Risk-benefit Trade-off Research Articles

Understanding Treatment Preferences of Australian Patients Living with Treatment-Resistant Depression.

BackgroundThere is evidence of improved adherence and treatment outcomes when patients’ treatment preferences are considered, and shared decision making is utilized.PurposeWe aimed to better understand treatment preferences among Australians with treatment-resistant depression (TRD), focusing on the specific treatment attributes that people value (such as effectiveness, risk of side effects and cost) and their relative importance. The risk-benefit trade-offs that characterize treatment choices were also examined.Patients and MethodsAn online survey of 75 patients with experience of TRD was conducted, consisting of two discrete choice experiment (DCE) components – a medication DCE and a treatment plan DCE. Participants were able to prioritize and trade off different features of medications and treatment plans. Additional questions aimed to better define this population group, which in Australia is poorly understood.ResultsIn both DCEs, two distinct latent classes were identified. In the medication DCE, the classes were distinguished by willingness to consider new treatment alternatives. Participants in class 1 were reluctant to give up current treatment, while those in the slightly larger class 2 preferred new treatment options. In both classes, treatment effectiveness and cost were the greatest contributors to preference. Similar behavior was seen in the treatment plan DCE, with the larger class more likely to choose a new plan over their current treatment arrangement. Participants preferred medications that were low-cost, taken orally, had a high percentage improvement in mood symptoms, high rate of remission and low risk of weight gain. A similar result was found in preferences for treatment plans such that plans with the greatest effectiveness and lowest cost were most favorable.ConclusionPatient preferences should routinely be considered and discussed to guide informed decisions regarding the value of new and existing medications for TRD and how they sit in the context of treatment plans.

Measuring Meaningful Benefit-Risk Tradeoffs to Promote Patient-Focused Drug Development in Prader-Willi Syndrome: A Discrete-Choice Experiment.

Background. Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder causing quality of life impairments such as insatiable hunger (hyperphagia) and obesity. We explored caregivers’ willingness to assume treatment risk in exchange for reduced hyperphagia according to a PWS-validated observer-reported outcome measure. Methods. We partnered with PWS patient organizations to develop a discrete-choice experiment exploring caregivers’ benefit-risk tradeoffs for emerging PWS treatments. The treatment benefit was a reduction in hyperphagia (as measured by a 0-, 5-, or 10-point change on the Hyperphagia Questionnaire for Clinical Trials [HQ-CT]). Treatment risks included weight gain (none, 5%, 10%), added risk of skin rash (none, 10%, 20%), and risk of liver damage (none, 1 in 1000, 10 in 1000). Preference models were estimated using mixed logistic regression and maximum acceptable risk. We explored differences in preferences across familial caregivers of patients with and without hyperphagia. Results. Four hundred sixty-eight caregivers completed the online survey. The majority of caregivers reported that patients experienced hyperphagia (68%) and half of patients experienced obesity (52%). Caregivers of patients without hyperphagia were willing to accept greater weight gain (16.4% v. 8.1%, P = 0.004) and a higher risk of skin rash (11.7% v. 6.2% P = 0.008) as compared to caregivers of patients with hyperphagia. Caregivers of patients with hyperphagia would accept a higher risk of liver damage as compared to caregivers of patients without hyperphagia (11.9 out of 1000 v. 6.4 out of 1000, P = 0.04). Conclusions. This research demonstrates that caregivers are willing to accept risk in exchange for a five-point improvement on the HQ-CT, a smaller marginal improvement than had been previously classified as meaningful. Patient experience with hyperphagia is a modifier in how much risk caregivers will accept.

Impact of anticoagulation on recurrent thrombosis and bleeding after hematopoietic cell transplantation.

