Safety surrogates

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],... 

Study Type. Metabolic and pharmacokinetic data from a rodent species and a nonrodent species (usually the dog) used for repeat dose safety assessments (14 days, 28 days, 90 days or six months) are recommended. If a dose dependency is observed in metabolic and pharmacokinetic or toxicity studies with one species, the same range of doses should be used in metabolic and pharmacokinetic studies with other species. If human metabolism and pharmacokinetic data also are available, this information should be used to help select test species for the full range of toxicity tests, and may help to justify using data from a particular species as a human surrogate in safety assessment and risk assessment. 

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. 

QT prolongation is a surrogate marker used in cardiac safety studies, but several lines of experimental evidence indicate that it is a poor surrogate of TdP a number of drugs, because of their complex pharmacological profile, can prolong the QTc with a relatively low proarrhythmic risk (e.g. amiodarone). 

As it is often very difficult to quantify therapeutic performance with pharmacodynamic and clinical studies, pharmacokinetic studies are usually the most suitable tool to describe the performance of the drug product in vivo. Once a relationship between the plasma concentration of the drug or active moiety and the therapeutic effect has been established, BA may be considered to be the perfect surrogate parameter for efficacy and/or safety of a drug product. 

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. 

However, the information derived from a detailed pharmacokinetic study will help to anticipate potential botanical product-drug interactions, to optimize the bioavailability, the quality, and hence the efficacy of herbal medicines, to support evidence for the synergistic nature of herbal medicines, and to better appreciate the safety and toxicity of the plant. Because pharmacokinetic studies with herbal medicines are often complicated by their chemical complexity and by the fact that the active compounds are often unknown, it could be one future issue to assess bioavailability by measuring surrogate parameters in plasma or tissue instead of directly assaying putative active compounds in the blood. In summary, to use HMPs in an evidence-based approach and to achieve the status rational phytomedicine, more experimental studies are needed to characterize the bioavailability and pharmacokinetics of botanical products. 

Ibid, Ibid. Part 5. Calibration of PETN for Use as a Surrogate for PBXN-5 in Safety Tests , Ibid (8 May 1973) [Rept RSLR 73-2 for the Naval Weapons Center, China Lake, Calif]... 

The value of an ADI is entirely dependent on the quality of the experimental data and the judicious selection of the safety (uncertainty) factor, which is entirely judgmental. Among the factors influencing the quality of the experimental data, beyond the mechanics, are the selection of the appropriate animal model as the human surrogate, the... 

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