Must New Drugs Be Superior to Those Already Available? The Role of Noninferiority Clinical Trials J. Rick Turner, BSc, PhD;1 Todd A. Durham, MS2 From Clinical Communications, Quintiles, Durham, NC;1 and Durham Statistical Consulting LLC, Durham, NC2

While visionary work was conducted earlier in the 20th century by the statistician Sir Ronald Fisher,1,2 the continued development and widespread adoption of the randomized clinical trial as the “gold standard” for demonstrating a drug’s efficacy was driven by the 1962 Kefauver-Harris Amendments to the US Federal Food, Drug, and Cosmetics Act of 1938.3 Initial attention focused on the superiority trial, in which our intent is to look for compelling evidence that an investigational (new) drug demonstrates superior efficacy compared with a control drug (either a placebo or an active control that may be the standard of care at the time). Other study designs have now been developed and widely adopted, one of which is the noninferiority trial. Given the global need for better hypertension control4,5 and the use of noninferiority trials in this therapeutic domain,6–9 this paper describes their fundamental components and overall approach.

FUNDAMENTALS OF THE NONINFERIORITY CLINICAL TRIAL DESIGN While a new drug’s efficacy is clearly of great interest to us, other factors influence its suitability for therapeutic use and the degree to which it will be successful in the marketplace if approved. These include its tolerability, its safety profile (and, hence, in combination with its efficacy, the overall benefit-risk profile), and its cost, which will be influential in the extent to which its use may be reimbursed by payers, and therefore the degree to which it may be prescribed. Consider an example in which the side-effect profile of a new drug is dramatically better than that of an existing (reference) drug for the same indication. In this scenario we may be prepared to accept a certain degree of reduced efficacy since, despite this reduced efficacy, the overall benefit-risk balance of the new drug may be considerably more favorable. The question of interest therefore becomes: What degree of reduced efficacy are we prepared to accept, given the other advantages of the drug? If the new drug has only this degree, or less than this degree, of reduced efficacy, we will declare it to be noninferior to the reference drug. Expressed slightly differently, the goal of a noninferiority trial is to look for compelling evidence that a new drug’s efficacy is, in the worst case, “acceptably worse” than (ie, is noninferior Address for correspondence: J. Rick Turner, BSc, PhD, Clinical Communications, Quintiles, 4820 Emperor Boulevard, Durham, NC 27703 E-mail: [email protected] DOI: 10.1111/jch.12489

to) that of the reference drug, typically the existing goldstandard treatment for the disease of interest.

DEFINING THE NONINFERIORITY MARGIN Establishing that a new drug is noninferior to a reference drug has two key components: defining noninferiority using clinical judgment, and then using an appropriate statistical test. Imagine a scenario where a new drug has such a better safety profile compared with the reference drug that we are prepared to accept a certain decrease in efficacy. The degree of reduced efficacy we are prepared to accept is a clinical question. The study team must choose this value, which is called the noninferiority margin. This decision must be made before the trial is conducted, and the noninferiority margin included in the study protocol. The noninferiority margin is therefore part of the study design. Given several attractive advantages of a new antihypertensive agent, let’s hypothetically say that a decrease in mean efficacy of 3.0 mm Hg in systolic blood pressure (SBP) is acceptable. Our choice means that, in our study design, the noninferiority margin will have a value of 3.0 mm Hg.

HYPOTHESIS CONSTRUCTION AND TESTING Unlike superiority trials, for which P values are employed to determine whether 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 (CIs).10 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline E911 states that, in this case, we should use a one-sided CI. The term one-sided CI conveys that our attention only need be paid to one limit, upper or lower, and the other one can therefore be left unspecified. In our explanations and our two hypothetical case studies, attention falls on the upper limit, or bound, of the commonly chosen one-sided 95% CI. The reason that we do not need the lower bound has two parts: (1) if the new drug’s efficacy actually turns out to be greater than that of the reference drug, that would be a perfectly acceptable outcome that would still lead to the drug being declared noninferior to the reference drug; and (2) this is a true statement no matter how much better its efficacy, and we therefore do not need a specific bound to be placed below the noninferiority margin. As for the superiority trial design, we will have a research question, a null hypothesis, and a research The Journal of Clinical Hypertension

Vol 17 | No 4 | April 2015



(sometimes called alternate) hypothesis. However, these will be phrased quite differently for our noninferiority trial. They are as follows:  Research question: Is the new drug noninferior to the reference drug?  Null hypothesis: The new drug is inferior to the reference drug.  Research hypothesis: The new drug is noninferior to the reference drug. The calculated CI will tell us whether we will reject the null hypothesis in favor of the research hypothesis, or whether we will fail to reject the null hypothesis. The location of the upper bound of the 95% CI that is placed around the treatment effect, calculated as mean reduction in SBP for the new drug minus mean reduction in SBP for the reference drug, determines whether the null hypothesis is rejected. If the value of the upper bound is

Must new drugs be superior to those already available? The role of noninferiority clinical trials.

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