Risk-benefit Decisions Research Articles

A Retrospective Case Series Analysis of Pregnancy and COVID-19 Based on a Global Postmarketing COVID-19 Surveillance Program

PurposeTo document and characterize COVID-19 cases involving pregnancy in the context of exposure to pharmaceutical products. MethodsThis retrospective case series analysis leveraged the Pfizer safety database containing worldwide adverse event data related to use of Pfizer products between October 1, 2019 and November 3, 2022. Selected Medical Dictionary for Drug Regulatory Activities (Version 25.0) Preferred Terms and subsequent clinical review were used to identify COVID-19 cases involving female patients who received Pfizer products during pregnancy and infants with intrauterine exposure to Pfizer products. FindingsAs of November 3, 2022, 504 pregnancy cases (426 maternal; 78 infants) were identified. Most maternal cases reported COVID-19 during the third trimester, and (when known) 52% of cases involved presentation or progression of severe COVID-19 with associated complications requiring hospitalization, and often intensive management (eg, mechanical ventilation, oxygen support) and emergent delivery. Twenty-three maternal cases were fatal; patients developed severe COVID-19 disease involving multisystem deterioration (eg, cardiopulmonary injury/decompensation, coagulopathies, septic/hemorrhagic shock) and frequently required risk-benefit decisions regarding maintaining/prolonging pregnancies to improve fetal viability while attempting to improve or stabilize maternal conditions or electing to either terminate pregnancies or induce emergent deliveries. Approximately 40% of maternal cases reported medical history involving at least one underlying condition (eg, diabetes, respiratory disorders, renal/hepatic disease, cardiac disease, obesity, autoimmune conditions) considered potentially associated with susceptibility to infection/adverse outcome of infection, or twin/triplet pregnancy, which may further complicate COVID-19 disease. Most cases with known fetal outcomes reported normal newborns including preterm/low birth weight infants, which occurred in many cases involving emergent preterm delivery due to deteriorating maternal conditions. The remaining smaller proportion of cases involved abnormal newborn/perinatal/postperinatal complications (eg, premature births, respiratory distress, alveolar damage, meconium aspiration with hypoxic-ischemic encephalopathy), intrauterine/neonatal death (due to multiple concurrent complications such as neonatal sepsis, hypoxemia/acute respiratory distress, potential cardiac damage, mucormycosis) and congenital anomaly (eg, intrauterine growth restriction in association with contracting COVID-19). Among infants tested within our dataset, 28 cases involved reference to infants who tested positive for COVID-19 infection at birth or shortly thereafter, with vertical transmission suspected only in 2 infants. ImplicationThis large retrospective case series provides additional perspectives regarding potential impact of COVID-19 on pregnancy outcomes, and its characterization of this case volume may contribute to the current information landscape related to COVID-19 in pregnancy. Further studies may be warranted to confirm the generalizability of our findings to the general pregnant patient population infected with COVID-19.

This Risk-Benefit Analysis Could Inform Decisions About Bleeding Risk With Thrombolysis in Those Who Had Pre-stroke Antiplatelet Therapy

This Risk-Benefit Analysis Could Inform Decisions About Bleeding Risk With Thrombolysis in Those Who Had Pre-stroke Antiplatelet Therapy

Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies.

