Comparative superiority trials

There are a number of issues in using such studies to achieve marketing authorisation. First, there needs to be a justification of the boundaries. Flow can we be sure that the choice of S is appropriate Second, has an appropriate choice comparator been made Is the dose of the comparator appropriate Is the population of patients appropriate Third, while for superiority trials it is generally accepted that the appropriate analysis population is an ITT population, it has been argued that for equivalence and non-inferiority studies that the as per protocol population also has a role to play. Finally we need to be sure that an equivalence or non-inferiority study is... 

In therapeutic equivalence trials and in non-inferiority trials we are often looking to demonstrate efficacy of our test treatment indirectly. It may be that for ethical or practical reasons it is not feasible to show efficacy by undertaking a superiority trial against placebo. In such a case we compare our test treatment to a control treatment that is known to be efficacious and demonstrate either strict... 

Formulate null and alternative hypotheses. In all cases the alternative hypothesis represents the desirable outcome. In a superiority trial this means that the null hypothesis is equality (or no effect/no change/no dependence) of whatever is being compared while the alternative hypothesis is inequality (there is an effect/a change/a dependence). 

In previous chapters, discussion has focused on superiority trials. These trials are conducted to demonstrate to the satisfaction of regulatory agencies that the investigational drug is superior in efficacy to a placebo, or possibly superior in efficacy to an active comparator. In addition, this chapter also introduces other study designs that are very informative and, in some cases, necessary. 

In the case of equivalence, noninferiority, and bioequivalence trials, the null hypotheses established are different from the null hypothesis established in superiority trials. In addition, the null hypothesis in each case is unique, and hence they all differ from each other. However, they share a basic similarity. The null hypothesis for each of these designs states, in effect, that the test drug and the comparator drug do not have similar efficacy. As in all hypothesis testing, the statistical methodologies used look for compelling evidence to reject the respective null hypothesis in each case. 

Consider the simple case of a superiority trial of an investigational drug (the test treatment) being compared with placebo with respect to a continuous outcome (for example, change from baseline SBP). The null hypothesis typically tested in such a trial and its complementary alternate hypothesis are ... 

Given that the research questions in these trials are different from those used in superiority trials, the formats of the null and alternate hypotheses are also different. The research question associated with an equivalence trial is Does the test drug demonstrate equivalent efficacy compared with the comparator drug The null hypothesis,... 

Standard PPI dosages (e.g., omeprazole 20 mg/day and lansoprazole 30 mg/day) reduce the risk of NSAID-induced gastric ulcer and duodenal ulcer. " In a large comparative multicenter trial, omeprazole 20 mg/day was superior to ranitidine 150 mg twice daily in preventing NSAID-induced gastroduodenal ulcers. Two randomized controlled trials have compared PPIs with misoprostol and placebo. 

Unlike superiority trials, for which p-values are employed to determine if a new drug s efficacy is statistically significantly superior to that of the comparator drug, p-values are not typically used in noninferiority trials. Establishing noninferiority is based on the use of confidence intervals. 

Quan H, Li M, Zhao PL et al (2013) Considerations for design and data analysis of noninferiority/ superiority cardiovascular trials. J Biopharm Stat 23 239-260 Rosenstock J, Marx N, Kahn SE et al (2013) Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy rationale for the active-comparator CAROLINA trial. Diab Vase Dis Res 10 289-301... 

Hutchison and Laville 2008 Mehrotra, Martin et al. 2008). Another advantage of lanthanum carbonate over calcium-based drugs is that rather than increasing the risk of hypercalcaemia and cardiovascular calcification, lanthanum carbonate actually prevents arterial calcification (in animal experiments) (Neven, Dams et al. 2009). Nevertheless, a recent meta-analysis of published clinical trials (Navaneethan, Palmer et al. 2009) concluded that there are as yet there are insufficient data to establish the comparative superiority of non-calcium-binding agents, such as lanthanum carbonate, over calcium-containing phosphate binders for such important patient-level outcomes as all-cause mortality and cardiovascular end points. 

Nortriptyline. Nortriptyhne, a tricychc antidepressant, has been shown in double-blind, placebo-controlled randomized trials to be superior to placebo for smoking cessation (Prochazka et al. 1998). Nortriptyline appears to have efficacy comparable to that of bupropion for smoking cessation (Hall et al. 2002). The efficacy of this agent may be improved with more intensive behavioral therapies (Hall et al. 1998). Nortriptyline s mechanism of action is thought to relate to its noradrenergic and serotonergic reuptake blockade, because these two neurotransmitters have been implicated in the neurobiology of nicotine dependence. Side effects of nortiptyline are typical of tricyclic antidepressants and include dry mouth, blurred vision, constipation, and orthostatic hypotension. Nortriptyline appears to have some utility for smokers with a past history of major depression, and it can be recommended as a second-... 

A number of randomized chnical trials have demonstrated the efficacy of CBT for treating substance use disorders, compared with no-treatment control conditions (see Carroll 1996 for review). However, the superiority of CBT over other psychosocial treatments is not as clear. Although some studies have found CBT to be more effective than other treatments, others have found this method to be comparable to other treatment approaches (Carroll 1996). In Project MATCH, for instance, CBT, MET, and 12-step facihtation produced similar outcomes, with each therapy leading to substantial improvement in alcohol-related symptoms during the 12-week treatment period (Project MATCH Research Group 1997). 

Two large trials, the Vioxx Gastrointestinal Outcomes Research (VIGOR) study and the Celecoxib Long-term Arthritis Safety Study (CLASS), compared selective COX-2 inhibitors and traditional, non-selective NSAID therapy in terms of their ability to prevent clinical PUD (i.e., symptomatic ulcers and ulcer complications). VIGOR (9-month median follow-up) demonstrated that rofecoxib (50 mg daily) therapy was significantly more efficacious than naproxen.28 The CLASS study (6-month median follow-up) found that high-dose celecoxib (400 mg twice daily) was superior to non-selective NSAID therapy (either ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily).29... 

Selective COX-2 inhibitors are not superior to PPIs in preventing NSAID-related PUD. One randomized, place-bo-controlled trial that included 267 patients at high risk for ulceration (arthritic patients with a previously healed bleeding ulcer) compared celecoxib 200 mg twice daily to the combination of diclofenac 75 mg twice daily plus omeprazole 20 mg daily.32 After 6 months, the risk for recurrent bleeding was found to be similar between groups (celecoxib, 4.9% and diclofenac/omeprazole, 6.4%) the authors concluded that neither of these therapies can completely prevent recurrent ulcer complications. 

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