FDA, NEJM Address DSHEA
In late December, The New England Journal of Medicine and the Food and Drug Administration (FDA) each released information relating to the Dietary Supplement Health and Education Act (DSHEA), which may raise the profile of the act as Congress heads into a new session. Here, HSR takes a look at FDA's plans to increase enforcement of DSHEA and to open the health claims field, as well as NEJM's articles attacking DSHEA and botanicals.
FDA Opens Health Claim Field, Plans Increased Enforcement of DSHEA
NEJM Editorials Rebuke Dietary Supplement Industry
FDA Opens Health Claim Field, Plans Increased Enforcement of DSHEA
by Heather Granato
"We are committed to improving opportunities for consumers to get scientifically accurate information about the health consequences of the foods they consume, and to enhancing our enforcement efforts against those who would make false or misleading claims for their products." -- Mark B. McClellan, M.D., commissioner, Food and Drug Administration
The Food and Drug Administration (FDA) made several major announcements Dec. 18 impacting the natural products and dietary supplement industries. Mark B. McClellan, M.D., commissioner of food and drugs, presented the Consumer Health Information for Better Nutrition Initiative. According to McClellan, the goal of the program is to encourage food and dietary supplement companies to make accurate, science-based label claims about products, and to eliminate fraudulent and misleading claims currently on the market.
In his announcement, McClellan covered three major areas. First, the agency issued guidance about qualified health claims for conventional foods and dietary supplements. Second, FDA established a task force charged with developing a framework to ensure consumers get health information they can use and understand. Finally, FDA released an enforcement report outlining an "aggressive enforcement strategy" against dietary supplement companies violating the Dietary Supplement Health and Education Act (DSHEA).
Qualified Health Claims Guidance
"Guidance for Industry: Qualified Health Claims in the Labeling of Conventional Foods and Dietary Supplements" appeared in the Dec. 20 Federal Register. The guidance is part of FDA's effort to implement the Pearson court decision, which found that FDA could not reject health claims unless the claims were both misleading and that no disclaimer would clear the misunderstanding. In October 2000, FDA released a Federal Register notice discussing "enforcement discretion." This amounted to permitting dietary supplement companies to use qualified health claims as long as the scientific evidence supporting the claim outweighed that against the claim, and the claim was appropriately qualified.
In the new guidance, FDA broadened the scope of the Pearson decision to allow conventional foods to also carry qualified health claims. In a statement from Emord & Associates, the legal firm that represented the Pearson plaintiffs, Jonathan Emord cheered FDA's decision. "The decision is nothing short of revolutionary [and] is an abrupt departure from the agency's long held view that no nutrient-disease claims should be allowed for foods or dietary supplements unless proven to a near conclusive degree," it read. "Far more information about the actual and potential health benefits of dietary supplements and foods will reach consumers than ever before."
Health claims will still be subject to preapproval by FDA and must meet a "weight of the evidence" standard. FDA will respond to health claim petitions in one of three ways. If the claim meets the "significant scientific agreement" standard, FDA will authorize the claim and consider expediting publication to permit faster use in the market. If the claim does not meet the "significant scientific agreement" standard but does meet a "weight of the evidence" standard, under which supporting evidence outweighs negative evidence, FDA will exercise "enforcement discretion," allowing companies to use the claim with an appropriate qualifier. If the claim does not meet either standard, FDA will deny the petition.
Current qualified health claims include folic acid and neural tube defects, omega-3 fatty acids and coronary heart disease (CHD), and B vitamins and CHD. Many national news articles speculated the authorized qualified omega-3 claim could be the first to appear on food products, as fatty fish such as salmon could carry claims promoting consumption of omega-3 fatty acids to reduce the risk of CHD. It is also worth noting that ingredients used in foods must be generally recognized as safe (GRAS). "This doesn't change the safety requirement, so you'll likely still see claims for supplements that won't apply to foods," said Diane McEnroe, partner with Sidley & Austin, legal counsel to the National Nutritional Foods Association (NNFA).
"This is a very positive move by FDA, which will help food companies to provide more accurate, science-based information on the health benefits of food products to consumers," said Rhona Applebaum, executive vice president of the National Food Processors Association (NFPA) (www.nfpa-food.org). NFPA and the Grocery Manufacturers Association (GMA) have long urged FDA to examine its criteria for health claims and to expand the qualified health claim category beyond supplements.
