Transforming Evidence Generation for Drug Label Changes: A Case Study.

Computer Modeling and Simulation (CM&S) provides the opportunity to drastically reduce clinical trial patient burden and advance regulatory decision making. At the suggestion of the US Food and Drug Administration (FDA), MannKind Corporation and Nudge BG submitted an application to the FDA Model-Informed Drug Development (MIDD) pilot program to support a label change for the initial dose of Afrezza® (insulin human), a novel inhalable insulin with a rapid pharmacokinetic and pharmacodynamic profile. The MIDD pilot program demonstrates the FDA's commitment to advancing regulatory science through the adoption of evidence generated by CM&S. A simulation framework was developed based on empirical data. It was used to generate evidence to support the label change. Briefing packages and presentations were prepared for two meetings with the FDA, over a period of four months. The model was thoroughly characterized, determined to be low risk for the question of interest, and submitted along with additional clinical evidence for validation. The FDA found the simulation framework to be helpful in providing insights into the question of interest and provides reasonable glycemic outcome predictions. At the conclusion of the MIDD paired meetings, FDA personnel from the Center for Drug Evaluation and Research review team accepted the simulation and requested additional, traditional clinical evidence to support the proposed label change. In the post-meeting comments, the FDA invited MannKind to submit a proposal for a data package including the CM&S evidence in a Type C meeting for further discussion on the label change. This MIDD pilot experience suggests that CM&S is a credible method for evidence generation. Collaboration between sponsor organizations as well as all stakeholders in the FDA, including proponents of CM&S, can further support regulatory decision-making. The learnings from early participants will allow the program to reach its full potential and thereby ultimately benefit patients, sponsors, and FDA.

Reducing Underserved Children's Exposure to Tobacco Smoke: A Randomized Counseling Trial With Maternal Smokers.

INTRODUCTION: Addressing maternal smoking and child tobacco smoke exposure is a public health priority. Standard care advice and self-help materials to help parents reduce child tobacco smoke exposure is not sufficient to promote change in underserved populations. We tested the efficacy of a behavioral counseling approach with underserved maternal smokers to reduce infant's and preschooler's tobacco smoke exposure. DESIGN: A two-arm randomized trial: enhanced behavior counseling (experimental) versus enhanced standard care (control). Assessment staff members were blinded. SETTING/PARTICIPANTS: Three hundred randomized maternal smokers were recruited from low-income urban communities. Participants had a child aged <4 years exposed to two or more maternal cigarettes/day at baseline. INTERVENTION: Philadelphia Family Rules for Establishing Smoke-free Homes (FRESH) included 16 weeks of counseling. Using a behavioral shaping approach within an individualized cognitive-behavioral therapy framework, counseling reinforced efforts to adopt increasingly challenging tobacco smoke exposure-protective behaviors with the eventual goal of establishing a smoke-free home. MAIN OUTCOME MEASURES: Primary outcomes were end-of-treatment child cotinine and reported tobacco smoke exposure (maternal cigarettes/day exposed). Secondary outcomes were end-of-treatment 7-day point-prevalence self-reported cigarettes smoked/day and bioverified quit status. RESULTS: Participation in FRESH behavioral counseling was associated with lower child cotinine (ß=-0.18, p=0.03) and reported tobacco smoke exposure (ß=-0.57, p=0.03) at the end of treatment. Mothers in behavioral counseling smoked fewer cigarettes/day (ß=-1.84, p=0.03) and had higher bioverified quit rates compared with controls (13.8% vs 1.9%, χ(2)=10.56, p<0.01). There was no moderating effect of other smokers living at home. CONCLUSIONS: FRESH behavioral counseling reduces child tobacco smoke exposure and promotes smoking quit rates in a highly distressed and vulnerable population. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT02117947.

SHS-Related Pediatric Sick Visits are Linked to Maternal Depressive Symptoms among Low-Income African American Smokers: An Opportunity for Intervention in Pediatrics.

