Rebecca Madley-Wright06.01.03
There will be approximately 250-400 clinical trials conducted on nutraceuticals in North America this year. Compare this to the pharmaceutical industry, which currently has approximately 80,000 trials ongoing in the U.S. alone. Does this huge discrepancy have an impact on innovation in the nutraceuticals industry? In other words, has the innovation engine stalled because the research piece is missing?
This is the premise for this year's Industry Innovators article, which speaks to the state of nutraceuticals research. While many continue to cite lack of research incentives, patent protection and borrowed science as reasons for the gulf that exists between pharmaceutical and nutraceutical research, the fact is, innovation in this industry will continue to wane unless research becomes more of a priority than an afterthought.
Anemic, lacking, misguided, shabby, limited, immature and spotty were the words used by some experts to describe the current state of research in this industry. One of those experts was Anthony Almada, B.Sc., M.Sc., founder and chief scientific officer of Imaginutrition and MetaResponse Sciences, Laguna Niguel, CA, who discussed the present situation from a company perspective. "Most companies in this industry are ignorant, fearful and non-experienced with research. Almost without exception, the people that make the decisions have come to achieve a CEO status through sales or marketing and the last time they took a science class was in high school," he said, adding, "So when you talk to these CEOs about putting money into advertising, marketing, promotion or a bigger sales force there's no problem because that is what they have lived with and what their mentors did before them."
Focusing on dietary supplements specifically, Dr. Paul Coates, director, Office of Dietary Supplements (ODS) at the National Institutes of Health (NIH), Bethesda, MD, pointed out that there is little financial incentive for companies to engage in the kind of research that characterizes bringing products to market in the drug industry, for example. "Essentially this is a generic industry. This doesn't mean that there aren't possibilities but for the most part, companies cannot justify doing research so the state of research, to be generous, is immature," he said. "For some parts of the market, research is well advanced but for others it really is immature. While money is one thing, it really is the environment in which dietary supplements are marketed that doesn't encourage the development of clinical research."
Bob DiSilvestro, professor-Nutrition, The Ohio State University, Columbus, OH, also discussed the state of nutraceuticals research by drawing a parallel to the drug industry. "I think there is still uncertainty of what the return (on investment) is in the nutraceuticals industry whereas in the pharmaceutical industry it is very well defined," he said. "Pharmaceutical companies sell to doctors, not really to the general public. They are trying to get doctors to write a prescription or recommend a product over-the-counter (OTC). The point is, doctors will still be there two years from now, so if a company does two years worth of testing it can go back to the physician and show them the results to catch their interest. In the nutraceuticals industry most companies are selling to the general public and that is a matter of where the interest is NOW." As a result, he said, some companies are afraid to do a research project because by the time the results are in, the public's interest may be somewhere else.
Dr. Stephen DeFelice, founder of the Foundation for Innovation in Medicine (FIM), Cranford, NJ, and creator of the Nutraceutical Research and Education Act (NREA), said the current environment requires that work be carried out to prove products work. "In order to know whether something works you have to test it in people-this is a very simple principle. However, less than one-tenth of one percent of products sold in this market are actually tested in people. Furthermore, no one is really testing the specific products sold and most of the claims are based on studies done in Uganda," he commented. "In surveys consumers have been asked what they want. They responded and said, 'Products that work and are safe.' That is exactly what the market does not deliver." He continued, "Unfortunately, it is the business aspect of this marketplace that is not familiar with real clinical work because it just isn't their culture. The bottom line is if you have clinical trials there is a friendly world out there."
Dr. Peter Goldman, Maxwell Finland professor of clinical pharmacology Emeritus, Harvard Medical School, Boston, MA, said the paucity of research is to some extent due to a lack of money, which in turn affects the attainment of a proprietary position for these products. However, he said, "I also think that a lot of people in the industry do not understand how drug research is structured in terms of the biological or medical sciences. As compared to the pharmaceutical industry, this industry lacks the appreciation for the integration of research with product development."
Lack of understanding and appreciation for clinical research is part of the problem, but according to Greg Stephens, vice president, sales and marketing, Nurture, Inc., Devon, PA, it also has a lot to do with unrealistic expectations. "Many in our industry have unrealistic expectations-expecting breakthrough outcomes from a single research study and expecting the findings to be proprietary," he said. "When a pharmaceutical company obtains a breakthrough, it is only after it has spent millions of dollars on, for instance, a new molecular entity, not thousands on what it would consider a pilot or proof of principle study."
Discussing how outsiders view this industry in terms of research was Loren Israelsen, president, LDI Group, Salt Lake City, UT. "There is a lot of poaching going on right now and we are all diminished because of that," he said. "People that come into this industry from the pharmaceutical world, the biotech industry and the agricultural industry all have a common perception of this industry and that is, 'This is a really unruly and undisciplined bunch who don't understand and respect the rules of the game and until they do, there will be no real advances.'"
In the industry's defense, Dr. Paul LaChance, professor of Food Science & Nutrition and director of the Nutraceuticals Institute, Rutgers University, New Brunswick, NJ, pointed out that a lot of companies are being cautious due to the current economic environment. "What they are doing is putting their marketing first because they cannot afford the research," he explained, adding that, "People are being extremely careful right now because of the market and what has been going on over the last few years. They want to make sure that what they are putting their money into is really going to pay off. What they don't realize, however, is that there are no 100% guarantees in science."
Others remain optimistic, including Annette Dickinson, president, Council for Responsible Nutrition (CRN), Washington, D.C., who feels research is moving forward at a good pace. "This is an area that has caught the interest of a wide variety of academics that have made a commitment to nutraceuticals and functional foods as research categories," she said. As a result, "These areas are receiving good research support."
