While human clinical studies have long been accepted as the “gold standard” of scientific research, the advent of dietary supplement ingredients being supported by human clinical trials is relatively new.This expensive and time-consuming process did not become common practice in the dietary supplement industry until the last 10 years, when regulatory requirements in the United States and abroad made them necessary for legal marketing of dietary supplements and functional foods.

While a substantial investment for ingredient suppliers, a successful study can yield significant returns—from health claims substantiation to use in scientific conference presentations and publication in peer-reviewed medical journals—all of which could result in increased sales and distribution. And making the practice an ongoing part of business can yield new discoveries and applications.

Safety First

When analyzing the steps to putting a research-based ingredient on the market, Suzanne McNeary, president of Vermont-based Nutragenesis, noted that safety and efficacy are two separate But equally important issues that need to be considered. “In order to satisfy IRB (Institutional Review Board) requirements for a human clinical study, you need to first and foremost have the safety component completely addressed. Then you can proceed with efficacy studies,” she said. “So the two go hand in hand, but are not done simultaneously.”

“Safety always comes first with any new food supplement,” agreed Vladimir Badmaev, MD, PhD, head of R&D with NattoPharma based in Norway. “Therefore, standardization of the product combined with acute toxicity, mutagenicity and 90-day subchronic toxicity study should be performed in addition to mandatory IRB approval of the protocol prior to the clinical study.”

When SierraSil Health Inc. was looking to launch its hydro-thermal mineral complex (HMC) joint health ingredient sourced in the U.S. Sierra Mountains (hence named SierraSil®), the company asked a number of experienced experts what research they recommended to both validate safety and efficacy.According to Michael Bentley, president of the Canadian-based company, they were able to accept all the recommendations, which included acute oral toxicity (AOT), sub acute oral toxicity (SAOT)And mechanism of action (MOA), and then could confidently enter into the human clinical trial phase.

“As we sought to verify safety and substantiate possible efficacy claims, the AOT and SAOT follow standardized protocol, the latter being in compliance with OECD (the Organisation for Economic Co-operation and Development) Guidelines for testing of chemicals (No. 408, Section 4: Health Effects). The AOT and SAOT are tests required of pharmaceutical products and provide an extra measure of confidence for safety,” he said. “A secondary benefit is the confidence provided to those who recommend our product.”

SierraSil has six human clinicals to date and is planning two more in the next 12 months. “This test rigor is exceptional, but as we have a single, proprietary product, it’s in our interest to ensure that the safety and efficacy is beyond question,” said Bentley, noting that the successful human testing enables SierraSil to make a Health Canada approved claim as well as consider some foreign markets that require human clinicals. “We have been using ‘promotes joint health and mobility,’ but we may need to update that to ‘used for the temporary relief of joint pain associated with osteoarthritis’ and possibly ‘improves joint mobility.’”

A Methodical Process

Attending this year’s Nutrition Business Journal Summit, Michael Jeffers, CEO of New Mexico-based Helios CORP, raised a question concerning how the FDA and FTC classify an un-biased, registered human clinical study vs. something other than un-biased. The response Jeffers received from the agencies was that the highest standard is the Gold Medal Standard, which in pharmaceuticals means a completed, Phase III human clinical with acceptable protocols per FDA and a significant study population.“For nutraceuticals, I deduced from this presentation that Gold Medal is a completed Phase I human clinical study and a USA-based, Phase II human clinical study as conducted in a registered and un-biased clinical environment,” said Jeffers. “This means that once the clinical protocols are submitted to the research site and the research team completing the study, data is presented that cannot be tainted or modified by the person(s) submitting the protocols at the beginning of the study.”

This is the approach Helios CORP implements as it, and its partner Sunbio, maintains four active, branded and nutra-based ingredients that hold at Least two human clinical studies with the second study conducted in the U.S. The company’s No. 1 ingredient is EstroG- 100 for Menopause, for which the company maintains a 12-month human Phase I clinical study, a U.S.-based fourmonth Phase II human clinical study, five toxicology studies, two anti-cancer studies, two non-estrogenic studies and two liver protective studies. In addition, it has a new dietary ingredient (NDI) noobjection from the FDA and a Health Canada Registration number that comes with eight end-point claims.

Prior to conducting human clinicals, California-based InterHealth Nutraceuticals invests heavily in animalbased research in order to develop “hypothesis” centered on efficacy that can be tested in human studies, according to James Lugo, PhD, director of R&D. “InterHealth starts with animal model systems as a guide toward identifying potential biomarkers and efficacy parameters as well as for established safety. We then apply what we learn from this preliminary research to the design of our human clinical research protocols,” he said.

