Use of Patient Preferences Data Regarding Multiple Risks to Inform Regulatory Decisions.

Background and Objectives. Risk-tolerance measures from patient-preference studies typically focus on individual adverse events. We recently introduced an approach that extends maximum acceptable risk (MAR) calculations to simultaneous maximum acceptable risk thresholds (SMART) for multiple treatment-related risks. We extend these methods to include the computation and display of confidence intervals and apply the approach to 3 published discrete-choice experiments to evaluate its utility to inform regulatory decisions. Methods. We generate MAR estimates and SMART curves and compare them with trial-based benefit-risk profiles of select treatments for depression, psoriasis, and thyroid cancer. Results. In the depression study, SMART curves with 70% to 95% confidence intervals portray which combinations of 2 adverse events would be considered acceptable. In the psoriasis example, the asymmetric confidence intervals for the SMART curve indicate that relying on independent MARs versus SMART curves when there are nonlinear preferences can lead to decisions that could expose patients to greater risks than they would accept. The thyroid cancer application shows an example in which the clinical incidence of each of 3 adverse events is lower than the single-event MARs for the expected treatment benefit, yet the collective risk profile surpasses acceptable levels when considered jointly. Limitations. Nonrandom sample of studies. Conclusions. When evaluating conventional MARs in which the observed incidences are near the estimated MARs or where preferences demonstrate diminishing marginal disutility of risk, conventional MAR estimates will overstate risk acceptance, which could lead to misinformed decisions, potentially placing patients at greater risk of adverse events than they would accept. Implications. The SMART method, herein extended to include confidence intervals, provides a reproducible, transparent evidence-based approach to enable decision makers to use data from discrete-choice experiments to account for multiple adverse events. Highlights: Estimates of maximum acceptable risk (MAR) for a defined treatment benefit can be useful to inform regulatory decisions; however, the conventional metric considers one adverse event at a time.This article applies a new approach known as SMART (simultaneous maximum acceptable risk thresholds) that accounts for multiple adverse events to 3 published discrete-choice experiments.Findings reveal that conventional MARs could lead decision makers to accept a treatment based on individual risks that would not be acceptable if multiple risks are considered simultaneously.

Patients' Willingness to Accept Mitral Valve Procedure-Associated Risks Varies Across Severity of Heart Failure Symptoms.

BACKGROUND: The Food and Drug Administration's Center for Drugs and Radiological Health issued Guidance in 2016 on generating patient preference information to aid evaluation of medical devices. Consistent with this guidance, we aimed to provide quantitative patient preference evidence on benefit-risk tradeoffs relevant to transcatheter mitral valve repair versus medical therapy for patients with heart failure and symptomatic secondary mitral regurgitation. METHODS: A discrete-choice experiment survey was designed to quantify patients' tolerance for 30-day mortality or serious bleeding risks to achieve improvements in physical functioning or reductions in heart failure hospitalizations. Two samples were recruited: an online US panel of individuals reporting a diagnosis of heart failure (n=244) and patients with heart failure treated at Duke University Health System (n=175). Random-effects logit regression was used to model treatment choices as a function of benefit and risk levels. RESULTS: Across both samples, approximately one-quarter (23.5%) consistently chose device profiles offering the higher level of physical functioning despite mortality and bleeding risks as high as 10%. Among respondents who at least once chose a device profile offering a lower level of functioning, improvement in physical functioning equivalent to a change from New York Heart Association class IV to III was ≈6 times more preferred than a change from New York Heart Association class III to II. Estimated discrete-choice experiment utility gains and losses revealed that respondents would accept up to a 9.7 percentage-point (95% CI, 8.2%-13.3%) increase in risk of 30-day mortality with devices that could improve functioning from New York Heart Association class IV to III, or up to 2.0% (95% CI, 1.4%-2.7%) for an improvement from New York Heart Association class III to II. CONCLUSIONS: Severity of heart failure symptoms influences patients' willingness to accept risks associated with mitral valve medical devices. These findings can inform shared decision-making discussions with patients who are being evaluated for transcatheter mitral valve repair.

