Inferior Treatments Research Articles

Bayesian Response Adaptive Randomization for Randomized Clinical Trials With Continuous Outcomes: The Role of Covariate Adjustment.

Study designs incorporate interim analyses to allow for modifications to the trial design. These analyses may aid decisions regarding sample size, futility, and safety. Furthermore, they may provide evidence about potential differences between treatment arms. Bayesian response adaptive randomization (RAR) skews allocation proportions such that fewer participants are assigned to the inferior treatments. However, these allocation changes may introduce covariate imbalances. We discuss two versions of Bayesian RAR (with and without covariate adjustment for a binary covariate) for continuous outcomes analyzed using change scores and repeated measures, while considering either regression or mixed models for interim analysis modeling. Through simulation studies, we show that RAR (both versions) allocates more participants to better treatments compared to equal randomization, while reducing potential covariate imbalances. We also show that dynamic allocation using mixed models for repeated measures yields a smaller allocation proportion variance while having a similar covariate imbalance as regression models. Additionally, covariate imbalance was smallest for methods using covariate-adjusted RAR (CARA) in scenarios with small sample sizes and covariate prevalence less than 0.3. Covariate imbalance did not differ between RAR and CARA in simulations with larger sample sizes and higher covariate prevalence. We thus recommend a CARA approach for small pilot/exploratory studies for the identification of candidate treatments for further confirmatory studies.

Assessing efficacy in non-inferiority trials with non-adherence to interventions: Are intention-to-treat and per-protocol analyses fit for purpose?

Non-inferiority trials comparing different active drugs are often subject to treatment non-adherence. Intention-to-treat (ITT) and per-protocol (PP) analyses have been advocated in such studies but are not guaranteed to be unbiased in the presence of differential non-adherence. The REMoxTB trial evaluated two 4-month experimental regimens compared with a 6-month control regimen for newly diagnosed drug-susceptible TB. The primary endpoint was a composite unfavorable outcome of treatment failure or recurrence within 18 months post-randomization. We conducted a simulation study based on REMoxTB to assess the performance of statistical methods for handling non-adherence in non-inferiority trials, including: ITT and PP analyses, adjustment for observed adherence, multiple imputation (MI) of outcomes, inverse-probability-of-treatment weighting (IPTW), and a doubly-robust (DR) estimator. When non-adherence differed between trial arms, ITT, and PP analyses often resulted in non-trivial bias in the estimated treatment effect, which consequently under- or over-inflated the type I error rate. Adjustment for observed adherence led to similar issues, whereas the MI, IPTW and DR approaches were able to correct bias under most non-adherence scenarios; they could not always eliminate bias entirely in the presence of unobserved confounding. The IPTW and DR methods were generally unbiased and maintained desired type I error rates and statistical power. When non-adherence differs between trial arms, ITT and PP analyses can produce biased estimates of efficacy, potentially leading to the acceptance of inferior treatments or efficacious regimens being missed. IPTW and the DR estimator are relatively straightforward methods to supplement ITT and PP approaches.

Bayesian phase II adaptive randomization by jointly modeling efficacy and toxicity as time-to-event outcomes

ABSTRACT The main goals of Phase II trials are to identify the therapeutic efficacy of new treatments and continue monitoring all the possible adverse effects. In Phase II trials, it is important to develop an adaptive randomization (AR) procedure that takes into account both the efficacy and toxicity. In most existing articles, toxicity is modeled as a binary endpoint through an unobservable random effect (frailty) to link the efficacy and toxicity. However, this approach does not capture toxicity profiles that evolve over time. In this article, we propose a new Bayesian adaptive randomization (BAR) procedure using the covariate-adjusted efficacy-toxicity ratio (ETR) index, where efficacy and toxicity are jointly modelled as time-to-event (TTE) outcomes. Furthermore, we also propose early stopping rules for toxicity and futility such that inferior treatments can be dropped at earlier time of trial. Simulation results show that compared to the BAR procedures based solely on the efficacy and that based on TTE efficacy and binary toxicity outcomes, the proposed BAR procedure can better identify the difference in treatment toxicity such that it can assign more patients to the superior treatment arm under some scenarios.

