Efficacy endpoints

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). 

The types of trials to be undertaken demand a flexible approach, and depend on the seriousness of the disease, other therapeutic options and the pharmacokinetics at different ages. For example, if the disease process and efficacy endpoints are similar in adults and children, then an extrapolation from adult efficacy data, together with pharmacokinetic studies in the appropriate paediatric age range, together with safety studies, could form the basis of a successful application. Likewise, it may be possible to extrapolate efficacy from older to younger paediatric groups, with pharmacokinetic and safety studies in the relevant younger study subjects. Where there is no known correspondence between efficacy and... 

The characteristics of an ideal surrogate efficacy endpoint include ... 

In the evaluation of pharmaceutical products, commonly used surrogate efficacy endpoints include ... 

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... 

The duration of action against the primary efficacy endpoint. 

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. 

Including too few subjects in a study can result in one or both of two kinds of error related to the efficacy endpoints. 

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. 

United Parkinson Disease Rating Scale (UPDRS) useful for monitoring efficacy endpoints... 

E. Therapeutic response The primary efficacy endpoint of two randomized, double-bund, placebo-controlled, multicenter trials was the proportion of patients who developed a biopsy-proven acute rejection episode within the first 6 months foUowing transplantation. These trials compared a dose of 1.0 mg/kg of Zenapax with placebo when each was administered as... 

The Superior Yield of the New Strategy of Enoxaparin Revascularization and GP llb/llla Inhibitors (SYNERGY) trial (20) was a randomized, open-label, international trial comparing enoxaparin and UFH among 10,027 high-risk patients with non-ST-segment elevation ACS to be treated with an intended early invasive strategy. The incidence of the composite primary efficacy endpoint (death/MI at 30 days) was similar in enoxaparin and UFH-treated patients (14.0% vs. 14.5%,... 

Hirudin has been studied extensively in ACS (Table 4), The TIM I 5 trial was conducted in 246 patients with AMI to compare the efficacy of UFH and hirudin as adjunctive therapy to t-PA (51). In the hirudin group, the rate of recanalization to achieve TIM I 3 coronary flow without death or reinfarction was greater than that in the UFH group (P = 0.07). No inter-group difference in the incidence of major hemorrhage was observed. In TIMI 6, the effects of UFH and hirudin were compared in 193 patients with AMI in combination with SK. The results of both groups were similar for both safety and efficacy endpoints (52). 

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... 

Optimization and then selection of final formulations, doses, regimens, and efficacy endpoints for larger scale, multicenter studies. Efficacy endpoints should be able to be measured reliably and should quantitatively reflect clinically relevant changes in the disease or condition of interest. 

Efficacy endpoints Efficacy variables are chosen according to the objectives of the trial. They may be the therapeutic effect itself (for example, irradication of infection, healing of peptic ulcer) or a factor related to the therapeutic effect or some surrogate effect. 

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