Particular attention should be paid to the issues of complex botanicals and clinical dosing. Quality control of complex botanicals is difficult, but must be accomplished, because it is not ethical to administer an unknown product to patients. The use of a suboptimal dose that is safe but ineffective does not serve the larger goals of NCCAM, the CAM community, or public health. Although the trial would indicate only that the tested dose of the intervention was ineffective, the public might conclude that all doses of the intervention are ineffective, and patients would be denied a possible benefit from the intervention. Overdosing, on the other hand, might produce unnecessary adverse effects. Phase I/II studies should be conducted first to determine the safety of various doses, and the optimal dose should then be tested in a phase III trial. As a result, maximum benefit would be seen in the trial; also, any negative result would be definitive.
To a great extent, the difference between a dietary supplement and a drug lies in the use of the agent, not in the nature of the agent itself. If an herb, vitamin, mineral, or amino acid is used to resolve a nutritional deficiency or to improve or sustain the structure or function of the body, the agent is considered a dietary supplement. If the agent is used to diagnose, prevent, treat, or cure a disease, the agent is considered a drug. This distinction is key when the FDA determines whether proposed research on a product requires an investigational new drug (IND) exemption. If the proposed investigation of a lawfully marketed botanical dietary supplement is to study its effects on diseases (i.e., to cure, treat, mitigate, prevent, or diagnose a disease and its associated symptoms), then the supplement is more likely to be subject to IND requirements. The FDA has worked with NCCAM to provide direction to investigators and recently created a Botanical Review Team to ensure consistent interpretation of the document Guidance for Industry--Botanical Drug Products.b Such FDA guidance is currently unavailable for other products (e.g., probiotics). bSee www.fda.gov/cder/guidance/index.htm under "Chemistry."
Similarly, little attention has been paid to the quality of probiotics. Quality issues for probiotic supplements may include:
- Viability of bacteria in the product
- Types and titer of bacteria in the product
- Stability of different strains under different storage conditions and in different product formats
- Enteric protection of the product
Therefore, for optimal studies, documentation of the type of bacteria (genus and species), potency (number of viable bacteria per dose), purity (presence of contaminating or ineffective microorganisms), and disintegration properties must be provided for any strain to be considered for use as a probiotic product. Speciation of the bacteria must be established by means of the most current, valid methodology.
Many of the challenges identified for research on dietary supplements, including issues of composition and characterization, are applicable to research on functional foods and whole diets. In addition, challenges of popular diet research include adherence to the protocol for longer-term studies, inability to blind participants to intervention assignment, and efficacy versus effectiveness.