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.

Preferences and Priorities for Relapsed Multiple Myeloma Treatments Among Patients and Caregivers in the United States.

Introduction/Background: This study aimed to describe patient and caregiver preferences for treatments of relapsed or refractory multiple myeloma (MM). Materials and Methods: A survey including discrete-choice experiment (DCE) and best-worst scaling (BWS) exercises was conducted among US patients with relapsed or refractory MM and their caregivers. The DCE included six attributes with varying levels including progression-free survival (PFS), toxicity, and mode and frequency of administration. In addition, the impact of treatment cost was assessed using a fixed-choice question. The BWS exercise included 18 items (modes and frequency of administration, additional treatment convenience, and toxicity items). The survey was administered online to patients recruited from the Multiple Myeloma Research Foundation CoMMpass study (NCT01454297). Results: The final samples consisted of 94 patients and 32 caregivers. Avoiding severe nerve damage was most important to patients, followed by longer PFS. Caregivers considered PFS to be the most important attribute. We estimate that a third or more of patients were cost-sensitive, meaning their treatment preference was altered based on cost implications. Caregivers were not cost-sensitive. The three most bothersome treatment features in the BWS exercise were risk of kidney failure, lowering white blood cell counts, and weakening the immune system. Conclusion: Patients with relapsed or refractory MM and their caregivers consider many factors including efficacy, toxicity, mode/frequency of administration, and cost in their decisions regarding treatment options. The study provides a basis for future Research on patient and caregiver treatment preferences, which could be incorporated into shared decision-making with physicians.

Exploring determinants of psoriasis patients' treatment choices: a discrete-choice experiment study in the United States and Germany.

BACKGROUND: Biologic psoriasis treatments are differentiated by efficacy, side effects, and other attributes. OBJECTIVE: Determine attributes of biologic psoriasis treatments that drive patients' treatment choices. METHODS: Respondents (USA: n = 300; Germany: n = 300) with moderate-to-severe psoriasis completed a discrete-choice-experiment survey, choosing between hypothetical treatments characterized by attributes with varying levels: chance of clear skin after 1 year, number of first-year treatments, first-year risks of mild-to-moderate injection site reaction (ISR) and serious infection, and years of proven efficacy/safety. RESULTS: U.S. respondents most valued clear skin (conditional relative importance, 1.88; p < .05). While other attributes were of generally equivalent importance, ISR risk outweighed serious-infection risk (1.06 vs. 0.70; p < .05). German respondents placed greatest importance on ISR risk (1.61; p < .05) and clear skin (1.49; p < .05). LIMITATIONS: Respondents evaluated hypothetical treatments and were recruited from web panels. CONCLUSIONS: Clear skin and ISR risk are stronger drivers of treatment choice than injection frequency and infection risk.

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.

Preferences for herpes zoster vaccination among adults aged 50 years and older in the United States: results from a discrete choice experiment.

BACKGROUND: Most adults, and disproportionately fewer African-Americans, have not received herpes zoster (HZ) vaccination despite current recommendations. This study (GSK study identifiers: 208677/HO-17-18066) assessed HZ vaccination preferences among adults aged ≥ 50 years. RESEARCH DESIGN AND METHODS: In this discrete choice experiment, respondents chose among a 'no vaccine' option and two HZ vaccine profiles, characterized by seven attributes, in a series of choice questions. Random-parameters logit results were used to predict likely vaccine uptake. Subgroup and latent class analysis of African-American's preferences were performed. RESULTS: The preference weight for choosing HZ vaccines over no vaccine was statistically significant among the 1,454 respondents (71.9% whites; 25.2% African-Americans). Out-of-pocket (OOP) cost and vaccine effectiveness (VE) were the most important attributes. The African-American and the non-African-American subgroups had statistically significant differences in preferences (χ2 = 59.91, p < 0.001), mainly driven by OOP cost and VE. Latent class analysis identified three groups of African-American respondents with systematically different preferences; two comprised likely-vaccinators, with one being more cost sensitive at lower price thresholds, and one likely non-vaccinators. CONCLUSIONS: For all respondents, HZ vaccine choices were most sensitive to total OOP cost, followed by VE.

