Guidance For Industry1 Botanical Drug Products I.

INTRODUCTION

This guidance explains when a botanical drug may be marketed under an over-the-counter (OTC) drug monograph and when FDA approval of a new drug application (NDA), submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 355(b), is required for marketing. In addition, this document provides guidance to sponsors on submitting investigational new drug applications (INDs) for botanical drug products, including those botanical products (or botanicals) currently lawfully marketed as foods and dietary supplements in the United States.

This guidance also discusses several areas in which, because of the unique nature of botanicals, FDA finds it appropriate to apply regulatory policies that differ from those applied to synthetic, semisynthetic, or otherwise highly purified or chemically modified drugs (including antibiotics). (This latter group of drug substances is referred to in this guidance as synthetic or highly purified drugs.) In particular, the guidance states that applicants may submit reduced documentation of preclinical safety and of chemistry, manufacturing, and controls (CMC) to support an IND for initial clinical studies of botanicals that have been legally marketed in the United States as dietary supplements or cosmetics without any known safety concerns.

II. BACKGROUND

Botanical products are finished, labeled products that contain vegetable matter as ingredients.2 The FD&C Act characterizes a product primarily based on its intended use. For a botanical product, the intended use may be as a food (including a dietary supplement), a drug (including a biological drug), a medical device (e.g., gutta-percha), or a cosmetic as shown by, among other things, the product_s accompanying labeling claims, advertising materials, and oral or written statements (21 CFR 201.128).

For the purposes of this document, the term botanicals includes plant materials, algae, macroscopic fungi, and combinations thereof. It does not include fermentation products such as products fermented with yeast, bacteria, and other microscopic organisms, even if previously approved for drug use or accepted for food use in the United States, nor does it include highly purified or chemically modified substances derived from botanical sources, such as paclitaxel, because these substances can readily be fully characterized. This guidance addresses only those botanical products that are regulated by CDER.

Although this guidance does not address drugs that contain animals or animal parts (e.g., insects, annelids, shark cartilage) and/or minerals, either alone or in combination with botanicals, many scientific principles described in this guidance may also apply to those products. When a drug product contains botanical ingredients in combination with either (1) a synthetic or highly purified drug or (2) a biotechnology- or other naturally-derived drug, this guidance only applies to the botanical portion of the product.

III. GENERAL REGULATORY APPROACHES

Many botanical products are used widely in the United States and are often marketed as dietary supplements. Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), an orally ingested product that meets the definition of a _dietary supplement_ under section 201(ff) of the FD&C Act may be lawfully marketed using a statement that (1) claims a benefit related to a classical nutrient deficiency disease (and discloses the prevalence of the disease in the United States), (2) describes how the product is intended to affect the structure or function of the human body, (3) characterizes the documented mechanism by which the product acts to maintain such structure or function, or (4) describes general well-being from consumption of the product (section 403(r)(6)(A) of the FD&C Act, 21 U.S.C. 343(r)(6)(A)). The manufacturer must have substantiation that such statement is truthful and not misleading (section 403(r)(6)(B) of the FD&C Act, 21 U.S.C. 343(r)(6)(B)). In addition, the statement must contain, prominently displayed and in boldface 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_ (section 403(r)(6)(C) of the FD&C Act, 21 U.S.C. 343(r)(6)(A)).3

FDA has issued regulations defining the types of statements that can be made concerning the effect of a dietary supplement on the structure or function of the body under section 403(r)(6)(a) of the FD&C Act (65 FR 1000; January 6, 2000). The regulations distinguish these statements from the types of statements that require prior approval as drug claims under section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), or prior authorization as health claims under section 403(r)(1)(B) and (r)(5)(D) of the FD&C Act.

A dietary supplement statement of the type described above may not claim to diagnose, mitigate, treat, cure, or prevent a specific disease or class of diseases (section 403(r)(6) of the FD&C Act, 21 U.S.C. 343(r)(6)). A botanical product is a drug under section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), if it is intended for use in diagnosing, mitigating, treating, curing, or preventing disease (except for a product marketed with certain health claims under sections 201(g)(1) and 403(r) of the act). Such a drug product must be marketed under an approved NDA4 unless the product is excluded from the definition of a new drug under section 201(p) of the FD&C Act. Certain products that FDA determines are generally recognized as safe and effective in accordance with section 201(p) may be marketed under FDA_s OTC drug monograph system.

