Many clinical trials comparing a test product with an active comparator are designed as noninferiority trials. To someone starting out in clinical research these three terms and. This column will outline the need for non inferiority testing and specifying the non inferiority margin using clinical trials and process improvement techniques as examples. Clinical trials and clinical research are important for the progress of modern medicine. The desiderata of trial conduct may work against you. In this users guide, mulla and coauthors present a practical approach to interpreting these increasingly common studies. Learn design and interpretation of clinical trials from johns hopkins university. By a close examination of these hypotheses we can see that there are some similarities between trials.
Using examples from real clinical trials, design and analysis of non inferiority trials brings together this body of. Using examples from real clinical trials, design and analysis of non inferiority trials brings together this body of research and confronts the issues involved in the design of a non inferiority trial. The consort consolidated standards of reporting trials statement, including a checklist and a flow diagram, was developed to help authors improve their reporting of randomized controlled trials. As well as all the usual issues of trial quality, interpretation of these trials is complicated by the need to establish and justify a minimal clinically important difference. This book brings together formulae for different trial objectives e. Pdf randomized clinical trial design for assessing. They are the traditional and most reliable cradle of information. Reporting of noninferiority and equivalence randomized trials. The term noninferiority is now well established, but if taken literally could be misleading. The outcome of one trial does not influence the outcome of the any other trial. Noninferiority design in clinical trials senguptas. Over the past 15 years there has been an increased use of noninferiority ni designs for randomized controlled trials, especially in cardiology 1, 2. The goal of a clinical study is to assess the safety, efficacy, and or the mechanism of action of an investigational medicinal product imp or procedure, or new drug or device that is in.
Design issues edgar r miller iii phd, md welch center for prevention, epidemiology and clinical research johns hopkins university school of medicine and bloomberg school of public health 2 type of studies nonexperimental observational case report case series crosssectional survey. Noninferiority clinical trials now comes fdas draft guidance. Design and analysis of noninferiority trials brings together this body of research and confronts the issues involved in the design of a noninferiority trial. Recommendations for the design, reporting, and interpretation of noninferiority trials. The equivalence design is useful when evaluating generic drugs. Design and analysis of noninferiority trials ebook, 2011. Many products have been approved by regulatory agencies with based on the pivotal studies in non inferiority design. Noninferiority trials attempt to establish whether or not a new treatment drug or nondrug is no worse than an established treatment for which efficacy has been determined in placebocontrolled trials. When starting a non inferiority trial, investigators need to make several assumptions and should be aware of not choosing inaccurate or unreasonably generous active control event rates or non inferiority margins. Although this is not its definitive version, the document provides important orientations.
The objective of a noninferiority trial is sometimes stated as being to demonstrate that the test product. Feb 11, 2012 noninferiority trials an overview hollie sturgeon, pharmd. Non inferiority clinical trials are being performed with an increasing frequency nowadays, because it helps in finding a new treatment that have approximately the same efficacy, but may offer other benefits such as better safety profile. There is a considerable amount of misunderstanding on the correct use of this experimental design, which certainly compromises the credibility of some clinical assessments. Such a conclusion cannot be drawn from the planned noninferiority design. Trials are sometimes designed with nested noninferiority and superiority hypotheses. Design and analysis of noninferiority trials 1st edition mark d. The terms superiority, equivalence and noninferiority are used frequently in publications on clinical trials. The developers must design an experiment to test the hypothesis that the response rate of the new treatment is at.
In non randomised controlled trials, participants are allocated into treatment and control arms by the investigator. However, in march 2010, the fds published a new and enclosing guidance 24 for the planning and analysis of noninferiority trials. Appropriate design of noninferiority trials entails four considerations. Noninferiority trials are more complex to design, conduct, and interpret than conventional superiority trials. Design and interpretation of clinical trials coursera. Clinical study design is the formulation of trials and experiments, as well as observational studies in medical, clinical and other types of research e. Free design and analysis of noninferiority trials download. Noninferiority clinical trials to establish effectiveness.
This is due, in part, to the challenge that new treatments must compete with preexisting, effective standard treatments, making placebocontrolled trials unethical in many situations. Its primary focus was on individually randomized trials with 2 parallel groups that assess the possible. Design and analysis of noninferiority trials request pdf. Standards for the design and reporting of superiority trials have been widely disseminated, but adherence to. If you notice closely, one more thing that is common in these studies, apart from being multicentric randomized trials, is the noninferiority study design. Design and analysis of noninferiority trials crc press book. Or, a noninferiority trial comparing a new treatment to an established treatment. A comprehensive discussion on the purpose and issues involved with noninferiority trials, design and analysis of noninferiority trials will assist current and future scientists and statisticians on the optimal design of noninferiority trials and in assessing the quality of noninferiority comparisons done in practice. Definition of noninferiority reasons for noninferiority trials different types of comparisons a history of. At present, however, success in a non inferiority trial in the usa depends upon success in the primary outcome measure, not on other aspects of benefit, such as safety, and regulatory success using non inferiority trial designs may require completion of more than one such trial. We consider designing a clinical trial to evaluate the performance of a new generation of drugeluting stent des test device with a noninferiority comparison to the first generation of des control device. These trials include studies designed for regulatory approval of new therapies and trials designed to compare established treatments. Design decisions regarding patient population, dosing, and efficacy and safety assessments should be done in a manner that is unbiased against the control to ensure a fair comparison.
