Large, simple study

Whilst the conditions under which large simple trials can provide efficacy data are fairly well worked out, it is important to consider whether (or which) tolerability issues can be precisely addressed in this way. If a tolerability factor (adverse event) relates to the efficacy variable of interest (e.g. a fatal adverse event in a patient survival study), then a simple case report form may provide relevant information. However, if the adverse event type is rare or unanticipated (e.g. the test drug causes unanticipated, significant anemia in 0.1% of patients, and the protocol and case report form do not collect hemoglobin values before and after treatment), then it is very likely that the adverse event will be missed. Large simple studies can thus create undue confidence in product tolerability ( thousands of patients were exposed to the agent during clinical trials ). 

Simple Tests It is usually profitable, however, to make simple preliminaiy tests, recognizing that the results may require confirmation through subsequent large-scale studies. 

Therapeutic confirmatory (Phase III) Demonstrate/confirm efficacy Establish safety profile Provide an adequate basis for assessing the benefit/risk relationship to support licensing Establish dose-response relationship Adequate and well controlled studies to establish efficacy Randomized parallel dose-response studies Clinical safety studies Studies of mortality/morbidity outcomes Large simple trials Comparative studies... 

Therapeutic use (Phase III/IV) Refine understanding of benefit/risk relationship in general or special populations and/or environment Identity less common adverse reactions Refine dosing recommendation Comparative effectiveness studies Studies of mortality/morbidity outcomes Studies of additional endpoints Large simple trials Pharmacoeconomic studies... 

Refine dosing recommendations Studies of additional endpoints Large simple trials Pharmacoeconomic studies... 

Interest in these species stems largely from study of the mechanism of conversion of coordinated dinitrogen to hydrazine and ammonia. It seems abundantly clear that hydrazido(2—) species are involved in the conversion, in simple molecular systems at least, of N2 to NH3, and there is evidence to suggest their involvement enzymatically. 

The gas reactions listed in Table 2 have high rates at room temperature and emission occurs not too far in the infrared. These restrictions are due to limitations of the experimental method which may be overcome in the future. The table could be considerably enlarged by including alkali-metal reactions which have largely been studied by molecular beam methods. 21> Though much discussed, chemical lasers on alkali halides have not yet been realized experimentally. Other results, obtained for instance by flash photolysis/absorption studies, or by the study of combustion, are less detailed and axe not included here. But even in this limited form. Table 2 indicates that nonequilibrium distributions which can lead to molecular amplification are often found and are perhaps the rule rather than the exception in simple chemical reactions. 

These conclusions were based on the severe curvature of the plots of chemical shift against reaction field calculated from both the simple Onsager and the more complex Diehl and Freeman equations. Fontaine et al. have found similar curvature in plots of for acetone versus the Onsager reaction field of cyclohexane-acetone mixtures. Some interesting results recently obtained show that if e is substituted for the dielectric function (e —l)/(e- - ) of equation (5), the curvature of these plots is effectively removed, especially for protons near the dipole location in the large molecules studies by Laszlo and Musher. No explanation for the dependence of on e has been offered. Deviations from linearity in plots of versus in some haloethylenes are explained by the occurrence of excess dispersion forces in the solvents producing the deviations. 

In conclusion, although it is yet to be definitively shown, much evidence supports a link between oxidation of lipoproteins and arteriosclerosis in human beings. If this relationship can be conclusively demonstrated, it is likely there will be a need to measure lipoprotein oxidation products in the clinical laboratory for risk assessment. Establishing a definitive link between oxidation and arteriosclerosis is not a simple task because not only will it be necessary to demonstrate that oxidation is a risk factor for arteriosclerosis in large prospective studies, but it will be important to show it is a marker independent of lipoprotein and inflammatory markers. Furthermore, it would be desirable to identify treatments by which modification of oxidation markers leads to reduction in disease (SI). To date, the failure of randomized trials with antioxidant nutrients to retard arteriosclerosis (Al, Y3) has made it clear that demonstrating a definite relationship in humans may be more difficult that expected. In the meantime, there is a need to measure these... 

At the conclusion of a clinical trial, patients may be continued on treatment and followed-up for a period of months or years, generating more long-term safety experience (these are known as open-label extensions). When clinical trials are conducted entirely after marketing, they may provide important new safety information provided that they contain enough patients, and have few exclusion criteria and clinically relevant outcomes that are easily measured (e.g. mortality). Such studies are often called large simple trials. ... 

Patient safety is of course underpinned by large-scale studies of adverse events. If we want to monitor progress over time, then surely we should repeat these studies, whether on a local or national level. At a national level though, the simple fact is that no country has had the courage to repeat a study of the incidence of adverse events as a formal comparison The Netherlands, however, has carried out a major study (Zegers et al 2009) and a follow-up study is planned to assess progress on patient safety. 

VITATOPS Trial Study Group, 2002. The VITATOPS (Vitamins to Prevent Stroke) Trial rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovascular Diseases. 13. 120-126. 

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