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Testing dietary supplements for quality, safety, and efficacy.
Testing is a crucial part of product development for today’s nutraceutical, functional food, and beverage manufacturers. Three important targets for product testing are quality, safety, and efficacy.
Most importantly, dietary ingredients must be tested to ensure they are reasonably certain to be safe for chronic human consumption. While safety is the most important aspect in manufacturing, dietary supplement companies also want to demonstrate their products’ efficacy in order to make truthful and not misleading health claims. As discussed later, demonstrating-and advertising-efficacy is a very tricky subject due to the regulations of the Dietary Supplement Health and Education Act (DSHEA) with regard to compliant structure-function claim language.
Safety can be determined in a number of ways. Literature reviews may reveal published toxicological studies that have assessed the safety of consumption of certain ingredients. Clinical trials, as well as a history of human consumption with the absence of reported adverse events, can also provide evidence of safety.
In the absence of such published studies, toxicological studies can be conducted in animals. When an appropriate safety factor is applied to account for the differences between animal species and humans, a safe and appropriate dosage level can be recommended for chronic human consumption. Often, analyzing such complex data requires the opinion of experts qualified by training and experience to evaluate the safety of dietary ingredients.
If well-documented safety assessments are not available in the public domain for a product or ingredient, it is necessary for companies to invest in a comprehensive safety assessment. This generally includes conducting studies to assess for various aspects of genotoxicity and common animal models of toxicology.
While many companies would prefer not to be involved with animal testing, at this time there is no better model for predicting toxicity that is accepted by the general scientific community and regulatory agencies. Of course, testing in humans is unethical, which is a very important reason for only selling products with a well-established safety profile.
Hopefully, in the future, non-animal models will be developed that will be accurate in their ability to predict safety. Potential methodologies may include techniques such as genomics, proteonomics, and metabonomics. Specialized in vitro assays or computer modeling may one day be able to ascertain the safety of oral products, without involving animal testing.
Product quality is of utmost importance to consumers and should be of utmost importance to product suppliers as well. With all dietary supplement manufacturers now required to be in compliance with established dietary supplement current Good Manufacturing Practices (cGMPs), the process by which companies must ensure quality is now open to FDA review, inspection, and warning. Yet, there is still a plethora of FDA announcements about warning letters reporting the adulteration of supplements with active pharmaceutical ingredients (APIs) or their analogs-adulteration most often unbeknownst to the manufacturer. To address this, the industry is continuing to self-regulate by doing its best to comply with the cGMP regulations.
Identity testing is now required for all raw materials and must be conducted by the company receiving the raw materials. This is often easier said than done, however.
CGMPs require that an appropriate, scientifically valid method must be used for dietary ingredient identity testing. Yet, consider, for example, a company that tests its stinging nettle (Urtica dioica) raw material using the chemical marker beta-sitosterol. If analytical testing reveals the presence of beta-sitosterol at the anticipated levels, does that ensure that the stinging nettle is properly identified (rather than being some closely related cousin) and of good quality? Or could it be possible that the ingredient contains a small amount of stinging nettle spiked with beta-sitosterol? Another example is Gingko biloba spiked with quercetin. Developing or using scientifically validated methods for testing remains exceedingly important. And, of course, finished-product testing should also be conducted to ensure product quality.
Aside from standard chromatographic and spectroscopic methods, some companies are beginning to offer more-advanced DNA-based technologies for botanical raw-material identification, which are able to identify botanical ingredients to the species level, with a high percentage of confidence.
Of course, routine testing to ensure dietary ingredients are free of microbials, heavy metals, and residual solvents, and that expiration dates have been backed by shelf-life studies, cannot be forgotten with regard to QA/QC.
What better way to market a product’s efficacy than with solid scientific evidence such as double-blinded placebo-controlled trials? Today’s consumer, as well the FTC, wants to know that there is competent and reliable research to support the intended use of a product.
How should a company go about this research? Study designs that have come to be standard for small-molecule drug products may not be optimal for complex natural products containing numerous constituents. How does one best characterize a complex product? What marker compounds should be chosen to study bioavailability by pharmacokinetic and pharmacodynamic studies? What in vitro studies should be conducted first to help develop hypotheses of mechanisms of action that can be later investigated in human study subjects?