Amyloid-related imaging abnormalities (ARIA) were the most common adverse events reported in the phase 3 ENGAGE and EMERGE trials of aducanumab, an anti-amyloid monoclonal antibody. APOE ε4 carrier status has been shown to increase risk of ARIA in prior trials of aducanumab and other anti-amyloid therapies; however, the remainder of the human genome has not been evaluated for ARIA risk factors. Therefore, we sought to determine in a hypothesis-free manner whether genetic variants beyond APOE influence risk of ARIA in aducanumab-treated patients. We performed genome-wide association studies (GWAS) of ARIA in participants in the ENGAGE and EMERGE trials. Participants had mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia and were amyloid-positive on PET scans. All participants underwent regular MRI monitoring to detect and diagnose ARIA. Of the 3,285 participants in the intent-to-treat population, this analysis included 1,691 with genotyping array data who received at least one dose of aducanumab with at least one post-baseline MRI. All participants in the study cohort were of European ancestry; 51% were female. The mean age was 70.3 years. 31% had ARIA-E, 19% had ARIA-H microhemorrhage, and 14% had ARIA-H superficial siderosis. We identified one genome-wide significant (p < 5.0 × 10-8) association at the chromosome 19 locus encompassing APOE. The APOE association with ARIA was stronger in ε4/ε4 homozygotes (OR = 4.28, 4.58, 7.84; p < 2.9 × 10-14 for ARIA-E, ARIA-H microhemorrhage, and ARIA-H superficial siderosis, respectively) than in ε3/ε4 heterozygotes (OR = 1.74, 1.46, 3.14; p ≤ 0.03). We found greater odds of radiographically severe ARIA (OR = 7.04-24.64, p ≤ 2.72 × 10-5) than radiographically mild ARIA (OR = 3.19-5.00, p ≤ 1.37 × 10-5) among ε4/ε4 homozygotes. APOE ε4 was also significantly associated with both symptomatic (ε4/ε4 OR = 3.64-9.52; p < 0.004) and asymptomatic (ε4/ε4 OR = 4.20-7.94, p < 1.7 × 10-11) cases, although among ARIA cases, APOE did not appear to modulate symptomatic status. No other genome-wide significant associations were found. We identified a strong, genome-wide significant association between APOE and risk of ARIA. Future, larger studies may be better powered to detect associations beyond APOE. These findings indicate that APOE is the strongest genetic risk factor of ARIA incidence, with implications for patient management and risk-benefit treatment decisions. Both trials (ENGAGE [221AD301]: NCT02477800 and EMERGE [221AD302]: NCT02484547) were registered in June 2015 at clinicaltrials.gov and enrolled patients from August 2015 to July 2018.

The Unseen Hand: AI-Based Prescribing Decision Support Tools and the Evaluation of Drug Safety and Effectiveness.

The use of artificial intelligence (AI)-based tools to guide prescribing decisions is full of promise and may enhance patient outcomes. These tools can perform actions such as choosing the 'safest' medication, choosing between competing medications, promoting de-prescribing or evenpredicting non-adherence. These toolscan exist in a variety of formats; for example, they may be directly integrated into electronic medical records or they may exist in a stand-alone website accessible by a web browser. One potential impact of these tools is that they could manipulate our understanding of the benefit-risk of medicines in the real world. Currently, the benefit risk of approved medications is assessed according to carefully planned agreements covering spontaneous reporting systems and planned surveillance studies. But AI-based tools may limit or even block prescription to high-risk patients or prevent off-label use. The uptake and temporal availability of these tools may be uneven across healthcare systems and geographies, creating artefacts in data that are difficult to account for. It is also hard to estimate the 'true impact' that a tool had on a prescribing decision. International borders may also be highly porous to these tools, especially in cases where tools are available over the web. These tools already exist, and their use is likely to increase in the coming years. How they can be accounted for in benefit-risk decisions is yet to be seen.

Age Matters: A Comparative Study of RF Heating of Epicardial and Endocardial Electronic Devices in Pediatric and Adult Phantoms during Cardiothoracic MRI.

This study focused on the potential risks of radiofrequency-induced heating of cardiac implantable electronic devices (CIEDs) in children and adults with epicardial and endocardial leads of varying lengths during cardiothoracic MRI scans. Infants and young children are the primary recipients of epicardial CIEDs, though the devices have not been approved as MR conditional by the FDA due to limited data, leading to pediatric hospitals either refusing the MRI service to most pediatric CIED patients or adopting a scan-all strategy based on results from adult studies. The study argues that risk-benefit decisions should be made on an individual basis. We used 120 clinically relevant epicardial and endocardial device configurations in adult and pediatric anthropomorphic phantoms to determine the temperature rise during RF exposure at 1.5 T. The results showed that there was significantly higher RF heating of epicardial leads than endocardial leads in the pediatric phantom, but not in the adult phantom. Additionally, body size and lead length significantly affected RF heating, with RF heating up to 12 °C observed in models based on younger children with short epicardial leads. The study provides evidence-based knowledge on RF-induced heating of CIEDs and highlights the importance of making individual risk-benefit decisions when assessing the potential risks of MRI scans in pediatric CIED patients.

