REGULATION OF DIETARY SUPPLEMENTS

 

Public Policy Debate between Liberty and Regulation

·       The issues to be decided include:

·       Should health claims be allowed for herbs and dietary supplements?

·       If yes, what level of evidence should be required?

·       Animal data?

·       Epidemiologic data?

·       Laboratory data?

·       Controlled trials?

·       The ideal system is absolute proof of safety and efficacy, as for prescription drugs, but this is impractical because the cost of bringing an herb to market would likely be $100 million to $200 million, and these costs cannot be recovered by the manufacturer because herbs are natural products and thus cannot be patented. (The estimated cost and time for developing a new drug is approximately $231 million and 12 years, according to a 1990 report by the Center for the Study of Drug Development at Tufts University).

 

Current U.S. System of Regulation (it doesn't work)

·       Absolute proof of safety and efficacy is required for placing a therapeutic claim on the label, but any herb can be sold over the counter if the label does not include any therapeutic claims.

·       There is no quality control of herbs sold over the counter.

·       There is no requirement to identify herbs by Latin binomial, and a number of common names for herbs such as yellowroot and snakeroot do NOT correspond to a single species of herb.

·       Dr. Varro Tyler, author of Herbs of Choice says that while Americans spent 1.13 billion dollars on herbs in 1993, the American public is "wallowing in ignorance."

 

Current German System of Regulation (it works)

·       Herbs are licensed and regulated as medicine, but while absolute proof of safety is required for marketing, only reasonable proof of efficacy is required (Varro Tyler points out that while traditional use should be one of the criteria in determining reasonable proof of efficacy, traditional use alone is not necessarily reasonable proof of efficacy)

·       Information on each licensed herb is published in a series of monographs which contain concise information about terminology, composition, uses, contraindications, side effects, drug interactions, dosage, mode of administration, and actions of the herb. These monographs are prepared by the German E Commission, formed in 1978 by the German government. A group of experts reviewed all available literature for each herb, both scientific and anecdotal. There are approximately 200 licensed herbs in Germany, based on this review.

·       The system encourages research because even though no patent is available, a positive study allows for a therapeutic claim, so that companies can recoup their costs.  Research costs are manageable because of the standard of reasonable proof of efficacy instead of absolute proof of efficacy.

·       There are also approximately 100 negative monographs explaining insufficient benefits or unacceptable risks for these herbs.

·       France, Sweden, and Australia have implemented similar strategies for licensing herbal remedies, and the European Commission, which governs all countries in the European Union, has introduced a draft directive which would implement a system similar to the German system for all member countries of the European Union.

·       The European Union (EU) issued a Traditional Herbal Medicinal Products Directive in 2004 –this established a regulatory process requiring herbal medicinal products to obtain authorization for marketing in the EU. The authorization process requires evidence of safety and scientific support for health claims.

 

Brief History of U.S. Regulation of Drugs and Herbs - liberty versus regulation (Tyler V. Herbs of Choice. 1994. Chapter 2; Hamburg MA. Innovation, Regulation, and the FDA. N Engl J Med.  2010. 363. 2228-2232).

·       1804 - isolation of the first modern drug, morphine, from the opium poppy.  Over the next 200 years, numerous other pharmaceutical drugs have been derived from plants, including atropine, colchicine, digoxin, quinidine, pilocarpine, reserpine, theophylline.

·       1820 - publication of first United States Pharmacopoeia. Many herbal products included.  In the 1930's most herbal products were dropped due to a general lack of use.

·       1906 – Pure Food and Drugs Act passed by Congress. This Act in conjunction with a 1912 amendment put an end to the widespread fraudulent practices of misbranding and adulteration of drugs, but did NOT effectively address the problems of drug safety and efficacy. The act specifically prohibited interstate commerce in adulterated or misbranded drugs and foods

·       1938 - Congress enacted the Food, Drug, and Cosmetic Act (FDC Act), creating the FDA and requiring some evidence of safety before a drug could be marketed.  The act stated that the drug must be safe for use as labelled, with safety data from the manufacturer submitted to the FDA prior to approval. This was prompted by a catastrophe in 1937 at which time 105 people died from acute kidney failure as a result of consuming a product consisting of 8.8% sulfanilimide and 72% diethylene glycol (DEG). Toxicity testing was not done prior to bringing this product to market, so it was not know until many individuals died that DEG was a poison (JAMA. 1937. 109. 1531-1539).

·       As an aside, the chief architect of this bill in the Senate was Dr. Royal Copeland, who was a homeopathically trained physician, and by defining drugs in this Act as “articles” recognized in “official compendia,” which included the Homeopathic Pharmacopeia of the United States, homeopathic remedies were placed into the same regulatory category as prescription and OTC drugs (Robins, Natalie. Copeland’s Cure: Homeopathy and the War Between Conventional and Alternative Medicine. Knopf. 2005).

