety, study objectives, scientific rigor, and budget (in that order of importance).
 
While there is always an element of risk and uncertainty in clinical investigation, a well-designed investigative approach is the best way to mitigate risk and improve the chances of meaningful outcomes. Early input from a regulatory point of view into the design of the clinical investigation is also a key to success.
 
Conclusion
For most businesses considering clinical studies, return on investment is an essential factor. In this article, we have not addressed the regulatory landscape and the way it shapes the use and opportunity of clinical results. Our focus has been on describing a rational pathway for considering clinical investigation.
 
However, whether your objective is internal knowledge, a GRAS application, product differentiation, or claim support, taking these steps is the best way to build a solid scientific foundation.

---

Jin Ji, PhD, is Executive Vice President and Chief Technology Officer of Brunswick Laboratories, Inc. (Southborough, MA). David N. Bell is President of Bell Advisory Services (New Bedford, MA).