The German Commission E Monograph System for ... - ACS Publications

Chapter 3

The German Commission E Monograph System for Phytomedicines: A Model for Regulatory Reform in the United States Downloaded by STANFORD UNIV GREEN LIBR on September 28, 2012 | http://pubs.acs.org Publication Date: April 15, 1998 | doi: 10.1021/bk-1998-0691.ch003

Mark Blumenthal American Botanical Council, P.O. Box 201660, Austin, TX 78720

No longer relegated solely to the shelves of health food stores, herbs have become mainstream products and constitute the fastest growing category in drugstores. This requires an appropriate regulatory mechanism to review and evaluate the quality, safety, and efficacy of these natural products. The German Commission E stands out as the most rational in the world. In Germany herbs are routinely prescribed by physicians and sold in pharmacies. The Commission E system consists of a panel of experts convened under the auspices of the former Federal Health Agency which reviewed bibliographic information on approximately 300 herbs sold in Germany, including historical and traditional use, chemical studies, pharmacological and toxicological research, clinical studies, epidemiological data, and patient case files. Safety was assessed on a doctrine of absolute certainty, but efficacy was based on a more relaxed standard—a doctrine of reasonable certainty. The monographs, published in the German Federal Gazette, offer therapeutic guidelines including approved uses, contraindications, side effects, interactions with other drugs, dosage information, and related data. The American Botanical Council has translated and published all Commission E monographs into English to provide health professionals and the general public with accurate, authoritative assessments of herbal products.

One of the biggest questions facing the herb industry, consumers, Congress, and regulators is what kind of rules are appropriate for the regulation of herbal products. Specifically, the biggest question lies with the issue of how to transmit the health and therapeutic properties of herbs to health consumers. The recent debate and eventual passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA) was marked by intense debate surrounding the issue of health claims and how such health benefits of dietary supplements would be

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©1998 American Chemical Society

In Phytomedicines of Europe; Lawson, L., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

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31 approved by the Food and Drug Administration (FDA). The Agency was concerned about the prospect that manufacturers wanted too lenient a standard for making health claims (long-term, dietary associated preventive claims as contrasted to therapeutic or drug claims which are more short-term and deal more with transient symptoms). On the other hand, industry and many consumer groups were concerned about the possible overzealous regulation of dietary supplements by F D A and the agency's attempt to classify as drugs any high potency supplements that it deemed intended for therapeutic uses, as evidenced by proposed rules FDA issued in June 1994. As a result of DSHEA, American health consumers now have assurance that many of the supplements they ingest in the belief that these products convey a health benefit will be protected from over-regulation by the FDA. The new law allows manufacturers to provide safety information and warnings that formerly were restricted to drug labeling. DSHEA also allows manufacturers to make limited "structure and function" claims as to how an herbal product affects the structure or function of the body so long as the claim is not therapeutic in nature and does not imply the treatment or cure of a pathology. Despite the gains claimed by the dietary supplement consumers and industry in the passage of the DSHEA, the new law does not deal with the widespread use of herbs and phytomedicines for their therapeutic benefits. A new regulatory framework is still needed to create an appropriate set of criteria and procedures for the approval of herbs as therapeutic agents or drugs. Unfortunately, the current system for the assessment of ingredients for use in nonprescription or OTC (over-the-counter) drugs is appropriate for only a few phytomedicines. In 1992, a group of European and American phytomedicine manufacturers and marketers (the European-American Phytomedicines Coalition, EAPC) filed a petition with the FDA that requested that Agency to classify as old drugs herbal medicines or phytomedicines marketed in Europe for a "material time" and for a "material extent." These would then fall under the F D A OTC Drug Review, rather than being classed as new drugs requiring the expensive and time-consuming New Drug Application (NDA) process established for most conventional drugs (1). On October 3, 1996, FDA published an Advanced Notice of Proposed Rulemaking which indicated that the Agency might be more willing to accept foreign market data in consideration of proposed OTC drug status for an ingredient; however, a number of conditions were suggested that may limit the likelihood that leading European phytomedicines might be reviewed (2). The proposed regulations are being reviewed by F D A in light of public comments made to the Agency (2). The American Botanical Council, a nonprofit research and education organization, has instituted a review of six major industrialized nations and how they approach the challenge of regulating herbs and phytomedicines as nonprescription medicines. In this review (called the Traditional Medicine Research Project), one particular model stands out, the German Commission E. This Commission is an independent division of the former Federal Health Agency, now the German Federal Institute for Drugs and Medical Devices (analogous to the FDA), that actively collected information on herbal medicines and evaluated them in relation to their safety and efficacy. These evaluations were published in the form of brief monographs in the German Federal Gazette (analogous to the Federal Register) and were intended as package inserts for herbal drugs sold in pharmacies.



