Sequential stopping rules software for clinical trials examples exercises. In november 2016, the fda released final guidance on noninferiority clinical trials to establish effectiveness providing researchers guidance on when to use noninferiority trials to demonstrate effectiveness along with how to choose the noninferiority margin, test the noninferiority hypothesis, and provide interpretable results. Fda taking more cautious approach to noninferiority trials. Federal register noninferiority clinical trials to. Figure 1 from current issues in noninferiority trials. Noninferiority tests noninferiority tests are onesided hypothesis tests in which the null and alternative hypotheses are arranged to test whether one group is almost as.
Non clinical safety studies for the conduct of human clinical trials for pharmaceuticals. Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the. Drug industry experts are urging the fda to rein in approvals based on noninferiority trials, such as the recent xarelto decision, saying drugs cleared by this route typically do not improve on lesscostly standards of care. Oct 25, 2017 non inferiority trial of dapaconazole versus ketoconazole the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. The fdas 2010 guidance for industry adaptive design clinical trials for drugs and biologics provides information regarding adaptive design clinical trials when used in drug development programs. Noninferiority ni trials enable a direct comparison of the relative benefittorisk profiles of an experimental intervention and a standardofcare regimen. Despite these structural complexities, non inferiority rcts are of substantial value because they can show unacceptable loss in efficacy of a tested drug for specific clinical conditions, such as eravacycline for therapy of urinary tract infection 38 and daptomycin for treatment of pneumonia. In addition, it supersedes the guidance for industry, antibacterial drug products. As the name suggests, the aim is to show that the new treatment is not inferior to the existing one that is, it is either equally effective or better. In november 2016 the fda released final guidance on noninferiority clinical trials to establish effectiveness providing researchers guidance on when to use noninferiority trials to demonstrate effectiveness along with how to choose the noninferiority margin, test the noninferiority hypothesis, and provide interpretable results. Typically, evidence in each of these paradigms is quantified with a variant of the null hypothesis significance test. This clinical trial webinar will explore the differences among superiority, noninferiority ni, and equivalence trials, including development of the precise research questions necessary for making a decision about appropriate clinical designs. Exploring how noninferiority and equivalence are assessed.
The draft fda guideline on noninferiority clinical trials. Noninferiority and equivalence trials require tailored methodology and therefore adequate conduct and reporting is an ambitious task. Noninferiority clinical trials to establish effectiveness. Any changes to a sponsors development program that result from the. In point of fact, device manufacturers have been doing noninferiority studies for years. If this can be established, the new treatment can be considered as a replacement for the existing treatment, especially. Keeping these in mind, we construct a bayesian approach for noninferiority trials with normal response.
Main concepts the fda has publicly expressed its expectations regarding the choice of noninferiority margins for some time, for example, in a presentation from february 2002 4. Clinical guidances fda regulatory consulting services. This training on noninferiority ni trials will highlight differences among ni, equivalence, and superiority study objectives and designs. Nonclinical safety studies for the conduct of human clinical trials for pharmaceuticals. The purpose of this guidance is to inform industry of the food and drug administrations fdas current thinking regarding appropriate clinical. In both noninferiority and equivalence trials, the largest difference between arms that would be clinically acceptable, namely the margin, is formulated according to earlier knowledge and clinical relevance,12 is a critical point in designing those trials and influenced the sample size calculation. Design, data monitoring, and analysis of clinical trials.
