Exposure-response relationship, safety

Seixas, N. S.. Robins, T. G., Attfield, M. D. Moulton, L. K 1992. Exposure-response relationships for coal-mine dust and obstructive lung-disease following enactment of the Federal Coal-Mine Health and Safety Act of 1969. American Journal of Industrial Medicine, 21, 715-734. 

Naive Pooled Approach. The naive pooled approach, proposed by Sheiner and Beal, involves pooling all the data from all individuals as if they were from a single individual to obtain population parameter estimates.Generally, the naive pooled approach performs well in estimating population pharmacokinetic parameters from balanced pharmacokinetic data with small between-subject variations, but tends to confound individual differences and diverse sources of variability, and it generally performs poorly when dealing with imbalanced data. Additionally, caution is warranted when applying the naive pooled approach for PD data analysis because it may produce a distorted picture of the exposure-response relationship and thereby could have safety implications when applied to the treatment of individual patients. ... 

The FDA document. Guidance for Industry Exposure-Response Relationships— Study Design, Data Analysis, and Regulatory Applications, has commented extensively on the exposure-response relationship (46). It states Exposure-response information is at the heart of any determination of the safety and effectiveness of... 

Although dose-response assessments for deterministic and stochastic effects are discussed separately in this Report, it should be appreciated that many of the concepts discussed in Section 3.2.1.2 for substances that cause deterministic effects apply to substances that cause stochastic effects as well. The processes of hazard identification, including identification of the critical response, and development of data on dose-response based on studies in humans or animals are common to both types of substances. Based on the dose-response data, a NOAEL or a LOAEL can be established based on the limited ability of any study to detect statistically significant increases in responses in exposed populations compared with controls, even though the dose-response relationship is assumed not to have a threshold. Because of the assumed form of the dose-response relationship, however, NOAEL or LOAEL is not normally used as a point of departure to establish safe levels of exposure to substances causing stochastic effects. This is in contrast to the common practice for substances causing deterministic effects of establishing safe levels of exposure, such as RfDs, based on NOAEL or LOAEL (or the benchmark dose) and the use of safety and uncertainty factors. 

Wang X et al. (2008) Dasatinib pharmacokinetics and exposure-response (E-R) relationship to safety and efficacy in patients (pts) with chronic myeloid leukemia (CML). J Clin Oncol. 26 (No 15 S) (May 20 Suppl, Abstract 3590)... 

Knowledge of the relationship between dose and response (effect), and the threshold for this, is crucial in defining the risk of exposure to a chemical. Safety evaluation is a legal requirement for drugs, food additives, and contaminants in food, and a risk assessment has to be carried out in order to set the limits of exposure. The relationship between the dose and the response (effect) can be established and plotted as a graph. This is called a dose-response curve (see Figure 29 and box), which often shows that there is a dose(s) of the chemical that has no effect and another, higher dose(s) which has the maximum effect. It is a visual representation of the Paracelsus principle that, at some dose, all chemicals are toxic. The corollary to this is that there is a dose(s) at which there is no effect. 

FDA approval. Usually evidence of efficacy from two or more adequate and well-controlled clinical trials along with safety information is required for the regulatory approval of a new indication for a drug. The idea is that replication of the results of a single trial is needed to rule out the possibility that a finding of efficacy in a single trial is due to chance. This example describes the application of exposure-response analysis to establish an FDA-approvable claim of drug efficacy based on a dose-reponse relationship that was obtained from two pivotal clinical trials that used different final-treatment doses. 

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