Regulatory benefit-risk assessment of oncology drugs: A systematic review of FDA and EMA approvals.

The European Medicines Agency (EMA) and FDA have policy goals of strengthening benefit-risk (B-R) capabilities; but how this has been translating into regulatory practice is unclear. A systematic review of oncology drug approvals between 2015 and 2020 was conducted with approvals identified through review of FDA and EMA annual reports, with extraction of information on submission, clinical program and B-R assessment from publicly available review documents. Data were extracted from 236 reviews (EMA: 66 new submissions, 100 label extensions; FDA: 70 new submissions). The standard of evidence for B-R assessments seems to have diversified over time; yet, despite policy targets to extend their use, these assessments rarely include patient experience or real-world data.

A Discrete Choice Experiment to Assess Patient Preferences for Asthma Rescue Therapy and Disease Management.

BACKGROUND: With the expanding treatment landscape for asthma, the process of identifying best-fit, individualized management options is becoming increasingly complicated. Understanding patients' preferences can inform shared decision-making between clinicians and patients. OBJECTIVES: To examine preferences of adults with asthma for therapeutic and management attributes and determine how these preferences vary among patients. METHODS: We conducted an online discrete choice experiment survey in US adults with asthma. Patient preferences were analyzed using logit models. Factors affecting patients' preferences were identified by least absolute shrinkage and selection operator analysis. RESULTS: A total of 1,184 patients completed the survey (60% female; mean [SD] age, 49.2 [15.0] years). Patients most valued fewer asthma attacks requiring urgent health care professional visits, fewer exacerbations requiring oral corticosteroids, and a reduced risk for oral thrush. Higher value was placed on reducing the risk of short-term (oral thrush) versus long-term side effects (diabetes). Patients were willing to increase rescue medication use in exchange for decreasing exacerbations requiring oral corticosteroids and attacks requiring urgent health care professional visits. Patients preferred a single inhaler for rescue and maintenance and least valued asthma action plans. Demographic, socioeconomic, and clinical factors affected patient preferences. CONCLUSIONS: Patients sought convenient management options that focused mainly on decreasing the short-term morbidity associated with asthma exacerbations and therapies. Preferences varied by demographics, clinical factors, and socioeconomics. It is important for shared decision-making discussions to include conversations about morbidity and how available therapeutic options align with individual patient preferences.

Conversations and Reactions Around Severe Hypoglycemia (CRASH) Study: Results From People With Diabetes and Caregivers in the United States.

A survey was conducted in eight countries to examine conversations around, and experiences and treatments during, severe hypoglycemia among people with diabetes and caregivers of people with diabetes. This article reports a subgroup analysis from the United States involving 219 people with diabetes and 210 caregivers. Most respondents (79.7%) did not use professional health care services during their most recent severe hypoglycemic event, and 40.3% did not report the event to their health care providers at a subsequent follow-up visit. Hypoglycemic events left respondents feeling scared (70.9%), unprepared (42.7%), and helpless (46.9%). These clinically important psychosocial impacts on people with diabetes and caregivers underscore the need for conversations about hypoglycemia prevention and management.

Suboptimal Control of Asthma Among Diverse Patients: A US Mixed Methods Focus Group Study.

Purpose: The US National Asthma Education and Prevention Program updates and Global Initiative for Asthma report encourage considering the patient perspective to improve asthma control. The objective of the present study was to collect data about the perceptions, experiences, and concerns of adult patients and caregivers of children with asthma regarding rescue, maintenance, and oral corticosteroid treatments. Patients and Methods: In-person focus groups were conducted in three cities across the US. Participants also completed patient-reported outcome measures assessing asthma control and experiences. Results: Focus groups were conducted in demographically and clinically diverse adults with asthma (five groups, n=34), caregivers of children with asthma (five groups, n=35), and adults with a dual diagnosis of asthma and chronic obstructive pulmonary disease (one group, n=5). Only 28% of patients were well-controlled by Asthma Control Test/Asthma Control Test-Caregiver Report and 18% by Asthma Impairment and Risk Questionnaire. Forty-four percent of participants reported not following their prescribed medical plan. Four key themes emerged from the focus groups: (1) asthma symptom control and monitoring are often inadequate; (2) treatments are often used incorrectly; (3) communication between health care professionals and patients or caregivers is often ineffective; and (4) concerns related to treatment and desires to improve treatment. Conclusion: Control of asthma symptoms is suboptimal in the vast majority of patients and both patients and caregivers do not feel sufficiently informed about asthma. Health care providers should be encouraged to engage patients and caregivers in shared decision making for managing asthma and selecting treatments that integrate patient values, preferences, and lifestyles.

