Life Sciences Research Office “Evaluating Adverse Event Reporting Systems for Dietary Supplements” Bethesda
Life Sciences Research Office “Evaluating Adverse Event Reporting Systems for Dietary Supplements” Bethesda, MD January 30-31, 2003 Considerations for botanical supplements and an overview of ephedra Steven Dentali, Ph.D. VP for Scientific and Technical Affairs American Herbal Products Association Today’s Talk An Overview of Ephedra – What it is, Does, and Regulatory Review – Scientific Reviews and Studies Review of DSHEA – Prior to and Findings of Special Case of Botanicals – Identification and Characterization – Extracts and Standardization American Herbal Products Association 2 American Herbal Products Association The National Trade Association and Voice of the Herbal Products Industry The American Herbal Products Association exists to serve its members by promoting the responsible commerce of products which contain herbs and which are used to enhance health and quality of life. American Herbal Products Association 3 American Herbal Products Association Founded in 1983, the American Herbal Products Association represents the manufacturers, growers, suppliers and retailers of herbal supplement products AHPA published Herbs of Commerce and wrote Botanical Safety Handbook HerbMed® searchable database. www.ahpa.org. American Herbal Products Association 4 What ephedra is … a generic name with forty species. ...standardized common name for ma huang (pharmacopeial term designating the dried stem of Tsao-ma-huang, Mu-tsei-ma-huang, San-ma-huang, and Chung-ma-huang or Ephedra sinica Stapf, E. equisetina Bunge, E. distachya L., and E. intermedia Schrenk & Meyer, respectively (Hsu et al. 1986). … the original source of the alkaloid ephedrine reportedly first isolated from E. equisetina in 1887 by Nagi. American Herbal Products Association 5 What ephedra is One of the oldest herbs in Chinese medicine, used extensively > 5,000 yrs Chen & Schmidt described pharmacodynamic characteristics of ephedrine in 1924. Value as a circulatory stimulant in surgical shock and bronchodilator in asthma. Traditional dosages of 3-9 g per day, equivalent to as much as 75-225 mg per day of ephedrine alkaloids. American Herbal Products Association 6 What ephedra is Products generally contain 8-24 mg ephedrine alkaloids per dose. Formulated using extracts containing 6% or 8% ephedrine alkaloids. Methods of quantification of ephedrine alkaloids: (primarily the first two) ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedrine, and methylpseudoephedrine are being validated. PPA not present (racemic mixture) Ephedrine usually predominates. American Herbal Products Association 7 What it does Indirect sympathomimetic adrenergics. Orally active causing bronchial dilation. CNS stimulant & vasopressor effects. Anorectic and thermogenic effects. American Herbal Products Association 8 Regulatory Review October 11-12, 1995 Special Working Group of the Food Advisory Committee of FDA on Foods Containing Ephedrine Alkaloids was Convened. – Considered significance and extent of serious adverse events reported in a passive reporting system RECOMMENDATIONS – Limit dosage of ephedrine alkaloids, per unit and per RDI – List ephedrine and caffeine content – List appropriate cautions and health risks, and statement to discourage taking more than recommended dose – Not for under 18, during pregnancy, long term use, or with certain diseases or disorders, or with certain drugs – Assure GMPs including identity and quantity of alkaloids – Develop appropriate analytical methods to control content – Conduct more laboratory and clinical research American Herbal Products Association 9 Regulatory Review August 27-28, 1996, Full Food Advisory Committee Meeting – Critical review of adverse event reports to weed out non-applicables was not done – Some adverse events apparent with short term use or long term low doses use – Approx. half of the panel recommended safe dose for ephedrine in ds as zero – Calls for the repeal of DSHEA were heard – One ridiculed herbs, homeopathy, astrology American Herbal Products Association 10 Regulatory Review June 4, 1997 Dietary Supplements Containing Ephedrine Alkaloids Proposed Rule (62 FR 30677-30724) – 8 mg per serving, 24 mg per day – Prohibits use with stimulant ingredients and claims requiring long term use (weight loss/body building) – Requires “Do not use this product for more than 7 days. ”If short term effects are promoted such as increased energy, mental alertness, or well being then the label shall state: “Taking more than the recommenced serving may result in heart attack, stroke, seizure or death.” American Herbal Products Association 11 Regulatory Review … and the following statement. WARNING: If you are pregnant or nursing, or if you have heart disease, thyroid disease, diabetes, high blood pressure, depression or other psychiatric condition, glaucoma, difficulty in urinating, prostate enlargement, or seizure disorder consult a health care provider before using