According to Section 26 of the Second Medicines Act, in accordance with applicable European drug law, bibliographic data were used to assess the safety and efficacy of medicines evaluated by Commission E. Members used 100-200 references from around the world to evaluate each herb (Schilcher, 1997b).

Unlike FDA drug reviews in which data is passively submitted to the agency by the manufacturer, the members of Commission E actively collected bibliographic data on the herbal drugs being reviewed. This work has been supported since 1992 by the industry and scientific coalition Kooperation Phytopharmaka (Steinhoff, 1997a). The following are examples of the data collected and reviewed:

1. Traditional use. Literature can reveal the long-term use of a botanical substance and can indicate relative safety and presumed efficacy.

2. Chemical data. Herbal drugs have been analyzed to determine their chemical composition, especially the main constituents. Knowledge of these chemical constituents can indicate the potential activity and/or toxicity of a botanical, depending on the known range of compounds and their relative quantities.

3. Experimental, pharmacological, and toxicological studies. Laboratory/experimental (in vitro) and pharmacological/toxicological (in vivo) studies are published worldwide on whole plant extracts or constituents of medicinal plants. These studies provide documentation of the historical or traditional uses of a plant, even though clinical studies may be lacking.

4. Clinical studies. In many European countries, clinical studies on leading medicinal plants and phytomedicines are conducted routinely, according to strict scientific controls. These studies can suggest and often confirm the safety and efficacy of herbs and their preparations. Many clinical studies conducted recently correspond to Good Clinical Practice (GCP) guidelines.

5. Field and epidemiological studies. The use of a medicinal plant by a particular population over time is also useful when evaluating safety and efficacy. The Commission reviewed such studies, if they were available.

6. Patient case records submitted from physicians' files. Case reports from individual patients in clinical practice, although not considered as important as controlled clinical studies, are nevertheless useful in obtaining information from the experiences of attending physicians using herbs and phytomedicines.

7. Additional studies, including unpublished proprietary data submitted by manufacturers. On occasion, a particular herb may have extensive chemical, toxicological, pharmacological, and clinical testing conducted by a manufacturer. The Commission was able to review such data, while maintaining the confidentiality of the information. Commission referee Dr. K. Keller of BfArM writes, "Due to the great number of individual drugs, the work of the committee was concentrated on the evaluation of active constituents. The evaluation is based on bibliographic data presented by manufacturers or organizations of manufacturers of herbal medicinal products. These documents are completed by data obtained from literature search, for example online research in EMBASE, MEDLARS, and TOXALL, and other data available to our office." (Keller, 1992.)

The proposed monograph format was published and reviewed in about three months by all Commission members, other scientists, scientific associations, universities, and other experts, who could make comments to the proposed monograph. All comments were then considered by the Commission in its final monograph (Schilcher, 1997b).

Readers will quickly notice that the Commission E monographs do not include any references to the literature used by the Commission members in assessing the safety and efficacy of the herbal drugs under review. This is unlike the format for the monographs published in 1990 and subsequently by ESCOP. Commission E and ESCOP monographs are similar insofar as they are therapeutic monographs and do not detail standards for quality as are found in a pharmacopeial monograph.

According to Prof. Schilcher every monograph has a Begrundung , an unpublished justification with most of the relevant references. This material is stored at the BfArM in Berlin and only in conflicts or cases of disputes to the Medical Act can an attorney or a scientific organization view these references. The references were originally included in data reviewed by members of the Commission in determining monograph evaluations (Schilcher, 1998a).

The Commission E monographs were developed to inform the consumer and to facilitate the companies' applications for registration of the herbs as licensed drugs. The monographs were created as official government documents. Although the monographs cannot serve as a guide to additional information, they are based on extensive review of the scientific and historical data as well as the interdisciplinary expertise of the members of the Commission. Also, some of the materials upon which the monographs were based were unpublished studies of proprietary products from manufacturers in Germany; thus, these references could not be published. The background material for these monographs, produced by Kooperation Phytopharmaka (KP), did contain references but these longer documents have not been published (Steinhoff, 1997). Thus, for these reasons, references are not included in Commission E's monographs.