32 The method of approval is quite interesting. Commission E reviewed information about each herb's history of use and chemistry, pharmacological, and experimental studies on animals, human clinical studies if available, epidemiological studies, and even subjective evaluations by patients and physicians from clinical experience. Emphasis was placed on safety when efficacy judgments were made. According to Varro E. Tyler, Distinguished Professor Emeritus of Pharmacognosy at Purdue University and long the senior author of the textbook Pharmacognosy, has noted, "Commission E evaluates efficacy based on a doctrine of reasonable certainty," as contrasted with our FDA's insistence on a "doctrine of absolute proof based on information that is passively submitted to FDA from drug manufacturers (3). The Commission E was established in 1978 and has since published over 400 monographs (including revisions) covering over 300 herbs and herb combinations sold in Germany. The Commission includes people with expertise in various aspects of medicinal plant research and use: physicians, pharmacists, pharmacologists, and toxicologists, as well as representatives of the pharmaceutical industry and lay persons. Of these monographs, about 200 are positive; that is, they approve the use of an herb for particular use or uses. About 100 are negative assessments, usually based on either lack of sufficient data to approve actions and/or significant toxicity concerns. Herbs and medicinal plant products have always been popular and widely respected in Germany. In his introduction to the American Botanical Council's forthcoming English translations of these monographs, Tyler writes (3): The therapeutic use of herbs and phytomedicines has always been very popular in Germany. About 600-700 different plant drugs are currently sold there, singly and in combination, in Apotheken (pharmacies), Drogerien (drugstores), Reformhaluser (health food stores), and M&rkte (markets). In addition to the self-selection of herbal products by consumers, about 70% of the physicians in general practice prescribe the thousands of registered herbal remedies, and a significant portion of the $1.7 billion annual sales (a conservative estimate) is paid for by government health insurance. In 1988, 5.4 million prescriptions were written for a single phytomedicine, Ginkgo biloba extract, a figure that does not include the substantial over-the-counter sales of the product. In view of this significant role which phytomedicines play in Germany, it is only natural that the government there would develop a mechanism to assure users of their safety and efficacy. The process is unique. For various reasons, even other advanced nations have not yet chosen to emulate it. But it is worthy of imitation, and it is probably only a matter of time before consumers in other countries are able to benefit from the German experience. A review of the first 285 monographs revealed that most have a positive assessment, while 66% mention various risks, and 58 have no plausible evidence of efficacy resulting in a negative assessment. The monographs list known contraindications for the various herbs. Some of the more frequently mentioned contraindications include allergy to active constituent (63 monographs), restricted use during pregnancy and/or lactation (24 monographs), gallstones (15 monographs) and inflammatory kidney disease (7 monographs). Thirty-five monographs limit the period of use to reduce side effects. Types of side effects include gastrointestinal disorders (35 monographs),



33 allergic reactions - mostly skin reactions with some more severe generalized reactions (30 monographs), photosensitivity (5 monographs). In addition, 7 monographs mention that the herb may influence the absorption of other drugs taken simultaneously (4, 5). The American Botanical Council has undertaken the translation and publication in English of the German Commission E Monographs. All monographs published in Germany through 1994 have been translated and will be published in the fall of 1997. Multiple cross references and indices are being created to increase the usefulness and ease of use of the monographs (6). Prof. Tyler has some glowing words for the Commission E Monographs: "They represent the most accurate information available in the entire world on the safety and efficacy of herbs and phytomedicines. As such, they are worthy of careful study by anyone interested in any type of drug therapy. Ignorance of the Commission E monographs is ignorance of a substantial segment of modern medicine" (3). Approved Uses and Dosage The following are examples of the approved uses for some of the leading phytomedicines sold in the U.S. according to the Commission E Monographs, with the suggested doses. Regarding doses, all begin with the phrase "Unless otherwise prescribed" and then the specific general dose recommendation is given. Also, the phrase "Equivalent preparations" is usually added in reference to the practice of prescribing and using preparations which are generally equivalent in active constituents to the drug form and dosage prescribed, e.g., the use of a water infusion or tincture which is equivalent to a stated dose of dried herb (drug). Other sections of the monographs (e.g., Contraindications, Side Effects, Mode of Administration, Duration of Application, Actions) are not included here. For a full text of each monograph, see Blumenthal et al. 1997 (6). Asian Ginseng root (Panax ginseng) • Tonic for invigoration and fortification in times of fatigue and debilitation or declining capacity for work and concentration. • Convalescence. Daily dosage: 1-2 g of root; equivalent preparations. Chaste Tree fruits (Vitex agnus-castus) • Irregularities of the menstrual cycle. • Premenstrual complaints. • Mastodyma. Note: In case of feeling of tension and swelling of the breasts and at disturbances of menstruation, a physician should be consulted for diagnosis. Daily dosage: aqueous-alcoholic extracts corresponding to 30-40 mg of the drug. German Chamomileflower(Matricaria recutita) • Externally: Skin and mucous membrane inflammations, as well as bacterial skin diseases, including those of the oral cavity and gums. Inflammations and irritations of the respiratory tract (inhalations). Ano-genital inflammation (baths and irrigation).



