US FDA Botanical Drug Development Guidance for Industry (2016)
Frequently Asked Questions
Are Investigational New Drug (IND) applications required for clinical studies of botanical products that are also lawfully marketed as dietary supplements in the U.S.?
Yes. If a lawfully marketed botanical dietary supplement is studied for its effects on diseases in the proposed investigation (i.e., to cure, treat, mitigate, prevent, or diagnose disease including its associated symptoms), then it is an investigational new drug and will be subject to IND requirements. This applies to studies in INDs sponsored for both commercial and academic research purposes.
Are INDs required for studies evaluating the uses of botanical dietary supplement as dietary supplements?
No. When a lawfully marketed botanical dietary supplement is studied for its dietary supplement use (i.e., structure and/or function claims), an IND is not required. Structure and function claims are statements that describe the effect a dietary supplement may have on the structure or function of the human body. Refer to FDA’s Center for Food Safety and Applied Nutrition (CFSAN) webpage on dietary supplements for further information.
What is a Dietary Supplement?
A dietary supplement is a product taken by mouth that contains a dietary ingredient intended to supplement the diet.
The dietary ingredients in these products may include: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites.
Dietary supplements can also be extracts or concentrates, and may be found in many forms such as tablets, capsules, softgels, gelcaps, liquids or powders.
Dietary supplements can also take other forms, such as a bar. If they do, information on their label must not represent the product as a conventional food or a sole item of a meal or diet.
Can an IND with a phase 3 study be submitted when the non-U.S. phase 1 and 2 studies were not conducted under an IND?
Yes. Clinical data collected from non-U.S. phase 1 and phase 2 studies may be used to support a phase 3 study in a new IND. The botanical product (drug substance and formulation/dosage form) used in the proposed phase 3 study should be the same as the product in phase 1 and phase 2 clinical studies and also in the preclinical studies. If different formulations were used, the bioequivalence of all tested products will need to be determined.
It appears that the changes in regulatory approaches described in the Botanical Guidance concern only IND applications. How will the regulatory approaches be applied to the final New Drug Application (NDA) requirements for botanical drugs?
To facilitate the clinical development of botanical drugs, CDER focuses discussions in the Guidance on INDs first, especially the initial phases of clinical development. For NDA approval, the standards for the safety and efficacy of a botanical drug are the same as those for a conventional chemical drug with the same indication. However, the quality standards for a botanical drug may be different from that for a purified chemical drug. The Guidance contains recommendations for establishing appropriate quality standards for botanical drugs.
Protecting intellectual property rights is a significant concern for sponsors developing new drugs from well-known botanical preparations. How does CDER protect the confidentiality of the sponsor’s submission? What kind of IND and NDA data may be released without prior permission from the sponsor?
IND information generally is not publicly available (see §§ 312.130, 314.430). Once an NDA is approved, FDA may release certain safety and efficacy information (§ 314.430(e)). Manufacturing information (including information related to growers and suppliers) provided in an NDA or a Drug Master File (DMF) is considered proprietary and may not be released (21 U.S.C. 331(j); 21 CFR 20.61).
One of the major premises of the new Botanical Guidance is that many botanical products have been used by a large population for long period of time; therefore, for many botanicals it is presumed that it is safe to proceed with clinical trials without conventional preclinical studies. What kinds of data are sponsors required to submit to document previous human experience?
CDER recognizes that prior human experiences with the botanical products may be documented in many different forms and sources, some of which may not meet the quality standards of modern scientific testing. Sponsors are encouraged to provide as much data as available. The quality of the submitted data will have to be assessed case-by-case. CDER maintains the same standards for safety and efficacy for marketing approval whether it is a botanical-sourced product or a purified chemical. The Botanical Guidance simply recommends the use of different types of data for preliminary safety consideration (e.g., large quantities of mostly anecdotal human data in place of well-controlled animal studies) of human trials in an IND.
In many cases, botanical therapies are highly individualized with variations in the relative contents of multiple plant ingredients tailored for each patient. Is a sponsor required to submit a separate IND for every change in the composition of individual constituents if similar patients are being treated for the same indication?
Multiple formulations may be included in one IND as long as they are being studied in a single clinical trial. It is important to provide in the IND application the rationale for using multiple formulations and the criteria used to assign patients to different treatment regimens. The final determination regarding formulation variations of this type is made by the review division.
Many medicinal plants with therapeutic potentials have toxicity. Is it possible to study known toxic botanicals?
Yes, in some cases this can be done. The CDER review division will evaluate the known risk and the potential benefit of an investigational new drug in the proposed study. When the potential benefit of an investigational drug outweighs its risk in the studied patient population, an IND is often allowed. For example, a relatively higher level of toxicity of an investigational drug used in a study of terminally-ill cancer patients may be acceptable.
Botanical preparations may be intravenous, topical, or inhalation formulations. Are these non-oral formulations evaluated any differently than oral formulations under the Botanical Guidance?
The Botanical Guidance applies to all dosage forms of botanical products. As with conventional chemical drugs, the type of quality testing for botanical products varies from dosage form to dosage form. For example, injectable products are required to be sterile and pyrogen-free whereas oral tablets may not. In addition, the human experience of an orally administered dietary supplement may not be applicable to an identical botanical product with the same ingredient(s) when given by a non-oral route of administration.
Once a botanical is studied under an IND or approved as a new drug in an NDA, is its status as a dietary supplement jeopardized?
No, dietary supplements lawfully marketed before the IND and subsequent NDA approval are not at risk. Please refer to the CFSAN website New Dietary Ingredients in Dietary Supplements for further information.
Will CDER give the same administrative considerations for botanical drug products as for other drugs?
Yes. Administratively, CDER treats botanical products the same as any other drug products.
How does a sponsor request a meeting?
Information on the meeting process is available in the Guidance for Industry - Formal Meetings for Sponsors and Applicants for PDUFA Products.