Hybrid Learning Modality Did Not Reduce the Risk of COVID-19 Among Colorado Students.

During the 2020-2021 school year, many schools adopted remote learning or a part-time in-person learning ("hybrid") approach to reduce the risk of in-school transmission of COVID-19. The purpose of this work is to describe case rates of COVID-19 in schools practicing different learning modalities on rates of COVID-19 to support risk-benefit decisions in the context of respiratory disease outbreaks. We conducted a person-time-at-risk analysis of rates of COVID-19, as well as testing and test positivity rates among Colorado students. Schools practicing remote learning had a lower adjusted rate of COVID-19 cases compared to either hybrid or in-person learning modalities. Students attending a school with remote learning had fewer reported tests, and test positivity was higher for remote learning. Our analysis found that both case rate and test positivity were similar in hybrid and in-person learning modalities, indicating that hybrid learning modalities may not reduce the risk of respiratory disease transmission.

Simpson's Grading Scale for WHO Grade I Meningioma Resection in the Modern Neurosurgical Era: Are We Really Asking the Right Question?

The Simpson grading scale for the classification of the extent of meningioma resection provided a tremendous movement forward in 1957 suggesting increasing the extent of resection improves recurrence rates. However, equal, if not greater, movements forward have been made in the neurosurgical community over the last half a century owing to improvements in neuroimaging capabilities, microsurgical techniques, and radiotherapeutic strategies. Sughrue et al proposed the idea that these advancements have altered what a "recurrence" and "subtotal resection" truly means in modern neurosurgery compared with Simpson's era, and that a mandated use of the Simpson Scale is likely less clinically relevant today. A subsequent period of debate ensued in the literature which sought to re-examine the clinical value of using the Simpson Scale in modern neurosurgery. While a large body of evidence has recently been provided, these data generally continue to support the clinical importance of gross tumor resection as well as the value of adjuvant radiation therapy and the importance of recently updated World Health Organization classifications. However, there remains a negligible interval benefit in performing overly aggressive surgery and heroic maneuvers to remove the last bit of tumor, dura, and/or bone just for the simple act of achieving a lower Simpson score. Ultimately, meningioma surgery may be better contextualized as a continuous set of weighted risk-benefit decisions throughout the entire operation.

Prosthesis preferences for those with upper limb loss: Discrete choice study of PULLTY® for use in regulatory decisions.

The patient's voice in shared decision-making has progressed from physician's office to regulatory decision-making for medical devices with FDA's Patient Preference Initiative. A discrete-choice preference measure for upper limb prosthetic devices was developed to investigate patient's risk/benefit preference choices for regulatory decision making. Rapid ethnographic procedures were used to design a discrete-choice measure describing risk and benefits of osseointegration with myoelectric control and test in a pilot preference study in adults with upper limb loss. Primary outcome is utility of each choice based conjoint (CBC) attribute using mixed-effects regression. Utilities with and without video, and between genders were compared. Strongest negative preference was for avoiding infection risk (B = -1.77, p < 0.001) and chance of daily pain (B = -1.22, p, 0.001). Strongest positive preference was for attaining complete independence when cooking dinner (B = 1.62, p < 0.001) and smooth grip patterns at all levels (B = 1.62, B = 1.28, B = 1.26, p < 0.001). Trade-offs showed a 1% increase in risk of serious/treatable infection resulted in a 1.77 decrease in relative preference. There were gender differences, and where video was used, preferences were stronger. Strongest preferences were for attributes of functionality and independence versus connectedness and sensation but showed willingness to make risk-benefit trade-offs. Findings provide valuable information for regulatory benefit-risk decisions for prosthetic device innovations. This study is not a clinical trial reporting results of a health care intervention so is not registered.

How to Make Smart COVID Risk-Benefit Decisions

How to Make Smart COVID Risk-Benefit Decisions

The 5Ms of Geriatrics in Gastroenterology: The Path to Creating Age-Friendly Care for Older Adults With Inflammatory Bowel Diseases and Cirrhosis.

