Testing food supplements on healthy volunteers or patients is crucial to validate the effectiveness or efficacy of food supplement products. Positive clinical data obtained under proper experimental conditions strongly support the health claims of these products. Clinical studies are a vital component for verifying health claims for food supplements. They provide the highest level of scientific evidence for establishing a cause-and-effect relationship. It is of utmost importance to ensure that all study objectives are included in the design of clinical studies and that Good Clinical Practice (GCP) guidelines are followed. This ensures that all data and outcomes collected at the end of the study are relevant to the proposed health claim.
DCC Convex is a private research institution specializing in the clinical testing of dietary supplements and nutraceuticals across various therapeutic areas. Our focus is to assess the safety and efficacy of your product and support health claims. Our team offers comprehensive services for clinical trials, including study design, protocol development, regulatory support, clinical study conduct, site/study management, data management, monitoring, and quality assurance. Our team of professionals with expertise in clinical research can provide guidance and support throughout the entire clinical trial process.
We collaborate with academic institutions, pharmaceutical companies, and government agencies to carry out research projects and clinical trials. Our team of experienced researchers, physicians, and scientists ensures adherence to international standards and guidelines for clinical testing of food supplements/ nutraceuticals. By following international guidelines, in accordance with European Union regulations for clinical testing, we can provide valuable insights into the effectiveness and safety of food supplements/ nutraceuticals.
Most regulatory authorities worldwide, as well as the market itself, require health claims about the efficacy and safety of dietary supplements to be supported by competent and reliable scientific evidence. In order to assist companies that develop and manufacture these products, our dedicated investigative team provides full services for food and dietary supplement clinical trials, including:
To initiate a clinical trial for your food supplement, please contact us directly to inquire about our services and discuss the specific requirements for testing your food supplement for claims. We will provide information regarding expertise, services, availability, specific requirements for testing your food supplement/ nutraceuticals for claims, potential study participants/patients/HVs, facilities, ethical considerations, and any associated costs.
We work closely with sponsors and regulatory authorities to ensure compliance with all necessary regulations and ethical considerations.
Interest in nutraceuticals and dietary supplements is on the rise, with global sales reaching USD 140 billion in 2018, and a projected increase to USD 216 billion by 2026. According to a 2017 survey, 76 percent of adults in the United States reported taking dietary supplements over the previous year. Among these supplements, vitamins and minerals are the top-selling category, followed by omega-3 fatty acids and probiotics. There is also a growing trend in the popularity of herbal ingredients
Several factors contribute to the growth in sales and consumption of dietary supplements. Firstly, there is an increasing awareness of the significant role nutrition plays in overall health. Lifestyle changes, such as a greater consumption of unhealthy foods, reduced physical activity, time constraints that limit engagement in healthy practices, a rising burden of chronic diseases, and a growing elderly population, all contribute to the increased use of dietary supplements. Additionally, dissatisfaction with the limited effectiveness of pharmaceutical drugs, particularly in the treatment and prevention of chronic diseases, concerns about adverse effects associated with pharmaceuticals, and the perception that dietary supplements are safer and better tolerated have further fuelled interest in and the popularity of dietary supplements.
One common criticism of nutraceuticals is their relative lack of strict regulation and the limited research supporting their effectiveness in promoting health, well-being, and treating diseases. Unlike pharmaceutical medications, which are subject to rigorous oversight by government agencies such as the Food and Drug Administration (FDA) in the USA, the European Medicines Agency (EMA) in Europe, and the Therapeutic Goods Administration (TGA) in Australia, dietary supplements are subject to less stringent regulation. However, due to the increasing sales and popularity of dietary supplements, this landscape is evolving and expected to become more rigorous over time. This underscores the growing importance of researching the safety, tolerance, and effectiveness of nutraceuticals.
Outlined below are various types of evidence used to establish the safety and efficacy of nutraceuticals, with greater emphasis placed on certain forms of evidence:
Nutraceutical firms are recognizing the growing significance of conducting clinical trials involving their product ingredients. As a result, there is a rising trend in the number of clinical trials focused on nutraceuticals. However, in order to optimize the reliability of evidence derived from these nutraceutical clinical trials, it is crucial that they maintain a high standard of quality and ideally, that their findings are published in reputable, peer-reviewed medical journals. The upcoming section offers recommendations on the proper approach to conducting nutraceutical research, with the goal of enhancing the credibility of evidence regarding the effectiveness and safety of nutraceutical products.
