Botanical/Drug Interaction Studies Should Be Based On Safety Risk - CHPA

"Extensive" investigation of drug-drug interactions for botanical drug products is not necessary unless a safety risk is indicated by adverse event reports or other animal or clinical data, the Consumer Healthcare Products Association asserts.

"Any interaction study should be triggered by a scientifically based rationale," CHPA maintains in Oct. 10 comments responding to FDA's August draft guidance on botanical drug products.

"The recommendation for 'extensive' research without a clue as to where the research should be directed puts an unreasonable financial burden on companies and results in a disincentive to undertake research on botanical drugs," CHPA states.

Among its provisions, the guidance states that "interactions with other commonly used medicines, either synthetic/highly purified or botanical, may occur with botanicals and should be investigated extensively."

The guidance explains when a botanical may be marketed under an OTC drug monograph and when NDA approval is required. It also provides direction on submitting investigational new drug applications for botanicals, including products currently marketed as foods and dietary supplements (¹ (Also see "Botanical Drug Product Guidance Sets Foreign Marketing Data Requirements" - Pink Sheet, 14 Aug, 2000.)).

CHPA says it supports the guidance's flexible approach regarding the scope and extent of documentation on preclinical safety and chemistry and manufacturing and controls (CMC) needed to support initial clinical studies of botanicals targeted for the NDA process, but seeks clarification in several areas, including required IND information for different categories of botanicals.

For botanicals legally marketed under the Dietary Supplement Health & Education Act, "there will often be very little new CMC or toxicologic data needed to initiate [Phase I and II clinical] trials, as long as there are no known safety issues associated with the product," the guidance states.

"It is important that FDA clarify what it means by 'no known safety issues,'" the trade association maintains.

"For example, CHPA does not believe that a botanical product such as St. John's wort with known and well-characterized drug-herb interactions (e.g., protease inhibitors) should have to initiate new toxicologic data, particularly if the clinical design precluded subjects on selected prescription drugs and it is proposed that the label bear an appropriate contraindication against concomitant use with prescription drugs," CHPA says.

Regarding CMC information, the draft guidance notes that in the initial stage of clinical studies on a botanical drug, "it is generally not necessary to identify the active constituents or other biological markers or to have a chemical identification and assay for a particular constituent or marker," but that by the time Phase III studies are underway, "efforts should...be made to identify active constituents."

However, CHPA asserts "identification of actives is simply not needed where clinical effect has been demonstrated and biological markers have been used for quality control purposes in the manufacturing process."

"Since there is acknowledgement in the FDA draft guidance that botanicals are complex materials, are clearly unique in the chemical composition from purified drug products, and are often characterized by marker compounds for analytical/quality purposes in the manufacturing process, then the guidance should not imply a requirement to find the active constituents," the association opines.

CHPA additionally is seeking more specific guidance on FDA's statement that active constituents "might not need to be identified during the IND stage or in an NDA submission if this is shown to be infeasible."

"Given that for botanicals it is not uncommon for the whole extract to be the 'active constituent,' why would it be necessary a priori to identify all individual constituents, especially where the active constituent is not known or activity cannot be attributed to one constituent," the association asks.

Finally, CHPA recommends the agency consider issuing a similar guidance for non-botanical dietary supplements containing animal parts, amino acids or vitamins and minerals.