Determining the sample size required to establish whether. In november 2016 the fda released final guidance on non inferiority clinical trials to establish effectiveness providing researchers guidance on when to use non inferiority trials to demonstrate effectiveness along with how to choose the non inferiority margin, test the non inferiority hypothesis, and provide interpretable results. Adaptive design clinical trials for drugs and biologics pdf 423kb17 cdercber february 2010 guidance for the use of bayesian statistics in medical device clinical trials pdf version pdf 388kb18 cdrhcber. Recently, fda issued a draft guidance document titled guidance for industry noninferiority clinical trials mar2010. The proliferation of statistical research in the area of clinical trials. In november 2016 the fda released final guidance on non inferiority clinical trials to establish effectiveness providing researchers guidance on when to use non inferiority trials to demonstrate effectiveness along with how to choose the non inferiority margin, test the non inferiority hypothesis, and provide. Exploring how noninferiority and equivalence are assessed in. The us fda has approved bimatoprost implant durysta 10 mcg for intracameral administration with this approval, durysta becomes the first intracameral, biodegradable sustainedrelease implant indicated to reduce intraocular pressure iop in patients with openangle glaucoma oag or ocular hypertension oht, allergan plc said. The efficacy and safety of medicinal products should be demonstrated by clinical trials which follow the guidance in good clinical practice. This guidance document is being distributed for comment purposes only. Noninferiority studies are used to show that a minimum level of efficacy has been achieved. The activecontrolled trial with a noninferiority design has gained popularity in recent years.
The activecontrolled trial with a non inferiority design has gained popularity in recent years. Moreover, in a scientific advice procedure, regulators give. If this can be established, the new treatment can be considered. Consolidated guideline ich e6 adopted by the ich, 1 may 1996.
Every book or guidance document i read has a different way of. Noninferiority versus superiority trial design for new. These and other non inferiority bayes factors for continuous data can be obtained by providing values for the sample size n, group means, group sds, and the non inferiority margin to the script. However, non inferiority trials present some methodological challenges, especially in determining the non inferiority margin. In confirmatory clinical trials, as often is the case, a single clinical outcome is selected as a primary endpoint. Regulatory guidelines provide some general statements on how a noninferiority trial should be conducted. In november 2016 the fda released final guidance on noninferiority clinical trials to establish effectiveness providing researchers guidance on when to use noninferiority trials to demonstrate effectiveness along with how to choose the noninferiority margin, test the noninferiority hypothesis, and provide. The guidance was issued by cder and cber because noninferiority trials require active controls rather than placebossomething new for the drug world. This guidance finalizes the draft guidance for industry, non inferiority clinical trials, published in 2010. Clinical guidances fda regulatory consulting services fda.
Superiority trials, noninferiority trials and equivalence if we let. The noninferiority trial is a useful alternative in such situations. However, noninferiority trials present some methodological challenges, especially in determining the noninferiority margin. The biologics price competition and innovation act of 2009 bpci act established an abbreviated approval pathway for biosimilar and interchangeable biological products that was intended to balance innovation and consumer interests. In comparison studies with a current therapy, non inferiority is used to demonstrate that the new therapy provides at least the same benefit to the patient. Noninferiority trial of dapaconazole versus ketoconazole the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. 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. Adaptive noninferiority margins under observable non. Fda guidance on noninferiority clinical trials to establish.
This includes fdas thoughts on how best to choose an appropriate noninferiority margin and how to analyze the results. Fda clears bimatoprost implant for glaucoma future. The fda has published several guidance documents to facilitate implementation of the bpci act. Drug industry experts are urging the fda to rein in approvals based on non inferiority trials, such as the recent xarelto decision, saying drugs cleared by this route typically do not improve on lesscostly standards of care. Non inferiority clinical trials pdf 976kb16 cdercber march 2010 draft guidance for industry. When the standard has clinical efficacy of substantial magnitude that is precisely estimated ideally using data from multiple adequate and wellcontrolled trials, with such estimates being relevant to the setting of the ni trial, then. Search for fda guidance documents guidance document deciding when to submit a 510k for a software change to an existing device guidance for industry and food and drug administration staff. Estimating the efficacy of hirudin using evidence from the ni oasis ii trial and from six historical trials evaluating efficacy of heparin. The guidance does not provide recommendations for how to evaluate the safety of a drug using a noninferiority trial design.
