A network of regulatory innovations to improve FDA quality assessments of human drug applications.

A network of regulatory innovations brings a holistic approach to improving the submission, assessment, and lifecycle management of pharmaceutical quality information in the U.S. This dedicated effort in the FDA's Center for Drug Evaluation and Research (CDER) aims to enhance the quality assessment of submissions for new drugs, generic drugs, and biological products including biosimilars. These regulatory innovations include developing or contributing: (i) the Knowledge-Aided Assessment and Structured Application (KASA), (ii) a new common technical document for quality (ICH M4Q(R2)), (iii) structured data on Pharmaceutical Quality/Chemistry, Manufacturing and Controls (PQ/CMC), (iv) Integrated Quality Assessment (IQA), (v) the Quality Surveillance Dashboard (QSD), and (vi) the Established Conditions tool from the ICH Q12 guideline. The innovations collectively drive CDER toward a more coordinated, effective, and efficient quality assessment. Improvements are made possible by structured regulatory submissions, a systems approach to quality risk management, and data-driven decisions based on science, risk, and effective knowledge management. The intended result is better availability of quality medicines for U.S. patients.

Team-based home blood pressure monitoring for blood pressure equity a protocol for a stepped wedge cluster randomized trial.

BACKGROUND: Home Blood Pressure Monitoring (HBPM) that includes a team with a clinical pharmacist is an evidence-based intervention that improves blood pressure (BP). Yet, strategies for promoting its adoption in primary care are lacking. We developed potentially feasible and sustainable implementation strategies to improve hypertension control and BP equity. METHODS: We assessed barriers and facilitators to HBPM and iteratively adapted implementation strategies through key informative interviews and guidance from a multistakeholder stakeholder team involving investigators, clinicians, and practice administration. RESULTS: Strategies include: 1) pro-active outreach to patients; 2) provision of BP devices; 3) deployment of automated bidirectional texting to support patients through education messages for patients to transmit their readings to the clinical team; 3) a hypertension visit note template; 4) monthly audit and feedback reports on progress to the team; and 5) training to the patients and teams. We will use a stepped wedge randomized trial to assess RE-AIM outcomes. These are defined as follows Reach: the proportion of eligible patients who agree to participate in the BP texting; Effectiveness: the proportion of eligible patients with their last BP reading <140/90 (six months); Adoption: the proportion of patients invited to the BP texting; Implementation: patients who text their BP reading ≥10 of days per month; and Maintenance: sustained BP control post-intervention (twelve months). We will also examine RE-AIM metrics stratified by race and ethnicity. CONCLUSIONS: Findings will inform the impact of strategies for the adoption of team-based HPBM and the impact of the intervention on hypertension control and equity. REGISTRATION DETAILS: www. CLINICALTRIALS: gov Identifier: NCT05488795.

Healthcare staff mental health trajectories during the COVID-19 pandemic: findings from the COVID-19 Staff Wellbeing Survey.

BACKGROUND: Cross-sectional studies have shown that the COVID-19 pandemic has had a significant impact on the mental health of healthcare staff. However, it is less well understood how working over the long term in successive COVID-19 waves affects staff well-being. AIMS: To identify subpopulations within the health and social care staff workforce with differentiated trajectories of mental health symptoms during phases of the COVID-19 pandemic. METHOD: The COVID-19 Staff Wellbeing Survey assessed health and social care staff well-being within an area of the UK at four time points, separated by 3-month intervals, spanning November 2020 to August 2021. RESULTS: Growth mixture models were performed on the depression, anxiety and post-traumatic stress disorder longitudinal data. Two class solutions provided the best fit for all models. The vast majority of the workforce were best represented by the low-symptom class trajectory, where by symptoms were consistently below the clinical cut-off for moderate-to-severe symptoms. A sizable minority (13-16%) were categorised as being in the high-symptom class, a group who had symptom levels in the moderate-to-severe range throughout the peaks and troughs of the pandemic. In the depression, anxiety and post-traumatic stress disorder models, the high-symptom class perceived communication from their organisation to be less effective than the low-symptom class. CONCLUSIONS: This research identified a group of health service staff who reported persistently high mental health symptoms during the pandemic. This group of staff may well have particular needs in terms of the provision of well-being support services.

Lessons from CDER's Quality Management Maturity Pilot Programs.