Yield response factor (Ky) and initial growth in black pepper in a tropical environment

Black pepper is widely produced in Brazil, though there are few studies related to its water requirements and the effects of water deficit (WD) applied under tropical conditions. The growth, sensitivity to WD, and first-year productivity of irrigated plants from the Bragantina cultivar were evaluated, employing an irrigation system with automatic management. The plants were cultivated in plastic pots installed in the field for 391 days using emitters with different flow rates (2.2 [T1], 3.3 [T2], 4.3 [T3], and 5.3 L h–1 [T4 – control]). Fresh weight of the leaves, stems, and shoots, and dry weight of the leaves, stem, roots, and shoots as well as the total dry weight of the plant, were evaluated. Productivity was determined by evaluating the grains and spikes from a single harvest. Yield results and the actual versus maximum evapotranspiration rate for the entire growing season was used for calculating the Ky coefficient. Despite 1,346 mm of rainfall, the irrigation system was activated 165 times, distributing a mean volume of 19.0 (T1), 28.5 (T2), 37.1 (T3), and 45.8 L per plant (control). All traits were negatively affected by the WD, and the Ky values obtained (from 1.72 to 2.96) indicate the high sensitivity of black pepper to WD. In general, the spikes produced with at least 81 % of the crop water demand were larger and more numerous than those subjected to inferior treatments. WD occurring during the flowering stage severely hampers the size, weight, and quality of the spikes and grains of black pepper.

Treatment recommendation with distributional targets

We study the problem of a decision maker who must provide the best possible treatment recommendation based on an experiment. The desirability of the outcome distribution resulting from the policy recommendation is measured through a functional capturing the distributional characteristic that the decision maker is interested in optimizing. This could be, e.g., its inherent inequality, welfare, level of poverty or its distance to a desired outcome distribution. If the functional of interest is not quasi-convex or if there are constraints, the optimal recommendation may be a mixture of treatments. This vastly expands the set of recommendations that must be considered. We characterize the difficulty of the problem by obtaining maximal expected regret lower bounds. Furthermore, we propose two (near) regret-optimal policies. The first policy is static and thus applicable irrespectively of the subjects arriving sequentially or not in the course of the experimentation phase. The second policy can utilize that subjects arrive sequentially by successively eliminating inferior treatments and thus spends the sampling effort where it is most needed.

Hospital Utilization, Treatment Modalities, and Mortality Using Different Biopsy Methods in Infants With Biliary Atresia

ObjectivesTo present a nationwide retrospective analysis of the sequelae and aftereffects of different liver biopsy methods in the care of pediatric patients with biliary atresia.MethodsThe National Inpatient Sample 2001-2013 database was queried for a primary diagnosis of biliary atresia and stratified based on biopsy type including percutaneous, surgical, laparoscopic, and transjugular. Patient demographics, length of stay, hospital costs, type of treatment, and mortality were compared by biopsy type. One-way analysis of variance test and multivariable logistic regression were used for analysis with α < 0.05.ResultsA total of 4,306 patients with biliary atresia were identified, of whom 2,293 underwent no biopsy, and 723 and 1,080 underwent a percutaneous or surgical biopsy, respectively. Significant differences in socio-demographics were demonstrated between the biopsy types. The length of stay and hospital charges were statistically significantly different between the biopsy types where patients without biopsies had the smallest length compared to percutaneous, surgical, and combination of biopsies. Overall, the Kasai procedure was done more frequently compared to direct liver transplantation, and compared to other biopsy types, undergoing a combination of biopsies had the highest odds of undergoing either procedure.ConclusionsWhen comparing different biopsy methods, surgical biopsies of the liver outperformed percutaneous biopsies in hospital utilization and progression to definitive treatments with the Kasai procedure. Our research indicated that vulnerable populations such as minorities or the indigent may undergo inferior treatments or infrequently undergo definitive treatment. The need for definitive diagnostic guidelines is understated in patients with biliary atresia.

