Clinical endpoint

Demographics and Trial-Specific Baseline Data 27 Concomitant or Prior Medication Data 27 Medical History Data 29 Investigational Therapy Drug Log 30 Laboratory Data 31 Adverse Event Data 32 Endpoint/Event Assessment Data 35 Clinical Endpoint Committee (CEC) Data 36 Study Termination Data 37 Treatment Randomization Data 38 Quality-of-Life Data 40... 

Laboratory data are most often associated with safety analyses, but they may play a part in efficacy analyses as well, especially if the laboratory data are part of the clinical endpoint definition. From a CDISC perspective, laboratory data are a finding, as they are a planned assessment. 

The problem with endpoint data usually occurs when they need to be reconciled against data collected by the clinical endpoint committee (CEO, which we discuss next. The endpoint/event data are almost always used for efficacy analyses but may be used for safety analyses as well. From a CDISC perspective, the endpoint/assessment is often considered a finding, as it is a planned examination, but it could also be considered an unplanned event. 

Time is a critical measure for clinical trial analysis. Time is captured in clinical trial databases in a study day variable. Study day can be defined as the number of days from therapeutic intervention to any given time point or event. By defining study day, you create a common metric for measuring time across a population of patients in a clinical trial. There can be a study day calculation for any time point of interest. Adverse event start, study termination, and clinical endpoint event date all make good choices for study day calculations. The study day calculation is performed with one of the two following approaches. 

Fluid administration should be titrated to clinical endpoints such as heart rate, urine output, blood pressure, and mental status. Isotonic crystalloids, such as 0.9% sodium chloride or lactated Ringer s solution, are commonly used for fluid resuscitation. 

Trospium chloride, a quaternary ammonium anticholinergic, is superior to placebo and is equivalent to oxybutynin IR and tolterodine IR. However, clinical studies are limited by their focus on cystometric rather than clinical endpoints, small absolute benefits compared with placebo, and lack of comparisons with LR formulations. 

In addition to coronary sclerosis, evidence is accumulating that high Lp(a) levels may be important in the development of cerebrovascular and peripheral arterial disease, as well (J6, T8, U2). Lp(a) levels not only correlated well with clinical endpoints such as transient ischemic attack and cerebral infarction, but also were associated with the extent and severity of carotid atherosclerosis, as assessed by bidirectional Doppler ultrasound (K23, M33, Z2). 

The robustness of the study results (i.e., how well established is the association between the pharmacogenetic enrichment biomarkers, drug exposure, and clinical endpoints )... 

Exposure-response data, using short-term biomarkers or surrogate endpoints, can sometimes make further exposure-response studies from clinical endpoints xmnecessary. For example, if it can be shown that the short-term effect does not increase beyond a particular dose or concentration, there may be no reason to explore higher doses or concentrations in the clinical trials. Similarly, short-term exposure-response studies with biomarkers might be used to evaluate early (i.e., first dose) responses seen in clinical trials. 

Surrogate endpoints, a subset of biomarkers, are laboratory measurements or physical signs used in therapeutic trials as a substitute for clinical endpoints expected to predict the effect of the therapy. A fully validated, surrogate endpoint predicts the clinically meaningful endpoint of a therapy consistently. ... 

Mechanism-based biomarker selection and correlation to clinical endpoints. 

The important point for patients is not so much that plasma cholesterol decreases but that the clinical endpoints decrease nonfatal heart attacks, coronary artery disease deaths, surgery for coronary artery disease, and total mortality. Subsequent to the approval of statins based on reduction of plasma cholesterol levels, several large, controlled clinical trials have been carried out to establish the effects of statin use on these clinical endpoints. ... 

The terms proof of principle and proof of concept are used more or less synonymously and pertain to the criteria that must be fulfilled in human studies before an NME can be considered to be a candidate for FD. These are particularly useful terms when applied to a drug thought to act by a novel mechanism of action. Eor example, a drug may be the first known inhibitor of a particular enzyme or receptor and the proof of principle will be a demonstration that such inhibition results in a desired pharmacodynamic or clinical endpoint. The terms are perhaps less... 

An important qualification must be made. While a biomarker may be of proven value in establishing whether a drug has the desired effect in patients or healthy volunteers (see Section 4.6.3) and for evaluation of the dose-response relationship, a biomarker may not be a surrogate for the clinical endpoint. Thus, suppression of testosterone after an initial rise will give an almost immediate endpoint for the effect of GnRH analogues in prostate cancer but the relationship breaks down later in the disease. Measures of blood glucose control are vital... 

Of course, it is not always necessary to rely on biomarkers for rapid evaluation of dose-response relationships in ED. Thus, efficacy of new drugs is readily demonstrated in terms of the clinical endpoint for diseases, such as migraine, inflammatory pain, asthma, psoriasis, glaucoma and many others. 

High predictive value for therapeutic or clinical endpoint. 

It is important when choosing a particular measurement scale to answer a number of questions. Is the choice that is made of clinical relevance How is the endpoint to be measured Can we measure the clinical endpoint directly, or must we choose an indirect approach Is the choice that is made sensitive enough to measure real treatment effects Having collected the information how are we to analyse it Some of these issues are illustrated in the following sections. 

In CEA, the total cost and the total benefits, measured in terms of an efficacy parameter, associated with two or more treatment pathways are added, and the increment is calculated. The incremental costs are then compared (in a ratio) with incremental outcomes (as measured in physical or natural emits). Physical and natural units can include both intermediate (surrogate) clinical endpoints (e.g. millimetres of mercury blood pressure reduction, changes in FEVi) or final endpoints (e.g. deaths averted or life-years gained). In a study that assessed the cost per deaths due to pulmonary embolism averted, Hull and associates reported that subcutaneous administration of... 

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. ... 

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