However, the health claim news was not universally cheered. "The supplement claims standard has led to a marketplace free-for-all of misleading claims that we fear will now spread to the much larger food industry," said Bruce Silverglade, legal affairs director of the Center for Science in the Public Interest (CSPI) (www.cspinet.org).
Consumer Information Task Force
To assist FDA in making this change to the health claim paradigm, FDA announced the formation of a Task Force to review issues involved. Headed by FDA Deputy Commissioner Lester Crawford, Ph.D., and Joseph Levitt, director of FDA's Center for Food Science and Nutrition (CFSAN), the Task Force has a six-month timeline to report back on a framework for facilitating consumer access to accurate, scientifically based health information.
Its first charge will be considering the "weight of the evidence" standard FDA will use in evaluating health claim petitions. As FDA noted, it is not only the number of studies, but "whether the pertinent data and information presented in those studies is sufficiently scientifically persuasive."
The Task Force will also:
- Propose a strategy to ensure FDA reaches decisions on health claim petitions in a timely fashion;
- Propose improvements in FDA's capability to identify false, misleading and/or unsubstantiated claims;
- Propose a strategy for FDA to prevent dissemination of such fraudulent claims; and
- Develop a research agenda to investigate how consumers view scientific information to help companies present such information in a non-misleading way.
DSHEA Enforcement
"FDA is committed to enforcing DSHEA in a manner that effectuates Congress's intent," the agency wrote in its Dietary Supplement Enforcement Report. "Congress's intent in passing [DSHEA] was to strike a balance between consumer access to dietary supplements and FDA's authority to act against supplements that present safety problems or bear false or misleading labeling."
FDA stepped up enforcement operations in this area in 2002, including carrying out more than 80 manufacturing facility inspections, seizing mislabeled product, seeking court injunctions and pursuing criminal prosecutions. It plans to continue with these operations in the coming year, as well as use the new CFSAN Adverse Event Reporting System (CAERS), due to come online in June 2003, to monitor dietary supplement safety and claims. McClellan specifically mentioned seizure actions, saying, "We're putting manufacturers on notice about what is coming. We had a major seizure this week, and you can expect more coming."
The Dec. 16 seizure involved U.S. marshals in California seizing $100,000 worth of product from Halo Supply Co. Its EverCLR capsules contained herbal extracts including echinacea, burdock and ashwaganda, and were promoted as having the ability to "restore your body's resistance to viruses." FDA said the products were unapproved new drugs because of labeling and were misbranded. A company spokeswoman told HSR the company had no public statement.
Such seizures are dramatic, and usually come at the end of discussions between FDA and companies. In its enforcement notice, FDA laid out a variety of examples of enforcement action taken against different companies, such as warning letters asking for voluntary corrections of problems or legal action enjoining product sale. It also outlined certain products that are "clearly problematic" and will draw the agency's close scrutiny in the coming months. These include:
- Products that purport to treat life-threatening diseases such as cancer, HIV/AIDS and lupus--"These products are ineffective and rely on unsubstantiated claims."
- Weight-loss products--"There is no evidence supporting the products' effectiveness." These products were just the subject of a Congressional hearing, and have been under the microscope by the Federal Trade Commission (FTC) as well.
- Products targeting children's conditions, such as autism, attention deficit disorder, mental retardation and Down's syndrome.
- Colloidal minerals and colloidal silver.
- Supplements for smokers and for drinkers.
Finally, FDA noted it "recognizes the need for dietary supplement current Good Manufacturing Practice requirements (cGMPs);" dietary supplement GMPs are, in fact, mandated as part of DSHEA. Industry associations were informed in October 2002 that publication of the proposed GMPs would happen before the end of 2002. At this point, however, there has been no further word on when the GMPs may be published in the Federal Register. In its enforcement document, FDA asked industry to develop "best practice" guidelines. According to representatives from NNFA, such "best practices" may refer to cGMPs in place from organizations such as NNFA, U.S. Pharmacopeia and NSF International that are practiced in the absence of established federal regulations.
On the whole, industry associations said they were pleased with FDA's decisions. "We applaud FDA for saying they will enforce DSHEA," said David Seckman, executive director and chief executive officer of NNFA (www.nnfa.org). "This is good for the industry and will offer more reliable information for consumers to make educated decisions."