Between October 2020 and March 2022, FDA's Center for Drug Evaluation and Research (CDER) completed two pilot programs to assess the quality management maturity (QMM) of drug manufacturing establishments. Mature quality systems promote proactive detection of vulnerabilities, prevent problems before they occur, and foster a culture that rewards process and system improvements. A CDER QMM program may help to advance supply chain resiliency and robustness and mitigate drug shortages. One pilot program evaluated seven establishments located within the U.S. that produce finished dosage form products marketed in the U.S. A second pilot program evaluated eight establishments located outside the U.S. that produce active pharmaceutical ingredients used in drug products marketed in the U.S. The execution of these pilot programs afforded FDA the opportunity to learn important lessons about the establishment QMM assessment process, scoring approach, assessor behaviors, and perceptions of the assessment questions, reports, and ratings. Many of the participating establishments reported that the QMM pilot assessments helped to identify their strengths, weaknesses, and new areas for improvement which they had not previously identified through internal audits or CGMP inspections. There has been a great deal of interest in the outcomes of CDER's QMM pilot programs and this paper describes, for the first time, the lessons CDER learned and will continue to heed in the development of a QMM program.

Benchmarking the Quality Practices of Global Pharmaceutical Manufacturing to Advance Supply Chain Resilience.

Over the past several decades, pharmaceutical manufacturing has become increasingly global and supply chains have become longer, more complex, and fragmented. While pharmaceutical products available to patients and customers typically conform with appropriate standards, supply chains are often affected by disruptive events and shocks that impact public health. One approach to assuring the availability of quality pharmaceutical products is to encourage drug manufacturers to invest in quality management maturity (QMM) and promote continual improvement. The interests of patients are served by risk-based drug shortage prevention and mitigation activities that help to proactively manage supply chain complexities and ensure availability of drugs. This paper demonstrates that adherence to certain quality practices enables improved manufacturing performance. Prior research has identified quality practices that are correlated with manufacturing performance. To better understand how these quality practices can be characterized, measured, and analyzed, this research project conducted a voluntary global study of pharmaceutical manufacturing establishments. Over 200 global pharmaceutical manufacturing establishments participated in this Quality Benchmarking Study (QBS) and provided data on manufacturing performance and self-assessments of adherence to quality practices. The analysis of these data found that the implementation level for selected quality management practices correlates positively with certain Key Performance Indicators (KPIs). More specifically, we found a significant positive correlation between (i) Delivery Performance and (ii) Application of QMM principles associated with Technical Production.

Evolution of Investigating Informed Assent Discussions about CPR in Seriously Ill Patients.

CONTEXT: Outcomes after cardiopulmonary resuscitation (CPR) remain poor. We have spent 10 years investigating an "informed assent" (IA) approach to discussing CPR with chronically ill patients/families. IA is a discussion framework whereby patients extremely unlikely to benefit from CPR are informed that unless they disagree, CPR will not be performed because it will not help achieve their goals, thus removing the burden of decision-making from the patient/family, while they retain an opportunity to disagree. OBJECTIVES: Determine the acceptability and efficacy of IA discussions about CPR with older chronically ill patients/families. METHODS: This multi-site research occurred in three stages. Stage I determined acceptability of the intervention through focus groups of patients with advanced COPD or malignancy, family members, and physicians. Stage II was an ambulatory pilot randomized controlled trial (RCT) of the IA discussion. Stage III is an ongoing phase 2 RCT of IA versus attention control in in patients with advanced chronic illness. RESULTS: Our qualitative work found the IA approach was acceptable to most patients, families, and physicians. The pilot RCT demonstrated feasibility and showed an increase in participants in the intervention group changing from "full code" to "do not resuscitate" within two weeks after the intervention. However, Stages I and II found that IA is best suited to inpatients. Our phase 2 RCT in older hospitalized seriously ill patients is ongoing; results are pending. CONCLUSIONS: IA is a feasible and reasonable approach to CPR discussions in selected patient populations.

COVID-19 Staff Wellbeing Survey: longitudinal survey of psychological well-being among health and social care staff in Northern Ireland during the COVID-19 pandemic.