·       Drugs already on the market were grandfathered

·       1962 – Congress passed the Kefauver-Harris amendment to the Food, Drug, and Cosmetic Act.  The FDA began to require adequate and well-controlled studies” to prove safety and efficacy of prescription drugs. This amendment was prompted by the deaths and birth defects in Europe attributed to use of thalidomide in pregnancy. This legislation also stipulated that drug manufacturers must report all adverse events to the FDA.  The loophole in this legislation was that herbs could still be sold without proof of safety or efficacy, as long as there were no therapeutic claims on the label. 

·       Historical note – legislation was proposed in advance of the issues with thalidomide, and initial legislation included a requirement of superior comparative effectiveness for “me-too” drugs. The entire bill died, and then was resurrected after the issues with thalidomide (Perspective: History of Medicine. N Engl J Med. 2012. 367. 1481-1483).

·       A National Academy of Sciences panel reviewed the ‘evidence’ of effectiveness which was required to be submitted to the FDA for all drugs approved prior to 1962. The academy found that 70% of the claims it reviewed could not be substantiated; almost 1/3 of all marketed drugs lacked even a single effective use and were removed from the market (Drug Efficacy Study: A Report to the Commissioner of Food and Drugs from the National Academy of Sciences. 1969).

·       OTC drugs approved between 1938 and 1962 were not covered by this legislation, but the commissioner of the FDA made a decision to retroactively apply these standards to OTC drugs approved before 1962. 

·       The Drug Efficacy Study was conducted by the FDA in conjunction with the National Research Council of the National Academy of Sciences. 

·       After a long series of preliminary investigations, in 1972, 17 panels of experts began to review the efficacy data on thousands of preparations of OTC drugs.

·       Herbs were classified at this time as OTC drugs, and the FDA declared that any grandfathered drug would be considered misbranded if any claims of efficacy were made on the label which were not in accordance with the findings of one of the 17 OTC drug evaluation panels.

·       Results of the FDA review of OTC drugs were not released until 1990. A few herbs were placed in category I (effective), including senna leaf and cascara bark, but 142 OTC drugs were placed in category II (ineffective) and another 116 OTC drugs were placed in category III (insufficient evidence). This method was arbitrary and not always accurate, as a long history of folk use was not considered a form of evidence.

·       1990 - Congress passed the Nutritional Labelling and Education Act (NLEA), an amendment to the Food, Drug, and Cosmetic Act, to provide the FDA with direction with regard to the regulation of dietary supplements.

·       New dietary supplements were to be regulated either as food or drugs, depending on their intended use. 

·       Supplements classified as food were subject to the food additive provisions of the FTC act, and supplements classified as a drug would need to go through an extensive and expensive pre-market approval process known as a new drug application. 

·       NLEA limited health claims for food and supplement labelling to seven categories: 1) calcium and osteoporosis, 2) sodium and hypertension, 3) saturated fat and cholesterol and heart disease, 4) dietary fat and cancer, 5) fiber-containing grain products and cancer, 6) fruits, vegetables and cancer, 7) fiber containing grain products, fruits, vegetables and heart disease.

·       Supplements marketed prior to 1990 were subject to the above categorization released in 1990 and an outcome of the process which was initiated in 1972.  Many of the herbs placed in categories II or III above continued to be marketed, but as foods, without any dose or suggested use on the label, to comply with the 1972 FDA ruling regarding misbranding.

·       1994 - Congress passed the Dietary Supplement Health Education Act (DSHEA), an amendment to the Food, Drug, and Cosmetic Act, based on many congressmen and many Americans feeling that the FDA response to NLEA was overzealous, placing excessive restrictions on claims made for dietary supplements. 

·       Part of the impetus for DSHEA was an embargo in California of ships carrying black currant seed oil capsules because the capsules (a supplement) were considered a food additive, and thus subject to NLEA pre-marketing demonstration of safety regulations. 

·       There was tremendous grassroots advocacy for DSHEA in the form it was passed, with an estimated 2 million supportive letters to Congress. 

·       Prior to the passage of this law, there was concern regarding some versions of the proposed new legislation that consumer access to almost all dietary supplements would be blocked (i.e. need a prescription to purchase vitamin E 400 IU).

·       A consequence of the passage of DSHEA is an explosion of the number of dietary supplements on the market in the US (from approximately 4000 in 1994 to approximately 75,000 in 2008).

·       This law called for the establishment of GMPs for dietary supplements – the FDA finally issued these regulations in 6/07 – for more details scroll down to ‘Quality.’

