ODS Product Integrity Guidance

Dietary Supplement Integrity and Rigorous Research

Dietary supplement ingredients and products must be sufficiently characterized to ensure research studies' reproducibility and comparability, critical components of building an evidence base for clinical research and healthcare practices. Dietary supplements consist of individual chemical constituents, metabolites, and numerous combinations of multiple ingredient categories including vitamins, minerals, fatty acids, amino acids and proteins, and dietary fiber, as well as herbs and botanicals, algae, fungi, and pre- and probiotics. Botanical and animal derived ingredients are chemically complex, with many dozens or hundreds of chemical constituents that can vary with growing conditions and harvest and processing practices.

Given this chemical complexity, the rigor of dietary supplement research is enhanced when experimental interventions and matched control(s) are reliably sourced, reproducibly prepared, and subjected to appropriate analytical testing for identity, purity, strength, composition, and stability. These quality parameters for a dietary ingredient/product are collectively described here as its “integrity”.

Additional information and resources for dietary supplement and natural product characterization in biomedical research are described in The Importance of Natural Product Characterization and Integrity for Dietary Supplement Research.

ODS Recommendations for Dietary Supplement Product Integrity

In conjunction with its evaluation of co-funding program requests, and in alignment with broader NIH guidelines, ODS assesses a research proposal's rigor and reproducibility specific to its key biological or chemical characterization of the dietary supplement or natural product interventions. Research co-funding applications with the potential to be supported by ODS are asked to provide detailed authentication and integrity information corresponding to the relevant criteria for the identity, purity, strength, composition, and stability of the dietary intervention(s) or natural product(s) and control material(s) being investigated, collectivity referred to as the application's “test articles".

Reproducibility and Integrity Guidance for Dietary Supplement Research Test Articles

ODS recommendations to support the demonstration of dietary supplement and natural product test articles integrity include,

  • Identity
    • Demonstrate the test articles' chemical and/or taxonomic identity. For example, determination of vitamin D2 versus D3, folate versus folic acid, Panax ginseng versus Panax quinquefolius, or identification of a specific probiotic bacterial species.
      • Non-specific characteristics for the analysis of purified chemicals, such as color or particle size, are unacceptable for demonstrating identity.
      • For isolated chemical compounds, provide standardized chemical name(s) (e.g., IUPAC or InChi) and common name(s).
      • For complex test articles derived from living organisms such as botanicals, provide the complete taxonomic/scientific name along with the common name and source of the plant/animal material/extract/phytochemical.
      • For probiotics, identify the test article for each genus, species, and strain. Methods of strain identification must assure absence of pathogenic variants, undesirable metabolites, and toxicity.
  • Purity
    • Quantify test article chemical purity. For example, a quantification of 99% pure epigallocatechin gallate by high-performance liquid chromatography, along with an assessment of what comprises the 1% impurity(ies).
    • Demonstrate isomeric purity or ratios where appropriate. For example, determination of α-, β-, γ-, and/or δ-tocopherol isomers in a vitamin E preparation.
    • For fatty acid test articles, such as preparations of omega-3 polyunsaturated fatty acids, quantify any lipid oxidation.
  • Strength
    • Demonstrate quantitative verification of the amounts of active or investigational substances provided by the test article. For example, specify and quantify the milligrams of calcium per tablet or grams of curcumin per kilogram of turmeric rhizome.
    • For probiotics, describe the measure of bioactivity (e.g., colony forming units, viable cell counts) and demonstrate that specification is replicable in the vehicle matrix.
  • Composition
    • Specify and verify the constituent(s), if any, to which the test article is standardized. For example, a Ginkgo biloba preparation that meets U.S. Pharmacopeia specifications of 22–27% flavonol glycosides.
    • Demonstrate the reproducibility of the test article's characteristics.
    • Where applicable, describe manufacturing processes that influence the test articles' chemical profile composition. For example, an ethanol versus an aqueous extract of ginger rhizome phytochemicals.
    • Demonstrate the composition of multi-component, complex preparations. For example, experimental and control animal diet formulations or withanolide and withanoside chemical profiles for an ashwagandha preparation. Complementing targeted analyses of anticipated constituents with untargeted analyses is preferable wherever feasible but is not required at the time of application.
    • For placebos and control materials used in clinical research - in addition to specifying and demonstrating identity, purity, and composition, verify that it matches the test article(s) on sensory characteristics, that the sensory characteristics are stable, and that it does not contain bioactive components that may confound the research data (e.g., a soy-based ingredient in a placebo used in a study of isoflavone health effects).
  • Stability
    • Demonstrate the stability of dietary ingredients in the matrix that will be used in the study (e.g., stability of vitamin D3 in animal chow, cell culture media, capsules, tablets, etc.) for at least the duration of the study.
    • Describe how the test articles will be monitored for stability throughout the study period, and plans for replacing test materials if degradation beyond the intervention's stability specifications is detected.

Safety considerations include,

  • Demonstrate that test articles are free of potentially harmful or deleterious contaminants/impurities (whether accidental or deliberate), e.g., pesticides, drugs, toxins, microbes, or toxic elements/heavy metals.
  • For probiotics, show that the chosen strain(s) is(are) sensitive to clinically relevant antibiotics.

Analytic methods must be adequately described and should be demonstrated to be scientifically valid (accurate and precise) and suitable for their intended purpose.

  • For studies that measure vitamin D metabolites in biological samples, proposals are expected to use appropriate reference materials (e.g., National Institute of Standards and Technology (NIST) standard reference materials SRM 972aexternal link disclaimer) to assure clinical data integrity.