BACKGROUND: Throughout the coronavirus disease 2019 (COVID-19) pandemic, health and social care workers have faced unprecedented professional demands, all of which are likely to have placed considerable strain on their psychological well-being. AIMS: To measure the national prevalence of mental health symptoms within healthcare staff, and identify individual and organisational predictors of well-being. METHOD: The COVID-19 Staff Wellbeing Survey is a longitudinal online survey of psychological well-being among health and social care staff in Northern Ireland. The survey included four time points separated by 3-month intervals; time 1 (November 2020; n = 3834) and time 2 (February 2021; n = 2898) results are presented here. At time 2, 84% of respondents had received at least one dose of a COVID-19 vaccine. The survey included four validated psychological well-being questionnaires (depression, anxiety, post-traumatic stress and insomnia), as well as demographic and organisational measures. RESULTS: At time 1 and 2, a high proportion of staff reported moderate-to-severe symptoms of depression (30-36%), anxiety (26-27%), post-traumatic stress (30-32%) and insomnia (27-28%); overall, significance tests and effect size data suggested psychological well-being was generally stable between November 2020 and February 2021 for health and social care staff. Multiple linear regression models indicated that perceptions of less effective communication within their organisation predicted greater levels of anxiety, depression, post-traumatic stress and insomnia. CONCLUSIONS: This study highlights the need to offer psychological support to all health and social care staff, and to communicate with staff regularly, frequently and clearly regarding COVID-19 to help protect staff psychological well-being.

Top Ten Tips Palliative Care Clinicians Should Know About Prognostication in Critical Illness and Heart, Kidney, and Liver Diseases.

Specialty palliative care (PC) clinicians are frequently asked to discuss prognosis with patients and their families. When conveying information about prognosis, PC clinicians need also to discuss the likelihood of prolonged hospitalization, cognitive and functional disabilities, and death. As PC moves further and further upstream, it is crucial that PC providers have a broad understanding of curative and palliative treatments for serious diseases and can collaborate in prognostication with specialists. In this article, we present 10 tips for PC clinicians to consider when caring and discussing prognosis for the seriously ill patients along with their caregivers and care teams. This is the second in a three-part series around prognostication in adult and pediatric PC.

Palliative Care Specialist Access is Associated With Rankings of Hospital Quality.

CONTEXT: Increasing evidence has shown that access to specialty palliative care, particularly outpatient palliative care clinics, can yield improved health outcomes and be a marker of hospital quality. OBJECTIVE: To determine whether an association exists between access to specialty palliative care programs and hospital rankings found in the 2020-2021 U.S. News & World Report Best Hospitals. METHODS: This study used publicly available data from the Center to Advance Palliative Care (CAPC) Provider Directory to determine access to in-patient and out-patient palliative care in the 2020-2021 U.S. News & World Report Best Hospitals Rankings. Descriptive statistics and chi-squares were performed. Data were also analyzed across the four U.S. Census Bureau regions (Northeast, South, Midwest, West). RESULTS: Around 100% of the Top 20 hospitals include hospital-based palliative care consultation teams, and 95% offered outpatient palliative care. Of the second cohort of 83 hospitals, 99% offered inpatient palliative care, and 65% offered outpatient palliative care. Of the third cohort of 75 hospitals ranked, 96% had inpatient palliative care services, while only 41.3% offered outpatient palliative care. This represents a significant association between rank position and access to outpatient palliative care (P < 0.01). Ranked hospitals also have significantly higher access to hospital-based palliative care teams compared to the national prevalence rate (P < 0.01). CONCLUSION: These findings reflect the association of access to specialty palliative care with USNWR rankings for hospital quality. Further study is necessary to determine the specific influence of access to palliative care and USNWR rank position.

Correction to: Nevus of Ota - an intraoral presentation: a case report.

In the publication of this article [1], the figures were accidentally omitted due to an error. This has now been updated in the original article within the Case presentation section.

Nevus of Ota - an intraoral presentation: a case report.