The Burden of Type 2 Diabetes and the Value of Achieving Near Normoglycemia from the Patient Perspective.

INTRODUCTION: Type 2 diabetes (T2D) is extremely burdensome to people with T2D and associated with impaired health-related quality of life. This study explores the impact of T2D and potentially relevant outcomes for new therapies using a unique approach to in-depth qualitative interviews where people with T2D are asked to think about their future with T2D. METHODS: A cross-sectional qualitative interview study among people with T2D from the USA and UK. Interviews explored their treatment journey, perceptions of their future with T2D, and the value of achieving normoglycemia (explored through presentation of two vignettes with hypothetical medications that reduced hemoglobin A1c [HbA1c] levels < 7% and < 5.7%). RESULTS: Patients with T2D (N = 50; US n = 25; UK n = 25) were 66.0% male, had a mean body mass index (BMI) of 30.8 ± 6.3 kg/m2, and had a mean of 13.0 ± 10.0 years since diagnosis. Current diabetes treatments included diet and exercise only (8.0%), oral medications only (62.0%), oral plus injections (24.0%), and insulin only (6.0%). Despite being treated, participants reported over 25 different unmet needs related to their T2D across a broad range of domains. The most common concerns were diet, diabetes-related complications, weight changes, and psychological and emotional issues. A large majority of participants indicated that achieving lower HbA1c values would change their life. When reflecting on the value of improved glycemic control, patients primarily anticipated physical improvements and improved psychological well-being. When presented with two hypothetical treatments, about 70% of participants preferred the < 5.7% treatment option over the < 7% HbA1c treatment option. CONCLUSIONS: People with T2D have a high disease burden, a broad range of unmet needs, and extremely varied experiences and expectations on the impacts of T2D on their lives and future. Many patients indicated that achieving near normoglycemia would substantially change their lives primarily in terms of their physical and emotional health.

Patient and physician preferences for attributes of biologic medications for severe asthma.

OBJECTIVE: Despite the increased availability of biologic treatments indicated for severe asthma, patient and physician preferences for these medications remains largely unknown. The purpose of this study was to understand perceptions of biologic therapies, barriers to care with biologic medications, and preferences for biologic therapy attributes. METHODS: This mixed-methods study involved quantitative surveys and qualitative telephone interviews with patients and physicians from the United States. Participants described preferences for relevant attributes, and barriers to use of biologic medications. Participants rated, ranked, and indicated importance of preferences for different levels of key attributes including: mode of administration, administration setting, dosing frequency, number of injections, and time to onset of effect. Other attributes unique to each group were also included. RESULTS: A total of 47 patients and 25 physicians participated. Patients ranked out-of-pocket costs, mode of administration, time to onset of efficacy, and administration setting as the most important attributes. Physicians ranked mode of administration, time to onset of efficacy, dosing frequency, and insurance reimbursement/access as most important. Both groups expressed preferences for less frequent administrations (Q8W over Q4W or Q2W) (all P<0.01) and subcutaneous (SC) over intravenous injection (both P<0.0001). Key patient barriers to biologic medications include location of treatment, administration time, scheduling, cost/insurance coverage, number of injections, and mode of administration. Physicians identified patient candidacy, convincing patients, administration setting, mode of administration, cost, and administrative burden as key barriers to initiating therapy; and efficacy, speed of onset, convenience of administration, cost, and patient compliance as barriers to staying on therapy. CONCLUSIONS: Patients and physicians expressed strong preferences for less frequent dosing, SC administration, and faster onset. Cost/insurance coverage and convenience issues were key barriers to use. Increased awareness and understanding of preferences and barriers may be useful in facilitating physician-patient conversations with the goal of individualizing treatment.

Content validity and electronic PRO (ePRO) usability of the Lung Cancer Symptom Scale-Mesothelioma (LCSS-Meso) in mesothelioma patients.