Clinical trials involving nutraceuticals should employ the highest standard of research methodologies, characterized by randomization, control groups, and double-blind procedures. While open-label and non-randomized trials can offer initial insights into the safety and tolerance of a nutraceutical, their inherent limitations hinder our ability to draw definitive conclusions about its effectiveness as a treatment. It’s well-established that the placebo effect can significantly influence trial outcomes, and without an appropriate control group, it becomes impossible to isolate and measure the treatment effects associated with nutraceutical use. Unfortunately, there have been instances where studies in the field of nutraceuticals have employed these suboptimal trial designs.
An essential aspect of planning clinical trials is to guarantee that the sample size is adequately large to detect meaningful treatment effects. This involves assessing similar trials conducted previously to estimate the potential magnitude of change that a treatment may bring about in the outcome measures used in the study. In the case of placebo-controlled trials, it’s important to predict an effect size in comparison to a placebo. In the field of nutraceutical research, it is common to encounter studies that are underpowered. For instance, it’s not unusual to come across placebo-controlled trials with fewer than 40 participants. In a study with just 40 individuals, a substantial effect size of 0.8 is required to have an 80 percent chance of detecting a statistically significant effect with a p-value less than 0.05 (assuming no dropouts occur during the study). When we examine effect sizes in pharmaceutical research, they often do not reach this magnitude. Therefore, expecting such a significant effect size from nutraceutical interventions is unrealistic.
Furthermore, there are studies that compare the efficacy of a nutraceutical to that of an established pharmaceutical intervention. When no significant differences in treatment outcomes are observed, it is sometimes erroneously interpreted as confirming similar treatment efficacy between the nutraceutical and the pharmaceutical. However, this result can be easily achieved by ensuring that the study is underpowered. Consequently, when making comparisons between a nutraceutical and a proven, effective pharmaceutical, it is imperative to employ large sample sizes. This is because if there is a difference in treatment efficacy, the effect size is likely to be small to medium. If a small effect size of 0.2 is anticipated, the sample size should encompass more than 600 individuals. If a medium effect size of 0.5 is expected, the sample size should include over 100 individuals. In many published studies where a nutraceutical was pitted against a pharmaceutical, sample sizes of fewer than 50 participants were often used. Inevitably, no statistically significant difference between the drug and the nutraceutical was detected, leading to the incorrect conclusion that the two treatments possessed similar efficacy. However, the more accurate conclusion should be that the study was underpowered, rendering any meaningful conclusions inconclusive.
When planning a clinical trial, it is crucial to define the precise population to be studied and establish eligibility criteria. This selection should be based on several factors, including the study’s objectives, the expected mechanism of action of the nutraceutical, practical considerations related to participant recruitment, the potential risks and benefits associated with trial participation, and ethical considerations. Subsequently, based on the trial’s outcomes, conclusions can be drawn regarding the nutraceutical’s effects on the selected population.
For example, if a nutraceutical is found to effectively reduce stress levels in college students experiencing academic stress, it can be reasonably concluded that it may be a useful intervention for individuals facing high academic stress. However, it would be inappropriate to generalize this efficacy to people experiencing other types of stress (e.g., physical stress), stress of different severity or chronicity, or individuals with a diagnosed anxiety disorder. Conclusions about the nutraceutical’s efficacy within a specific population should only be made if the research has specifically investigated that population. The same principles apply when drawing conclusions based on factors such as gender, age, symptom severity, individuals with co-existing medical conditions, or the use of the nutraceutical as an adjunct treatment. If a particular population has not been studied, any conclusions regarding the efficacy for that population should be made cautiously.
A challenge in nutraceutical research lies in the necessity to carry out studies on individuals considered “healthy.” While nutraceuticals hold promise in the prevention and treatment of diseases, making claims related to disease treatment requires a substantial body of high-quality evidence, typically seen in the domain of pharmaceutical drugs. Establishing robust evidence for health claims in diseased populations often necessitates clinical trials with multi-million-dollar budgets.
