Noninferiority

Specihc analysis objectives were to estimate the best dose(s) to show noninferiority, to evaluate the design and synthesize alternatives, and to evaluate the likelihood of success for each alternative design. 

If only active comparator trials were available, then the trial objectives would have to be very precise from the beginning of a trials programme as to whether superiority, equivalence or noninferiority is being tested. Demonstration of... 

Lewis JA. Switching between superiority and noninferiority. Br J Clin Pharmacol 2001 52 223-80. 

Nathan N, Borel T, Djibo A, Evans D, Djibo S, Corty JE et al. Ceftriaxone as effective as long-acting chloramphenicol in short-course heatment of meningococcal meningitis during epidemics a randomised noninferiority study. Lancet 2005 366(9482) 308-13. 

Although conventional p-values have no role to play in equivalence or noninferiority trials there is a p-value counterpart to the confidence intervals approach. The confidence interval methodology was developed by Westlake (1981) in the context of bioequivalence and Schuirmann (1987) developed a p-value approach that was mathematically connected to these confidence intervals, although much more difficult to understand It nonetheless provides a useful way of thinking, particularly when we come later to consider type I and type II errors in this context and also the sample size calculation. We will start by looking at equivalence and use A to denote the equivalence margins. 

We will focus our attention to the situation of non-inferiority. Within the testing framework the type I error in this case is as before, the false positive (rejecting the null hypothesis when it is true), which now translates into concluding noninferiority when the new treatment is in fact inferior. The type II error is the false negative (failing to reject the null hypothesis when it is false) and this translates into failing to conclude non-inferiority when the new treatment truly is non-inferior. The sample size calculations below relate to the evaluation of noninferiority when using either the confidence interval method or the alternative p-value approach recall these are mathematically the same. 

A more recent area of application for meta-analysis is in the choice of the noninferiority margin, A. As mentioned in Section 12.8, A is often chosen as some proportion of the established treatment effect (over placebo) and meta-analysis can be used to obtain an estimate of that treatment effect and an associated confidence interval. 

By taking every point in Figure 4.18 as point p successively, all the inferior points can be removed by applying those three rules, only the noninferior or Pareto Optimal points remain. 

An adequately powered trial initially designed to demonstrate the noninferiority of a new compound compared with a standard treatment can also demonstrate the superiority of the new compound provided that a statistically significant difference in favor of the new1 treatment was detected. However, trials intended to show the superiority of one of the treatments cannot be interpreted, in the case of a statistically non-significant difference, as showing non-inferiority of the new1 chemical entity compared with the standard treatment. 

Paromomycin sulfate is an aminoglycoside antibiotic that until recently was used in parasitology only for oral therapy of intestinal parasitic infections (see previous text). It has recently been developed for the treatment of visceral leishmaniasis. A phase 3 trial in India showed excellent efficacy for this disease, with a daily intramuscular dosage of 11 mg/kg for 21 days yielding a 95% cure rate, and noninferiority compared with amphotericin. The drug was registered for the treatment of visceral leishmaniasis in India in 2006. In initial studies, paromomycin was well tolerated, with common mild injection pain, uncommon ototoxicity and reversible liver enzyme elevations, and no nephrotoxicity. Paromomycin is much less expensive than liposomal amphotericin or miltefosine, the other promising new therapies for visceral leishmaniasis. 

Hasegawa, S., Shimizu, K. Noninferior Periodic Operation of Bioreactor Systems. Vol. 51, p. 91... 

In REPLACE-2, treatment with bivalirudin plus provisional GPIIb/llla inhibitors was noninferior to heparin plus routine GPIIb/llla in patients undergoing urgent or elective PCI with respect to the combined efficacy plus safety endpoint. However, the noninferiority conclusion depended more on... 

Kaul S, Diamond GA. Making sense of noninferiority a clinical and statistical perspective on its application to cardiovascular clinical trails. Prog in Cardio Dis 2007 49 284-299. 

Fifty-six percent of patients underwent PCI, 32% had medical therapy, and 12% had surgery. The primary endpoint showed noninferiority for the net clinical outcome 11.7% heparin + llb/llla groups versus 11.8% bivalirudin + llb/llla groups, P < 0.001. The ischemic composite was 7.3% versus 7.7%, P = 0.015, for noninferiority and major bleeding was 5.7% versus 5.3%, P < 0.001 for noninferiority. 

On the whole, while not demonstrating superiority of LMWH with regard to bleeding complications, death, infarction, and urgent revascularization over UFH, the above results do support its noninferiority. In view of LMWH s simplicity of use in ACS, which makes most centers prefer it to UFH, it is important to recognize it as an acceptable alternative to UFH when the patient must be treated soon after their last subcutaneous dose. 

Ringleb PA, AllenbergJ, Bruckmann H, etal. 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients a randomised noninferiority trial. Lancet 2006 368 1239-1247. 

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