History of venous thromboembolism (VTE) is prevalent among patients undergoing hematopoietic cell transplantation (HCT). Management of anticoagulation is particularly challenging as most patients will have chemotherapy-induced thrombocytopenia while awaiting engraftment post-HCT. We conducted a retrospective study of autologous and allogeneic HCT recipients with prior VTE from 2006-2015 to 1) compare anticoagulant strategies on short-term VTE recurrence and bleeding and 2) assess predictors for VTE recurrence beyond 30 days. Patients with VTE were allocated to two cohorts based on anticoagulant strategy at thrombocytopenia onset and underwent inverse probability weighting to assess primary outcomes of VTE recurrence and bleeding within 30 days post-HCT. Subsequently, multivariable logistic regression model was used to assess the association of 100-day VTE recurrence by the HIGH-2-LOW VTE risk assessment score and whether patients resumed anticoagulation at platelet recovery. Thirteen percent of recipients had VTE prior to HCT; of those meeting inclusion criteria, 227 continued anticoagulation and 113 temporarily discontinued it. Anticoagulant strategy was not significantly associated with decreased risk of VTE recurrence within 30 days (3% vs 4%, p=0.61); however, risk of overall bleeding was non-significantly higher in those who continued vs discontinued anticoagulation (41% vs 31%, p=0.08). In a subgroup of 250 allogeneic HCT patients, every one-point increase of HIGH-2-LOW score was significantly associated with VTE recurrence at 100 days (OR 1.57 [95% CI 1.10-2.23]), while anticoagulation resumption upon platelet engraftment was associated with lower recurrent risk (OR 0.48 [0.20-1.14]). Temporarily withholding anticoagulation during thrombocytopenia may optimize risk-benefit tradeoffs, though additional strategies are essential to prevent VTE recurrence after hematopoietic recovery.

Making Patient-Specific Treatment Decisions Using Prognostic Variables and Utilities of Clinical Outcomes.

Simple SummaryClinicians often erroneously discount prognostic information as unlikely to change patient management. This is fueled by the mistaken belief that only “predictive” subgroups or biomarkers can modify the differences in clinical benefit between treatment choices. We use the treatment of metastatic clear cell carcinoma as an example to illustrate how clinical decisions can be informed by prognostic variables. Diametrically opposite decisions can be made depending on individual patient prognosis and on the clinical outcome of interest that clinicians choose to focus on. We also demonstrate why such patient-specific treatment decisions inevitably should be guided by each patient’s goals and values, which can be explicitly represented by utility functions.We argue that well-informed patient-specific decision-making may be carried out as three consecutive tasks: (1) estimating key parameters of a statistical model, (2) using prognostic information to convert these parameters into clinically interpretable values, and (3) specifying joint utility functions to quantify risk–benefit trade-offs between clinical outcomes. Using the management of metastatic clear cell renal cell carcinoma as our motivating example, we explain the role of prognostic covariates that characterize between-patient heterogeneity in clinical outcomes. We show that explicitly specifying the joint utility of clinical outcomes provides a coherent basis for patient-specific decision-making.

PMS24 Decision-Making and Benefit-Risk Tradeoffs for Duchenne Muscular Dystrophy Treatment

Duchenne muscular dystrophy (DMD) is a rare pediatric-onset neuromuscular disorder. Emflaza, a corticosteroid, is the only therapy approved for all patients, regardless of genotype. Corticosteroids are standard of care and modestly delay the disease course. This study, led by Parent Project Muscular Dystrophy, uses a community-engaged approach to understand corticosteroid decision making and experiences. Teenagers and adults with DMD and parents participated in semi-structured interviews via Zoom led by experienced interviewers. Three vignettes were used to glean information about values in decision-making and willingness to try a new therapy that, compared to corticosteroids, had (1) improved efficacy, but worse side effects, (2) reduced efficacy, no side effects, and (3) improved efficacy, but no information on long-term risks or benefits. Data were systematically analyzed by corticosteroid-use and cohort using a rapid analysis approach. 25 respondents were parents and 16 living with DMD. 26 of DMD index cases were current corticosteroid users; 3 prior users; and 10 parents were deciding whether to initiate use in young children. Parents deciding to start corticosteroids were critical of options with more side effects despite increased benefits. Current users with DMD were more willing to try an option with improved efficacy and increased side effects, citing ability to manage current effects. They preferred that option to the one with uncertain long-term outcomes. Parents of corticosteroid-users preferred a treatment with improved efficacy, even with limited long-term outcome data. Current corticosteroid-users preferred improved efficacy even with worse side effects while non-users were unwilling to accept worse side effects despite added benefits. Parents of current users expressed more tolerance for uncertainty than patients. Most prior research in this patient population finds that, for novel therapies, expected benefits far exceeded potential risks in anticipated choices. Comparisons of approved versus novel therapies provide important data about motivations.

