Discovering why human intervention studies are essential to human studies

The key legislation covering health claims in Europe is regulation number 1924/2006. Introduced in 2007, this regulation covers all nutrition and health claims made on foods and is overseen by the European Food Safety Authority (EFSA).

Essentially, this legislation is a source of scientific advice for the risks associated with the food chain for EFSA and the European Commission. Its primary purpose is to protect consumers and ensure such claims are truthful, clear and reliable. Health claims under this piece of legislation fall under three key articles of the legislation; article 13.1, 13.5 and 14 claims.

This article will focus on article 13.5 claims - claims that are alleged to be based on proprietary, newly developed scientific data from an applicant and can carry a five-year period of data exclusivity in addition to any patent protection.

The first product to achieve an article 13.5 claim

Fruitflow – a water-soluble tomato concentrate - was the first product to achieve an article 13.5 claim in 2009. This tomato extract contained a diverse group of more than 30 bioactive polyphenolic compounds that contributed to its overall cardiovascular health benefits, which improved blood flow through an antiplatelet effect.

One of the key factors in any successful EFSA claim appears to be the consistency of experimental findings, particularly in human studies that effectively demonstrate a clear cause and effect.

However, the real reason this sequence of studies was so influential was that the study sequentially answered a logical series of questions. With strong consistency of outcome measures and findings across the studies, an element of dose response could be shown, which is not always present in a functional food ingredient.

The importance of human study data

The EFSA describes human study data as being at the top of the hierarchy to inform their decisions. The gold standard for human studies is randomized control trials (RCTs).

The EFSA frequently talks about weighing the evidence. A package of studies is evaluated on a study-by-study basis to determine which ones are of sufficient relevance, quality and design to be included in the final evaluation. Therefore, weighing the evidence is intrinsically linked to the quality and not just quantity of the studies.

Health claims: Failures and successes

Over the last decade, only around ten claims have been successful. This is due to the applicant's lack of understanding regarding the claim itself as well as its modern standards. Success isn't about the size of a company, nor is it about just one health benefit area. Instead, success depends on the conditions under which the applicant proves cause and effect.

Claims are limited by the dose, the dosing regimen, the population studied and choice of comparator. These conditions of use have an effect on commercial usability and success.

Failed health claims

The C21 coffee claim from February this year is one that has previously been tried twice. Common to many applications, this claim included studies on a product that was not the same specification as the one at the center of the claim, and this is why it did not succeed. With regard to weighing evidence, in this situation, the evidence was not compelling.

The high protein moderate carbohydrate meals claim goes back to 2017, and it failed not on the amount or quantity of data but simply on the fact that the study showed mixed results. The EFSA felt that the results were not compelling enough in either the setting or duration of the study long term or short term.

Finally, there is the Stablor claim from 2017 that had four human intervention studies at its core. But with three of them being uncontrolled studies with no comparator, they were quickly dismissed, left with just one study, which will never be enough to prove cause and effect.

The three largest areas of human intervention studies that the EFSA question are statistics, reporting and outcomes. More recently, the focus has been on power calculations, the randomization process and blinding of studies.

Successful health claims

The most frequently asked questions by prospective health claim applicants are how many intervention studies they need and if they have enough human study data completed or planned.

In short, one study will never be enough to prove a reproducible cause and effect. Two studies are also unlikely to be a winning formula except under specific circumstances. But a package of three to five well-designed, high-quality studies could and has been enough on more than one occasion. That is providing there is consistency in the outcomes. The answer lies in quality, not quantity.

For example, a claim based on black tea was recently approved after failing the first time around. The original claim submitted contained a large number of studies that were mainly historical data, but when scrutinized individually, EFSA felt that they had to exclude a significant number of these studies either because they didn't report on the specific bio and active content of the test product itself, or because it wasn't even clear that the test product was black tea in origin.

Nonetheless, the second claim ultimately succeeded because of the wealth of supporting data on caffeine and its known benefits to attention.

Conclusion

Looking at the examples of both positive and negative claims, a core package of three to five well-designed, randomized controlled trials can be adequate to deliver a health claim.

The product tested in the human trials must match the one specified in the proposed claim. Studies must have an appropriate statistical powering assumption associated with the primary outcome and the target for the claim, and they must also have an appropriate analysis for the study design that's chosen.

Weighing of the evidence and a well-established, plausible mechanism of action is influential in EFSA's thinking, and the outcome measures identified must show a beneficial physiological change. It is also essential to use the appropriate literature to identify all potentially relevant studies.

Whether EFSA health claims are in your field of vision currently, or perhaps some way off, the choices you make now when designing and conducting any inhuman intervention trials will determine their future value.

The same mistakes that caused health claims to be rejected in the past are still being made, and so the value of well-designed, randomized controlled trials cannot be underestimated. Health claims can be achieved with a handful of consistent human intervention studies supported by a plausible mechanism of action.

About Atlantia Clinical Trials

Atlantia Clinical Trials Ltd is a CRO that specializes in conducting studies in foods, beverages and supplements for companies world-wide that want to scientifically validate their functional ingredients to support an: EFSA (European Food Safety Authority) Health Claim; FDA (Food & Drug Administration) Structure Function Claim; or General Product Marketing Claim.

Atlantia works with world leading scientists (among the top cited 1% internationally, in the areas of digestive health and functional foods) at the: APC Microbiome Institute in University College Cork, Ireland; Teagasc, Moorepark, Ireland and recognized centers of excellence globally.

Atlantia runs and operates its own clinic sites and conducts all studies to ICH-GCP standard (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use - Good Clinical Practice). Its team includes physician experts in digestive health, mental health (psychological stress and cognition), cardiovascular health, sports performance, metabolic disease, bone health, immune health and healthy ageing. The clinical team also includes project managers, research nurses, nutritionists, certified sports trainers and lab researchers.

Atlantia manages all elements from protocol design, placebo manufacture, recruitment, and study execution, to sample and data analysis, statistics and report/dossier preparation to provide a service which is technically, scientifically and clinically superior.

The clinical studies cover a broad spectrum of functional food and beverage categories, such as dairy, cereal, probiotic, different protein forms, infant-specific foods, vitamins/minerals, plant or marine extracts and medical foods.


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Last updated: Feb 8, 2022 at 9:22 AM

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