·       2006 – Congress passed the Dietary Supplement and Nonprescription Drug Consumer Protection Act, which will go into effect 12/07. The bipartisan legislation was supported by the dietary supplement industry (i.e. Council for Responsible Nutrition), consumer advocates (i.e. Consumers Union), and the American Medical Association. For the provisions of this act, scroll down to ‘Safety’ in this outline.

·       REGULATORY SCIENCE is defined as the science of the assessment and evaluation of the safety, effectiveness, potency, quality, and performance of a product

 

DSHEA (Public Law 103-417) Specifications: Note that physician knowledge of dietary supplement regulation and adverse event reporting is poor (Arch Intern Med. 2007. 167. 966-969)

 

Definitions

·       Dietary supplement is defined as “ a product (other than tobacco) intended to supplement the diet that bears one or more of the following dietary ingredients:

·       vitamin;

·       mineral;

·       herb or other botanical (botanical is defined as a plant or plant part valued for its medicinal or therapeutic properties, flavour and/or scent);

·       amino acid;

·       dietary substance for use by man to supplement the diet by increasing the total dietary intake; or

·       concentrate, metabolite, constituent, extract, or combination of any ingredient described above (i.e. enzymes, glandulars)

 It is a product that:

·       is intended for ingestion (as opposed to parenteral administration);

·       is not represented for use as a conventional food or as a sole item of a meal or the diet; and

It is labelled as a dietary supplement.

·       For the complete definition, go to www.fda.gov/opacom/laws/dshea

·       Dosage forms of dietary supplements include capsules, tablets, liquids, gels or powders.

·       Certain hormones such as DHEA and melatonin are regulated as dietary supplements and not prescription drugs.

·       Dietary supplements are clearly distinguished from food additives; food additives are subject to much stricter regulation (i.e. pre-marketing demonstration of safety).

 

Labelling

·       As part of an ongoing process at the FDA as a result of this 1994 legislation, the actual specific regulations for supplement labels were issued 3/23/99, following publication in 11/97 of recommendations of the President’s Commission on Dietary Supplement Labels. However, the FDA at that time only had 5 staff members devoted to monitoring and enforcing the provisions listed below.

·       The "Honest Label" section of this legislation states that the label on dietary supplements must include:

·       Name of product, including the word supplement.

·       Net quantity of contents

·       Name and place of business of manufacturer

·       Directions for use, including a suggested dose

·       Name and amount of each ingredient

·       Identity of any part of the plant from which a botanical ingredient is derived.

·       List of all nondietary ingredients such as fillers, artificial colors, sweeteners, flavors, and binders.

·       Supplement facts panel.

·       Manufacturers can place "structure/function" claims on the label, as long as the label includes the disclaimer that the FDA has not evaluated the claim.  The structure/function claims do need to be registered with the FDA, but the FDA does not evaluate these claims unless a problem arises.

·       DSHEA states that the manufacturer is responsible for the truthfulness of claims made on the label, and must have evidence that the claims are supported, but does not provide a standard for the evidence needed.

·       The FDA can require a manufacturer to change a label if the FDA decides that there is not evidence to support the claim on the label.

·       If the FDA determines that a dietary supplement is mislabelled or adulterated, the supplement can be removed from the market without the burden of the FDA proving lack of safety.  The definition of “adulterated” in the legislation is a broad definition (for details, see Herbalgram. 1996, 38. 25)

·       Many types of literature were removed from the definition of labelling. Thus even though manufacturers cannot place therapeutic claims on the label, health food stores could make promotional literature available to their customers as long as the publication is reprinted in its entirety.

·       In order to place a therapeutic claim (i.e. claim of effectiveness for the prevention or treatment of a specific disease) on the label of a dietary supplement, manufacturers must show "significant scientific agreement."  

·       The exact meaning of “significant scientific agreement” is unclear, but in general the requirements for a therapeutic claim are data of safety and efficacy “beyond a reasonable doubt.” 

·       Specifically, two positive RCTs are usually required (the FDA is not necessarily dissuaded from approving a therapeutic claim by additional negative RCTs – for example, Paxil was approved for depression based on 2 positive trials and 7 negative trials). 

·       Manufacturers who petition the FDA usually are informed within 120 days as to whether the therapeutic label claim has been approved or denied.

·       As of 2002, only 6 health claims have been approved for use on either food or dietary supplement labels - calcium for osteoporosis, folate for neural tube defects, sugar alcohol for cavities, and oat fiber 3 grams, psyllium seed fiber 7 grams, and soy protein 25 grams for coronary heart disease.

