Guidance for Industry Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications

iV. DOSE-CONCENTRATION-RESPONSE RELATIONSHIPS

AND EFFECTS OVER TIME

Depending on the purpose of the study and the measurements made, exposure-response information can be obtained at steady state without consideration of the impact of fluctuations in exposure and response over time, or can be used to examine responses at the various concentrations attained after a single dose during the dosing interval or over the course of treatment. Where effectiveness is immediate and is readily measured repeatedly in the course of a dosing interval (e.g., analgesia, blood pressure, blood glucose), it is possible to relate clinical response to blood concentrations over time, which can provide critical information for choosing a dose and dosing interval. This is standard practice with antihypertensives, for example, where effect at the end of the dose interval and at the time of the peak plasma concentration is routinely assessed and where 24-hour automated BP measurements are often used. Controlled-release decongestants have also been assessed for their effects over the dosing interval, especially the last several hours of the dosing interval.

Often, however, the clinical measurement is delayed or persistent compared to plasma concentrations, resulting in an exposure-response relationship with considerable hysteresis. Even in this case, exposure-response relationships can be informative. Furthermore, safety endpoints can have a time-dependent concentration-response relationship and it could be different from that of the desired effect.

A. Dose and Concentration-Time Relationships

As noted in the ICH E4 guidance for industry on Dose-Response Information to Support Drug Registration, dose-response information can help identify an appropriate starting dose and determine the best way (how often and by how much) to adjust dosage for a particular patient. If the time course of response and the exposure-response relationship over time is also assessed, time-related effects on drug action (e.g., induction, tolerance, and chronopharmacologic effects) can be detected. In addition, testing for concentration-response relationships within a single dosing interval for favorable and adverse events can guide the choice of dosing interval and dose and suggest benefits of controlled-release dosage forms. The information on the effects of dose, concentration, and response can be used to optimize trial design and product labeling.

Although dose is the measurement of drug exposure most often used in clinical trials, it is plasma concentration measurements that are more directly related to the concentration of the drug at the target site and thus to the effect. Relationships between concentration and response can, of course, vary among individuals, but concentration-response relationships in the same individual over time are especially informative because they are not potentially confounded by dose-selection/titration phenomena and inter-individual PK variability.

B. Concentration-Response Relationships: Two Approaches

There are two fundamentally different approaches to examining plasma concentration-response relationships: (1) observing the plasma concentrations attained in patients who have been given various doses of drug and relating the plasma concentrations to observed response; and (2) assigning patients randomly to desired plasma concentrations, titrating dose to achieve them, and relating the concentration to observed response. In some cases, concentration-response relationships obtained from these studies can provide insight over and above that obtained through looking at the dose-response relationship.

The first kind of study (# 1 above) is the usual or most common way of obtaining exposure-response information, but this kind of study can be misleading unless it is analyzed using specialized approaches (e.g., Sheiner, Hashimoto, and Beal 1991). Even when appropriately analyzed, potential confounding of the concentration-response relationship can occur and an observed concentration-response relationship may not be credible evidence of an exposure-response relationship. (See ICH E4). For example, if it were found that patients with better absorption, and thus higher concentrations, had greater response, this might not be related to the higher concentrations but to another factor causing both the greater absorption and the greater response. Similarly, renal failure could simultaneously lead to increased plasma concentrations and susceptibility to adverse effects, leading to an erroneous conclusion that concentration is related to adverse effects. Also, a study that titrated only nonresponders to higher doses might show a lower response with higher concentrations (i.e., a bell-shaped concentration-response (or dose-response) curve, a result that would not reflect the true population exposure-response relationship). Thus, although it is useful to look in data for such relationships, we suggest that they be subjected to further evaluation. The potential problem of interrelated factors leading to both an effect on pharmacokinetics and an effect on response and therefore an erroneous concentration-response relationship when individuals are not randomized to concentrations generally does not occur when concentration-response relationships in the same individual are observed over time (e.g., over a dosing interval).
The second kind of study (# 2 above) is the randomized, concentration-controlled trial (e.g., Sanathanan and Peck 1991). While less common than the first kind of study, it is a credible controlled effectiveness study. Unlike the first approach, this approach is not affected by the potential confounding factors noted above, such as an unrecognized relationship between pharmacokinetics and responsiveness, or by the random imbalance of influential factors in the way patients are chosen to receive higher doses.

V. DESIGNS OF EXPOSURE-RESPONSE STUDIES

As noted above, exposure-response studies can examine the relationships between randomly assigned dose or plasma concentration and PD response (biomarker, surrogate, or clinical endpoint) or examine the relationship between attained plasma concentration and PD response. The appropriate designs depend on the study purpose. Randomization of patients to different doses or concentrations is an essential aspect of the design of well-controlled studies to establish efficacy, but other designs can also be informative or can suggest further study. The designs of exposure-response studies discussed here thus also include nonrandomized approaches that can assume mechanistic models for relationships and that do not rely on randomization for making comparisons.