| Epidemiological studies involving safety‐related endpoints |
The population studied in the epidemiology study vs. the population for which the product is intended (e.g., age, gender, race, cultural factors) The composition of the material (i.e., key constituents, particularly any with anticipated toxicity) evaluated in the epidemiology study vs. the composition of the proposed product How the material was used by the population in the epidemiology study vs. the proposed product uses (e.g., food vs. dietary supplement, duration of use)
|
Ability to study rare events Ability to evaluate risk under “real world” conditions of use (however, note the first three key considerations when applying available epidemiology data to a specific product) Ability to measure exposure‐specific incidence and prevalence of an outcome
|
Requires additional information to address causality Retrospective measurement of exposure is imprecise Inability to totally control confounding factors High cost of prospective studies
|
| Clinical studies |
High‐active monitoring of safety endpoints (these might include vital signs, blood chemistry, hematology, urinalysis, or relevant end points based on the known or anticipated biological effects of the constituents) and recording of adverse events. Moderate—Recording of adverse events, Low—No information reported on adverse events
Duration of the clinical study(ies) compared to anticipated duration of use by consumers. Dosing regimen employed in the clinical study(ies) compared to the dosing instructions in product labelling Demographics of patients studied in the clinical study(ies) vs. intended consumer demographics (e.g., age race, gender, any medical exclusions in the clinical study(ies)) Number of patients studied in the clinical study(ies). Comparison of the composition of the test material used in the clinical study(ies) to the composition of product. Focus on constituents with known or anticipated biological effects particularly any constituents known to have the potential to cause adverse effects. Nature and incidence of the adverse events. Have serious adverse events been reported? Placebo controlled vs. uncontrolled. Is there a difference in the incidence of adverse events relative to placebo?
|
Conducted in the species of interest for safety assessment (i.e., humans) Often conducted under carefully controlled conditions Provide a quantitative estimate of the frequency of adverse events Ability to obtain subjective data pertinent to safety assessment from study participants
|
Low capability to detect rare events Low capability to obtain data under actual use condition Inability to evaluate events requiring a long time to manifest Measurements limited to non‐invasive/minimally invasive procedures Establishment of causality of adverse events can be difficult
|
| Human use experience (outside the context of epidemiology studies and clinical trials) |
Is the total daily exposure associated with the history of use comparable to anticipated total daily exposure via product use? Comparison of the temporal pattern of historical use of the herbal preparation relative to intended use of the product (i.e., daily use, occasional use, etc.) Comparison of the composition of the material used historically to the composition of our product. Focus on constituents with known or anticipated biological effects particularly any constituents known to have the potential to cause adverse effects. Consideration of the known or anticipated biological effects of the constituents and the nature of any potential adverse event concerns that arise as a consequence of those effects. This is necessary to assess the degree of confidence that potential adverse events would be identified from the human use experience. For example, carcinogenic potential can be difficult to detect via spontaneous adverse event reports whereas acute effects are more readily identifiable. Nature of monitoring systems in place to evaluate outcomes of exposure. Are the adverse event data available for review? Factors influencing reporting rate of adverse events. Is reporting mandatory for product manufacturers in the country(ies) where there is a history of use? Nature of the adverse events. Have serious adverse events been reported? Are the known biological properties of the constituents consistent with the nature of the adverse events reported?
|
Capable of detecting rare events when a robust monitoring system is in place Ability to collect information under “real world” conditions of use (however, note the first three key considerations above when applying adverse event reports from historical human use to a specific product)
|
Accuracy and completeness of the information in spontaneous adverse event reports is sometimes poor, particularly in cases where the report is not made by a health care professional Quantitation of adverse events is limited to reporting rate and it is not possible to draw firm conclusions regarding the incidence of certain events Difficult or impossible to evaluate causality (however, note the last point under key considerations above)
|
| Nonclinical animal studies |
Types of toxicological end points evaluated. Studies addressing endpoints relevant to serious adverse events that are not easily identifiable in humans in either clinical studies or as a result of human use experience (i.e., cancer, congenital anomaly) are particularly useful. This is especially true in cases where there are no epidemiological data addressing these endpoints. However, under certain circumstances, and even in the absence of data in humans, animal data on carcinogenicity or developmental toxicity may not be necessary. For carcinogenicity this would include situations where there are data to indicate lack of genotoxicity and no known pharmacological effects relevant to human carcinogenic potential (e.g., hormonal activity, immune suppression). Developmental toxicity data would not be necessary when the product would not be used in women of child‐bearing potential. Other types of animal studies (e.g., subchronic toxicity, chronic toxicity, pharmacology) may be helpful in identifying what types of effects to look for in evaluating the human data and in adding to the weight of the evidence supporting the safety of long term use. Access to sufficient detail concerning the study design, methods, and results of the animal studies to allow a judgment to be made regarding the study quality and reliability of the results. Comparison of the composition of the test material used in the animal study(ies) to the composition of our product. Focus on constituents with known biological effects and any constituents expected to have the potential to cause adverse effects.
|
Conducted under carefully controlled conditions Incorporate the full spectrum of an in vivo response (in contrast to in vitro studies) Ability to conduct invasive procedures and to euthanize animals for complete histopathological evaluation Ability to evaluate the effects of life time exposure Ability to define dose‐response and time‐response relationships Can provide information on the mechanisms of toxicity
|
No animal species mimics humans in all respects Limited capability to detect rare events Study design and methods may limit the ability to extrapolate the findings to humans (e.g., testing at high doses may produce results due to saturation of detoxification and elimination pathways)
|
|
In vitro studies |
Types of toxicological endpoints evaluated. Genotoxicity studies are particularly useful because this type of data is helpful in making a weight of the evidence assessment regarding carcinogenic potential. In vitro assays for other biological activities may serve to guide the evaluation of other types of data. For example, in vitro evidence of estrogen receptor binding activity leads to the need to consider the potential for reproductive and developmental effects in animals and humans. Access to sufficient detail concerning the study design, methods, and results of the in vitro studies to allow a judgment to be made regarding the study quality and reliability of the results. Comparison of the composition of the test material used in the in vitro study(ies) to the composition of the ingredient to be used in our product. Focus on constituents with structural alerts that suggest the potential for certain biological properties.
|
Low cost, speed, reduction in animal usage May provide the opportunity to use human tissues/cells. Simplified systems allow measurement of key biological events/responses (e.g., estrogen receptor binding) Can provide information on the mechanisms of toxicity
|
|
| Structure‐activity relationships |
This capability is available for individual constituents of botanicals |
Low cost, speed, no animal usage May be able to provide both qualitative and quantitative estimates of toxicity
|
Provides only an estimate of toxicity Quality of the estimate is dependent on the quality and quantity of available data used to create the database. Requires an extensive data set for reliable estimates Still an evolving technology with variable acceptance among the scientific/regulatory community May not replace the need for animal studies
|