Dierdre Allen, president, Canadian American Resources and co-founder of Intramedicine, Fayetteville, NY, said the work being done on the research front varies, but this is a positive thing. "We certainly have a full spectrum of researchers. There are those whose work borders on the unethical and those who are doing excellent sound, science," she said. "[But] it is our remarkable diversity that gives us unlimited opportunities in product development and related clinical application." However, she qualified, "It is that same diversity that makes our progress toward consistent, sound science a very lengthy process."
When it comes to research there are issues that are easier to solve and others that are not. Likewise, there are some issues that can be solved quickly and others that will take time. One issue that must be addressed immediately is the lack of self-policing, according to Imaginutrition's Mr. Almada. "Do we continue to allow products like Fat Trapper and Exercise in a Bottle to line the landscape of our industry and continue to sell? The FTC hasn't gotten around to it and the FDA hasn't stepped in because people aren't dying-and they are more concerned about bioterrorism at the moment anyway," he said. "Unfortunately our industry has never been one from the beginning to weed out its own kind and this behavior will continue until the government says that research is required to make a claim."
FIM's Dr. DeFelice said another issue is lack of definition, especially in the case of the word nutraceutical. "I coined it for a reason," he said. "I coined it to give Congress a concrete way to identify something in order to pass laws that create a proprietary, high margin market as opposed to a commodity, low margin market. It is a food, a dietary supplement or anything that you consume that has an impact on your health, which is mainly the prevention and treatment of disease." He also explained that while others may disagree, surveys show that consumers are going to health food stores to prevent and treat disease. "Yet we have a Congress and regulations that say that health claims are different than disease claims when in reality they are the same thing," he said.
Everyone-industry, academia, government-has a part to play in the research game but it is frequently debated as to who should be doing what. Discussing the roles of government, academia and industry was Dr. Coates of ODS. "Organizations like ours need to serve as catalysts for appropriate research in this area. Industry can help to guide, support and encourage the types of research being carried out and academia's function is clearly to uncover new knowledge," he said. "What I would suggest is that we, as a Federal agency that supports research, help academia identify the areas of urgent need when it comes to supplement research. In some cases that may mean starting at the very beginning with basic research and in other cases this may require embarking on large public health intervention trials and clinical trials. Eventually, however, I think large-scale clinical trials will inevitably require a partnership through a combination of all three."
Ian Newton, director, business development and regulatory affairs-Human Nutrition, Roche Vitamins, Parsippany, NJ, said that while he sees NIH (and ODS) being there to help industry with the large trials, he has concerns as well. "ODS is doing a lot of work on efficacy and that is really aimed at looking at the fraudulent claims but they should be concentrating more of safety because that is really the number one issue," he stated. "Research on efficacy should really come from the companies themselves. If there is a problem with fraudulent claims then FDA really needs to step in and prove or disprove that."
Speaking from an investment perspective was Roger Wyse, managing director, Burrill & Company, San Francisco, CA. "Companies need to understand what science needs to be done and how to protect that investment and recover it in the marketplace. In other words, if I develop a differentiated product based on the science that I do, how can I protect that investment? Traditional ways include patents or a unique source, however, the regulatory environment should also serve to provide incentives for research as well," he explained. "If you think about the huge investment that goes into drugs, companies are able to protect the investment, in part, through patenting and regulatory approval. It is this degree of protection that will attract investors, which is something not typically seen in the nutraceuticals market."
Discussing the issues with functional foods research was Barry Sears, president and founder, Sears Labs, Danvers, MA. "The studies required are much more complex than any functional food or mainstream food manufacturer wants to undertake. Companies basically want a champagne taste on a beer budget," he said. "That is why there is a call out to the nutraceuticals world to do these kinds of studies. If you want to play in the nutraceuticals business on the premise that you are producing products that are nutritional but have pharmaceutical like actions then your research model calls for doing the work drug companies do."
We clearly have two different cultures in conflict with each other, according to LDI's Mr. Israelsen. As a result, there is a segment of the industry that doesn't buy into the classical clinical study methodology and another segment that feels the double-blind, placebo-controlled trial is indeed the "gold standard." Mr. Israelsen discussed the former. "If natural products were evaluated via the double-blind, placebo-controlled study, all of the 'life force' and 'good stuff' that comes along with the loving and caring intervention, which is all part of the natural healing environment, would be lost. The natural products people often say we will never know the true effects of these products on top of a lab bench because that is not where the magic happens," he offered, adding, "In response to this, conventional scientists and researchers will say they have heard that excuse for the longest time."
Mr. Israelsen continued, "This is truly a faith versus reason argument and you can't prove one using the other as a tool. We need to find a way to let both sides live and respect each other. Those that want to take the scientific approach to validate their products should have a pathway to do so because that is realistic and provides an honest return on investment. There also needs to be a path for those that don't want clinical studies because they feel there is enough traditional wisdom and knowledge. These are deeply personal choices and I respect either one."
From a practical standpoint, Ken Keirstead, chairman, Lyceum Research, Fredericton, News Brunswick, Canada, said the industry definitely needs a new research model because the gold standard just doesn't work for this business. "I think what we should do is address the reality of the global village that we are in because there is a lot of work being done all over the world and we are not taking advantage of those studies," he explained. At the very least, he said, three things must be accomplished in evaluating nutraceuticals. "First, the nature and character of an ingredient or ingredients must be understood. That is basic science and the systems are all available for that. The second thing is to make sure that there is bioactivity because you should be able to demonstrate how it works," he said, adding, Third, we are proponents of using something along the lines of a clinical outcomes assessment as opposed to full clinical trials."
