FDA Clarifies Requirements for Marketing Botanical Drugs Under an NDA

Companies planning to market a botanical drug under an NDA must be able to prove the therapeutic consistency of the product, since the potential for variation is critical, the FDA says.

This can be achieved via analytical tests and process validation, biological assays, clinical data and controls of the botanical raw material, according to revised guidance released last week.

Specific information on the plants and agricultural practices used, geographic locations and collection and processing methods should be provided, along with any chemical tests that were performed. The manufacturing sites used to produce the drug should be the same that produced the drug used in the Phase 3 efficacy trials.

The guidance, which updates a 2004 version, adds new sections on NDA submissions and late-phase development.

Sponsors also need to perform stress stability studies to identify any degradation of the drug substance and establish retest periods and expiration dates based on those studies, the FDA says. The agency encourages companies to schedule a pre-NDA meeting at least two months before making a formal submission.

Any postapproval changes, such as agricultural sites or collection practice, should be carefully considered and may require additional studies to ensure that potency and other characteristics of the drug aren’t affected. How much data is needed to support a change will be determined case by case, the agency says.  

For Phase 3 studies, the FDA suggests using multiple batches of the botanical drug to examine the clinical effects across batches. This will help the sponsor understand what variations are clinically relevant and the range of variability that can be tolerated to maintain a botanical drug’s identity, efficacy and safety.

Sponsors should also provide a comparison of the investigational drug to be used in the INDand botanical drugs used in studies referenced in earlier phases of development, the FDA says. When there is a change in the manufacturing process, sponsors should provide a comparison of the changes because even minor modifications can alter clinical effects and raise questions about the applicability of earlier clinical data, the agency adds.

The FDA says bridging studies may be needed if there is uncertainty about the similarity of different batches. Sponsors should retain sufficient quantities of the botanical raw material and drug product from different batches in case future chemical characterization or pharmacological or toxicological testing is needed.

To read the revised draft guidance, go to www.fdanews.com/08-17-17-BotanicalDraft.pdf. — Kellen Owings