Ultimate validation proof

When tungsten is deposited by means of CVD there is almost no adhesion to dielectric materials like silicon dioxide and silicon nitride. To overcome this problem an adhesion promoting layer prior to the tungsten deposition is deposited. Sputtered films such as TiW and TiN have received the most attention [Ellwanger et al.7, Rana et al.8] and have proven to provide adequate adhesion. With respect to this it must be emphasized that macroscopic adhesion (Scotch tape test or bond pull test) in itself is not a valid proof of adhesion. The ultimate evidence can only be obtained when... 

Of ultimate importance are the full reports of the clinical studies in humans and their results. These data will be treated statistically for their validity. The number of studies for a specific compound or combination of compounds will vary with the type of drug being tested, as will the number of tests needed to appraise relative or absolute safety and to clearly demonstrate efficacy. The basic requirement is the proof of safety and efficacy of the product being submitted under the NDA system. A drug that does not contribute to therapy, such as a new antihistamine that does not demonstrate greater safety or efficacy, or both, compared with drugs already on the market, will have a difficult or impossible time achieving approval. 

The observed CEPH population mean IC50 for both docetaxel and 5-fluorouracil was similar to IC50 values observed across the NCI60 panel of human tumor cell lines (http //dtp.nci.nih.gov) (17). In addition, docetaxel- and 5-fluorouracil-induced cell death is mediated by caspase-3 cleavage, similar to that observed in tumor cells (17). These data are encouraging for the use of CEPH pedigrees as a discovery tool. However, the ultimate proof of the value of the cell-based models will be the human validation of markers derived from this process. These studies he ahead and will help position cell-based models in their correct place in the drug development process. 

From a regulatory point of view, computer systems must be validated. The user has the ultimate responsibility for validation but he can delegate some parts, for example validation during development, to the vendor. If he does this, the user should have some proof that his software has been validated at the vendor s site. Using software development practices... 

Pathos, however, the passionate belief of faith, does not apply. A programmer may know his code is sound a manager may be confident her workers are well trained a supervisor may be convinced the system is reliable. These beliefs are critical, and are not to be disparaged effective control would not be possible without ultimate reliance on such well-placed and reality-tested faith. Pathos is noneviden-tiary, however it cannot be evaluated independently and falls beyond the realm of science or regulation. Validation must rely on proof confidence may point to the path toward obtaining such evidence, but is not a substitute for it. 

The first CBIs have been published recently and, considering the limited amount of optimization work performed on these compounds thus far, their moderate affinity holds great promise for significant improvement. As such, these compounds provide a very good basis for optimization, proof-of-concept and selectivity studies. Independent of the ultimate biological validity ofthese compounds, these recent studies show that small molecules can be found that inhibit the nuclear receptor-coactivator interaction. 

Practically, in the innovation of new drugs, one can classify the set of research and development activities into four primary areas or clusters of activities, technologies, and responsibilities. The classifications are target identification, lead finding, lead optimization, and proof of product or product realization. Note that target validation, a critical element in research and development, is ultimately demonstrated in successful phase III clinical studies. 

The first part of this book has treated a number of systems from a fairly physical viewpoint, using intuition as much as possible. Now, armed with the concepts already developed, the reader should be in a better position to understand the more formal foundation to be described in this chapter. This foundation is presented as a set of postulates. From these follow proofs of various theorems. The ultimate test of the validity of the postulates comes in comparing the theoretical predictions with experimental data. The extra effort required to master the postulates and theorems is repaid many times over when we seek to solve problems of chemical interest. 

On the other hand, the same system of N particles at equilibrium can be described by only a few thermodynamic parameters, such as volume, temperature, and pressure. Such a drastic reduction in the number of parameters is achieved by averaging over all possible locations and momenta of all the particles involved in the system. The rules employed in averaging are contained in the theory of statistical thermodynamics. This remarkable theory provides a set of relationships between thermodynamic quantities on the one hand and molecular quantities on the other. These relationships are presented in this chapter, and will be referred to as our rules of the game the ultimate proof of their validity is provided a posteriori by the success of ST in predicting the thermodynamic quantities of a real system from knowledge of the molecular properties of its constituent particles. 

In case the validity of the ratio fjf = 2 between the ultimate compressive strength /, and yield strength (0.2% proof stress) could be considered, Rondal Rasmussen (2004), then the characteristic value of yield strength is 300 MPa and the design value may be estimated as 190 MPa. It is known that the tensile strength may be considered about one third of the compressive strength (about 60 MPa). 

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