Statistics clinical endpoints

Cost-minimisation analysis are performed when the clinical outcomes (e.g. efficacy and safety) of the comparator groups are virtually identical and for all practical purposes can be considered to be equal. Because no decision can be made based on differences in the clinical endpoints, decisions are based on the incremental costs of the treatment pathways. Such was the case in a study that assessed the cost-effectiveness of treating proximal deep vein thromboses (DVT) at home with low molecular weight heparin versus standard heparin in hospital therapy. A cost-minimisation approach was chosen for this analysis because the results from a comparative clinical trial confirmed that there were no statistically significant differences in safety or efficacy between the two treatment groups. The study authors concluded that for patients with acute proximal DVTs, treatment at home with low molecular weight heparin was less costly than hospital treatment with standard heparin. ... 

The statistical relationships between patterns of in vitro activities and clinical endpoints lead to a new understanding of both the therapeutic beneht and adverse effect predictions. 

The clinical endpoint is a clinically meaningful measure of how patients feel, function or survive. Investigator-rated or self-assessed rating instruments are the most frequently used clinical endpoints. A primary endpoint is the main outcome that a study protocol is designed to evaluate. The statistical power and the sample size calculation of a particular trial are determined by the primary endpoint. Depending on the purpose of a study the primary endpoint can be... 

To explain the framework for statistical surrogacy (see Figure 17.1), dehne Z as the treatment, S as the biomarker, and T as the true chnical endpoint The effect of the treatment (Z) on the biomarker (S) is called or, the effect of the treatment on the clinical endpoint (T) is called and the effect of the biomarker (5) on the clinical endpoint (T) is called 7(10). Statistically speaking, the biomarker can only be used as a surrogate endpoint if an estimated treatment effect on S (a 5 0) can be used to predict a treatment effect on T 0) and if no treatment effect on S (a= 0) predicts no treatment effect on T (P= 0) with sufficient accuracy (10). 

The result of the Phase II trial is information needed to determine the effective dose and the dosing regimen of frequency and duration. Specific clinical endpoints or markers are used to assess interaction of drug and disease. There are two types of markers definitive and surrogate. For example, in the case of cancer or hypertension, the definitive markers are mortality and stroke, respectively, and the surrogate markers may be tumor size, or cancer-associated proteins p53, TGF-a in the case of cancer, and blood pressure or cholesterol level in hypertension. Statistical analysis is carried out to evaluate the influence of the drug on different patient groups, to determine the optimum conditions. 

Compound 34 (BCZ-1812, RWJ-270201, peramivir) showed selective inhibition of influenza virus sialidases over bacterial and mammalian sialidases (Babu et al. 2000 Bantia et al. 2001 Sidwell and Smee 2002). Successful inhibition of influenza virus infectivity in vitro (Smee et al. 2001) and upon oral administration in vivo [mice (Bantia et al. 2001) and ferrets, reviewed in Sidwell and Smee 2002] led to human clinical trials of orally administered peramivir (Barroso et al. 2005). While orally administrated peramivir successfully completed animal studies and Phase I and Phase II clinical trials, in which the compound was showing neither major side effects nor toxicity (Sidwell and Smee 2002), preliminary results of the Phase III trials (June 2002) demonstrated no statistically significant difference in the primary efficacy endpoint, possibly due to low bioavailability (Barroso et al. 2005). 

Clinical trials generate vast quantities of data, most of which are processed by the sponsor. Assessments should be kept to the minimum that is compatible with the safety and comfort of the subject. Highest priority needs to be given to assessment and recording of primary endpoints, as these will determine the main outcome of the study. The power calculation for sample size should be based on the primary critical endpoint. Quite frequently, trials have two or more evaluable endpoints. It must be stated clearly in the protocol whether the secondary endpoints are to be statistically evaluated, in which case power statements will need to be given, or are simply... 

The magnitude of the effect expected on the primary efficacy endpoint - for between-group studies, the focus of interest is the level of difference that constitutes a clinically significant effect note that this may not be the same as a statistically significant effect. 

The efficacy endpoints defined in the protocol will be primary or secondary, and each of these maybe a therapeutic or a surrogate endpoint. For each of these there is a statistical and a clinical interpretation of the results. 

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. 

In each of these situations there are clinical arguments that support the use of the particular endpoint concerned. From a statistical point of view, however, each of these endpoints gives an analysis that is subject to bias in a clear violation of the principle of intention-to-treat. We will look at each of the settings in turn. 

Clearly it is very important that we get the hierarchy correct. Generally this would be determined by the clinical relevance of the endpoints, although under some circumstances it could be determined, in part, by the likelihood of seeing statistical significance with the easier hits towards the top of the hierarchy. 

This was a multi-centre, pan-European, randomised double-blind placebo-controlled clinical trial in acute stroke to evaluate the effect of ancrod, a natural defribrinogenating agent (Hennerici et al. (2006)). The primary endpoint was based on the Barthel Index a favourable score of 95 or 100 or a return to the pre-stroke level at three months was viewed as a success. The primary method of statistical analysis was based on a logistic model including terms for treatment, age category, baseline Scandinavian Stroke Scale and centre. 

The primary endpoint is that endpoint which provides the best measure of treatment response/success and such choices are based on clinical arguments rather than statistical ones. It seems unlikely that a change in this could be justified. 

In an open comparative study of androgenetic alopecia in 90 men oral finasteride (1 mg/day for 12 months n = 65) was compared with 5% topical minoxidil solution twice daily (n = 25) (22). The cure rates were 80% for oral finasteride and 52% for topical minoxidil. The adverse effects were all mild, and did not lead to withdrawal of treatment. Of the 65 men given oral finasteride, six had loss of libido, and one had an increase in body hair at other sites irritation of the scalp was seen in one of those who used minoxidil. These adverse events disappeared as soon as the treatment was withdrawn. The laboratory data did not show any statistically or clinically significant changes from baseline values to the endpoint, except for the serum total testosterone concentration, which was increased, and free testosterone and serum prostate-specific antigen in the finasteride group which were reduced from baseline values. 

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