A central assumption in the design and conduct of noninferiority trials is that the activecontrol therapy will have the same degree of effectiveness in the planned noninferiority trial as in the prior placebocontrolled trials used to define the noninferiority margin. Rethink noninferiority trials as approval basis, fda urged. Fda guidance on use of ni trials october 2007 ni study designs may be appropriate when there is adequate evidence of a defined effect size for the control treatment so that the proposed ni margin can be supported. Bayes factors for superiority, noninferiority, and. Superiority trials versus noninferiority trials to. Regulatory scientific advice on noninferiority drug trials. Noninferiority clinical trials pdf 976kb16 cdercber march 2010 draft guidance for industry.
Noninferiority trial of dapaconazole versus ketoconazole. Here we discuss the role of comparative clinical studies in. Deciding when to submit a 510k for a software change to. In clinical trials, study designs may focus on assessment of superiority, equivalence, or noninferiority, of a new medicine or treatment as compared to a control. Last friday, fda issued two new draft guidance documents regarding clinical trial designs. The guidance gives advice on when ni studies intended to demonstrate effectiveness of an investigational drug can provide interpretable. Fda is announcing the availability of a guidance for industry entitled noninferiority clinical trials to establish effectiveness. Non inferiority ni trials enable a direct comparison of the relative benefittorisk profiles of an experimental intervention and a standardofcare regimen.
Thus, the pharmaceutical industry was eagerly awaiting the draft guidance on non inferiority clinical trial 5, which was released. Guidance for industry cdercber, november 2016 human factors studies and related clinical study considerations in combination product. Main concepts the fda has publicly expressed its expectations regarding the choice of non inferiority margins for some time, for example, in a presentation from february 2002 4. Regulatory guidelines provide some general statements on how a non inferiority trial should be conducted. Issues and challenges explains how to choose the ni margin as a small fraction of the therapeutic effect of the active control in a clinical trial. Objectives explore superiority, equivalence, and noninferiority ni trial designs compare critical differences between superiority and ni trials and stumbling blocks involving issues such as the noninferiority margin examine potential issues with noninferiority studies.
Sample size software for adaptive clinical trial designs. A null hypothesis is assumed null effect, inferior by a specific amount, inferior by a specific amount and. The role of statistics clinical trial design and analysis is acknowledged as essential in that ich guidance document. Oct 12, 2012 the importance of equivalence and noninferiority studies for clinical research has increased steadily over the past 20 years, as can be seen from the number of pubmed hits for the search terms bioequivalence, noninferiority study trial, and equivalence study trial over the years 19912011 figure 1. Noninferiority versus superiority trial design for new antibiotics in an era of high antimicrobial resistance. This clinical trial webinar will explore the differences among superiority, non inferiority ni, and equivalence trials, including development of the precise research questions necessary for making a decision about appropriate clinical designs. Requiring no prior knowledge of ni testing, the book is easily accessible. Superiority trials are always used when comparisons are made to placebo or vehicle treatments. In the march draft guidance the fda covers in greater detail the key principles involved in using noninferiority trials to establish a drugs effectiveness.
This document provides guidance to sponsors and applicants submitting investigational drug applications inds, new drug applications ndas, biologics licensing applications blas, or supplemental applications on the appropriate use of noninferiority ni study designs to provide evidence of the effectiveness of a drug or biologic, usually. Design and analysis of noninferiority trials request pdf. Requiring no prior knowledge of ni testing, the book is easily. These and other noninferiority bayes factors for continuous data can be obtained by providing values for the sample size n, group means, group sds, and the noninferiority margin to the script. Adaptive design clinical trials for drugs and biologics february 2010 and guidance for industry. The selection of the noninferiority margin is critical in designing a noninferiority trial and the majority of the fda guidance focuses on this. Tougher indicationspecific guidance is supported by a march 2010 document focused on noninferiority trials. Bayesian approach to noninferiority trials for normal. Establishing equivalence or non inferiority in clinical trials part 20 of a series on evaluation of scientific publications dtsch arztebl int 2012. Fda guidance on non inferiority clinical trials to establish effectiveness.
