'Functional Foods' A Fruitful Research Field, But Various Regulatory Obstacles Persist

But Various Regulatory Obstacles Persist Date: March 4, 1996 (The Scientist, Vol:10, #5, pg.1 & 8, March 4, 1996) (Copyright ©, The Scientist, Inc.) SIDEBAR : Functional Foods: An AG Biotech Boom? Life scientists are finding new opportunities to test wise words uttered by the ancient Greek physician Hippocrates: "Let your food be your medicine, and your medicine be your food." OPPORTUNITY KNOCKS: Louis Lasagna notes the field's potential. In academic and industry labs across the United States, researchers are hunting for the cancer-fighting ingredients in fruit, vegetables, and dietary fiber. These scientists are building the emerging field of "functional foods"-those with an added health benefit beyond traditional nutritional value. Functional food proponents like Stephen DeFelice, chairman of the Foundation for Innovation in Medicine (FIM)-a Cranford, N.J.-based nonprofit group that promotes natural therapies-put the field's market potential at up to $250 billion. Biomedical scientists say interdisciplinary research opportunities abound. "This is a field brimming with opportunity," declares Louis Lasagna, dean of the Sackler School of Graduate Biomedical Sciences at Tufts University. "Of course, there are some serious hurdles as well." 'DISAPPOINTING': NCI's Peter Greenwald abruptly ended a study of beta carotene supplements. Those hurdles include the need to prove the basic safety and efficacy of nutrient-fortified products and to overcome regulatory uncertainty over patents and product health claims. The regulatory abyss keeps the food industry teetering on the brink of major R&D investment, while drug companies appear reluctant to invest at all. "Many food companies are holding off on clinical research until these regulatory points are taken care of," says Norman Jangaard, vice president of business development for the NutraSweet Kelco Co. in Deerfield, Ill. "But I do think those points will be resolved. When that occurs, the market will explode." And with the exploding market, according to Jangaard, will come research jobs: for nutritionists and biochemists, who can sort through the haystack of food products for disease-fighting ingredients; for epidemiologists, who can design studies to demonstrate an ingredient's beneficial effect; and for plant scientists, who can isolate and purify compounds from food crops. Even now, some industry research could lead to newfound disease-prevention ingredients or clarify the functional health effects of existing products. For example, the Cincinnati-based Quaker Oats Co. plans to pursue epidemiology and clinical studies to determine the effects of oat bran on blood pressure and energy. Meanwhile, academic researchers are seeking molecular explanations for certain foods' disease-fighting qualities. Since 1992, the National Cancer Institute (NCI) has awarded more than $15 million to scientists isolating and studying the beneficial effects of active plant compounds, called phytochemicals, found in fruit and vegetables. Over the past 60 years, epidemiological studies have linked diet and cancer. "We can almost say with certainty that you can reduce cancer and heart disease risk with a diet that's low in fat and rich in fruits and vegetables," says Peter Greenwald, director of NCI's Division of Cancer Prevention and Control. Food's disease-fighting features have generated countless nutrition products, including vitamins, vitamin-enriched food, dietary supplements -- and functional foods. This last category originated in the 1960s, when biologist Paul LaChance -- now at Rutgers University's food science department -- added calcium to the powdered drink Tang. National Aeronautics and Space Administration astronauts slurped the nutrition-packed punch in space. Tang soon found its way into kitchen cabinets across the U.S. CONFOUNDING ISSUE: Rhonda Witwer notes that definitions pose a problem. But here on Earth, industry researchers interested in functional food compounds ran into regulatory walls, notes Rhonda Witwer, industry liaison for the Functional Foods for Health Program at the University of Illinois in Chicago, which is dedicated to developing health-promoting food products. "So far, there has been a lot of confusion about definitions for functional foods, which are also called 'nutraceuticals,'" Witwer explains. "Plus, there is a lot of confusion over marketing issues." The result, she says, was that food companies essentially abandoned the concept -- until recently, when improving biochemical techniques, increased public interest, and encouraging academic studies renewed corporate curiosity. Even while industry research lagged, academic scientists began investigating everyday foods for disease-fighting ingredients (C. Marwick, Journal of the American Medical Association, 274:1328-30, 1995). At one end of the academic spectrum are epidemiological reports that