Mark Braman, president and CEO, Efficas, Boulder, CO, also said that using the pharmaceutical model would be disadvantageous. "There is no need to subject nutraceuticals to the rigorous scrutiny required of a pharmaceutical drug in order to establish clinical efficacy," he said. "There would never be a return on investment for doing clinical research on a nutraceutical bioactive if you did it to pharmaceutical standards-it would not be a good business proposition."
Imaginutrition's Mr. Almada offered a different view. He suggested that while the double-blind, placebo-controlled trial may have its weaknesses, there are no alternatives right now, particularly in the eyes of the medical community. "It only invites more criticism to our industry not to use the best model we have at the moment," he said.
Dr. Coates ODS agreed. "I think the gold standard is appropriate in most circumstances and I would continue to use it as the standard against which I would compare other research strategies," he said. "It doesn't mean that the gold standard is going to be met or should necessarily be met for every single ingredient, for every single indication. However, due to the fact that some of these products are often used in a treatment sense, whether or not the manufacturer says it or not, there is a real obligation to use the highest quality research methodology possible."
CRN's Ms. Dickinson believes a combination of approaches may serve as a good study model for nutraceuticals. "I think a combination of epidemiological research based on food intake patterns and biological research on the functionality of a substance makes for a good model for evaluating nutraceuticals," she commented.
According to Joerg Gruenwald, president, Phytopharm Consulting, Berlin, Germany, companies do not necessarily have to conduct research on the pharmaceutical level. "Certainly if you want to make a drug claim you should use a drug equivalent study but if you want to make a food claim there does not necessarily have to be studies involving hundreds of patients. There are lower levels of trials, which can also be considered acceptable."
But what about the cost of doing a clinical study? Burrill's Mr. Wyse said double-blind, placebo-controlled trials can be done at relatively low cost. "The price of a trial might cost a company anywhere between $200,000-500,000. What causes high cost on the pharmaceutical side is the number of subjects that have to be in a trial to get statistical significance," he explained, adding, "In the nutraceuticals area you may be looking at substances that have an effect on a biomarker or have a readily perceived effect on the subject. What is prohibitive, on the other hand, is running the long term trials to show an effect on some kind of chronic disease like cancer."
Dr. Tieraona Low Dog, adjunct faculty, University of Arizona School of Medicine, Fellowship in Integrative Medicine, Tucson, AZ, and a recent appointee to the advisory panel for the National Center for Complementary and Alternative Medicine (NCCAM), said in terms of finding a new model, it really depends on what's being studied. "If someone drinks a cup of chamomile tea in the evening because it's relaxing then how many double-blind trials are really needed to prove that? If we believe that the product is safe because of its widespread use then I don't know that we need double-blind studies on this," she said, adding, "However, if a company is claiming that its astragalus is an immune tonic and therefore treats AIDS or cancer then it better have double-blind, randomized studies to validate that premise and claim."
The Dietary Supplement Health and Education Act (DSHEA) birthed a new category of claims for dietary supplements, which, it was hoped at the time, would create increased consumer awareness for dietary supplements and a marketing edge for companies. In today's market, however, it seems structure/function claims have lost their meaning and appeal.
Discussing the latter was Imaginutrition's Mr. Almada. "Structure/function claims are a regulatory and marketing exercise that has become obscured and highly duplicated," he stated. "If one company comes out with a structure/function claim, within days or months another company will come out with the same exact claim." He added, "Typically structure/function claims are done in a tic-tac-toe approach in that companies will have claims for four ingredients and combine them together with 10 other ingredients. But the question is, who knows if they all work well together or in the way that is claimed? Even more important, what about interactions and adverse reactions?"
Nurture's Mr. Stephens said a lot of nutraceuticals companies will do the research without knowing what they want to claim when it should really be the other way around. "Determine what the goal or claim should be for a particular product and design a trial to answer that question," he said. "This sounds simple and common sense but so many companies in this industry design a study and THEN try to determine what can be claimed by the result."
Kelley Fitzpatrick, market and research development manager, Richardson Center for Functional Foods, University of Manitoba, Winnipeg, Canada, offered a similar point of view. "The science should follow the claims and I don't think that we should get rid of a high degree of science if we are making pharmaceutical like claims," she said.
Another problem with structure/function claims is that they may be limiting in terms of describing the "real" benefits of certain products. Harvard's Dr. Goldman discussed this issue. "Unfortunately, the situation for claims is rather paradoxical in the sense that, in the case of ginkgo, there are several randomized trials with reasonably reproducible ginkgo products that show a benefit to certain patients with Alzheimer's disease," he said, adding, "However, according to the regulations, you can't make a disease claim for a dietary supplement. Here you have a product that by conventional standards may be of as much benefit for Alzheimer's disease as some of the approved drug products but you can't say that."
In terms of claim substantiation, Kathie Wrick, principal-Food Nutrition & Health Practice, Tiax LLC, Cambridge, MA, offered, "Claim substantiation for many products is being left to the NIH's Office of Dietary Supplements, which may or may not support the message intended for consumers. "If companies continue to leave claim substantiation research in the hands of universities and government, they may or may not get the studies designed the way they need to be in order to prove a particular point.
The nutraceuticals industry no doubt faces some significant challenges going forward. In that respect it is important to discuss what are the research options. Some suggest that partnerships be forged between industry, government and academia, while others speak in favor of changing current legislation (i.e., amending DHSEA to make room for research incentives in the form of stronger patent protection, for example) or reviving old ideas in the form of new legislation (i.e., amending the NREA and proposing a newer version to Congress).