Smaller pilot clinical trials can be extremely helpful in determining the design and primary outcome measures for larger trials. Pilot studies can be useful for determining a treatment effect and therefore can be a cost-effective measure for determining how to design (e.g., the ideal number of study subjects) a larger clinical trial that is more likely to show statistical significance. Hiring an expert contract research organization and monitoring scientists is a key step when beginning to make strategic plans for an effective and efficient research road map.
Perhaps the greatest challenge for the dietary supplements industry is determining how to use research to market products, without making disease-treatment claims, which are not allowed according to DSHEA and FDA regulations. While most dietary supplements are not intended to replace drugs, they are often formulated with the intention of supporting wellness and preventing health problems throughout the aging process. Unless a company has an ingredient with an FDA-approved health claim, or unless an ingredient is intended for a condition that is not considered a disease (such as menopause), how can a clinical trial be designed to show efficacy?
It’s not easy to get a clinical trial funded to study the effects of a supplement on blood pressure in a healthy population, when the strongest compliant structure-function claim might be, “Helps support healthy blood pressure that is already in the normal range.” Such claims are required to be truthful and not misleading, according to section 403(r)(6) of the Federal Food Drug and Cosmetic (FD&C) Act, in addition to not claiming to prevent, treat, or mitigate a disease, according to DSHEA. Indeed, thoughtful and creative design of such trials is an art.
Focusing on intended use is also imperative in proper study design. For example, if an ingredient is intended to be marketed to help reduce nervousness for occasional stressful situations, such as public speaking, the study should not be conducted in patients with diagnosed generalized anxiety disorder.
These are important considerations, as truthfulness in advertising is also subject to enforcement by the FTC Act. Hence, study results demonstrating the therapeutic benefit of consumption of a supplement in patients diagnosed with a particular disease state cannot be used to substantiate claims for the maintenance of health in normal individuals-unless there is adequate scientific evidence to rationalize the generalization of the results from the diseased population to healthy subjects.
While FDA and the FTC have somewhat different regulatory jurisdictions with regard to dietary supplements-FDA oversees safety and labeling, while the FTC oversees advertising-both share an interest in the substantiation of claims that address the quantitative performance or health benefits associated with a particular product. The two agencies’ jurisdictions have blurred somewhat recently, with the increasing popularity of direct-to-consumer Internet sales. Websites are considered labeling by FDA and advertising by the FTC.
February 1 marked the first time FDA issued a warning letter concerning alleged drug claims for dietary supplements marketed on websites. In the letter, FDA cited not only violations of the FD&C Act but also violations of the FTC Act. Moreover, the letter threatened legal action by the FTC and directed the recipient to “notify FTC…within fifteen (15) working days…of the specific actions [it has] taken to address FTC’s concerns.”
This warning letter suggests that in the future, there will be a higher degree of mutual interagency enforcement. And the industry should be aware of the agencies’ intertwining enforcement capabilities. The frequency of mutual FDA and FTC enforcement will undoubtedly increase, as both agencies are short-staffed and underfinanced.
Moreover, the FTC considers the totality of scientific evidence when evaluating the substantiation of claims in dietary supplement advertising. The agency considers the size of the study, the quality of the study, and the number of studies, as well as other relevant historical and scientific evidence when passing its judgment. It’s imperative that a study’s endpoints be carefully considered, from the initial design phase, to ensure that research dollars are being maximized to fulfill the complex regulatory requirements of the dietary supplement industry.
In conclusion, natural products research is an endeavor that requires forward thinking, as well as a substantial investment of time, resources, and intellect. Some of the rewards from a well-planned research strategy are: expanded market reach, credibility in the industry, generation of health or structure-function claims, and decreased liability.
Ingredient suppliers, industry trade associations, and government agencies will and must continue to work together to develop accepted research methods for food ingredients and dietary supplements related to safety, quality, and efficacy so that the industry can begin to find answers to its long list of questions related to product testing.
The bottom line for selling products and increasing sales over time is an effective marketing plan. What better way to support excellent marketing than through an excellent and ongoing scientific research program?
A step that is often overlooked in the process of research and development is publishing. Whether a company has performed a battery of toxicology studies, a clinical study, or wants to support the “generally recognized” aspect of Generally Recognized as Safe (GRAS) self-declarations, the publication of the results in a peer-reviewed academic journal is beneficial in many ways. In fact, if a company is marketing a product based on unpublished studies, with no plans to publish its studies, one has to wonder why.