Nutraceutical Trails
There are several ways in which the nutraceutical industry has mimicked the pharmaceutical industry. The latest of these involves conducting clinical trials. Being able to say that a product performed as advertised in a clinical trial is a competitive advantage over other products that simply state a traditional use.
While clinical trials are not required for compliance, using clinical trials to produce a better product does result in higher quality. This is a positive trend, both because it adds legitimacy to nutraceuticals and because it provides a better value for consumers. However, there are several points to consider.
Why Existing Studies Won’t Cut It
Existing research can be useful to formulators — but only as an indication of what a certain ingredient might do if included in products. Using existing studies to substantiate claims is risky, and product developers need to consider 1) the type of study and 2) the ingredient(s).
Take, for example, a nutraceutical company that wants to market its berberine extract as an effective way to regulate blood sugar. Product developers look at existing studies and find one showing that berberine does, in fact, control blood sugar. However, the study was conducted on animals. This may not be adequate support for a claim if the Federal Trade Commission (FTC) investigates. The type of animal, route of administration, dosage, extraction process and concentration of the extract are all factors that may make this study inadequate. As far as regulatory bodies are concerned, the best evidence comes from well-controlled human clinical studies1, although this is not the only kind of acceptable evidence.
The other factor is making sure that the ingredient from the study matches the product’s formulation. Going back to the berberine example, a study using goldenseal cannot be used to substantiate claims about a berberine extract. While goldenseal does contain berberine, the intervention must be specific to the formulation that the company intends to use. Similarly, a combination supplement that contains berberine and other ingredients is not validated by a positive study that solely examines the effects of berberine. If a combination is being sold, the study must substantiate that combination, not its components.
Use Extreme Caution When Marketing
The U.S. Food and Drug Administration (FDA) might have jurisdiction when it comes to the nutraceutical itself, but the FTC has jurisdiction when it comes to advertising. Even with a successful clinical trial, there are still limitations on what advertising can say or imply. In terms of messaging, the FTC is concerned with the overall impression. If you don’t say that your glucosamine product treats arthritis, but you say that a clinical trial showed it supports joint health, this is still considered a health claim and requires substantiation. Other points worth considering include:
– The entire body of evidence: The company may have a legitimate, well-designed study showing that the product performs as advertised. However, if one positive study is outnumbered by many more negative ones, this is considered misleading, and the FTC can take action.
– Disclosure of qualifying information: If a company has positive studies supporting its product, but doesn’t include all relevant information, the advertising is misleading. A good example of this is a weight-loss supplement. If there are multiple studies fitting the above-mentioned criteria that show this supplement helps participants lose weight, advertising can reflect that. However, if the participants of these studies also went on a diet plan and underwent an exercise program for the duration of the study, this must be disclosed.
Finishing What You Start
Conducting a clinical trial is a new concept to many nutraceutical companies, and the process is complex and difficult to manage. Part of that difficulty arises from the massive amount of documentation required by the FDA. This at least partially explains why so many clinical trials involving dietary supplements go unfinished. Over the past 10 years, the number of registered clinical trials has steadily increased, as has the amount of clinical trials that make it to completion. However, over the same time period, the amount of published results from year to year has virtually remained the same. At the time of this writing, of the 5,622 completed dietary supplement clinical trials on ClinicalTrials.gov, only 516 have published results — a mere 9 percent!
Not completing and publishing the results of a clinical trial defeats the purpose of conducting one in the first place. The air of legitimacy from clinical trials only comes with published results, and the clinical trial isn’t really complete until this happens. Some companies may hesitate to publish negative results, but this also adds credibility to the company and should serve to point its product development process in the right direction.
What You Need
The amount of documentation required for a clinical trial is staggering. The location of all that documentation is known as the trial master file, and fortunately, many companies offer an electronic version known as an eTMF. The eTMF houses all the content needed for a clinical study and also allows third parties to review and collaborate on that information. However, the guidelines for what should be included in an eTMF were designed for pharmaceutical companies. Since nutraceutical companies don’t have to meet the same requirements and clinical trials are completely optional, how does this affect the amount of paperwork? It depends.
According to FDA guidance on the subject, the purpose of the clinical trial and what is being tested determine what is needed for compliance. Just one example of this is the Investigation New Drug Application (IND). The dividing line here is whether the nutraceutical is marketed to affect structure or bodily function, or if it’s marketed for therapeutic purposes. The former does not require an IND because the FDA doesn’t see it as a drug. Whereas the latter fits the definition of a drug and does require an IND2.