continue to clarify diet's role in cancer. Last month, for instance, researchers reported that high dietary fiber may reduce the risk of coronary heart disease among men (E.B. Rimm et al., JAMA, 275:447-51, 1996). At the other end of the spectrum are new molecular investigations into food ingredients. For example, at Johns Hopkins University, researchers are studying a class of plant chemicals called isothiocyanates, found in broccoli and other cruciferous vegetables (T. Prestera, P. Talalay, Proceedings of the National Academy of Sciences, 92:8965-9, 1995). These anticancer agents partly act by inhibiting enzymes that activate carcinogens. One common research approach is to isolate and feed a compound (at high concentration) to cancer-infected rodents, which may respond with fewer or shrinking tumors. Researchers at Indiana University in Indianapolis use this tactic to study perillyl alcohol, a compound found in cherries (P.L. Crowell et al., Biochemical Pharmacology, 47[8]:1405-15, 1994). Perillyl alcohol belongs to a family of plant compounds called monoterpenes, which hold potential as disease fighters, explains Pamela Crowell, a biologist at Indiana. "Our findings indicate that perillyl alcohol induces tumor cell death," Crowell says. "We're now using it in basic research with hamsters as a model to study pancreatic cancer." Crowell, who got into phytochemicals while a postdoctoral researcher at the University of Wisconsin in Madison, notes that the field invites interdisciplinary collaboration. "I think the best researchers in this field have a little training in nutrition, oncology, and biochemistry. Plus, researchers from these groups come together. As time goes by, it is becoming more and more practical to integrate lab and human studies." Scientists say they hope these studies can fill in large gaps in understanding about the relationship between food and cancer. In particular, cautious functional food advocates sound the call for more clinical trials. "There aren't even good clinical trials telling people to use vitamin E," remarks Anne Goldberg, an associate professor of medicine at Washington University in St. Louis. "The data is epidemiological. I do think there's probably value in nontraditional medicines; most of what we have is from plants, anyway. But I want to see some serious data." "Part of the problem is that we have so little sound basic science in nutrition these days," adds Gerald Gaull, director of the Center for Food and Nutrition Policy at Georgetown University in Washington, D.C. "We have a tendency to over-promise with a 'magic bullet' kind of concept. But cancer is multifactored and polygenic. Cancer is biologically complex." That lesson came painfully to light in January, when Greenwald and other researchers at NCI held a news conference to announce the abrupt end of a study on beta carotene supplements. NCI is a high-profile sponsor of academic research examining health-related compounds in garlic extract, licorice root, citrus juice, and flax seed (P. Greenwald et al., Advances in Experimental Medicine and Biology, 369:229-39, 1995). Beta carotene is one of the most highly touted compounds in the phytochemical group. Found in carrots and other vegetables, beta carotene is a chemical precursor to vitamin A and a celebrated antioxidant, a compound that binds to and disables cancer-causing substances in the body. Beta carotene was so promising that NCI launched a large-scale clinical trial testing the chemical's ability to prevent lung cancer in high-risk men and women. But this winter, about three-fourths of the way through the trial, researchers reviewing the data were shocked to find study participants taking beta carotene had a 28 percent higher incidence of lung cancer than the placebo group. The results mirrored another trial conducted in Finland several years ago. NCI immediately stopped the study. "Needless to say, it was disappointing," comments Greenwald. "But it also shows the value of clinical trials. Before, it wasn't possible to separate what might be a specific effect of beta carotene from the overall effect of fruits or vegetables." Now, Greenwald says, researchers know beta carotene isn't the cancer-preventer in those foods. "It raises a very important issue: the promotion of supplements. What sort of evidence do we have of efficacy for [functional foods]?" Not enough, asserts William Jarvis, a professor of public health at Loma Linda University in California and president of the Loma Linda-based National Council Against Health Fraud. "All of us in the scientific community believe we can make the world better by studying nature and applying the lessons to our lives," says Jarvis. "But the fact is that any product that goes to market with a health claim must have a solid scientific basis. We should not let the conclusions run ahead of the data. We need more research." Of course, from an industry standpoint, product safety and efficacy are only half the equation. The other half involves bringing that product to market. Without a reasonable profit forecast, companies won't even invest in clinical research, says Stephen McNamara, an attorney with the Washington, D.C.