Obstacles to Biosimilar Acceptance and Uptake in Oncology: A Review.

Importance: Biosimilar drugs provide cost-effective yet clinically indistinguishable replications of target drugs. During initial development, this class of biologic medicines was expected to revolutionize pharmaceutical markets; however, following US Food and Drug Administration approval of the first biosimilar drug in 2015, the commercialization of biosimilars has been limited. The lack of biosimilar use may be especially salient in oncology, given that biosimilar distribution in this particularly high-cost area of medicine would bring savings on the order of many billions of dollars. Observations: While researchers have focused on salient economic barriers to biosimilar uptake in the US, the present review provides insight regarding noneconomic barriers. This review discusses psychological, attitudinal, and educational factors among both health care professionals and payers in the US that may play a role in slowing biosimilar uptake. More specifically, these factors include a lack of health care professional education, concerns of safety and efficacy, and overly complex product naming systems. Conclusions and Relevance: The pathway to biosimilar use has been obstructed by economic elements as well as attitudinal and psychological factors. For biosimilar drugs to achieve their potential in decreasing treatment costs and thus increasing patient access, it will be essential for both economic and noneconomic factors to be identified and systematically addressed.

Medical Oncologists' Knowledge and Perspectives on the Use of Biosimilars in the United States.

PURPOSE: Despite increasing availability of biosimilar cancer treatments, little is known about oncologists' knowledge and concerns regarding biosimilar use in the United States. We surveyed medical oncologists to examine their knowledge, attitudes, and experience with biosimilars. METHODS: Oncologists recruited via the ASCO Research Survey Pool completed a 29-question survey in 2020 designed with input from clinical and health care system experts and literature review. RESULTS: Of the 269 respondents, most treated patients with biosimilars (n = 236, 88%) and reported that biosimilars were required at their institution (n = 168, 63%). Approximately half (n = 140, 52%) of oncologists correctly responded that biosimilars were not the same as generic medicines. Commonly reported barriers to use of biosimilars included concerns regarding a perceived lack of relevant research (n = 85, 33% reporting quite a bit/very much), the potential for extrapolation (n = 83, 33%), and efficacy limitations (n = 77, 30%). More oncologists from university hospitals (n = 36, 22%) than from community/private hospitals (n = 28, 38%) or private practices (n = 13, 38%) were concerned about biosimilar efficacy. A high proportion of oncologists reported that information on safety (n = 259, 99%) and efficacy (n = 255, 99%) is important when considering whether to use biosimilars. Less than half reported that their institution provided education about biosimilars (n = 108, 40%). CONCLUSION: In this sample of medical oncologists, knowledge about basic features of biosimilars was limited and access to information about biosimilars was insufficient. The present study determined that educational programs on biosimilars for oncologists are needed and identified priorities for such efforts.

Impaired Valuation Leads to Increased Apathy Following Ventromedial Prefrontal Cortex Damage.

Apathy is defined by reduced goal-directed behavior, and is common in patients with damage to the ventromedial prefrontal cortex (vmPFC). Separately, in neuroeconomics research, the vmPFC has been shown to play a role in reward processing-namely, in "stimulus valuation," or the computation of the subjective reward value of a stimulus. Here, we used a sample of patients with focal brain lesions (N = 93) and matched healthy controls (N = 21) to determine whether the association between vmPFC damage and increased apathy is driven by impaired valuation. An auction task was used to measure valuation, and apathy was assessed via caregiver ratings of patients' day-to-day behavior. Lesion-symptom mapping identified the locus of impaired valuation in the vmPFC, and patients with damage to this region demonstrated increased apathy relative to patients with damage to dorsomedial prefrontal cortex (dmPFC), patients with damage to other brain regions, and healthy controls. Critically, the association between vmPFC damage and apathy was mediated by impaired valuation, with no effect as a function of dmPFC damage. Our results implicate a valuation-based mechanism underlying the relationship between vmPFC integrity and apathy, bridging findings from both the clinical literature and neuroeconomics research.

Networks underlying trait impulsivity: Evidence from voxel-based lesion-symptom mapping.

