Botanicals: A Current Regulatory Perspective for ... - ACS Publications

Chapter 4

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Botanicals: A Current Regulatory Perspective for the United States

Loren D. Israelsen Utah Natural Products Alliance, 2046 E. Murray-Holladay Road, Suite 204, Salt Lake City, UT 84117 Herbs enjoy a unique regulatory status because of the Dietary Supplement Health and Education Act of 1994 (DSHEA). Scientific literature may now be used in connection with the sale of herbs to consumers. A new class of claims called Statements of Nutritional Support are being used to promote the physiological effects and benefits of herbs. This has resulted in an extraordinary growth of herb sales in the U. S. Important issues are now being debated concerning the establishment of pharmacopeial standards for herbs, the OTC status of herbs such as valerian and ginger, the major changes in new drug review standards for botanicals, and the protection of proprietary research on standardized plant extracts. This chapter will present an overview of these issues, with detailed analysis of current law and emerging policies.

Botanicals have always been a challenge to regulators. The very scope of these products and their wide and varied uses make legal definitions and regulatory policy difficult. For many reasons, the F D A has either ignored or attacked botanicals for over 50 years. Following World War n, the rise of synthetic drugs, patent protection and great success in conquering feared diseases were key factors that molded FDA's structure, priorities and expertise. The Center for Drug Evaluation and Research (CDER) employs 1475 persons (1), many of whom hold Ph.D.'s or M.D.'s, while only a handful have academic or research experience in pharmacognosy or related disciplines. Botanicals, once the core of businesses such as Parke Davis, Merck, Upjohn and Lilly, became reception room artifacts and the trade of ephemera collectors. Between 1900 and 1960, the vast majority of botanicals lost their USP status. Without industrial support and patent protection, research funds disappeared. Unable to meet stricter new drug approval requirements, botanicals were relegated to haphazard review under the 1972 OTC drug review system. Today, only a handful of botanicals of commercial importance are recognized as OTC

©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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38 active ingredients such as capsaicin (Category I), senna, cascara sagrada (Category HI) and slippery elm bark (a crude drug). On the food side, the 1958 Generally Recognized as Safe (GRAS) list recognized a number of botanicals as Generally Recognized As Safe. However, this recognition extended largely to the flavoring uses of botanicals for alcoholic beverages. Where would gin be without juniper berries? Later in 1974, the agency published a compliance policy guideline which purported to classify selected herbs as safe, unsafe, or of undetermined safety. This was done in response to a field inquiry following a complaint about the use of herbs by the White Woman's Magic Society of Houston, Texas. This document listed 27 herbs as unsafe, and between 1974 and 1986 this was the principal basis for enforcement action against herbs by FDA. The industry in turn widely criticized this document as lacking scientific legitimacy or factual accuracy. Passage of the Nutrition Labeling Education Act (NLEA) in 1990 brought renewed hope that botanicals would enjoy an improved status, particularly with respect to the new health claim provisions which, for the first time, allowed disease/nutrient relationship claims. FDA's subsequent rule-making proposed to treat botanicals as nonnutrients barring any chance of health-claim approvals. FDA rejected extensive industry comments objecting to this proposal. This was the last straw. With no other options available, the Utah botanical industry which represents nearly $1 billion in annual sales, joined forces and laid out a set of legislative principles they believed were necessary to resolve these regulatory attacks. In June of 1992, Senator Orrin Hatch introduced the Health Freedom Act, modeled after the Utah template. This legislation passed in 1994 as the Dietary Supplement Health and Education Act (DSHEA). It became the largest constituent issue before the U.S. Congress since the Vietnam War. Now widely regarded as the model for consumer-driven campaigns, the dietary supplement industry accomplished the nearly impossible. So stunning was this victory, that renowned food and drug lawyer Peter Barton Hutt remarked, "They therefore went to Congress and succeeded in obtaining what was without question the single worst legislative defeat that F D A has ever encountered in its entire history...This was an extraordinary and humiliating defeat for FDA...Thus, the impact of the 1994 statute is enormous."^ Passage of the DSHEA signaled two things: (1) A fundamental reform of FDA's haphazard and ineffective regulation of botanicals, and (2) Dietary supplement consumers are a political and economic force to be reckoned with. Central to the bill (and a constant point of negotiating friction) was the status and regulation of botanicals. I have "reconstructed" the DSHEA to focus exclusively on how it defines and now treats botanicals. While many of these provisions also apply to other dietary ingredients, review of the law with an eye toward botanicals provides a useful and concise picture of the new regulatory framework for this specific class of products.


