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Are Botanical Drugs, Herbal Medicinal Supplements, and Natural Product Drugs 505(b)(2)s, Too?

For centuries, botanical remedies have been used in many cultures to treat various diseases. In recent years, pharmaceutical companies have turned to botanical drugs for alternative medicines to treat diseases with unmet medical needs.

The FDA also recognizes the interest in developing botanical products and released a draft guidance in 2004, finalized in 2016 as Botanical Drug Development Guidance for Industry (Guidance used in place throughout), which outlines the unique drug development and review process for botanical drug products. Botanical drug products can be approved via the 505(b)(2) pathway. However, knowledge of how to leverage existing information in the literature to reduce the size and scope of the development program is key to a botanical drug’s 505(b)(2) success.

What Is a Botanical Drug?

According to the Guidance, botanical products that can be regulated as drugs include “plant materials, algae, macroscopic fungi and any combinations thereof […] with the intended use of diagnosing, curing, mitigating, or preventing disease.” It is important to distinguish botanical drug products from botanical products marketed as dietary supplements. Dietary supplements are not considered drugs and cannot make labeling claims about treating diseases. For a more in‑depth discussion on how dietary supplements are regulated, refer to our previous blog post.

To date, there are two botanical products that have been approved for marketing as prescription drugs: Veregen® (sinecatechins topical ointment, Fougera Pharmaceuticals, Inc.) and Mytesi™ (crofelemer oral delayed release tablets, Napo Pharmaceuticals, Inc.). Veregen® was approved in 2006 for the treatment of genital warts, and Mytesi™ was approved in 2012 for the treatment of non-infectious diarrhea in HIV/AIDS patients also taking antiretroviral therapy.

Setting Precedents

In the approval documents for Mytesi™, the FDA acknowledged that while INDs for botanicals were becoming more common, NDAs were quite infrequent in 2012. Therefore, the FDA’s approach to specific regulatory concerns associated with botanicals were still evolving.2 The FDA used the Mytesi™ approval as an opportunity to summarize the Guidance and explain the reasoning behind the precedent-setting issues.

The FDA states “botanical drug products may remain as complex mixtures; both purification and identification of the active ingredients in botanicals are optional and not required.” Further, the FDA notes that the interpretation of regulations, including definitions of ‘identity’, ‘active ingredient’, ‘purity’, needs to be “extended from a narrow, chemical mindset to accommodate the complex nature of botanical drug substance.” For example, the ‘identity’ of botanicals must include, in addition to the standard chemical analyses, the source of raw materials and other non-CMC data (e.g. species identification, geographic location of harvesting, processing, and bioassays, if available).

The FDA discusses utilizing clinical information from the extensive human use of well-known botanical products to help with new drug development and regulatory review. Information ranging from chemical characterization to pharmacological and clinical studies can give some hint about the therapeutic consistency and safety of botanical drug products. Botanical drug products can utilize existing published evidence of safety in humans in place of new nonclinical toxicity studies. Botanical drug products fall under the 505(b)(2) pathway by utilizing existing data conducted not by or for the new drug applicant.

Since botanical substances are typically mixtures of several related chemical entities, the FDA acknowledges it is revising the policy on combination drug products to facilitate the development of new botanical drugs. The FDA states “natural mixtures in a single part of a single plant will not be considered as a fixed combination drug product and thus is not subject to the combination requirement.”

Important Considerations for Botanical Drug Development

The heterogenous nature of botanical drugs can make it difficult to ascertain if one or all the constituents are active. Thus, it is critical to ensure the consistency of therapeutic effect across product batches. According to the Guidance, therapeutic consistency can be supported by a “totality of evidence” based upon the following:

Botanical drugs must adhere to current Good Manufacturing Processes (cGMP), which start at the raw material level. It is important to ensure consistency in geographic and seasonal harvesting to prevent variations in the botanical substance.

  • Quality control by chemical test(s) and manufacturing control

Standard CMC characterizations with multiple analytical techniques should be conducted.

  • Biological assay

For botanicals with several possible active ingredients, a clinically relevant bioassay is important for ensuring quality control in post-approval manufacturing.

  • Clinical data

Differences in clinical effects of various product batches can be tested in Phase 3 studies to determine if there is a “treatment-by-batch” effect.

Based on the chemistry reviews for the approved botanical drugs Veregen® and Mytesi™, quality control of the botanical drug substance was one the critical factors that led to roadblocks during development. For example, the Agency did not initially recommend approval of Mytesi™ (crofelemer) due to insufficient information to assure the identity, strength, purity and quality of the drug product.3 The Agency determined the characterization of the botanical drug substance was not satisfactorily carried out to determine its structural identity, and the botanical drug substance and product specifications were not adequate. To address those issues, the Sponsor provided additional analyses to ascertain the identity of crofelemer. However, the Agency still determined that the identity tests were insufficient to give an unequivocal identity of the drug. Nevertheless, the Agency acknowledged that the composite results from the combined tests were expected to provide reasonable insight to the identity of crofelemer. The Agency’s subsequent recommendations for quality control of crofelemer were eventually incorporated into the Guidance on therapeutic consistency listed above.

Botanical Drugs as 505(b)(2)s

Many botanical substances have a long-documented history of human use. Since these drugs may have been previously marketed unapproved or evaluated in clinical studies reported in public literature, this information can be used to support a 505(b)(2) NDA. Are you considering developing a botanical drug or unsure if your current product can be approved via the 505(b)(2) pathway? Premier Consulting can provide an assessment of your product and help facilitate interactions with the Agency regarding your development program. To learn more about how Premier Consulting can help, contact us.


Angela Drew, PhD
Product Ideation Consultant