Impulsivity is considered a multidimensional construct that encompasses a range of behaviors, including poor impulse control, premature decision-making, and the inability to delay gratification. In order to determine the extent to which impulsivity and its components share a common network, a voxel-based lesion-symptom mapping (VLSM) analysis was performed in a large sample of patients (N = 131) with focal, penetrating traumatic brain injuries (pTBI). Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11), a standard self-report measure that allows for unique estimates of global impulsivity and its factor analysis-derived components (e.g., "motor impulsivity"). Heightened global impulsivity was associated with damage to multiple areas in bilateral prefrontal cortex (PFC), left superior, middle and inferior temporal gyrus, and left hippocampus. Moreover, a cluster was identified within the left PFC associated specifically with motor impulsivity (defined as "acting without thinking"). The results were consistent with the existing literature on bilateral prefrontal cortical involvement in behavioral impulsivity, but also provided new evidence for a more complex neuroanatomical representation of this construct, characterized by left-lateralized temporal and hippocampal involvement, as well as a left-lateralized prefrontal network specifically associated with motor impulsivity. Hum Brain Mapp 38:656-665, 2017. © 2016 Wiley Periodicals, Inc.

A latent variable model approach to estimating systematic bias in the oversampling method.

The method of oversampling data from a preselected range of a variable's distribution is often applied by researchers who wish to study rare outcomes without substantially increasing sample size. Despite frequent use, however, it is not known whether this method introduces statistical bias due to disproportionate representation of a particular range of data. The present study employed simulated data sets to examine how oversampling introduces systematic bias in effect size estimates (of the relationship between oversampled predictor variables and the outcome variable), as compared with estimates based on a random sample. In general, results indicated that increased oversampling was associated with a decrease in the absolute value of effect size estimates. Critically, however, the actual magnitude of this decrease in effect size estimates was nominal. This finding thus provides the first evidence that the use of the oversampling method does not systematically bias results to a degree that would typically impact results in behavioral research. Examining the effect of sample size on oversampling yielded an additional important finding: For smaller samples, the use of oversampling may be necessary to avoid spuriously inflated effect sizes, which can arise when the number of predictor variables and rare outcomes is comparable.

Stimulus-specific enhancement of fear extinction during slow-wave sleep.

Sleep can strengthen memory for emotional information, but whether emotional memories can be specifically targeted and modified during sleep is unknown. In human subjects who underwent olfactory contextual fear conditioning, re-exposure to the odorant context in slow-wave sleep promoted stimulus-specific fear extinction, with parallel reductions of hippocampal activity and reorganization of amygdala ensemble patterns. Thus, fear extinction may be selectively enhanced during sleep, even without re-exposure to the feared stimulus itself.

Exposure therapy triggers lasting reorganization of neural fear processing.

A single session of exposure therapy can eliminate recalcitrant and disabling fear of phobogenic objects or situations. We studied neural mechanisms of this remarkable outcome by monitoring changes in brain activity as a result of successful 2-h treatment. Before treatment, phobogenic images excited activity in a network of regions, including amygdala, insula, and cingulate cortex, relative to neutral images. Successful therapy dampened responsiveness in this fear-sensitive network while concomitantly heightening prefrontal involvement. Six months later, dampened fear-network activity persisted but without prefrontal engagement. Additionally, individual differences in the magnitude of visual cortex activations recorded shortly after therapy predicted therapeutic outcomes 6 mo later, which involved persistently diminished visual responsiveness to phobogenic images. Successful therapy thus entailed stable reorganization of neural responses to initially feared stimuli. These effects were linked to fear-extinction mechanisms identified in animal models, thus opening new opportunities for the treatment and prevention of debilitating anxiety disorders.

Establishing a relationship between activity reduction in human perirhinal cortex and priming.

Perirhinal neurons exhibit reduced firing rates with stimulus repetition, a phenomenon termed "repetition suppression." However, relationships between perirhinal repetition suppression and behavioral expressions of memory remain unclear. We used anatomically constrained functional magnetic resonance imaging (fMRI) to assess relationships between perirhinal activity and priming, a type of implicit memory. Priming was expressed as speeded animacy judgments for old versus new words. Concurrently, old words elicited less neural activity in bilateral perirhinal cortex. The magnitude of the left perirhinal activity reduction selectively predicted the magnitude of behavioral priming in an across-subjects hierarchical linear regression analysis. These findings have implications for considering how perirhinal cortex may contribute to different neurocognitive functions, possibly including both implicit memory and familiarity-based recognition. This study documents the first evidence linking behavioral measures of priming to information processing in perirhinal cortex.

An Examination of Content Overlap and Disorder-Specific Predictions in the Associations of Neuroticism with Anxiety and Depression.

This study examines whether content overlap artificially inflates estimates of the associations of emotional disorders with neuroticism and whether disorder-specificity of prediction exists. We demonstrated a statistical approach for testing the validity of hypothesized facets of neuroticism. In a sample of 627 adolescents, we indentified six facets of neuroticism, one intermediate facet, and a general neuroticism factor (GNF). Only the GNF and the depression facet were significantly associated with depressive symptomatology. The GNF and all facets significantly predicted anxiety symptomatology. This study offers a new statistical approach for addressing content overlap, testing for disorder specific prediction and identifying facets of a broad personality trait, while indicating that content overlap does not largely explain the associations of neuroticism with psychopathology.