2021 National Survey on Prior Authorization Burden and Its Impact on Gastroenterology Practice.

INTRODUCTION:Prior authorizations (PAs) are intended to control prescription drug expenditures.METHODS:One hundred fifty-six physician and advanced practice provider members of the American College of Gastroenterology completed a national survey to assess PA burden and impact.RESULTS:One-half of PA requests relate to prescription refills. Greater than 50% of the respondents choose inferior treatments at least weekly because of perceived PA burden for preferred agents. One-half of the respondents reported a patient who experienced serious adverse events due to PA-related care delays.DISCUSSION:PA is an administrative burden that exhausts practice resources and may have a negative impact on patient care.

Consent in the time of COVID-19

The COVID-19 pandemic crisis has necessitated widespread adaptation of revised treatment regimens for both urgent and routine medical problems in patients with and without COVID-19. Some of these alternative treatments...

A Multiarmed Bandit Approach to Adaptive Water Quality Management.

ABSTRACTNonpoint source water quality management is challenged with allocating uncertain management actions and monitoring their performance in the absence of state‐dependent decision making. This adaptive management context can be expressed as a multiarmed bandit problem. Multiarmed bandit strategies attempt to balance the exploitation of actions that appear to maximize performance with the exploration of uncertain, but potentially better, actions. We performed a test of multiarmed bandit strategies to inform adaptive water quality management in Massachusetts, USA. Conservation and restoration practitioners were tasked with allocating household wastewater treatments to minimize N inputs to impaired waters. We obtained time series of N monitoring data from 3 wastewater treatment types and organized them chronologically and randomly. The chronological data set represented nonstationary performance based on recent monitoring data, whereas the random data set represented stationary performance. We tested 2 multiarmed bandit strategies in hypothetical experiments to sample from the treatment data through 20 sequential decisions. A deterministic probability‐matching strategy allocated treatments with the highest probability of success regarding their performance at each decision. A randomized probability‐matching strategy randomly allocated treatments according to their probability of success at each decision. The strategies were compared with a nonadaptive strategy that equally allocated treatments at each decision. Results indicated that equal allocation is useful for learning in nonstationary situations but tended to overexplore inferior treatments and thus did not maximize performance when compared with the other strategies. Deterministic probability matching maximized performance in many stationary situations, but the strategy did not adequately explore treatments and converged on inferior treatments in nonstationary situations. Randomized probability matching balanced performance and learning in stationary situations, but the strategy could converge on inferior treatments in nonstationary situations. These findings provide evidence that probability‐matching strategies are useful for adaptive management. Integr Environ Assess Manag 2020;16:841–852. © 2020 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)

Global Perspectives for Implant Dentistry.

Dr Harold Boyd's 1954 Presidential Address to the American Academy of Orthopedic Surgeons, observed: “Modern transportation and communication have contracted the world until all nations are neighbors. To promote peace and to live to the best advantage of all, we should know and understand each other. . . . This is particularly true of those engaged in the practice of medicine and surgery. We speak an international language as no other group can. Anatomy, physiological response to trauma or disease, and psychological reactions of patients are little influenced by race or place of residence.”1This observation is as true for implant dentistry today as it was 66 years ago for orthopedic surgery. Whenever we read an issue of JOI, we see how interconnected and interdependent all implant dentists are, regardless of their country of practice. JOI publishes research papers and clinical case reports written by authors from around the world, as do all implant-specific journals. All readers, regardless of where they reside, learn from these articles. Published research discoveries in peer reviewed journals originating from parts of the world other than our own can inspire all clinicians, and perhaps offer better ways to provide improved patient care worldwide.1 Some countries do not have access to the products found in other countries because of regulations on human donor materials. An example would be allografts that are available in the United States, but not in Japan. Clinicians faced with different choices do not necessarily deliver inferior treatments, but rather different treatments that may end up with comparable results. We should, at a minimum, be familiar with how others make treatments work using different materials or techniques.In the most recent issue of JOI, manuscripts originated from Brazil, Germany, India, Japan, Saudi-Arabia, South Korea, Spain, and the United States.2–9 This mixture of articles can be found in most dental journals. Just as importantly, JOI is read by researchers and clinicians worldwide. The American Board of Oral Implantology/Implant Dentistry (ABOI/ID) now permits international clinicians to become Board Certified. This reinforces how the principles used in practicing implant dentistry are becoming universal.Patients throughout the world suffer from tooth loss and have a need for dental implant treatments. Clinicians and researchers, regardless of location, offer innovations that when subject to peer review may become the next “new best thing” for patient care. Clinicians must continue to speak the international language of implant dentistry so they can share knowledge and skills worldwide. This has become more important and relevant today than ever before. The current COVID-19 pandemic travel restrictions may have reduced our abilities to attend international conferences, but we can still learn from our international colleagues through JOI.

