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Providing Efficacy In Theory And Practice

K2VITAL®
 
Albion Minerals®

Researchers, suppliers and manufacturers are stepping up efforts to prove ingredient efficacy—but it’s often consumers who have the last word.

While it may have specific meanings in different fields, the definition of the word “efficacy” is the power to produce an effect. In the supplement industry, how suppliers, scientists, manufacturers and, ultimately, consumers perceive the effect of an ingredient is not always so clearly defined.

Ray A. Matulka, PhD, director of toxicology with Florida-based Burdock Group, explained that if an ingredient is added to a dietary supplement as an antioxidant to protect other ingredients in the supplement from degradation, then the ingredient must be tested for its efficacy for this specific action. “You have to answer the question: Does the ingredient do what it is claimed to do? If for example, the ingredient does not act as an antioxidant for other ingredients, but only for the consumer of the substance, it is not considered totally efficacious.” 

Reza Kamarei, PhD, vice president of science and technology with New Jersey-based Sabinsa Corporation, said that after safety, efficacy is the most important feature of an ingredient— usually as a component of conventional food or dietary supplement. “Efficacy means the ability of an ingredient to produce beneficiary effect. In this context, the proven efficacy may be considered as competent and reliable scientific evidence for substantiation of claim(s).” 

For the consumer experience, which is important for continued use, efficacy has everything to do with their perception that they are indeed getting a benefit, Kamarei explained. “For a number of ingredients, they either do or don’t experience a difference in how they feel. If they take a joint health product, for example, every day for four months and don’t feel better, they will stop buying and using that product. So proved efficacy for the manufacturer deciding which ingredients to include in a product, the body of science may be more compelling, but for the consumer, it is often their personal experience that determines efficacy.”

Clinical Proof 

Straight to the point, an ingredient’s efficacy needs to be determined by scientific research, said Victor Ferrari, CEO of Horphag Research (USA) in New Jersey, supplier of Pycnogenol®. “The ultimate efficacy has to be shown in human clinical trials. The time for testtube experiments, such as ORAC and other arbitrary figures, is running out. The consumer deserves a clear message of what benefits a nutrient will provide.”

And the overriding focus of an efficacy study is that it must directly evaluate the desired effect, Matulka explained. “If the ingredient is an antioxidant provided to help support oxidative status of the consumer, then the endpoint evaluated must be oxidative status in the cells of the consumer that consumed the ingredient (some endpoints that may be appropriate for evaluating oxidative status in clinical trials include examination of blood serum levels of antioxidant enzymes, such as glutathione peroxidase or the lipid peroxidation marker malondialdehyde, or evaluating urinary isoprostane levels).

“A theoretical, test-tube determination of ORAC value may not be sufficient,” he added. “Substantiating efficacy for broad or general statements (e.g., ‘helps maintain colon function’) is much more difficult than a concise, clearly defined effect (e.g., ‘helps maintain natural flow through the colon’). Regardless of the product type, proving the efficacy of ingredients utilizing parameters for Which there are no validated methods available is more difficult than for endpoints that have clearly defined, wellresearched and validated protocols for specific endpoints.” 

Those endpoints must have meaning to the consumer. California-based InterHealth Nutraceuticals’ CEO Paul Dijkstra said the company invests heavily in clinical research to ensure it provides ingredients that can substantiate meaningful product claims. “Product claims should be backed by welldesigned clinical studies so as to not mislead consumers of any expected benefits,” he said. “From a supplier’s perspective, finding better ingredients or better forms of existing ingredients will help support many health issues Americans face, such as blood sugar, joint and weight problems.”

Gold Standards 

In terms of ingredient efficacy, the studies necessary to prove that an ingredient does what is stated on the package vary as greatly as the different types of ingredients themselves.

“Stating that an ingredient has a high antioxidant capacity is relatively easy to prove by utilizing the oxygen radical absorbance capacity (ORAC) assay,” said Burdock Group’s Matulka. “However, stating that an ingredient helps maintain or increases antioxidant status in the consumer is more difficult, as it requires at least one clinical trial (there has been some discussion of requiring two clinical trials, but nothing definitive has been stated by regulators).”

The “gold standard” of clinical trials is the double-blind, placebo-controlled, crossover trial. FDA has stressed that the totality of the evidence, including evaluating criteria, such as quality, quantity (number of various types of studies and sample sizes), relevance of exposure, and consistency and replication of the findings, is necessary to determine if a claim is truthful and not misleading, Matulka explained. A clinical trial must be able to cause a statistically significant change in a specific biologic endpoint (that the regulatory agency agrees to be representative of the desired biological outcome), and that effect must be directly related to the consumption of the ingredient.