Effective Partnering in Conducting Benefit-Risk Patient Preference Studies: Perspectives From a Patient Advocacy Organization, a Pharmaceutical Company, and Academic Stated-Preference Researchers.

BACKGROUND: Formal incorporation of patients' perspectives is becoming increasingly important in medical product development and decision making. This article shares practical advice regarding how patient advocacy organizations, the pharmaceutical industry, and academic experts in stated-preference research can effectively partner on benefit-risk patient preference studies. METHODS: The authors partnered on a benefit-risk patient preference study related to the treatment of psoriasis. The authors from Duke Clinical Research Institute also share their experiences in collaborating with numerous other organizations in conducting benefit-risk patient preference studies. RESULTS: Upon initiation of the study partnership with appropriate experts, training is important to ensure all collaborators have a common understanding of the methodology, what objectives stated-preference methods can support, and expectations for the project. To the extent possible, partners should align on and document relevant clinical and logistical details prior to study implementation. During study implementation, partners should use good communication practices and document and maintain a record of any changes to the original plan. Presentation of the study results should be tailored to the particular audience, with the appropriate partner leading the presentation based on its format and audience. CONCLUSION: Partners from patient advocacy organizations, the pharmaceutical industry, and academia can effectively collaborate on benefit-risk patient preference studies with sufficient planning and ongoing communication. This article is a call for action for other organizations to engage in sharing of experiences regarding effective partnering in quantifying patient preferences in medical product development.

What is clearance worth? Patients' stated risk tolerance for psoriasis treatments.

PURPOSE: The purpose of this study was to provide quantitative evidence of patients' tolerance for therapeutic risks associated with psoriasis treatments that could offer psoriasis improvements beyond the PASI 75 benchmark. MATERIALS AND METHODS: We used a discrete-choice experiment in which respondents chose between competing psoriasis treatments characterized by benefits (i.e. reduced plaque severity, reduced plaque area), risks (i.e. 10-year risk of tuberculosis, 10-year risk of death from infection), and treatment regimen. We analyzed choice data using random-parameters logit models for psoriasis affecting the body, face, or hands. RESULTS: Of 927 eligible members of the National Psoriasis Foundation who completed the survey, 28% were unwilling to accept any greater risk of treatment-related infection mortality. Among the remaining 72%, respondents were willing to accept higher risks of infection-related mortality associated with treatment to completely remove plaques covering only 1% of the body, compared to reducing lesions from 10 to 1% of the affected area. This finding was more pronounced for lesions on the face. CONCLUSIONS: Most patients placed greater value on eliminating even very small plaques compared to avoiding treatment-related risks. The perceived importance of complete versus near-complete clearance was stronger than previously documented.

Inflammatory Bowel Disease Patients' Willingness to Accept Medication Risk to Avoid Future Disease Relapse.

OBJECTIVES: Biomarkers, endoscopy and imaging tests can identify patients at increased risk for early recurrence of symptomatic inflammatory bowel disease (IBD). However, patients may be unwilling to accept additional medical therapy risks related to therapy escalation to avoid a future disease relapse. We sought to quantify IBD patients' willingness to accept medication risk to avoid future disease relapse. METHODS: We conducted a discrete-choice experiment among 202 patients with IBD who were offered choices of therapies with varying risks of lymphoma and infection, and varying time to next IBD relapse. Random parameters logit was used to estimate patients' willingness to accept tradeoffs among treatment features in selecting medication therapy to avoid future disease relapse. RESULTS: To avoid a disease relapse over the next 5 years, IBD patients were willing to accept an average of a 28% chance of a serious infection; and an average of 1.8% chance of developing lymphoma. These results did not significantly change when patients were offered 10 years until their next disease relapse, but were lower (11 and 0.7%, respectively) when offered 1.5 years until the next disease relapse. Patients with active disease symptoms were significantly less willing to accept medication risk for time in remission. CONCLUSIONS: IBD patients are willing to accept high levels of lymphoma and serious infection risk to maintain disease remission. These preferences are congruent with the treatment paradigms emphasizing mucosal healing and early aggressive therapy and highlight patients' strong preferences for therapies resulting in durable remission of at least 5 years.

