Efficacy non-inferiority

Of course, almost every clinical trial, including most non-inferiority trials with efficacy primary endpoints, will collect and analyze safety data. The safety analyses done in an efficacy non-inferiority trial are essentially no different than those in an efficacy superiority trial. However, one possible distinction relates to the interpretation of the safety information in assessing the experimental treatment s relative benefits and harms. As stated previously, in some cases, improvement in safety might be an expected ancillary benefit of a treatment, and therefore, the lack of improvement might be seen as problematic. In addition, any unexpected harm caused by the experimental treatment might be less acceptable if the experimental treatment has simply demonstrated similar efficacy to a control than if it had demonstrated superior efficacy. 

The approach described previously is clearly meant to ensure that a conclusion of non-inferiority can also be interpreted as a conclusion that (Pr - Pp) > 0, that is, that the experimental treatment has at least some efficacy. In a sense, therefore, an efficacy non-inferiority trial can be thought of as part of an indirect comparison of the experimental treatment to placebo, with a null hypothesis Hq (p - pp) = 0 versus the alternative H (pr - Pp) > 0. This concept is discussed in detail by Snapinn and Jiang (2011). 

The facf fhat an efficacy non-inferiority trial involves an indirect comparison between the experimental treatment and placebo, while a safety noninferiority trial does not, underlies nearly all of the key differences between these types of trials, as discussed in the following. 

While the constancy assumption has important implications for efficacy non-inferiority trials, this is an example of an issue that is related to the indirect comparison aspect of those trials and therefore has no relevance for safety non-inferiority trials. 

Because of concern with the assumption of assay sensitivity and constancy, the non-inferiority margin used in efficacy non-inferiority trials is sometimes reduced or discounted (Snapinn 2004 Snapinn and Jiang 2008a U.S. Food and Drug Administration 2010). Since safety non-inferiority trials also rely on the assumption of assay sensitivity, the concept of discounting could apply in this setting as well. However, to our knowledge, this has not been done. 

However, there is a second approach in common use for efficacy non-inferiority trials, and there is no consensus on which approach is more appropriate (Peterson et al. 2010 U.S. Food and Drug Administration 2010). This approach, known as the synthesis method (Flasselblad and Kong 2001 Holmgren 1999 Rothmann et al. 2003), specifically addresses fhe indirect comparison of the experimental treatment with placebo that is, it is meant to test the hypothesis Flo (p - - pp) = 0 versus the alternative H (pr - Pp) > 0. Using this approach, one sums the estimate of the effect of the experimental treatment relative to the control from the non-inferiority trial with the estimate of fhe effect of the control relative to placebo from the historical trials to obtain an indirect estimate of the effect of the experimental treatment relative to placebo. Let pcp represent the estimate of the mean difference between the control and placebo based on the historical trials. 

Because the s)mthesis method is specifically focused on the indirect comparison aspect of efficacy non-inferiority trials, it does not apply in the context of safety non-inferiority trials therefore, all safety non-inferiority trials use the fixed margin method. 

Efficacy non-inferiority trials are often conducted in situations where a placebo-controlled trial would not be ethical, for example, when there exists effective therapy for a serious or life-threatening condition. Despite this, the ethical basis for non-inferiority trial has been called into question. For example, Garattini and Bertele (2007) argue that"... it is unethical to leave to chance whether patients receive a treatment that is anticipated to provide no extra benefit, but could be less safe and less effective than existing treatment options." While their comments were in the context of efficacy non-inferiority trials, the issue could be even greater in the context of a safety non-inferiority trial. The primary objective of a safety non-inferiority trial is to determine whether or not an experimental treatment causes an important harm on this basis alone, there would be little incentive for a prospective patient to participate. Patients must be fully informed of the purpose of such a trial, including the potential benefits and harms, before they can consent to participate. 

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... 

Alternatively there may be commercial reasons why we want to demonstrate the non-inferiority of our treatment against an active control. Maybe our treatment potentially has fewer side effects than the active control and we are prepared to pay a small price for this safety advantage in relation to efficacy. If this were the case then of course we would need to show advantages in terms of a reduction in side effects but we would also need to demonstrate that we do not lose much with regard to efficacy. 

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. 

Finally, before we move on to look at statistical methods, it is worth mentioning that many people feel uncomfortable with the term non-inferiority. In a strict sense, any reduction in the mean response is saying that the new treatment is not as good as the existing treatment and so is inferior. We, however, are using the term non-inferiority to denote a non-zero, but clinically irrelevant reduction in efficacy, which we need to define in an appropriate way. Some practitioners use the term one-sided equivalence as an alternative to non-inferiority. 

For non-inferiority, the first step involves defining a non-inferiority margin. Suppose that we are developing a new treatment for hypertension and potentially the reason why the new treatment is better is that it has fewer side effects, although we are not anticipating any improvement in terms of efficacy. Indeed, suppose that we are prepared to pay a small price for a reduction in the side effects profile say up to 2 mmHg in the mean reduction in diastolic blood pressure. 