P244 Clinician preferences in treating steroid resistant ulcerative colitis: a discrete-choice experiment (DCE) survey

Abstract Background The optimum treatment for steroid resistant ulcerative colitis (SRUC) is not clear and a range of options can be considered. The aim of this study was to quantify the relative importance of different treatment characteristics to clinicians and understand their preferences for benefit-risk trade-offs. Methods A discrete choice experiment (DCE) was conducted in the UK via online survey of clinicians with expertise in inflammatory bowel disease. This involved 12 tasks where respondents selected a preferred treatment option when presented with two competing, hypothetical treatment profiles for a SRUC scenario. Profiles described five treatment characteristics focusing on clinical outcomes and safety, identified from qualitative interviews with clinicians and evidence from systematic reviews. DCE responses were analysed using conditional logistic regressions. Regression coefficients were used to calculate benefit-risk trade-offs, to find the rate at which clinicians are willing to trade levels of risks in exchange for the preferred levels of clinical outcomes. Regression coefficients were also used to predict uptake rates for selected drugs currently prescribed to patients with SRUC. Results 116 clinicians completed the survey (age 46y; female 42%; consultant 60%; nurse 26%; mean experience 11y). Figure 1 shows the treatment characteristics that make respondents more likely (positive coefficient) or less likely (negative coefficient) to choose a treatment. One unit increase in both lymphoma risk and serious infection risk were strongly considered when clinicians were choosing a treatment compared to one unit increase in the symptom improvement characteristics. Clinicians would accept a higher lymphoma risk of 5 per 10,000 patient years for a 10% improvement in remission rate compared to 4 and 2 cases per 10,000 patient years for 10% better rates of clinical response and mucosal healing respectively. Clinicians at secondary hospitals accepted a lymphoma risk of 4 cases per 10,000 patient years for a 10% improvement in remission vs 7 per 10,000 patient years at tertiary centres. Similar trade-off results were found for serious infection risks. Predicted uptake comparing preferred characteristics to existing treatments was infliximab (62%), tofacitinib (18%), vedolizumab (15%) and adalimumab (5%). Conclusion Clinicians are willing to make difficult trade-offs and tolerate elevated safety risks in exchange for therapeutic benefits. Risk tolerance was highest if the treatment improved long term remission rate, lowest for mucosal healing and higher in clinicians at tertiary centres. The results help to better understand treatment decisions and identify outcomes that might be considered in choosing agents to evaluate in clinical trials.

Current Opinion on the use of Direct Oral Anticoagulants for the Prophylaxis of Venous Thromboembolism among Medical Inpatients.

Venous thromboembolism (VTE) is a known cause of morbidity and mortality, especially among acutely ill medical patients. Although VTE prophylaxis is part of post-discharge clinical care in surgical patients, there is controversy regarding its use in acutely ill medical patients and the current guideline statements suggest against its routine use. Recent clinical trials (APEX, MAGELLAN and MARINER) compared the safety and efficacy of direct oral anticoagulants (including betrixaban and rivaroxaban) with the standard of the care, enoxaparin, to identify the risk–benefit tradeoff. In this review, we summarized the key findings from these trials and substudies and recent updates in society guidelines regarding VTE prevention. In addition, we discussed the potential barriers, cost-effectiveness, and COVID-19 with respect to the implementation of extended-duration or post-discharge usage of direct oral anticoagulants.