this product. Do not use if you are using monoamine oxidase inhibitors (MAOI) or for 2 weeks after stopping a MAOI drug; certain drugs for depression, psychiatric or emotional conditions; drugs for Parkinson's disease; methyldopa; or any product containing ephedrine, pseudoephedrine or phenylpropanolamine (ingredients found in allergy, asthma, cough/cold and weight control products). Stop use and call a health care professional immediately if dizziness, severe headache, rapid and/or irregular heart beat, chest pain, shortness of breath, nausea, noticeable changes in behavior, or loss of consciousness occur. Do not exceed recommended serving. American Herbal Products Association 12 AHPA Code of Ethics March 1994 (revised March 2001) Ephedra Trade Recommendations – Warning statement – Serving limits per dose and per day – Use of standard common name (HOC) – NO added synthetic alkaloids – *List amounts of ephedrines and caffeine – *NO legal high or “legal” illicit drug claims – (*added since 1994) American Herbal Products Association 13 AHPA’s Cautionary WARNING. Not intended for use by anyone under the age of 18. Do not use this product if you are pregnant or nursing. Consult a health care professional before using this product if you have heart disease, thyroid disease, diabetes, high blood pressure, depression or other psychiatric conditions, glaucoma, difficulty in urinating, prostate enlargement, or seizure disorder, if you inhibitor (MAOI) or any other prescription drug, or you are using an over-the-counter drug containing ephedrine, pseudoephedrine or phenylpropanolamine (ingredients found in certain allergy, asthma, cough/cold and weight control products). Exceeding recommended serving will not improve results and may cause serious adverse health effects. Discontinue use and call a health care professional immediately if you experience rapid heartbeat, dizziness, severe headache, shortness of breath, or other similar symptoms. American Herbal Products Association 14 GAO Report House Committee on Science request August 4, 1999, Dietary Supplements: Uncertainties in Analyses Underlying FDA's PR on Ephedrine Alkaloids. Concerns about reported adverse events in supporting proposed dosing level and duration of use limit. April 3, 2000, withdrawal of Proposed Rule limits on level and duration. American Herbal Products Association 15 More Info Needed August 8-9, 2000 Public Meeting – Department of Health and Human Services' Office on Women's Health December 2000 Cantox Report – Formal risk assessment (nutrient based) St. Luke’s Hospital/Columbia Study – Boozer CN et al. An herbal spl containing Ma Huang-Guarana for weight loss: a randomized, double-blind trial. Int J Obes Relat Metab Disord 2001 25:316-24. American Herbal Products Association 16 More Info Needed Haller and Benowitz AER Review – Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000 343:1833-8. Mayo Clinic AER Review – Samenuk D et al. Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin Proc 2002 77:12-6. American Herbal Products Association 17 More Info Needed Greenway Literature Review – Greenway FL. The safety and efficacy of pharmaceutical and herbal caffeine and ephedrine use as a weight loss agent. Obes Rev 2001 Aug;2(3):199-21. Harvard/Columbia Study – Boozer CN et al. Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. International Journal of Obesity (2002) 26:593–604 American Herbal Products Association 18 More Info Needed Phenylpropanolamine Data Review – Morgenstern LB et al. Use of Ephedracontaining products and risk for hemorrhagic stroke. Neurology 2003 60:132-5 RAND Corporation Report – HHS funded comprehensive review of the existing science on ephedrine alkaloids – NIH to use information to guide expanded research effort to better understand the safety of ephedrine alkaloids. American Herbal Products Association 19 Prior to DSHEA 1972 FDA Proposed to Regulate Vitamins and Minerals as Drugs 1976 Rogers-Proxmire Amendment Exempted Drug Status by Potency 1990 Nutrition Labeling and Education Act (NLEA) – Award winning nutrition facts box Food Additive Provisions Used to Remove Dietary Supplements American Herbal Products Association 20 Prior to DSHEA June 18, 1993 ANPR-Dykstra Report – rules on safety levels for vitamins/minerals – regulating amino acids as drugs – food additive/drug status for some herbs Problems of the day included: – – – – – no claims, dosage, cautions, warnings allowed no third party literature proof of safety-manufacturer’s burden food or not food? If not food then what is it? uncertain and inconsistent enforcement American Herbal Products Association 21 DSHEA: Findings Improving Citizen Health - Top National Priority Preventative Health Measures (diet, lifestyle, and use of supplements) Can Reduce Chronic Disease and Health Care Costs Consumers are Increasingly Relying on Alternative Health Methods Almost 50% of Americans Take Supplements Consumers Should Be Empowered to Make Choices Based on Data from Scientific Studies of Health Benefits from