Walking into a Washington, D.C. courtroom on May 24 for the latest battle in their war with the Federal Trade Commission (FTC), the undisputed champions of pomegranate, POM Wonderful, appeared well-armed. The company had spent $35 million on research, according to legal briefs, and supported “more than 90 scientifi c investigations with over 65 studies on POM products, including 17 clinical trials.”
But those numbers did not impress FTC attorney Heather Hippsley. After the hearing, she told the swarming press that POM’s studies lacked adequate control-group comparisons, were too small, measured the wrong biomarkers, and that the company “repeatedly ignored warning signs that the marketing didn’t match the science.”
Just how this latest embarrassment in deceptive advertising will play out remains to be seen, but the moral of the story is already loud and clear: In an age when regulatory agencies crack down ever harder on claims, and policymakers cast sharper eyes on dietary supplement research as they update critical health recommendations, quality matters as much—if not more—than quantity.
“When I started 10 years ago, I used to do presentations about why companies should even do research,” says Jay Udani, MD, founder of Medicus Research, a contract research organization for the natural products industry. “Now, the conversations are all about how to do it better.”
In Search of Better Research
While many policymakers insist that the randomized controlled trial (RCT) The Supplement Industry’s Search for Better Science Attention shifts away from hard clinical endpoints to mechanisms of action and surrogate biomarkers should be held as the gold standard, some supplement industry leaders say such trials (originally designed for testing drugs) are ill fit for evaluating nutrients. Many in the industry are now calling for a new “evidence-based nutrition” paradigm. Meanwhile, the cash-strapped National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements (ODS) recently released five-year strategic plans which promise to pull back on splashy clinical trials (which to date have been largely disappointing) and instead prioritize studies exploring mechanisms of action and biological markers.
Udani believes it’s also time for companies to get smarter about designing their own trials on both ingredients and fi nished products, assuring at the onset that populations are appropriate, anticipated results are realistic, and that—if the outcome is positive—they can legally boast about it without treading into the dangerous waters of drug claims.
“A lot of the studies coming out now were designed years ago,” says Udani, a time when claims enforcement was less stringent and there was less understanding about the Dietary Supplement Health and Education Act (DSHEA). “In a lot of ways, they were set up to fail.”
The Tired, Old Paradigm
Ask Douglas “Duffy” MacKay, ND, what needs to be done to improve the quality of dietary supplement research and his answer is simple: Remember that supplements are not drugs.
“One of the greatest lessons we have learned in the past 10 years of research is that nutrients and botanicals cannot be studied in the same fashion as drugs,” says MacKay, vice president of scientific and regulatory affairs for the Council for Responsible Nutrition (CRN).
While drugs tend to have singular effects on targeted organs, nutrients often work in concert and impact multiple organs. While drugs tend to work fast to eliminate symptoms, nutrients often work gradually to prevent or reduce them. While it’s easy to find a control group who has had no exposure to, say, a statin drug, it’s impossible to find a placebo group with no omega-3 fatty acids or calcium in their body. All of these nuances can make it costly and messy to design a clinical trial.
In a lengthy treatise in the December 2010 issue of Natural Medicine Journal, MacKay and former CRN executive Andrew Shao, PhD (now of Herbalife) argue that “evidence-based medicine” and its cornerstone, the RCT, have been tragically misapplied to nutrients and bioactives, leading to skewed research results, a misinformed public, and poor public health policies.
For instance, during the famous Women’s Health Initiative (an RCT which found, among other things, that calcium and vitamin D supplementation did not benefit bone health), the so-called “placebo group” actually had a median calcium intake of about 1,100 mg per day. The trial has been recycled repeatedly in meta-analyses nonetheless.
In the Physician’s Health Study II, which concluded that vitamins E and C had no impact on cardiovascular disease, the antioxidants were studied independently, rather than in concert.
Shao and MacKay note that an over-reliance on such trials can paralyze or taint those making public health recommendations. When the National Institutes of Health held a state-of-the-science conference on multivitamins in 2006, they relied only on 63 RCTs, omitting thousands of other studies. Their conclusion? Not enough evidence to recommend multivitamins. In November, when the Institute of Medicine (IOM) unveiled new calcium and vitamin D recommendations lower than many in the industry had hoped for, “the near total reliance of the committee on clinical trials essentially excluded all observational data,” says CRN’s John Hathcock, PhD, noting a glaring double standard. “How many RCTs were needed to establish that cigarette smoking causes lung cancer? Or that fruits and vegetables help to lower cancer risk?”
As part of its five-year strategic plan, the Office of Dietary Supplements expressly vows to use updated research to revisit Daily Recommended Intakes for other nutrients. (Up next: omega-3 fatty acids and folate).
The New Paradigm
But if the lens of evidence-based medicine is flawed, what should we use instead? MacKay envisions a new “evidence- based nutrition” paradigm in which policymakers value epidemiological studies and practitioner surveys alongside RCTs, and aren’t afraid to make recommendations when RCTs are not feasible.
CRN also advises researchers to measure baseline nutrient status before the onset of a trial to determine if, for instance, some participants in an omega-3 trial are already eating a lot of fish. CRN would like to see more studies of how nutrients and other practices act in concert. For instance, a trial could look at a natural cholesterol-lowering or allergyrelief protocol (including supplements, lifestyle and dietary changes) compared to the standard drug therapies. “It’s imperative that we place supplements back in the context of a healthy lifestyle and study that lifestyle,” says MacKay.
While CRN calls for a bigger-picture approach to evaluating supplements, NCCAM and ODS are zeroing in on details. “These very large studies that look at hard clinical endpoints need to be built upon a body of translational evidence,” says NCCAM Director Josephine Briggs, MD. That translational evidence includes a better understanding of a nutrient’s active compounds, their mechanism of action, and the biological markers they influence. “We are now building that database,” says Briggs.