The number of Americans 65 years or older in 2060 will be more than double what it was in 2014. Approximately 40% of patients seen in gastroenterology (GI) and hepatology practices in the United States are 60 years or older. Adapting care delivery models, curating data on shifting risk-benefit decisions with geriatric syndromes, understanding appropriate assessments, and focusing on tailored implementation strategies are challenges that are actively confronting us as we provide care for a burgeoning population of older adults. Limited availability of geriatric specialists results in an onus of specialists caring for older adults, such as gastroenterologists, to innovate and develop tailored, comprehensive, and evidence-based care for adults in later life stages. In this article, we present the 5M framework from geriatrics to achieve age-friendly healthcare. The 5Ms are medications, mind, mobility, multicomplexity, and what matters most. We apply the 5M framework to 2 chronic conditions commonly encountered in clinical GI practice: inflammatory bowel diseases and cirrhosis. We highlight knowledge gaps and outline future directions to expand evidence-based care and advance the creation of age-friendly GI care.

553 Myocarditis after COVID-19 vaccination—a case series

Myocarditis has been recognized as a rare complication of SARS-CoV-2 infection even in the absence of lung involvement and recent histological findings suggest that COVID-19-related myocardial damage may differ from other typical lymphocytic myocarditis associated with other viruses and could be possibly linked to diffuse infiltration of monocytes and macrophage leading to microvascular dysfunction and cell necrosis. SARS-CoV-2 vaccines have been well tolerated and associated with decreasing burden of disease in areas with high vaccination rates. Minor side-effects have been frequently described, mainly after second dose. Here, we report our findings in four male patients consistent with acute myocarditis at our Institutional Hospital; all four had recently received a second-dose mRNA vaccine. All presented with acute chest pain associated with biomarker evidence of myocardial injury and were hospitalized. None of them had a previous history of SARS-CoV2 infection. All of them showed markedly abnormal EKG findings with diffuse ST segment elevation and laboratory tests revealed elevated high-sensitivity (hs) troponin T levels and C-reactive protein with no peripheral eosinophilia. All patients underwent nasopharyngeal swabbing and the specimens were tested for common respiratory viruses by RT-PCR and resulted all negative. All patients underwent CMR scan during hospitalization. The hospital course was benign for all patients without evidence of arrhythmias or heart failure, in all cases we performed a conservative treatment with nonsteroidal anti-inflammatory drugs and colchicine with progressive normalization of troponin levels before discharge. Our cases presented features of acute myocarditis with a temporal association with the mRNA Covid-19 vaccination, in absence of other apparent causes (in fact none had viral prodromes) nor COVID-19 infection in the prior year. Several reports in the past months had suggested a possible association between the mRNA Covid-19 and myocarditis, most of the cases presenting in young males, after the second dose and with a favourable course. Thus, given the potential risk of cardiac involvement after SARS-CoV-2 infection even in younger adults, the risk-benefit decisions favours vaccination for population immunity. Despite this, the potential mechanisms of SARS-CoV-2 vaccine-related myocarditis seem different from the previously described eosinophilic myocarditis after smallpox vaccination remain unclear and vaccine adverse event reporting remains of high importance. Figure 1 shows one acute MRI scan with STIR, T2-map and LGE in short-axis and apical four-chamber view.

A review on generation of real-world evidence

Real-world evidence can generate credible evidence to inform treatment decisions. Real-world evidence is in developmental stage and is fast evolving yet there are many unexplained attributes of real-world evidence. Real-world evidence informs benefit-risk decisions and is increasingly being used to support regulatory decision making. Potential benefits of real-world data include determination of extended outcomes including long-term outcomes, opportunities to partner with patients in innovative ways, and reduction in time and cost to generate dependable evidence. Limitations of real-world evidence include uncertainty in the quality of datasets and lack methodologic rigor in real-world studies. Use of real-world evidence for healthcare practices and policies is limited. Ensuring completeness, homogeneity, and linkage of datasets can enhance utility for epidemiological investigations and improvement in health outcomes. Research should be strengthened for real-world studies and technical standards should be reinforced. Collaborations of stakeholders is key to formulation and adoption of guidance for real-world evidence. Real-world data cannot be a substitute to randomized clinical studies but can possibly augment the generated evidence.

