Efficacy endpoints, clinical trials

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). 

In this form, event would be replaced by some clinical finding such as myocardial infarction, stroke, seizure, or the like. This example form is extremely simplified, as there are usually a number of associated data variables captured as well. The event/endpoint page data must be clean, because it likely captures the primary efficacy data for the clinical trial. 

Phase II investigates the compound s efficacy and safety in controlled clinical trials for a specific therapeutic indication. To eliminate as many competing factors as possible, Phase II trials are narrowly controlled. They are characterized as small—several hundred subjects with the indicated disease or symptoms—and are closely monitored. The control may be either a placebo study arm or an active control arm. The endpoint measured may be the clinical outcome of interest or a surrogate. Phase II trials may last for several months or even several years. Early pilot trials to evaluate safety and efficacy are called Phase Ila. Later trials, called Phase lib, are important tests of the compound s efficacy. These trials may constitute the pivotal trials used to establish the drug s safety and efficacy. At least one pivotal trial (most frequently a large, randomized Phase III study) is done. Only about one third of compounds entered into Phase II will begin Phase III studies [61],... 

These scales may be used either as part of a clinical trial or as major endpoints in an efficacy trial. Here they are described as a means of obtaining ancillary data on psychological factors in a clinical trial. If these scales are used to demonstrate efficacy, it is mandatory to include only those scales known to be valid. 

A good clinical trial is designed to take account of the variability in response (either efficacy or adverse event) that is expected when a new active drug is tested. This response depends on an individual s genetic make-up, and on a number of environmental factors, such as disease state, other drugs and age. The size of the trial and the selection of study subjects are carefully determined to reduce the variability in response to a minimum (i.e. to maximise the sensitivity of the trial) so that the trial endpoints can be determined with as much certainty as possible. 

Improvements in medical treatments have been substantial, so much so that benefits of recently introduced medicines over existing ones are smaller than when these standard treatments were originally developed and compared with remedies that existed then. The mean difference in some clinical efficacy endpoints between treatments maybe less than 20%. This requires a large population sample in clinical trials in order to achieve sufficient power to detect a difference, if it really exists, with confidence. Most medical conditions (for instance, peptic ulcers) present rather infrequently at any single hospital centre and it would therefore be impossible for a single... 

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 use of intermediate endpoints to demonstrate clinical efficacy is common in clinical trials, because it reduces both the cost of the clinical development process and the time needed to demonstrate the efficacy of the therapy. Intermediate endpoints are most appropriate in clinical research if they have been shown to be related to the clinical outcome of interest, as in the following ... 

In the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-llb trial, the effects of UFH and hirudin in combination with either t-PA or SK were compared in 3289 patients with AMI (53), When dosed in combination with SK, the benefit of hirudin over UFH was observed in the clinical efficacy endpoint with the same levels of bleeding complications, In the TIMI 9b trial, 3002 patients with AMI were dosed with hirudin or UFH in combination with t-PA or SK, but no difference between the groups was observed in the clinical efficacy endpoint up to 30 days after administration (54). The administration of UFH or hirudin was not initiated... 

The efficacy of gene transfer approaches to therapeutic angiogenesis is now being tested in clinical trials. Controlled phase II trials are providing positive but not definitive results. Gene therapy appears to be safe based on these data. Hard clinical endpoints, such as mortality, myocardial infarction, and the need for revascularization are lacking, as is long-term follow-up. 

In order to decide to enter Phase III or not, all available knowledge has to be used to predict the clinical outcome (efficacy and safety) in Phase III. Phase III clinical trials differ in several aspects from Phase II trials, which makes this step not always easy. These aspects are basically (1) the patient population, (2) the dose range studied, and (3) the primary endpoint. 

When preclinical studies are conducted in house or are reported in peer-reviewed journals and intended to support clinical trials, they should be well-controlled and designed to answer specific toxicological questions. The data should also be available in sufficient detail to allow an independent review of the studies. Ideally study designs include not only efficacy but toxicological endpoints such as defined clinical laboratory parameters, macroscopic, and microscopic evaluation of tissues. 

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