BACKGROUND: Nevus of Ota or "oculodermal melanocytosis" is a rare congenital hamartoma of dermal melanocytes causing a blue-gray hyperpigmentation of the eye and surrounding structures. The condition, originally described by Ota and Tanino in 1939, mainly affects the ophthalmic and maxillary divisions of the trigeminal nerve. We describe the first reported case of unilateral oculodermal melanocytosis in a Caucasian woman with oral buccal mucosal involvement. Oral involvement of nevus of Ota is very rare. CASE PRESENTATION: A 48-year-old Caucasian woman was referred by the dermatology division to the oral medicine department at the University of Liverpool School of Dentistry with new-onset oral pigmentation to the left buccal mucosa. The patient had a previous diagnosis of oculodermal nevus. CONCLUSION: An incisional biopsy of the left buccal mucosa was completed. The report stated that histological and immunohistochemical features were in keeping with a blue nevus, but within the context of the preexisting occulodermal pigmentation, a diagnosis of oculodermal melanocytosis, also known as "nevus of Ota," was made. The patient will be kept under review in the oral medicine department because the progression of the lesion on the left buccal mucosa requires active monitoring owing to the potential for malignant change. The patient also requires regular review in the dermatology and ophthalmology divisions.

Adjustment to hand injury: Cross-sectional survey exploring adjustment in relation to illness perceptions and coping strategies.

STUDY DESIGN: Cross-sectional descriptive. INTRODUCTION: Hand injuries are highly prevalent, and the impact they have on physical, emotional, and functional adjustment is well recognized. Increasingly, adjustment to health conditions including hand injuries is being understood in terms of psychological variables. PURPOSE OF THE STUDY: To examine the role of illness beliefs and coping strategies in adjustment to hand injury. Adjustment was considered from a complete perspective including quality of life (QOL) and functional ability as well as mood and trauma symptoms. METHODS: Cross-sectional survey whereby consecutive patients (n = 65) attending the regional plastic surgery service with hand injuries were invited to complete a questionnaire assessing illness perceptions, coping strategies, QOL, hand functioning, depression, and trauma symptoms. Data were analyzed in SPSS (IBM Corporation, Armonk, NY) by correlation and then hierarchical regression analysis. RESULTS: Illness perceptions and coping strategies were significantly related to the adjustment outcomes (hand functioning, QOL, depression, and trauma symptoms). Specifically, poorer adjustment was associated with more negative illness beliefs (r = 0.31-0.47), greater use of denial (r = 0.24-0.53), and avoidance-based (r = 0.41-0.64) coping strategies. DISCUSSION: Illness beliefs and coping play an important role in adjustment after hand injury. Adjustment is multifaceted with a need to consider physical and emotional functioning. More optimistic beliefs and adaptive coping styles are associated with improved adjustment. CONCLUSION: The role of psychological variables in optimizing adjustment is an important consideration for the design of psychological interventions, but because this study was cross sectional and cannot assume directional effects, future longitudinal studies are needed. LEVEL OF EVIDENCE: N/A.

Impact of an Antibiotic-specific Sepsis Bundle on Appropriate and Timely Antibiotic Administration for Severe Sepsis in the Emergency Department.

BACKGROUND: Guidelines recommend initiation of appropriate antimicrobial therapy within 1 h of severe sepsis diagnosis. Few sepsis bundles exist in the literature emphasizing initiation of specific antibiotic therapy. OBJECTIVE: To determine the impact of an antibiotic-specific sepsis bundle on the timely initiation of appropriate antibiotics. METHODS: For this before-and-after interventional study, the sepsis bundle at this 803-bed academic tertiary-care facility was redesigned to include specific antibiotic selection and dosing, based on suspected source of infection and susceptibility patterns. Protocol education and advertising was completed and bundle-specific antibiotics were put in the automated medication cabinet. RESULTS: Stepwise analysis of timely initiation of appropriate antibiotics included: 1) Was the initial antibiotic appropriate? 2) If so, was it initiated within 1 h of diagnosis? 3) If so, were all necessary appropriate antibiotics started? and 4) If so, were they started within 3 h of diagnosis? In comparing the 3-month-before group and 3-month-after group (n = 124), the appropriate initial antibiotic was started in 33.9% vs. 54.8% of patients (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.19-0.93, p = 0.03) and within 1 h in 22.6% vs. 14.5% of patients (OR 1.71, 95% CI 0.62-4.92, p = 0.36), respectively. All necessary appropriate antibiotics were initiated in 16.1% vs. 12.9% of patients (OR 1.30, 95% CI 0.42-4.10, p = 0.80), and within 3 h in 14.5% vs. 9.7% of patients, respectively (OR 1.58, 95% CI 0.46-5.78, p = 0.58). CONCLUSIONS: An updated antibiotic-specific sepsis bundle, with antibiotics put in an automated medication cabinet, can result in improvements in the initiation of appropriate initial antibiotic therapy for severe sepsis in the emergency department.

