Derivation of a Probabilistic Default Uncertainty Factor to Account for Increased Sensitivity in Critically Ill or Injured Patients. R. Brown, US Food and Drug Administration, MD
To derive a Tolerable Intake (TI) value for a compound released from medical device materials, the ISO/DIS 10993-17 standard instructs the user to apply a default uncertainty factor (UF) of 10 to account for interindividual variability in patient response in the absence of specific experimental data. One subpopulation that may be especially sensitive to the toxic effects of compounds are critically ill or injured patients. Since the population of interest with regard to setting TI values for compounds released from medical device materials is sick and injured patients, it is important to determine if the default UF of 10 intended to account for interindividual variability adequately characterizes the variability in response in this potentially sensitive subpopulation.
Data on the relative response of healthy and compromised populations (animal and human) to drugs were identified in the literature. The dose associated with the mean response of the healthy population was compared to the dose associated with the response of the 5th percentile of the compromised population (assumed to be equivalent to the dose 2 SDs below the mean). Using this approach, it was found that diseased or injured animals or humans are often more sensitive to the effects of drugs or toxic compounds than healthy individuals of the population. However, in most cases, individuals in the lower 5th percentile of the compromised population are no more than 2- to 3-fold more sensitive to these effects than individuals at the mean of the healthy population. A default UF of 10 applied to the mean response of a healthy population will be protective of the 5th percentile of a compromised population approximately 97% of the time. As a result, in the absence of experimentally derived data, the default UF of 10 to account for interindividual variability is adequate when deriving a TI values for compounds released from medical device materials.
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