Drugs endpoint measurement

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],... 

Sometimes it is not possible to measure the direct effect of the drug. Endpoints or surrogate biomarkers are used to monitor the pharmacodynamics and pharmacokinetics of the drug. These markers may be changes in blood pressure, cholesterol level, concentrations of certain enzymes, proteins, blood glucose levels, and similar factors (see Table 6.2 for serum tumor markers and Appendix 7 for general biomarkers). 

When modeling real data, an important first step is to carefully consider and specify the intended use of the model to be developed. With this in hand, an appropriate strategy and analysis plan can be crafted to ensure the appropriateness of the model (15). For the purposes of this chapter, a simulated data set is used to mimic a typical Phase 2 trial of a novel compound where an endpoint measurement is collected at each study visit. In this case, the endpoint of interest is the presence or absence of a particular adverse event. Various demographic variables are available for possible correlation with the endpoint in addition to a calculated measure of individual exposure to the drug. 

It is important to point out that while most of the burden and expertise for impact are borne by the proposing researcher, it is often the chemists on the overall drug discovery team that have the appropriate domain expertise to evaluate the competitive landscape. It is also important for the assay development team to review and verify the assay development and optimization data of the benchtop assay. Sometimes the fundamental assumptions made are faulty, for example that the steady-state conditions are not met for an enzyme assay (i.e., nonlinear progress curves with too high a level of substrate consumption), that endpoint measurements were taken when a progress curve had already plateaued (this is a surprisingly common error, whose impact has been analyzed) [see Fi f. 3 in [4] for simulation, discussion of reasons for nonlinearity with respect to substrate depletion, and workable off-linearity for HTS], or that substrate concentration-to-7Cm ratio is set inappropriately and so will not allow detection of the desired types of inhibitors... 

Degree of immune function preservation also correlates with decreased viral replication, and is measured by CD4+ T-cell counts. CD4 measures are the best predictor of progression to AIDS, and help decide when to initiate treatment. At CD4+ T-cell counts of 200 cells/mm3 and lower, patients require drug prophylaxis for opportunistic infections. Table 84—2 details the monitoring endpoints of HIV treatment for HIV RNA and CD4+ T-cell counts. 

Temple, R.J., A regulatory authority s opinion about surrogate endpoints, in Clinical Measurement in Drug Evaluation, Nimmo, W.S. and Tucker, G.T., Eds., WUey, Indianapolis, 1995. 

An important qualification must be made. While a biomarker may be of proven value in establishing whether a drug has the desired effect in patients or healthy volunteers (see Section 4.6.3) and for evaluation of the dose-response relationship, a biomarker may not be a surrogate for the clinical endpoint. Thus, suppression of testosterone after an initial rise will give an almost immediate endpoint for the effect of GnRH analogues in prostate cancer but the relationship breaks down later in the disease. Measures of blood glucose control are vital... 

The aim of any clinical trial is to have low risk of Type I and II errors and sufficient power to detect a difference between treatments, if it exists. Of the three factors in determining sample size, the power (probability of detecting a true difference) is arbitrarily chosen. The magnitude of the drug s effect can be estimated with more or less accuracy from previous experience with drugs of the same or similar action, and the variability of the measurements is often known from published experiments on the primary endpoint, with or without the drug. These data will, however, not be available for novel substances in a new class and frequently the sample size in the early phase of development has to be chosen on an arbitrary basis. 

In clinical trials intended to provide sufficient evidence for marketing approval of drugs, what is most important is to collect rmequivocal evidence of a positive risk-benefit profQe relative to an active comparator or placebo. For diseases that are life-threatening or those associated with severe morbidity, it is preferable that the primary endpoint is of clinical relevance, examples being mortality, a measurement of the patient s quality of life, such as rehef of disease-related s)unp-toms, improvement in ability to carry out normal activities or reduced hospitalization time. Unfortunately such trials may need to be very large consequently they tend to have a long duration, and can be extremely costly. 

A number of limitations related to PK/PD modeling are also a reality in situations where predictability of the animal model to man is questionable, where the time course of the pharmacodynamic effect cannot be assessed for drug candidates and when, for example, no accessible/ valid pharmacodynamic endpoint for PK/PD is available. The relevance of the animal model for human could be addressed to some extent at least by measuring relative potency in animal versus man in vitro. In situations where no relevant PD endpoint is available (e.g., for CNS efficacy models), effects at target level (i.e., enzyme inhibition, receptor occupancy) might represent a valuable alternative. In this context however the level and duration of target effect required for clinical efficacy requires careful considerations. 

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