Adult Patient Preferences for Long-Acting ADHD Treatments: A Discrete Choice Experiment.

Background and ObjectiveTreatment for attention deficit hyperactivity disorder (ADHD) requires a multifaceted approach including psychosocial interventions and pharmacological treatment. This study evaluates preferences for specific attributes associated with different long-acting stimulant treatment among US adults with ADHD.MethodsPatients completed an online, cross-sectional survey, incorporating a discrete choice experiment to assess preferences for attributes.ResultsAnalyses included 200 adults with ADHD (mean age 33.0 years; 60% self-reporting moderate severity); the mean (SD) Adult ADHD Self-Report Scale-v1.1 score was 45.9 (12.4). Overall, patients valued speed of onset most and risk of rebound least. Three population groups with distinct preferences were identified: side effect-driven (n=69, 35%), quick onset-driven (n=47, 24%) and quick onset and long duration-driven (n=84, 42%).ConclusionThis study shows differences in how adults with ADHD value and assess benefit-risk trade-offs when considering the desired attributes of stimulant treatments, highlighting the importance of patient-physician shared decision-making to optimize the desired benefits of individualized treatment.

Patient-reported outcomes in breast cancer FDA drug labels and review documents

BackgroundPatient-reported outcomes (PROs) can provide valuable information about drug benefit-risk tradeoffs from the patient perspective and are particularly important to patients with breast cancer due to its symptoms and adverse events from breast cancer treatments. The United States Food and Drug Administration (U.S. FDA) has acknowledged PROs as important approval endpoints used in clinical trials of cancer drugs. However, previous studies found that PROs are rarely mentioned in cancer drug labels, a widely used and trusted source of information about drugs. Our objectives were to compare PRO data reported in FDA labeling versus FDA medical review documents for breast cancer drugs approved in the U.S. between 2000 and 2019 to identify possible causes for PRO-data labeling exclusions.MethodsWe included new molecular entities (NMEs) and biologic license applications (BLAs) initially approved for breast cancer treatment by the FDA between 1/1/2000 and 12/31/2019. Product labeling and FDA medical review documents were collected from the FDA-Approved Drugs database (Drugs@FDA). From these resources, details on PRO measures used in trials, design of trials using PRO measures, PRO-endpoint status, analytical methods, and FDA reviewer comments regarding PRO measurement were extracted.ResultsOf 633 FDA-approved drugs, 13 were indicated for breast cancer treatment; none of their prescribing information contained information about PROs. However, 11 of 13 (85%) included PRO measures and endpoint information in FDA medical review documents. PRO measures were used in 14 different clinical trials, and FDA reviewers’ comments regarding PRO measurement were related to lack of meaningfulness and clinical significance, lack of content validity, and inadequate analytical methods.ConclusionsDespite the importance of PROs to patients with breast cancer, PRO measures were only described in FDA medical review documents of breast cancer drugs, but not in drug product labeling. Therefore, it appears that PRO data are often collected in breast cancer trials, but have not been methodologically acceptable to FDA reviewers. Collaborative efforts between the FDA and industry are warranted to increase the number of breast cancer drug applications with appropriate use of PRO measures and endpoints.

Treatment preferences for preventive interventions for rheumatoid arthritis: protocol of a mixed methods case study for the Innovative Medicines Initiative PREFER project

IntroductionAmidst growing consensus that stakeholder decision-making during drug development should be informed by an understanding of patient preferences, the Innovative Medicines Initiative project ‘Patient Preferences in Benefit-Risk Assessments during the...

UTPI: A utility-based toxicity probability interval design for phase I/II dose-finding trials.