In terms of collaboration, Steven Dentali, vice president of scientific and technical affairs, American Herbal Products Association (AHPA), Silver Spring, MD, said industry participation in government research activities is paramount "Each and every company in our industry should be intimately familiar with what ODS and NCCAM are doing because these groups respond to public input," he said. "Right now agendas are set and studies funded without much of the essential guidance and perspective that only industry experts can offer and this is a shame."
Todd Norton, president and COO, Sabinsa, Piscataway, NJ, said patent and trademark protection are available and can serve a purpose, but it is an expensive undertaking. "Patent and trademark protection are available and in large measure can do a lot to establish points of differentiation on ingredients or products (property) that have some form of research pedigree," he explained. "The real challenge comes in the costs associated in the enforcement and protection of that property, which may factor into the price of the good(s) being offered."
Patent protection is costly indeed, according to LDI's Mr. Israelsen. And is it even worth it? "The patenting process can be tricky for products in this industry because they don't lend themselves to very clear patent positions," he said. "Getting a patent is like getting a fishing license in that you still have to go out and catch a fish and protect yourself from people who are infringing on your patents. Very often the cost of defending a patent will be magnitudes more than it costs to get the patent in the first place. For a small research-based company there's hardly room in the budget to spend that kind of money."
Another idea relates to the resurrection of the NREA. According to its creator, Dr. DeFelice, this is probably the best course of action. "We have a regulatory structure at the moment where you can't say certain things or tell the truth about products. This is why I stepped in and proposed the term 'nutraceutical' and why I proposed the NREA-which is similar in structure to the Orphan Drug Act (ODA)."
To recap, the ODA was passed based on the premise that a company could file a new drug application (NDA) without doing extensive studies, plus it gave a company exclusivity to make a claim for a period of seven years. "The right to make that claim is a very powerful marketing tool," said Dr. DeFelice. "The ODA was a success based on the simple principle of exclusivity of the claim as long as there was a reasonable amount of research done on the product. The NREA would have worked in the same fashion in that a company would do research on its specific product and then have an exclusive right to a specific claim for a period of 10 years."
So what happened? According to Dr. DeFelice, the NREA garnered little interest from industry and Congress. "Senator Frank Pallone introduced the NREA and not one advocate stepped forward. It was very disappointing," he said.
Other experts, such as Dr. David Eisenberg, director of the Osher Institute, Harvard Medical School, Boston, MA, have also said the NREA is worth a second look. "The NREA could be jointly refined by tweaking the definition of a nutraceutical health claim,by creating criteria necessary to support a nutraceutical claim and by determining an appropriate term of exclusivity for a claim," he suggested. "The proposal should be amended to address issues of quality, better information for consumers, better protection of investment and increased privately funded R&D." These issues, Dr. Eisenberg said, should be discussed with the Institute of Medicine (IOM) and Congress and tested in the marketplace.
LDI's Mr. Israelsen said the NREA had some good points but there were some unappealing aspects as well. "First, the approval mechanism through FDA is not going to happen partly because FDA drags its feet every time our industry proposes a different regulatory model. Frankly, there has never really been enthusiasm from FDA to do anything with natural products because they are not familiar with them, they are difficult to work with, etc." Case in point, he said, "Right now there are 100 drug applications at FDA for botanicals, which have been there for several years. It is now 2003 and we have yet to have an approved drug that is botanically-based make it through the process. We haven't seen where the end of that rainbow is yet. It may be that if a company is successful in getting a botanically-based drug approved, then it would garner confidence in the eyes of medical professionals and the general public because it now has a government approved product."
Phytopharm's Dr. Gruenwald said it is time to sit down and re-think DSHEA. "I think there really needs to be a change in the legislation. DSHEA was good in its time because there was no real market for these products and there were no regulations. It also gave a good boost to the market initially but according to a free market system, several players jumped in and looked for the cheapest way to cheat the system," he said, adding, "It is this cheating of the system that has ruined the market for the time being."
LDI's Mr. Israelsen said a lot of people are frightened at the mention of changing DSHEA, but, he said, the legislation has already been dismantled over the last few years due to bioterrorism legislation and proposed GMPs. He commented, "The DSHEA passed in 1994 does not exist today nor does the world we lived in back then."
Intramedicine's Ms. Allen recommended that the industry establish a forum in which its scientists could collaborate, share ideas and work on reaching consensus on issues that are specific to the development of nutraceuticals. "We have some incredibly talented people in this industry but we don't have any way for them to work together or showcase their ideas and thoughts," she said. "There is a high amount of interest from the scientific community for creating a scientific forum but so far there is very little support from the CEO level. The reason for this is because there is so little proprietary space in this industry, there is fear that withheld information will come out at a meeting."
Also supporting the idea of creating a meeting for the industry's scientists was Lyceum's Mr. Keirstead. "Someone really has to emerge as an advocate or leader. To that end, we really need a forum to be convened that would bring more intelligence or expert opinions to this area as a whole instead of everyone working in isolation," he offered.
Mr. Almada from Imaginutrition addressed the issue of borrowed science. "Companies that use the 'pirated' science excuse are completely ignorant. If you let somebody use your data then you don't know how to defend your data," he said. "One option of defense would apply primarily to a unique composition. An example of this would be two companies using the same tree to get their green tea leaves. One company will process or extract it one way, while the other will do it a different way." In the end, he said, one company could have a product that increases metabolic rate by 20%, while the other company's product increases metabolic rate by 4%. If the company with the 4% product tries to use the data from the company with the 20% product then that company would be involved in false attribution and thus likely in violation of a Federal law called the Lanham Act.NW
This is the premise for this year's Industry Innovators article, which speaks to the state of nutraceuticals research. While many continue to cite lack of research incentives, patent protection and borrowed science as reasons for the gulf that exists between pharmaceutical and nutraceutical research, the fact is, innovation in this industry will continue to wane unless research becomes more of a priority than an afterthought.
