Equivalence trials

The number of clinical communications published per year has increased to staggering proportions. Matthews (2006) noted that there are currently on the order of20,000 biomedical journals that publish on the order of two million articles a year. This makes it extremely difficult for a clinician who would like to research a particular topic to locate all of the relevant articles. Accordingly, two kinds of review papers can be very helpful. The first is narrative reviews. These collate, compare, discuss, and summarize the current state of knowledge (Matthews, 2006). Narrative reviews are descriptive in nature. The second kind of review incorporates meta-analysis. These reviews are quantitative in nature. 

For many reasons, there are likely to be more than one publication that address the same research question. Even when the results are not identical (which is very likely to be the case), consistency in the interpretation of the results is reassuring Recall the discussion of consistency between ITT and per-protocol analyses in Section 11.2.3. Additionally, results from many smaller studies that are inconclusive can sometimes be combined to paint a picture that is very compelling, and the overall result can be put in a broader context, since it has been attained from different treatment regimens and different subject populations (Matthews, 2006). 

The goal of equivalence trials is to demonstrate that the test drug and an active comparator drug are equivalent. Like several words that we have already encountered in this book (e.g., significance), the word equivalent is used in both everyday language and in Statistics, but its use in Statistics is specific. In this context, equivalence means that, in the best case scenario, the test treatment is 

Equivalence trials are also appropriate when the disease being treated is particularly serious (e.g., cancer) and the use of placebo controls would be unethical. 

The research question in equivalence trials is structured differently from the research question in superiority trials. The hypothesis testing approach that works so well in superiority trials is of little value in an equivalence trial. As Matthews (2006) commented, Failing to establish that one treatment is superior to the other is not the same as establishing their equivalence.  

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Trials may be designed to determine equivalence or superiority between therapies. An equivalence trial is designed to show that there is no clinically significant difference between therapies, and a superiority trial is intended to show that one therapy is significantly better than another. 

Edelman ER, Rogers C. Stent-versus-stent equivalency trials-are some stents more equal than others. Circulation 1999 100 896-898. 

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... 

In an equivalence trial we are looking to show that we are similar to some reference treatment, bioequivalence trials are the most common examples of this type of trial. 

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... 

Equivalence trials are, of course, routinely used in the evaluation of bioequivalence and the methodology there is well established, both European and FDA guidelines exist. More recently we have seen the need to establish therapeutic equivalence and Ebbutt and Frith (1998) provide a detailed case study in the development of an alternative propellant for the asthma inhaler. More usually,... 

Statistical analysis is generally based on the use of confidence intervals. For equivalence trials, two-sided confidence intervals should be used. Equivalence is inferred when the entire confidence interval falb within the equivalence margins. ... 

Similar comments apply to therapeutic equivalence trials also. 

Ebbutt AF and Frith F (1998) Practical issues in equivalence trials Statistics in Medicine, 17, 1691-1701... 

Bisser S et al Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness. J Infect Dis 2007 195 322. [PMID 17205469]... 

This chapter introduces basic concepts in statistical analysis that are of relevance to describing and analyzing the data that are collected in clinical trials, the hallmark of new drug development. (Statistical analysis in nonclinical studies was addressed earlier in Chapter 4.) This chapter therefore sets the scene for more detailed discussion of the determination of statistical significance via the process of hypothesis testing in Chapter 7, evaluation of clinical significance via the calculation of confidence intervals in Chapter 8, and discussions of adaptive designs and of noninferiority/equivalence trials in Chapter 11. 

Having seen why the hypothesis testing used in superiority trials is inappropriate for equivalence trials, the appropriate approach in this context is now discussed. The first step in this approach is to establish the equivalence margin for the trial. 

The next step in the case of equivalence trials is quite different from the strategy used in superiority trials. Once the treatment effect has been determined,... 

For the sake of this example, let us say that a decrease in mean efficacy of 3 mmHg in SBP is acceptable. (Please note again that this is a hypothetical example.) The resulting value of minus 3 mmHg yields the noninferiority margin. The trial is then conducted. The treatment effect is calculated, as in superiority trials and equivalence trials, as the difference between the treatment group means. 

As in the case of equivalence trials, it is necessary to use statistical analysis in conjunction with clinical judgment when conducting a noninferiority trial. The choice of the noninferiority margin, which must be made before the trial is conducted, is a clinical judgment. Once the data have been collected, a statistical technique is used to determine whether the new drug is deemed to be noninferior compared with the reference drug. 

There are in general, two t5rpes of equivalence trials in clinical development, bio- and clinical equivalence. In the former, certain pharmacokinetic variables of a new formulation have to fall within specified (and regulated) margins of the standard formulation of the same active entity. The advantage of this type of trial is that, if bioequivalence is proven then proof of clinical equivalence is not required. Proof of clinical equivalence of a generic product to the marketed product can be much more difficult to demonstrate. 

Indinavir has been compared with abacavir in a randomized equivalence trial in 562 patients who were also taking lamivudine and zidovudine (10). The only significant difference in adverse effects was that there was hyperbilirubinemia in 8% of those taking indinavir and 2% of those taking abacavir. It has been postulated that indinavir-induced hyperbilirubinemia is due to inhibition of bilirubin UDP glucuronyl transferase activity, since it is more common in individuals with Gilbert s syndrome (11). 

Staszewski S, Keiser P, Montaner J, Raffi F, Gathe J, Brotas V, Hicks C, Hammer SM, Cooper D, Johnson M, TorteU S, CutreU A, Thorborn D, Isaacs R, Hetherington S, Steel H, Spreen W CNAAB3005 International Study Team. Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zidovudine in antiretroviral-naive HIV-infected adults A randomized equivalence trial. JAMA 2001 285(9) 1155-63. 

Equivalence trials Usually large patient populations needed Cannot demonstrate superiority Scientific demonstration of a negative Standard of care context challenged... 

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