PURPOSE: Obtaining qualitative data directly from the patient perspective enhances the content validity of patient-reported outcome (PRO) instruments. The objective of this qualitative study was to evaluate the content validity of the Lung Cancer Symptom Scale for Mesothelioma (LCSS-Meso) and its usability on an electronic device. METHODS: A cross-sectional methodological study, using a qualitative approach, was conducted among patients recruited from four clinical sites. The primary target population included patients with pleural mesothelioma; data were also collected from patients with peritoneal mesothelioma on an exploratory basis. Semi-structured interviews were conducted consisting of concept elicitation, cognitive interviewing, and evaluation of electronic patient-reported outcome (ePRO) usability. RESULTS: Participants (n = 21) were interviewed in person (n = 9) or by telephone (n = 12); 71% were male with a mean age of 69 years (SD = 14). The most common signs and symptoms experienced by participants with pleural mesothelioma (n = 18) were shortness of breath, fluid build-up, pain, fatigue, coughing, and appetite loss. The most commonly described symptoms for those with peritoneal mesothelioma (n = 4) were bloating, changes in appetite, fatigue, fluid build-up, shortness of breath, and pain. Participants with pleural mesothelioma commonly described symptoms assessed by the LCSS-Meso in language consistent with the questionnaire and a majority understood and easily completed each of the items. The ePRO version was easy to use, and there was no evidence that the electronic formatting changed the way participants responded to the questions. CONCLUSIONS: Results support the content validity of the LCSS-Meso and the usability of the electronic format for use in assessing symptoms among patients with pleural mesothelioma.

Experience of Symptoms and Disease Impact in Patients with Adenomyosis.

BACKGROUND: Adenomyosis is a poorly understood, benign disease of the uterus. OBJECTIVE: In this study, patient interviews were conducted to characterize the symptoms and impact of adenomyosis. METHODS: This was a cross-sectional study in which women with adenomyosis were recruited from five US clinics and a health-related social network forum. Participants (aged 18-55 years) were pre-menopausal with a history of regular menstrual cycles. Participants were interviewed about their experiences with adenomyosis, symptoms and impacts on day-to-day activities (concept elicitation), and subsequently about the occurrence, relative severity, and impact of symptoms (card-sorting exercise). RESULTS: In total, 31 women were interviewed. Mean duration since onset of first adenomyosis symptom was 5.7 years; 41.9% reported severe/very severe adenomyosis. Over 50 symptoms and 30 impacts of adenomyosis were reported in the concept elicitation; 87% of symptoms were reported after 7 interviews and 78% of impacts after 5 interviews, indicating a condition with a significant symptom burden and a consistent presentation. The most common symptoms were heavy menstrual bleeding (87%), cramps (84%), and blood clots during menstrual bleeding (84%). The most common impacts were burdensome self-care hygiene (71%), and fatigue/low energy (71%). In the card-sorting exercise, the most commonly endorsed symptoms were pain during menstruation/menstrual cramps and heavy menstrual bleeding (both frequently rated as severe). The symptom with the highest impact was heavy menstrual bleeding. CONCLUSION: Initiatives to understand women's experiences with adenomyosis may improve management of the condition. This study provides a first step in understanding their experience and new information on the symptom profile of adenomyosis.

Content validity and ePRO usability of the BPI-sf and "worst pain" item with pleural and peritoneal mesothelioma.

BACKGROUND: The Brief Pain Inventory-short form (BPI-sf) is widely used in self-reported pain assessment, incorporates pain numeric rating scales (NRS) and is commonly utilized in electronic format in clinical trials, however, there is no published information about its usability as an electronic patient-reported outcome (ePRO) measure. The objective of this qualitative study was threefold: 1) to better understand pain experiences among patients with pleural or peritoneal mesothelioma; 2) to assess the interpretability of the instructions, item stem, recall period, and response option of the "worst pain" item of the BPI-sf; and 3) to examine the usability of the TrialMax Touch™ (CRF Health, Inc., Plymouth Meeting, PA) screen-based handheld device and the electronic format of the BPI-sf in a sub-sample of pleural mesothelioma patients. METHODS: A cross-sectional qualitative study was conducted among participants with pleural and peritoneal mesothelioma recruited from 4 clinical sites in the US. Semi-structured telephone or in-person interviews were conducted consisting of concept elicitation, cognitive interviewing of the 11-item BPI-sf, and in-person interview evaluation of ePRO assessment usability in pleural mesothelioma patients. RESULTS: Twenty-one participants recruited from 4 clinical sites in the US were interviewed in-person (n = 9) and by telephone (n = 12); 71% male; mean age 68.7 ± 13.6 years. Pleural and peritoneal patients described pain as ranging from discomfort to intense pain and reported being able to distinguish tumor pain from treatment pain. The BPI-sf "worst pain" item was relevant to, and easily understood by, study participants with pleural and peritoneal mesothelioma. The ePRO version was found to be easy to use, but readability of small font may be an issue. Participants reported minimal differences between their responses on the paper and ePRO version for all of the pain severity and pain interference items. CONCLUSIONS: Results support the relevance and ease of understanding of the "worst pain" item and provide support for its content validity in patients with pleural and peritoneal mesothelioma. Usability of the ePRO format of the BPI-sf was confirmed for use in clinical trials among patients with pleural mesothelioma.