In Figure 12.2, and P2 e mean reductions in diastolic blood pressure in the test treatment and active control groups respectively. If the difference in the means is above zero then the test treatment is superior to the active control, if the difference is zero then they are identical. If the difference falls below zero the test treatment is not as good as the active control. This, however, is a price we are prepared to pay, but only up to a mean reduction in efficacy of 2 mmHg beyond that, the price is too great. The non-inferiority margin is therefore set at —2 mmHg. 

A finding of no significant difference in outcome between two treatments is ambiguous unless a non-inferiority design is used. Two-arm non-inferiority designs require much larger sample sizes to test adequately the statistical hypothesis of no true difference in efficacy between a test and reference drug. 

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. 

Some non-inferiority trials have safety as their primary endpoint. This is often the case for a marketed treatment where a new safety concern has arisen. As in the case of an efficacy endpoint, unless the drug actually improves safety, no trial will ever be able to rule out harm entirely therefore, the goal of these trials is to determine whether or not the magnitude of harm exceeds the prespecified margin, 8. This is the type of a trial we refer to as a safety non-inferiority trial and that we discuss in this chapter. 

Non-inferiority trials for safety received some attenhon in the International Conference on Harmonisation (ICH) guidance document (2010). The document states that it is meant to apply primarily to efficacy trials, but that many of the considerations discussed also apply to safety hypotheses. The most relevant comment in that document is the following Tlacebo-controlled trials seek to show a difference between treatments when they are studying effectiveness, but may also seek to show lack of difference (of specified size) in evaluating a safety measurement hi that case, the question of whether the trial could have shown such a difference if there had been one is critical (see Sechon 1.5)." Note that Section 1.5 refers to the issue of assay sensitivity, which we discuss later. 

The concept of margin selection has mostly been discussed in the context of efficacy non-inferiorify frials, and this is perhaps the most important distinction between efficacy and safety trials. The earliest examples of non-inferiority trials typically used margins based on clinical considerations. The weakness of this approach becomes apparent when one considers the possibility that the margin chosen in this way could be greater than the effect of the active control. Let ip represent the mean value of the variable of interest when patients are treated with a placebo. When 8 > (pc Pp)/ the condition pr - can... 

While preservation of effect is an important consideration for efficacy noninferiority trials and is discussed in both the FDA and EMA guidance documents, it is not relevant to the design of a safety non-inferiority trial. 

This hierarchical approach can be prespecified and applied to either efficacy or safety non-inferiority trials. However, the superiority hypothesis is less likely to be of interest in the safety setting than in the efficacy setting, since it is less likely that an experimental treatment could be hypothesized to be superior to placebo with respect to a safety endpoint than it is that an experimental treatment could be hypothesized to be superior to an active control with respect to an efficacy endpoint. 

Non-inferiority trials are designed to demonstrate that one treatment has an effect that is either superior to that of another treatment, or similar to it. Safety non-inferiority trials are non-inferiority trials with a primary safety endpoint and with a prespecified margin. Non-inferiority trials for efficacy and safety endpoints have some similarities, but also some fundamental... 

Kenemans P, Hundred NJ, Foidart JM, Kubista E, von Schoultz B, Sismondi P, Vassilopoulou-Sellin R, Yip CH, Egberts J, Mol-Arts M, Mulder R, van Os S, Beckmann MW. Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms a double-blind, randomised, non-inferiority trial. Lancet Oncol 2009 10 135-46. 

Molina JM, Lamarca A, Andrade-Villanueva J, Clotet B, Clumeck N, Uu YP, et al. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis 2012 12(l) 27-35. 

More debatable is the use of placebo in conditions when effective treatments already exist. In these situations, ethical objections can be made to assigning patients to an inferior treatment. Moreover, families may refuse enrollment into such studies, thus decreasing the representativeness of the study sample. When testing an experimental medication in situations where effective treatment already exists, different types of questions can arise. We may be interested in testing whether the novel treatment is (2) better than no treatment (or non-specific treatment), (2) comparable to an established treatment of proven efficacy, or (3) superior to... 

As alternative to DES DCB were developed since it was found that a single short exposure to PTX using non-ionic contrast media or balloon catheter coatings as carriers for local drug delivery provided similar protection from restenosis as the most efficacious DES [16, 101, 102], Since these first preclinical observations more than 10 years ago different DCB concepts were proven (Table 15.3). Regarding their deliverability a clear inferiority of PTX-coated balloons using low-molecular excipients in comparison to uncoated balloon catheters was demonstrated [16]. Furthermore, it was stated that a PTX dose of 3 pg/mm is effective and tolerable for the DCB utilization [16,103-105]. 

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