Unlike chemotherapy, the maximum tolerated dose (MTD) of molecularly targeted agents and immunotherapy may not pose significant clinical benefit over the lower doses. By simultaneously considering both toxicity and efficacy endpoints, phase I/II trials can identify a more clinically meaningful dose for subsequent phase II trials than traditional toxicity-based phase I trials in terms of risk-benefit tradeoff. To strengthen and simplify the current practice of phase I/II trials, we propose a utility-based toxicity probability interval (uTPI) design for finding the optimal biological dose, based on a numerical utility that provides a clinically meaningful, one-dimensional summary representation of the patient's bivariate toxicity and efficacy outcome. The uTPI design does not rely on any parametric specification of the dose-response relationship, and it directly models the dose desirability through a quasi binomial likelihood. Toxicity probability intervals are used to screen out overly toxic dose levels, and then the dose escalation/de-escalation decisions are made adaptively by comparing the posterior desirability distributions of the adjacent levels of the current dose. The uTPI design is flexible in accommodating various dose desirability formulations, while only requiring minimum design parameters. It has a clear decision structure such that a dose-assignment decision table can be calculated before the trial starts and can be used throughout the trial, which simplifies the practical implementation of the design. Extensive simulation studies demonstrate that the proposed uTPI design yields desirable as well as robust performance under various scenarios.

Prioritization and Refinement of Patient-Informed Value Elements as Attributes for Chronic Obstructive Pulmonary Disease Treatment Preferences.

Formative research studies can inform stated-preference instrument development to quantify the importance of various attributes of healthcare treatments. The objective of this study was to elicit from patients with chronic obstructive pulmonary disease the prioritization of an established set of patient-informed value elements. Using an iterative mixed-methods study design, we engaged individuals living with chronic obstructive pulmonary disease in Phase 1 value element elicitation and Phase 2 language refinement. Study participants were recruited from March to July 2019. Four guided activities, administered in an online instrument, elicited individual preferences for 40 disease-agnostic value elements that were aligned with treatment, outcomes, or care process. Responses from the guided activities were summarized and then presented to a patient advocate and additional patient participants for further refinement of the value elements and the phrasing. Twenty-three participants, 18 male and five female, mean age of 66 years (standard deviation = 7) were enrolled in Phase 1. Participant responses informed the selection of eight elements as the key candidates for the Phase 2 language refinement: Side Effects, New Therapeutic Option, Available Treatment, Appropriateness of Care, Predictable Healthcare Needs, Physical Activities: Endurance and Symptom Control, and Explanation of Treatment. With feedback from a patient advocate and additional patient participants, elements were refined, rephrased, or modified and this list was narrowed to six value elements (Side Effects, New Therapeutic Option, Willingness to Pay, Physical Activities, Explanation of Treatment, and Access to Care) to serve as attributes in a conceptual framework for a future quantitative stated-preference instrument. This patient-engaged formative work identified patients with chronic obstructive pulmonary disease key attributes of value-based decision making that underpin benefit-risk trade-offs between physical endurance, treatment side effects, care access, and cost. This study illustrates an iterative process for eliciting and refining a comprehensive list of value elements, resulting in a subgroup of elements important to a specific patient population.

Review of Stakeholder Preferences for Non-Metastatic Castration-Resistant Prostate Cancer Treatments

The goals of treating non-metastatic castration-resistant prostate cancer (nmCRPC) patients are to delay metastasis and prolong life, while maintaining the quality of patients’ survival. The recent approval of second-generation androgen-receptor inhibitors (SGARIs) in the United States has expanded the treatment landscape for nmCRPC. Large-scale randomized controlled trials showed that SGARI treatment options have similar efficacy, but different safety profiles. Two recent discrete choice experiment (DCE) studies conducted in the United States, evaluated the benefit-risk tradeoffs of patients, caregivers and physicians for nmCRPC treatments. The aim of this review is to summarize these two studies and highlight differences in the preferences among these three stakeholder groups with respect to adverse events (AEs) of specific interest in nmCRPC. Both DCE studies included 5 AE attributes: frequency or level of severity of fatigue, skin rash, cognitive impairment, risk of serious fracture, risk of serious fall. Survey results from patients (n=143), caregivers (n=149), and physicians (n=74 oncologists, n=75 urologists) were analyzed using random parameters logit models generating preference weights for each attribute level. AE reduction was more important than improving OS for physicians and even more prominently for patients and caregivers. As government healthcare agencies, globally, continue integrating patient feedback and evidence into their decision-making processes, the role of preference methodology in generating such evidence, may be expected to grow.

