Active control equivalence studies

Statistical Issues in Drug Development, 2nd E tion. Stephen Senn 2007 John Wiley Sons, Ltd. ISBN 978-0-470-01877-4 

In the rest of this chapter, it will be assumed that some general approach via classical confidence intervals, one-side for the case of noninferiority and two-sided for genuine equivalence) will be used. In fact, for true equivalence there are various technical controversies surrounding the use of two-sided confidence intervals (Mehring, 1993 Senn, 2001b). These will be taken up in Chapter 22. 

In fact it is possible to show in a Bayesian formulation that if some prior doubt is allowed that the trial may not be competent to find a difference, then although, conditional upon a belief in competence, the posterior probability of equivalence will rise the more patients are studied and the more that prognosis is found to be the same in the two groups, the more the posterior belief must increase that the trial is not competent to find a difference (Senn, 1993). In short, the whole field is summed up by the oxymoron equivalence is different . 

Equivalence Proving that apples are pears by comparing the weight. 

The use of such trials is not unproblematic, however. First, it may be claimed that a trial which is competent to show a difference from placebo is not necessarily competent to detect a difference between active treatments. Thus the initial problem 

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Makuch RW, Johnson MF. 1989. Issues in planning and interpreting active control equivalence studies . J. Clin. Epidemiol. 42 503—511. 

In recent years a number of vigorous criticisms have been made of placebo-controlled trials stressing the ethical problems in giving placebo where effective remedies exist (Rothman, 1996 Rothman and Michels, 2000). Anderson has gone so far as to criticize the usual assumption that placebo-controlled trials are more convincing than active controlled equivalence studies, arguing (correctly in my view) that even... 

Senn SJ (1993) Inherent difficulties with active control equivalence studies. Statistics in Medicine 12 2367-2375. 

Active control equivalence study. A trial with the purpose of attempting to demonstrate that an experimental treatment is similar in effects to a standard therapy. 

Mononuclear amidinate tin(II) alkoxides, (282) and (283), have also been examined the latter consumes 92 equivalents rac-LA over 165 min in toluene at 80 °C (Mn calc = 28,900, Mn calc= 14400, Mw/Mn= 1.18).859 Reproducibility of the polymer chain length is problematic, but the addition of 1 equivalent of an alcohol serves to deliver greater control. Kinetic studies reveal that the rate law is 0.33 ( 0.02) in [Sn], suggesting that aggregation of the active species may occur. 

Active control studies intended to show equivalence... 

Most efficacy trials with reboxetine have so far only been published in review articles ( 178). Most of these articles did not have peer review and do not contain the full details concerning methodology or results. This fact limits the ability to accurately determine its relative efficacy and tolerability. In short-term (4 to 8 weeks), placebo-controlled clinical trials, reboxetine produced a response (defined as at least a 50% reduction in severity scores) in 56% to 74% of patients. These results were statistically superior to placebo in most studies. Reboxetine was also found to be as effective as imipramine and desipramine in four double-blind, randomized, active-controlled (but not placebo-controlled) studies involving more than 800 outpatients or inpatients with major depression. Reboxetine produced equivalent antidepressant response rates compared with fluoxetine in two clinical trials, one of which was also placebo-controlled. However, reboxetine was reported to have improved social motivation and behavior more than fluoxetine as assessed by the newly developed Social Adaptation Self-Evaluation Scale. In all of the studies, reboxetine had a similar time (i.e., 2 to 3 weeks) to onset of the antidepressant efficacy as do other antidepressants. 

Oxcarbazepine is closely related to carbamazepine and useful in the same seizure types, but it may have an improved toxicity profile. Oxcarbazepine has a half-life of only 1-2 hours. Its activity, therefore, resides almost exclusively in the 10-hydroxy metabolite, to which it is rapidly converted and which has a half-life similar to that of carbamazepine, ie, 8-12 hours. The drug is mostly excreted as the glucuronide of the 10-hydroxy metabolite. Oxcarbazepine is less potent than carbamazepine, both in animal models of epilepsy and in epileptic patients clinical doses of oxcarbazepine may need to be 50% higher than those of carbamazepine to obtain equivalent seizure control. Some studies report fewer hypersensitivity reactions to oxcarbazepine, and cross-reactivity with carbamazepine does not always occur. Furthermore, the drug appears to induce hepatic enzymes to a lesser extent than carbamazepine, minimizing drug interactions. Those adverse effects—such as hyponatremia—that do occur with oxcarbazepine are similar in character to reactions reported with carbamazepine. 

Fortical s PD equivalence was shown in a double-blind, active-controlled, 24-week study in 134 postmenopausal women randomized to Fortical (200IU per day) or Miacalcin (200IU per day). The primary outcome measure was change in serum beta-CTx from baseline. The results fell within prespecified PD equivalence limits (-0.08 to 0.06ng/mL equivalence margin of 0.2ng.mL) and indicated Fortical was not inferior to Miacalcin. 

Roof acceleration time histories are shown in Figure 6. As it follows from this figure, using an optimal set of active controlled devices yields a significant reduction in peak roof accelerations of the stmcture under all ground motions that were used in the study. Like in the case of peak displacements, also roof accelerations for cases 3 and 4 were equivalent. It proves that using lever arms as amplifiers for connection of active controlled devices (Case 4) yields the same reduction in stmctural response like an optimal limited set... 

The slow (deep sleep) -waves probably originate in the eortex beeause they survive separation from, or lesions of, the thalamus. However, the rhythm and appearanee of spindles in earlier phases of the sleep eyele do depend on links with the thalamus (see Steriade 1999). Unlike stimulation of the specific sensory relay nuclei in the thalamus, which only affects neurons in the appropriate sensory areas of the cortex, the nonspecific nuclei can produce responses throughout the cortex and may not only control, but also generate, cortical activity. Certainly, in vitro studies show that neurons of the non-specific reticular thalamic nucleus (NspRTN) can fire spontaneously at about 8-12 Hz (equivalent to EEG a-rhythm) or lower, and that low-frequency stimulation of this area can induce sleep. 

Ciprofloxacin has an excellent activity against enteric pathogens and Gram-negative Enterobacteriaceae associated with immunosuppressive properties. Ciprofloxacin 1 g/daily was compared to mesalazine 4 g/daily in a controlled study in mildly to moderately active CD. After 6 weeks an equivalence in efficacy was registered, offering an alternative treatment in active CD [39],... 

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