Fda clears bimatoprost implant for glaucoma future. Adaptive design clinical trials for drugs and biologics february 2010 and guidance for industry. Margin selection and result interpretation in noninferiority. Regulatory guidelines provide some general statements on how a non inferiority trial should be conducted. These draft guidance documents are products of fdas critical path initiative cpi. Sample size software for adaptive clinical trial designs.
Rethink noninferiority trials as approval basis, fda urged. Typically, evidence in each of these paradigms is quantified with a variant of the null hypothesis significance test. Content of premarket submissions for software contained in. 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. Recently, fda issued a draft guidance document titled guidance for industry noninferiority clinical trials mar2010. Thus, the pharmaceutical industry was eagerly awaiting the draft guidance on non inferiority clinical trial 5, which was released. Superiority trials, noninferiority trials and equivalence if we let. Federal register noninferiority clinical trials to. A null hypothesis is assumed null effect, inferior by a specific amount, inferior by a specific amount and. Adaptive noninferiority margins under observable non. Fda is announcing the availability of a guidance for industry entitled noninferiority clinical trials to establish effectiveness.
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%. Noninferiority versus superiority trial design for new antibiotics in an era of high antimicrobial resistance. 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. Bayes factors for superiority, noninferiority, and. 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. 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. This training on noninferiority ni trials will highlight differences among ni, equivalence, and superiority study objectives and designs. Any changes to a sponsors development program that result from the. 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. 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. Fda guidance on noninferiority clinical trials to establish. This guidance document is being distributed for comment purposes only.
Jan 01, 2011 non inferiority studies are used to show that a minimum level of efficacy has been achieved. Noninferiority studies are used to show that a minimum level of efficacy has been achieved. Two proportions noninferiority, superiority, equivalence. 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. Nonclinical safety studies for the conduct of human clinical trials for pharmaceuticals. Conclusion a noninferiority testing paradigm provides a useful framework for determining if an implant meets the required performance defined by an external benchmark. The activecontrolled trial with a non inferiority design has gained popularity in recent years. Consolidated guideline ich e6 adopted by the ich, 1 may 1996. Noninferiority clinical trials pdf 976kb16 cdercber march 2010 draft guidance for industry. The guidance gives advice on when ni studies intended to demonstrate effectiveness of an investigational drug can provide interpretable. This guidance finalizes the draft guidance for industry, noninferiority clinical trials. 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. Keeping these in mind, we construct a bayesian approach for non inferiority trials with normal response.
If this is what you seek to do, than this guidance may be of some help. 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 clinical trials guidance the noninferiority draft guidance explores fdas thinking on the use of noninferiority study designs to provide evidence of a drugs effectiveness. Fda guidance on non inferiority clinical trials to establish effectiveness.
Here we discuss the role of comparative clinical studies in. 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. 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. Statistical considerations in evaluating a biosimilar. However, non inferiority trials present some methodological challenges, especially in determining the non inferiority margin. This training on non inferiority ni trials will highlight differences among ni, equivalence, and superiority study objectives and designs. Noninferiority clinical trials to establish effectiveness. 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. Please use the document number 1728 to identify the. Noninferiority ni trials enable a direct comparison of the relative benefittorisk profiles of an experimental intervention and a standardofcare regimen.
The role of statistics clinical trial design and analysis is acknowledged as essential in that ich guidance document. Clinical guidances fda regulatory consulting services fda. We searched the medline database and the cochrane central register for reports of randomised noninferiority and equivalence trials published in. Bayesian approach to noninferiority trials for normal means. A noninformative prior is assumed for the mean response of the experimental treatment and jeffreys prior for its corresponding variance when it is unknown. Fda guidance on noninferiority clinical trials to establish effectiveness. 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. Establishing equivalence or noninferiority in clinical trials. This guidance finalizes the draft guidance for industry, non inferiority clinical trials, published in 2010. The guidance was issued by cder and cber because noninferiority trials require active controls rather than placebossomething new for the drug world. Requiring no prior knowledge of ni testing, the book is easily accessible. Superiority trials versus noninferiority trials to. 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. The fda has published several guidance documents to facilitate implementation of the bpci act.