34 • Internally: Gastrointestinal spasms and inflammatory diseases of the gastrointestinal tract. Daily dosage: Boiling water (ca. 150 ml) is poured over a heaping tablespoon of chamomile (ca. 3 g), covered, and after 5-10 minutes passed through a tea strainer. Unless otherwise prescribed, for gastrointestinal complaints a cup of the freshly prepared tea is drunk three to four times a day between meals. For inflammation of the mucous membranes of the mouth and throat, the freshly prepared tea is used as a wash or gargle. External: for poultices and rinses, 3-10% infusions; as a bath additive, 50 g to 10 liters (approx. 2.5 gal.) water; semi-solid formulations with preparations corresponding to 3-10% herb. Echinacea purpurea herb (Echinacea purpurea) • Internally: Supportive therapy for colds and chronic infections of the respiratory tract and lower urinary tract • Externally: For use on poorly healing wounds and chronic ulcerations. Internal daily dosage: 6-9 ml expressed juice. (This refers to fresh juice of aboveground parts.) [Dosage is also offered for injectible preparations.] External dosage: Semi-solid preparations containing at least 15% pressed juice. Echinacea pallida root (Echinacea pallida) • Supportive therapy for influenza-like infections. Daily dosage: Tincture (1:5) with 50% (v/v) ethanol from native dry extract (50% ethanol, 7-11:1), corresponding to 900 mg herb. Eleuthero (Siberian) Ginseng rhizome (Eleutherococcus senticosus) • Tonic for invigoration and fortification in times of fatigue and debilitation or declining capacity for work and concentration. • Convalescence. Daily dosage: 2-3 g of root. Garlic (Allium sativum) • Supports dietary measures to reduce serum cholesterol levels. • Preventative measure for age-related vascular changes. Daily dosage: 4 g fresh garlic; equivalent preparations. Ginger root (Zingiber officinale) • Indigestion. • Prevention of motion sickness. Daily dosage: 2-4 g rhizome; equivalent preparations. Ginkgo biloba leaf extract (Ginkgo biloba) [This preparation is a concentrated dry extract (35-67:1, average 50:1) extracted with acetone and water. The preparation is standardized at 22 to 27% flavone glycosides and 5-7% terpene lactones, of which approximately 2.8-3.4% consists of ginkgolides



35 A , B , and C, as well as approximately 2.6-3.2% bilobalide. Ginkgolic acid should be less than 5 ppm. The given ranges include manufacturing and analytical variances.] Uses: • (a) For symptomatic treatment of disturbed performance in organic brain syndrome within the regimen of a therapeutic concept in cases of demential syndromes with the following principal symptoms: memory deficits, disturbances in concentration, depressive emotional condition, dizziness, tinnitus, and headache. The primary target groups are dementia syndromes, including primary degenerative dementia, vascular dementia, and mixed forms of both. Note: Prior to starting treatment with ginkgo extract, clarification should be obtained as to whether the pathological symptoms encountered are not based on an underlying disease requiring a specific treatment • (b) Improvement of pain-free walking distance in peripheral arterial occlusive disease in Stage II of Fontaine (claudicatio intermittens) in a regimen of physical therapeutic measures, in particular walking exercise. •(c) Vertigo and tinnitus of vascular and involutional origin. Daily dosages: Indication (a): 120-240 mg extract in 2 or 3 doses. Indications (b) and (c): 160 mg extract in 2 or 3 doses. Hawthorn leaf with flower (Crataegus monogyna; C. laevigata) • Decreasing cardiac output as described in functional level II by the N Y H A (New York Heart Association). Daily dosage: 160-900 native, water, ethanol extract (ethanol 45% v/v or methanol 70% v/v, drug-extract ratio = 4-7:1, with defined flavonoid or procyanidin content), corresponding to 30-168.7 mg procyanidins, calculated as epicatechin, or 3.5-19.8 mg flavonoids, calculated as hyperoside in accordance with D A B 10 (German Pharmacopoeia 10 ed.). th

