Rebecca Wright, Editor10.03.11
Science is the engine that drives many industries, including dietary supplements and functional foods. Integral parts of that engine include testing and research, which are equally important in expanding the knowledge about these products as they pertain to human health.
Many experts when talking about these two similar yet distinct categories will often bring up the past in order to make sense of the present. By way of comparison, they typically remark that the industry has made great strides but still has a long way to go.
What they mean, basically, is that these disciplines were rarely discussed in conjunction with dietary supplements and functional foods a decade ago—mostly because making the right investments in science was not a top priority for a majority of companies. Today, to the relief of many both inside and outside the industry, things have changed, as the current market has given companies several reasons to spend that money.
Whatever forces are driving increases in testing and research, Frank Jaksch, CEO, Chromadex, Irvine, CA, said things always work out in favor of companies that want to invest in science. “You always stand on a firm ground when you have science underpinning your ingredient or product.”
Putting the Industry to the Test
The heightened need for both testing and research comes from many corners of the market. Doug Kalman, PhD, RD, FACN, director, BD—Nutrition & Applied Clinical Trials, Miami Research Associates, Miami, FL, said today’s state of affairs appears to be driven by a combination of factors, including Good Manufacturing Practice (GMP) enforcement, litigation regarding substantiation for claims (plaintiff’s counsel, FTC and NAD challenges) and enhanced media coverage.
Dr. Kalman said while the dietary supplement industry is getting much better at ingredient testing and verification, in terms of applying clinical research to finished products, he said there is still a lot of room for improvement. “The industry is still growing in the understanding and application of finished product clinical trials to determine if a product does what it is [supposed to] do, and substantiating marketing claims,” he commented.
Najla Guthrie, president/CEO, KGK Synergize, London, Canada, focused on the impact of the media. “The media has brought to light those cases where safety of products was an issue, and so our whole industry is now being looked at very critically,” she opined. “Although we have a very educated consumer, our industry has also confused the consumer by marketing products with unsubstantiated claims and in some cases, unsafe products. [These] unsubstantiated claims on products have brought about the need for clinical research.”
Darryl Sullivan, director of scientific and regulatory affairs, Covance, Inc., Madison, WI, said testing is being carried out so consumers can feel greater confidence in consuming dietary supplement and functional food products. At the same time, he said GMPs are also playing a huge role. “Testing is primarily being driven by FDA due to GMPs. This is because auditors’ questions can easily be answered by testing.”
And how are those GMP audits going? Mr. Sullivan weighed in with some of his thoughts. “Some companies are feeling the pain because they are on their second round of audits. The first time FDA came through very casually and made suggestions. Now they are coming back a second time and citing those that didn’t take their comments seriously,” he explained. “This industry will get through the short term with a little pain, but at the end of the day there will be better quality control and confidence in our products.”
“FDA just wants companies to take these audits seriously because ultimately the agency is on the hook to make sure consumers are safe. It’s as simple as that,” Mr. Sullivan added.
Like Mr. Sullivan, Chromadex’s Mr. Jaksch believes companies shouldn’t necessarily consider themselves safe if they passed the first inspection—because it doesn’t mean the second inspection will give you the same result.
On that note, Mr. Jaksch discussed the significance of warning letters and 483s. “There is an increase in inspections happening on monthly basis. Further, the amount of effort going into these inspections is growing, especially when you look at the length of comments being made in warning letters and 483s. These are setting the record straight in letting companies know that the rules are not open to interpretation.”
Kerri LeVanseler, PhD, technical manager of NSF International’s Chemistry Laboratory, Ann Arbor, MI, believes testing is often carried out in reaction to an adverse event in an attempt to figure out what went wrong. “In the last several years, there has been a pronounced increase in the number of product recalls. This then can lead to increases in testing as companies [work to] avoid whatever problem caused the recall (e.g., melamine in protein products),” she said, adding that it would be better to see testing and research employed in a proactive way to prevent and avoid recalls and adverse events in the first place.
Misleading claims and adulteration are also prompting more testing. “The products that are marketed for weight loss/weight control and immune system support are ones that appear to be higher on FDA’s/FTC’s radar,” said Dr. Kalman. “In general, from what we see in sports and legal cases, products marketed for weight loss, male enhancement and muscle building seem to have greater issues in terms of adulteration.”
On a related note, Matt Arveseth, Silliker laboratory director, Chicago, IL, said he sees a lot of growth coming from contaminant testing. “[This] will offer the most growth potential as adulteration is a major concern, and economic adulteration and spiking continue to be a hot topic.”
