Primary endpoints multiplicity

It is also necessary to decide how the primary endpoint variables will be analysed, what factors will be taken into account and how the result will be expressed. This most frequently involves analysis of variance or covariance. Predetermined comparisons of two or more treatments or doses can be made at specific time points, (e.g. each visit or selected visits) or may be assessed over time, giving an area imder the time curve analysis which will avoid multiple time-point analyses. 

Choosing a single primary endpoint is part of a strategy to reduce multiplicity in statistical testing. We will leave discussion of the problems arising with multiplicity until Chapter 10 and focus here on the nature of endpoints both from a statistical and a clinical point of view. 

As mentioned in the previous section, multiplicity can lead to adjustment of the significance level. There are, however, some situations when adjustment is not needed although these situations tend to have restrictions in other ways. We will focus this discussion in relation to multiple primary endpoints and in subsequent sections use similar arguments to deal with other aspects of multiple testing. 

A significant benefit for both primary endpoints, lung function and the symptom based clinical endpoint, should be demonstrated so that no multiplicity adjustment to significance levels is indicated. ... 

Another way of avoiding adjustment is to combine the multiple measurements into a single composite variable. Examples would be disease-lfee survival in oncology, where the variable is the time to either disease recurrence or death, whichever occurs first, or a composite of death, non-fatal stroke, MI and heart failure, a binary outcome in a cardiovascular setting. This approach does not require adjustment of the significance level we are back to having a single primary endpoint. 

MULTIPLE PRIMARY ENDPOINTS Table 10.1 Hierarchical testing... 

Primary question, primary endpoint and primary analysis Another way to avoid the hazards of multiple testing is to highlight one particular route through the experimentation and data analysis. Whatever conclusion arises from this route will then be claimed as definitive. 

Specify a primary question, primary endpoint and primary analysis of that endpoint. The answer obtained from these can legitimately be claimed as definitive with no contamination by multiplicity. 

Having a single primary objective has an additional advantage in a study. It means that sample-size estimation can be based on that objective and the associated estimated treatment effect of interest (recall our discussion of sample-size estimation in Section 12.2). Having multiple primary endpoints requires adjustments for multiplicity and can be difficult to interpret if only one of multiple primary endpoints is found to have a statistically significant effect. 

Strong evidence supports the natural idea that recanalization of the occlusion and resulting tissue reperfusion translate into improved clinical outcomes (Fig. 12.4) [6, 9, 10]. While there is no randomized controlled trial data comparing lAT and intravenous therapy for PAO, multiple studies demonstrate improved rates of revascularization with lAT [6,11-13]. The promise of endovascular stroke therapy has led to the recent emergence of multiple stroke devices. Prospective, industry-sponsored trials of these devices have utilized reperfusion as their primary endpoint [6, 14, 15]. However, there is growing criticism of this emphasis on revascularization in lieu of clinical outcome [16,17]. Indeed, the clinical success of the endovascular approach is highly variable for incompletely understood reasons. 

Chuang-Stein C, Stryszak P, Dmitrienko A, Offen W (2007) Challenge of multiple co-primary endpoints a new approach. Statistics in Medicine 26 1181-1192. 

Olfen W, Chuang-Stein C, Dmitrienko A, et al. (2007) Multiple co-primary endpoints medical and statistical solutions-A report from the Multiple Endpoints Expert Team of the Pharmaceutical Research and Manufacturers of America. Drug Information Journal 41 31-46. 

Telovac is 16-mer peptide which can be presented by multiple MHC Class II and also processed into Class I epitopes. Patients receive the vaccine in two combinations with gemcitabine and capecitabine chemotherapy, either together with chemotherapy for 8 weeks or starting 1 week after chemotherapy (in week 9). GM-CSF is coinjected with the vaccine. The primary endpoint is survival at 12 months. The aim is to enroll 1,100 patients. 

Mammalian cells in culture are exposed to the test substance. Established cell lines are treated both with and without metabolic activation. Cells are incubated for an appropriate length of time, then rinsed, fixed, and dried. Slides are developed, stained, and exposed silver grains are counted. The endpoint of UDS is measured by determining the uptake of labeled nucleosides in cells that are not undergoing scheduled (S-phase) DNA synthesis. The most widely used technique is the determination of the uptake of H-TdR by autoradiography. Primary cultures (e.g., rat hepatocytes), human lymphocytes, or established cell lines (e.g., human diploid fibroblasts) may be used in the assay. Multiple concentrations of the test substance over a range adequate to define the response, should be used. 

It is legitimate to declare in advance that the primary purpose of the work is to answer one identified question, and that one specified endpoint and statistical analysis will be used to answer that question. Limitless additional analyses can then be undertaken, so long as any conclusions are recognized as subject to the hazards of multiple testing and cannot be considered definitive. 

With advances of adjunctive pharmacotherapy for PCI, multiple trials sought to confirm superiority of primary PCI to thrombolytic therapy in STEMI. In a review of 23 trials, primary PCI had better outcomes than thrombolytic therapy by reducing the combined endpoint of death, nonfatal reinfarction, and stroke (8% versus 14%), independent of the type of the thrombolytic agent used (124). 

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