Efficacy markers

The more logical approach is to categorize patients depending on the AUC of the neutralizing antibody levels. This type of analysis also allows study of the dose-response relation between antibody levels and clinical effects. In some cases the unpredictable disease progression, the lack of good efficacy markers and the extended effect after treatment has stopped, may complicate the evaluation of the clinical effects of immunogenicity. 

Efficacy markers allow monitoring of the efficacy of a given drug treatment [serum CYFRA 21-1 (cytokeratin-19 fragments) in breast cancer (Nakata et al., 2004)]. 

During the last decade, commercially available kits have made available for plasma/serum and urinary biomarkers of bone formation and bone resorption. Some of the assays have been shown to be applicable in rats and dogs, but not all assays work across the species, and there is inherent variability with these markers. Some of the tests are listed in Table 6.6, and a number of references are provided. These tests will have a place in animal models, and they may be useful efficacy markers in the development of novel therapeutic agents. 

The first issue lies in the whole realm of the human disease process itself. Many adverse drug events mimic diseases and vice versa. Is an adverse event really an adverse event, or is it merely a natural occurrence of a disease process that is entirely independent of drug exposure The science of drug safety is often complicated by the lack of objective markers of drug toxicity that can systematically separate a disease process from an adverse drug event process [2]. Clinical trials, often viewed as the gold standard to assess efficacy, are simply too limited in scope to answer safety questions in a systematic way. 

Rininger JA et al. Differential gene expression technologies for identifying surrogate markers of dmg efficacy and toxicity. DDT 2000 5 560-568. 

Droloxifene (3-hydroxy-tamoxifen) behaves as an estrogen agonist in bone tissue and several lipid and coagulation markers in castrated rat models and does not show stimulation of the endometrial epithelium in preclinical studies (Ke et al. 1997). Endometrial stimulation has, however, been observed in clinical trials, which, together with the fact that as an estrogen agonist it is ten times less potent than tamoxifen in bone tissue and lipid metabolism (Hendrix et al. 2001) and that in a recent head-to-head comparison with tamoxifen droloxifene was demonstrated not to be superior in any parameter of breast cancer treatment efficacy (Buzdar et al. 2002), has resulted in cancellation of its clinical development. 

There will be an ethical advantage to this approach as well. Instead of using markers such as ApoE4 to predict safety and efficacy, which may carry significant collateral (and sensitive) information, the use of SNPs should minimize the risk of release of additional information. 

By best research evidence Sackett means clinically relevant research, often from the basic sciences of medicine, but especially from patient centred clinical research into the accuracy and precision of diagnostic tests (including the clinical examination), the power of prognostic markers, and the efficacy and safety of therapeutic,... 

AUC and Cmax are commonly measured to identify safety ratios for new chemical entities. Since the analytical methods used for biotechnologically derived pharmaceuticals may lack specificity, a clinical marker of biological activity or efficacy may sometimes be more appropriate than exposure data. 

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. 

Constituents that have some known pharmacological activity that contributes to some extent to the efficacy of the product have been identified. These are known as active markers. An example of this category is alliin, which is converted to allicin in presence of allinase enzyme, and is present in garlic. These active markers may or may not have clinically proven efficacy in their own right. A minimum content or range for active markers is usually specified in pharmacopeial articles. A quantitative determination of active marker(s) during... 

Phase I studies evaluate the pharmacokinetics and safety of the drug in a small number (tens) of healthy volunteers. Phase I studies are sometimes conducted in a small patient population (Proof of Concept studies) with a specific objective such as the validation of the relevance of preclinical models in man. The purpose of these studies may be the rapid elimination of potential failures from the pipeline, definition of biological markers for efficacy or toxicity, or demonstration of early evidence of efficacy. These studies have a potential go/no-go decision criteria such as safety, tolerability, bioavailability/PK, pharmacodynamics, and efficacy. Dosage forms used in Phase I or Proof of Concept studies must be developed with the objectives of the clinical study in mind. 

As a surrogate or clinical marker of efficacy during all phases of human clinical trials... 

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