 

Advertising

·       This falls under the oversight of the Federal Trade Commission (FTC), not the FDA.

·       The FTC tends to use a standard of ‘reasonable basis’ in evaluating truth of advertised claims, whereas the FDA tends to use a ‘beyond reasonable doubt’ standard in deciding whether to approve a therapeutic label claim.  For example, even in the absence of clinical trials for a product, testimonials with a disclaimer that ‘results may vary’ may be satisfactory from the standpoint of the FTC.

·       The FTC can order companies to provide documentation to support claims and can order products off the market if it decides that substantiation is not sufficient.

·       FTC maintains a consumer hotline (1-877-FTC-HELP) and online complaint form, www.ftc.gov/ftc/complaint.  HOWEVER, resources at the FTC are limited too. The FTC tends to focus on potentially dangerous products in terms of scrutiny of the content of print or media advertising.

·       Online sources of herbal product information

  • Despite regulations prohibiting specific disease claims, a search of the internet using the 5 most common search engines and the names of the 8 most widely used herbal supplements located 443 web sites that met the inclusion criteria for a study.  In this study, 81% of the 338 retail web sites made one or more disease claims, and 52% of the sites with a health claim omitted the standard federal disclaimer. Only 12% of the 443 sites provided referenced information (JAMA. 2003. 290. 1505-1509). Critique of the article – unclear how many of the “health claims” were merely references to the results of published studies.
  • An online search of 13 common herbals, reviewing the top 50 Web sites for each using a Google search (a total of 1179 web sites were examined) showed that “Less than 8% of the retail sites provided information regarding potential adverse effects, drug interactions, and other safety information; only 10.5% recommended consultation with a healthcare professional. Less than 3% cited scientific literature to accompany their claims.” The conclusion in the abstract is “Key safety information is still lacking from many online sources of herbal information.” (Am J Med. 2014. 127. 1090115).

    

Quality

·       1994 DSHEA legislation called for the establishment of GMP’s for dietary supplements, to be modelled after GMP’s for food as opposed to modelled after GMP’s for drugs. Until these GMPs were established (in 2007), manufacturers of supplements needed only to meet FDA GMP’s for foods.

·       In 1999, the FDA held public meetings and published an advance notice of the proposed rule to establish GMP’s.

·       The FDA finally on March 7, 2003 issued a proposed rule to establish good manufacturing practices for dietary supplements.  This 547 page document was published in the Federal Register 3/13/03.  These will be less stringent in several ways than GMP’s for pharmaceutical products.  Public comment on the proposed GMP’s ended 8/11/03.

·       The OMB in Congress was concerned about the impact of these regulations on small businesses, and spent much time studying this issue, further delaying the final rule until 6/22/07.

·       The final rule itself, issued 6/22/07, is 814 pages, and published in the Federal Register, is posted at http://www.fda.gov/OHRMS/DOCKETS/98fr/cf0441.pdf.

·       To limit any disruption for dietary supplements produced by small businesses, the rule has a three-year phase-in for small businesses. Companies with more than 500 employees have until June 2008 to comply, companies with less than 500 employees have until June 2009 to comply, and companies with fewer than 20 employees have until June 2010 to comply with the regulations.

·       Now that GMP’s are established, the next issue will be staffing and funding for the FDA to enforce them.  FDA priorities (appropriately) are:

  • Public health emergencies and products which may have caused injury or illness.
  • Fraudulent or illegal products.
  • Finished product analysis.

 

Safety

·       As per DSHEA, manufacturers must notify the Secretary of Health and Human Services within 30 days after marketing a new dietary supplement (supplements on the market before 10/15/94 grandfathered). 

·       The notification must include submission of evidence supporting “a reasonable expectation of safety.”

·       The FDA may then choose to review safety data, and may ban the product from the market if it determines that there is inadequate safety data.  However, there is no prior approval necessary from the FDA in terms of a company bringing a new dietary supplement to market – the manufacturing company is responsible for the safety of the product.

·       Guidelines are provided regarding what constitutes an unsafe product. The burden of proof is on the FDA to show lack of safety. Part of the FDA judgement is to be based on labelling (i.e. warnings on label).

·       At the time DSHEA was passed, there were an estimated 4000 distinct dietary supplements on the market in the US; in 2011 there are an estimated 55,000. Not all of the estimated 51,000 new dietary supplements on the market include novel ingredients, but FDA has received adequate notification for only 170 dietary supplement ingredients since 1994 (Perspective. N Engl J Med. 2012. 366. 389-391).

·       This legislation does NOT prohibit manufacturers from including extensive safety information on the label, and the American Botanical Council has piloted a project in conjunction with Nature’s Resources in which a peel back label on the supplement container lists extensive safety information.