Priorities for Evaluating Palliative Care Outcomes in Intensive Care Units.

Defining the quality of intensive care unit (ICU) care when patients are dying is challenging. Palliative care has been recommended to improve outcomes of dying ICU patients; however, traditional ICU quality indicators do not always align with palliative care. Evidence suggests that some aspects of ICU care improve when palliative care is integrated; however, consensus is lacking concerning the outcomes that should be measured. Overcoming challenges to measuring palliative care will require consensus development and rigorous research on the best way to evaluate ICU palliative care services.

Quality measures for palliative care in patients with cancer: a systematic review.

PURPOSE: Quality assessment is a critical component of determining the value of medical services, including palliative care. Characterization of the current portfolio of measures that assess the quality of palliative care delivered in oncology is necessary to identify gaps and inform future measure development. METHODS: We performed a systematic review of MEDLINE/PubMed and the gray literature for quality measures relevant to palliative care. Measures were categorized into National Quality Forum domains and reviewed for methodology of development and content. Measures were additionally analyzed to draw summative conclusions on scope and span. RESULTS: Two hundred eighty-four quality measures within 13 measure sets were identified. The most common domains for measure content were Physical Aspects of Care (35%) and Structure and Processes of Care (22%). Of symptom-related measures, pain (36%) and dyspnea (26%) were the most commonly addressed. Spiritual (4%) and Cultural (1%) Aspects of Care were least represented domains. Generally, measures addressed processes of care, did not delineate benchmarks for success, and often did not specify intended interventions to address unmet needs. This was most evident regarding issues of psychosocial and spiritual assessment and management. CONCLUSION: Within a large cohort of quality measures for palliative, care is often a focus on physical manifestations of disease and adverse effects of therapy; relatively little attention is given to the other aspects of suffering commonly observed among patients with advanced cancer, including psychological, social, and spiritual distress.

Strategies to combat chronic critical illness.

PURPOSE OF REVIEW: The population of chronically critically ill patients is growing as advances in intensive care management improve survival from the acute phase of critical illness. These patients are characterized by complex medical needs and heavy resource utilization. This article reviews evidence supporting a comprehensive approach to the prevention and management of chronic critical illness (CCI). RECENT FINDINGS: The most efficient approach to weaning patients with CCI at long-term acute care hospitals is daily unassisted breathing trials through a tracheostomy collar. However, a substantial number of patients transferred to long-term acute care hospitals pass their spontaneous weaning trials. Transfer to long-term acute care hospitals is associated with higher acute care costs and payments, but lower costs through the entire episode of illness. Universal decontamination is more effective than targeted decontamination or screening and isolation for preventing nosocomial bloodstream infections. SUMMARY: Combating CCI begins with prevention in the acute phase of illness. Management strategies include a spectrum of ventilatory, nutritional, and rehabilitation support. Further patient-centered outcome-based research in this specific population is needed to continue to help guide optimal care.

Alcohol delays the emergence of the fetal elicited startle response, but only transiently.

Prenatal exposure to alcohol may exert a significant detrimental effect on the functioning of the individual's brain, however few studies have examined this before birth. This longitudinal study examined the effect of maternal alcohol consumption on the elicited startle response of the fetus. Two groups of fetuses were examined: one whose mothers drank alcohol (approximately 10 units per week); the other whose mothers did not drink alcohol. Fetuses were examined at 29, 32 and 35 weeks gestation and their startle response observed using ultrasound in response to 2 presentations of a pink noise (70-250Hz) at 90dB(A) separated by 30s. Fetuses exposed to alcohol exhibited a weaker startle response at 29 weeks gestation than did fetuses not exposed to alcohol. There was no difference in the response at 32 and 35 weeks gestation. To ensure that the effects were not due to a more general effect of alcohol on fetal movement, a second experiment compared the spontaneous movements (observed on ultrasound for 45 min) of fetuses whose mothers drank alcohol and fetuses of mothers who didn't drink alcohol. There were no differences in movements exhibited by the fetuses. The results suggest that exposure to alcohol delays the emergence of the elicited startle response at 29 weeks gestation but this delay has disappeared by 32 weeks gestation. The possible role of altered neural development, acute exposure to alcohol and disruptions to the fetus's behavioural repertoire, in mediating these effects are discussed.