On December 28, 2016, FDA released its final guidance on botanical drug development. According to FDA, “the unique nature of botanical drugs” requires “regulatory policies that differ from those applied to nonbotanical drugs, such as synthetic, semi-synthetic, or otherwise highly purified or chemically modified drugs, including antibiotics derived from microorganisms.”
Definition of Botanicals
FDA defines botanicals to mean products “that include plant materials, algae, macroscopic fungi, and combinations thereof.” Products that contain animals, animal parts, or minerals are not considered botanicals, nor are products derived from a genetically modified botanical species, or products that are the result of fermentation.
FDA will require the following information for each botanical compound:
- Scientific name of the plant species (genus and specific epithet);
- Name of botanist who originally described the species;
- Subspecies rank and cultivars;
- Family name;
- Botanical parts used as the botanical raw material;
- Common or usual name of the plant in English and in the language of the “region in which the species and the raw material have medicinal or other significance”;
- Active constituents or chemical constituents, as appropriate; and
Prior Human Experience
FDA will require information to “bridge the past experience” of the botanical in traditional medicine to the current clinical investigation. Examples of such data include comparisons of the botanical raw material with traditional preparations, and comparisons of the clinical settings with traditional uses.
CMC for Botanical Raw Materials
FDA will require that trained personnel “identify the plant species, plant parts, alga, or macroscopic fungus used via methods including organoleptic, macroscopic, and microscopic examination.” Botanical raw material suppliers and drug substance manufacturers for each batch must retain samples of the plant and the plant parts.
FDA will require sponsors to provide habitat information for the plant species. The sponsor must tell FDA whether the plant species is subject to either the Endangered Species Act or the Convention on International Trade in Endangered Species of Wild Fauna and Flora, or if the plant species grows in a critical habitat. FDA regards an application for a drug derived from plants taken from the wild as an “extraordinary circumstance” requiring the submission of an Environmental Assessment.
FDA will require sponsors to comply with both Good Manufacturing Practices and Good Agricultural and Collection Practices, “to cover the way in which the botanical raw material is grown, collected, processed, and stored.” FDA will also require sponsors to explain the rationale “for the point at which production of the drug substance begins.”
Batch Control & Change Management
FDA is concerned about the therapeutic consistency of botanical drugs because “[b]atch-to-batch variations . . . are known to exist in different batches of the botanical drug substances.” As a result, FDA finds it “of both scientific and regulatory interest to learn the impact of such variations on the therapeutic effect of botanical drug products. “
FDA recommends that sponsors establish three or more large cultivation sites or farms that are representative of each growing region for each of the botanical raw materials. FDA also urges sponsors to exercise cautions with post-approval changes in the agricultural location or harvesting practices. FDA notes that “[f]or botanical drug products, the effect of changes may not be easily evident.” FDA also notes that changes to collection and processing methods “could change the chemical profile of the drug substance in the resulting botanical drug product and may warrant bridging studies to justify reliance of previous clinical testing results.”
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In most other material respects, FDA will subject an application for a new botanical drug to the same process as an application for any other new drug. Botanicals will receive the same market exclusivity as any other new drug, and botanical drugs will be eligible for OTC and generic status as appropriate.
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