The State of Nutraceuticals Research: Telling it Like it is
Anemic, lacking, misguided, shabby, limited, immature and spotty were the words used by some experts to describe the current state of research in this industry. One of those experts was Anthony Almada, B.Sc., M.Sc., founder and chief scientific officer of Imaginutrition and MetaResponse Sciences, Laguna Niguel, CA, who discussed the present situation from a company perspective. "Most companies in this industry are ignorant, fearful and non-experienced with research. Almost without exception, the people that make the decisions have come to achieve a CEO status through sales or marketing and the last time they took a science class was in high school," he said, adding, "So when you talk to these CEOs about putting money into advertising, marketing, promotion or a bigger sales force there's no problem because that is what they have lived with and what their mentors did before them."
Focusing on dietary supplements specifically, Dr. Paul Coates, director, Office of Dietary Supplements (ODS) at the National Institutes of Health (NIH), Bethesda, MD, pointed out that there is little financial incentive for companies to engage in the kind of research that characterizes bringing products to market in the drug industry, for example. "Essentially this is a generic industry. This doesn't mean that there aren't possibilities but for the most part, companies cannot justify doing research so the state of research, to be generous, is immature," he said. "For some parts of the market, research is well advanced but for others it really is immature. While money is one thing, it really is the environment in which dietary supplements are marketed that doesn't encourage the development of clinical research."
Bob DiSilvestro, professor-Nutrition, The Ohio State University, Columbus, OH, also discussed the state of nutraceuticals research by drawing a parallel to the drug industry. "I think there is still uncertainty of what the return (on investment) is in the nutraceuticals industry whereas in the pharmaceutical industry it is very well defined," he said. "Pharmaceutical companies sell to doctors, not really to the general public. They are trying to get doctors to write a prescription or recommend a product over-the-counter (OTC). The point is, doctors will still be there two years from now, so if a company does two years worth of testing it can go back to the physician and show them the results to catch their interest. In the nutraceuticals industry most companies are selling to the general public and that is a matter of where the interest is NOW." As a result, he said, some companies are afraid to do a research project because by the time the results are in, the public's interest may be somewhere else.
Dr. Stephen DeFelice, founder of the Foundation for Innovation in Medicine (FIM), Cranford, NJ, and creator of the Nutraceutical Research and Education Act (NREA), said the current environment requires that work be carried out to prove products work. "In order to know whether something works you have to test it in people-this is a very simple principle. However, less than one-tenth of one percent of products sold in this market are actually tested in people. Furthermore, no one is really testing the specific products sold and most of the claims are based on studies done in Uganda," he commented. "In surveys consumers have been asked what they want. They responded and said, 'Products that work and are safe.' That is exactly what the market does not deliver." He continued, "Unfortunately, it is the business aspect of this marketplace that is not familiar with real clinical work because it just isn't their culture. The bottom line is if you have clinical trials there is a friendly world out there."
Dr. Peter Goldman, Maxwell Finland professor of clinical pharmacology Emeritus, Harvard Medical School, Boston, MA, said the paucity of research is to some extent due to a lack of money, which in turn affects the attainment of a proprietary position for these products. However, he said, "I also think that a lot of people in the industry do not understand how drug research is structured in terms of the biological or medical sciences. As compared to the pharmaceutical industry, this industry lacks the appreciation for the integration of research with product development."
Lack of understanding and appreciation for clinical research is part of the problem, but according to Greg Stephens, vice president, sales and marketing, Nurture, Inc., Devon, PA, it also has a lot to do with unrealistic expectations. "Many in our industry have unrealistic expectations-expecting breakthrough outcomes from a single research study and expecting the findings to be proprietary," he said. "When a pharmaceutical company obtains a breakthrough, it is only after it has spent millions of dollars on, for instance, a new molecular entity, not thousands on what it would consider a pilot or proof of principle study."
Discussing how outsiders view this industry in terms of research was Loren Israelsen, president, LDI Group, Salt Lake City, UT. "There is a lot of poaching going on right now and we are all diminished because of that," he said. "People that come into this industry from the pharmaceutical world, the biotech industry and the agricultural industry all have a common perception of this industry and that is, 'This is a really unruly and undisciplined bunch who don't understand and respect the rules of the game and until they do, there will be no real advances.'"
In the industry's defense, Dr. Paul LaChance, professor of Food Science & Nutrition and director of the Nutraceuticals Institute, Rutgers University, New Brunswick, NJ, pointed out that a lot of companies are being cautious due to the current economic environment. "What they are doing is putting their marketing first because they cannot afford the research," he explained, adding that, "People are being extremely careful right now because of the market and what has been going on over the last few years. They want to make sure that what they are putting their money into is really going to pay off. What they don't realize, however, is that there are no 100% guarantees in science."
Others remain optimistic, including Annette Dickinson, president, Council for Responsible Nutrition (CRN), Washington, D.C., who feels research is moving forward at a good pace. "This is an area that has caught the interest of a wide variety of academics that have made a commitment to nutraceuticals and functional foods as research categories," she said. As a result, "These areas are receiving good research support."