Using examples from real clinical trials, design and analysis of noninferiority trials brings together this body of research and confronts the iss. When planning a noninferiority trial, one should adequately understand its concept and the possible drawbacks. A major problem in noninferiority trials lacking a placebo arm is ensuring that both. And so, in that scenario, we can say that weve shown noninferiority, and we have also shown superiority. Using examples from real clinical trials, the book discusses general and regulatory issues and. It is much easier to establish non inferiority than superiority. Use an mid based on cohens book statistical power analysis, which suggests.
Sealed envelope power calculator for continuous outcome non. Design and analysis of noninferiority trials edition 1 by. Many of the same issues that are critical for designing an equivalence trial also are critical for designing a noninferiority trial, namely, appropriate selection of an active control and appropriate selection of the zone of clinical noninferiority defined by hypertensive example. The noninferiority trial design has gained popularity within the last decades to compare a new treatment to the standard active control.
In comparison studies with a current therapy, noninferiority is used to demonstrate that the new therapy provides at least the same benefit to the patient. Superiority, equivalence, and noninferiority trial designs. Its primary focus was on individually randomized trials with. Design and analytic considerations for such experiments are different than those used in noninferiority trials with clinical outcomes such as the example. How to design and interpret the results of such studies so that they can support a. Nov 23, 2012 a clinical trial should have the ability to distinguish effective treatments from those that are less effective, or ineffective. An itt analysis in a superiority trial tends to reduce the treatment effect, minimizing the. Ethical problems with placebocontrolled trials andor the existence of a proven. Noninferiority trials are designed to test whether a new treatment is not unacceptably less efficacious than an active control. Mar 16, 2009 non inferiority trials usually require larger sample sizes than superiority trials because the non inferiority margin is smaller than the treatment effects assessed by superiority trials and study power needs to be higher usually 90% for a non inferiority trial, to minimise the risk that a non inferior treatment is missed due to chance. The superiority comparison is a subset of the non inferiority and will have a sample size that is similar to the non inferiority or a sample size that is much larger.
This calculator is designed for continuous outcomes such as walking distance, blood pressure, white blood cell count in parallel group non inferiority trials. Superiority, non inferiority, and equivalence trials are three types of widely used clinical trials. Each chapter begins with a non technical introduction, making the text easily understood by those without prior knowledge of this type of trial. Design and analysis of noninferiority trials chapman. Equivalence and non inferiority trials are becoming more frequent as use of a placebo control group is no longer justified in many diseases. Choice of the noninferiority margin is critical in designing noninferiority trials. Design and analysis of noninferiority trials researchgate. Superiority, equivalence, and noninferiority trials. Randomized clinical trial design for assessing noninferiority when superiority is expected article pdf available in journal of clinical oncology 2531. We will explain the difference between noninferiority trials and more typical clinical trial designs to help build understanding of the noninferiority limit. Noninferiority studies are used to show that a minimum level of efficacy has been achieved. This important book is relevant because this type of trial is preferred when an.
For this reason, we offer you a list of 5 fundamental books that researchers, recruiters, project managers and any other dealing with clinical studies should read. Investigators might design the trial so that if noninferiority is established when the study is finished, then they can go on and test for superiority. Noninferiority trials an overview hollie sturgeon, pharmd. Jun 01, 2008 in this report, i will endeavor to contrast the basic philosophy of superiority, equivalence, and noninferiority trials. In the noninferiority trial above, the null hypothesis started at the position of inferiority, with telephone delivery being inferior to the standard delivery of face to. The design and conduct of non inferiority trials, including selection of non inferiority margins, should account for many factors that can induce bias in the estimated effect of standard in the. Noninferiority analysis some of the choices made in the analysis of the trial are not in line with the chosen noninferiority design, again raising question as to whether noninferiority was in place here. Using examples from real clinical trials, design and analysis of noninferiority trials brings together this body of research and confronts the issues involved in the design of a noninferiority trial. Noninferiority trials incorporate the process of statistical hypothesis testing, although the approach is an adaptation of the traditional one used in superiority trials.