To enable nutraceutical health claims, research typically focuses on individuals who are considered healthy. However, conducting trials on such populations presents a unique challenge. Since healthy individuals have little room for improvement, it becomes challenging to clearly identify the benefits of treatment. Consequently, careful consideration of the selected population is essential to maximize the likelihood of detecting the treatment’s benefits.
The choice of outcome measures plays a critical role in assessing the effectiveness of an intervention. The selection of these measures should align with the study’s objectives and involve the use of instruments that are both reliable and valid.
For instance, if the aim of an intervention is to determine whether a nutraceutical treatment is effective in addressing depression, it is essential to employ reliable and valid tools, such as self-report questionnaires and clinician-rated assessments, specifically designed to evaluate depressive symptoms. Alternatively, if the focus is on investigating the impact of an intervention on cortisol levels, meticulous procedures for collecting and measuring cortisol must be implemented.
However, it’s crucial to recognize that a reduction in cortisol levels, for example, cannot automatically lead to the inference that the intervention is an effective treatment for depression simply because cortisol is often dysregulated in individuals with depression. In such cases, the only valid conclusion would be that the intervention lowers cortisol, potentially serving as a mechanism of action for the nutraceutical. Without a comprehensive assessment of depressive symptoms, it would be inappropriate to conclude that the intervention is an effective treatment for depression.
A similar principle applies to research involving cardiovascular drugs, such as statins, which are frequently demonstrated to lower cholesterol levels. While it is reasonable to conclude that the statin has reduced cholesterol, it would not be appropriate to confidently infer that it reduces the risk of cardiovascular disease unless the study also incorporates outcome measures related to cardiovascular mortality and morbidity.
When assessing treatment outcomes, it is essential to employ suitable statistical analyses. In trials that include a control group, it is necessary to conduct comparisons between the treatment and control groups. In nutraceutical trials, it is not uncommon to encounter statistical analyses focused on changes within each group over time. In other words, these analyses aim to determine whether there were improvements over time within each treatment group. However, this approach is flawed because we know that even a placebo can lead to improvements over time, owing to the well-established placebo effect. Therefore, to evaluate the effectiveness of an intervention, analyses should be designed to assess whether the magnitude of changes in outcome measures differs between the two groups. Furthermore, the appropriate statistical tests must be chosen to examine these between-group differences. This entails selecting the most suitable parametric or non-parametric tests for the analysis.
In cases where multiple statistical comparisons are conducted, it is also important to adjust significance values to account for the increased likelihood of finding a statistically significant effect by chance. For example, with a significance level set at p < 0.05, there is a 5 percent chance of finding a statistically significant result by chance. If two separate analyses are performed and both yield a p-value of 0.05, the cumulative chance of finding a statistically significant effect by chance increases to 10 percent (0.05 x 2). This probability of discovering an effect by chance continues to rise as more analyses are conducted.
A common critique of interventional studies pertains to the disproportionate emphasis on results that are “statistically significant” in contrast to those that are “clinically meaningful.” In some studies, an outcome measure may exhibit a statistically significant change, but the change may be so minor that it lacks clinical significance. For instance, there could be a statistically significant 5 percent reduction in a self-report measure compared to a placebo, yet this change may not be perceptibly meaningful to individuals in terms of symptomatic relief.
One approach to address this issue is to calculate treatment effect sizes. Effect sizes provide a measure of how substantial the treatment’s impact is compared to the placebo. A small effect size typically corresponds to 0.2, a medium effect size to 0.5, and a large effect size to 0.8 or higher. Calculating effect sizes in clinical trials is valuable because it offers insights into the magnitude of treatment effects.
However, there is a caveat associated with effect size calculations. Even if an effect size is considered large, which is generally desirable, it does not convey the level of effort, financial expenditures, or other resources required to achieve this treatment effect. For example, a 12-month intervention involving frequent practitioner visits, costing thousands of dollars, and associated with numerous adverse effects may yield a large treatment effect. In contrast, taking a nutraceutical twice daily, costing only $30 per month, may result in a small treatment effect, but it demands minimal resources. Simply comparing effect sizes might lead to the conclusion that one treatment is superior to the other without considering the financial or other costs incurred by individuals and the community. These factors should be taken into account when interpreting study results.
