FDA Sets Expectations for Improving Therapeutic Consistency in the Development of Botanical Drugs

By James E. Valentine* –

On August 17, 2015, FDA announced the availability of an update to its 11 year old guidance on botanical drug development.  Botanicals are plant materials, algae, macroscopic fungi, and combinations of those things that can be regulated as a food (including a dietary supplement), drug/biologic, medical device, or cosmetic under the Federal Food, Drug, and Cosmetic Act.  The updated guidance covers the development of those botanicals that are that are regulated as drugs (i.e., under an investigational new drug application to support a future new drug application submission, as part of over-the-drug monograph system).  While the general approach to botanical drug development has remained unchanged in the updated guidance, FDA has primarily modified and expanded the 2004 draft guidance to address late-phase development and NDA submission.  The updated guidance still covers these topics in drug development:

1. Description of the product and documentation of prior human experience;
2. Chemistry, manufacturing, and controls (CMCs);
3. Nonclinical safety assessment, including pharmacology and toxicology;
4. Clinical pharmacology and bioavailability; and,
5. Clinical considerations.

Therapeutic Consistency

While there are a number of smaller changes to what FDA requests of sponsors when embarking on clinical trials for botanical drugs, the Agency significantly expanded the quality control measures.  Given the heterogeneous nature of botanical drug products, and that it can be technically challenging to determine a botanical drug’s identity and ensure its consistency, the draft guidance maintains a “totality-of-the-evidence approach” to demonstrate that the commercial batches will be therapeutically consistent with those batches observed during premarket clinical development.  Such quality controls still consist of a combination of (a) botanical raw material controls (e.g., agricultural practice and collection), (b) quality controls by chemical tests, and (c) manufacturing controls.  However, it seems that FDA would like to see additional evidence that supports therapeutic consistency.  As such, the updated guidance includes two new quality control aspects: biological assays and clinical data.

Biological Assays.  While raw material controls and other CMC measures can help establish the identity and ensure the quality of botanical drug products, the draft guidance states that in certain cases information on correlations between such quality parameters and the pharmacological activity or clinical effect may be warranted to ensure that variations in raw materials and drug substance will not affect the product’s therapeutic consistency.  For a biological assay, FDA prefers one that reflects the drug’s known or intended mechanism of action.  At a minimum, FDA would like to see an appropriately validated biological assay that demonstrates accuracy, precision, specificity, linearity, and range.

Clinical Data.  The updated guidance requests clinical data beyond the primary efficacy analyses to show that clinical response to a botanical drug will not be affected by variations of different batches in two ways.  The first approach is to conduct multiple batch analyses, looking at batch effects on clinical endpoints.  This allows quantification of potential heterogeneity in clinical outcomes for subjects who receive different batches in the study.  This is in principle similar to other types of subgroup analysis.  The second approach is to show that clinical response is not sensitive to dose, while also demonstrating that the studied doses are more effective than placebo or control, or not inferior to active treatment.

Applicability of Combination Drug Regulations

Another major expansion to the updated guidance is the addition of a discussion on the applicability of FDA's combination drug regulations.  For a fixed-dose combination drug product, current regulations require sponsors to demonstrate each component’s contribution toward overall efficacy and/or safety.  However, the draft guidance clarifies that these regulations generally do not apply to naturally derived mixtures, such as those found within a single botanical raw material.  Therefore, botanical drug products derived from a single botanical raw material are generally not considered fixed-dose combination drugs because FDA considers the entire botanical mixture to be the active ingredient. 

On the other hand, botanical drug products derived from multiple botanical raw materials are currently considered by FDA to be fixed-combination drugs.  Since demonstrating each botanical raw material’s contribution to efficacy and safety in such a botanical product is not always feasible, FDA is reviewing the requirements for fixed-combination drugs and how they should be applied to botanical drugs.  For now, FDA is requesting nonclinical data from animal disease models or pharmacological in vitro assays to help show the contribution of individual components to the claimed effects.

Other Modifications

In addition, the guidance document’s discussion of Phase 1 and Phase 2 clinical studies for botanical drugs is no longer split into separate recommendations and requirements for (a) marketed products without safety concerns and (b) non-marketed products or products with known safety concerns.  The new document has blended these requirements.  For example, the nonclinical pharmacology and toxicology information needed to support Phase 1 and Phase 2 clinical studies of botanical products still depends on the extent of previous human use, and if currently lawfully marketed in the United States as a dietary supplement, initial clinical studies may still be allowed to proceed without further nonclinical testing.  In the updated guidance, FDA has now further explained that regardless of whether the drug is currently lawfully marketed in the United States, if the anticipated exposure in the proposed clinical trials exceeds that in prior human use (e.g., higher doses or a longer duration), an additional nonclinical pharmacological/toxicological assessment is warranted to adequately address the difference between the prior human use and the proposed clinical trial.

Comments on the draft guidance can be submitted to the public docket through October 16, 2015 here.

*Admitted only in Maryland. Work supervised by the Firm while D.C. application pending.