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Botanical Summary of DSHEA 1) (Section 3^ E)efinition. The term "dietary supplement" means an herb or other botanical or a concentrate, constituent, extract or combination of any botanical that is intended for ingestion as a tablet, capsule or liquid form and is not represented for use as a conventional food or as a sole item of a meal or the diet and is labeled as a dietary supplement This includes new drugs which were marketed as botanicals prior to such approval but does not include a botanical approved as a new drug or authorized for investigation as a new drug for which substantial clinical investigations have begun and made public and which was not before such time marketed as a dietary supplement 2) Botanicals are Not Food Additives. 3) (Section 4V A botanical is considered unsafe if it presents a significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling, or it is a new botanical for which there is inadequate information to provide reasonable assurance that such botanical does not present a significant or unreasonable risk of illness or injury. In any preceding under this paragraph, the United States shall have the burden of proof to show that a botanical is adulterated. 4) (Section 5) Botanical Supplement Claims. A publication including an article, a chapter in a book or an official abstract of a peer-reviewed scientific publication that appears in an article and was prepared by the author or editors of the publication which is reprinted in its entirety shall not be defined as labeling when used in connection with the sale of botanicals to consumers when, (1) it is not false or misleading, (2) does not promote a particular manufacturer or brand of botanical, (3) is displayed or presented with other items on the same subject matter so as to present a balanced view of the available scientific information on a botanical, and (4) if displayed in an establishment, is physically separate from the botanical and does not have appended to it any information by sticker or other method. This provision shall not apply to or restrict a retailer of botanicals from selling books or publications as a part of their business. 5) Section 6, A,statement for a botanical may be made if: (a) The statement describes the role of a botanical intended to affect the structure or function in humans, characterizes the documented mechanism by which a botanical acts to maintain such structure or function or describes general well-being from consumption of a botanical; (b) The manufacturer of the botanical has substantiation that such a statement is truthful and non-misleading, and (c) The statement contains prominently displayed and in bold-faced type the following: "This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease." Such statements cannot claim to diagnose, mitigate, treat, cure or prevent any disease. The manufacturer of a botanical making such a statement shall notify the secretary (FDA) within 30 days after first marketing such a statement 6) Botanical dietary supplements are misbranded if: (a) It is a botanical dietary supplement and the label or labeling of the botanical fails to list the name of each ingredient, the quantity of such ingredients, or, if a proprietary blend, the total quantity of all ingredients. (b) The label or labeling of the botanical fails to identify the product by the term "dietary supplement"



40 (c) The label or labeling of the botanical fails to identify any part of the plant from which the ingredient is derived. (d) The botanical is: • Covered by the specifications of an official compendium; • Is represented as conforming to such official compendium and fails to do so; or • The botanical is not covered by an official compendium and fails to have the identity and strength that it represents to have, or • It fails to meet the quality, purity or compositional specifications based on validated assays or other appropriate methods that it is represented to meet. 7) (Section 81 A botanical shall be deemed adulterated unless: (a) The product contains only botanicals which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered, or (b) There is a history of use or other evidence of safety establishing that a new* botanical, when used under conditions recommended in the labeling, will reasonably be expected to be safe and at least 75 days before introduction into commerce to provide the secretary with information on which the manufacturer has concluded that the botanical will reasonably be expected to be safe. * A new botanical means one that was not marketed in the United States before October 15,1994. 8) (Section 9} Good Manufacturing Practices. A botanical is unsafe if it is prepared, packed or held under conditions that do not meet current good manufacturing practices. The secretary may by regulation prescribe good manufacturing practices for botanicals which shall be modeled after current GMP's for food and may not impose standards for which there is no current and generally available analytical methodology. 9) (wSection 10V A botanical is not a drug solely because its label or labeling contains a statement of nutritional support. Also, a botanical shall not be deemed misbranded if its label or labeling contains directions or conditions of use or warnings. 10) (Section 12^ Commission on Dietary Supplement Labels. A commission shall conduct a study on and provide recommendations for the regulation of label claims and statements for botanicals including the use of literature in connection with the sale of botanicals and procedures for evaluation of such claims. The commission shall evaluate how best to provide truthful, scientifically valid and not misleading information to consumers. 11) (Section 13^ Office of Dietary Supplements. The secretary shall establish an Office of Dietary Supplements (ODS) within the National Institutes of Health (NIH). The purposes of the office are as follows: (a) To explore the potential role of botanicals to improve health care. (b) To promote scientific study of the benefits of botanicals in maintaining health and preventing chronic disease. (c) The Director of the ODS shall: • Conduct and coordinate scientific research relating to botanicals


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which can limit or reduce the risk of diseases such as heart disease, cancer, birth defects, osteoporosis, cataracts or prostatism. Collect and compile results of scientific research related to botanicals. Serve as a principle advisor to the NIH, the Centers for Disease Control and Prevention (CDCP) and the Commissioner of F D A on issues relating to botanicals including botanical regulations, the safety of botanicals, scientific issues arising in connection with the labeling and composition of botanicals and shall compile a database of scientific research on botanicals.