Another trend Mr. Sullivan has noticed is hiring quality control personnel who have a background in pharmaceuticals. “This seems to be working out well because the pharmaceutical industry is downsizing and these quality managers are stepping in and doing a very good job crafting high quality testing programs. These guys have a hardcore mindset and know what we are lacking on the testing front.”
Much has been said and written about FDA’s New Dietary Ingredient (NDI) guidance released in July. But before the doom and gloom sets in, Mr. Jaksch was quick to point out that “it’s a draft guidance that won’t be an official document” until all comments have been taken into consideration.
“The essence of the NDI Guidance is about whether the ingredient(s) in the product should be there in the first place. Ultimately the NDI process is about safety,” Mr. Jaksch commented.
Mr. Sullivan also feels it is too soon to tell what will happen to the industry’s products in light of the NDI guidance. “I don’t really feel like we have yet felt the impact of the NDI guidance. But it could be good in that it will drive a lot more testing and build more rigor into some of the newer ingredients we’re using.”
‘It’s Complicated’
Research and testing, while sharing similar goals—to prove or disprove something—are complicated, especially when it comes to the ingredients that go into both dietary supplements and functional foods.
Vitamins and minerals are pretty straightforward, but ingredients such as herbs and botanicals are complex substances. And when you add several ingredients to a “formula” the analytical challenges can catch even the most seasoned professionals off guard.
“Dietary supplement testing is often made more difficult based on the combination of ingredients used,” explained NSF’s Ms. LeVanseler. “[For example,] a method that has been shown to be scientifically valid for a single ingredient type product may not be valid with the addition of other ingredients in a complicated finished product.”
Further, she said, with GMP testing requirements for identity, purity, strength and composition, and with enhanced emphasis on trace level test capability, testing requirements could seem overwhelming.
“For any size organization, the costs related to dietary supplement testing are significant,” Ms. LeVanseler said. “Tests are often not the proximate type tests that are applicable to foods, which may be quite reasonable in terms of costs; instead the methods may be quite involved and therefore demand higher prices for execution. Nonetheless, many companies do make testing a high priority.”
Also problematic is the presence of potential adulterants, which might be similar to the compound being measured. As a result, Ms. LeVanseler said, “The method may not adequately differentiate the compound of interest from related contaminants.”
For instance, she said, for joint health products containing chondroitin sulfate, glucosamine and hyaluronic acid, it can be challenging to have selective methods for each of these ingredients ensuring that closely related chemicals are not acting to give erroneously high results.
Silliker’s Mr. Arveseth also raised some important issues. “Many large companies have had a history of testing and have been able to quickly adopt GMPs. Many medium and small companies are still trying to get a handle on testing especially when it comes to herbal products,” he commented. “Testing methods vary quite significantly from supplier to supplier and understanding the scientific validity of test methods and comparability of test methods will take years for companies to gain a firm understanding.”
He went on to describe some of the categories where testing is being emphasized. “Active component testing: Manufacturers must have information and data that show their products contain the labeled amount of each ingredient. It is vital to perform both raw material testing and finished product testing to ensure that products are compliant with label and shelf-life claims.”
In terms of contaminant testing, Mr. Arveseth added, “Manufactures are responsible for establishing specifications for contaminants for their supplement products. Heavy metals, microbiological, pesticides, active pharmaceuticals and even economic adulterants are tests most common in the industry.”
Speaking about botanicals specifically, Steven Dentali, chief science officer, American Herbal Products Association (AHPA), Silver Spring, MD, said, “The dietary supplement industry is continuing the process of developing appropriate quality standards and raw material sources. This can be seen through AHPA’s standard-setting efforts, such as the publication of Herbs of Commerce, which is universally used, our Good Agricultural and Collection Practices guidance and many more, including defining what an extract is and how to label them. In addition, collaborating with the alphabet soup of ODS, NCCAM, USP, AOAC, NIST, and others, as we do, helps to move important processes along.”
In general, Dr. Dentali said, there is a lack of understanding and appreciation of botanical products in this country because, unlike the rest of the world, this nation walked away from them about 60 years ago.
“Instead, we developed a different model of medical materials—the single-ingredient/single constituent model historically favored by the pharmaceutical industry,” he explained. “Consequently, we are now faced with establishing standards we should have been building on for some time now. But due in part to the passage of DSHEA, we’re making a lot of progress in establishing standards that consumers can rely on to provide them with safe and efficacious products.”