·       This legislation hinders the FDA from promptly removing potentially dangerous products, especially for those products in commerce in the U.S. prior to the passage of DSHEA.

·       Dietary Supplement and Nonprescription Drug Consumer Protection Act provisions (AMA News. 1/15/07. 5-6).

  • Requires manufacturers and distributors of dietary supplements and non-prescription drugs to report serious adverse events to the FDA within 15 business days, using the FDA MedWatch system.
  • Serious adverse events defined as an event resulting in death, a life-threatening experience, inpatient hospitalization, a persistent or significant disability or incapacity, a congenital anomaly or birth defect, or a medical treatment to prevent any of these outcomes.
  • Requires any supplement or non-prescription drug to have on the label a U.S. address or phone number to which consumers can report adverse events.
  • Allows the general public to report and access information through the FDA’s MedWatch system.
  • Specifies that the submission of any adverse event report is not an admission that the drug or supplement contributed to the adverse event.

·       FDA in 7/11 issued “Draft Guidance for Industry: dietary supplements: new dietary ingredient notifications and related issues”

  • As per this draft, the safety of supplements would be evaluated according to 3 key factors: documented history of use, formulation, and proposed daily dose
  • For products intended to be ingested at doses higher than historically ingested, the FDA would rquire in vitro, animal, and long term tolerability testing
  • The guidance would specify that any ingredient prepared or formulated in a novel manner would be considered a new ingredient.
  • Some believe that these regulations do not go far enough, and suggest requiring experimental data even for substances intended to be ingested at doses similar to those used historically, suggest a requirement for human data on tolerability for new ingredients, and suggest a requirement that all data (favourable and unfavourable) be submitted to the FDA (Perspective. N Engl J Med. 2012. 366. 389-391).
  • Industry and some users of supplements have protested that this guidance is too stringent and will restrict consumer choice because companies will not be able to afford to bring many novel ingredients to market. As of January 2012, FDA has received 146,000 pages of comments arguing that the guidance is overly stringent.

·       NOTE that by means of comparison, legislation to assure prescription drug safety has been suboptimal, especially prior to the passage of FDAAA on 9/27/07. Prior to this, when the FDA did obtain new data about a drug’s risks, it had no authority to order a change in labelling. Key drug safety provisions of the FDAAA are as follows (N Engl J Med. 2007. 357. 2117-2119):

  • FDA given the authority to require postmarketing studies, order changes in a drugs label, and restrict distribution of a drug.
  • FDA provided $225 million funding over 5 years, to be devoted to enhancing drug safety.
  • Modernization of the Adverse Event Reporting System and access to large government and private databases on adverse drug reactions
  • Escalation of the status of the drug safety group within the beaurocracy of the FDA.

 

Research, compilation and dissemination of information on dietary supplements

·       DSHEA legislation required the establishment of the Office of Dietary Supplements (ODS) at the National Institutes of Health to disseminate information on NIH funded research.

·       The ODS budget has increased from $1 million in 1996 to $25 million in 2004.

·       The ODS IBIDS database currently contains over 690,000 unique scientific citations and abstracts.

·       The ODS exhibits at national meetings such as the Annual Session of the ACP.

·       The ODS in collaboration with other NIH Institutes and Centers funds six research centers that focus on botanical ingredients used in dietary supplements. ODS often partners with NCCAM.

·       ODS sponsors evidence-based reviews of dietary supplements.

·       ODS sponsors conferences and workshops.

·       ODS publishes an annual bibliography of significant advances in dietary supplement research.

·       ODS has developed a series of fact sheets on vitamins, minerals, and botanicals.

 

The story of ephedra (Holistic Primary Care. Spring 2004)

·       Ephedra (also known as ma huang) has a long (5000 year) history of safe use in Traditional Chinese Medicine (TCM), in combination with other plants to treat respiratory conditions.  Ephedra was approved by the German Commission E for treatment of diseases of the respiratory tract.

·       The alkaloid ephedrine was first isolated from ephedra in 1887 – it is a mixed sympathomimetic amine with norepinephrine(adrenalin)-like effects on hypothalamic satiety (sense of fullness after eating) centers in the brain.

·       Ephedrine has been used in the U.S. since the 1930’s in over-the-counter cold medicines; it was not promoted as a weight-loss aide until the early 1990’s.

·       Ephedra has been under FDA scrutiny since 1994 when a cluster of 200 adverse events associated with an ephedra product was reported in Texas.

·       The FDA convened a meeting in 10/95 in response to more than 300 adverse event reports.  The working group found sufficient evidence that the reported adverse events were associated with the use of ephedrine alkaloids and recommended that safe levels be established and that warning labels appear on the products.

