Biomarker endpoints

In studies conducted with sediments, comparisons have been reported for artificial (formulated) and natural sediments (Barrett, 1995 Fleming et al., 1998), bioassay and biomarker endpoints (Gillis et al., 2002), bioassay responses (Ahlf et al., 1989 Becker et al., 1995 Day et al., 1995a Kwan and Dutka, 1995 Suedel et al., 1996 Barber et al., 1997 Day et al., 1998 Fuchsman et al., 1998 Guzzella,... 

Concerns relating to the inhibition of kinases known to phosphorylate tau relate to degree of inhibition. For any given kinase a balance is necessary. Thus, full inhibition of GSK-3 is probably not required to affect disease progression. Also, it is still unclear whether transient inhibition or sustained inhibition of GSK-3 is required to attenuate tau phosphorylation for an extended period of time. A detailed evaluation of the pharmacokinetic and pharmacodynamic relationship of a GSK-3 inhibitor coupled with biomarker endpoints could help contribute to overcoming similar issues. 

Residue and biomarker endpoints can be measured in field and lab studies. Ecological endpoints, however, can only truly be examined in the field. Survival, reproduction and population endpoints are the most studied ecological endpoints 70, 80). Careful monitoring of nestling health and parental breeding behavior may reveal responses to a contaminant that are not identified by overt physiological changes. 

Laughlin NK University of Wisconsin, Madison, Wl Evaluate blood and soft tissue in adult and geriatric monkeys previously exposed to lead to compare these biomarkers with behavioral endpoints National Center For Research Resources... 

Furthermore, it is necessary to evaluate the isolated and complex physiological effects of some toxic and essential metals on such endpoints (biomarkers) as the neurobehavioral and psycho-physiological parameters and also cardiovascular and immune parameters. The effect depends on metals content in the human body. Moreover, it depends on physiological effects, not only the daily intake. 

Association of American Universities (2000). Task Force on Research Accountability Report on University Protection of Human Beings Who are the Subjects of Research. Washington, D.C., June 28, 2000. www.aau.edu/HumSUbRpt06.28.00pdf Biomarkers Definitions Working Group (2001). Biomarkers and surrogate endpoints Preferred definitions and conceptual frameworks. Clin. Pharmacol. Ther. 69 89-95. 

The robustness of the study results (i.e., how well established is the association between the pharmacogenetic enrichment biomarkers, drug exposure, and clinical endpoints )... 

Exposure-response data, using short-term biomarkers or surrogate endpoints, can sometimes make further exposure-response studies from clinical endpoints xmnecessary. For example, if it can be shown that the short-term effect does not increase beyond a particular dose or concentration, there may be no reason to explore higher doses or concentrations in the clinical trials. Similarly, short-term exposure-response studies with biomarkers might be used to evaluate early (i.e., first dose) responses seen in clinical trials. 

Some biomarkers are more remote from the clinical benefit endpoint (e.g., the degree of binding to a receptor or inhibition of an agonisf). 

Surrogate endpoints, a subset of biomarkers, are laboratory measurements or physical signs used in therapeutic trials as a substitute for clinical endpoints expected to predict the effect of the therapy. A fully validated, surrogate endpoint predicts the clinically meaningful endpoint of a therapy consistently. ... 

Mechanism-based biomarker selection and correlation to clinical endpoints. 

Lesko, L.J. and Atkinson, A.J., Jr., Biomarkers and surrogate endpoints — Use in drug development and regulatory decision making criteria, validation, strategies, Ann. Rev. Pharmacol. Toxicol, 41, 347-366, 2001. 

We all realize that we need better disease-specific endpoints in very many diseases. There are tremendous opportunities to use imaging and certain biomarkers, if only they could be relied upon. Patient-centered outcome measures are also extremely important in most chronic and symptomatic diseases yet, they are not used as extensively as they need to be. Agreement on acceptable composite endpoints is needed in many diseases. 

The biomarker is not used because no synthetic analysis has been done. The data need to be pooled, synthesized, and analyzed. We have to xmderstand what the data are telling us about that biomarker and what the remaining gaps in understanding are. Studies have to be identified that will fill those gaps, and then somebody has to do that work, whatever it is and for a surrogate endpoint, of course, that work involves correlation with clinical outcomes. 

The purpose of a surrogate endpoint is use for regulatory approval in lieu of a clinical oufcome. Surrogate endpoints have the very same set of issues as biomarkers but at a higher level. Once surrogate endpoint data are analyzed, the gap in xmderstanding often... 

In clinical trials, biomarkers are used to indicate a particular disease state and its progression. They may be used as surrogate markers in the evaluation of the effectiveness of a drug as representative of the natural endpoint such as survival rate or irreversible morbidity. 

Source Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints preferred definitions and conceptual framework, Clinical Pharmacology and Therapeutics 69 89-95 (2001). 

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). 

In the past few years the use of rotifers in ecotoxicological studies has substantially increased. The main endpoints used are mortality, reproduction, behavior, cellular biomarkers, mesocosms, and species diversity in natural populations [126]. Several workers have used Brachionus calyciflorus for various types of toxicity assessments. Thus, comprehensive evaluation of approximately 400 environmental samples for the toxicity assessment of solid waste elutriates, monitoring wells, effluents, sediment pore water, and sewage sludge was carried out by Persoone and Janssen [127]. The mortality of rotifers hatched from cysts is evaluated after 24 hours exposure. This microbiotest has been commercialized in a Rotoxkit F [128,129]. 

For some substances, information on some toxicological endpoints is available from clinical and physiological investigations such as provocation tests for detecting allergy, lung function tests, and analyses of biochemical parameters and biomarkers for exposure or effects. 

The limitations of the use of biomarkers in healthy volunteers must be recognised. For example, although there have been attempts to simulate migraine headache in volunteers, to date none of these models can be considered adequate to serve as a surrogate endpoint. Patients with migraine are not difficult to recruit and are usually healthy apart from their migraine. In this case, it maybe more appropriate to establish tolerability and pharmacokinetics in healthy volunteers and then to select a maximum well-tolerated dose with which to perform a small proof of principle clinical trial in patients. This will need to be followed by larger trials to establish the dose-response relationship. 

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