Mr. Arveseth also touched on the inherent difficulties of testing herbals and “novel” ingredients. “[These categories] have the most testing issues, especially when tested by a non-specific method (i.e., a method that looks at categories of chemicals instead of single chemical components),” he said.
“Some raw material suppliers modify and alter methods in order to inflate the active claims for a product. This makes it very difficult for other laboratories to match claims unless they follow the exact modifications,” Mr. Arveseth continued. “This leads me to question the scientific validity of the alterations to the methods. What was the scientific basis for modifying the method? This also makes it extremely difficult for manufactures to compare ingredients that claim the same active levels, but use different test methods to verify the claim.”
Ms. LeVanseler discussed the issue of reference materials. “Some dietary supplements that are growing in popularity may have not had the method development efforts made to ensure they are suitable. For some herbals, the difficulty may be related to whether the specific phytochemicals are commercially available as a reference standard for instrument calibration,” she said, adding, “Even when the chemicals are available, they may be very expensive (greater than $400 for milligram quantities). This can be the case even for common herbs like ginger, where the cost of the isolated constituents is quite high, let alone the cost of reference standards for chemicals that exist in more exotic plants.”
Under the cGMP environment, companies are struggling to reduce the turnaround time as well as the operation testing cost. In an effort to overcome the challenges in analytical testing, BASF QTA (Quality Trait Analysis) Group, Cincinnati, OH, offers a quality control system that can be set up on site, where multiple analyses can be completed within two minutes without sample preparation or chemicals. In essence, said Kangming Ma, business director, BASF QTA Group, “We are setting up a virtual laboratory with patented technology and service.”
Over the last decade, BASF QTA Group has developed a comprehensive database of dietary ingredients and developed systems that can be installed on the production floor. Using infrared technology, this system has the ability to quantitatively analyze samples. The simple user interface, said Dr. Ma, allows everyone to perform the test.
“The spectral data are sent to BASF, which are processed with pre-developed algorithms. The results are returned to customers in real time,” he explained. “The benefit to the customer is that it is hassle-free to implement and instantly establishes testing capabilities with minimum risk, even without capital investment. We also provide 24-7 technical support over the Internet to monitor the performance and manage the database.”
He went on to say that fish oils and blended oils are very easily analyzed using the technology. Methods for botanical mixtures, which are a little more complicated, can be developed in four to eight weeks, depending on the type and amount of testing a company wants to do.
Research: The Industry’s Achilles’ Heel
According to Alex Schauss, PhD, FACN, senior research director, Natural & Medicinal Products Research, AIBMR Life Sciences, Inc., Puyallup, WA, the lack of competent and reliable clinical studies will continue to be the industry’s Achilles’ heel.
In just the last several weeks, Dr. Schauss said, “Companies called us to evaluate protocols for randomized, placebo-controlled clinical trials, before seeking approval by an Institutional Review Board for Human Experimentation (IRB). By the time we completed the review of the protocols, the pages were bleeding red ink because there were so many flaws in the design of the study—from inadequate sample size due to inappropriate power calculations, to a lack of critical subject inclusion or exclusion criteria. These are expensive studies that deserve a second or even third opinion before commencing.”
Despite these issues, the fact that the number of companies pursuing research programs is growing is good for the industry. “No longer can you line your pockets with anecdotal information,” said Chromadex’s Mr. Jaksch. “As companies increasingly create the science they need to protect themselves, they are solving another problem in the industry by creating more clinically proven products.”
KGK’s Ms. Gutherie feels similarly, and offered an historical perspective. “KGK has been around since 1997 and since that time I have seen clients transition from thinking they could market their product with testimonials to requesting a safety and efficacy clinical trial to be conducted on their product prior to bringing it to market,” she said. “Our clients are first investigating what type of claims they can make and designing clinical trials that address those claims.”
Covance’s Mr. Sullivan agrees that the industry is definitely in a different place as far as research is concerned. “I think we have moved the needle tremendously in the last several years. People used to do very informal studies, which did not collect enough data to impose statistical significance,” he said. “Today, however, carrying out clinical research has become serious business for many companies.”
To that end, Mr. Sullivan said he sees more people piggy-backing on the clinical research NIH is doing. “The difference today is that there is more replicating of studies rather than pirating of studies.”
Looking at clinical substantiation from a testing standpoint, Mr. Jaksch said, “We still see a significant problem with ingredients going into clinical trials. If you can’t prove what you put in those people, then how can you claim the study has any validity whatsoever.”