Horse Chestnut seed (Aesculus hippocastanum) (This drug is defined as a dry extract adjusted to 16-20% triterpene glycosides, calculated as anhydrous aescin.) • Treatment of complaints found in pathological conditions of the veins of the legs (chronic venous insufficiency), for example pain and a sensation of heaviness in the legs, nocturnal systremma (cramps in the calves), pruritis, and swelling of the legs. Note: Other non-invasive treatment measures prescribed by a physician, such as leg compresses, wearing of supportive elastic stockings, or cold water applications, must be observed under all circumstances. Daily dosage: 100 mg aescin (escin) corresponding to 250-312.5 mg extract two times per day in delayed release form. Kava Kava root (Piper methysticum) • Conditions of nervous anxiety, stress, and restlessness. Daily dosage: Herb and preparations equivalent to 60-120 mg kava pyrones. Milk Thistle fruit (Silybum marianum) • Crude drug (dried seeds): indigestion.


36 • Standardized extract: toxic liver damage and supportive treatment of chronic inflammatory diseases of the liver and liver cirrhosis. Daily dosage of crude drug: 12-15 g ; of standardized preparation: 200-400 mg of silymarin, calculated as silibinin.


Saw Palmetto fruit (Serenoa repens) • Urination problems in benign prostate hyperplasia stages I and 2. Daily dosage: 1-2 g sabal berry or 320 mg lipophilic ingredients extracted with lipophilic solvents (hexane or ethanol 90% v/v). St John's wort herb (Hypericum perforatum) • Internally: For psychovegetative disorders, depression, anxiety and/or nervous restlessness. Oily hypericum preparations for indigestion. • Externally: Oily hypericum preparations for treatment in post-therapy of acute and contused injuries, myalgia and first degree bums. Daily dosage for internal use: 2-4 g of drug or 0.2-1.0 mg of total hypericin in other forms of drug application. Valerian root (Valeriana officinalis) • Restlessness, sleeping disorders based on nervous conditions. Dosage: Infusions (teas): 2-3 g drug per cup, once to several times per day. Tincture: Vt-\ teaspoon (2-5 ml), once to several times per day. Extracts: Amount equivalent to 2-3 g of drug, once to several times per day. External use: 100 g for one full bath; equivalent preparations. Literature Cited 1. Pinco, R.G. and L.D. Israelsen. European-American Phytomedicines Coalition Citizen PetitiontoAmend FDA's OTC Drug Review Policy Regarding Foreign Ingredients. July 24, 1992. 2. Food and Drug Administration. Eligibility Criteria for Considering Additional Conditions in the Over-the-Counter Drug Monograph System Request for Information and Comments. Federal RegisterVol.61 (193): 51625-31. Oct. 3, 1996. 3. Tyler, V.E. In German Commission E Monographs: Therapeutic Monographs on Medicinal Plants for Human Use; Blumenthal, M.,; Gruenwald, J.; Hall, T.; Riggins, C.W.; Rister, R.S. (eds.); Klein, S.; Rister, R.S. (transl.).; American Botanical Council: Austin, TX, 1997. 4. Bergner, P. HerbalGram 1994, 30: 17 & 64. 5. Keller, K. Zeitschrift Phytotherapie 1992, 13; 116-120 (English). 6. Blumenthal, M.; Gruenwald, J.; Hall, T.; Riggins, C.W.; Rister, R.S. (eds.); Klein, S.; RS. Rister (transl.). German Commission E Monographs: Therapeutic Monographs on Medicinal Plants for Human Use. American Botanical Council: Austin, TX, 1997.


The German Commission E Monograph System for ... - ACS Publications

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