Dierdre Allen, president, Canadian American Resources and co-founder of Intramedicine, Fayetteville, NY, said the work being done on the research front varies, but this is a positive thing. "We certainly have a full spectrum of researchers. There are those whose work borders on the unethical and those who are doing excellent sound, science," she said. "[But] it is our remarkable diversity that gives us unlimited opportunities in product development and related clinical application." However, she qualified, "It is that same diversity that makes our progress toward consistent, sound science a very lengthy process."
Addressing Fundamental & Complex Issues
When it comes to research there are issues that are easier to solve and others that are not. Likewise, there are some issues that can be solved quickly and others that will take time. One issue that must be addressed immediately is the lack of self-policing, according to Imaginutrition's Mr. Almada. "Do we continue to allow products like Fat Trapper and Exercise in a Bottle to line the landscape of our industry and continue to sell? The FTC hasn't gotten around to it and the FDA hasn't stepped in because people aren't dying-and they are more concerned about bioterrorism at the moment anyway," he said. "Unfortunately our industry has never been one from the beginning to weed out its own kind and this behavior will continue until the government says that research is required to make a claim."
FIM's Dr. DeFelice said another issue is lack of definition, especially in the case of the word nutraceutical. "I coined it for a reason," he said. "I coined it to give Congress a concrete way to identify something in order to pass laws that create a proprietary, high margin market as opposed to a commodity, low margin market. It is a food, a dietary supplement or anything that you consume that has an impact on your health, which is mainly the prevention and treatment of disease." He also explained that while others may disagree, surveys show that consumers are going to health food stores to prevent and treat disease. "Yet we have a Congress and regulations that say that health claims are different than disease claims when in reality they are the same thing," he said.
Everyone-industry, academia, government-has a part to play in the research game but it is frequently debated as to who should be doing what. Discussing the roles of government, academia and industry was Dr. Coates of ODS. "Organizations like ours need to serve as catalysts for appropriate research in this area. Industry can help to guide, support and encourage the types of research being carried out and academia's function is clearly to uncover new knowledge," he said. "What I would suggest is that we, as a Federal agency that supports research, help academia identify the areas of urgent need when it comes to supplement research. In some cases that may mean starting at the very beginning with basic research and in other cases this may require embarking on large public health intervention trials and clinical trials. Eventually, however, I think large-scale clinical trials will inevitably require a partnership through a combination of all three."
Ian Newton, director, business development and regulatory affairs-Human Nutrition, Roche Vitamins, Parsippany, NJ, said that while he sees NIH (and ODS) being there to help industry with the large trials, he has concerns as well. "ODS is doing a lot of work on efficacy and that is really aimed at looking at the fraudulent claims but they should be concentrating more of safety because that is really the number one issue," he stated. "Research on efficacy should really come from the companies themselves. If there is a problem with fraudulent claims then FDA really needs to step in and prove or disprove that."
Speaking from an investment perspective was Roger Wyse, managing director, Burrill & Company, San Francisco, CA. "Companies need to understand what science needs to be done and how to protect that investment and recover it in the marketplace. In other words, if I develop a differentiated product based on the science that I do, how can I protect that investment? Traditional ways include patents or a unique source, however, the regulatory environment should also serve to provide incentives for research as well," he explained. "If you think about the huge investment that goes into drugs, companies are able to protect the investment, in part, through patenting and regulatory approval. It is this degree of protection that will attract investors, which is something not typically seen in the nutraceuticals market."
Discussing the issues with functional foods research was Barry Sears, president and founder, Sears Labs, Danvers, MA. "The studies required are much more complex than any functional food or mainstream food manufacturer wants to undertake. Companies basically want a champagne taste on a beer budget," he said. "That is why there is a call out to the nutraceuticals world to do these kinds of studies. If you want to play in the nutraceuticals business on the premise that you are producing products that are nutritional but have pharmaceutical like actions then your research model calls for doing the work drug companies do."
Do We Need A New Research Model?
We clearly have two different cultures in conflict with each other, according to LDI's Mr. Israelsen. As a result, there is a segment of the industry that doesn't buy into the classical clinical study methodology and another segment that feels the double-blind, placebo-controlled trial is indeed the "gold standard." Mr. Israelsen discussed the former. "If natural products were evaluated via the double-blind, placebo-controlled study, all of the 'life force' and 'good stuff' that comes along with the loving and caring intervention, which is all part of the natural healing environment, would be lost. The natural products people often say we will never know the true effects of these products on top of a lab bench because that is not where the magic happens," he offered, adding, "In response to this, conventional scientists and researchers will say they have heard that excuse for the longest time."
Mr. Israelsen continued, "This is truly a faith versus reason argument and you can't prove one using the other as a tool. We need to find a way to let both sides live and respect each other. Those that want to take the scientific approach to validate their products should have a pathway to do so because that is realistic and provides an honest return on investment. There also needs to be a path for those that don't want clinical studies because they feel there is enough traditional wisdom and knowledge. These are deeply personal choices and I respect either one."
From a practical standpoint, Ken Keirstead, chairman, Lyceum Research, Fredericton, News Brunswick, Canada, said the industry definitely needs a new research model because the gold standard just doesn't work for this business. "I think what we should do is address the reality of the global village that we are in because there is a lot of work being done all over the world and we are not taking advantage of those studies," he explained. At the very least, he said, three things must be accomplished in evaluating nutraceuticals. "First, the nature and character of an ingredient or ingredients must be understood. That is basic science and the systems are all available for that. The second thing is to make sure that there is bioactivity because you should be able to demonstrate how it works," he said, adding, Third, we are proponents of using something along the lines of a clinical outcomes assessment as opposed to full clinical trials."