PLAIN LANGUAGE SUMMARYWhat is the context?Herpes zoster, or shingles, is a viral disease characterized by a painful, localized skin rash. It affects approximately 32% of US citizens at least once in their lifetime.The risk of contracting shingles increases with age.Most American adults over 50 years have not received the shingles vaccine, and vaccination rates are especially low for African-Americans. What is new?This is the first study to evaluate what drives shingles vaccination decisions among US adults ≥ 50 years of age. We also assessed the differences between African-American and non-African-American adults, and inside the African-American group.In this choice experiment, 1,454 people ≥ 50 years completed a survey of 8 choice questions, as well as questions on their previous experiences with vaccines, socioeconomic, and demographic characteristics. Seven factors were evaluated.We found that American adults preferred to get vaccinated, and the most influential factors were costs and vaccine effectiveness while location of vaccination was the least important. There were differences in preferences between African-American and non-African-American adults, mainly driven by costs and vaccine effectiveness. 3 different groups of African-American adults with systematically different preferences could be identified; two were likely to vaccinate, with one being more cost sensitive at lower price thresholds, and the third was unlikely to vaccinate.What is the impact?Decisions on shingles vaccination appear to be mostly driven by costs, which could be a barrier to those who do not have appropriate insurance, especially among some African-Americans.However, healthcare professionals should continue to educate patients on other vaccine characteristics, as they also influence vaccination decisions.

Patients' and caregivers' maximum acceptable risk of death for non-curative gene therapy to treat Duchenne muscular dystrophy.

BACKGROUND: Gene therapy offers an etiologically targeted treatment for genetic disorders. Little is known about the acceptance of mortality risk among patients with progressive, fatal conditions. We assessed patients' and caregivers' maximum acceptable risk (MAR) of mortality for gene therapy when used to treat Duchenne muscular dystrophy (DMD). METHODS: The threshold technique was used to assess tolerance for mortality risks using a hypothetical vignette. Gene therapy was described as non-curative and resulting in a slowing of progression and with a 10-year benefit duration. MAR was analyzed using interval regression for gene therapy initiated "now"; in the last year of walking well; in the last year of being able to bring arms to mouth; and in newborns (for caregivers only). RESULTS: Two hundred eighty-five caregivers and 35 patients reported the greatest MAR for gene therapy initiated in last year of being able to lift arms (mean MAR 6.3%), followed by last year of walking well (mean MAR 4.4%), when used "now" (mean MAR 3.5%), and when used in the newborn period (mean MAR 2.1%, caregivers only). About 35% would accept ≥200/2000 risk in the last year of being able to lift arms. Non-ambulatory status predicted accepting 1.8 additional points in MAR "now" compared with ambulatory status (p = 0.010). Respondent type (caregiver or patient) did not predict MAR. CONCLUSION: In this first quantitative study to assess MAR associated with first-generation DMD gene therapy, we find relatively high tolerance for mortality risk in response to a non-curative treatment scenario. Risk tolerance increased with disease progression. Patients and caregivers did not have significantly different MAR. These results have implications for protocol development and shared decision making.

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.

Patient and physician preferences for multiple sclerosis treatments in Germany: A discrete-choice experiment study.

OBJECTIVE: To assess heterogeneity in patient and physician preferences for multiple sclerosis treatment features and outcomes via a discrete-choice experiment. METHOD: Patients with self-reported multiple sclerosis and treating physicians participated in an online discrete-choice experiment. Patients, each considering a better or worse reference condition, and physicians, each considering two patient profiles, chose between hypothetical treatment profiles defined by seven attributes with varying levels: years until disability progression, number of relapses in the decade, mode of administration, dosing frequency, and risks of mild, moderate, and severe side effects. Latent class analysis was used to measure respondent preferences and identify potential subgroups with distinct preferences. RESULTS: Distinct treatment preferences emerged among subgroups of patients (n = 301) and physicians (n = 308). Patients in class 1 (43% of sample) were most concerned about side effects; chief concerns of class 2 patients (57%) were delaying disability progression and avoiding severe side-effect risks. The most important attributes for physicians (by class) were delaying disability (class 1, 45%), avoiding severe side-effect risks and (class 2, 33%), and avoiding all side-effect risks (class 3, 22%). CONCLUSION: Patients and physicians have diverse preferences for multiple sclerosis treatments, reflecting heterogeneity in the disease course and available therapies and the need for shared decision making.

Efficacy is Not Everything: Eliciting Women's Preferences for a Vaginal HIV Prevention Product Using a Discrete-Choice Experiment.

As new female-initiated HIV prevention products enter development, it is crucial to incorporate women's preferences to ensure products will be desired, accepted, and used. A discrete-choice experiment was designed to assess the relative importance of six attributes to stated choice of a vaginally delivered HIV prevention product. Sexually active women in South Africa and Zimbabwe aged 18-30 were recruited from two samples: product-experienced women from a randomized trial of four vaginal placebo forms and product-naïve community members. In a tablet-administered survey, 395 women chose between two hypothetical products over eight choice sets. Efficacy was the most important, but there were identifiable preferences among other attributes. Women preferred a product that also prevented pregnancy and caused some wetness (p < 0.001). They disliked a daily-use product (p = 0.002) and insertion by finger (p = 0.002). Although efficacy drove preference, wetness, pregnancy prevention, and dosing regimen were influential to stated choice of a product, and women were willing to trade some level of efficacy to have other more desired attributes.