Evidence-based Guideline for Therapeutic Drug Monitoring of Vancomycin: 2020 Update by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.

Clinical practice guidelines or recommendations often require timely and regular updating as new evidence emerges, because this can alter the risk-benefit trade-off. The scientific process of developing and updating guidelines accompanied by adequate implementation can improve outcomes. To promote better management of patients receiving vancomycin therapy, we updated the guideline for the therapeutic drug monitoring (TDM) of vancomycin published in 2015. Our updated recommendations complied with standards for developing trustworthy guidelines, including timeliness and rigor of the updating process, as well as the use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. We also followed the methodology handbook published by the National Institute for Health and Clinical Excellence and the Spanish National Health System. We partially updated the 2015 guideline. Apart from adults, the updated guideline also focuses on pediatric patients and neonates requiring intravenous vancomycin therapy. The guideline recommendations involve a broadened range of patients requiring TDM, modified index of TDM (both 24-hour area under the curve and trough concentration), addition regarding the necessity and timing of repeated TDM, and initial dose for specific subpopulations. Overall, 1 recommendation was deleted and 3 recommendations were modified. Eleven new recommendations were added, and no recommendation was made for 2 clinical questions. We updated an evidence-based guideline regarding the TDM of vancomycin using a rigorous and multidisciplinary approach. The updated guideline provides more comprehensive recommendations to inform rational and optimized vancomycin use and is thus of greater applicability.

Benefit-Risk Tradeoffs in Assessment of New Drugs and Devices.

Balancing benefits and risks is a complex task that poses a major challenge, both to the approval of new medicines and devices by regulatory authorities and in therapeutic decision-making in practice. Several analysis methods and visualization tools have been developed to help evaluate and communicate whether the benefit-risk profile is favorable or unfavorable. In this White Paper, we describe approaches to benefit-risk assessment using qualitative approaches such as the Benefit Risk Action Team framework developed by the Pharmaceutical Research and Manufacturers of America, and the Benefit-Risk Framework developed by the United States Food and Drug Administration; and quantitative approaches such as the numbers needed to treat for benefit and harm, the benefit-risk ratio, and Incremental Net Benefit. We give illustrative examples of benefit-risk evaluations using 4 treatment interventions including sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes; a direct antithrombin agent, dabigatran, for reducing stroke and systemic embolism in patients with nonvalvular atrial fibrillation; transcatheter aortic valve replacement in patients with symptomatic severe aortic valve stenosis; and antiplatelet agents vorapaxar and prasugrel for reducing cardiovascular events in patients at high cardiovascular risk. Regular applications of structured benefit-risk assessment, whether qualitative, quantitative, or both, enabled by easy-to-understand graphical presentations that capture uncertainties around the benefit-risk metric, may aid shared decision-making and enhance transparency of those decisions.

Benefit-Risk or Risk-Benefit Trade-Offs? Another Look at Attribute Ordering Effects in a Pilot Choice Experiment.

Studies recommend randomising the order of attributes in discrete choice experiments (DCEs) to avoid bias; however, in a benefit-risk setting, this may increase the cognitive burden of respondents who compare the benefits and risks of treatments, or may affect their decision-making process. Based on these concerns, this paper explored attribute ordering effects in a benefit-risk DCE. Attribute ordering effects were explored in a large pilot DCE relating to the medical treatment of insomnia. Participants were randomised to one of three presentation orders: (1) benefits were presented before risks (BR); (2) risks were presented before benefits (RB); (3) all attributes were randomised (RN). For the RB and BR presentation orders, attributes were randomised within benefits and risks. Responses were assessed in three ways. First, variations in respondents' self-reported choice certainty were obtained. Second, variations in failure rates of stability and dominance tests were calculated. Third, a heteroscedastic error component model tested for differences in choice consistency across the three attribute orderings. The final analysis included 156 respondents (RN: 54; BR: 49; RB: 53). No differences were found between the presentation orders with respect to stated choice certainty, or the proportion of respondents failing either the dominance or stability test. However, deterministic attribute grouping was associated with higher choice consistency. To increase choice consistency, DCE attributes should be randomised within logical groups that may be further randomised to reduce the risk of ordering effects.

