In many respects, 2005 is beginning to look a lot like 2004. The Food and Drug Administration (FDA; Rockville, MD) is still promising the “imminent” publication of good manufacturing practices (GMPs) for dietary supplements.
In many respects, 2005 is beginning to look a lot like 2004. The Food and Drug Administration (FDA; Rockville, MD) is still promising the “imminent” publication of good manufacturing practices (GMPs) for dietary supplements. Lester Crawford, PhD, is still acting commissioner of FDA. And the media and Congress are still hostile to the supplement industry. But the similarities end there. Change is in the air, and recent events could have a profound impact on the industry in the near future.
BLIZZARD FORECAST INACCURATE
At the Council for Responsible Nutrition’s (CRN; Washington, DC) annual conference in 2004, Crawford predicted that the industry would soon be seeing a “blizzard of materials” related to the new GMPs. But that was last October. The GMPs still haven’t arrived, and manufacturers are growing restless. “Responsible manufacturers want to see GMPs in place as soon as possible,” says Steve Mister, CRN’s president and CEO. “Having mandatory requirements for all dietary supplement manufacturers will not only reinforce consumer confidence but will also level the playing field for manufacturers.”
According to Mister, negative publicity created by a few companies with subpar quality standards can damage the credibility of manufacturers that are already following proposed GMPs. “Knowing there are uniform standards for all supplements and that FDA has the resources, tools, and resolve to enforce them will give consumers even more reason to turn to dietary supplements to maintain good health,” Mister says.
Despite the long delay, many industry experts still hope to see the GMPs later this year. “Clearly, FDA has been dealing with other issues that require more urgent attention,” Mister says. “However, we remain cautiously optimistic that GMPs will be issued by year’s end.”
AND THE NOMINEE IS. . .
Another thing that never arrived in 2004 was a permanent FDA commissioner. Crawford has been filling in as acting commissioner since March 2004, when former commissioner Mark McClellan left to become head of the Centers for Medicare and Medicaid Services (Washington, DC). Although President Bush nominated Crawford to fill the position on February 15, 2005, Crawford’s nomination has met resistance in the Senate over issues apparently unrelated to supplements.
While the Senate Committee on Health, Education, Labor, and Pensions approved Crawford’s nomination on June 15, 2005, the full Senate can’t vote on it yet because three senators-Patty Murray (D–WA), Hillary Rodham Clinton (D–NY), and Tom Coburn (R–OK)-put a hold on the nomination. Murray and Clinton cited concerns over FDA’s unwillingness to decide whether or not to approve over-the-counter sales of the contraceptive Plan B. Meanwhile, Coburn opposes the nomination because FDA has been slow to enact certain changes in condom labeling.
“At a time when FDA needs a strong leader to restore its reputation, I fear that Dr. Crawford’s record demonstrates a lack of vision and drive to ensure that FDA upholds its gold standard of drug regulation,” Clinton said on June 15. “He has failed to address the concerns raised by his own employees about the needs of the agency. And he cannot provide assurances that FDA will make science, not ideology or other interests, the cornerstone of its decision making.”
In 2004, the media turned up the heat on supplements with a series of controversial articles on antioxidants and other ingredients. Consumer Reports began the barrage with a May 2004 exposé on its “Dirty Dozen” list of unsafe supplement ingredients, which included aristolochia and androstenedione.
Other publications followed. The journal Circulation, for instance, had a science advisory from the American Heart Association (AHA; Dallas) in its August 3, 2004, issue that warned that antioxidants do not help protect against heart disease. Similarly, the October 2, 2004, issue of the Lancet included a meta-analysis of 14 clinical trials that found that antioxidants offered no protection against several forms of cancer. Finally, a study in the December 15, 2004, issue of the Journal of the American Medical Association found that many ayurvedic products are contaminated with heavy metals.
Industry trade groups decried the sensationalism of the articles. CRN, for instance, cited flaws in study methodology and accused AHA of “trying to prematurely close the door on supplement use.” CRN also noted that several large studies have found that vitamins C and E reduce the risk of coronary disease. Furthermore, in September 2004, the Dietary Supplement Education Alliance presented the results of a study by the Lewin Group (Falls Church, VA) that estimated that taking supplements could save billions in healthcare costs. And the American Herbal Products Association (Silver Spring, MD) noted that products contaminated with heavy metals are already considered adulterated under the Dietary Supplement Health and Education Act of 1994 (DSHEA).