In 1992 Kooperation Phytopharmaka was established as an umbrella organization of about 150 pharmaceutical manufacturers particularly active in the field of phytomedicine. Kooperation Phytopharmaka is advised by three associations of the pharmaceutical industry, Bundesfachverband der Arzneimittel-Hersteller e.V. (BAH, the Federal Association of Pharmaceutical Manufacturers), Bundesverband der Pharmazeuthischen Industrie e.V. (BPI, the Federal Association of the Pharmaceutical Industry), and the Verband der Reformwaren-Hersteller e.V. (VRH, the Association of Manufacturers of Health Foods), as well as the Deutsche Gessellschaft für Phytotherapie e.V. (GPhy, the German Society of Phytotherapy), a scientific organization. One of the main objectives of KP since its beginning has been the collection and preparation of scientific material on medicinal plants, evaluation of this material by experts in the field of phytomedicine, and submission of this prepared material (comparable to an expert report) to Commission E (Steinhoff, 1997). These summaries consist of exhaustive literature reviews on chemistry, toxicology, pharmacology, and clinical experience (some exceeding 100 pages). No positive or negative recommendation is included in these summaries (Busse, 1997c). Many of the Commission E monographs are based on material prepared by KP, but the KP monographs served as only one basis for the development of the Commission E monographs. In the past few years KP has taken on the task of revising the "old" material, i.e., collecting information, (e.g., clinical studies) published since the publication of the Commission E monograph. This updated material is now being used by manufacturers to lend support to substantiation of individual therapeutic indications and efficacy of herbal drug products during the process of re-registration for drug status with the BfArM (Steinhoff, 1997).

The Commission E review process is only slightly comparable to the OTC review process of old drugs conducted by the U.S. Food and Drug Administration since 1972. The results of field studies and single cases were only eligible when evaluated according to standards. When lacking controlled studies, safety and efficacy for known substances still can be determined on the basis of other information, such as well documented review articles, older clinical trials, and well documented knowledge on traditional use (Busse, 1996). However, experience from long-term therapeutic or traditional use without supplementary data cannot be accepted as sufficient evidence of safety (Busse, 1997c).

In comparing the German legal and regulatory situation with that of the U.S., Commission E member M. Wiesenauer notes that plant drugs were equated with synthetic drugs in Germany by legislative fiat. Then the Commission set about the task of determining the safety and effectiveness of each preparation (Wiesenauer, 1989). Approved and unapproved herbs are divided into separate sections of this book. There are several ways to distinguish between a positive and negative monograph. Positive monographs always show the approved use and dosage. If no approved uses are given in a monograph, if there is no dosage listed, and if the efficacy of the plant has not been sufficiently proven, or there are risks that outweigh the documented benefits (e.g., Monkshood, Male Fern), the assessment will be a negative one (Steinhoff, 1994a).

Several of the herbs approved by Commission E are relatively powerful, pharmacologically active, and also potentially toxic herbs. "It is important to realise that Commission E does not restrict its activities to mildly acting products, but also prepares monographs on potent herbal remedies, such as Hyoscyamus niger [Henbane], Rauvolfia serpentina [Indian Snakeroot] and Urginea maritima [Squill], all of which should be treated as prescription only drugs. In other words, the existence of a positive Commission E monograph does not imply that the herbal drug is sufficiently harmless to be treated as an over-the-counter product. However, as each monograph outlines the accepted uses and health risks of the herb in question, the work of the Commission E provides useful information if one has to assess the safety of individual source plants." (Gericke, 1995.)

In a few cases new data necessitated the change of an herbal drug from approved status to unapproved as in the case of Bishop's Weed fruit, originally published as an approved monograph in 1986. However, in 1994, as a result of a new risk-benefit assessment based on toxicological data and case reports of adverse reactions, the original monograph was replaced (not revised) with a new negative monograph that noted the risks of this herb (Keller, 1998; Steinhoff, 1997b). The same process also occurred with Madder root, granted a positive monograph for treatment of kidney stones in 1986, but replaced in 1992 with a negative monograph, due to new pharmacological research on rats indicating that the compound lucidin may be mutagenic and carcinogenic. Reclassification of both Bishop's Weed fruit and Madder root to negative monograph status (Unapproved) because of new data indicating potential risks that outweigh possible benefits attests to the rationality of the Commission E process. This constant vigilance by Commission members regarding what has been termed the "doctrine of absolute proof" to assess safety is a significant characteristic of the Commission E evaluation process.

As is true for any body of scientists evaluating the benefits and marketability of medicines, Commission E was concerned about the safety of the herbs and phytomedicines it reviewed. According to Professor Varro E. Tyler, Dean and Distinguished Professor of Pharmacognosy Emeritus at Purdue University, the Commission reviewed safety data according to a "doctrine of absolute proof" for safety (Tyler, 1994). The Commission attempted to ensure that these medicines were reasonably safe when used according to the dosage, contraindications, and other warnings and provisions specified in the monographs.

Regarding efficacy, the Commission was guided by what Professor Tyler has termed the "doctrine of reasonable certainty." (Tyler, 1994.) That is, as long as the scientific data provided reasonable verification of particular historical use, the Commission would grant a positive evaluation. Accordingly, some of the early work of the Commission (1978 - 1989) was characterized by positive evaluations for some herbs for which a significant body of clinical studies did not exist. Most positively evaluated monographs are based on open clinical studies or data derived from field studies, patient case records, and pharmacological research or proprietary data submitted by individual companies (Schilcher, 1997b). Numerous negative evaluations also were made during this period.

