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Adaptive Designs: Lessons for Inflammatory Bowel Disease Trials

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Adaptive Designs: Lessons for Inflammatory Bowel Disease Trials Journal of Clinical Medicine Review Adaptive Designs: Lessons for Inflammatory Bowel Disease Trials Ferdinando D’Amico 1,2, Silvio Danese 1,3 and Laurent Peyrin-Biroulet 2,* 1 Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milan, Italy; [email protected] (F.D.); [email protected] (S.D.) 2 Department of Gastroenterology and Inserm NGERE U1256, Nancy University Hospital, University of Lorraine, 54500 Vandoeuvre-lès-Nancy, France 3 Department of Gastroenterology, Humanitas Clinical and Research Center-IRCCS, Rozzano, 20089 Milan, Italy * Correspondence: [email protected]; Tel.: +33-3831-53661 Received: 22 June 2020; Accepted: 22 July 2020; Published: 23 July 2020 Abstract: In recent decades, scientific research has considerably evolved in the field of inflammatory bowel diseases (IBD) and clinical studies have become increasingly complex, including new outcomes, different study populations, and additional techniques of re-randomization and centralized control. In this context, randomized clinical trials are the gold standard for new drugs’ development. However, traditional study designs are time-consuming, expensive, and only a small percentage of the tested therapies are approved. For this reason, a new study design called “adaptive design” has been introduced, allowing to accumulate data during the study and to make predefined adjustments based on the results of scheduled interim analysis. Our aim is to clarify the advantages and drawbacks of adaptive designs in order to properly interpret study results and to identify their role in upcoming IBD trials. Keywords: adaptive designs; study design; inflammatory bowel disease 1. Introduction Randomized clinical trials are considered the gold standard for clinical research and have enormously contributed to the development of new drugs and to the advancement of scientific knowledge [1]. However, clinical trial phases of a new drug are very long and expensive, requiring more than 10 years from the research start until drug approval [2]. Furthermore, clinical trials are becoming more and more complex and ever larger sample sizes are needed to achieve adequate statistical power, making patient recruitment difficult [1]. These limitations are evident in the field of inflammatory bowel diseases (IBD), as several new molecules have been tested since the biological drugs’ era began [3]. In fact, the molecules must pass a clinical trial phase in vitro or on animals and then be tested on humans [2]. Firstly, their safety and their pharmacokinetic and pharmacodynamic profiles have to be investigated (phase I), and secondly their efficacy has to be evaluated, identifying the optimal dose drug (phase II) [2]. If all these steps are passed, the drug can be experimented in large phase III studies aiming to confirm efficacy and evaluate safety, assessing the onset of rare adverse events, which would not be found in small sample investigations [2]. Finally, once the drug has been approved, pharmacovigilance studies (phase 4) are conducted on thousands of people to monitor the drug safety profile [4]. The experimental phase can be interrupted in any of the described phases [2]. Importantly, an apparently safe and effective drug in I and II phases may result as ineffective or dangerous in phase III trials [5,6]. Similarly, severe adverse events may be detected during the post-marketing phase resulting in drug withdrawal [7]. For this reason, as the cost of new drugs’ J. Clin. Med. 2020, 9, 2350; doi:10.3390/jcm9082350 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, x FOR PEER REVIEW 2 of 9 J. Clin. Med. 2020, 9, 2350 2 of 9 drugs’ development ranges from ~USD 3 billion to more than USD 30 billion per approval, it is developmentnecessary to ranges optimize from resources ~USD 3 and billion to reduce to more resear thanch USD times 30 [8]. billion To overcome per approval, these it limitations, is necessary new to optimizestudy designs, resources called and adaptive to reduce designs, research timeshave [b8een]. To specifically overcome theseconceived limitations, [1]. They new use study data designs,accumulated called adaptive during designs,the trial haveat one been or specifically several interim conceived time-points [1]. They to use decide data accumulatedpredetermined duringmodifications the trial at of one the or study several design interim without time-points underminin to decideg the statistical predetermined validity modifications of the results of (Figure the study1) [9]. design According without to underminingthe modification the performed, statistical validity different of adaptive the results designs (Figure can1)[ be9 recognized]. According [1]. to The thepurpose modification of our performed, review was di toff erentsummarize adaptive literature designs ev canidence be recognizedon adaptive [ 1designs,]. The purpose highlighting of our their reviewadvantages was to summarize and drawbacks literature in order evidence to identify on adaptive their role designs, in the highlightingupcoming IBD their trials. advantages and drawbacks in order to identify their role in the upcoming IBD trials. Figure 1. Comparison between standard and adaptive study designs. 