Quantitative Benefit-Risk Assessment in Medical Product Decision Making: A Good Practices Report of an ISPOR Task Force.

Benefit-risk assessment is commonly conducted by drug and medical device developers and regulators, to evaluate and communicate issues around benefit-risk balance of medical products. Quantitative benefit-risk assessment (qBRA) is a set of techniques that incorporate explicit outcome weighting within a formal analysis to evaluate the benefit-risk balance. This report describes emerging good practices for the 5 main steps of developing qBRAs based on the multicriteria decision analysis process. First, research question formulation needs to identify the needs of decision makers and requirements for preference data and specify the role of external experts. Second, the formal analysis model should be developed by selecting benefit and safety endpoints while eliminating double counting and considering attribute value dependence. Third, preference elicitation method needs to be chosen, attributes framed appropriately within the elicitation instrument, and quality of the data should be evaluated. Fourth, analysis may need to normalize the preference weights, base-case and sensitivity analyses should be conducted, and the effect of preference heterogeneity analyzed. Finally, results should be communicated efficiently to decision makers and other stakeholders. In addition to detailed recommendations, we provide a checklist for reporting qBRAs developed through a Delphi process conducted with 34 experts.

Use of Bayesian decision analysis to maximize value in patient-centered randomized clinical trials in Parkinson's disease.

A fixed one-sided significance level of 5% is commonly used to interpret the statistical significance of randomized clinical trial (RCT) outcomes. While it is necessary to reduce the false positive rate, the threshold used could be chosen quantitatively and transparently to specifically reflect patient preferences regarding benefit-risk tradeoffs as well as other considerations. How can patient preferences be explicitly incorporated into RCTs in Parkinson's disease (PD), and what is the impact on statistical thresholds for device approval? In this analysis, we apply Bayesian decision analysis (BDA) to PD patient preference scores elicited from survey data. BDA allows us to choose a sample size (n) and significance level (α) that maximizes the overall expected value to patients of a balanced two-arm fixed-sample RCT, where the expected value is computed under both null and alternative hypotheses. For PD patients who had previously received deep brain stimulation (DBS) treatment, the BDA-optimal significance levels fell between 4.0% and 10.0%, similar to or greater than the traditional value of 5%. Conversely, for patients who had never received DBS, the optimal significance level ranged from 0.2% to 4.4%. In both of these populations, the optimal significance level increased with the severity of the patients' cognitive and motor function symptoms. By explicitly incorporating patient preferences into clinical trial designs and the regulatory decision-making process, BDA provides a quantitative and transparent approach to combine clinical and statistical significance. For PD patients who have never received DBS treatment, a 5% significance threshold may not be conservative enough to reflect their risk-aversion level. However, this study shows that patients who previously received DBS treatment present a higher tolerance to accept therapeutic risks in exchange for improved efficacy which is reflected in a higher statistical threshold.

Patients' Preferences for Adjunctive Parkinson's Disease Treatments: A Discrete-Choice Experiment.

Background: Several adjunctive medications are available to reduce OFF time between levodopa/carbidopa (LD/CD) doses for people with Parkinson's disease (PD). Objective: To explore how individuals with PD balance benefits and burdens when considering adjunctive medications. Methods: US adults (30-83 years) with self-reported PD, currently treated with LD/CD, who experienced OFF episodes were recruited through the Fox Insight study to complete a discrete-choice experiment survey. Respondents selected among experimentally designed profiles for hypothetical adjunctive PD treatments that varied in efficacy (additional ON time), potential adverse effects (troublesome dyskinesia, risk of diarrhea, risk of change in bodily fluid color), and dosing frequency or the option "No additional medicine". Data were analyzed with random-parameters logit models. Results: Respondents (N=480) would require ≥60 additional minutes of daily ON time to accept either a 40% risk of change in bodily fluid color or 10 additional minutes with troublesome dyskinesia daily. Respondents would require 40 additional minutes of daily ON time to accept a 10% risk of diarrhea and 22 additional minutes of daily ON time to switch from 1 additional pill each day to 1 pill with each LD/CD dose. On average, respondents preferred adjunctive PD medication over no additional medication. Results predicted that 59.1% of respondents would select a hypothetical treatment profile similar to opicapone, followed by no additional medication (27.5%) and a hypothetical treatment profile similar to entacapone (13.4%). Limitations: The data collected were based on responses to hypothetical choice profiles in the survey questions. The attributes and levels selected for this study were intended to reflect the characteristics of opicapone and entacapone; attributes associated with other adjunctive therapies were not evaluated. Conclusion: Patients with PD expressed interest in adjunctive treatment to increase ON time and would accept reduced ON time to avoid adverse effects.

Including People with Parkinson's Disease in Clinical Study Design and Execution: A Call to Action.

