Non-inferiority trial

Kullberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients a randomised non-inferiority trial. Lancet 2005 366 1435-1442. 

Non-inferiority trials are more common than equivalence trials in Phase III drug development. In these, the objective is to show that a new treatment is no less effective than existing treatment. It... 

Finally, in a non-inferiority trial we are trying to demonstrate that we are at least as good as or not worse than some active control reference treatment in some pre-defined sense. 

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... 

Non-inferiority trials are becoming more and more common as time goes on. This in part is due to the constraints imposed by the revised Helsinki Declaration (2004) and the increasing concern in some circles regarding the ethics of placebo use. These trials however require very careful design and conduct and we will discuss this whole area in a subsequent chapter. 

In equivalence and non-inferiority trials (see Chapter 12), the full analysis set and the per-protocol set have equal status and are treated as co-primary. The requirement, therefore, is to show significance for each of these analyses. This is another case where significance is needed on all endpoints with both analyses being conducted at the usual 5 per cent significance level. 

As mentioned in Section 1.10, there are essentially two areas where we would want to conduct non-inferiority trials firstly where inclusion of a placebo for either practical or ethical issues is not possible and we are therefore looking to demonstrate the efficacy of the new treatment indirectly by showing similarity to an established active treatment and secondly where it is necessary to show that there is no important loss of efficacy for a new treatment compared to an existing treatment. 

A good overview of various aspects of non-inferiority trials is provided by Kaul and Diamond (2006). 

One concern with equivalence and non-inferiority trials is that a positive conclusion of equivalence/non-inferiority could result from an insensitive trial by default. If, for example, equivalence is established then this could mean either that the two treatments are equally effective, or indeed equally ineffective. If chosen endpoints are insensitive, dosages of the drugs too low, patients recruited who are not really ill and the trial conducted in a sloppy fashion with lots of protocol deviators and dropouts, then the treatments will inevitably look very similar Clearly we must ensure that a conclusion of equivalence/non-inferiority from a trial is a reflection of the true properties of the treatments. The regulatory guidelines (ICH ElO) talk in terms of assay sensitivity as a requirement of a clinical trial that ensures this. 

In superiority trials, the full analysis set is the basis for the primary analysis. As discussed in Section 7.2, the regulators prefer this approach, in part, because it gives a conservative view of the new treatment. In equivalence/non-inferiority trials, however, it is not conservative and will tend to result in the treatments looking more similar than, in reality, they are. This is because the full analysis set will include the patients who have not complied with the medication schedules and who have not followed the study procedures and the inclusion of such patients will tend to weaken treatment differences. 

For equivalence and non-inferiority trials, therefore, the regulators like to see analyses undertaken on both the full analysis set and the per-protocol set with positive conclusions being drawn from both. In this sense these two analyses are considered co-primary. There is a common misconception here that for equivalence/non-inferiority trials the per-protocol set is primary. This is not the case. The per protocol set is still potentially subject to bias because of the exclusion of randomised patients and so cannot supply the complete answer both analysis sets need to be supporting equivalence/non-inferiority in order to have a robust conclusion. 

In a non-inferiority trial, the full analysis set and the per-protocol analysis set have equal importance and their use should lead to similar conclusions for a robust interpretation. ... 

One of the most difficult aspects of the design of equivalence and non-inferiority trials, with the exception of bioequivalence, is the choice of the margin(s). 

The issue of constancy concerns the conditions under which the current active control trial is being conducted compared to the conditions under which the active control was established historically. Things may well have changed. For example, the nature of the underlying disease or the effectiveness of ancillary care may be such that the active control performs rather differently now than it did when the original placebo-controlled trials were undertaken. This may well be true, for example, for antibiotics where populations of patients will have developed resistance to certain treatments. If this were the case then the current non-inferiority trial could lead to a misleading conclusion of effectiveness for the new active when in fact the comparator treatment is ineffective. 

As with sample size in superiority trials we generally power on the basis of the per-protocol set and increase the sample size to account for the non-evaluable patients. This is particularly important in non-inferiority trials where the full analysis set and the per-protocol set are co-primary analyses. Note also, as before in superiority trials further factoring up may be needed if there are randomised patients who are being systematically excluded from the full analysis set, as is the case, for example, in anti-infective trials. 

There is a perception that non-inferiority trials are inevitably larger than their superiority counterparts. Under some circumstances this is true, but is by no... 

Figure 12.5 Concluding superiority in a non-inferiority trial What conclusions can we draw in this situation Can we conclude superiority even though this was not the original objective Well generally the answer is yes, superiority can be claimed.

Non-inferiority trials are more difficult to design assay sensitivity and the choice of non-inferiority margin are just two of the issues that would additionally need to be considered. 

Non-inferiority trials can often require large sample sizes. 

Pooled 95 per cent confidence interval well away from zero (or unity for odds ratios, or the pre-defined margin for non-inferiority trials)... 

Statistical thinking and practice is very much determined by the regulatory guidelines that are in place. Primarily it is ICH E9 Statistical Principles for Clinical Trials , published in 1998, which sets down the broad framework within which we operate. In 2001 we saw the publication of ICH ElO Choice of Control Group which contained advice on the appropriate choice of concurrent control group and in particular first introduced the concept of assay sensitivity (see Section 12.5) in active control, non-inferiority trials. 

The correct design, analysis and interpretation of non-inferiority trials -remember conventional p-values have no role... 

Kaplan EL and Meier P (1958) Non-parametric estimation from incomplete observations Journal of the American Statistical Association, 53, 457-M81 Kaul S and Diamond GA (2006) Good enough a primer on the analysis and interpretation of non-inferiority trials Annals of Internal Medicine, 145, 62-69 Kay R (1995) Some fundamental statistical concepts in clinical trials and their application in herpes zoster Antiviral Chemistry and Chemotherapy, 6, Supplement 1, 28-33 Kay R (2004) An explanation of the hazard ratio Pharmaceutical Statistics, 3, 295-297... 

Szegedi, A., Kohnen, R., Dienel, A., Kieser, M. 2005, Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John s wort) randomised controlled double blind non-inferiority trial versus paroxetine, Br.Med.J., vol. 330, no. 7490, p. 503. 

Rerkasem K, Bond R, Rothwell PM (2004). Local versus general anaesthetic for carotid endarterectomy. Cochrane Database of Systematic Reviews 2 CD000126 SPACE Collaborative Group (2006). 30-day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients a randomised non-inferiority trial. Lancet 368 1239-1247... 

Non-inferiority trials are more common than equivalence trials in Phase III drug development. In these, the objective is to show that a new treatment is no less effective than existing treatment. It may be more effective or equivalent, but using the confidence interval approach, the only interest is a possible difference in one direction. Hence the 95% confidence interval should be entirely to the right of the point estimate for superiority and other trials (see Figure 6.2). 

Nauck MA, Meininger G, Sheng D, Terranella L, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared to the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone A randomized, double-blind, non-inferiority trial. Diabetes Obesity Metab 2007 9 194-205. 

Chen, M.-H., Ibrahim, J. G., Lam, R, Yu, A., and Zhang, Y. (2011) Bayesian design of non-inferiority trials for medical devices using historical data, Biometrics 67,1163-1170. 

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