Background Master protocols, classified as basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies (e.g., multiple treatments or populations or that allow adding/removing arms during the trial), offering enhanced efficiency and a more ethical approach to trial evaluation. Despite the many advantages of these designs, they are infrequently used. Methods We conducted a landscape analysis of master protocols using a systematic literature search to determine what trials have been conducted and proposed for an overall goal of improving the literacy in this emerging concept. On July 8, 2019, English-language studies were identified from MEDLINE, EMBASE, and CENTRAL databases and hand searches of published reviews and registries. Results We identified 83 master protocols (49 basket, 18 umbrella, and 16 platform trials). The number of master protocols has increased rapidly over the last five years. Most have been conducted in the US (n = 44/83) and investigated experimental drugs (n = 82/83) in the field of oncology (n = 76/83). The majority of basket trials were exploratory (i.e., phase I/II; n = 47/49) and not randomized (n = 44/49), and more than half (n = 28/48) investigated only a single intervention. The median sample size of basket trials was 205 participants (interquartile range, Q3-Q1 [IQR]: 500–90 = 410), and the median study duration was 22.3 (IQR: 74.1–42.9 = 31.1) months. Similar to basket trials, most umbrella trials were exploratory (n = 16/18), but the use of randomization was more common (n = 8/18). The median sample size of umbrella trials was 346 participants (IQR: 565–252 = 313), and the median study duration was 60.9 (IQR: 81.3–46.9 = 34.4) months. The median number of interventions investigated in umbrella trials was 5 (IQR: 6–4 = 2). The majority of platform trials were randomized (n = 15/16), and phase III investigation (n = 7/15; one did not report information on phase) was more common in platform trials with four of them using seamless II/III design. The median sample size was 892 (IQR: 1835–255 = 1580), and the median study duration was 58.9 (IQR: 101.3–36.9 = 64.4) months. Conclusions We anticipate that the number of master protocols will continue to increase at a rapid pace over the upcoming decades. More efforts to improve awareness and training are needed to apply these innovative trial design methods to fields outside of oncology.
With advancements in biomarkers and momentum in precision medicine, biomarker‐guided trials such as basket trials and umbrella trials have been developed under the master protocol framework. A master protocol refers to a single, overarching design developed to evaluate multiple hypotheses with the general goal of improving the efficiency of trial evaluation. One type of master protocol is the basket trial, in which a targeted therapy is evaluated for multiple diseases that share common molecular alterations or risk factors that may help predict whether the patients will respond to the given therapy. Another variant of a master protocol is the umbrella trial, in which multiple targeted therapies are evaluated for a single disease that is stratified into multiple subgroups based on different molecular or other predictive risk factors. Both designs follow the core principle of precision medicine—to tailor intervention strategies based on the patient's risk factor(s) that can help predict whether they will respond to a specific treatment. There have been increasing numbers of basket and umbrella trials, but they are still poorly understood. This article reviews common characteristics of basket and umbrella trials, key trials and recent US Food and Drug Administration approvals for precision oncology, and important considerations for clinical readers when critically evaluating future publications on basket trials and umbrella trials and for researchers when designing these clinical trials.
Background In September 2018 the FDA provided a draft guidance on master protocols reflecting an increased interest in these designs by industry. Master protocols refer to a single overarching protocol developed to evaluate multiple hypotheses and may be further categorized as basket, umbrella, and platform trials. However, inconsistencies in reporting persist in the literature. We conducted a systematic review to describe master protocol reporting with the goal of facilitating the further development and spread of these innovative trial designs. Methods We searched MEDLINE, EMBASE, and CENTRAL from inception to April 25, 2019 for English articles on master protocols. This was supplemented by hand searches of trial registries and of the bibliographies of published reviews. We used the FDA's definitions of master protocols as references and compared them to self-reported master protocols. Results We identified 278 master protocol publications, consisting of 228 protocols and 50 reviews. Sixty-six records provided unique definitions of master protocol types. We observed considerable heterogeneity in definitions of master protocols, and over half (54%) used oncology-specific language. The majority of self-classified master protocols (57%) were consistent with the FDA's definitions of master protocols. Conclusion The terms ‘master protocol’, ‘basket trial’, ‘umbrella trial’, and ‘platform trial’ are inconsistently described. Careful treatment of these terms and adherence to the definitions set forth by the FDA will facilitate better understanding of these trial designs and allow them to be used broadly and to their full potential in clinical research. We encourage trial methodologists to use these trial designations when applicable.