According to Herbert D. Woolf, PhD, technical marketing manager for BASF Corp. (Florham Park, NJ), the negative press has been having an impact on consumer demand for letter vitamins. “Our research shows that consumers are becoming increasingly confused by the information that is being reported,” Woolf says. “While there is an increase in the percentage of consumers surveyed who believe vitamin E should not be taken in large dosages, there is also an increase in the percentage who believe that it may not be as good as some people think, but that it is not harmful.”
Woolf adds that some nuances of the research have also been overlooked. “It’s important to understand that the vitamin E study, a meta-analysis of 19 clinical studies, investigated a potential dose-response relationship of vitamin E supplements on total mortality in humans,” he says. “The conclusions indicated that vitamin E caused no benefit and observed the potential for negative effects of long-term high dosages of vitamin E in high-risk individuals. This should not have translated into negative news, since there is no evidence of potential harmful effects in healthy populations.”
Congress didn’t exactly lend a sympathetic ear to the industry either. In fact, during 2004, calls to revise DSHEA became increasingly strident. One of the first major recent pieces of legislation to affect DSHEA was the Anabolic Steroid Control Act, which Congress passed in October 2004. The law, which was supported by five supplement industry trade associations, added steroid precursors such as androstenedione to the Drug Enforcement Agency’s (Alexandria, VA) controlled substances list. Attempts are now under way to add another hormone ingredient, dehydroepiandrosterone (DHEA), to the list with a new senate bill that was introduced this year, S 1137.
“Some members of Congress wrongly believe that DHEA is an anabolic steroid and that it should be removed from the marketplace,” explains David Seckman, executive director and CEO of the National Nutritional Foods Association (NNFA; Washington, DC). “This appears to be a misguided attempt to ensure that professional athletes won’t have access to DHEA to try to improve performance.” Seckman notes that the science behind DHEA doesn’t support its use as a performance enhancer or raise safety concerns. He adds that the industry is ready to fend off future attempts to ban DHEA.
“Last year, NNFA fought hard to ensure that DHEA was not added to the list of controlled substances as part of the Anabolic Steroid Control Act of 2004, and we’ll redouble our efforts to oppose S 1137,” Seckman says.
BAN IN QUESTION
An April 13 decision by U.S. District Court Judge Tena Campbell to partially overturn FDA’s ban on ephedra also appears to have provoked congressional opponents of DSHEA. FDA banned ephedra in 2004, but in response to a lawsuit filed by Nutraceutical Corp. (Park City, UT), Campbell ruled that FDA had not proven that ephedra posed a significant or unreasonable risk of injury and ordered the agency to carry out toxicology studies. The judge also enjoined FDA from taking action to prevent Nutraceutical from selling supplements containing less than 10 mg of ephedra per dose.
The issue is far from settled, however, because FDA has appealed the ruling. “FDA’s appeal of Judge Campbell’s decision to the U.S. Court of Appeals for the Tenth Circuit could easily take one year to be decided by the panel,” explains Shane Freedman, a senior associate in the litigation department at Latham & Watkins LLP (Newark, NJ). “In the interim, it is risky for companies to sell ephedra-containing dietary supplements given the limited scope of the district court ruling and the uncertain status of the law.”
In the meantime, manufacturers have been turning to other ingredients to take the place of ephedra. According to Bill Arthur, principal of Nutraceutical Solutions Consulting (Miami Beach, FL), the industry had been exploring alternatives to ephedra even before 2004. “Since the regulatory wrangling over ephedra has been going on for years, manufacturers were clamoring for ephedra alternatives well before the ban went into effect,” says Arthur, who is also a marketing consultant for Nutratech Inc. (Wayne, NJ), which distributes the bitter orange (Citrus aurantium) ingredient Advantra Z.
