Test performance evaluation clinical examples

The analytical performance of the methods used for many clinical tests has improved dramatically over the past 4 decades. However, a highly accurate and precise test may provide less clinicai information than a different test that is less accurate and less precise. For example, a test for total creatine Idnase is often more accurate and precise than one for creatine kinase isoenzymes, yet knowledge of the total enzyme activity is of less value in the diagnosis of cardiac damage. How does one evaluate the information content of a test What procedure should one use to decide among different tests based on their disease discrimination ability This chapter discusses these and other nonanalytical aspects of test performance that affect a test s overall medical usefulness. 

Each batch of IT prepared for clinical use should pass quality-control tests described in Table 2 as well as evaluations of purity and sterility. An example of the quality control tests performed on two ITs is presented in Table 2. 

The FDA evaluates each tumor marker test against its own labeling claims as to how well it performs and compares it with other cleared and marketed devices identified in the 510(k) submission. The intended use claim for monitoring must be supported by valid scientific and clinical data. Labeling a tumor marker test for a particular claim can mean that the testing system may have to show supporting data for that claim. For example, a tumor marker proposed for a monitoring claim will require laboratory and clinical data to support that claim (4,5). 

Performance trials and evaluation tests on the technique indicate that it is both rehable and accurate, and, in addition, that the specificity is sufficient to cope with most chnical requirements. An evaluation was made by Haeckel et al. [19]. If this approach is successful, the dispensers and tubes in laboratories will become redundant. It may well become possible for a clinical test to be undertaken close to the patient rather than in the laboratory. Whilst the techniques have as yet been used only for clinical analyses, there are many other potential applications, for example in the water industry. However, the very nature of the technique necessitates development by Eastman Kodak. Very few users will be able to influence the choice of analytical problems to be tackled by this unique approach. 

An additional consideration is the safety assessment of agents that will be used for challenge stimuli in the evaluation of pharmacodynamics. In some cases, there is a long history of uneventful clinical use of tests, for example, bronchial challenge with histamine and methacholine. If used in a similar manner, there may be no need to consider performing safety studies in... 

Tissue cross-reactivity studies are required by FDA for monoclonal antibody products to determine if the product binds to target and/or nontarget tissues. They are also performed for nonmonoclonal biopharmaceuticals if warranted. For example, ARANESP was tested in a human tissue panel ex vivo to determine if it bound to nontarget tissues or cross-reacted with related cytokine receptors. These studies are also used to explore known or potential clinical adverse safety events (i.e., mechanism of toxicity). For example, one patient in a Raptiva study developed unilateral hearing loss. This finding was further evaluated by cross-reactivity studies with human optic chiasm, acoustic nerve, and inner ear tissues. 

The function of clinical chemistry in toxicology (as well as in human and veterinary medicine) is to provide, via laboratory analysis, evaluations of the qualitative and quantitative characteristics of specific endogenous chemical components present in samples of blood, urine, feces, spinal fluid, and tissues. The purpose is to help identify abnormal or pathological changes in organ system functions. The most common specimens used in clinical chemistry are blood and urine, and many different tests exist to test for almost any type of chemical component in blood or urine for example, blood glucose, electrolytes, enzymes, hormones, lipids (fats), other metabolic substances, and proteins. The tests used were all initially applied to human clinical medicine, and may not possess the same utility when performed as part of nonclinical toxicity studies in a wide variety of other species. 

The perspective from which an economic evaluation is performed affects the design, conduct, and results of the evaluation. The perspective may, for example, be that of a patient, a payer (government health agency or health insurance company), or society. The perspective may be long term or short term. The perspective is a practical consideration when attempting to assess the benefit of a particular test or device as part of a more complex clinical protocol. Perspective is also important in relation to many of the routine decisions made about a diagnostic test. The questions below illustrate the importance of perspective ... 

Nonspecific nonspecificity results from interference of matrix components that are structurally unrelated to the analyte of interest. Examples of such interfering matrix components would include serum proteins, lipids, heterophilic antibodies, rheumatoid factor, proteases, and so on. Nonspecific nonspecificity is often referred to as matrix effect. Figure 4.3 depicts the impact of matrix on the assay performance. Matrix interference is one of the chief reasons that LB As often require more method development and validation prior to switching from one species matrix to another or even within the same species. In addition, we recommend during clinical study support that matrix from the relevant disease populations be tested for matrix effects as soon as that matrix becomes available. Matrix effects should be evaluated by comparing the concentration response relationship of both spiked and unspiked samples of the biological matrix (recommendation is 10 or more lots of individual sources) to a comparable buffer solution. It is recommended that the spiked sample... 

Clinical Simulation Studies. These protocols allow assessment of each of the characteristics of the proposed indications described in Table 4 [27] and include the basic principles articulated by the Antimicrobial I Panel (Table 2). The design is also based on reviewer experiences gained from the development of topical antibiotic and antimicrobial drug products through the NDA process. Examples of changes or recommendations include the incorporation of a positive control to validate the performance of the study, a test product vehicle arm, and proposed statistical methods of analysis to evaluate the data. Studies must be... 

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