Surrogate endpoints safety

Endpoint. An indicator measured in a patient or biological sample to assess safety, efficacy, or another trial objective. Some endpoints are derived from primary endpoints (e.g., cardiac output is derived from stroke volume and heart rate). Synonyms include outcome, variable, parameter, marker, and measure. See surrogate endpoint in the text. Also defined as the final trial objective by some authors. 

Phase I. Clinical pharmacology in small numbers (tens) of healthy non-patient (or patient) volunteers to assess tolerability, preliminary safety, pharmacokinetics, and pharmacod)mam-ics where practicable [i.e. biological effect using surrogate endpoints (see Section 6.6.5.1) or, rarely, therapeutic effect]. 

The characteristics of an ideal surrogate endpoint for use in Phase I-IV trials would depend on whether the emphasis is on the efficacy or the safety evaluation of the potential medicine. 

Because the safety profiles defined by safety pharmacology studies can have a significant impact on the successful development of new therapeutic agents, it is important that the techniques and assays used in safety pharmacology studies minimize the occurrence of false negative and false positive results. For this reason, techniques that provide direct measures of respiratory parameters should be used. A direct measure is one that provides the endpoint of interest, in contrast to an indirect measure that provides a surrogate endpoint,... 

Ha Clinical pharmacology in patients with the target disease (small numbers - tens to 100-200) to assess pharmacodynamics, pharmacokinetics, and dose-(or concentration-) effect responses for preliminary efficacy and safety, and to validate surrogate endpoints... 

Prior to large-scale device use, safety is often assumed and estimated on the basis of assumptions and surrogate endpoints. The safety board can demand verification and extra tests where legislative regulatory standards are considered inadequate. 

Phase II investigates the compound s efficacy and safety in controlled clinical trials for a specific therapeutic indication. To eliminate as many competing factors as possible, Phase II trials are narrowly controlled. They are characterized as small—several hundred subjects with the indicated disease or symptoms—and are closely monitored. The control may be either a placebo study arm or an active control arm. The endpoint measured may be the clinical outcome of interest or a surrogate. Phase II trials may last for several months or even several years. Early pilot trials to evaluate safety and efficacy are called Phase Ila. Later trials, called Phase lib, are important tests of the compound s efficacy. These trials may constitute the pivotal trials used to establish the drug s safety and efficacy. At least one pivotal trial (most frequently a large, randomized Phase III study) is done. Only about one third of compounds entered into Phase II will begin Phase III studies [61],... 

The scope of the toxicity studies when surrogate molecules have been used includes pharmacology studies, subchronic and chronic studies, reproductive toxicity studies, immunotoxicity studies, and even carcinogenicity studies. Short-term assays like safety pharmacology studies are too short for there to be an antisense effect, so we have not used the surrogate approach in these assays. However, when safety pharmacology endpoints are included in subchronic or chronic studies, surrogates are assessed. 

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