Guidance for industry cdercber, november 2016 human factors studies and related clinical study considerations in combination product. Last friday, fda issued two new draft guidance documents regarding clinical trial designs. Adaptive design clinical trials for drugs and biologics. Exploring how noninferiority and equivalence are assessed. Reflecting the vast research on noninferiority ni designs from the past 15 years, noninferiority testing in clinical trials. The noninferiority trial is a useful alternative in such situations. The draft fda guideline on noninferiority clinical trials. 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. However, noninferiority trials present some methodological challenges, especially in determining the noninferiority margin. 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. If this can be established, the new treatment can be considered. 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. Superiority, noninferiority, or equivalence trials.
Deciding when to submit a 510k for a software change to. Thus, the pharmaceutical industry was eagerly awaiting the draft guidance on noninferiority clinical trial 5, which was released. Listing a study does not mean it has been evaluated by the u. Noninferiority trial of dapaconazole versus ketoconazole the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. 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. Non inferiority clinical trials pdf 976kb16 cdercber march 2010 draft guidance for industry. Guidance for industry noninferiority clinical trials. 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.
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. 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. The fda recently published new draft guidance on adaptive trials and are actively encouraging sponsors to use adaptive trials. Regulatory guidelines provide some general statements on how a noninferiority trial should be conducted.
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. Establishing equivalence or noninferiority in clinical trials part 20 of a series on evaluation of scientific publications dtsch arztebl int 2012. 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. Regulatory scientific advice on noninferiority drug trials. Noninferiority trial of dapaconazole versus ketoconazole. Noninferiority and equivalence trials require tailored methodology and therefore adequate conduct and reporting is an ambitious task. Sequential stopping rules software for clinical trials examples exercises. This includes fdas thoughts on how best to choose an appropriate noninferiority margin and how to analyze the 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. 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. 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. Superiority trials are always used when comparisons are made to placebo or vehicle treatments. 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. Requiring no prior knowledge of ni testing, the book is easily.
The efficacy and safety of medicinal products should be demonstrated by clinical trials which follow the guidance in good clinical practice. Apr 03, 2017 superiority trials, noninferiority trials and equivalence if we let. 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. In confirmatory clinical trials, as often is the case, a single clinical outcome is selected as a primary endpoint. 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. Clinical guidances fda regulatory consulting services. Tougher indicationspecific guidance is supported by a march 2010 document focused on noninferiority trials. For an ni study, having an adequately justified ni margin is essential to having an informative study. Fda taking more cautious approach to noninferiority trials. In addition, it supersedes the guidance for industry, antibacterial drug products. Non clinical safety studies for the conduct of human clinical trials for pharmaceuticals.
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. Estimating the efficacy of hirudin using evidence from the ni oasis ii trial and from six historical trials evaluating efficacy of heparin. This guidance finalizes the draft guidance for industry, noninferiority clinical trials, published in 2010. The activecontrolled trial with a noninferiority design has gained popularity in recent years. 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. Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the. Statistical principles for clinical trials ich topic e9. Moreover, in a scientific advice procedure, regulators give. Determining the sample size required to establish whether. 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.
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 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. 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. 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. 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. 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. 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. 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. Every book or guidance document i read has a different way of. The purpose of this guidance is to inform industry of the food and drug administrations fdas current thinking regarding appropriate clinical. The guidance does not provide recommendations for how to evaluate the safety of a drug using a noninferiority trial design. Design, data monitoring, and analysis of clinical trials. If this can be established, the new treatment can be considered as a replacement for the existing treatment, especially. 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 ni trials enable a direct comparison of the relative benefittorisk profiles of an experimental intervention and a standardofcare regimen. 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. 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 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. The selection of the noninferiority margin is critical in designing a noninferiority trial and the majority of the fda guidance focuses on this. Noninferiority versus superiority trial design for new. Blinded internal pilot sample size reestimation for two sample. Bayesian approach to noninferiority trials for normal. In the march draft guidance the fda covers in greater detail the key principles involved in using noninferiority trials to establish a drugs effectiveness. In point of fact, device manufacturers have been doing noninferiority studies for years.
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