Resist the Temptation of Response-Adaptive Randomization.

Response-adaptive randomization (RAR) has recently gained popularity in clinical trials. The intent is noble: minimize the number of participants randomized to inferior treatments and increase the amount of information about better treatments. Unfortunately, RAR causes many problems, including (1) bias from temporal trends, (2) inefficiency in treatment effect estimation, (3) volatility in sample-size distributions that can cause a nontrivial proportion of trials to assign more patients to an inferior arm, (4) difficulty of validly analyzing results, and (5) the potential for selection bias and other issues inherent to being unblinded to ongoing results. The problems of RAR are most acute in the very setting for which RAR has been proposed, namely long-duration "platform" trials and infectious disease settings where temporal trends are ubiquitous. Response-adaptive randomization can eliminate the benefits that randomization, the most powerful tool in clinical trials, provides. Use of RAR is discouraged.

Prediction of Critical Periods for Weed Interference in Soybean

Ten competition periods as treatments (T1-10) could be valuable for predicting increase productivity (W) T1 to T5 were allowed to infest the crop and (WF) T6 to T10 was kept weed free, weed competition periods for W and WFi.e. 3, 6, 9, 12 Weeks after emergence (WAE) and up to harvest. So, two field experiments were conducted season 2018 and 2019. Critical Periods for Weed Control (CPWC) was determined based on relative percentage yield ton/h-1 (SY %) of weed free as a check by fitting curves regression models (linear and non-linear, which recommended losing yield value 10%. with seed yield reduction t/h-1 declined from 2.3, 2.28 WF to 0.39- 0.36 W as a checked treatment for 1st, 2nd seasons, respectively about 83.33%, 85% due to relative seed yield. Gompertz as a non linear regression equation recorded 0.99* The effects of treatment classified into 3 groups where A involved 5 superior treatments (T1, T7, T8, T9 and T10). However, T4 and T5 described inferior treatments which located in group C. Low of weed density and increasing of weed index (WI %) 80% observed for 1st season of T4 but T5 was translocated with increasing both weeds number and severed for weed index. It could be summarized that it should be keeping crop weed-free during stages 2nd week and continue until 8th week after crop emergence, which is providing maximum seed yield of soybean.

Compatibility of biological control agents with fungicides against root rot diseases of wheat

Root - rot diseases are considered the most serious diseases of wheat in Egypt, causing a considerable loss seed germination, plant stand and grain yield. The present study aims to evaluate the fungicidal activity of four chemical fungicides and two biological control agents. Four fungicides (i.e. triticonazole, carbendazim, carboxin + thiram and metalaxyl M + fludioxonil) and two biological control agents (i.e. Trichoderma harzianum and Bacillus subtilis) were evaluated separately and their compatibility against two pathogenic fungi, Rhizoctonia solani and Fusarium graminearum that causing root rot diseases of wheat. The in vitro studies showed that the fungicidal activity of the tested fungicides against R. solani mycelial growth was descendingly arranged as follows; metalaxyl M + fludioxonil > carbendazim > triticonazole > carboxin + thiram, while it was metalaxyl M + fludioxonil > triticonazole > carbendazim > carboxin + thiram against F. graminearum mycelial growth. In greenhouse trials, the fungicides were applied at 1.5 and 3.0 g kg-1 seeds as seed treatment, while biological control agents were applied at 4.5 and 9.0 x 106 spores mL-1 water as soil treatment. The results showed that all the treatments significantly reduced disease incidence and increased emergence and plant stands and the biological control agents were the inferior treatments. Generally, the most effective treatments for controlling root rot diseases were metalaxyl M + fludioxonil followed by carbendazim, triticonazole, while the lowest were carboxin + thiram, B. subtilis and T. harzianum as compared with the control treatment. Moreover, the results concluded that the efficiency of T. harzianum and B. subtilis in controlling R. solani and F. graminearum was obviously enhanced by their compatibility with low rates of the tested fungicides. In conclusion, the biological strategy which used throughout integrated pest management could be improved by using fungicides at low rates.