When assessing the effectiveness of an intervention, it’s crucial to determine the most efficient and well-tolerated treatment dosage. This encompasses decisions regarding the quantity, frequency, and duration of treatment. While insights into dosage and safety can be gleaned from animal experiments, it’s imperative to rely on human trials to establish definitive conclusions. The appropriate dosage may also vary based on factors such as the characteristics of the study population, the duration of treatment (e.g., short-term versus long-term), the specific medical condition being addressed, and the composition of the nutraceutical extract utilized.
Regrettably, in many nutraceutical trials, a uniform dosage is commonly employed across various studies. However, even if a certain dosage demonstrates efficacy in a given trial, it is plausible that more substantial treatment benefits could be attained at different dosages. Furthermore, it is conceivable that some studies yielding negative results might not be indicative of the nutraceutical’s ineffectiveness but rather the administration of a dosage that falls short of delivering therapeutic benefits.
The most rigorous research studies employ randomized, controlled, double-blind designs, which involve the random assignment of participants to different groups and the concealment of treatment assignments from both participants and investigators. Since many nutraceuticals possess distinctive attributes such as color, taste, or odor, it is essential to match placebos to the active treatment based on these characteristics. Moreover, the dose, method of administration (e.g., tablet, powder, liquid), and dosing frequency must be identical between the treatment groups to enhance effective blinding. Continuous monitoring should be in place to assess whether blinding remains effective throughout the study.
In addition to ensuring that participants remain unaware of their assigned treatment, adequate measures must be taken to ensure that investigators are also blinded to treatment allocations. Detailed information regarding the randomization and blinding procedures should be included in the study’s publication for transparency and clarity.
In an ideal scenario, data collection in clinical trials should span not only the treatment period but also include a follow-up phase. The duration of this follow-up period should be determined based on the treatment objectives, potential mechanisms of action associated with the nutraceutical, and the characteristics of the study population. Incorporating a follow-up phase allows for the evaluation of prolonged benefits, safety, and tolerance of the nutraceutical.
For instance, if there are observed advantages in taking a nutraceutical during the treatment phase, it becomes essential to investigate whether these benefits persist after the treatment has been discontinued. Regrettably, including follow-up assessments is not a common practice in either nutraceutical or drug-based clinical trials. This may be attributed to the added costs and challenges associated with retaining study participants over an extended period.
In contrast to pharmaceutical studies, where the effectiveness of a standardized, reproducible compound can be examined, plant extracts can exhibit significant variability in terms of quality and composition. This variability can have a profound impact on safety, tolerability, and treatment efficacy. Even though two extracts from herbs, plants, fruits, or vegetables may share the same name (e.g., St. John’s Wort, saffron, turmeric, cranberry, etc.), there can be substantial differences in the concentrations of their active ingredients. To illustrate, expecting two oranges grown in distinct countries to have identical levels of vitamin C would be unrealistic. A similar principle applies to herbal or plant extracts. This variance arises from factors such as differing geographical locations, climates, soil qualities, cultivation methods, harvest times, storage practices, and even variations in extraction processes. These factors can significantly influence the composition, quality, and presence of contaminants in the final product.
As a result, it is prudent to exercise caution when attempting to generalize findings from a study conducted on a specific, uniquely formulated extract to apply them to all other extracts. To address this issue, many manufacturers are now producing standardized and patented plant extracts. These extracts adhere to consistent manufacturing processes over time, enhancing the likelihood of producing replicable extracts. Furthermore, these extracts may be standardized for specific active ingredients to ensure reproducibility. While there are criticisms associated with standardization, particularly related to the potential neglect of other valuable components within the plant, it does help ensure the consistency of plant extracts.
Therefore, it is crucial to recognize that due to the variations in plant extracts, conclusions drawn from a study should pertain solely to the particular extract that was investigated in that study and should not be extended to the plant as a whole. Manufacturers who intend to make claims regarding their specific extract should conduct studies on their unique formulation rather than solely relying on evidence from other studies to assert the effectiveness of their extract.