A 2-fold Approach to Polyoma Virus (BK) Nephropathy in Kidney Transplants: Distinguishing Direct Virus Effects From Cognate T Cell-mediated Inflammation.

BK nephropathy (BKN) in kidney transplants diagnosed by histology is challenging because it involves damage from both virus activity and cognate T cell-mediated inflammation, directed against alloantigens (rejection) or viral antigens. The present study of indication biopsies from the Integrated Diagnostic System in the International Collaborative Microarray Study Extension study measured major capsid viral protein 2 (VP2) mRNA to assess virus activity and a T cell-mediated rejection (TCMR) classifier to assess cognate T cell-mediated inflammation. Biopsies were assessed by local standard-of-care histology and by genome-wide microarrays and Molecular Microscope Diagnostic System (MMDx) algorithms to detect rejection and injury. In a subset of 102 biopsies (50 BKN and 52 BKN-negative biopsies with various abnormalities), we measured VP2 transcripts by real-time polymerase chain reaction. BKN was diagnosed in 55 of 1679 biopsies; 30 had cognate T cell-mediated activity assessed by by MMDx and TCMR lesions, but only 3 of 30 were histologically diagnosed as TCMR. We developed a BKN probability classifier that predicted histologic BKN (area under the curve = 0.82). Virus activity (VP2 expression) was highly selective for BKN (area under the curve = 0.94) and correlated with acute injury, atrophy-fibrosis, macrophage activation, and the BKN classifier, but not with the TCMR classifier. BKN with molecular TCMR had more tubulitis and inflammation than BKN without molecular TCMR. In 5 BKN cases with second biopsies, VP2 mRNA decreased in second biopsies, whereas in 4 of 5 TCMR classifiers, scores increased. Genes and pathways associated with BKN and VP2 mRNA were similar, reflecting injury, inflammation, and macrophage activation but none was selective for BKN. Risk-benefit decisions in BKN may be assisted by quantitative assessment of the 2 major pathologic processes, virus activity and cognate T cell-mediated inflammation.

How Should the Precautionary Principle Apply to Pregnant Women in Clinical Research?

The precautionary principle is often invoked in relation to pregnant women and may be one of the underlying reasons for their continuous underrepresentation in clinical research. The principle is appealing, because potential fetal harm as a result of research participation is considered to be serious and irreversible. In our paper, we explore through conceptual analysis whether and if so how the precautionary principle should apply to pregnant women. We argue that the principle is a decision-making strategy underlying risk-benefit decisions in clinical research, which can be applied to pregnant women. However, the current application is a strong one, leading to the promotion of absolute exclusion or, less often, absolute inclusion of pregnant women. In order to change this paralyzing situation, a shift toward weak precautionary thinking is necessary. Instead of automatic extreme precaution, a balance will be found between harms and potential benefits of including pregnant women in clinical research.

Progressive Multifocal Leukoencephalopathy Risk Perception in Patients Considering Natalizumab for Multiple Sclerosis

Progressive multifocal leukoencephalopathy (PML) remains a concern when considering natalizumab for multiple sclerosis (MS) treatment. Extensive research has identified factors that increase PML risk, and it is important that providers and patients accurately understand risk to make appropriate benefit-risk decisions. One hundred adult US patient-candidates for natalizumab therapy were questioned about their PML risk perception, the maximum PML risk they deemed acceptable, and sources of information used to understand risk. Differences in group distributions were compared. Patients estimated their potential PML risk from 0.1% to 87% (mean, 31.5%). Maximum PML risk deemed acceptable ranged from 0.1% to 45% (mean, 14.5%). Actual risk (mean, 0.01%), based on published risk estimates, was calculated as a function of time receiving therapy, anti-John Cunningham virus antibody index, and previous use of immunosuppressants. The sexes perceived their risks similarly and had similar risk acceptance. Patient perception of PML risk increased with age, whereas willingness to accept risk remained similar among all ages. Higher levels of education correlated with more accurate risk perception and lower risk tolerance. Neither risk perception nor tolerance was correlated with disability level. Sixty-three percent of patients indicated that their primary/referring physician's concern level regarding potential risk of PML during the benefit-risk discussion was their main source of information about risk. Patients with MS substantially overestimated their PML risk, often by three orders of magnitude. Patients with MS could benefit from accurate risk education, and providers could play an essential role in presenting PML risk information in a manner understandable to each individual patient.