Mark Braman, president and CEO, Efficas, Boulder, CO, also said that using the pharmaceutical model would be disadvantageous. "There is no need to subject nutraceuticals to the rigorous scrutiny required of a pharmaceutical drug in order to establish clinical efficacy," he said. "There would never be a return on investment for doing clinical research on a nutraceutical bioactive if you did it to pharmaceutical standards-it would not be a good business proposition."
Imaginutrition's Mr. Almada offered a different view. He suggested that while the double-blind, placebo-controlled trial may have its weaknesses, there are no alternatives right now, particularly in the eyes of the medical community. "It only invites more criticism to our industry not to use the best model we have at the moment," he said.
Dr. Coates ODS agreed. "I think the gold standard is appropriate in most circumstances and I would continue to use it as the standard against which I would compare other research strategies," he said. "It doesn't mean that the gold standard is going to be met or should necessarily be met for every single ingredient, for every single indication. However, due to the fact that some of these products are often used in a treatment sense, whether or not the manufacturer says it or not, there is a real obligation to use the highest quality research methodology possible."
CRN's Ms. Dickinson believes a combination of approaches may serve as a good study model for nutraceuticals. "I think a combination of epidemiological research based on food intake patterns and biological research on the functionality of a substance makes for a good model for evaluating nutraceuticals," she commented.
According to Joerg Gruenwald, president, Phytopharm Consulting, Berlin, Germany, companies do not necessarily have to conduct research on the pharmaceutical level. "Certainly if you want to make a drug claim you should use a drug equivalent study but if you want to make a food claim there does not necessarily have to be studies involving hundreds of patients. There are lower levels of trials, which can also be considered acceptable."
But what about the cost of doing a clinical study? Burrill's Mr. Wyse said double-blind, placebo-controlled trials can be done at relatively low cost. "The price of a trial might cost a company anywhere between $200,000-500,000. What causes high cost on the pharmaceutical side is the number of subjects that have to be in a trial to get statistical significance," he explained, adding, "In the nutraceuticals area you may be looking at substances that have an effect on a biomarker or have a readily perceived effect on the subject. What is prohibitive, on the other hand, is running the long term trials to show an effect on some kind of chronic disease like cancer."
Dr. Tieraona Low Dog, adjunct faculty, University of Arizona School of Medicine, Fellowship in Integrative Medicine, Tucson, AZ, and a recent appointee to the advisory panel for the National Center for Complementary and Alternative Medicine (NCCAM), said in terms of finding a new model, it really depends on what's being studied. "If someone drinks a cup of chamomile tea in the evening because it's relaxing then how many double-blind trials are really needed to prove that? If we believe that the product is safe because of its widespread use then I don't know that we need double-blind studies on this," she said, adding, "However, if a company is claiming that its astragalus is an immune tonic and therefore treats AIDS or cancer then it better have double-blind, randomized studies to validate that premise and claim."
The Claims Conundrum
The Dietary Supplement Health and Education Act (DSHEA) birthed a new category of claims for dietary supplements, which, it was hoped at the time, would create increased consumer awareness for dietary supplements and a marketing edge for companies. In today's market, however, it seems structure/function claims have lost their meaning and appeal.
Discussing the latter was Imaginutrition's Mr. Almada. "Structure/function claims are a regulatory and marketing exercise that has become obscured and highly duplicated," he stated. "If one company comes out with a structure/function claim, within days or months another company will come out with the same exact claim." He added, "Typically structure/function claims are done in a tic-tac-toe approach in that companies will have claims for four ingredients and combine them together with 10 other ingredients. But the question is, who knows if they all work well together or in the way that is claimed? Even more important, what about interactions and adverse reactions?"
Nurture's Mr. Stephens said a lot of nutraceuticals companies will do the research without knowing what they want to claim when it should really be the other way around. "Determine what the goal or claim should be for a particular product and design a trial to answer that question," he said. "This sounds simple and common sense but so many companies in this industry design a study and THEN try to determine what can be claimed by the result."
Kelley Fitzpatrick, market and research development manager, Richardson Center for Functional Foods, University of Manitoba, Winnipeg, Canada, offered a similar point of view. "The science should follow the claims and I don't think that we should get rid of a high degree of science if we are making pharmaceutical like claims," she said.
Another problem with structure/function claims is that they may be limiting in terms of describing the "real" benefits of certain products. Harvard's Dr. Goldman discussed this issue. "Unfortunately, the situation for claims is rather paradoxical in the sense that, in the case of ginkgo, there are several randomized trials with reasonably reproducible ginkgo products that show a benefit to certain patients with Alzheimer's disease," he said, adding, "However, according to the regulations, you can't make a disease claim for a dietary supplement. Here you have a product that by conventional standards may be of as much benefit for Alzheimer's disease as some of the approved drug products but you can't say that."
In terms of claim substantiation, Kathie Wrick, principal-Food Nutrition & Health Practice, Tiax LLC, Cambridge, MA, offered, "Claim substantiation for many products is being left to the NIH's Office of Dietary Supplements, which may or may not support the message intended for consumers. "If companies continue to leave claim substantiation research in the hands of universities and government, they may or may not get the studies designed the way they need to be in order to prove a particular point.
Research Solutions
The nutraceuticals industry no doubt faces some significant challenges going forward. In that respect it is important to discuss what are the research options. Some suggest that partnerships be forged between industry, government and academia, while others speak in favor of changing current legislation (i.e., amending DHSEA to make room for research incentives in the form of stronger patent protection, for example) or reviving old ideas in the form of new legislation (i.e., amending the NREA and proposing a newer version to Congress).