The selection of the non inferiority margin is critical in designing a non inferiority trial and the majority of the fda guidance focuses on this. Please use the document number 1728 to identify the. If this is what you seek to do, than this guidance may be of some help. Keeping these in mind, we construct a bayesian approach for non inferiority trials with normal response.
Conclusion a noninferiority testing paradigm provides a useful framework for determining if an implant meets the required performance defined by an external benchmark. This guidance finalizes the draft guidance for industry, noninferiority clinical trials. Jan 01, 2011 non inferiority studies are used to show that a minimum level of efficacy has been achieved. The first part is a general discussion of regulatory, study design, scientific, and statistical issues associated with the use of ni studies to establish the effectiveness. Thus, the pharmaceutical industry was eagerly awaiting the draft guidance on noninferiority clinical trial 5, which was released.
Reflecting the vast research on noninferiority ni designs from the past 15 years, noninferiority testing in clinical trials. This endpoint serves as the basis for the trial design including sample size determination, interim data monitoring, final analyses and the reporting of the trial results. Blinded internal pilot sample size reestimation for two sample. Statistical considerations in evaluating a biosimilar. Margin selection and result interpretation in noninferiority.
In clinical trials, study designs may focus on assessment of superiority, equivalence, or non inferiority, of a new medicine or treatment as compared to a control. This guidance document is intended to provide information to industry regarding the documentation that we recommend you include in premarket submissions for software devices, including standalone software applications and hardwarebased devices that incorporate software. Current contemporary benchmarking standards have limited power to detect noninferiority, and substantially larger samples sizes, in excess of 3200 procedures, are required to achieve a power greater than 60%. Bayesian approach to noninferiority trials for normal means. The importance of equivalence and noninferiority studies for clinical research has increased steadily over the past 20 years, as can be seen from the number of pubmed hits for the search terms bioequivalence, noninferiority study trial, and equivalence study trial over the years 19912011 figure 1. Despite these structural complexities, noninferiorityrcts are of substantial value because they can show unacceptable loss in efficacy of a tested drug for specific clinical conditions, such as eravacycline for therapy of urinary tract infection 38 and daptomycin for treatment of pneumonia. The fda recently published new draft guidance on adaptive trials and are actively encouraging sponsors to use adaptive trials. The purpose of a ni trial is usually to show a new treatment is effective or similar to an active control in terms of efficacy but with better toxicity profile or other benefit. Adaptive design clinical trials for drugs and biologics. Superiority, noninferiority, or equivalence trials.
Establishing equivalence or noninferiority in clinical trials. A non informative prior is assumed for the mean response of the experimental treatment and jeffreys prior for its corresponding variance when it is unknown. This guidance is intended to give direction to sponsors in the design, conduct, analysis, and evaluation of clinical trials of an investigational product in the context of its overall clinical development. Non inferiority tests non inferiority tests are onesided hypothesis tests in which the null and alternative hypotheses are arranged to test whether one group is almost as good not much worse than the other group. Content of premarket submissions for software contained in.
A noninformative prior is assumed for the mean response of the experimental treatment and jeffreys prior for its corresponding variance when it is unknown. Guidance for industry noninferiority clinical trials. Statistical principles for clinical trials ich topic e9. Establishing equivalence or noninferiority in clinical trials part 20 of a series on evaluation of scientific publications dtsch arztebl int 2012. Two proportions noninferiority, superiority, equivalence. For an ni study, having an adequately justified ni margin is essential to having an informative study. We searched the medline database and the cochrane central register for reports of randomised noninferiority and equivalence trials published in. Fda guidance on noninferiority clinical trials to establish effectiveness. In both non inferiority and equivalence trials, the largest difference between arms that would be clinically acceptable, namely the margin, is formulated according to earlier knowledge and clinical relevance,12 is a critical point in designing those trials and influenced the sample size calculation. Apr 03, 2017 superiority trials, noninferiority trials and equivalence if we let.
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