Each chapter begins with a nontechnical introduction, making the text easily understood by those without prior knowledge of this type of trial. Comparisons of superiority, noninferiority, and equivalence. A comprehensive discussion on the purpose and issues involved with noninferiority trials, design and analysis of noninferiority trials will assist current and future scientists and statisticians on the optimal design of noninferiority trials and in assessing the quality of. Further, i will illustrate the practical problems pertaining to setting up and conducting a noninferiority trial. The us food and drug administration fda on monday finalized guidance for pharmaceutical and biotech sponsors looking for more advice on when non inferiority studies demonstrating effectiveness of an investigational drug can provide interpretable results, how to choose the non inferiority margin and how to test the non inferiority hypothesis. A level of inferiority is selected that is considered to be of no clinical. Using examples from real clinical trials, design and analysis of noninferiority trials brings together this body of research. Using examples from real clinical trials, the book discusses general and regulatory issues and illustrates how they affect analysis. Instead of testing for equivalence, the use of non inferiority experimental designs is a useful technique to accomplish this goal. In addition, we consider the application of noninferiority concepts and design. Design of a noninferiority trial with two treatment arms for medical devices. Two wrongs dont make a right, but three rights do make a left.
Strict attention to numerous aspects of trial design and conduct are important to ensure accurate inferences from noninferiority trials. The increased use of non inferiority analysis has been accompanied by a proliferation of research on the design and analysis of non inferiority studies. Superiority trials are always used when comparisons are made to placebo or vehicle treatments. In noninferiority trials, where noninferiority of a new experimental drug compared to an active control has to be shown, it may be advisable to use an additional placebo group for internal. Making sense of equivalence and noninferiority trials. Clinical trials are experiments designed to evaluate new interventions to prevent or treat disease in humans. Jan 01, 2011 thus a calculated sample size for a non inferiority trial is usually the smallest of the three hypothesis. The author discusses how trial objectives impact the study design with. Design and analysis of non inferiority trials brings together this body of research and confronts the issues involved in the design of a non inferiority trial. In this blog we will discuss a particular type of clinical trial design, the noninferiority trial. The classification of phase 3 trials as superiority or noninferiority has become routine, and it is widely accepted that there are important differences between the two types of trial in their design, analysis and interpretation. Not only are there clinical indications to perform a noninferiority trial, but also the costs of a randomized trial are very high, and the stakes for. The usual reason for using a noninferiority active control study design.
Using examples from real clinical trials, design and analysis of noninferiority. Noninferiority trial an overview sciencedirect topics. In non inferiority trials, where non inferiority of a new experimental drug compared to an active control has to be shown, it may be advisable to use an additional placebo group for internal. Apr 27, 20 using examples from real clinical trials, design and analysis of non inferiority trials brings together this body of research and confronts the issues involved in the design of a non inferiority trial. Testing statistical hypotheses of equivalence and noninferiority crc press book while continuing to focus on methods of testing for twosided equivalence, testing statistical hypotheses of equivalence and noninferiority, second edition gives much more attention to noninferiority testing. Design and analysis of noninferiority trials edition 1. Learn the types, as well as the different clinical trial phases. Challenges in the design and interpretation of noninferiority. Noninferiority trials compare a novel treatment with the existing standard in order to determine if the new approach might lessen potential harms or burdens for the patient.
Apr 03, 2017 your sample size or power calculation for clinical trials depends on your trial design. This is defined as assay sensitivity and there is a question of whether noninferiority trials have the power to detect a beneficial treatment against a placebo even if a placebo group is included in the trial. Critical issues in the design and conduct of noninferiority trials include. Using examples from real clinical trials, design and analysis of noninferiority trials brings together this body of. Noninferiority trials chapter clinical trials in neurology. For example, superiority is a special case of non inferiority.
Guidance assessing equivalence and noninferiority ncbi. The mean outcome is compared between the experimental and standard treatment groups. For readers, to objectively interpret non inferiority trial results, one must be conscious of several pitfalls of the methodology. Bayesian design of noninferiority trials for medical. Look at what they are and why we use them cover the basic info needed to analyze the quality of these reports and draw appropriate conclusions. Generally speaking, non inferiority trials are considered less credible than a more common trial design, the superiority trial, which determines whether one treatment outperforms another treatment. Because a noninferiority trial design allows for the possibility that the experimental therapy is superior to the active control therapy, the noninferiority design is preferred over the equivalence design. Even though there have been tons of presentations, workshops, and text books about the non inferiority clinical trials, there is no formal guidance from fda regarding the inferiority clinical trials until this week. The increased use of noninferiority analysis has been accompanied by a proliferation of research on the design and analysis of noninferiority studies.