Lugo described what InterHealth has brought to the industry as a “mini-pharma approach,” as it aspires to do two clinical studies for each of the company’s Top brands. “This is comprised of the consistent use of randomized controlled trials done under double-blind, placebo-controlled conditions and the deployment of animal-based toxicological studies,” he said. The company’s top ingredients are UC-II®, shown in published, randomized, double-blind research to reduce key parameters for joint pain; Zychrome®, which was demonstrated in published, randomized, double-blind, placebo-controlled research to significantly decrease insulin resistance and fasting insulin levels by 30 percent; and Meratrim™, which has two randomized, double-blind, placebo- controlled research studies that showed taking 400 mg twice a day significantly reduced body weight and waist and hip size better than diet and exercise alone.

Facing an increasingly tight regulatory environment, Lugo shared that this substantiation is just the beginning of what product manufacturers need to look for. “With increased FDA activity, solid scientific substantiation for product claims is critical. Product claims should be backed by well-designed human clinical studies so as to not mislead consumers regarding expected benefits and to ensure the product is safe,” he said. “Responsible companies ensure that structure/ function claims are based on solid scientific research, and develop manufacturing competencies that are GMP certified or GMP compliant.”

Ongoing Evidence & Discovery

Operating within two categories that are always under careful FDA and FTC scrutiny—weight loss and sports nutrition— New Jersey-based Nutratech, Inc., maker of the proprietary bitter orange extract Advantra Z®, is clear about the necessity for meeting regulatory requirements, but also the benefits that come with success.

“DSHEA, the FDA and FTC are very specific about what ingredient suppliers and manufacturers can and cannot say when it comes to marketing claims— and watch suspect products closely. If your marketing claims are supported by a wealth of science—especially human clinical studies—it’s unlikely that you’ll have regulatory issues,” said Bob Green, president of Nutratech.

While Green noted that all research is Important in gaining the fullest understanding of an ingredient, he expressed that it’s of equal importance that the research process never truly end. For Advantra Z, which is most commonly used in weight management, sports nutrition and energy supplements that are typically multi-ingredient formuals, Green said that the company continues its research investment with the company’s and its manufacturer partners’ interests in mind.

“In addition to looking to assess the safety and efficacy of our branded ingredient, we’re interested in interaction with other formula ingredients from both the efficacy and safety perspectives,” he noted. “We feel strongly that research must be ongoing because of all the variables that exist.We’ve been participating in and supporting human clinical studies on Advantra Z/bitter orange for more than 15 years, and we will continue to do so. You can always come up with one positive—or one negative—study, but scientists know that the truth lies in the preponderance of evidence. So you need many studies to truly assess an ingredient’s safety and efficacy.”

More than 30 research studies support the safety and efficacy of bitter Orange (Citrus aurantium) and its dominant amine, p-synephrine, and multiingredient formulas that contain them, Green explained. “Not only are most of these human clinical studies, the majority have used Advantra Z rather than generic bitter orange extracts because of its consistent quality,” he said, adding that all the research studies can be viewed in their entirety at the company’s website (www.nutratechinc. com/advz/advz.php?p=2).

InterHealth’s Lugo offered that his company sees its continual research investment as not only creating confidence with customers, but also adding to the perception of the industry.

“Through our IP activities and research studies, InterHealth’s customers benefit from patent protection, unique claims, validated efficacy and a strong safety profile. InterHealth’s brands add value to products in every market category,” he said. “Supplying products with functional ingredients backed by published peer-reviewed science is key in overcoming skepticism about functional products and their advertised benefits.”

Badmaev agreed that the process of scientific discovery never stops, and shared how it has lead to important developments for NattoPharma, which has been dedicated to defining natto, a traditional fermented Japanese food and source of vitamin K2, through research, which lead to its menaquinone-7 brand MenaQ7®.

“The research work necessary for market introduction is the initial work based on a current knowledge. The follow- up research helps reassure the safety, but also reposition the product to provide the most recent understanding and application,” he said. “The continuous research also provides better knowhow for use of the product and reconfirms that the original finding was not a one-time finding, but a principal finding that is validated over time.”