Maternal smoking and depressive symptoms are independently linked to poor child health outcomes. However, little is known about factors that may predict maternal depressive symptoms among low-income, African American maternal smokers - an understudied population with children known to have increased morbidity and mortality risks. The objective of this study was to test the hypothesis that secondhand smoke exposure (SHSe)-related pediatric sick visits are associated with significant maternal depressive symptoms among low-income, African American maternal smokers in the context of other depression-related factors. Prior to randomization in a behavioral counseling trial to reduce child SHSe, 307 maternal smokers in Philadelphia completed the CES-D and questionnaires measuring stressful events, nicotine dependence, social support, child health and demographics. CES-D was dichotomized at the clinical cutoff to differentiate mothers with significant vs. low depressive symptoms. Results from direct entry logistic regression demonstrated that maternal smokers reporting more than one SHSe-related sick visit (OR 1.38, p<.001), greater perceived life stress (OR 1.05, p<.001) and less social support (OR 0.82, p<.001) within the last 3 months were more likely to report significant depressive symptoms than mothers with fewer clinic visits, less stress, and greater social support. These results suggest opportunities for future hypothesis-driven evaluation, and exploration of intervention strategies in pediatric primary care. Maternal depression, smoking and child illness may present as a reciprocally-determined phenomenon that points to the potential utility of treating one chronic maternal condition to facilitate change in the other chronic condition, regardless of which primary presenting problem is addressed. Future longitudinal research could attempt to confirm this hypothesis.

The psychological consequences of weight change trajectories: evidence from quantitative and qualitative data.

We use quantitative and qualitative data to explore the psychological impact of weight change among American adults. Using data from the Midlife Development in the United States (MIDUS) study, a survey of more than 3000 adults ages 25-74 in 1995, we contrast underweight, normal weight, overweight, obese I, and obese II/III persons along five psychosocial outcomes: positive mood, negative mood, perceived interpersonal discrimination, self-acceptance, and self-satisfaction. We further assess whether these relationships are contingent upon one's body mass index (BMI) at age 21. We find a strong inverse association between adult BMI and each of the five outcomes, reflecting the stigma associated with high body weight. However, overweight adults who were also overweight at age 21 are more likely than persons who were previously slender to say they were "very satisfied" with themselves. Results from 40 in-depth semi-structured interviews reveal similarly that persons who were persistently overweight or obese accept their weight as part of their identity, whereas those who experienced substantial weight increases (or decreases) struggle between two identities: the weight they actually are, and the weight that they believe exemplifies who they are. We discuss implications for stigma theory, and the ways that stigma exits and entries affect psychological well-being.

Proactive recruitment predicts participant retention to end of treatment in a secondhand smoke reduction trial with low-income maternal smokers.

Improving smoking intervention trial retention in underserved populations remains a public health priority. Low retention rates undermine clinical advancements that could reduce health disparities. To examine the effects of recruitment strategies on participant retention among 279 low-income, maternal smokers who initiated treatment in a 16-week behavioral counseling trial to reduce child secondhand smoke exposure (SHSe). Participants were recruited using either reactive strategies or methods that included proactive strategies. Logistic regression analysis was used to test associations among retention and recruitment method in the context of other psychosocial and sociodemographic factors known to relate to retention. Backwards stepwise procedures determined the most parsimonious solution. Ninety-four percent of participants recruited with proactive + reactive methods were retained through end of treatment compared to 74.7% of reactive-recruited participants. Retention likelihood was five times greater if participants were recruited with proactive + reactive strategies rather than reactive recruitment alone (odds ration [OR] = 5.36; confidence interval [CI], 2.31-12.45). Greater knowledge of SHS consequences (OR = 1.58; CI, 1.07-2.34) was another significant factor retained in the final LR model. Proactive recruitment may improve retention among underserved smokers in behavioral intervention trials. Identifying factors influencing retention may improve the success of recruitment strategies in future trials, in turn, enhancing the impact of smoking interventions.

Residential smoking restrictions are not associated with reduced child SHS exposure in a baseline sample of low-income, urban African Americans.