Today, it has become common for dietary supplement companies to manufacture products that include multiple ingredients. The underlying hypothesis is that consuming a combination of ingredients may yield more potent therapeutic benefits compared to using a single ingredient. Although the decision to create multi-ingredient products may be grounded in solid theoretical principles that potentially enhance treatment effectiveness, it is essential to substantiate their safety and efficacy through clinical trials. Claims regarding a product should not rely solely on research conducted on individual ingredients within the formula. This is because we lack information about potential interaction effects among these ingredients, the stability of the ingredients when used in combination, or the appropriate dosages required when used together.
In certain clinical trials, the criteria for participant eligibility are so stringent that the study results have limited relevance for the broader population. For instance, eligibility criteria may require participants to maintain a healthy weight, possess no existing medical conditions, refrain from medication use, avoid supplements, be non-smokers, and consume minimal to no alcohol. The strictness of these eligibility requirements means that the individuals recruited for the study do not adequately mirror the characteristics of the individuals likely to use the nutraceutical in real-world settings. While some degree of criteria is necessary in clinical trials, it is crucial that the selected cohort genuinely represents the target audience for the nutraceutical to ensure the findings have practical applicability.
To establish the effectiveness of a nutraceutical, it is imperative to conduct research into its mechanisms of action. In addition to studying treatment efficacy, trials should also aim to unravel how a nutraceutical exerts its effects. This investigative process should encompass laboratory studies (in vitro), experiments on animals, and human trials. Demonstrating that a nutraceutical can influence physiological mechanisms that may be linked to the underlying causes of a disease plays a crucial role in validating its efficacy as a treatment. Although unraveling potential mechanisms of action can be challenging (even for many pharmaceutical drugs, their precise mechanisms remain unknown), designing studies that incorporate appropriate biological outcome measures to scrutinize the processes of change should be actively considered.
Due to the costs associated with conducting a clinical trial, many nutraceutical intervention studies are conducted in countries where it is cheapest to implement. Initial trials in these countries are encouraged as it can provide preliminary evidence of safety and efficacy. However, to increase robustness and confidence in findings, trials should be conducted on multiple populations. This is particularly pertinent if the ingredient will be sold internationally. By conducting studies in multiple sites around the world, we can establish a product’s efficacy and tolerability in diverse populations. Moreover, because many herbal treatments are based on traditional practices, exposure to a plant may be commonplace in a specific country/culture but not another. This can potentially influence tolerability and efficacy in different populations.
Conducting in-house studies can be valuable for manufacturers seeking to assess the potential efficacy and safety of their ingredients or products. This is especially advisable before embarking on widespread commercialization efforts. However, for larger and more comprehensive studies, it is crucial to enlist the services of independent clinical trial organizations. These organizations can include universities or independent contract research organizations (CROs). Entrusting an independent organization to conduct a clinical trial serves to mitigate the potential for bias and enhances the perceived credibility of the study’s findings.
When selecting a research organization, several factors must be taken into consideration. These factors encompass the expertise and publication track record of the researchers involved, the fixed and pre-agreed costs for conducting the study, adherence to good clinical practices, adherence to ethical approval and trial registry procedures, ease of communication with research personnel, recruitment strategies employed, intellectual property agreements, accessibility of the trial site to relevant populations, and the efficiency in conducting the study and submitting results for publication.
Following the completion of a study, the results should be disseminated by publishing them in a high-quality, reputable, peer-reviewed journal. While in-house reports can provide evidence of safety and efficacy, the credibility of the findings is substantially enhanced when an article undergoes peer review by experts in the respective field. Unfortunately, a significant number of nutraceutical trials either remain unpublished or are published in low-quality journals. Moreover, careful consideration is needed when selecting the most appropriate journal for publication, as this choice can significantly impact the extent of awareness and recognition a research study receives.
The market now features a growing number of available journals. However, regrettably, many of these journals have subpar reputations and limited impact (meaning few people read them). Additionally, some journal publishers may misleadingly inflate their impact factors, which serve as a measure of a journal’s popularity.
It is essential to emphasize that even when the outcomes of a trial are negative, the findings should still be published. Not every trial involving a nutraceutical can yield positive results, and negative outcomes can provide valuable insights for shaping future directions in nutraceutical research. Demonstrating a commitment to publishing all trial results, irrespective of their outcome, can bolster consumer confidence and trust in a company or brand.