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Drug efficacy and effectiveness are assessed respectively through clinical trials and pharmaco-epidemiological studies. However, relative and absolute benefits of drugs are distinct measures that must be considered in relation to the baseline risk of disease incidence, complication or progression. On the other hand, adverse drug reactions are independent of the basic risk but depend on the characteristics of the population treated. Given these prerequisites, how can we balance the benefits and risks of drugs? We use the example of therapeutics evaluated during Covid to describe how assessing the benefit-risk balance of drugs is a complex process. Clinical trials are not designed to identify rare adverse events, underscoring the necessity for a pharmacovigilance system. Evaluating the balance between the benefits and risks of drugs is an ongoing process, demanding the simultaneous analysis of data from clinical trials, potential drug-drug interactions, pharmacovigilance monitoring and pharmaco-epidemiological studies, to identify potential safety concerns. In addition, pharmacologists must play a major role in educating the general public about drugs, aiding in the accurate interpretation of the benefit-risk balance and preventing misinformation. [ABSTRACT FROM AUTHOR]

Abstract Over the past decade, we have witnessed the development of cell transplantation as a new strategy for repairing spinal cord injury (SCI). However, due to the complexity of the central nervous system (CNS), achieving successful clinical translation remains a significant challenge. Human umbilical cord mesenchymal stem cells (hUMSCs) possess distinct advantages, such as easy collection, lack of ethical concerns, high self-renewal ability, multilineage differentiation potential, and immunomodulatory properties. hUMSCs are promising for regenerating the injured spinal cord to a significant extent. At the same time, for advancing SCI treatment, the appropriate benefit and risk evaluation methods play a pivotal role in determining the clinical applicability of treatment plans. Hence, this study discusses the advantages and risks of hUMSCs in SCI treatment across four dimensions—comprehensive evaluation of motor and sensory function, imaging, electrophysiology, and autonomic nervous system (ANS) function—aiming to improve the rationality of relevant clinical research and the feasibility of clinical translation.

Over the past decade, we have witnessed the development of cell transplantation as a new strategy for repairing spinal cord injury (SCI). However, due to the complexity of the central nervous system (CNS), achieving successful clinical translation remains a significant challenge. Human umbilical cord mesenchymal stem cells (hUMSCs) possess distinct advantages, such as easy collection, lack of ethical concerns, high self-renewal ability, multilineage differentiation potential, and immunomodulatory properties. hUMSCs are promising for regenerating the injured spinal cord to a significant extent. At the same time, for advancing SCI treatment, the appropriate benefit and risk evaluation methods play a pivotal role in determining the clinical applicability of treatment plans. Hence, this study discusses the advantages and risks of hUMSCs in SCI treatment across four dimensions—comprehensive evaluation of motor and sensory function, imaging, electrophysiology, and autonomic nervous system (ANS) function—aiming to improve the rationality of relevant clinical research and the feasibility of clinical translation. [ABSTRACT FROM AUTHOR]

With limited understanding of most new biotechnologies, how do citizens form their opinion and what factors influence their attitudes about these innovations? In this study, we use gene drive biotechnology in agricultural pest management as an example and theoretically propose that given low levels of knowledge and awareness, citizens' acceptance of, or opposition to, gene drive is significantly shaped by two predisposition factors: individuals' general orientation toward science and technology, and their specific benefit‐risk assessment frame. Empirically, we employ data collected from a recent US nationally representative public opinion survey (N = 1220) and conduct statistical analyses to test the hypotheses derived from our theoretical expectations. Our statistical analyses, based on various model specifications and controlling for individual‐level covariates and state‐fixed effects, show that citizens with a more favorable general orientation toward science and technology are more likely to accept gene drive. Our data analyses also demonstrate that citizens' specific gene drive assessment frame—consisting of a potential benefit dimension and a potential risk dimension, significantly shapes their attitudes as well—specifically, people emphasizing more on the benefit dimension are more likely to accept gene drive, whereas those who place more importance on the risk dimension tend to oppose it. We discuss contributions of our study and make suggestions for future research in the conclusion. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the benefit-risk of 3 commonly used Chinese medicine injections, Aidi Injection (ADI), Cinobufagin Injection (CINI) and Compound Kushen Injection (CKI), in the treatment of primary liver cancer (PLC), so as to provide a reference for clinical decision-making. Methods: Randomized controlled trials (RCTs) of ADI, CINI and CKI in the treatment of PLC published in the databases of China National Knowledge Infrastructure, Wanfang, China Science and Technology Journal Database, SinoMed, PubMed, Cochrane Library, and Web of Science were retrieved from January 2020 to October 2022. The data of benefit and risk indicators were combined to obtain the effect value. The multi-criteria decision analysis (MCDA) model was applied to build the decision tree. The benefit value, risk value and benefit risk value of the 3 injections in PLC treatment were calculated. Monte Carlo simulation was carried out to calculate the 95% confidence interval and probability of differences among the 3 injections, so as to optimize the evaluation results. Results: A total of 71 RCTs were included. The benefit values of ADI, CINI and CKI combined with transcatheter arterial chemoembolization (TACE) were 42, 38 and 36, respectively. The risk values were 42, 25 and 37, respectively. The benefit risk values were 42, 31 and 37, respectively. The benefit risk differences of ADI vs. CINI, ADI vs. CKI, and CKI vs. CINI were 11 (−0.86, 17.75), 5 (−5.01, 11.09), and 6 (−1.87, 12.63), respectively. The probability that ADI superior to CINI, ADI superior to CKI, and CKI superior to CINI was 96.26%, 77.27%, and 92.62%, respectively. Conclusion: Based on the results of MCDA model, CINI combined with TACE has the greatest risk in the treatment of the PLC. Considering the efficacy and safety, the possible priority of the 3 Chinese medicine injections combined with TACE in the treatment of PLC is ADI, CKI and CINI. [ABSTRACT FROM AUTHOR]