Response-adaptive treatment allocation for non-inferiority trials with heterogeneous variances

In clinical studies, patients usually accrue sequentially. The response-adaptive design has been shown to be a valuable treatment allocation apparatus that skews the treatment allocation probabilities to achieve certain objectives such as reducing the number of patients who receive inferior treatments. The doubly adaptive biased coin design was successfully derived for the three-arm non-inferiority (NI) trial. For an NI study, an experimental treatment can be considered a possible substitute for the standard treatment if the loss of clinically tolerable efficacy is compensated by benefits such as the alleviation of side effects. Previous applications of the doubly adaptive biased coin design in NI trials were developed only for homogeneous treatment variances. However, it is worth to examine the more complicated, but nevertheless popular, scenarios in which the treatment variances are heterogeneous. The proposed treatment allocation scheme is superior when the treatment variances differ and remains very competitive when they are homogeneous. A clinical example is given for demonstrative purposes.

The role of Imaging and Radiation Oncology Core for precision medicine era of clinical trial.

Imaging and Radiation Oncology Core (IROC) services have been established for the quality assurance (QA) of imaging and radiotherapy (RT) for NCI's Clinical Trial Network (NCTN) for any trials that contain imaging or RT. The randomized clinical trial is the gold standard for evidence-based medicine. QA ensures data quality, preventing noise from inferior treatments obscuring clinical trial outcome. QA is also found to be cost-effective. IROC has made great progress in multi-institution standardization and is expected to lead QA standardization, QA science in imaging and RT and to advance quality data analysis with big data in the future. The QA in the era of precision medicine is of paramount importance, when individualized decision making may depend on the quality and accuracy of RT and imaging.

The Real-World Ethics of Adaptive-Design Clinical Trials.

From the earliest application of modern randomized controlled trials in medical research, scientists and observers have deliberated the ethics of randomly allocating study participants to trial control arms. Adaptive RCT designs have been promoted as ethically advantageous over conventional RCTs because they reduce the allocation of subjects to what appear to be inferior treatments. Critical assessment of this claim is important, as adaptive designs are changing medical research, with the potential to significantly shift how clinical trials are conducted. Policy-makers are swiftly moving to encourage greater use of adaptive designs. In 2016, the newly enacted 21st Century Cures Act instructed the Food and Drug Administration to help product sponsors incorporate adaptive methods into proposed clinical trial protocols and applications for investigational drugs and also biological products. In this article, we review the ethical justifications commonly offered for adaptive designs, explore these arguments in the context of actual trials, and contend that clinical equipoise is a useful standard for adaptive-trial ethics. We distinguish between theoretical and clinical equipoise and explain why ethical arguments related to adaptive trials tend to focus on the former. Yet we contend that theoretical equipoise can be an unreliable standard for adaptive ethics. While we contend that clinical equipoise is the most critical principle for the primary ethical concerns posed by adaptive trials, we suggest ethical approaches to deal with some additional concerns unique to adaptive designs.

Adaptive sequential selection procedures with random subset sizes

ABSTRACTWe introduce a new family of sequential selection procedures wherein the subsets selected have random sizes. In comparison to subset selection procedures that select subsets of fixed size, the new procedures alleviate the need to specify the subset size prior to the experiment. We discuss the application of such procedures in the context of early phase clinical trials. The new procedures retain the adaptive features of the Levin-Robbins-Leu family of sequential subset selection procedures for selecting subsets of fixed size, namely, sequential elimination of inferior treatments and sequential recruitment of superior treatments. These two adaptive features respectively address ethical concerns that diminish interest in nonadaptive procedures and also allow promising treatments to be brought forward for further testing without having to wait until the end of the trial. The new procedures differ from the classical subset selection procedures of Shanti S. Gupta in terms of their respective goals and operating characteristics and we compare the two approaches in a simulation study. The findings suggest that whereas Gupta’s procedure achieves its goal of including the single best treatment in the final selected subset with high probability, it does so by virtue of a nonadaptive, fixed sample size procedure that lacks necessary flexibility in the context of clinical research. By contrast, the new procedures aim to select treatment subsets that satisfy a different criterion, that of acceptable subset selection with high probability, while allowing adaptive elimination and recruitment and other flexibilities which we discuss to fit the practical needs of selection methods in clinical research.