NSF’s Ms. LeVanseler also offered a critical view of research. “It appears there is a lot of research activity in U.S. universities to correlate diet and health, but the role of dietary supplement companies helping with these efforts is unclear,” she said. “Unless companies elect to move an ingredient or product off the dietary supplement/functional food path and onto the drug path, it seems that few investments are being made in research.”
In terms of claim substantiation, Miami Research’s Dr. Kalman believes the industry is on the right track. Further, he said, “It would be beneficial for the companies who are in this space to have a line item budget or set percentage of dollars spent on marketing earmarked for clinical trials (i.e., 10% of marketing budget). It is not as cumbersome or as costly as people think to have two well-designed, randomized, double-blind, placebo-controlled clinical trials performed.”
Mr. Jaksch said besides the bottom line, there are several very important reasons companies should want to accumulate data behind their products. “Data will help you defend your products against rogue competitors. It will also offer regulatory protection and help you avoid FDA and/or FTC involvement. The bottom line is you stand on much safer ground when you have data.”
In the end, said Covance’s Mr. Sullivan, the goal of research is to further legitimize these categories of products. “The lines continue to be blurred between foods and supplements and it would be nice to get them categorized properly and then apply the necessary quality controls. There are some really nice dietary supplements and functional foods and we just need to get our hands around how to handle them.”
AIBMR’s Alex Schauss, PhD, shares his perspectives on what it takes to carry out research in the nutraceuticals field.
Understanding the complexities of research, much less interpreting the results, is a never-ending challenge. That’s what makes being a research scientist so exciting, particularly in the nutraceuticals field.
But there are frustrations, and the need to keep the totality of research in mind is paramount when drawing conclusions.
A recent paper of interest to the nutraceuticals industry appeared in the August 26th edition of British Medical Journal (BMJ)1. The subject was chocolate and its relationship to cardiovascular disease, diabetes, heart failure, stroke and gender, and the types of chocolate consumed. A total of 4576 references were initially identified by the research group; 1221 were duplicates and excluded.
As this was a meta-analysis, what I found fascinating, and usually do when these type of studies are reported, was that almost all published papers were excluded from analysis. In fact, 3302 papers were excluded. That left 53 articles for retrieval. Assessment of those 53 papers resulted in seven (yes, seven!) eligible studies from which the meta-analysis was performed.
Based on those seven studies, the media reported that adding chocolate to the diet could contribute to the prevention of cardiovascular disease, diabetes and stroke. But no effort was made by the authors in either the title of the paper or the abstract to explain that any benefit seen was restricted to dark chocolate consumption only.
What didn’t make headlines around the same time was a paper that appeared in the Journal of Food Composition and Analysis2, which reported on the soluble oxalate content in commercially produced cocoa and dark chocolate. This is certainly a subject of interest to anyone who has ever experienced a kidney stone attack. The results of this human study confirmed that the dietary intake of oxalate following the consumption of 68 grams of dark chocolate increased oxalate output by a mean of 70% above base value.
Those 68 grams of dark chocolate resulted in the consumption of 232 mg total oxalate, which as the authors point out is “almost three times higher than the maximum intake (80 mg) of oxalate recommended in a low oxalate diet.”
The above discussion points out the importance of doing thorough research rather than relying on sound bites from headlines to determine a product’s health benefits.
Keeping up with the literature on food ingredients is one thing, but imagine the challenge of understanding the cutting edge biotechnologies used to determine the mechanisms of action of those ingredients.
In a recent co-authored paper in Experimental Gerontology3 performed at the NIH’s National Institute on Aging, we studied the effect of açai pulp on modulating lifespan. In our paper we reported that, “acai increased the transcript level of l(2)efl, a small heat-shock-related protein, and two detoxification genes, GstD1 and MtnA, while decreasing the transcript level of phospoenol-pyruvate carboxykinase (Pepck), a key gene involved in gluconeogenesis.”
If that sentence makes little sense, welcome to the new world of nutraceutical research with a lexicon all its own, which studies cell transduction, ubiquitous transcription factors, targets reporter vectors and uses bioinformatics to analyze changes in protein expression. —A.S.
References
1. “Chocolate consumption and cardiometabolic disorders: systematic review and meta-analysis.” British Medical Journal (BMJ), August 26, 2011;343:d4488. doi: 10.1136/bmj.d4488.
2. “Oxalate content in commercially produced cocoa and dark chocolate.” Journal of Food Composition and Analysis, 2011;24(7):916-922.
