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By Brad Douglass, EAS Consulting Group Independent Consultant

The Food and Drug Administration’s approval of Fulyzaq (crofelemer), an anti-diarrheal drug for HIV/AIDS patients, was a first for an oral, prescription botanical drug. Prior to that approval, the topical preparation Veregen (sinecatechins), a green tea extract used to treat genital warts, was the sole prescription, botanical drug awarded New Drug Application (NDA) approval.

With the experience gained from these two approvals and a number of other botanical Investigational New Drug (IND) applications, the Botanical Review Team (BRT) of the Center for Drug Evaluation and Research (CDER) has been working on developing an updated Botanical Drug Products Guidance for Industry.

A distinct regulatory category for “herbal medicine products” does not exist in the U.S. as it does in Canada and Europe. Instead, a botanical drug product, like all drugs, is defined by the intended use in the diagnosis, cure, mitigation, prevention or treatment of disease in humans. Any dosage form or route of administration available to drugs as a class (liquid, capsule, topical, injection, etc.) is also possible for the subset of botanical drugs.

One characteristic that makes botanical drugs unique is composition. They may consist of vegetable material derived from plants, algae, and macroscopic fungi, but not highly purified or chemically modified substances of botanical origin. Botanical drugs are likely to be complex mixtures that lack a distinct active ingredient or even discernible active components. This can make product consistency and stability more challenging, and is reflected in additional Chemistry, Manufacturing, and Controls (CMC) requirements.

In addition, prior human use often sets botanical products apart. For this reason, the agency reviews botanical IND applications to determine if existing data can stand in for typical requirements. For example, non-clinical toxicity studies are often waived for botanicals extensively used in traditional systems of medicine or as dietary supplements.

A new guidance document will likely refine the agency’s treatment of a few key areas. These include the means for controlling product consistency and how a product composed of multiple parts of the same plant will be evaluated.

FDA’s primary concern is the therapeutic consistency of marketed batches of a drug product. But unlike with purified non-botanical drugs, CMC requirements for botanical drugs may not be relied upon solely to control therapeutic consistency. Updates in this area are expected, including refined criteria for analytical fingerprinting and further recommendations for developing clinically relevant bioassays. Clinical dose response data, especially in cases of relatively flat dose response (cf. Veregen) will probably be addressed. Further recommendations for demonstrating negative batch-to-batch treatment effects and for monitoring post-marketing issues are also likely.

The updated guidance may also seek to clarify what constitutes a single ingredient botanical drug product and what constitutes a combination product. To date, FDA has not objected to naturally occurring mixtures of components in a single plant part as constituting a single ingredient. However, using different parts (e.g. root and leaves) of the same plant creates a combination product, as does mixtures of more than one botanical.

Many in the pharmaceutical industry have commented that the existing botanical dietary supplements are a disincentive to rigorous drug development because their existence may negate exclusivity. Meanwhile, many in the dietary supplement industry consider the cost of NDA approval too high.

The cost of botanical drug approval is unlikely to diminish, as the U.S. regulatory framework established for botanical drugs is here to stay. However, this does not necessarily imply that botanical drugs will remain a category that averages 1-2 approvals per decade.


Changing Industry Dynamics

As dietary supplement ingredient manufacturers continue to innovate and develop ever more sophisticated, clinically substantiated products, the cost differential between launching a dietary supplement ingredient and obtaining approval of a botanical drug will decrease. The supplement industry may find that harmonizing ingredient R&D strategies with botanical drug regulatory expectations will provide both a pre-clinical/clinical and a funding runway for botanical drug development.

As the pharmaceutical industry continues to move further into the dietary supplement space, there will be an increasing intermingling of resources and ideas amongst business units. This could revive past natural product discovery paradigms. Some firms may even attempt to use the Orphan Drug and FDA Breakthrough Therapy to facilitate botanical drug approval.

Although an abbreviated new drug application (ANDA) path is possible for botanical drugs, in principle, FDA recognizes that it may be extremely difficult to prove the necessary equivalence amongst two “similar” products to demonstrate that they are pharmacologically identical or therapeutically interchangeable. In practice this may preclude generic botanical drugs.

If dietary supplement manufacturers made comparative claims to botanical drugs, FDA could act to stamp out such illegal disease/treatment claims. This could help diminish one projected threat to exclusivity. And unlike dietary supplements, prescription botanical drugs would be reimbursable under [some] medical insurance plans, helping their competitiveness.

In summary, the long-term prospects for botanical drugs may be rosier than they currently appear. In fact, firms in the business of producing health products may miss an opportunity if they fail to consider this relatively new regulatory path.

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