Risk willingness in multiple system atrophy and Parkinson's disease understanding patient preferences

Abstract

Disease-modifying therapeutics in the α-synucleinopathies multiple system atrophy (MSA) and Parkinson's Disease (PD) are in early phases of clinical testing. Involving patients' preferences including therapy-associated risk willingness in initial stages of therapy development has been increasingly pursued in regulatory approval processes. In our study with 49 MSA and 38 PD patients, therapy-associated risk willingness was quantified using validated standard gamble scenarios for varying severities of potential drug or surgical side effects. Demonstrating a non-gaussian distribution, risk willingness varied markedly within, and between groups. MSA patients accepted a median 1% risk [interquartile range: 0.001-25%] of sudden death for a 99% [interquartile range: 99.999-75%] chance of cure, while PD patients reported a median 0.055% risk [interquartile range: 0.001-5%]. Contrary to our hypothesis, a considerable proportion of MSA patients, despite their substantially impaired quality of life, were not willing to accept increased therapy-associated risks. Satisfaction with life situation, emotional, and nonmotor disease burden were associated with MSA patients' risk willingness in contrast to PD patients, for whom age, and disease duration were associated factors. An individual approach towards MSA and PD patients is crucial as direct inference from disease (stage) to therapy-associated risk willingness is not feasible. Such studies may be considered by regulatory agencies in their approval processes assisting with the weighting of safety aspects in a patient-centric manner. A systematic quantitative assessment of patients' risk willingness and associated features may assist physicians in conducting individual consultations with patients who have MSA or PD by facilitating communication of risks and benefits of a treatment option.

Fig. 1. Patients’ attitudes towards drug-related risks.

Patients were presented with a priori-defined lists of possible side effects of drugs that they would suffer from permanently. They were asked to tick the three cognitive and emotional as well as the three physical side effects that they considered to be most severe (a) or most bearable (b). Percentages of chosen side effects are displayed.

Fig. 2. Patients’ willingness to take risks regarding severity of drug side effects.

Individuals’ answers to standard gamble (SG) scenarios are shown. Each dot represents one patient and his or her maximum accepted risk for the respective scenario. Horizontal lines show median and interquartile ranges. No significant group differences between MSA and PD regarding the 3 SG could be detected (Wilcoxon-tests). a Maximum accepted risk of most bearable drug side effects. Side effects such as tiredness and listlessness were most commonly reported as bearable. Tiredness was noted by 86% of MSA patients and 82% of PD patients, while listlessness was reported by 71% of MSA and 63% of PD patients. Other minor side effects like loss of taste were considered bearable more frequently by PD patients (61%) compared to MSA patients (33%). b Maximum accepted risk of most severe drug side effects. This category includes both cognitive and emotional as well as physical drug side effects that significantly affect quality of life. Cognitive and emotional side effects deemed most severe included memory loss (MSA: 80%, PD: 66%), personality changes (MSA: 50%, PD: 58%), and hallucinations or aggressiveness. Physical side effects such as visual disturbances and nausea/vomiting were commonly rated severe by both groups (MSA: 45%, PD: 47%). PD patients particularly noted sleep disturbances as severe (40%) compared to MSA patients (12%). c Maximum accepted risk of fatal adverse reaction. Represents the ultimate risk, which is death.

Fig. 3. Variable importance of clinical and psychosocial features in association with risk decision making for investigational drugs.

In (a) the x-axis displays the conditional variable importance obtained from random forest regression analyses conducted separately for MSA (red) and PD (blue) patients. Shown are point estimates and 95% confidence intervals obtained from 200 runs. The variable with the highest importance is assigned a value of 100%, and all other variables are expressed as a percentage relative to that value. Any variables with confidence intervals that include zero or negative values are considered to have no predictive power in our model and are assigned a value of zero. In (b–i) bivariate associations between clinical, psychosocial features, and the median accepted risk of drug side effects are presented. MSA and PD patients are represented as red triangles and blue dots, respectively. Pearson correlation coefficients (“r”) were used to analyze continuous variables such as satisfaction with life situation (b), RPS (c), quality of life: nonmotor subscore (d), quality of life: emotional subscore (e), age (f), required social support (g), disease duration (h) and sex (i). Point-biserial correlation (“r”) was used for categorical variables, and Spearman correlation coefficients (“ρ”) were employed for ordinal scaled variables like the degree of required social support. Regression curves and 95% confidence intervals are provided for continuous variables. P values (“p”), both raw and adjusted following the Benjamini-Hochberg procedure, were computed (raw p values are shown in brackets).

Fig. 4. Standard gamble scenario for measuring therapy-associated risk willingness.

Participants had to make direct explicit trade-offs between decreasing probabilities of being cured and increasing probabilities of side effects (answer yes or no for 18 response options at different percentages, e.g., “… it had a 100% chance of cure and the most bearable side effects you can think of occurred permanently at 0%”).