Annette Dickinson, Ph.D., vice president of scientific and regulatory affairs at the Council for Responsible Nutrition (CRN) (www.crnusa.org), agreed with the assessment. "We support efforts by the regulatory agencies to reign in companies that are engaging in misleading dietary supplement advertising," she said. "The dietary supplement industry is regulated ... and companies that do not comply with the legal requirements for truthful advertising do a grave disservice to both consumers and the responsible companies providing quality products."
What Consumers Should Know
The National Nutritional Foods Association (NNFA) released two new consumer brochures in its "What You Should Know" series about the natural products industry. Designed to educate and inform consumers about key topics concerning natural products and dietary supplements, the brochures cover such topics as nutrition bars, kava and organic certification.
The first new brochure is "What you should know about dietary supplement regulation." Sponsored by the Sabinsa Corp., the brochure is designed to help retailers convey the message to consumers that the dietary supplement industry is regulated under the Dietary Supplement Health & Education Act (DSHEA), the types of labeling they will see on products and allowed claims for supplements. It includes additional resources where consumers can find further details, such as the Food and Drug Administration's (FDA) Center for Food Safety and Applied Nutrition (CFSAN) Web site (www.cfsan.fda.gov) and the Dietary Supplement Information Bureau (www.supplementinfo.org).
The second brochure, which was issued after FDA's announcement on health claims labeling, is "What you should know about health claims." NNFA's brochure lays out the different types of health claims consumers will see on the market, explains the scientific rationale behind the different claims, and explains how claims are regulated by FDA and the Federal Trade Commission (FTC).
NNFA sells the printed brochures for retailers and manufacturers to distribute, and makes available one-page fliers free of charge. The flier is also available online at www.nnfa.org/services/publications/index.htm.
NEJM Editorials Rebuke Dietary Supplement Industry
by Kim Schoenhals
A veritable bashing of the dietary supplement industry was delivered in the Dec. 19 issue of The New England Journal of Medicine (NEJM) (www.nejm.org). The gist of the three articles was that the dietary supplement industry is not well-regulated under the Dietary Supplement Health & Education Act (DSHEA), herbal remedies may pose health risks, and good manufacturing practices (GMPs) are not in place to guarantee quality assurance.
Herbal Remedies
"Herbal Remedies" (347, 25:2046-56, 2002), by Peter A.S.M. De Smet, Pharm.D., Ph.D., from The Netherlands discussed regulation, quality, safety and efficacy of herbal remedies. He began by noting herbal products, which are considered dietary supplements in the United States, are not required to meet the same regulatory standards as drugs. He added herbal products might be manufactured without quality assurance as guided by GMPs (although he stated these standards are currently being developed) and may be marketed without FDA approval of safety and/or efficacy. De Smet also commented on labeling claims for herbal products, some of which suggest they can be used to treat disease.
As for quality assurance, De Smet stated it is important to make sure herbal remedies are controlled to avoid contamination with adulterants. "For commonly used herbal remedies, the U.S. Pharmacopeial Convention is developing standards for product quality and monographs that review chemical, pharmacologic and therapeutic data," De Smet wrote. "When an herbal product is labeled, 'U.S. Pharmacopeia' or 'National Formulary,' the DSHEA requires that the product comply with the standards for product quality. Although this system may be useful to the extent that manufacturers are willing to abide by it, its voluntary nature leaves the door open for inferior products."
In his discussion of safety, De Smet stated, "Contrary to popular belief, the use of herbal remedies can pose serious health risks." Among the adverse effects of herbal remedies, De Smet listed neurotoxicity and renal toxicity as possibilities, and named ma huang and kava as possibly dangerous herbs.
On the plus side, De Smet noted that Ginkgo biloba, hawthorn, saw palmetto and St. John's wort all show promise in terms of efficacy. In terms of ginkgo, De Smet noted it has been shown in long-term, randomized, placebo-controlled trials to have positive effects in patients with Alzheimer's disease and multiinfarct dementia. As for hawthorn, De Smet stated it has shown efficacy in animal models for having "a positive inotropic action and prolongation of the effective refractory period, some vasodilating properties and increased coronary blood flow."