Manufacturers are not the only ones interested in Citrus aurantium, however, as FDA has expressed some safety concerns. In an April 19, 2004, speech to members of the American Society for Pharmacology and Experimental Therapeutics (Bethesda, MD) and the American Society for Nutritional Sciences (Bethesda, MD), Crawford said FDA’s Office of Dietary Supplements was reviewing research on Citrus aurantium because it is reported to contain potentially bioactive substances, such as synephrine, octopamine, and tyramine. “Synephrine is a sympathomimetic compound that has been shown to increase systemic arterial pressure in humans and animals,” Crawford noted.
But Bob Green, president of Nutratech, says that the ingredient has suffered unfairly from misstatements and misperceptions about bitter orange. And Arthur notes that in 2004, an FDA spokesperson mistakenly said there were adverse-event reports related to Citrus aurantium products. “This ingredient has been used safely around the world for thousands of years,” Green says. “Bitter orange, and specifically Advantra Z, has been shown in numerous studies to assist in increasing metabolism and weight loss without raising blood pressure or heart rate.”
NEW DIETARY INGREDIENTS
In 2004, FDA also expressed concerns about another class of ingredients, namely, new dietary ingredients. At a public meeting held on November 15, 2004, FDA asked for public comments about the type, quantity, and quality of evidence manufacturers should provide on new dietary ingredients, which are defined in DSHEA as ingredients that were not marketed in the United States prior to October 15, 1994. According to DSHEA, manufacturers that intend to use new dietary ingredients in their products must notify FDA and provide the agency with relevant safety information.
“In looking at our notification program over the past few years, we’ve noticed that there have been many more notifications and that FDA has been objecting to a larger percentage of these notifications,” Susan Walker, MD, director of FDA’s division of dietary supplement programs, told attendees at the meeting. “We want to determine why this is happening.”
Walker noted that although there are several factors, the basic problem is that when FDA receives a description of a new dietary ingredient, it is often inadequate. “We need to know what it is, and that actually sounds like a very simple question, but it’s a very complex issue, particularly with botanicals,” Walker said.
Several industry stakeholders who spoke at the meeting said they were encouraged that FDA was looking into the issue but worried that FDA’s interpretation of the new dietary ingredients provision in DSHEA was overly restrictive. Some said they were worried that FDA’s approach resembled its policy for food additives. Others called for more-consistent enforcement in order to produce a level playing field.
At the meeting, FDA officials said the process of reviewing public comments could take months.
Although concerns about product purity have been a perennial challenge for the industry, some products have made great strides over the past year. Omega-3 ingredients, in particular, have benefited from CRN’s voluntary omega-3 working group monograph, which specifies purity standards. So far, at least 17 companies comply with the monograph.
On March 30, the nonprofit organization Environmental Defense (New York City) conducted a survey of 54 companies that sell fish oils and asked for information about how much mercury, polychlorinated biphenyls (PCBs), and dioxins the products contained. According to the group, “many of the companies contacted provided high-caliber responses, indicating that they take potential health risks from contaminated fish oils seriously.” Environmental Defense said that most companies reported using molecular distillation and steam distillation to remove environmental pollutants. More than two- thirds of the companies verified that they met the strictest U.S. standards for environmental contaminants.
“Fish oil has many health benefits, yet most American diets fall short of critically important omega-3 fatty acids,” says David Smith, PhD, chief scientific officer of Pharmavite (Northridge, CA), which received a “best choice” rating from Environmental Defense for its Nature Made–brand fish oil. “Fish oil supplements are a convenient, inexpensive choice for consumers who want to incorporate fish oil into their diet. Pharmavite commends Environmental Defense for directing consumers to high-quality fish oil supplements.”
THE MORE THINGS CHANGE
Judging from the events of 2004 and 2005, it’s tempting to recall Yogi Berra’s famous quote: “It’s déjà vu all over again.” Problems that have plagued the supplement industry in the past, such as the lack of GMPs, have not gone away. But it’s important not to overlook the fact that things are slowly improving. Many companies are already complying with the standards of the proposed GMPs, and some are even adopting more-rigorous standards. Furthermore, FDA is beginning to enforce DSHEA more vigorously, albeit in a manner that is not always to the industry’s liking. These trends could ultimately result in a more level playing field, leaving the state of the industry in 2005 much stronger than it was in 2004.