“When it comes to efficacy, you really need to look at the preponderance of evidence produced over a period of time—not just a single study. That’s difficult for some in our Western, allopathic world to understand and accept,” Said Bob Green, president of New Jersey-based Nutratech, Inc. “Too often they want to apply Western clinical designs to nutritional research, seeking only double-blind, placebo-controlled clinical research studies. But natural ingredients affect multiple systems and functions in the body. In our category— weight management—for example, there are so many different pathways to weight loss that you simply can’t apply the single magic bullet theory. It doesn’t always give the complete picture of an ingredient’s efficacy.

“Scientists and researchers are always telling me, there are many valid markers of high-quality research, which are often dictated by the nature of the research itself,” Green added. He explained that a single, double-blind, placebo-controlled study, no matter how state-ofthe- art, can never represent the be-all and end-all in evaluating an ingredient’s efficacy. That’s why it is necessary to look at the body of research, which usually includes many different study designs (from double-blind, placebocontrolled clinical studies to epidemiological studies to meta-analysis reviews to animal research to in-vitro studies, etc.)—and the collective direction of that research to determine the true markers of ingredient efficacy.

Horphag’s Ferrari pointed out that food supplements are by definition not intended to cure diseases, but are a powerful alternative to promote overall health and wellness. “We are in the wellness industry, contrary to the pharmaceutical industry which clearly targets illness,” he said. “To this effect, clinical trials are more targeted to people who want to make a qualified choice with regard to prevention, wellness and better life performance.”

Problem Solving 

Suppliers face a myriad of obstacles— ingredient to ingredient—from agricultural, costs, providing consistency and reliability, to marketing.

“In the last three years, the natural product industry has witnessed several challenges, a primary one being the supply situation of natural extracts,” said Sabinsa’s Kamarei. “These plants and herbs, which were once seen as an abundance, were negatively impacted either by changes in climate, which caused harvests to fail, or by poor agricultural practices. Yet, there are other reasons, some not widely known of, such as exploitation by the farmers themselves for a penny more. Hoarding and even looting of supplies to gain a more attractive price also occurs. Ultimately, it leaves our dietary supplement industry without the very essential extracts that consumers have taken for many years.” 

A good example of this is curcumin, according to Kamarei, who said the ingredient was introduced and pioneered in this industry by Dr. Muhammed Majeed and Sabinsa (with its Curcumin C3 Complex®) as a rich antioxidant and now as an anti-inflammatory ingredient. “To pay tribute to how successful Sabinsa’s Curcumin C3 Complex has become, just look at the knock-offs, claiming that this bio-availability or that oil fraction are better than Sabinsa’s original curcumin, which has been the gold standard for many years and the predominant material studied at universities around the world.”

Yet for Sabinsa to sustain a curcumin market was no easy task; in the last two years alone, prices nearly tripled, Kamarei added. “Our customers who bought elsewhere because we couldn’t supply paid upwards of $300 plus per kilo, while we went to great effort to keep our price below $200 per kg, which we felt was the right move in order to keep the curcumin business alive. Our own cultivation efforts in India could not keep up with demand created by the growing body of science, and the prices we were paying for turmeric skyrocketed.”

Kamarei said Sabinsa pursued a course that ensured the welfare of the farmers and the survival of this ingredient in the marketplace today. “Interestingly, while supply to our customers was limited, Sabinsa made sure that the research centers and universities around the world received their share of curcumin for their clinicals. Sabinsa kept the research alive on curcumin.” 

Another example of an ingredient challenge Kamarei pointed to is coleus. Introduced by Sabinsa in the mid-90s as an ingredient for lean body mass (ForsLean®), it had major breakthroughs in the sports nutrition market and further into high-end weight management systems. This ingredient, derived from a simple pickle from India, would go on to win major awards for Sabinsa and ultimately changed how future weight management ingredients were launched in the nutraceutical industry, Kamarei said. 

“ForsLean, the patented and branded coleus ingredient from Sabinsa, became a $100 million brand, literally overnight, which caused severe shortages worldwide. Cultivation programs were put into place immediately, but we were able to only meet 20 percent of the demand; the rest were left to sourcing from wherever we could get material,” said Kamarei. “That led to quality issues by other suppliers who wanted to make a quick buck, ignoring basic GMPs and, unfortunately, led to ingredient spiking. It seems that shortages brings out the worst in certain suppliers, which we consider a challenge for the entire industry.” 