3. “Acai palm fruit (Euterpe oleracea Mart.) pulp improves survival of flies on a high fat diet.” Experimental Gerontology, 2010;45(3):243-251.
Many experts when talking about these two similar yet distinct categories will often bring up the past in order to make sense of the present. By way of comparison, they typically remark that the industry has made great strides but still has a long way to go.
What they mean, basically, is that these disciplines were rarely discussed in conjunction with dietary supplements and functional foods a decade ago—mostly because making the right investments in science was not a top priority for a majority of companies. Today, to the relief of many both inside and outside the industry, things have changed, as the current market has given companies several reasons to spend that money.
Whatever forces are driving increases in testing and research, Frank Jaksch, CEO, Chromadex, Irvine, CA, said things always work out in favor of companies that want to invest in science. “You always stand on a firm ground when you have science underpinning your ingredient or product.”
Putting the Industry to the Test
The heightened need for both testing and research comes from many corners of the market. Doug Kalman, PhD, RD, FACN, director, BD—Nutrition & Applied Clinical Trials, Miami Research Associates, Miami, FL, said today’s state of affairs appears to be driven by a combination of factors, including Good Manufacturing Practice (GMP) enforcement, litigation regarding substantiation for claims (plaintiff’s counsel, FTC and NAD challenges) and enhanced media coverage.
Dr. Kalman said while the dietary supplement industry is getting much better at ingredient testing and verification, in terms of applying clinical research to finished products, he said there is still a lot of room for improvement. “The industry is still growing in the understanding and application of finished product clinical trials to determine if a product does what it is [supposed to] do, and substantiating marketing claims,” he commented.
Najla Guthrie, president/CEO, KGK Synergize, London, Canada, focused on the impact of the media. “The media has brought to light those cases where safety of products was an issue, and so our whole industry is now being looked at very critically,” she opined. “Although we have a very educated consumer, our industry has also confused the consumer by marketing products with unsubstantiated claims and in some cases, unsafe products. [These] unsubstantiated claims on products have brought about the need for clinical research.”
Darryl Sullivan, director of scientific and regulatory affairs, Covance, Inc., Madison, WI, said testing is being carried out so consumers can feel greater confidence in consuming dietary supplement and functional food products. At the same time, he said GMPs are also playing a huge role. “Testing is primarily being driven by FDA due to GMPs. This is because auditors’ questions can easily be answered by testing.”
And how are those GMP audits going? Mr. Sullivan weighed in with some of his thoughts. “Some companies are feeling the pain because they are on their second round of audits. The first time FDA came through very casually and made suggestions. Now they are coming back a second time and citing those that didn’t take their comments seriously,” he explained. “This industry will get through the short term with a little pain, but at the end of the day there will be better quality control and confidence in our products.”
“FDA just wants companies to take these audits seriously because ultimately the agency is on the hook to make sure consumers are safe. It’s as simple as that,” Mr. Sullivan added.
Like Mr. Sullivan, Chromadex’s Mr. Jaksch believes companies shouldn’t necessarily consider themselves safe if they passed the first inspection—because it doesn’t mean the second inspection will give you the same result.
On that note, Mr. Jaksch discussed the significance of warning letters and 483s. “There is an increase in inspections happening on monthly basis. Further, the amount of effort going into these inspections is growing, especially when you look at the length of comments being made in warning letters and 483s. These are setting the record straight in letting companies know that the rules are not open to interpretation.”
Kerri LeVanseler, PhD, technical manager of NSF International’s Chemistry Laboratory, Ann Arbor, MI, believes testing is often carried out in reaction to an adverse event in an attempt to figure out what went wrong. “In the last several years, there has been a pronounced increase in the number of product recalls. This then can lead to increases in testing as companies [work to] avoid whatever problem caused the recall (e.g., melamine in protein products),” she said, adding that it would be better to see testing and research employed in a proactive way to prevent and avoid recalls and adverse events in the first place.
Misleading claims and adulteration are also prompting more testing. “The products that are marketed for weight loss/weight control and immune system support are ones that appear to be higher on FDA’s/FTC’s radar,” said Dr. Kalman. “In general, from what we see in sports and legal cases, products marketed for weight loss, male enhancement and muscle building seem to have greater issues in terms of adulteration.”
On a related note, Matt Arveseth, Silliker laboratory director, Chicago, IL, said he sees a lot of growth coming from contaminant testing. “[This] will offer the most growth potential as adulteration is a major concern, and economic adulteration and spiking continue to be a hot topic.”