A. Marketing Under OTC Monograph Versus Approved NDA

A botanical drug product may be marketed in the United States under (1) an OTC monograph or (2) an approved NDA or ANDA. A botanical product that has been marketed in the United States for a material time and to a material extent for a specific OTC drug indication may be eligible for inclusion in an OTC monograph codified in 21 CFR Parts 331-358. The manufacturer would need to submit a petition to amend the monograph to add the botanical substance as a new active ingredient in accordance with 21 CFR 10.30.

Under current regulations, if there is no marketing history in the United States for a botanical drug product,5 if available evidence of safety and effectiveness does not warrant inclusion of the product in an OTC monograph, or if the proposed indication would not be appropriate for nonprescription use, the manufacturer must submit an NDA to obtain FDA approval to market the product for the proposed use (sections 201(p) and 505 of the FD&C Act). An NDA for a botanical drug could seek approval for either prescription or OTC use, depending on the indication and characteristics of the product and whether it is safe for use outside of the supervision of a practitioner licensed by law to administer it. If existing information on the safety and efficacy of a botanical drug product is insufficient to support an NDA, new clinical studies will be needed to demonstrate safety and effectiveness.6

When a final OTC drug monograph is published for a specific use of a botanical drug, any person can market a product containing the same substance and for the same use, provided the labeling and other active ingredients (if present) are in accord with all relevant monographs and other applicable regulations. In contrast, when a product is approved under an NDA, the approval is specific to the drug product that is the subject of the application (the applicant's drug product), and the applicant may be eligible for marketing exclusivity for either 5 years (if it is a new chemical entity) or 3 years from the time of approval, even in the absence of patent protection. During the period of exclusivity, FDA will not approve, or in some cases even review, certain competitor products unless the second sponsor conducts all studies necessary to demonstrate the safety and effectiveness of its product. Therefore, if a person who wishes to market a botanical drug product that is not included in an existing OTC monograph desires marketing exclusivity for the product, they should seek approval of an NDA rather than petition the agency to amend a monograph. Appendix A contains a schematic showing different regulatory approaches that can be taken for marketing botanical drug products in the United States, including OTC monograph and NDA procedures.

B. CMC Information for Botanical Drug Products

Botanical drug products have certain unique characteristics that should be taken into account in the application of FDA regulations and guidance. Botanical drugs are derived from vegetable matter and are usually prepared as complex mixtures. Their chemical constituents are not always well defined. In many cases, even the active constituent in a botanical drug is not identified, nor is its biological activity well characterized. Therefore, the CMC documentation that should be provided for botanical drugs will be different from that for synthetic or highly purified drugs, whose active constituents can be more readily chemically identified and quantified. For example, active constituents in a botanical drug might not need to be identified during the IND stage or in an NDA submission if this is shown to be infeasible. In such circumstances, FDA will rely instead on a combination of other tests (e.g., spectroscopic or chromatographic fingerprints, chemical assay of characteristic markers, and biological assay), controls (e.g., strict quality controls of the botanical raw materials and adequate in-process controls), and process validation (especially for the drug substance) to ensure the identity, purity, quality, strength, potency, and consistency of the botanical drug.

C. CMC and Toxicology Information to Support Initial Studies

Many botanical products are legally available in the United States as dietary supplements. Given the wide availability of such products outside of clinical trials, it is important to assess the effectiveness of such products. The preclinical pharmacology and toxicology information that should be provided for legally available botanical products with no known safety issues during initial clinical trials may be markedly reduced (in most cases, additional toxicology and CMC data will not be required) compared to that expected for synthetic or highly purified new drugs that are not legally marketed and for which there is no prior human experience (see 21 CFR 312.22(b)).

D. Applicability of Combination Drug Regulations

Botanical drug products that are derived from a single part of a plant (e.g., leaves, stems, roots, seeds), or from an alga or macroscopic fungus (e.g., a mushroom), are not considered to be fixed-combination drugs within the meaning of 21 CFR 300.50 and 330.10(a)(4)(iv). Consequently, they would not have to meet the requirements for combination drugs, principally the need to demonstrate that each component or active ingredient makes a contribution to claimed effects. Botanical drugs composed of multiple parts of a single plant species, or of parts from different plant species, currently are subject to the combination drug requirements. However, FDA intends to propose revisions to its regulations to allow for the exemption of such botanical drugs from application of the combination drug requirements under certain circumstances.

NUTRI SPORT PHARMACAL INC.
200 NORTH CHURCH ROAD FRANKLIN, NJ 07416

PHONE 1-973-209-7200
TOLL FREE 1-888-703-3300
FAX 1-973-209-4422

EMAIL Vince Paternoster or William Di Bernard or John Heck - Sales