Saw palmetto didn't come off too badly under De Smet's microscope, as he noted the herb has been shown in clinical trials to have a superior effect to placebo for treating symptoms of mild to moderate benign prostatic hyperplasia. St. John's wort, however, didn't fare as well. De Smet stated the use of this herb and its major constituent, hyperforin, in clinical trials for mild to moderate depression may have had methodologic quality issues or publication bias. While De Smet did mention several trials in which St. John's wort proved effective, he latched on to the recent government-funded trial that demonstrated the herb was no more effective than placebo for treating major depression. And, of course, he highlighted the interactions St. John's wort has with prescription pharmaceuticals.
In conclusion, De Smet stated, "Clinicians should not prescribe or recommend herbal remedies without well-established efficacy as if they were medications that had been proved effective by rigorous study. However, these products continue to have great appeal to patients, and this reality cannot be ignored."
Herbal Medicines
"Herbal Medicines: What's in the Bottle?" (347, 25:1997-8, 2002), by Stephen Straus, M.D., of the National Center for Complementary and Alternative Medicine (NCCAM) in Bethesda, Md., opened by saying the popularity of herbal medications has caught us "in the midst of a public health experiment." Straus stated that the fact that millions of people worldwide are turning "back" to traditional herbal medicines to prevent illness is occurring "in spite of the greatest health and longevity in history in the United States and Europe." Straus stated the comments offered up by the other two articles were timely in light of this herbal trend, and that "Both articles identify serious problems with the overall quality, safety and efficacy of herbal products."
Straus' main point is that herbal medicines may not always contain what is labeled, and just because herbal products are "natural" does not make them safe. Straus pointedly mentioned PC-SPES, an herbal product touted for prostate cancer that was recently found to contain several pharmaceuticals, including diethylstilbestrol and warfarin. "What have been the reactions to reports that some herbal medicines are contaminated or toxic or that they interfere with the metabolism of drugs used to treat cancer or AIDS?" Straus posed. "Understandably, the enthusiasm of consumers for these 'natural' cures has been tempered by increasing skepticism, and sales of herbal products in the United States have actually declined during the past two years." He went on to say that the public is now seeking additional information before purchasing herbal products and that physicians are more often asking patients about their use of herbal medicine, "and we are less judgmental toward patients who use them," Straus said. "An open dialogue results in better information so that consumers can choose products according to the existing evidence, such as it is, as to which herbal products appear to be the least harmful and most helpful."
The American Botanical Council (ABC) released a statement in light of the NEJM articles, and promoted the idea of an open dialogue. "ABC welcomes the opportunity for a national dialogue on improving the regulatory environment for herbal products," said Mark Blumenthal, founder and executive director of ABC. "For many years, ABC has proposed that a special expert committee be established to evaluate the literature on herbs sold in the United States to determine their safety and benefits. The primary reasons ABC translated and published The Complete German Commission E Monographs in 1998 were to offer the public reliable guidelines for the responsible use of many of the herbs officially recognized as medicines in Germany, and also to propose a Commission E-like model for the United States."
Straus finished his article by stating that while there are challenges facing the supplement industry, herbal medicines offer research opportunities that should not be ignored. "[W]e have not yet surveyed all of nature for its healing potential," he wrote. "However, both the quality of the data and the quality of the herbal products themselves must improve greatly if herbal medicines are to assume a respected place in the contemporary health care arena."
Botanical Medicines
"Botanical Medicines: The Need for New Regulations" (347, 25:2073-6, 2002), by Donald M. Marcus, M.D., of Baylor College of Medicine in Houston and Arthur P. Grollman, M.D., of the State University of New York in Stony Brook, addressed DSHEA, saying the supplement industry needs new regulations. "By broadly defining herbs and other botanicals as 'dietary supplements,' DSHEA substantially altered the definitions, standards and mechanisms under which claims about the effectiveness and safety of these products are evaluated and enforced," Marcus and Grollman wrote. "This classification, which we believe to be inappropriate, has resulted in a serious and growing public health problem."
Marcus and Grollman suggest the industry suffers a lack of standardization. "Consistency in composition and biologic activity are essential requirements for the safe and effective use of therapeutic agents," they wrote. "However, botanical preparations rarely meet this standard, as a result of problems in identifying plants, genetic variability, variable growing conditions, differences in harvesting procedure and processing of extracts, and above all, the lack of information about active pharmacologic principles."
