The study design that you choose to test your product needs to support the final claim that will be made for the product. Your goal may be an application to EFSA in Europe or the FDA in the United States. You may be interested in providing support to your marketing by publishing the results your study. Your chosen design and number of studies will depend on the goals of your product development program.
A product development program may include proof of concept or exploratory studies such as bioavailability or pilot studies, to learn more about the effect size of your product or the dosing levels that will be required, prior to engaging in pivotal or confirmatory studies to prove a cause-and-effect relationship (efficacy) and learn more about population variability following from supplementation with the study product.
Clinical studies in the pharmaceutical space are typically discussed in terms of discreet and sequential clinical trial phases. Depending on the goals of a company’s product development program some clinical study phases may not be applicable or may be combined, especially for dietary supplement and functional food ingredient companies. There are four commonly recognised phases of clinical studies, Phase I-IV and terms such as bioavailability, proof-of-concept, exploratory and confirmatory and pivotal are often use interchangeably with the phases of clinical studies.
Bioavailability, Safety & Tolerability Studies (Phase I)
Phase I studies can include bioavailability or safety and tolerability studies, either in the target population for the product or more commonly in a healthy population. Bioavailability studies can be used to understand the behaviour of a dose of the product in the body. Safety and tolerability studies can be used to demonstrate that a product is safe to consume, whether there is likely to be any dose limiting adverse events and is generally well-tolerated by the individuals consuming it. A phase I trial may not be necessary if there is evidence available to support a products safety either through pre-clinical safety and toxicological studies or published human studies. No efficacy data is collected in a safety and tolerability study.
Proof-of-Concept or Exploratory Studies (Phase II)
Phase II studies are commonly positioned as proof of concept, pilot or exploratory studies with the primary purpose to explore if the product has some initial evidence of clinical efficacy. The aim of exploratory trials is to provide data that can guide definitive power calculations and objectives for future confirmatory studies. They can also be used to determine the future of a product’s development. It important to remember that Phase II studies are still considered exploratory. Statistical significance observed in these studies should not generally be regarded as confirmation of product efficacy as they are generally conducted without firm power calculations, in a relatively small number of participants, without understanding of the characteristics or variability of the study population, the placebo effect or the effect size of the product.
Confirmatory or Pivotal Studies (Phase III)
Phase III studies are typically larger than phase II studies and can often be conducted across several sites, although this is not always necessary. The requirements for phase III studies often depends on the findings of previous studies and the regulatory requirement of the region of the proposed claim. A confirmatory study requires a clearly described primary outcome (using outcome measures endorsed by EFSA/FDA), a clear power calculation based on the previously completed studies and/or a similar product and population and a well-documented, prospectively planned, statistical analysis. In Europe it is more typical for two or more confirmatory studies to be required to demonstrate a reproducible cause and effect relationship in the eyes of a regulator and to support a health claim for product, but it should be noted that one once claim has been approved by EFSA based on two human studies.
Phase IV Studies
Phase IV studies are post-marketing studies conducted to learn more information about the product after it is placed on the market. These include post-marketing surveillance studies and studies intended to support publications, not changes to the label or registration changes. This phase does not generally apply for nutritional supplements/products.
EFSA views human intervention studies as being either “exploratory” or “confirmatory” studies. This classification, driven entirely by the design and quality or the study has an important bearing on the assessment of claims. A number of key factors relating to study design and implementation determine EFSA’s view on this categorisation e.g., a clear power calculation and a well-documented, prospectively planned, statistical analysis.
Both EFSA, for claims made under the EU Nutrition & Health Claim Regulation (NCHR), and FDA, for claims made under The Dietary Supplement Health and Education Act (DSHEA) will examine the supporting studies provided for quality and efficacy and will weigh the “Totality of the Evidence” or look for “Significant Scientific Agreement”.