In the case of an NCCAM-funded 2010 study on Echinacea (which found its impact on shortening colds miniscule at best), Briggs would have preferred to know how it impacted specific immune markers, like white blood cell counts.
She points to a May 6, 2010 study in the New England Journal of Medicine as the way she sees biomarker research going in the future. Rather than vaguely asking whether vitamin E can ameliorate fatty liver disease, the study looked at whether the antioxidant impacted inflammation and the presence of certain liver enzymes. It did. “That’s something we can build another study around,” Briggs says.
CRN’s MacKay agrees that looking at “surrogate biomarkers” (short-term indicators that a nutrient may have a long-term impact) is worthwhile, and he adds that it “dramatically improves the feasibility of human trials both in terms of duration and cost.” But he’d like to see policymakers broaden their “disappointingly brief” definition of what constitutes a valid biomarker. For instance, the carotenoids lutein and zeaxanthin have been shown repeatedly to improve macular pigment density in the eye, a lack of which is believed to be a precursor to macular degeneration. But when it comes to claims, these biomarkers mean very little. “If you went to the FDA wanting to get a health claim for macular degeneration based on this, they wouldn’t consider it,” MacKay says.
The New Uncle Sam
The government’s giant step back from large human clinical trials is already evident in NCCAM’s funding choices: In 2003, when the organization spent $48 million on dietary supplement research, 50% was spent on clinical trials. In 2008, with a $58 million budget, it spent only 33%. And this year, as NCCAM doles out its $61.9 million (down from $63.1 million in 2010), it’s five-year plan prioritizes initiatives like defining the antiinflammatory actions of omega-3 fatty acids, studying the effects of probiotics on the human microbiome, and identifying the biological effects of “small molecules that are constituents of natural products … like quercetin and curcumin.”
At ODS, which doled out $21.7 million in research projects in 2010, Director Paul Coates envisions a sharper focus on shorter-term biomarkers on the one hand and—when it comes to longer-term studies—a greater emphasis on nutrients already believed to reduce chronic diseases such as cancer, heart disease, diabetes, mental health and cognitive decline. ODS is already contributing to the multi-center, multi-year VITAL trial, which will test the impact of vitamin D and omega-3s on cancer, heart disease and stroke in 20,000 subjects.
“We don’t know for sure,” says Coates, “but we are certainly getting messages that there is going to be a sharp cut in spending. We are having to rein things in and be very thoughtful about our spending.”
With the federal government tightening its spending belts and clamping down on claims, supplement companies are under more pressure than ever to invest in research on their own ingredients and finished products. But Udani says they too need to be careful who and what they study.
“The U.S. Food and Drug Administration has issued guidance that if you use a diseased population in a study, then what you are testing is a drug, and the same goes for endpoints,” he says. That means a supplement trial might test “glucose-intolerant people” rather than “diabetics” and look for “improved blood sugar” instead of “diabetes relief.”
So, what about POM Wonderful’s $35 million in research, which concluded that its products slow prostate cancer and treat heart disease and erectile dysfunction? “It is great to see a company doing so much research,” Udani says politely. “But I don’t believe they followed the spirit of DSHEA when choosing their endpoints and populations.”
Greg Leyer, global business development director for probiotics ingredient firm Danisco, says the company has already bolstered its attention to quality research significantly in recent years, honing in on how certain strains impact specific demographic populations with particular ailments. (For the record: Leyer believes the RCT is a good fit for probiotics, since their biological impact is often easy to measure). One successful study, recently published in Pediatrics, found that children age three to five who took Lactobacillus acidophilus NCFM and Bifidobacterium animalis for six months experienced fewer cold and influenza-like symptoms.
“The number of subjects we use is increasing, and we’re taking care to study a more relevant population,” says Leyer. “We don’t want there to be any confusion that we might be doing a drug trial.”
At least not yet. In some rare cases, industry observers say, when the foundational science is strong enough, RCTs prove positive, and the company has the willingness and staying power to invest in large, long-term studies, the grand payoff for doing good science may ultimately be drug status—and many companies are peering down that road.
In 2004, a then-obscure Norway-based company called Pronova Biopharma earned FDA approval for the world’s first prescription omega-3 fatty acid, now known as the blockbuster Lovaza.
In 2006, the FDA approved the topical green-tea extract Veregen (a wart treatment) as the first botanical extract ever to be approved for prescription.
Today, a half-dozen companies, including omega-3 therapy maker Amarin Pharmaceuticals, are lined up to unveil the next dietary supplement turned prescription drug. “We have partnered with pharmaceutical companies and are certainly looking at drug applications of probiotics,” says Leyer.
But for those who wisely plan their research for the supplement realm, there’s also a payoff: staying power.
Bob Rountree, a long-time naturopathic doctor and the chief medical officer for 25-year-old supplement company Thorne Research, says Thorne has built its reputation around solid research. It formulates products with the specific doses and compounds used in safety and efficacy trials and then tests the finished products for things like bioavailability.
In May, Thorne announced it is receiving a minority investment from the Helsinn Group, a pharmaceutical company based in Lugano, Switzerland. But Rountree says it has no intention of becoming a drug company.
“If a pharmaceutical company is willing to buy into Thorne without telling us we have to change anything,” says Rountree, “that says a whole lot about the quality of products we are putting out. No, we are not going to make drugs in our facility. Our core competency is making natural products. But what about making super-high-quality natural products comparable to Lovaza? Reliable, consistent, and pure. That, we can do.”