However, after 1990 the Commission began to focus more on good clinical practices (GCP) clinical studies to document the uses. In some cases, monographs for herbs that previously were granted approval for several uses were amended to a more restricted indication. A good example is the monograph for Hawthorn, originally published in 1984. The Hawthorn monograph initially contained a range of cardiovascular indications that included applications between stages I and II of the New York Heart Association's functional classification for heart disease. The approved indications formerly read as follows: "sensation of pressure and anxiety in the heart area," "geriatric heart condition that does not yet require digitalis," and "mild forms of bradycardia." However, in July 1994 the Commission published four separate monographs for various parts of the hawthorn plant. Only Hawthorn leaf with flower was approved for the more limited indication "for decreasing cardiac performance as described in functional Stage II of NYHA." This approval was based on clinical studies published for proprietary medicines made of both hawthorn parts and based on observations by physicians from clinical experience. Other hawthorn preparations made individually from berry (fruit), leaf, or flower were negatively evaluated due to the lack of evidence in clinical trials. However, they are still sold as "traditionally used Hawthorn preparations" only to support general heart function, according to provisions of Article 109a of the AMG (Schilcher, 1997b). (See Traditional Medicines above.)

This process of negative evaluations of the older dosage forms was challenged by the BAH. BAH suggested that because hawthorn preparations "form an important part of the German phytomedicines market with respect to self-medication," therefore, "when new clinical studies become available, it is important to check, and possibly amend, the older monographs, because the status of scientific knowledge represented by them may change owing to new research results. This, however, must under no circumstances automatically mean that the older results published in a monograph are no longer valid, and, unless there is a direct conflict, those results must maintain their status as scientific documentation and be included in a monograph as before, perhaps with a slightly modified indication claim." Unfortunately, Commission E did not agree with this proposition, and the final monographs on Crataegus [Hawthorn] were published on 19 July 1994 without the same indications published in the 1984 monograph (Steinhoff, 1997). (For more on Hawthorn, please see pages 39 and 63.)

Negative assessments (i.e., Unapproved monographs) were made by Commission E in cases where "no plausible evidence of efficacy" was available or when safety concerns outweighed the potential benefits. The objective of the Commission was to "eliminate drugs with even minor risks, because these risks are not tolerable if they are not balanced by an acceptable benefit." (Keller, 1992.) Also, the Commission published negative monographs for medicinal plants which had no clinical or pharmacological studies or no plausible evidence of efficacy reported in traditional medicine or empirical medicine (Schilcher, 1997b). Herbs that were evaluated negatively are published in the Unapproved Herbs section of this book. Monographs on these herbal drugs and their phytomedicinal preparations are published without dosage recommendations. "Herbs which pose a risk have to be withdrawn immediately." (Busse, 1997c.) Unapproved Herbs that do not pose a health risk can be sold in the German market only until the year 2004.

According to Prof. Schilcher, the fact that by 1995 the Commission had negatively evaluated at least 115 herbal drugs is evidence that in Germany "scientifically oriented criteria for assessment apply for plant medicines." (Schilcher, 1997b.)

Interestingly, the 126 unapproved monographs, although they constitute only 33 percent of the total monographs published, produce 97 of the total number of categories of adverse side effects. This is consistent with the fact that 45 herbs were negatively evaluated precisely due to documentation or reasonable suspicion of these types of risks. By comparison, the 254 positive monographs contain only 75 types of side effects (mostly adverse; not all side effects listed are adverse). This constitutes 29 percent more side effects noted for Unapproved herbs than for Approved herbs. (This data is found in Table 13.)

If there is neither a risk nor sufficiently documented efficacy, the monograph is termed null by Commission E. The term neutral is preferred by the German manufacturers. Null (neutral) monographs do not note any risk associated with the use of the herbs (Steinhoff, 1997). Nevertheless, despite the fact that the industry uses the term neutral , "the official position [of BfArM] is that they are negative monographs because there is a negative vote on individual claims promoted by industry." (Keller, 1998a, b.) The term "null" is used internally by the Commission to refer to these so-called "neutral" monographs, but they are published as "negative" in the Bundesanzeiger (Schilcher, 1997b). Because they have received a negative evaluation due to lack of scientific documentation, they are included in the Unapproved Herbs section of this book. As seen in Table 14, many of these 46 herbs are common foods (Figs and Spinach leaf), spices (Dill weed and Oregano), and tea ingredients (Hibiscus, Raspberry leaf, and Rose Hip), which, despite lack of documentation, are relatively safe in normal use. Prof. Schilcher notes that if the industry is able to provide new studies to document efficacy, they may be able to achieve positive status as drugs, but no new monographs will be produced (Schilcher, 1998a). Table 14 provides a complete list of negative monographs without documented risk.