In June, the U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) issued its final guidance for members of the herb and pharmaceutical industries for the development of drug products from botanicals. The Guidance for Industry: Botanical Drug Products¹ finalizes draft guidance issued in August 2000² which was described in HerbalGram 50.³

To clarify, the final guidance pertains to the process of developing a drug product from a chemically complex botanical and does not apply to the development of highly purified, single chemical compounds derived from botanical sources, like numerous conventional drugs that are made from plants. For example, atropine is made from deadly nightshade (Atropa belladonna L., Solanaceae) and other plant sources (such as Duboisia spp., Solanaceae), colchicine from autumn crocus (Colchicum autumnale L., Liliaceae), digoxin from foxglove (Digitalis purpurea L., Scrophulariaceae), lanoxin from woolly foxglove (D. lanata Ehrh., Scrophulariaceae), and many others. Nor does this guidance deal with the development of dietary supplements from botanicals under the Dietary Supplement Health and Education Act of 1994 (DSHEA).⁴

FDA’s guidance clarifies when a botanical may be marketed under an over-the-counter (OTC) drug monograph and when a New Drug Application (NDA) will be required. More significantly, however, the document explains data requirements for submitting Investigational New Drug Applications (INDs) and NDAs to the FDA for botanical products, including botanicals currently marketed as dietary supplements in the U.S. and abroad. (Note: INDs should not be confused with NDIs [New Dietary Ingredients], the subject of an article in HerbalGram 63.⁵) The guidance also clarifies when, because of the unique nature of botanicals, FDA’s regulatory policies will differ from those applied to synthetic, highly purified drugs. Significantly, when a botanical has been legally marketed as a dietary supplement in the United States and/or a foreign country without any known safety concerns, applicants are not required to submit the same level of documentation concerning preclinical safety (e.g., toxicological studies on animals) and chemistry manufacturing and controls (CMC) that is required for synthetic, highly purified drug substances.

A botanical product is one that is finished and labeled and contains vegetable matter as ingredients. A botanical product may be a drug, food, medical device, or cosmetic, and it is generally regulated depending on its intended use, not its content. When a botanical product is intended for use in diagnosing, mitigating, treating, curing and/or preventing disease, the product is regulated as a “drug.”

Botanical drugs may be marketed under an OTC drug monograph if the indication is subject to nonprescription use (i.e., the drug is indicated for a condition that is self-diagnosable, self-treatable, and, in most cases, self-limiting).

FDA pre-market approval will be required unless the product is an “old drug,” that is, generally recognized as safe and effective (GRASE) for an indication included in the OTC Drug Review. This can be accomplished via a petition to amend an existing OTC drug monograph or via an NDA. A botanical that has been marketed in the United States or in a foreign country for a material time and to a material extent for a specific OTC drug indication may be eligible for consideration in the OTC drug monograph system. The FDA changed its policy to expand “use” to include foreign marketing experience because it believed that under certain circumstances use outside of the United States may appropriately be considered to satisfy the “use” requirements of 21 U.S.C. 321(p).⁶

The manufacturer (or responsible company) of the product would need to submit a citizen petition to FDA to amend the monograph for the addition of the botanical substance as a new active drug ingredient. There should be quality standards established for the botanical drug in the drug section (not the National Formulary or other non-drug sections) of the United States Pharmacopeia (USP). If there is no USP drug monograph, the petitioner should include suitable quality standards in the citizen petition and simultaneously petition the USP for adoption of the standards.

If there is no information on market experience and the available evidence of safety and effectiveness do not warrant inclusion of the product in an OTC drug monograph, the manufacturer must submit an NDA to obtain FDA approval for the botanical drug’s intended use. An NDA for a botanical drug could be used to seek approval for either OTC or prescription use, depending on the indication and safety concerns if used outside a doctor’s care. If the current evidence on safety and effectiveness is insufficient to support an NDA, new clinical studies would be required to establish safety and effectiveness. In this case, an IND would generally be required.

When a drug is published in a final OTC monograph for a specific use, any person (i.e., company) may market a product containing the same active ingredient for the same use. However, when a product is approved under an NDA, the approval is specific to the drug product in the application. Even in the absence of patent protection, the NDA applicant may be eligible for marketing exclusivity for five years (if it is a new chemical entity) or for three years from the time of approval. Therefore, if a company desires marketing exclusivity and the drug is not currently included in an OTC monograph, the company should seek approval of an NDA rather than petition the FDA to amend the monograph. That is, drug approval under an NDA affords the seller more market protection than a petition to amend the OTC monograph, but such a route is obviously more expensive, with potentially larger financial benefits.