From drug-delivery device to disease management tool: a study of preferences for enhanced features in next-generation self-injection devices.

PURPOSE: To quantify rheumatology patient preferences and willingness to pay (WTP) for features differentiating enhanced from standard self-injection devices and to investigate differences among subgroups. PATIENTS AND METHODS: Patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) were recruited in the UK. A discrete-choice experiment was used to elicit preferences; respondents were presented with 10 choices between 3 different devices: a free standard disposable device, and 2 hypothetical reusable devices characterized by presence/absence of skin sensor, injection speed control, on-screen instructions, injection reminders, electronic log, and large grip. Every hypothetical device included a cost component to assess WTP for each enhanced feature. A random-parameters logit model was used to estimate preference weights and WTP. RESULTS: Data were collected from 323 respondents by electronic survey (15/11/2017-15/02/2018; RA: 108; PsA: 103; axSpA: 112). On average, the skin sensor was the most preferred feature (£30), followed by injection speed control, injection reminders, electronic log (~£20 each), on-screen instructions (~£12), and a device with a small, rather than large grip (~£7). Similar preferences for attributes were observed across condition subgroups except for grip size: axSpA patients preferred small grip (~£27); PsA patients preferred large grip (~£19). Overall, respondents preferred reusable devices with all enhanced features (WTP value: £85) over the standard device. RA patients exhibited a higher WTP (£145) than PsA (£102) or axSpA (£62) for the same enhanced device. CONCLUSION: Patients positively valued reusable self-injection devices with enhanced features, which may improve patient experience, potentially improving treatment adherence, clinical, and economic outcomes.

Priorities when deciding on participation in early-phase gene therapy trials for Duchenne muscular dystrophy: a best-worst scaling experiment in caregivers and adult patients.

PURPOSE: Several gene therapy trials for Duchenne muscular dystrophy initiated in 2018. Trial decision making is complicated by non-curative, time-limited benefits; the progressive, fatal course; and high unmet needs. Here, caregivers and patients prioritize factors influencing decision making regarding participation in early-phase gene therapy trials. METHODS: We conducted a best-worst scaling experiment among U.S. caregivers and adults with Duchenne (N = 274). Participants completed 11 choice sets, choosing features they cared about most and least when deciding whether to participate in a hypothetical gene therapy trial. We analyzed the data using sequential conditional logistic regression. RESULTS: Participants prioritized improved muscle function in trial decision making. Concerns about participation limiting later use of gene transfer and editing were also important, as were improved lung and heart function. Low risk of death fell near the middle. Participants cared least about muscle biopsies and potential for randomization to placebo. Adults with Duchenne and caregivers of non-ambulatory children significantly prioritized improved lung function compared to caregivers of ambulatory children. CONCLUSION: Our data demonstrate prioritization of anticipated benefits and opportunity costs relative to potential harms and procedures in gene therapy trial decision making. Such data inform protocol development, education and advocacy efforts, and informed consent.

Administration options for pegfilgrastim prophylaxis: patient and physician preferences from a cross-sectional survey.

OBJECTIVE: Although clinical guidelines recommend administration of pegfilgrastim 1-4 days after a myelosuppressive chemotherapy cycle to decrease the incidence of febrile neutropenia (FN), some physicians administer pegfilgrastim on the same day as chemotherapy administration. A novel on-body injector (OBI) that automatically delivers pegfilgrastim the day after chemotherapy is also available. Our objective was to estimate patient and physician preferences among the pegfilgrastim administration options. METHODS: We conducted a cross-sectional survey of patients receiving pegfilgrastim and physicians prescribing pegfilgrastim. Respondents' preferences for pegfilgrastim administration options were elicited using direct elicitation; the relative importance of features associated with the options was estimated in a point-allocation exercise. Physicians considered two hypothetical patient profiles when completing the exercises. RESULTS: The samples included 200 patients and 200 physicians. Patients generally preferred the administration option with which they had experience. Among patients, 48.5% with previous in-clinic injections 24 hours after chemotherapy preferred this option; 56.8% with previous OBI administration preferred this option. For a clinically compromised patient, 37.5% of physicians preferred an in-clinic injection option; 49.5% preferred the OBI. For a less compromised patient, 55.5% preferred an in-clinic injection option; 28.0% preferred the OBI. Avoiding the need to return to the clinic was chosen most often as the most important treatment feature for patients and physicians. CONCLUSIONS: Patients and physicians identified that returning clinic visits for pegfilgrastim administration may be burdensome. A potential solution to mitigate this burden is the OBI, which allows adherence to the labeled use of pegfilgrastim without return visits to the clinic.