As can be seen, the DSHEA lays down a new and unique approach to defining and regulating botanicals. I am unaware of any other regulatory system or approach like this in the world. It is nearly two years since the DSHEA became law. A great deal of work has been done, both by industry and by FDA, to implement and to further develop various aspects of this law. The following are important areas of general interest. 1) Statements of Nutritional Support. The FDA has received over 1,000 notices for statements of nutritional support, the majority of which are of botanical origin. Unfortunately, no accompanying sales data are presently available to determine how successful this new class of claims is in the marketplace. 2) Nutrition and Other Labeling Regulations. The F D A has issued proposed regulations setting out formats for botanical dietary supplement labels, nutrition labeling, etc. After careful review, the botanical industry identified several serious concerns and filed extensive comments objecting to various aspects of these regulations. 3) Good Manufacturing Practices. The agency has recently published the industry's draft GMP's as an Advanced Notice of Proposed Rulemaking (Docket No. 96N-0417). Following a public comment period, it is expected these regulations will proceed through formal rule-making and be officially adopted. This is seen as a very favorable step for both FDA and the botanical industry. Important issues remain with regard to how nutrients and botanicals will be treated with respect to identification of raw materials, microbiological contamination, appropriate analytical techniques, etc. 4) The Commission on Dietary Supplement Labels. This Commission was a political compromise when the Senate Labor and Human Resources Committee could not agree on how dietary supplements should fit into the larger N L E A health claims scheme. Hie Commission is composed of seven members. Members with expertise in botanicals include Dr. Norman Farnsworth, University of Illinois at Chicago, and Robert McCaleb, President, Herb Research Foundation. The Commission has held field hearings and received extensive comments from interested parties and is now preparing a report of theirfindingsand recommendations for the President and the Congress. The Commission hopes to have their report completed by June of 1997. The Commission appears to have been persuaded that botanicals should be distinguished from nutrients and accorded separate status as either herbal remedies, traditional medicines or similar. Many believe this is appropriate as it pertains to claims structures but not at the expense of losing dietary supplement status with respect to other provisions of the DSHEA.



42 5) The Office of Dietary Supplements (ODSV The ODS is now headed by Dr. Bernadette Marriott Initially, its focus has been on nutrients. However, more recently, the ODS has begun to focus attention on the role of botanicals in health care and is establishing a priority list of botanicals based on sales and on therapeutic importance in order to identify appropriate research and public education priorities. Much of the important work regarding the long-term place of botanicals in the U.S. marketplace is yet to be decided. Many important decisions will be made over the next 18 months that will greatly affect both the requirements for the manufacture and sale of these products but also allow the claims, creation of research incentives or recognition of botanicals as new prescription or OTC drugs. Other Developments Affecting the Regulatory Status of Botanicals 1) U.S. Pharmacopeia. In July 1996 the U.S. Pharmacopeia (USP) held an open conference to discuss approaches for establishment of quality standards and use information for botanicals. Four draft monographs on valerian, ginger, garlic and ginkgo have been published in the pharmacopoeial forum for comment. Further monographs are expected to be published as well. The establishment of USP standards for botanicals would serve three important purposes: • To legitimize and distinguish quality botanicals in the mind of the public and professionals. • Open the way for FDA drug review and approval of botanicals as drugs (traditional medicines) for which USP standards may exist • Become an authoritative source of usage information for health care professionals. • Set the stage for reimbursement or health insurance coverage for botanicals. • Create incentives for compliance with GMP's in order to meet USP standards. 2) EDA. There are signs of activity within FDA. The agency has acted as a co-sponsor of several conferences on botanicals over the last 18 months and is now rumored to be organizing a botanical review committee within the Center for Drug Evaluation and Research (CDER). The role of such a committee remains unclear but signals an intent to devote greater resources to the botanical area. The agency has also hinted that it will soon publish a notice in the Federal Register responding to the 1992 citizen petition of the European American Phytomedicine Coalition (EAPC) which seeks recognition of well-established phytomedicines as old drugs in the U.S. for OTC drug review purposes. Summary and Conclusions For many years, botanicals held a very unsure and tenuous place in both American society and FDA regulation. The recent resurgence of botanicals for dietary and medical use has, in part, led to passage of the DSHEA which affected important changes with respect to the regulation of botanicals. This new status as dietary supplements creates both opportunity and also many new questions.


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Ultimately, botanicals in the U.S. may hold no less than five levels of regulatory recognition. They are: • New Prescription Drugs • OTC Drugs • Traditional Medicines • Dietary Supplements • Conventional Foods Depending on the scientific and commercial resources available, various companies may elect to market botanicals in one or more of these categories. Barring an unforeseen reversal of law, botanicals as dietary supplements will continue to enjoy impressive growth, and as the American consumer becomes more familiar with the various dietary and medicinal benefits of these products, they will continue to include botanicals as a part of their life both in the kitchen and in the medicine chest. Literature Cited 1. FDA Almanac, Fiscal Year 1995. 2. Guide to U.S. Food Labeling Law, February 1996.


Botanicals: A Current Regulatory Perspective for ... - ACS Publications

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