Second hand smoke exposure (SHSe) relates to many chronic and acute illnesses. Low income African American (AA) maternal smokers and their children have disproportionately higher tobacco-use and child SHSe-related morbidity and mortality than other populations. While public health officials promote residential smoking restrictions to reduce SHSe and promote smoking cessation, little is known about the impact of restrictions in changing smoking behavior and SHSe in this population. Thus, the purpose of this study was to examine associations between residential smoking restrictions, maternal smoking, and young children's SHSe in the context of other factors known to influence low income AA mothers' smoking behavior. For this study, we used cross-sectional, baseline data from 307 AA maternal smokers' pre-treatment interviews completed as part of a subsequent behavioral counseling trial to reduce their young (< 4 years old) children's SHSe. Residential smoking restriction was dichotomized as 0 = no restrictions and 1 = some restrictions. Child urine cotinine provided a biomarker of SHSe. Mothers reported cigarettes/day smoked, cigarettes/day exposed to child, and intention to quit. Multivariate regressions modeled effects of restriction as the primary predictor of smoking and exposure outcomes. Maternal smoking patterns such as cigarettes per day (ß = 0.52, p < 0.001) and years smoked (ß = -0.11; p = 0.03) along with presence of additional smokers in the home (ß = 0.10; p = 0.04), but not residential restriction (ß = -0.09, p = 0.10), predicted reported SHSe. Restriction did not relate to baby cotinine or maternal intention to quit. Thus, residential smoking restrictions may contribute to efforts to reduce children's SHSe and promote maternal smoking change; but alone, may not constitute a sufficient intervention to protect children. Multi-level intervention approaches that include SHSe-reduction residential smoking policies plus support and cessation assistance for smokers may be a necessary approach to smoke-free home adoption and adherence.

Perceived interpersonal mistreatment among obese Americans: do race, class, and gender matter?

OBJECTIVE: We examine the extent to which body weight affects three types of perceived interpersonal mistreatment, and evaluate whether these patterns vary by race, social class, and gender in a large sample of American men and women. METHODS AND PROCEDURES: We use data from the first wave (1995) of the Midlife Development in the United States (N = 3,511), a survey of persons aged 25-74, to contrast underweight, normal weight, overweight, obese I, and obese II/III persons' reports of three types of perceived interpersonal mistreatment: disrespectful treatment; harassment/teasing; and being treated as if one has a character flaw. We assess whether these relationships are contingent upon one's gender, race, and occupational status. We control for possible confounding influences, including physical and mental health. RESULTS: In the total sample, obese I and obese II/III persons report significantly higher levels of all three types of perceived mistreatment (compared to normal weight persons), even when demographic, socioeconomic status, and health characteristics are controlled. Among black men, however, obese II/III persons report significantly lower levels of all three types of perceived mistreatment, compared to their normal weight peers. Among both men and women, obese professional workers report significantly more perceived interpersonal mistreatment, compared to obese persons of lower socioeconomic status. DISCUSSION: These findings reveal the ways that intersecting social identities may shape obese Americans' perceptions of stigmatizing interpersonal encounters.

Understanding the relationship between obesity and positive and negative affect: the role of psychosocial mechanisms.

We examined the relationship between body mass index (BMI) and positive and negative affect, and evaluated whether this relationship is mediated (or suppressed) by physical health, intrusiveness of weight on physical functioning, and distressing interpersonal interactions. Analyses were based on a national sample of more than 3,000 adults ages 25 to 74. Class II (BMI 35-39.9) and Class III (BMI> or =40) obesity were associated with more frequent negative affect and less frequent positive affect, even after demographic and socioeconomic status characteristics were controlled. After the purported pathway variables were controlled, however, obese I persons reported significantly more frequent positive affect, while overweight, obese I, and obese II persons reported significantly less frequent negative affect, compared to normal weight persons. These patterns did not differ significantly by race or gender. Our findings suggest that excessive body weight is not necessarily distressing, yet the physical and interpersonal strains associated with obesity may impair one's mood. We discuss the implications for policy and practice.

Mothers' attitudes toward fat, weight, and dieting in themselves and their children.

We examined how a mother's view of her body, and fatness in general, affects her attitude toward her child's weight and eating. Mothers (N=118) of 3-5-year-old children filled out a questionnaire designed to assess weight satisfaction, anti-fat attitudes, and how concerned and restrictive they are with regards to their child's weight and eating. We found mothers who were more fearful of being or becoming overweight themselves worried more for their children, although fearful attitudes did not predict restricting a child's eating. These results suggest that maternal attitudes toward their own weight affect their beliefs about their children's weight.