IMPORTANCE The first 1000 days of life represent a critical window for child development. Pregnancy, exclusive breastfeeding (EBF) period (0-6 months), and complementary feeding (CF) period (6-24 months) have different growth requirements, so separate considerations for intervention strategies are needed. No synthesis to date has attempted to quantify the associations of interventions under multiple domains of micronutrient and balanced energy protein and food supplements, deworming, maternal education, water sanitation, and hygiene across these 3 life periods with birth and growth outcomes. OBJECTIVE To determine the magnitude of association of interventions with birth and growth outcomes based on randomized clinical trials (RCTs) conducted in low-income and middle-income countries (LMICs) using Bayesian network meta-analyses. DATA SOURCES MEDLINE, Embase, and Cochrane databases were searched from their inception up to August 14, 2018. STUDY SELECTION Included were LMIC-based RCTs of interventions provided to pregnant women, infants (0-6 months), and children (6-24 months). DATA EXTRACTION AND SYNTHESIS Two independent reviewers used a standardized data extraction and quality assessment form. Random-effects network meta-analyses were performed for each life period. Effect sizes are reported as odds ratios (ORs) and mean differences (MeanDiffs) for dichotomous and continuous outcomes, with 95% credible intervals (CrIs). This study calculated probabilities of interventions being superior to standard of care by at least a minimal clinically important difference. MAIN OUTCOMES AND MEASURES The study compared ORs on preterm birth and MeanDiffs on birth weight for pregnancy, length for age (LAZ) for EBF, and height for age (HAZ) for CF. RESULTS Among 302 061 participants in 169 randomized clinical trials, the network meta-analyses found several nutritional interventions that demonstrated greater association with improved birth and growth outcomes compared with standard of care. For instance, compared with standard of care, maternal supplements of multiple micronutrients showed reduced odds for preterm birth (OR, 0.54; 95% CrI, 0.27-0.97) and improved mean birth weight (MeanDiff, 0.08 kg; 95% CrI, 0.00-0.17 kg) but not LAZ during EBF (MeanDiff, −0.02; 95% CrI, −0.18 to 0.14). Supplementing infants and children with multiple micronutrients showed improved LAZ (MeanDiff, 0.20; 95% CrI, 0.03-0.35) and HAZ (MeanDiff, 0.14; 95% CrI, 0.02-0.25). The study found that pregnancy interventions (continued) Key Points Question Which interventions under the domains of nutrition, deworming, maternal education, and water, sanitation, and hygiene can improve birth and linear growth outcomes during the first 1000 days of life in low-income and middle-income countries (LMICs)? Findings This study used Bayesian network meta-analyses of 169 randomized clinical trials including 302 061 participants and showed that several nutritional interventions demonstrating greater associations with improved outcomes compared with standard of care, whi...
eHealth is one perceived mechanism to extend the range and reach of limited health-care resources for older adults. A decade-scoping review (2007-2017) was conducted to systematically search and synthesize evidence to understand the intended and unintended consequences of eHealth initiatives, informed by a health equity impact assessment framework. Scoping review sources included international academic and grey literature on eHealth initiatives (e.g., eHealth records, telemedicine/telecare, and mobile eHealth application) focused on the varying needs of older adults (aged 60+), particularly individuals experiencing sociocultural and economic difficulties. Findings suggest that eHealth has several potential benefits for older adults, but also the possibility of further
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