These examples showcase not only the present challenges, but also the ongoing obstacles that the natural product industry is facing, Kamarei added. “There is no right answer, nor a solution that will come up overnight. It is a deep and thorough understanding of the issues by customers and consumers alike that will help ensure stability in an unstable market. Now, while competition is certainly healthy, the less ethical suppliers will have a harder time surviving under GMP requirements as their enforcement has become more robust.” 

Providing a safe, efficacious product to consumers in the quickest amount of time at the lowest cost is a major challenge, Burdock’s Matulka agreed, while also supplying novelty and functional attributes.

“Consumers continually look for innovation, and ingredient suppliers must check to make sure an ingredient is appropriately regulated for its proposed use,” Matulka said. “For example, rosemary extract is approved for use as a flavor (typically used at a low concentration in food), but is not necessarily approved for use as a preservative, which would most likely require much higher concentrations of the extract. The safety of an ingredient is dependent on the intended use, and efficacy must be proven prior to making a claim on the food package that contains the ingredient.” 

Highly dependent on cost and functionality is the marketability of an ingredient, noted InterHealth’s Dijkstra. “We have seen more functional beverage products, such as waters and fruit juices, along with dairy products, snack bars and cereals become more popular in the marketplace in the last few years,” he said. “The effect a functional ingredient can have on the taste profile of a product is an important consideration when developing new product formulations. Selecting ingredients that are tasteless, odorless and colorless in solution will have little or no impact on the overall organoleptics of a finished product. This can also help reduce the amount of sugar or artificial flavors needed to ensure a consumer-friendly taste profile. This makes it more attractive to the consumer and helps cut down on manufacturing costs as well as the retail price of the finished product.” 

It is important to consider stability when formulating with nutraceuticals, said Dijkstra, adding that stability data confirming the ingredient has retained its structural integrity for the life of the product is needed to ensure efficacy. InterHealth takes several steps to help ensure that the finished products containing its ingredients contain the appropriate nutritional profile and Attributes.

“For example, we conduct extensive research to ascertain that the stability of our ingredients will be maintained in the final form in which it will be formulated,” said Dijkstra. “It is not only increasingly important to ensure the stability of functional ingredients, but that these ingredients are absorbed efficiently and effectively in the body. Bioavailability guarantees the nutrient’s usefulness to the consumer.”

Efficacy Cases 

One of the most recent examples of efficacy supported by meta-analysis is regarding the role of cinnamon intake in lowering fasting blood glucose (Davis and Yokoyama, J Med Food, 14 (0) 2011, 1-6). The industry brought to market cinnamon dietary supplements for type 2 diabetes, which have been welcomed by consumers. “In this particular case, it is interesting to see how the combination of cinnamon with another plant extract representing two classes of compounds and mechanisms of action would improve the efficacy of combined ingredients in type 2 diabetes,” said Kamarei.

Another example is a recent (March 2012) meta-analysis that looked at the potential cardiovascular benefits of consumption of cocoa products, and found a positive correlation between cocoa consumption and specific cardiovascular endpoints (e.g., lower LDL cholesterol and better blood flow). “It will be hard to determine the effect on the industry, as the ability to substantiate efficacy claims depends on the totality of evidence for the stated claim, and so one published study may not have a significant effect on such a well-studied ingredient as cocoa,” said Matulka. The authors themselves stated that longer duration and larger trials are required to confirm these benefits. 

“When a positive study is published demonstrating support for dietary supplements and dietary supplement ingredients, it reflects positively on the industry,” Dijkstra pointed out. “If mainstream media picks up on the study and it makes national news, consumers are affected by the message, which increases their perception of the industry and their willingness to purchase dietary supplements.” 

Moving Forward 

As the supplement industry has evolved and matured, it has instituted more systems and processes. “That is now beginning to include efficacy research,” said Green. “In the past, there was a tendency to focus more on safety and toxicity. Now, with structure/function claims, manufacturers are requiring suppliers to support those claims—especially for condition-specific applications— like weight management, sports nutrition and energy.

“Certainly, efficacy will take center stage when the final NDI guidance document is issued by the FDA,” he added. “Substantial efficacy research will be required for the approval of every new dietary ingredient.”

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