-based law firm of Hyman, Phelps and McNamara and former associate chief counsel for food at the Food and Drug Administration (FDA). Today, McNamara points out, the functional food market does not offer a clear profit. "For one thing, many of these products would be familiar food substances that probably would not be eligible to be patented," he notes. "So if a company proves in studies that a food substance has a medical benefit, they may find competitors can get a free ride on that work. It's only logical for the board of directors to ask if it should be spending money on this kind of research." For example, in January, Quaker Oats won FDA's first recommendation for a food-specific health claim. Based on various past clinical trials, the agency agreed to a company proposal that certain Quaker Oats oatmeal products carry labels reading: "Eating oat bran or oatmeal daily may reduce heart disease risk." But because Quaker Oats cannot patent bran -- a natural food substance -- bran's heart-health benefit is now in the public domain. If, as expected this spring, FDA formally approves bran's health claim, any food manufacturer can use it. "We feel that consumer recognition of the Quaker Oats name will allow the company to benefit from the claim," says Steven Ink, chief nutritionist at the company. However, Ink notes that in the future, Quaker will not invest as heavily in research for potential functional foods -- unless those foods are guaranteed an exclusive health claim. Still, Quaker currently plans to build off earlier research by distributing funding grants to academic researchers interested in exploring oat products' ability to control blood pressure, improve heart health, and sustain energy. Quaker's efforts show that companies are willing to do some functional food research without a patent, according to McNamara. "Things like brand names, consumer confidence, and controlled costs help push the functional food industry along, even without patents. But it would be an incentive for useful public-oriented research if companies could see there was likely to be a payback." Another incentive for R&D funding, says Witwer, would be a clear regulatory road map for clinical trials. "The FDA is considering classifying functional foods in the 'foods for special dietary uses' product category," Witwer says. "But at this early stage, nobody's even quite sure how long it's going to take or what's going to be required to get an FDA-approved health claim." Product and regulatory uncertainty are likely to prevent drug companies from entering the functional food business, observes David Trecker, head of central research at Pfizer Inc. of New York. "The pharmaceutical industry has so many diseases to attack directly with discrete drugs," Trecker says. "The economics are so beneficial that to go with a murky, natural product is a foreign concept. The thrust for this field definitely will come from the food industry." Taking te initiative that thrust could come soon. This May, nutritionists, food executives, legislators, and regulators will discuss market issues at the sixth annual "Nutraceutical Update From Washington," in Washington, D.C. FIM is organizing the event. In fact, for the past six years, FIM has lobbied for functional foods, hoping to gain clear market claims and easy regulatory access. TAKING INITIATIVE: Stephen DeFelice's group plans to draft legislation This could be the year, according to DeFelice. He says participants in the May conference will draft proposed legislation carving a functional food niche into FDA product review. "I'm going to go to the blackboard, and we're going to actually write the legislation," he states. "We're going to take the initiative." DeFelice is confident that the functional food market will succeed: "It's a high-profit, quick-to-market venture." If he's right, in-house industry and academic scientists may not be the only researchers who benefit. Smaller food companies also may outsource clinical research on health benefits to contract research organizations (CROs) specializing in a particular area (M. E. Watanabe, The Scientist, Dec. 11, 1995, page 1). Crowell of Indiana says researchers across the spectrum may find jobs. "Just over the last year, I've experienced a tremendous amount of interest in this research," Crowell says. "What's exciting is that when you put it all together, we can integrate nutrition, cancer, and biochemistry research. Hopefully, working together, we can actually improve diets to truly reduce the risk of cancer." Kathryn S. Brown is a freelance science writer based in Columbia, Mo.

'Functional Foods' A Fruitful Research Field, But Various Regulatory Obstacles Persist

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