Another trend Mr. Sullivan has noticed is hiring quality control personnel who have a background in pharmaceuticals. “This seems to be working out well because the pharmaceutical industry is downsizing and these quality managers are stepping in and doing a very good job crafting high quality testing programs. These guys have a hardcore mindset and know what we are lacking on the testing front.”
Much has been said and written about FDA’s New Dietary Ingredient (NDI) guidance released in July. But before the doom and gloom sets in, Mr. Jaksch was quick to point out that “it’s a draft guidance that won’t be an official document” until all comments have been taken into consideration.
“The essence of the NDI Guidance is about whether the ingredient(s) in the product should be there in the first place. Ultimately the NDI process is about safety,” Mr. Jaksch commented.
Mr. Sullivan also feels it is too soon to tell what will happen to the industry’s products in light of the NDI guidance. “I don’t really feel like we have yet felt the impact of the NDI guidance. But it could be good in that it will drive a lot more testing and build more rigor into some of the newer ingredients we’re using.”
‘It’s Complicated’
Research and testing, while sharing similar goals—to prove or disprove something—are complicated, especially when it comes to the ingredients that go into both dietary supplements and functional foods.
Vitamins and minerals are pretty straightforward, but ingredients such as herbs and botanicals are complex substances. And when you add several ingredients to a “formula” the analytical challenges can catch even the most seasoned professionals off guard.
“Dietary supplement testing is often made more difficult based on the combination of ingredients used,” explained NSF’s Ms. LeVanseler. “[For example,] a method that has been shown to be scientifically valid for a single ingredient type product may not be valid with the addition of other ingredients in a complicated finished product.”
Further, she said, with GMP testing requirements for identity, purity, strength and composition, and with enhanced emphasis on trace level test capability, testing requirements could seem overwhelming.
“For any size organization, the costs related to dietary supplement testing are significant,” Ms. LeVanseler said. “Tests are often not the proximate type tests that are applicable to foods, which may be quite reasonable in terms of costs; instead the methods may be quite involved and therefore demand higher prices for execution. Nonetheless, many companies do make testing a high priority.”
Also problematic is the presence of potential adulterants, which might be similar to the compound being measured. As a result, Ms. LeVanseler said, “The method may not adequately differentiate the compound of interest from related contaminants.”
For instance, she said, for joint health products containing chondroitin sulfate, glucosamine and hyaluronic acid, it can be challenging to have selective methods for each of these ingredients ensuring that closely related chemicals are not acting to give erroneously high results.
Silliker’s Mr. Arveseth also raised some important issues. “Many large companies have had a history of testing and have been able to quickly adopt GMPs. Many medium and small companies are still trying to get a handle on testing especially when it comes to herbal products,” he commented. “Testing methods vary quite significantly from supplier to supplier and understanding the scientific validity of test methods and comparability of test methods will take years for companies to gain a firm understanding.”
He went on to describe some of the categories where testing is being emphasized. “Active component testing: Manufacturers must have information and data that show their products contain the labeled amount of each ingredient. It is vital to perform both raw material testing and finished product testing to ensure that products are compliant with label and shelf-life claims.”
In terms of contaminant testing, Mr. Arveseth added, “Manufactures are responsible for establishing specifications for contaminants for their supplement products. Heavy metals, microbiological, pesticides, active pharmaceuticals and even economic adulterants are tests most common in the industry.”
Speaking about botanicals specifically, Steven Dentali, chief science officer, American Herbal Products Association (AHPA), Silver Spring, MD, said, “The dietary supplement industry is continuing the process of developing appropriate quality standards and raw material sources. This can be seen through AHPA’s standard-setting efforts, such as the publication of Herbs of Commerce, which is universally used, our Good Agricultural and Collection Practices guidance and many more, including defining what an extract is and how to label them. In addition, collaborating with the alphabet soup of ODS, NCCAM, USP, AOAC, NIST, and others, as we do, helps to move important processes along.”
In general, Dr. Dentali said, there is a lack of understanding and appreciation of botanical products in this country because, unlike the rest of the world, this nation walked away from them about 60 years ago.
“Instead, we developed a different model of medical materials—the single-ingredient/single constituent model historically favored by the pharmaceutical industry,” he explained. “Consequently, we are now faced with establishing standards we should have been building on for some time now. But due in part to the passage of DSHEA, we’re making a lot of progress in establishing standards that consumers can rely on to provide them with safe and efficacious products.”
Mr. Arveseth also touched on the inherent difficulties of testing herbals and “novel” ingredients. “[These categories] have the most testing issues, especially when tested by a non-specific method (i.e., a method that looks at categories of chemicals instead of single chemical components),” he said.