Another point to consider is what you’re doing to protect your study participants. While informed consent and its requirements are well known, what is not well known is how to handle those requirements. You have to provide uniform information about the study to potential participants, screen out those candidates who don’t meet your criteria, keep track of ones that drop out, keep participants on schedule, etc. Doing all this requires a good document control system, part of any good quality management system. Some companies provide specific clinical versions of this, called a clinical quality management system (CQMS). Ideally, the CQMS would be on the same platform as your eTMF, providing visibility that is unavailable with disparate systems.
Clinical Research: Support Nutraceutical Product Claim
Nutraceuticals are the products that have both nutritional and pharmaceutical characters. Therefore they are used as a dietary supplement to modulate the symptoms of various diseases and conditions by providing physiological benefits against chronic diseases.
Due to higher consumer acceptability in the US and Japan, these countries have the most potential markets worldwide.
As the nutraceutical industry is growing, likewise various commissions and regulations are also under enforcement to control and to approve such health products and their health claims.
In the last decade, nutraceuticals have emerged as a booming market in India. Food Safety and Standards Authority of India (FSSA) is responsible for the regulation and approval of nutraceuticals in India. This authority was established by the enforcement of the Food Safety and Standard Act, 2006.
As per the regulatory requirement, the nutraceutical benefits must be justified through scientific as well as clinical evidence regarding their therapeutic claim for market approval. The claim can be substantiated either by selecting ‘generic claim’ authorized for vitamin/multivitamin and minerals (Limited number of substances) or by opting for a clinical trial/clinical research.
Types of health claims usually are:
General level health claim: Refers to a nutrient of a substance/product
High level health claim: Refers to a nutrient which relates to a biomarker towards therapeutic claim.
Once a manufacturer ensures a health claim of a nutraceutical product, scientific justification in the favor of ‘made claim’ is the main concern which requires supporting data to obtain marketing approval from the regulatory authorities.
Since manufacturers are involved only in the manufacturing of products, they may lack knowledge, dedicated experts and resources to initiate a clinical study.
Most common hurdles in clinical trials of nutraceutical are:
Study design: pragmatic planning and design of the study involving nutraceutical products is crucial. While drafting the protocol, appropriate sample size calculation, selection of the pattern of study design (like: parallel, crossover, placebo control design), treatment allocation, endpoint biomarkers selection, and statistical techniques should be considered that have the potential to provide a proper conclusion of the study.
Logistic concerns: Such types of studies usually do not have pharmacokinetic endpoints, therefore more logistic concerns arise which can impact the outcomes. Even very small changes in the recruited volunteer’s life style can affect the biomarker values and in turn the study results. Therefore, proper synchronization of the recruited volunteer’s activities should be insisted.
Inclusion criteria: More stringent inclusion criteria (like: narrow BMI/age range, gender, race, life style) are required as compared to conventional drug based clinical studies to minimize the differences in body anatomy and physiology. Increased dedication of the volunteers is also required. This can result in more screen failures and reduced availability of eligible volunteers.
Trained personnel: Highly trained personnel are necessary to assure the study is conducted in compliance with the protocol requirements.
Sensitive methods and instruments: To analyze the samples accurately, Sometimes, a pilot study may be conducted, to evaluate nutraceutical prior to a large scale trial to answer the therapeutic efficacy and justify the claim. Such pilot trials are observational in nature and provide the basis for progressing further.
Considering all the above challenges, opting for a CRO is the best option for a manufacturer to conduct the clinical research and it is a clear advantage to work with a CRO which has expertise to conduct clinical studies of nutraceutical without bias. To initiate a clinical study of a nutraceutical, appropriate recruitment of volunteers, logistic procedures, data handling, appropriate statistical analysis and regulatory expertise are important. A CRO is able to provide the entire service of relevant activities right from clinical trial planning, dedicated staff and professional conduct to execute, analyze the results and develop the report, all in compliance with GCP and regulatory requirements. The CROs can support the manufacturer until the regulatory approval, and also help in post-marketing studies too.
Aqlivia, being a well established CRO, has the expertise in planning and conduction of such studies. Many nutraceutical studies have been successfully completed. Some of the studies are rice bran oil study, fermented milk having beta glucan fiber clinical study, etc.