2. Types of Adaptive DesignsFigure 1. Comparison between standard and adaptive study designs. Several types of adaptive designs have been described and are currently available [10,11]. Adaptive 2. Types of Adaptive Designs dose-finding designs are often used in early-phase studies [11]. They consist of multiple study arms and areSeveral frequently types based of adaptive on a continual designs reassessment have been methoddescribed [11 ].and They are allowcurrently to perform available interim [10,11]. analysesAdaptive of the dose-finding accumulated designs data andare often to modify used patients’in early-phase allocations studies to [11]. identify They the consist optimal of multiple drug dosagestudy to arms be used and in are later frequently phases (Table based1 )[on10 a continual,11]. Adaptive reassessment hypothesis method designs [11]. include They aallow pre-planned to perform modificationinterim analyses of the studyof the hypothesisaccumulated (e.g., data non-inferiority, and to modify superiority)patients’ allocations or endpoints to identify (primary the optimal and secondary)drug dosage based to onbe preliminaryused in later studyphases results (Table [ 101) ].[10,11]. Other Adaptive adaptive hypothesis designs allow designs to modify include dose a pre- or treatmentplanned modification duration (adaptive of the groupstudy sequentialhypothesis design), (e.g., non-inferiority, to re-estimate thesupe sampleriority) size or (sampleendpoints size(primary re-estimation and secondary) design), to based switch on a preliminary patient from stud a treatmenty results [10]. group Other to another adaptive due designs to a loss allow of to responsemodify to dose initial or therapy treatment (adaptive duration treatment-switching (adaptive group se design),quential or design), to adjust to randomization re-estimate the schedules, sample size increasing(sample the size number re-estimation of patients design), randomized to switch to thea pa mosttient beneficial from a treatment groups (adaptive group to randomization another due to a design)loss of [10 response]. In pick-the-winner to initial therapy/drop-the-loser (adaptive treatm designs,ent-switching study arms design), can be modified, or to adjust removing randomization less effectiveschedules, ones increasing and possibly the addingnumber groups of patients that seemrandomized effective to according the most tobeneficial the accumulated groups (adaptive data at interimrandomization [10]. Other design) trials [10]. can In be pick adapted-the-winner/drop-the-loser based on treatment response designs, tostudy biomarkers arms can (biomarker be modified, adaptiveremoving design) less [ 10effective]. Moreover, ones someand possibly studies may adding combine groups phases that IIseem and IIIeffective of clinical according trials in theto the so-calledaccumulated “seamless data phase at interim II/III design” [10]. Other [10,11 ].trials These can studies be adapted are designed based ason phasetreatment III studies response but to includebiomarkers an intermediate (biomarker “phase adaptive II” analysis design) to[10]. assess More whetherover, some to continue studies may or to combine stop the studyphases [10 II ,and11]. III Finally,of clinical if multiple trials in adaptive the so-called designs “seamless are combined phase inII/III the design” same study, [10,11]. it isThese called studies multiple are adaptivedesigned as designphase [10 III]. studies but include an intermediate “phase II” analysis to assess whether to continue or to stop the study [10,11]. Finally, if multiple adaptive designs are combined in the same study, it is called multiple adaptive design [10]. Table 1. Characteristics of adaptive designs. J. Clin. Med. 2020, 9, 2350 3 of 9 Table 1. Characteristics of adaptive designs. Adaptive Designs Main Characteristic To modify patients’ allocations to identify the optimal drug Adaptive dose-finding design dosage To modify the study hypothesis (e.g., non-inferiority, Adaptive hypothesis designs superiority) or endpoint (primary and/or secondary) Adaptive group sequential design To modify dose or treatment duration Sample size re-estimation design To re-estimate the sample size To switch a patient from a treatment group to another due to Adaptive treatment-switching design loss of response to initial therapy To adjust randomization schedules
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