“Some raw material suppliers modify and alter methods in order to inflate the active claims for a product. This makes it very difficult for other laboratories to match claims unless they follow the exact modifications,” Mr. Arveseth continued. “This leads me to question the scientific validity of the alterations to the methods. What was the scientific basis for modifying the method? This also makes it extremely difficult for manufactures to compare ingredients that claim the same active levels, but use different test methods to verify the claim.”
Ms. LeVanseler discussed the issue of reference materials. “Some dietary supplements that are growing in popularity may have not had the method development efforts made to ensure they are suitable. For some herbals, the difficulty may be related to whether the specific phytochemicals are commercially available as a reference standard for instrument calibration,” she said, adding, “Even when the chemicals are available, they may be very expensive (greater than $400 for milligram quantities). This can be the case even for common herbs like ginger, where the cost of the isolated constituents is quite high, let alone the cost of reference standards for chemicals that exist in more exotic plants.”
Under the cGMP environment, companies are struggling to reduce the turnaround time as well as the operation testing cost. In an effort to overcome the challenges in analytical testing, BASF QTA (Quality Trait Analysis) Group, Cincinnati, OH, offers a quality control system that can be set up on site, where multiple analyses can be completed within two minutes without sample preparation or chemicals. In essence, said Kangming Ma, business director, BASF QTA Group, “We are setting up a virtual laboratory with patented technology and service.”
Over the last decade, BASF QTA Group has developed a comprehensive database of dietary ingredients and developed systems that can be installed on the production floor. Using infrared technology, this system has the ability to quantitatively analyze samples. The simple user interface, said Dr. Ma, allows everyone to perform the test.
“The spectral data are sent to BASF, which are processed with pre-developed algorithms. The results are returned to customers in real time,” he explained. “The benefit to the customer is that it is hassle-free to implement and instantly establishes testing capabilities with minimum risk, even without capital investment. We also provide 24-7 technical support over the Internet to monitor the performance and manage the database.”
He went on to say that fish oils and blended oils are very easily analyzed using the technology. Methods for botanical mixtures, which are a little more complicated, can be developed in four to eight weeks, depending on the type and amount of testing a company wants to do.
Research: The Industry’s Achilles’ Heel
According to Alex Schauss, PhD, FACN, senior research director, Natural & Medicinal Products Research, AIBMR Life Sciences, Inc., Puyallup, WA, the lack of competent and reliable clinical studies will continue to be the industry’s Achilles’ heel.
In just the last several weeks, Dr. Schauss said, “Companies called us to evaluate protocols for randomized, placebo-controlled clinical trials, before seeking approval by an Institutional Review Board for Human Experimentation (IRB). By the time we completed the review of the protocols, the pages were bleeding red ink because there were so many flaws in the design of the study—from inadequate sample size due to inappropriate power calculations, to a lack of critical subject inclusion or exclusion criteria. These are expensive studies that deserve a second or even third opinion before commencing.”
Despite these issues, the fact that the number of companies pursuing research programs is growing is good for the industry. “No longer can you line your pockets with anecdotal information,” said Chromadex’s Mr. Jaksch. “As companies increasingly create the science they need to protect themselves, they are solving another problem in the industry by creating more clinically proven products.”
KGK’s Ms. Gutherie feels similarly, and offered an historical perspective. “KGK has been around since 1997 and since that time I have seen clients transition from thinking they could market their product with testimonials to requesting a safety and efficacy clinical trial to be conducted on their product prior to bringing it to market,” she said. “Our clients are first investigating what type of claims they can make and designing clinical trials that address those claims.”
Covance’s Mr. Sullivan agrees that the industry is definitely in a different place as far as research is concerned. “I think we have moved the needle tremendously in the last several years. People used to do very informal studies, which did not collect enough data to impose statistical significance,” he said. “Today, however, carrying out clinical research has become serious business for many companies.”
To that end, Mr. Sullivan said he sees more people piggy-backing on the clinical research NIH is doing. “The difference today is that there is more replicating of studies rather than pirating of studies.”
Looking at clinical substantiation from a testing standpoint, Mr. Jaksch said, “We still see a significant problem with ingredients going into clinical trials. If you can’t prove what you put in those people, then how can you claim the study has any validity whatsoever.”