Dietary Supplements Federal Government Should Take Swift Action Against Unsafe or Adulterated Products American Herbal Products Association 22 DSHEA: Findings Federal Gov Should Not Restrict or Slow the Flow of Safe Products and Accurate Information DS are Safe Within a Broad Range of Intake Safety Problems with DS are Relatively Rare Legislative Action That Protects Consumer’s Access to Safe Dietary Supplements is Necessary to Promote Wellness Rational Federal Framework Must be Established to Supersede the Current ad hoc, Patchwork Regulatory Policy on DS American Herbal Products Association 23 Dietary Supplement A product (not tobacco) intended to supplement the diet: vitamin, mineral, herb or other botanical, amino acid, or concentrate, metabolite, constituent, extract, or combination of the above …intended for ingestion in form…not food or food replacement ….labeled as a dietary supplement and is not formerly a drug…. American Herbal Products Association 24 DSHEA Enacted Food Additive Exclusion Presumption of Safety Statements of Nutritional Support New Dietary Ingredients Unsafe GMPs to be Modeled After Foods (Feb 6, 1997 ANPR of Dietary Supplement cGMPs from Industry Proposal submitted Nov 20, 1995) June 18, 1993 ANPR Withdrawn Commission Labels Established Office of DS Established (ODS/NIH) American Herbal Products Association 25 Special Case of Botanicals (AERs) Closer to foods than most drugs – Complex mixtures derived from plants Regulated as foods + DSHEA Identification of material is critical (‘97) – digitalis with plantain from Europe – germander not skullcap in Belgium – aristolochia root for stephania root – Periploca sepium for eleuthero American Herbal Products Association 26 The Hairy Baby Case Androgenized baby boy born to mother taking “Siberian ginseng” – toxicity attributed to “Siberian ginseng” – silk vine (Periploca sepium) substituted for eleuthero (Eleutherococcus senticosus) – 'Ci Wu Jia' (eleuthero) frequently confused with Southern 'Wu Jia Pi' and 'Xiang Jia Pi' – Product actually labeled Panax ginseng root Misidentification or Adulterations American Herbal Products Association 27 Characterization for Publication (or AERs) Study material needs explicit definition – Proper identification, collection – Plant part, method of extraction – Solvent, ratio of solvent to herb – Ratio of herb to finished extract – Percent native extract in total extract – Percent of identified markers – Manufacturer, part and lot numbers American Herbal Products Association 28 Types of Extracts Wide spectrum extracts – Exhaustive extracts, solvent nonspecific St. John’s wort, black cohosh Multiple groups of chemical constituents Narrow spectrum extracts – Selective, solvent specific or purifications Milk thistle, saw palmetto, green tea catechin Intermediate extracts Ginkgo – 30% flavonols/terpenes, 70% other American Herbal Products Association 29 Botanical Process Flow Chart Crude Dried Botanical Specifications Simple Extract (Select Solvent) Acetone/Water Maceration Residue (discard) Soluble Material (Total Crude Extract) Finished Extract Hexane Extraction Lipid Solubles (discard) Water Soluble Constituents (Enriched Bioactivity) Acid/Base Extraction Acids Neutrals Bases Finished semi-purified Extract Chemically Define American Herbal Products Association 30 Semi-Purified Extracts Prepared for a Specific Purpose – Not a whole plant extract – Not a single isolated compound Isolation of “Active” Fractions Ratio is Starting to Final (ex. 50:1) – Ginkgo, silymarin, green tea catechins – Not a conc. of all possible extractables American Herbal Products Association 31 Guidance Documents for the Manufacture and Sale of Botanical Extracts Retail Labeling – extract ratios/ranges Manufacture and Sale of Bulk Extracts – Extract types and approaches, QA/QC Marker Compounds in Manufacturing and Labeling of Botanical Products Standardization White Paper American Herbal Products Association 32 How to Standardize In order to produce a consistent product, controls must be implemented over both the raw material supply and the manufacturing process. The ultimate purpose of each of these controls is to reduce variability in the composition of the raw material. American Herbal Products Association 33 What to Standardize Good Agricultural Practices (material) – Seed, growing, harvesting (wild), drying Good Manufacturing Practices (process) – Powdering, extraction, granulation Safe and Effective Products – Adequate specifications (expertise) – Validated methods of analysis American Herbal Products Association 34 Standardized Quality Standardization requires a thorough description of the starting plant material and of the whole extraction process…It is more than the assay of an active principle or marker. “Standardization signifies the body of information and controls that are necessary to guarantee constancy of composition…” – A. Bonati (1991) journal of ethnopharmacol., 32:195-197 American Herbal Products Association 35
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