When the available data are insufficient to support an NDA for a botanical drug, additional data must be developed under an IND. Under FDA’s regulations applicable to drug products generally, an IND must contain sufficient information to demonstrate that the drug product is safe for testing in humans and that the clinical protocol is properly designed for the intended objectives. The amount of information submitted in an IND depends on a number of factors, including the novelty of the drug, the extent to which it has been studied previously, the drug product’s known or suspected risks, and the developmental phase of the drug. For botanical INDs, the guidance outlines three different scenarios that would require different levels of supporting information, depending on the available marketing data and safety concerns associated with the product:

•Initial clinical trial (Phase 1 and 2) of a marketed botanical product with no known safety issues (Sec. VII). INDs submitted under Section VII would require the least amount of information to show that the product is safe for testing in humans. The IND would need to have information regarding the identity of the botanical and chemical class of the active constituent or marker compound, documentation of use (both historical and current), and limited CMC information. If the product has not been previously marketed in the United States, additional use data, including data on adverse events, CMC, and non-clinical safety information may be needed.

• Initial clinical trial (Phase 1 and 2) of a non-marketed botanical product or a marketed botanical product with known safety issues (Sec. VIII). INDs submitted under Section VIII require more CMC information and documentation of use than Section VII because there is some concern with safety. If the product is the same as a traditional preparation, meets official compendia or other standards, and is used in the traditional manner, previous human experience may be sufficient to support safety. If it is not from a traditional preparation, additional non-clinical safety information may be needed.

• Expanded clinical trial (Phase 3) of any botanical product (Sec. IX). Section IX INDs require more information than Section VII as well. To conduct expanded clinical studies, more detailed information on CMC and nonclinical safety data is required. Additional toxicology studies would generally be needed to support wider use, regardless of whether the product is currently marketed in the United States or elsewhere as a dietary supplement.

The FDA’s new guidance document contains recommendations for establishing quality standards for botanical drugs. The guidance also clarifies that FDA’s regulatory policies toward botanical INDs (i.e., chemically complex herbal preparations) differ somewhat from those applied to synthetic, highly purified drugs. FDA’s new policy facilitates the clinical development of botanical drugs during the early phases of drug development (Phase 1 and 2). Indeed, this is a positive development.

Significantly, however, in order to gain marketing approval as a drug, FDA indicates that “a botanical will be treated like any other new drug under development”—that is, a conventional single chemical entity drug. [See Section IX; C. Nonclinical Safety Assessment in meeting requirements of FDA regulations at 21 CFR Section 312.23.] At the NDA stage, an array of tests will generally be required that may not be appropriate or feasible for chemically complex botanical preparations, including nonclinical pharmacokinetic/toxicokinetic studies and in vivo bioavailability and pharmacokinetic studies. In addition, when the active constituent is not known, the characteristic markers should be demonstrated to be clinically relevant by direct or indirect correlation to the clinical outcome. In practice, this approach may preclude chemically complex botanical preparations from obtaining drug status under an NDA. While a goal of the FDA’s guidance is to provide the botanical industry with greater direction for engaging in the early clinical phases of botanical drug research, the agency does not appear to be willing to apply a rational policy throughout the entire process to permit approval of a botanical drug under an NDA.

Rakesh M. Amin is a pharmacist and attorney in Chicago specializing in intellectual property issues, labeling, and related matters regarding dietary supplements (www.amin-law.com). Holly M. Bayne is an attorney in the Washington, D.C. area specializing in legal and regulatory matters related to herbs and dietary supplements.

References:

1. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), Guidance for Industry: Botanical Drug Products. June 14, 2004. Available at: http://www.fda.gov/cder/guidance/index.htm.

2. U.S. Food and Drug Administration. Draft Guidance for Industry on Botanical Drug Products; Availability. Docket No. 00D-1392, CDER 97113. Pages 49247-49248. FR Doc. 00-20343. August 2000. Available at: http://www.fda.gov/OHRMS/DOCKETS/98fr/001392gd.pdf.

3. Bayne H. FDA Publishes New Draft Guidance for Botanical Drug Products. HerbalGram. 2000;No. 50:68-69.

4. 21 U.S.C.A. §342(f)(1)(A)(i)(ii), Dietary Supplement Health and Education Act of 1994, Public Law 103-417, 103^rd Congress, October 25, 1994. Available at http://www.fda.gov/opacom/laws/dshea.html.

5. Noonan C, Noonan WP. New dietary ingredients: DSHEA provides protection from potentially unsafe new ingredients with no prior market history in the U.S. HerbalGram. 2004;No. 63:70-74.

6. U.S Food and Drug Administration. Additional Criteria and Procedures for Classifying Over-the-Counter Drugs as Generally Recognized as Safe and Effective and Not Misbranded. 67 Fed. Reg. 3060 January 23, 2002.