Out of Control - Privacy Calculus and the Effect of Perceived Control and Moral Considerations on the Usage of IoT Healthcare Devices.

People are increasingly applying Internet of Things (IoT) devices that help them improve their fitness and provide information about their state of health. Although the acceptance of healthcare devices is increasing throughout the general population, IoT gadgets are reliant on sensitive user data in order to provide full functioning and customized operation. More than in other areas of IoT, healthcare applications pose a challenge to individual privacy. In this study, we examine whether actual and perceived control of collected data affects the willingness to use an IoT healthcare device. We further measure actual behavior as a result of a risk-benefit trade-off within the framework of privacy calculus theory. Our experiment with N = 209 participants demonstrates that while actual control does not affect the willingness to use IoT in healthcare, people have a higher intention to use an IoT healthcare device when they perceive to be in control of their data. Furthermore, we found that, prior to their decision, individuals weigh perceived risks and anticipated benefits of information disclosure, which demonstrates the potential to apply the privacy calculus in the context of IoT healthcare technology. Finally, users’ moral considerations of IoT in healthcare are discussed.

The East Asian Paradox: An Updated Position Statement on the Challenges to the Current Antithrombotic Strategy in Patients with Cardiovascular Disease.

East Asian patients have reduced anti-ischemic benefits and increased bleeding risk during antithrombotic therapies compared with Caucasian patients. As potent P2Y12 receptor inhibitors (e.g., ticagrelor and prasugrel) and direct oral anticoagulants are commonly used in current daily practice, the unique risk-benefit trade-off in East Asians has been a topic of emerging interest. In this article, we propose updated evidence and future directions of antithrombotic treatment in East Asian patients.

BOIN12: Bayesian Optimal Interval Phase I/II Trial Design for Utility-Based Dose Finding in Immunotherapy and Targeted Therapies

For immunotherapy, such as checkpoint inhibitors and chimeric antigen receptor T-cell therapy, where the efficacy does not necessarily increase with the dose, the maximum tolerated dose may not be the optimal dose for treating patients. For these novel therapies, the objective of dose-finding trials is to identify the optimal biologic dose (OBD) that optimizes patients' risk-benefit trade-off. We propose a simple and flexible Bayesian optimal interval phase I/II (BOIN12) trial design to find the OBD that optimizes the risk-benefit trade-off. The BOIN12 design makes the decision of dose escalation and de-escalation by simultaneously taking account of efficacy and toxicity and adaptively allocates patients to the dose that optimizes the toxicity-efficacy trade-off. We performed simulation studies to evaluate the performance of the BOIN12 design. Compared with existing phase I/II dose-finding designs, the BOIN12 design is simpler to implement, has higher accuracy to identify the OBD, and allocates more patients to the OBD. One of the most appealing features of the BOIN12 design is that its adaptation rule can be pretabulated and included in the protocol. During the trial conduct, clinicians can simply look up the decision table to allocate patients to a dose without complicated computation. The BOIN12 design is simple to implement and yields desirable operating characteristics. It overcomes the computational and implementation complexity that plagues existing Bayesian phase I/II dose-finding designs and provides a useful design to optimize the dose of immunotherapy and targeted therapy. User-friendly software is freely available to facilitate the application of the BOIN12 design.

PO-0816: Organs at Risk in Re-Irradiation of Head and Neck Cancer: An Individual Risk-Benefit Tradeoff

PO-0816: Organs at Risk in Re-Irradiation of Head and Neck Cancer: An Individual Risk-Benefit Tradeoff