NSF’s Ms. LeVanseler also offered a critical view of research. “It appears there is a lot of research activity in U.S. universities to correlate diet and health, but the role of dietary supplement companies helping with these efforts is unclear,” she said. “Unless companies elect to move an ingredient or product off the dietary supplement/functional food path and onto the drug path, it seems that few investments are being made in research.”
In terms of claim substantiation, Miami Research’s Dr. Kalman believes the industry is on the right track. Further, he said, “It would be beneficial for the companies who are in this space to have a line item budget or set percentage of dollars spent on marketing earmarked for clinical trials (i.e., 10% of marketing budget). It is not as cumbersome or as costly as people think to have two well-designed, randomized, double-blind, placebo-controlled clinical trials performed.”
Mr. Jaksch said besides the bottom line, there are several very important reasons companies should want to accumulate data behind their products. “Data will help you defend your products against rogue competitors. It will also offer regulatory protection and help you avoid FDA and/or FTC involvement. The bottom line is you stand on much safer ground when you have data.”
In the end, said Covance’s Mr. Sullivan, the goal of research is to further legitimize these categories of products. “The lines continue to be blurred between foods and supplements and it would be nice to get them categorized properly and then apply the necessary quality controls. There are some really nice dietary supplements and functional foods and we just need to get our hands around how to handle them.”
AIBMR’s Alex Schauss, PhD, shares his perspectives on what it takes to carry out research in the nutraceuticals field.
Understanding the complexities of research, much less interpreting the results, is a never-ending challenge. That’s what makes being a research scientist so exciting, particularly in the nutraceuticals field.
But there are frustrations, and the need to keep the totality of research in mind is paramount when drawing conclusions.
A recent paper of interest to the nutraceuticals industry appeared in the August 26th edition of British Medical Journal (BMJ)1. The subject was chocolate and its relationship to cardiovascular disease, diabetes, heart failure, stroke and gender, and the types of chocolate consumed. A total of 4576 references were initially identified by the research group; 1221 were duplicates and excluded.
As this was a meta-analysis, what I found fascinating, and usually do when these type of studies are reported, was that almost all published papers were excluded from analysis. In fact, 3302 papers were excluded. That left 53 articles for retrieval. Assessment of those 53 papers resulted in seven (yes, seven!) eligible studies from which the meta-analysis was performed.
Based on those seven studies, the media reported that adding chocolate to the diet could contribute to the prevention of cardiovascular disease, diabetes and stroke. But no effort was made by the authors in either the title of the paper or the abstract to explain that any benefit seen was restricted to dark chocolate consumption only.
What didn’t make headlines around the same time was a paper that appeared in the Journal of Food Composition and Analysis2, which reported on the soluble oxalate content in commercially produced cocoa and dark chocolate. This is certainly a subject of interest to anyone who has ever experienced a kidney stone attack. The results of this human study confirmed that the dietary intake of oxalate following the consumption of 68 grams of dark chocolate increased oxalate output by a mean of 70% above base value.
Those 68 grams of dark chocolate resulted in the consumption of 232 mg total oxalate, which as the authors point out is “almost three times higher than the maximum intake (80 mg) of oxalate recommended in a low oxalate diet.”
The above discussion points out the importance of doing thorough research rather than relying on sound bites from headlines to determine a product’s health benefits.
Keeping up with the literature on food ingredients is one thing, but imagine the challenge of understanding the cutting edge biotechnologies used to determine the mechanisms of action of those ingredients.
In a recent co-authored paper in Experimental Gerontology3 performed at the NIH’s National Institute on Aging, we studied the effect of açai pulp on modulating lifespan. In our paper we reported that, “acai increased the transcript level of l(2)efl, a small heat-shock-related protein, and two detoxification genes, GstD1 and MtnA, while decreasing the transcript level of phospoenol-pyruvate carboxykinase (Pepck), a key gene involved in gluconeogenesis.”
If that sentence makes little sense, welcome to the new world of nutraceutical research with a lexicon all its own, which studies cell transduction, ubiquitous transcription factors, targets reporter vectors and uses bioinformatics to analyze changes in protein expression. —A.S.
References
1. “Chocolate consumption and cardiometabolic disorders: systematic review and meta-analysis.” British Medical Journal (BMJ), August 26, 2011;343:d4488. doi: 10.1136/bmj.d4488.
2. “Oxalate content in commercially produced cocoa and dark chocolate.” Journal of Food Composition and Analysis, 2011;24(7):916-922.
3. “Acai palm fruit (Euterpe oleracea Mart.) pulp improves survival of flies on a high fat diet.” Experimental Gerontology, 2010;45(3):243-251.