The proactive inclusion of patients in the design and execution of clinical studies has been an emerging focus for decades. Such participatory research helps to design studies better, by addressing relevant research questions and defining outcomes that matter to patients. Yet, much remains to be learned about the best methods and exact impacts of patient engagement in research in general, and more specifically, about the specific challenges that come with Parkinson's disease. Here we present the lived experiences of patient researchers living with Parkinson's disease, as a motivation for the value of their perspectives in research and as a call to action for empirical research on how to successfully include patient researchers.

Patient-Centered Identification of Meaningful Regulatory Endpoints for Medical Devices to Treat Parkinson's Disease.

Introduction. A growing literature has developed on identifying outcomes that matter to patients. This study demonstrates an approach involving patient and regulatory perspectives to identify outcomes that are meaningful in the context of medical devices for Parkinson's disease (PD). Methods. A systematic process was used for specifying relevant regulatory endpoints by synthesizing inputs of various sources and stakeholders. First, a literature review was conducted to identify important benefits, risks, and other considerations for medical devices to treat PD; patient discussion groups (n = 6) were conducted to refine the list of considerations, followed by a survey (n = 29) to prioritize them; and patient and Food and Drug Administration (FDA) reviewers informed specification of the final endpoints. Two FDA clinicians gave clinical and regulatory perspectives at each step. Results. Movement symptoms were ranked as most important (ranked 1 or 2 by 72% of participants) and psychological and cognitive symptoms as the next most important (ranked 1 or 2 by 52% of participants). Within movement symptoms, falls, impaired movement, bradykinesia, resting tremor, stiffness, and rigidity were ranked highly. Overall, nine attributes were identified and prioritized as patient-centric for use in clinical trial design and quantitative patient preference studies. These attributes were benefits and risks related to therapeutics for PD as well as other considerations, including time until a medical device is available for patient use. Discussion. This prospective approach identified meaningful and relevant benefits, risks, and other considerations that may be used for clinical trial design and quantitative patient preference studies. Although PD was the focus of this study, the approach can be used to study patient perspectives about other disease or treatment areas.

Parkinson's Patients' Tolerance for Risk and Willingness to Wait for Potential Benefits of Novel Neurostimulation Devices: A Patient-Centered Threshold Technique Study.

Background. Parkinson's disease (PD) is neurodegenerative, causing motor, cognitive, psychological, somatic, and autonomic symptoms. Understanding PD patients' preferences for novel neurostimulation devices may help ensure that devices are delivered in a timely manner with the appropriate level of evidence. Our objective was to elicit preferences and willingness-to-wait for novel neurostimulation devices among PD patients to inform a model of optimal trial design. Methods. We developed and administered a survey to PD patients to quantify the maximum levels of risks that patients would accept to achieve potential benefits of a neurostimulation device. Threshold technique was used to quantify patients' risk thresholds for new or worsening depression or anxiety, brain bleed, or death in exchange for improvements in "on-time," motor symptoms, pain, cognition, and pill burden. The survey elicited patients' willingness to wait to receive treatment benefit. Patients were recruited through Fox Insight, an online PD observational study. Results. A total of 2740 patients were included and a majority were White (94.6%) and had a 4-year college degree (69.8%). Risk thresholds increased as benefits increased. Threshold for depression or anxiety was substantially higher than threshold for brain bleed or death. Patient age, ambulation, and prior neurostimulation experience influenced risk tolerance. Patients were willing to wait an average of 4 to 13 years for devices that provide different levels of benefit. Conclusions. PD patients are willing to accept substantial risks to improve symptoms. Preferences are heterogeneous and depend on treatment benefit and patient characteristics. The results of this study may be useful in informing review of device applications and other regulatory decisions and will be input into a model of optimal trial design for neurostimulation devices.

Successful use of bivalirudin for combined carotid endarterectomy and coronary revascularization with the use of cardiopulmonary bypass in a patient with an elevated heparin-platelet factor 4 antibody titer.

We report a combined carotid endarterectomy and coronary revascularization surgery with cardiopulmonary bypass using bivalirudin for systemic anticoagulation in a patient with a positive titer for the heparin-platelet factor 4 antibody. The patient experienced procedural success for both the carotid and coronary surgeries. Increased blood and blood product transfusion was required postoperatively.

Charting the waves of prevention: two steps forward, one step back.

BACKGROUND: Over the past 30 years, the political response to child maltreatment and its prevention in the US has experienced periods of frantic activity, often followed by long periods of benign neglect. In reflecting on this history, Dick Krugman has referred to this uneven level of attention as a series of "waves" in which apparent progress is often minimized by an inability to sustain political commitment to a given reform or course of action. To an extent, this pattern reflects deep differences among child welfare advocates, researchers, and practitioners on how best to proceed. While most everyone agrees that "it shouldn't hurt to be a child," how to prevent this hurt and at what cost is less clear. METHOD: To address this dilemma, prevention advocates, researchers, and practitioners have struggled with a variety of conceptual frameworks and programmatic reforms. This article summarizes the relative gains and limitation of three such efforts and outlines the lessons these efforts offer those formulating future prevention policies and programs. RESULTS: Specifically, the authors suggest that future prevention efforts will need to take care in avoiding some of the most common mistakes experienced by earlier efforts. CONCLUSIONS: These mistakes or pitfalls include oversimplifying the problem of child abuse; overstating preventions' potential and appropriate target populations; failing to establish a significant partnership with child protective services; compromising depth or quality in an effort to maximize breadth or coverage; and failing to fully engage the public.