Adaptive Designs for Non-inferiority Trials with Multiple Experimental Treatments.

The increase in the popularity of non-inferiority clinical trials represents the increasing need to search for substitutes for some reference (standard) treatments. A new treatment would be preferred to the standard treatment if the benefits of adopting it outweigh a possible clinically insignificant reduction in treatment efficacy (non-inferiority margin). Statistical procedures have recently been developed for treatment comparisons in non-inferiority clinical trials that have multiple experimental (new) treatments. An ethical concern for non-inferiority trials is that some patients undergo the less effective treatments; this problem is more serious when multiple experimental treatments are included in a balanced trial in which the sample sizes are the same for all experimental treatments. With the aim of giving fewer patients the inferior treatments, we propose a response-adaptive treatment allocation scheme that is based on the doubly adaptive biased coin design. The proposed adaptive design is also shown to be superior to the balanced design in terms of testing power.

P3.02b-025 Rapid and Highly Sensitive EGFRdelEx19 and KRAS Exon 2 Mutation Detection in EBUS-TBNA Specimen of Lung Adenocarcinoma: Topic: EGFR Biomarkers

First-line treatment with afatinib prolongs overall survival in patients with metastatic non-small-cell lung cancer (NSCLC) harboring EGFR exon 19 deletion mutations. Conversely, somatic KRAS mutations are negative predictors for benefit from EGFR-targeting agents. Rapid availability of these biomarker results is mandatory to prevent delayed or inferior treatments. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is well-established for lung cancer diagnosis and staging. Next generation sequencing (NGS) via targeted resequencing allows simultaneous interrogation for multiple mutations, but has its limitations based on the amount of tumor tissue required and assay times. RT-PCR using Light-Cycler technology (LC-RTPCR) is a rapid and sensitive assay to detect somatic mutations in various tissues from NSCLC patients. The study’s aim was to analyze if LC-RTPCR is feasible for rapid EGFRdelE×19 and KRAS Exon 2 mutation detection in EBUS-TBNA samples and to compare results with results obtained via standard NGS mutation analyses. 48 surplus EBUS-TBNA samples (38 lymph nodes, 10 primary tumor) from 47 patients with pulmonary adenocarcinoma were analyzed. Two samples were collected per lymph node. One was used for routine cytology, the other was freshly frozen (ff). DNA from ff-biopsies was extracted using Genomic DNA buffer set (QIAgen, Germany). Mutation analysis by LC-RTPCR was conducted as previously described. NGS was performed on MiSeq (Illumina) via targeted resequencing using a customized multiplex-PCR panel covering 36 exons from 11 genes. Mutations were annotated with a minimum frequency of 2%. Processing time was approximately 4 days for NGS and 2 hours for LC-RTPCR analyses. NGS of EBUS-TBNA samples was technically feasible for both markers in 22 (46%) samples, for EGFR testing in 32 (67%) samples, and for KRAS in 23 (48%) samples. EGFRdelEx19 mutations were detected in four (8.3% of intention-to-screen), and KRAS Exon 2 mutations in 15 cases (31%) cases. LC-RTPCR was technically feasible in all cases. All mutations detected by NGS were also detected by LC-RTPCR. LC-RTPCR detected three additional KRAS Exon 2 mutations and three additional EGFRdelEx19 mutations. NGS detected additional mutations in 4 cases (2 EGFR Exon 21, 1 KRAS Codon 61, 1 PIK3CA). LC-RTPCR is a rapid, highly sensitive method to detect mutations of immediate therapeutic relevance, such as EGFRdelEx19 and KRAS Exon 2 mutations, in limited EBUS-TBNA specimens from metastatic NSCLC patients. It is of value as rapid and sensitive initial assay in a two-step diagnostic process for first-line treatment decision, incorporating broader biomarker panels as second step.

Clinicaltrials.gov: Is the Glass Half Full?

Clinicaltrials.gov: Is the Glass Half Full?