·       At this time, the FDA accepted the 1994 American Herbal Products Association (AHPA)"25/100" guideline which suggested that a single dose of 25 mg and a maximum daily intake of 100 mg would safeguard against adverse events. 

·       In 8/96, at which time the number of adverse events reported to the FDA had doubled to more than 600, the FDA convened another meeting to examine safety of ephedrine-containing foods and supplements.  This led in 1997 to an FDA proposed rule of a dosage limit of 8 mg ephedrine alkaloid per serving, a daily limit of 24 mg per day, and a duration limit of 7 consecutive days of use.

·       In 7/99 the GAO reported that the FDA had insufficient evidence to support the dosage and duration limits – in 2000 the FDA withdrew a large part of the 1997 proposal.

·       Sales of ephedra reached an estimated 3 billion doses per year in the late 1999, based on a year 2000 survey conducted by the manufacturers of ephedra-containing supplement products.  Use of the supplement was primarily for weight loss and enhancement of athletic performance

·       In 2000, an Arthur Anderson survey commissioned by herbal trade associations showed that adverse event rates were declining despite rising ephedra sales, suggesting that the better public education on dosage recommendations was at least partly effective.

·       In 2001 the non-profit group Public Citizen filed a petition asking the FDA to ban production and sale of ephedra products.

·       The New York Times reported 8/16/02 that 13,000 complaints had been registered with the manufacturer of Metabolife 356, a product containing ephedra, caffeine, and several herbs, and these reports include several hundred hospitalizations and 80 incidents of serious injury or death, but the manufacturer as per DSHEA regulations was under no obligation to forward these reports to the FDA, and did not do so. A report published in 2004 provides a plausible mechanism for harm from Metabolife - ingestion of Metabolife 356, a botanical combination product containing 20 mg ephedra per dose, produced measurable changes in heart rate, blood pressure, and QT intervals on EKG at 1, 3, and 5 hours post ingestion (JAMA. 2004. 291. 216-221).

·       As all of this data became available, the FDA requested the Justice Department to initiate a criminal investigation of the manufacturer of Metabolife because of false statements that claim an absence of adverse effects, but did not propose to ban the product, leaving it available in the U.S. for purchase over the counter.

·       In contrast, Canadian health authorities requested a voluntary recall of ephedra containing products, similar to the recent recall in the U.S. of phenylpropanolamine products after a published report showed dangers.

·       As of 2003, approximately 1500 adverse reactions related to ephedra had been reported to the FDA.  However, at a conference on obesity sponsored by the Food and Drug Law Institute, Dr. Johanna Dwyer of the NIH Office of Dietary Supplements acknowledged that only approximately 150 of the adverse events were well documented in the medical literature (Holistic Primary Care. Spring 2004).

·       A study published in 2003 found that although ephedra products represent less than 1% of all herbs sold in this country, they account for 64% of all adverse reactions reported to the FDA (Ann Intern Med. 2003. 138. 468-471).

·       Another study published in 2003 reported based on a meta-analysis of 52 controlled trials and 65 case reports that at doses of only 60-80 mg per day, products containing ephedra or ephedrine alone or in combination with caffeine produced a 2-3 fold greater risk of nausea, vomiting, psychiatric symptoms, and autonomic hyperactivity, compared with placebo (JAMA. 2003. 289. 1537-1545).

·       In the meantime, based on 2001 Congressional appropriations, The FDA had commissioned an evidence report from the RAND Corporation, an independent, non-profit, scientific institute. The RAND report, released 2/28/03, found based on a comprehensive literature review and a subsequent synthesis of the literature:

·       Based on data from 20 trials of reasonable quality and including 678 subjects, there is evidence for effectiveness of ephedra in achieving weight loss of 2 pounds per month more than placebo for up to 4-6 months.  Contrast this with a statement from New York State Health Commissioner Dr. Antonia Novello published in MSSNY News of New York 4/04 that “All Americans deserve to know the truth about ephedra and its false and misleading promises of weight loss and performance enhancement.”

·       Based on data from 7 trials there is data to support a modest effect of ephedrine plus caffeine on very short term athletic performance.

·       Controlled trial data shows an association of ephedra use with a 2-3 fold increased risk of nausea, vomiting, psychiatric symptoms, autonomic hyperactivity, and palpitations.

·       The majority of case reports were insufficiently documented to make an informed judgement about the relationship between ephedra consumption and adverse events.  Nonetheless 43 possible sentinel events were identified, along with 22 sentinel events - 2 deaths, 3 heart attacks, 9 strokes, 3 seizures, and 5 psychiatric cases. A sentinel event does not prove causality, but only indicates that there is a probable causal relationship.  Contrast these statistics with a statement in MSSNY News of New York 4/04 that “ephedra has been linked to 155 deaths and dozens of heart attacks and strokes.”