Despite the epidemiological evidence showing that dietary intake of vitamin K2 may improve the overall health status, it was not until the threeyear “breakthrough” study of MenaQ7 that there has been a clinical study showing that supplemental vitamin K, especially menaquinone-7, improves bone mineral density, bone strength and cardiovascular health.1

“It is deemed a ‘breakthrough’ study because it shows for the first time clinically statistically significant protection of the vertebrae and the hip (femoral neck) against osteoporosis, cardiovasCular deterioration and metabolic deterioration. One of the most important findings from the study was that clinically relevant improvement became evident no sooner than after two and three years of MenaQ7 supplementation,” Badmaev explained.“This finding explains for the first time why shorter studies (12 months) typically failed to show benefits of vitamin K on bone health and cardiovascular health. Establishing a correlation between length of administration and efficacy of menaquinone-7 intake is a clinically significant ‘breakthrough’ established in this three-year study of MenaQ7.”

Science Leading Marketing

Nutragenesis currently has eight ingredients supported by human clinical trials. Its flagship product, Sensoril®, enjoys a very strong research platform that shows significant reductions in stress and anxiety, an increase in cognitive function, reductions in fatigue, reductions in serum cortisol, increase in serum DHEA, improved cardiovascular profile and reductions in C-reactive protein, according to McNeary.

She explained that once safety has been clearly established, the ultimate Goal for Nutragenesis going into a human clinical trial is to establish efficacy and statistically significant results in the condition-specific areas the company is seeking to address with its ingredients. “Of equal importance is to make sure that the end points support the substantiation for the structure/function claims that we want to make, that the claims are marketable and attractive to our customers, and will translate to consumers,” she said.

Yet Badmaev cautioned that the main objective of a sound clinical research plan is to acquire knowledge of the product without preconditions, and he views it as a main misstep of the industry not to take this approach.

“Often in our industry there is a reluctance to step into the field of research without some assurance that the outcome of the research will be favorable for marketing of the product.This attitude is probably the most common fallacy in the research field of nutritional supplements, preventing true reign of science,” he said. “In my experience, more often than otherwise, the hypothetical expectations for the research were not met, but nevertheless a well-executed study provided a Valuable experience and better understanding of the researched product.

“Unpredictable and revealing outcomes of clinical research, like the one shown in our recent three-year duration study, point to a great advantage of following the science rather than the marketing concepts,” he added. “Only that approach will ultimately lead to a genuine nutritional supplement supported by science.”

Reference: 

1 Cees Vermeer et al., 2012 VitaFoods Presentation.

Extra! Extra!

Go to www.niemgazine.com for participants’ advice on avoiding missteps when conducting human clinical testing or vetting ingredients for finished products.

FORMOREINFORMATION:

.Helios CORP, (505) 982-8836

.InterHealth Nutraceuticals, (707) 751-2800

.NattoPharma, (+47) 40 00 90 08

.Nutragenesis, LLC, (802) 257-5345

.Nutratech, Inc., (973) 882-7773

.SierraSil Health Inc., (877) 743-7720

Providing strong scientific backing for ingredients is not only necessary, but provides a wealth of opportunity, the least of which is confidence for manufacturing partners.

Frank Investment Advice

Based on his company’s experience, SierraSil’s Michael Bentley noted that a 100- to 150-person human clinical study in North America is $350,000 to $500,000 plus publication costs. “This assumes that a smaller pilot study verifying likely safety is already in the books, and such pilot studies can be as modest as $15,000 to $25,000,” he said, adding that doing studies off-shore can be much less expensive. “A 90-day SAOT test (following OECD protocols) can be in the neighborhood of $150,000. A cheaper option is a 28-day SAOT, but in our case, we chose the more rigorous 90-day standard.”

Helios CORP conducts a review of the cultural remedy; develops the formula based on proof of performance in a historical context; conducts a soft, animal review of performance; then the Phase I and the Phase II U.S. study. According to Michael Jeffers, bridge support studies might also be implemented to support further claims derived from the Phase II. “In the case of the EstroG-100 study, we created nine bridge studies to support, thus The costs went up,” he said. “Our investment will average about $500,000 to $1.2 million based on how deep we get into fleshing out endpoint claims.

“The level of investment increases with each part. The study protocols shape out based on the performance of the previous study evaluation. If endpoint claim goals are not met in any portion of the process, we halt evaluations for a later date,” he added.

But Bentley noted an important piece of advice for companies: “Rule of thumb—take the research vendor time estimates and double them! Take the dollar estimates and realize that’s a starting point! From start to finish, including study design protocol, ethical review, government regulatory approval, patient recruitment, study, data crunching and results, about two years is not unreasonable as a planning horizon,” he said, but noted that the cost is not only compulsory, but completely worthwhile. “We look at topflight testing simply as a necessary cost of doing business and protecting what we hope is a stellar reputation.”