Patient preferences for surgical versus medical therapy for ulcerative colitis.

BACKGROUND: Therapy options for mesalamine-refractory ulcerative colitis (UC) include immunosuppressive medications or surgery. Chronic immunosuppressive therapy increases risks of infection and cancer, whereas surgery produces a permanent change in bowel function. We sought to quantify the willingness of patients with UC to accept the risks of chronic immunosuppression to avoid colectomy. METHODS: We conducted a state-of-the-art discrete-choice experiment among 293 patients with UC who were offered a choice of medication or surgical treatments with different features. Random parameters logit was used to estimate patients' willingness to accept trade-offs among treatment features in selecting surgery versus medical treatment. RESULTS: A desire to avoid surgery and the surgery type (ostomy versus J-pouch) influenced patients' choices more than a specified range of 10-year mortality risks from lymphoma or infection, or disease activity (mild versus remission). To avoid an ostomy, patients were willing to accept a >5% 10-year risk of dying from lymphoma or infection from medical therapy, regardless of medication efficacy. However, data on patients' stated choice indicated perceived equivalence between J-pouch surgery and incompletely effective medical therapy. Patient characteristics and disease history influenced patients' preferences regarding surgery versus medical therapy. CONCLUSIONS: Patients with UC are willing to accept relatively high risks of fatal complications from medical therapy to avoid a permanent ostomy and to achieve durable clinical remission. However, patients view J-pouch surgery, but not permanent ileostomy, as an acceptable therapy for refractory UC in which medical therapy is unable to induce a durable remission.

Quantifying benefit-risk preferences for medical interventions: an overview of a growing empirical literature.

Decisions regarding the development, regulation, sale, and utilization of pharmaceutical and medical interventions require an evaluation of the balance between benefits and risks. Such evaluations are subject to two fundamental challenges-measuring the clinical effectiveness and harms associated with the treatment, and determining the relative importance of these different types of outcomes. In some ways, determining the willingness to accept treatment-related risks in exchange for treatment benefits is the greater challenge because it involves the individual subjective judgments of many decision makers, and these decision makers may draw different conclusions about the optimal balance between benefits and risks. In response to increasing demand for benefit-risk evaluations, researchers have applied a variety of existing welfare-theoretic preference methods for quantifying the tradeoffs decision makers are willing to accept among expected clinical benefits and risks. The methods used to elicit benefit-risk preferences have evolved from different theoretical backgrounds. To provide some structure to the literature that accommodates the range of approaches, we begin by describing a welfare-theoretic conceptual framework underlying the measurement of benefit-risk preferences in pharmaceutical and medical treatment decisions. We then review the major benefit-risk preference-elicitation methods in the empirical literature and provide a brief overview of the studies using each of these methods. The benefit-risk preference methods described in this overview fall into two broad categories: direct-elicitation methods and conjoint analysis. Rating scales (6 studies), threshold techniques (9 studies), and standard gamble (2 studies) are examples of direct elicitation methods. Conjoint analysis studies are categorized by the question format used in the study, including ranking (1 study), graded pairs (1 study), and discrete choice (21 studies). The number of studies reviewed here demonstrates that this body of research already is substantial, and it appears that the number of benefit-risk preference studies in the literature will continue to increase. In addition, benefit-risk preference-elicitation methods have been applied to a variety of healthcare decisions and medical interventions, including pharmaceuticals, medical devices, surgical and medical procedures, and diagnostics, as well as resource-allocation decisions such as facility placement. While preference-elicitation approaches may differ across studies, all of the studies described in this review can be used to provide quantitative measures of the tradeoffs patients and other decision makers are willing to make between benefits and risks of medical interventions. Eliciting and quantifying the preferences of decision makers allows for a formal, evidence-based consideration of decision-makers' values that currently is lacking in regulatory decision making. Future research in this area should focus on two primary issues-developing best-practice standards for preference-elicitation studies and developing methods for combining stated preferences and clinical data in a manner that is both understandable and useful to regulatory agencies.