·       Half of the sentinel events occurred in individuals under age 30.

·       There was a trend toward a higher risk of adverse events with higher doses of ephedrine.

·       On 2/28/03, coinciding with the release of the RAND report, the FDA proposed new regulations with strong warnings for the labelling of ephedra supplements.  In the 3/5/03 Federal Register the FDA published a notice reopening the comment period for 30 days on its proposed additions to the1997 proposed rule.

·       The death of Baltimore Orioles pitcher Steve Bechler in 3/03 led to consumer advocacy groups and various professional organizations such as the AMA and AHA and AAFP calling for a ban.  The media focused on this and not on the specifics of the recently released RAND report.

·       New York, Illinois, and California passed their own state bans.

·       Ephedra sales decreased with all this bad publicity, but despite the bad publicity, the Nutrition Business Journal estimated $500 million in ephedra sales in 2003, down from $1.3 billion in 2002.

·       The FDA announced a consumer alert on December 30, 2003, indicating the intention to ban ephedra.

·       According to Mark Blumenthal, Executive Director of the American Botanical Council, availability of ephedra for purchase dropped dramatically after the announcement of the ban because manufacturers and companies marketing ephedra products had much difficulty purchasing liability insurance.

·       The final rule regarding the ban of ephedra was published on 2/6/04, and became effective 4/11/04.

·       This was the first time since the passage of DSHEA in 1994 that the FDA has actually taken action to ban a dietary supplement.

·       The ban is on ephedra in weight loss products, which should still allow for the use of ephedra in TCM combination products for treatment of respiratory conditions, since TCM products are regulated as foods.

·       Many supplement companies are now promoting the herb Bitter Orange (Citrus aurantium) as a substitute for ephedra in weight loss products.  This herb contains synephrine, a sympathomimetic amine which can induce weight loss by increasing basal metabolic rate (thermogenesis).  It is controversial as to whether this supplement is safer than ephedra – some argue that it is safer because of a phenomenon known as “selective binding.”    Senator Charles Schumer (D-N.Y.) in early 2004 sent a strongly worded letter to the Commissioner of the FDA requesting immediate action for the removal of these products from the market (Internal Medicine News. 3/1/04).

·       On 4/14/05 a federal judge struck down the year old ban, allowing the marketing of doses of less than 10 mg, based on DSHEA and the fact that the proof of danger is for doses greater than 10 mg.

 

The androstenedione story – since this supplement was not marketed in the U.S. prior to 1994 and thus not “grandfathered,” the FDA was able to ban it in March, 2004 on the basis of the inability of manufacturers to prove safety.

 

Recognize that while DSHEA is a significant step forward from NLEA in terms of allowing the manufacturer and/or seller to provide the consumer with meaningful information on dose and uses, the current regulations do NOT guarantee safety. 

·       Nonetheless, Jane Henney, MD, a past FDA Commissioner, in testimony before the U.S. House of Representatives on 3/25/99, stated “FDA has tools at its disposal to take enforcement actions against dietary supplements found to have safety, labeling, or other violations of the FD&C Act, as amended by DSHEA…also believe DSHEA provides FDA with the necessary legal authority to protect the public health.”

·       Nonetheless, Stephen McNamara, in an article in Herbalgram concludes “… as documented above in this article, it appears that the FDA has substantial and sufficient regulatory authority to protect the American public from any dangerous or otherwise unsafe herbs or other dietary ingredients in dietary supplements despite statements to the contrary by FDA officials” (Herbalgram. 1996. 38. 25).

·       Regarding consumer access to supplements and scientific information about supplements, Congress noted in the “findings” section of DSHEA that “consumers should be empowered to make choices about preventive health care programs based on data from scientific studies of health benefits related to particular dietary supplements.”


 

Legislative proposals to address safety and quality concerns without denying consumers access to dietary supplements (N Engl J Med. 2002. 347. 2046-2056).

·       The address and telephone number of all companies involved in manufacturing dietary supplements for sale in the U.S. should be registered with the FDA.  Now required as part of the Bioterrorism Act passed after 9/11/01.

·       Manufacturers of dietary supplements should provide evidence of good manufacturing practices.  No new legislation required; final rule due soon in Federal Register.

·       Manufacturers of dietary supplements should obtain premarketing approval from the FDA by demonstrating data on safety. The burden of proof of safety should be shifted from the FDA to the manufacturer.

·       Manufacturers of dietary supplements should be required to report all adverse events promptly to the FDA.