COVID-19 convalescent plasma: Interim recommendations from the AABB.

COVID-19 convalescent plasma (CCP) has emerged as a potential treatment for COVID-19. However, efficacy data and recommendations for its use are limited. AABB commissioned a panel of experts to develop interim recommendations based on limited data to guide use of this scarce resource. The panel performed a literature review using the search terms "COVID-19," "SARS-CoV-2" and "convalescent plasma." The interim recommendations reflect a consensus of expert opinion. INTERIM RECOMMENDATION 1: When making risk benefit decisions, one should consider the risk of CCP as comparable to standard (SARS-CoV-2 non-immune) plasma. INTERIM RECOMMENDATION 2: CCP is optimally effective when transfused as close to symptom onset as possible. CCP is unlikely to provide benefit for patients with late-stage disease or on mechanical ventilation. INTERIM RECOMMENDATION 3: The effectiveness of CCP is related to the antibody quantity within a unit; high-titer CCP is superior to low-titer CCP. A single high-titer unit should be sufficient for most patients. INTERIM RECOMMENDATION 4: If group B or group AB CCP is unavailable, transfusion of group A or group O CCP with low anti-A/B titer may be acceptable for group B and group AB patients. INTERIM RECOMMENDATION 5: Additional randomized controlled trial (RCT) data are needed to fully assess CCP efficacy and to identify which specific patient populations and unit characteristics might confer the greatest benefit. These interim recommendations are based on the best-available evidence at the time of writing. Additional data from on-going RCTs will lead to clinical practice guidelines in the future.

The COVID-19 crisis as an opportunity to strengthen global regulatory coordination for sustained enhanced access to diagnostics and therapeutics.

The coronavirus disease 2019 (COVID-19) pandemic presents an unparalleled opportunity for regulators globally to strengthen coordination, advance alignment initiatives, and exercise regulatory agility to facilitate access to the surge in diagnostics, therapies and vaccines without compromising public safety. We describe international collaborative initiatives, summarise key experiences, and urge the global regulatory community to apply lessons from the current pandemic to strengthen and sustain cooperation for future public health emergencies and enhanced health products access.

In Reply: The Coronavirus Disease 2019 Global Pandemic: A Neurosurgical Treatment Algorithm.

In Reply: The Coronavirus Disease 2019 Global Pandemic: A Neurosurgical Treatment Algorithm.

Quantifying Preferences in Drug Benefit‐Risk Decisions

Benefit-risk assessment is used in various phases along the drug lifecycle, such as marketing authorization and surveillance, health technology assessment (HTA), and clinical decisions, to understand whether, and for which patients, a drug has a favorable or more valuable profile with reference to one or more comparators. Such assessments are inherently preference-based as several clinical and nonclinical outcomes of varying importance might act as evaluation criteria, and decision makers must establish acceptable trade-offs between these outcomes. Different healthcare stakeholder perspectives, such as those from patients and healthcare professionals, are key for informing benefit-risk trade-offs. However, the degree to which such preferences inform the decision is often unclear as formal preference-based evaluation frameworks are generally not used for regulatory decisions, and, if used, rarely communicated in HTA decisions. We argue that for better decisions, as well as for reasons of transparency, preferences in benefit-risk decisions should more often be quantified and communicated explicitly.

Why Do Promising Therapies Stall in Development and How Can We Move Them Forward?

There are many reasons that molecules fail to progress to market and various principles of risk-benefit decisions that can help drive the molecule through development. This symposium included discussions on global strategies involved in pushing promising molecules to market, what to do when a molecule stalls in its progress to market, and options for rescuing the molecule and pushing it forward again. Innovative partnerships that bring stalled drugs back into clinical development were also addressed. A regulatory perspective on common reasons for a molecule to fail in its forward progress was presented. In addition, situations arise when a third-party advisory committee can provide input to help overcome issues identified by a regulatory agency. Using examples from the private and public domain, presentations centered on how to repurpose a molecule and when more science is needed.