In terms of collaboration, Steven Dentali, vice president of scientific and technical affairs, American Herbal Products Association (AHPA), Silver Spring, MD, said industry participation in government research activities is paramount "Each and every company in our industry should be intimately familiar with what ODS and NCCAM are doing because these groups respond to public input," he said. "Right now agendas are set and studies funded without much of the essential guidance and perspective that only industry experts can offer and this is a shame."
Todd Norton, president and COO, Sabinsa, Piscataway, NJ, said patent and trademark protection are available and can serve a purpose, but it is an expensive undertaking. "Patent and trademark protection are available and in large measure can do a lot to establish points of differentiation on ingredients or products (property) that have some form of research pedigree," he explained. "The real challenge comes in the costs associated in the enforcement and protection of that property, which may factor into the price of the good(s) being offered."
Patent protection is costly indeed, according to LDI's Mr. Israelsen. And is it even worth it? "The patenting process can be tricky for products in this industry because they don't lend themselves to very clear patent positions," he said. "Getting a patent is like getting a fishing license in that you still have to go out and catch a fish and protect yourself from people who are infringing on your patents. Very often the cost of defending a patent will be magnitudes more than it costs to get the patent in the first place. For a small research-based company there's hardly room in the budget to spend that kind of money."
Another idea relates to the resurrection of the NREA. According to its creator, Dr. DeFelice, this is probably the best course of action. "We have a regulatory structure at the moment where you can't say certain things or tell the truth about products. This is why I stepped in and proposed the term 'nutraceutical' and why I proposed the NREA-which is similar in structure to the Orphan Drug Act (ODA)."
To recap, the ODA was passed based on the premise that a company could file a new drug application (NDA) without doing extensive studies, plus it gave a company exclusivity to make a claim for a period of seven years. "The right to make that claim is a very powerful marketing tool," said Dr. DeFelice. "The ODA was a success based on the simple principle of exclusivity of the claim as long as there was a reasonable amount of research done on the product. The NREA would have worked in the same fashion in that a company would do research on its specific product and then have an exclusive right to a specific claim for a period of 10 years."
So what happened? According to Dr. DeFelice, the NREA garnered little interest from industry and Congress. "Senator Frank Pallone introduced the NREA and not one advocate stepped forward. It was very disappointing," he said.
Other experts, such as Dr. David Eisenberg, director of the Osher Institute, Harvard Medical School, Boston, MA, have also said the NREA is worth a second look. "The NREA could be jointly refined by tweaking the definition of a nutraceutical health claim,by creating criteria necessary to support a nutraceutical claim and by determining an appropriate term of exclusivity for a claim," he suggested. "The proposal should be amended to address issues of quality, better information for consumers, better protection of investment and increased privately funded R&D." These issues, Dr. Eisenberg said, should be discussed with the Institute of Medicine (IOM) and Congress and tested in the marketplace.
LDI's Mr. Israelsen said the NREA had some good points but there were some unappealing aspects as well. "First, the approval mechanism through FDA is not going to happen partly because FDA drags its feet every time our industry proposes a different regulatory model. Frankly, there has never really been enthusiasm from FDA to do anything with natural products because they are not familiar with them, they are difficult to work with, etc." Case in point, he said, "Right now there are 100 drug applications at FDA for botanicals, which have been there for several years. It is now 2003 and we have yet to have an approved drug that is botanically-based make it through the process. We haven't seen where the end of that rainbow is yet. It may be that if a company is successful in getting a botanically-based drug approved, then it would garner confidence in the eyes of medical professionals and the general public because it now has a government approved product."
Phytopharm's Dr. Gruenwald said it is time to sit down and re-think DSHEA. "I think there really needs to be a change in the legislation. DSHEA was good in its time because there was no real market for these products and there were no regulations. It also gave a good boost to the market initially but according to a free market system, several players jumped in and looked for the cheapest way to cheat the system," he said, adding, "It is this cheating of the system that has ruined the market for the time being."
LDI's Mr. Israelsen said a lot of people are frightened at the mention of changing DSHEA, but, he said, the legislation has already been dismantled over the last few years due to bioterrorism legislation and proposed GMPs. He commented, "The DSHEA passed in 1994 does not exist today nor does the world we lived in back then."
Intramedicine's Ms. Allen recommended that the industry establish a forum in which its scientists could collaborate, share ideas and work on reaching consensus on issues that are specific to the development of nutraceuticals. "We have some incredibly talented people in this industry but we don't have any way for them to work together or showcase their ideas and thoughts," she said. "There is a high amount of interest from the scientific community for creating a scientific forum but so far there is very little support from the CEO level. The reason for this is because there is so little proprietary space in this industry, there is fear that withheld information will come out at a meeting."
Also supporting the idea of creating a meeting for the industry's scientists was Lyceum's Mr. Keirstead. "Someone really has to emerge as an advocate or leader. To that end, we really need a forum to be convened that would bring more intelligence or expert opinions to this area as a whole instead of everyone working in isolation," he offered.
Mr. Almada from Imaginutrition addressed the issue of borrowed science. "Companies that use the 'pirated' science excuse are completely ignorant. If you let somebody use your data then you don't know how to defend your data," he said. "One option of defense would apply primarily to a unique composition. An example of this would be two companies using the same tree to get their green tea leaves. One company will process or extract it one way, while the other will do it a different way." In the end, he said, one company could have a product that increases metabolic rate by 20%, while the other company's product increases metabolic rate by 4%. If the company with the 4% product tries to use the data from the company with the 20% product then that company would be involved in false attribution and thus likely in violation of a Federal law called the Lanham Act.NW