Neuroticism and introversion are associated with salivary cortisol patterns in adolescents.

Previous studies have yielded equivocal findings on the relationship between personality and cortisol activity. The present study examined associations between personality and cortisol activity in a large, diverse adolescent sample, while partialling the effects of relevant demographic and health-related covariates. A subsample of 230 participants (57% of whom reported elevated neuroticism) was selected from a larger sample of 16-18-year olds involved in a study on risk factors for emotional disorders. Subsample participants completed a battery of personality questionnaires, and saliva collection was requested several months later on three consecutive days at six time points per day, from wakeup to bedtime. Associations between personality and cortisol rhythms were examined using multilevel growth curve modeling. Neuroticism (N) and introversion (I) were significantly and differentially associated with features of diurnal cortisol patterns. Specifically, a significant N x gender interaction was observed, demonstrating flatter cortisol rhythms across the waking day among male participants with higher N. Elevated I, however, was associated with lower cortisol awakening responses for both male and female participants, and higher cortisol at the time of waking for male participants only. The present study supports personality as a significant predictor of diurnal cortisol patterns in late adolescence, after accounting for the effects of demographic and health covariates, and suggests that gender plays a role in moderating associations between personality and cortisol.

A subtype of speech delay associated with developmental psychosocial involvement.

This report presents findings supporting the hypothesis of a clinically relevant subtype of childhood speech sound disorder, provisionally titled speech delay-developmental psychosocial involvement (SD-DPI). Conversational speech samples from 29 children who met inclusionary criteria for SD-DPI were selected from a case record archive at a university speech clinic for children. Participants with SD-DPI had been characterized by speech clinicians and caregivers as having speech delay with psychosocial issues that required attention in the course of at least 1 semester of speech treatment. The 29 participants were divided into 2 subgroups, based on clinicians' and parents' records indicating either approach-related negative affect (n = 23) or withdrawal-related negative affect (n = 6). Each participant with SD-DPI was matched by age, gender, and type of speech involvement to 3 comparison speakers with speech delay of unknown origin (n = 87). Analyses of the conversational speech samples indicated that in comparison with participants in the control group, those with SD-DPI had significantly more severe speech delay, averaging approximately 7% to 10% lowered speech competence in conversation. The clinical prevalence of SD-DPI was estimated at approximately 12% of children referred to the university speech clinic in the present study. The authors interpret the present findings to indicate that approach-related or withdrawal-related negative affect, negative emotionality or mood, and decreased task persistence or attention are risk factors for increased severity of expression of speech delay.

Transitioning from analog to digital audio recording in childhood speech sound disorders.

Few empirical findings or technical guidelines are available on the current transition from analog to digital audio recording in childhood speech sound disorders. Of particular concern in the present context was whether a transition from analog- to digital-based transcription and coding of prosody and voice features might require re-standardizing a reference database for research in childhood speech sound disorders. Two research transcribers with different levels of experience glossed, transcribed, and prosody-voice coded conversational speech samples from eight children with mild to severe speech disorders of unknown origin. The samples were recorded, stored, and played back using representative analog and digital audio systems. Effect sizes calculated for an array of analog versus digital comparisons ranged from negligible to medium, with a trend for participants' speech competency scores to be slightly lower for samples obtained and transcribed using the digital system. We discuss the implications of these and other findings for research and clinical practise.

Stressful events, personality, and mood disturbance: gender differences in alcoholics and problem drinkers.

The present study examined relationships among stressful events, personality characteristics, and affective status in males and females of various alcohol drinking patterns. We examined a total of 154 participants from three distinct alcohol subgroups: alcohol dependent, problem drinker, and light social drinker. These subjects did not meet criteria for any concurrent nonalcohol comorbid psychiatric disorder. The study included an alcohol quantity-frequency interview and self-report questionnaires on stressful life events, depressive symptoms, trait anxiety, and personality characteristics. Results showed female alcoholics reported significantly greater depression, anxiety, and neuroticism compared to their male counterparts (and all other drinking groups). Female problem drinkers reported significantly greater depressive symptoms and health-related stressful events compared to male problem drinkers and the light drinkers. In contrast, male problem drinkers did not show elevations on these dimensions and more closely resembled light drinkers, of whom no gender differences were found. The findings support theories suggesting a "telescoping" of complications, health-related stress, and mood dysfunction in women at a lower threshold level of alcohol consumption compared to their male counterparts.