·       Dietary supplement labels should be required to contain a list of constituents that identifies herbs by their botanical and common name, and information on possible adverse effects and herb-drug interactions. Partially addressed in new regulation issued by FDA 8/28/03.

·       The Department of HHS should organize expert panels to review the safety of all dietary supplements, with the process modelled after the National Academy of Sciences Drug Efficacy Study, which evaluated the safety and efficacy of 4000 drugs.

 

Additional legislative issues

·       Legislation to allow a therapeutic claim based on data from a well designed randomized, controlled trial rather than requiring “significant scientific agreement.”  This would encourage manufacturing companies to perform and publish good quality research.

·       Amend DSHEA such that dietary supplement GMP’s may be modelled after both food and drug GMP’s, not just food GMP’s.

·       Regulate hormones such as melatonin and DHEA as drugs, not dietary supplements (i.e. a prescription required to purchase).

 

Self Regulation

·       American Herbal Products Association (www.ahpa.org)

·       Trade association, founded in 1983, that provides guidance to its members with regard to issues of safety and quality, in order to promote the responsible commerce of products.

·       Published Herbs of Commerce in 1992 as self-governing guidance for its members to reduce confusion in labelling botanical ingredients.  This document was incorporated into the FDA labelling regulations as first formulated in 1997 and issued in 1999. Second edition of Herbs of Commerce published in 2000.  Second edition includes 2048 separate species of plants, including 1500 added since publication of the first edition.  A “standardized common name” is established for each herb, and this nomenclature replaces the Latin name.  The FDA published a final rule in the Federal Register on 8/28/03 to amend regulations on labelling of dietary supplements to include the second edition.  This new rule does not become effective until 1/1/06.

·       Published Botanical Safety Handbook (BSH) in 1997.  This book provides information on safety and toxicity of herbs, with an explicit classification scheme (classes 1,2,3, and 4) based on available safety data.  Information in the book comes from expert herbalists and naturopathic practitioners. Relative risks of herbs available in American commerce is based upon expert opinion and the scientific literature, with over 300 citations listed.

 

·       National Nutritional Foods Association (NNFA)

·       Establishment and monitoring with regard to industry GMP’s.

·       These GMP’s include raw material handling procedures including identification techniques, sanitation in all aspects of production, process controls, instrument calibration, laboratory testing procedures, and record keeping and retention.

·       Council for Responsible Nutrition (CRN) – predominantly an advocacy trade association.

·       Utah Natural Products Alliance – predominantly an advocacy trade association.

 

Tort System Regulation

·       Companies can be sued for marketing an unsafe product.

·       Companies need to carry liability insurance, and insurance for companies which market potentially unsafe products can be very expensive, or even unavailable.

·       High cost of liability insurance markedly limits availability of potentially unsafe products.

 

The Future

·       Implementation and enforcement of GMP’s will add substantial cost to the manufacture of supplements by companies not currently meeting proposed GMP standards.

·       There will be a marked consolidation in the market from the hundreds of companies currently marketing supplements, similar to what happened decades ago in the automobile industry.

·       There will be less innovation because of the added cost of testing each new product.

·       Low-selling but effective supplements will be discontinued.

 

References:

·       Blumenthal, Mark. FDA Proposes new rules on dietary supplement structure-function claims: agency redefines “disease” in what critics call an attempt to limit claims and weaken DSHEA. Herbalgram: The Journal of the American Botanical Council. 1998. 43. 26.

·       Blumenthal, Mark and Watts, Daron. FDA issues proposed GMP’s for dietary supplements. Herbalgram: The Journal of the American Botanical Council. 2003. 58. 62-65.

·       Blumenthal, Mark. FDA proposes strong warnings for ephedra, releases independent RAND report on ephedra safety and efficacy. Herbalgram: The Journal of the American Botanical Council. 2003. 58. 68-70.

·       Blumenthal, Mark. FDA published rule to incorporate AHPA’s Herbs of Commerce in herb labelling. Herbalgram: The Journal of the American Botanical Council. 2003. 60. 66.

·       Greenfield, Russell. Behind the banning of ephedra: misuse, abuse, dangers. Alt Med Alert. 2004. 7. 25-33.

·       Liu FX and Salmon JW. Herbal Medicine Regulation in China, Germany, and the United States. IMCJ. 2010. 9[6]. 42-49.

·       McNamara, Stephen.  The FDA has adequate power and authority to protect the public from unsafe dietary supplements. Herbalgram: The Journal of the American Botanical Council. 1996. 38. 25.

·       Soller, William R. Regulation in the herb market: the myth of the unregulated industry.  Herbalgram: The Journal of the American Botanical Council. 2000. 49. 64.


 

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