Morbid obesity is an independent determinant of death among surgical critically ill patients.

OBJECTIVE: To determine whether extreme obesity (morbid obesity; body mass index > or =40 kg/m(2)) is an independent risk factor for death among critically ill patients; this objective is most salient in the subset of patients who sustain a prolonged intensive care unit stay during which the burdens of care imposed by obesity and its consequences would become most apparent. DESIGN: Cohort analysis of data from the Project Impact database used to catalog admissions and outcomes to a surgical intensive care unit, with predetermined end point analyses of outcomes. SETTING: Surgical intensive care unit serving Tufts-New England Medical Center, a tertiary care and university medical center in Boston. PATIENTS: All critically ill surgical patients admitted to the Tufts-New England Medical Center surgical intensive care unit from January 1998 to March 2001. INTERVENTIONS: Intensive care unit and hospital mortality and lengths of stay were compared with body mass index subclassified into five groups: underweight, normal weight, overweight, obese, and extremely obese. Data were examined for all admissions during the study period and for a predetermined subgroup with a prolonged intensive care unit stay (> or =4 days). MEASUREMENTS AND MAIN RESULTS: The prevalence of obesity in the surgical intensive care unit was 26.7%; extreme obesity was observed in 6.8%. In the full cohort of patients (n = 1373), median length of stay was short (2 days) and there were no differences in mortality in patients among any of the body mass index classes. In the subgroup of prolonged stay patients (n = 406), intensive care unit and hospital mortality rates were significantly increased in extremely obese patients compared with all other patients (intensive care unit, 33.3% vs. 12.3%, p = .009; hospital, 33.3% vs. 16%, p = .045). Multivariate analysis showed that extreme obesity was an independent predictor of death in surgical critically ill patients with prolonged intensive care unit stay after controlling for age, gender, and severity of illness. The odds of death increased 7.4 times in patients with morbid obesity. CONCLUSIONS: Morbid obesity (body mass index > or =40 kg/m(2)) is an independent risk factor for death in surgical patients with catastrophic illness requiring prolonged intensive care. The prevalence of obesity is growing, both in the intensive care unit and in the general population. The increased risk of complications and death in this population mandates that we adapt customized processes of care to specifically address this unique and very challenging subset of patients.

How reliable is the Bispectral Index in critically ill patients? A prospective, comparative, single-blinded observer study.

OBJECTIVE: To establish a correlation between a reliable subjective measure, the Sedation-Agitation Scale (SAS), and an objective tool, the Bispectral Index (BIS), for monitoring critically ill patients with a decreased level of consciousness. DESIGN: Prospective, comparative, single-blinded observer study. SETTING: Surgical and medical intensive care units of the Tufts-New England Medical Center, a 349-bed tertiary care, academic medical center. PATIENTS: A convenience sample of 20 adult, critically ill patients with a decreased level of consciousness. The data from one patient were excluded because the patient did not meet inclusion criteria. MEASUREMENTS AND MAIN RESULTS: Patients were prospectively evaluated by a blinded observer using the SAS to subjectively determine their level of consciousness. Sedation levels varied from unarousable (SAS score of 1), to very sedated (SAS score of 2), to mildly sedated (SAS score of 3). Simultaneously, the patients were continuously monitored for 4-6 hrs with the BIS device. There was wide variability in BIS scores for any given level of consciousness as compared with the SAS. Unarousable patients had BIS scores ranging from 23 to 97, with a median score of 50 and an interquartile range of 24. Very sedated patients had BIS scores ranging from 35 to 98, with a median score of 68 and an interquartile range of 36. Mildly sedated patients had BIS scores ranging from 67 to 91, with a median score of 76 and an interquartile range of 8. Overall, there was a less than satisfactory correlation between BIS values and SAS scores (r =.36, p <.001). However, the correlation improved with subgroup analysis when BIS values associated with excessive muscle movement were excluded (r =.50, p <.001). CONCLUSIONS: The correlation between SAS and BIS scores was suboptimal and inconsistent in a heterogeneous group of critically ill patients. The generation of BIS hardware and software, studied herein, is neither reliable nor valid for routinely monitoring the level of consciousness in the critically ill patient. Excessive muscle movement by the patient is an important and spurious influence on BIS values and seriously undermines BIS reliability.