E4 Dose Response Information to Support Drug Registration Guideline Step 4 1994

This guideline covers the following topics: (i) introduction (purpose of doseresponse information, use of dose-response information in choosing doses, use of concentration-response data, problems with titration designs, interaction between dose-response and time), (ii) obtaining dose-response information (dose-response assessment should be an integral part of drug development, studies in life-threatening diseases, regulatory considerations when dose-response data are imperfect, examining the entire database for dose-response information), (iii) study designs for assessing dose-response (general, specific trial designs), and (iv) guidance and advice.

The reader is strongly encouraged to read this guideline since it lays out the fundamental value and benefit of the exposure (i.e., dose and/or concentration)—response information in drug development and evaluation, and recognizes past inadequacies as well as practical limitations in generation of this information base. As per the guideline, where a drug can be safely and effectively given only with blood concentration monitoring, the value of concentration-response information is obvious. In other cases, an established concentration-response relationship is often not needed, but may be useful for ascertaining the magnitude of the clinical consequences of (i) pharmacokinetic differences, such as those due to drug-disease (e.g., renal failure) or drug-drug interactions, or (ii) for assessing the effects of the altered pharmacokinetics of new dosage forms (e.g., controlled release formulation) or new dosage regimens without need for additional clinical data, where such assessment is permitted by regional regulations. Prospective randomized concentration-response studies are critical to defining concentration monitoring therapeutic "windows" but are also useful when pharmacokinetic variability among patients is great; in this case, a concentration-response relationship may in principle be discerned in a prospective study with a smaller number of subjects than could be the dose response relationship in a standard dose-response study. Note that collection of concentration-response information does not imply that therapeutic blood level monitoring will be needed to administer the drug properly. Concentration-response relationships can be translated into doseresponse information. Alternatively, if the relationships between concentration and observed effects (e.g., an undesirable or desirable pharmacologic effect) are defined, patient response can be titrated without the need for further blood level monitoring. Concentration-response information can also allow selection of doses (based on the range of concentrations they will achieve) most likely to lead to a satisfactory response.

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