A cross-sectional survey of patient satisfaction and subjective experiences of treatment with fingolimod.

BACKGROUND: Fingolimod is the first oral disease-modifying therapy indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical relapses and delay the progression of physical disability caused by MS. OBJECTIVE: To obtain data from MS patients who have taken fingolimod regarding their treatment choice, first-dose observation (FDO) experience, and treatment satisfaction. METHODS: Patients ≥ 18 years old with physician-diagnosed MS in the United States who had taken at least one dose of fingolimod for the treatment of MS were invited to complete a web-based survey, which captured information on the reasons for starting fingolimod, FDO experience, and treatment satisfaction as measured by the Treatment Satisfaction Questionnaire for Medication (TSQM). A high TSQM scale score denotes high satisfaction. RESULTS: Survey respondents (n = 380; 55% female) had a mean (standard deviation) age of 39.8 (12.6) years, and a mean (standard deviation) duration of MS of 9.8 (10.3) years. Overall, more than 80% of patients reported the first dose was moderately/very/extremely manageable, convenient, and easy to take. Although 80% of patients reported experiencing a side effect with the first dose, most were highly tolerable and only eleven patients (2.9%) reported they were "Not at all" satisfied with the FDO experience. TSQM scale scores were highest for the side effect (79.4), followed by convenience (71.7), effectiveness (70.1), and global satisfaction (68.9) domains; relatively higher scores were observed among treatment-experienced patients. Both treatment-naïve and treatment-experienced patients indicated physician recommendation as the primary reason for starting fingolimod. Among treatment-experienced respondents (n = 273), 58% reported that their first choice for MS treatment would be fingolimod if selecting today. CONCLUSION: Most fingolimod patients were satisfied with their FDO experience. Satisfaction with fingolimod was high and observed higher among treatment-experienced compared to treatment-naïve patients. Additional research is needed to understand key clinical and medication attributes underlying treatment satisfaction with fingolimod and other disease-modifying therapies.

Suppression of the endoplasmic reticulum calcium pump during zebrafish gastrulation affects left-right asymmetry of the heart and brain.

Vertebrate embryos generate striking Ca(2+) patterns, which are unique regulators of dynamic developmental events. In the present study, we used zebrafish embryos as a model system to examine the developmental roles of Ca(2+) during gastrulation. We found that gastrula stage embryos maintain a distinct pattern of cytosolic Ca(2+) along the dorsal-ventral axis, with higher Ca(2+) concentrations in the ventral margin and lower Ca(2+) concentrations in the dorsal margin and dorsal forerunner cells. Suppression of the endoplasmic reticulum Ca(2+) pump with 0.5 microM thapsigargin elevates cytosolic Ca(2+) in all embryonic regions and induces a randomization of laterality in the heart and brain. Affected hearts, visualized in living embryos by a subtractive imaging technique, displayed either a reversal or loss of left-right asymmetry. Brain defects include a left-right reversal of pitx2 expression in the dorsal diencephalon and a left-right reversal of the prominent habenular nucleus in the brain. Embryos are sensitive to inhibition of the endoplasmic reticulum Ca(2+) pump during early and mid gastrulation and lose their sensitivity during late gastrulation and early segmentation. Suppression of the endoplasmic reticulum Ca(2+) pump during gastrulation inhibits expression of no tail (ntl) and left-right dynein related (lrdr) in the dorsal forerunner cells and affects development of Kupffer's vesicle, a ciliated organ that generates a counter-clockwise flow of fluid. Previous studies have shown that Ca(2+) plays a role in Kupffer's vesicle function, influencing ciliary motility and translating the vesicle's counter-clockwise flow into asymmetric patterns of gene expression. The present results suggest that Ca(2+) plays an additional role in the formation of Kupffer's vesicle.