In terms of supplement safety, Marcus and Grollman noted pre-market safety testing is not required for supplements, and there is no mandatory requirement for manufacturers to record, investigate or forward adverse event reports to FDA. However, they also noted that while drug manufacturers are required to forward adverse event reports to the FDA, only an estimated 10 percent of serious adverse events associated with pharmaceuticals are actually reported to FDA. "The lack of reporting of adverse events to the FDA has generated concern at the level of the federal Office of the Inspector General," Marcus and Grollman wrote. "The Inspector General's report estimates that less than 1 percent of adverse events caused by dietary supplements, including herbs, are reported to FDA. Only a fraction of these are adequately investigated."
In their discussion of current regulations for the industry, Marcus and Grollman chastised the passage of DSHEA. "The Food and Drug Acts passed in the 20th century, which provided important protection to the public, were subverted by the passage of the DSHEA. This misguided legislation freed the dietary supplement industry from effective oversight by the FDA, transferring the burden of proof for establishing the safety of herbal medicines from the manufacturer to the FDA." Marcus and Grollman claim FDA is "hindered" in promptly removing dangerous products, as exemplified by the case of ephedra. The authors claimed the U.S. public supports the idea of new rules for the industry that would require FDA to review the safety of new supplements before they go to market and would regulate advertising claims regarding health benefits. In order to accomplish the new rules and regulations, Marcus and Grollman outlined six legislative proposals would be needed:
1) All companies involved in manufacturing dietary supplements would register their address and phone number with FDA. This will actually be required as of December 2003 as part of the Bioterrorism Preparedness Act of 2002.
2) Manufacturers should provide evidence of GMPs and FDA should be given authority to inspect the manufacturers' records. Marcus and Grollman claim the botanical industry has "consistently blocked such a proposal." Michael McGuffin, president of the American Herbal Products Association (AHPA), stated, "That is not true. We have worked hard to try to get FDA to get dietary supplement GMPs in place. Now, the other implication of this paragraph is that in the meantime there are no GMPs that govern our class of goods, and that is not true either. FDA has stated to us in writing that until such time as there are dietary supplement GMPs, manufacturers of dietary supplements are required to conform to food GMPs."
3) Manufacturers should obtain pre-marketing approval from FDA by demonstrating product safety. In response to this comment, Blumenthal noted under current federal law, all new dietary ingredients--including herbs and other supplements that are introduced into the United States after October 1994--do require FDA approval of safety data supplied by the company before a product can be sold. "Under the current situation, pre-market approval on safety and claims for herbal products is untenable," Blumenthal said. He added, "Despite the potential benefits for a scientific review of the safety and efficacy of popular herbs, it is clearly not in the interests of the American consumer for the FDA to take seven to eight years to review and approve the OTC drug status of herbs when other Western industrialized nations have already done so."
4) Manufacturers should be required to report all adverse events to FDA. "AHPA has taken the position that reports of serious adverse effects should be required to be forwarded to FDA by manufacturers of dietary supplements and manufacturers of OTC drugs," McGuffin said. "That's already required for manufacturers of prescription drugs, but not generally for OTC drugs. The position we've taken is that it should be required for all of these classes, and I believe we went so far as to say also for foods. We also proposed that all of that information be readily accessible to consumers."
5) Labeling should identify herbs by their botanical and common names (which the authors failed to note is already required by FDA).
6) The Department of Health and Human Services should organize expert panels to review the safety of all dietary supplements, except for essential nutrients and single-vitamin and multivitamin preparations.
The Council for Responsible Nutrition released a statement regarding the suggestion that the dietary supplement industry needs new regulations. "It is the responsibility of every company to ensure product quality, to provide accurate and fully informative labeling, to have evidence supporting safety, and to substantiate all claims," said Annette Dickinson, Ph.D., CRN's vice president of scientific and regulatory affairs. "A company that fails to fulfill these responsibilities is not only misleading consumers but is engaging in unfair business practices to the detriment of the entire industry. Just as importantly, it is the responsibility of FDA to go after those companies that are not complying with the law. We do not need to create new laws or regulations. We need the regulators to reign in companies that are not abiding by DSHEA." Dickinson added that the issues raised by the NEJM articles can be effectively addressed by strengthening the implementation of DSHEA.
McGuffin added, "It is obvious that these articles were not reviewed by regulatory experts. These articles clearly show that NEJM has abdicated any sense of responsibility to conduct peer analysis on issues related to regulation. The article by the two doctors is so filled with errors, misrepresentations and distortions that any qualified reviewer who knows the regulations would have objected to it being published as is."