In Part I of this series on claim substantiation, we addressed the fact that a health claim has two essential components: a substance and a disease or health-related condition. The health claim can be made for a food, food ingredient or dietary supplement ingredient provided that the claim is substantiated by clinical data.
Regulation allows Health Claims (HC) and Qualified Health Claims (QHC) to be made for food, food ingredients and dietary supplements that demonstrate a relationship between a food, food component and/or a dietary supplement ingredient, and the reduction in the risk of a disease or health-related condition (21 CFR 101.14(a)(1)). Structure/Function Claims (STC) can also be made for food, food ingredients and dietary supplements, but can only address the effect of a substance on the structure or function of the body. These criteria are in stark contrast to that of a drug, which is defined by the Food and Drug Administration (FDA) as a substance intended in the “diagnosis, cure, mitigation, treatment, or prevention of disease in man” (Federal Food, Drug & Cosmetic Act, Section 201(g)(1)).
Utilizing an evidence-based review system, FDA evaluates the strength of the scientific evidence to support a proposed claim about a substance/disease relationship. The substantiation standard for claims used by both FDA and the FTC (Federal Trade Commission) that has met with competent and reliable scientific evidence needs to adequately address four separate issues: (1) the meaning of the claim being made; (2) the relationship of the evidence to the claim; (3) the quality of the evidence; and (4) the totality of the evidence (FDA/CFSAN, 2009).
In the case of food and dietary supplement ingredients, demonstrating efficacy through clinical testing is critical for substantiating a claim, but above all, the claim must be “truthful and not misleading” and based on appropriate scientific criteria and appropriate endpoints. Therefore, the key component of the scientific evidence necessary to substantiate a claim is the clinical data; and the quality of the data is by far more important than the quantity, as attested by both the FDA and the FTC. Further, all claims made on the label are subject to review and approval by FDA, while FTC polices claims in the media.
There is no “cookie cutter” approach to the development and performance of human studies for claim substantiation. However, the overall conduct must adhere to established principles for clinical trials that include the presence and strength of the safety data, prior evidence of efficacy, and the establishment of what effect (or outcome) is to be studied.
The credibility of clinical data is established on well-defined, reproducible and unbiased response criteria that adequately address the study hypothesis. One caveat that applies to clinical trials for claim substantiation is the fact that the studies have to be conducted with healthy individuals, unlike the pharmaceutical studies which are designed to show amelioration of a disease or its symptoms.
Establishing the research question based on what hypothesis has the highest chance of being adequately answered, represents the first step in designing the study and has to be decided prior to study initiation.
The exact wording for the claim (which means understanding not only the meaning of the claim, but also clearly identify each implied and express claim) is absolutely critical and represents the basis for developing the hypothesis and protocol for the human study. This step cannot be emphasized enough and generally requires significantly more time, effort and clinical and regulatory expertise than initially anticipated.
Study design of the clinical trial in support of a specific claim is critical – there must be a straight line relationship between the findings of the trial and the claim. If the trial does not support the desired claim, an expensive clinical trial may be rendered useless. An incorrectly worded claim can have grave consequences culminating with conducting the inappropriate clinical trial that leads to the denial of the claim by the
FDA (for a HC or QHC).
The key is careful planning. Once the research question is established, the complex process of developing the blueprint for the clinical study can begin, with the study protocol being one of several consequential pieces in the design and conduct of a human trial.
A shotgun approach of administering a substance to humans and analyzing changes for possible claims is rarely a successful strategy. A well thought-out protocol is essential to get the petitioner to where he needs to be, with statistically demonstrable efficacy for the test ingredient/product, supporting the claim he has determined to be most marketable.
The “gold standard” in clinical study design remains that of interventional studies, specifically prospective, randomized, blinded or double-blinded, controlled studies.
Critical in developing the inclusion/exclusion criteria, screening and baseline evaluations as part of a well thought-out protocol is the necessity for clinical experience.
Supplemental standards in the study design process include:
Identifying the appropriate study population (including sex, race, and age)
Estimating the sample size to allow attainment of statistical significance (including an estimate of the number of drop-outs)
Determining the length of the study (there is no standard for how long a clinical trial should run – that determination is based on the effect under investigation)
Establishing patient management procedures to improve compliance
Instituting monitoring procedures for safety
Describing the exact approach to classifying and handling anticipated and unanticipated adverse events (AER) represents an important part of the protocol that is well scrutinized by the Institutional Review Boards (IRB) during the review process. Blinding or masking, prospective randomization of subjects to treatment and control groups, and/or multi-center studies help to minimize potential bias, a frequently found systematic error in study design and conduct.