Background There is no risk and benefit assessment of COVID-19 vaccination for children younger than 5 years using a single health outcomes scale. The objective of this study is to compare the expected risk and benefits of the mRNA primary series of COVID-19 vaccines for children aged 6 months to 4 years in the United States using a single health outcome scale in the Omicron era. Methods The expected benefits and risks of the primary two-dose series of mRNA COVID-19 vaccines for children aged 6 months to 4 years were stratified by sex, the presence of underlying medical conditions, the presence of infection-induced immunity, and the type of mRNA vaccine (BNT162b2 or mRNA-1273). A scoping literature review was conducted to identify the indicators in the decision tree model. The benefit–risk ratio was the outcome of interest. Results The benefit–risk ratios ranged from 200.4 in BNT162b2 for males aged 6–11 months with underlying medical conditions and without infection-induced immunity to 3.2 in mRNA-1273 for females aged 1–4 years without underlying medical conditions and with infection-induced immunity. Conclusions The expected benefit of receiving the primary series of mRNA vaccines outweighed the risk among children ages 6 months to 4 years regardless of sex, presence of underlying medical conditions, presence of infection-induced immunity, or type of mRNA vaccines. However, the continuous monitoring of the COVID-19 epidemiology as well as vaccine effectiveness and safety is important. [ABSTRACT FROM AUTHOR]

A fundamental problem in the regulatory evaluation of a therapy is assessing whether the benefit outweighs the associated risks. This work proposes designing a trial that assesses a composite endpoint consisting of benefit and risk, hence, making the core of the design of the study, to assess benefit and risk. The proposed benefit risk measure consists of efficacy measure(s) and a risk measure that is based on a composite score obtained from pre-defined adverse events of interest (AEI). This composite score incorporates full aspects of adverse events of interest (i.e. the incidence, severity, and duration of the events). We call this newly proposed score the AEI composite score. After specifying the priorities between the components of the composite endpoint, a win-statistic (i.e. win ratio, win odds, or net benefit) is used to assess the difference between treatments in this composite endpoint. The power and sample size requirements of such a trial design are explored via simulation. Finally, using Dupixent published adult study results, we show how we can design a paediatric trial where the primary outcome is a composite of prioritized outcomes consisting of efficacy endpoints and the AEI composite score endpoint. The resulting trial design can potentially substantially reduce sample size compared to a trial designed to assess the co-primary efficacy endpoints, therefore it may address the challenge of slow enrollment and patient availability for paediatric studies. [ABSTRACT FROM AUTHOR]

Study Objective: The purpose of this study is to rank the factors that are most and least important to patients with symptomatic uterine fibroids when considering surgical treatment options. Materials and Methods: Using a best worst scaling (BWS) preference elicitation approach, participants completed an online survey to rank factors associated with fibroid surgical treatments. Survey content was based on a literature review and included the following factors: symptom relief; surgical complications; repeat treatment; recovery time; cosmetic effects; risk of spreading undiagnosed cancer; sexual outcomes; maintenance of child-bearing; continuation of menses; unpredictable menses; and location of procedure. Participants completed 11 BWS tasks. For each task, we presented participants with a subset of 5 factors from the possible 11, and participants chose the most important and least important factor. Participants' responses were analyzed using conditional logistic regression to determine the relative importance of factors. Patient priorities were further explored via age and race. Results: 285 respondents with symptomatic uterine fibroids (69 physician-confirmed and 216 self-reported) who had not undergone prior surgical treatment completed the survey. Respondents were enrolled from two clinical sites (clinical site cohort) and an online consumer panel (panel cohort). Both cohorts identified symptom relief, cancer risk, repeat treatment and complications as the most important factors in selecting surgical treatment options and location of procedure, return to normal activities after surgery, and cosmetic effects like presence of a scar after the surgical treatment as the least important factors. Of note, younger women (≤ 40) placed greater importance on the ability to have children after the procedure. Conclusion: Information regarding the factors most and least important to patients with symptomatic uterine fibroids might inform development and regulatory evaluation of new technologies and procedures. Study results may be useful in efforts to develop a set of outcomes to include in future fibroids clinical studies. [ABSTRACT FROM AUTHOR]

Objective: Patients have unique insights and are (in-)directly affected by each decision taken throughout the life cycle of medicinal products. Patient preference studies (PPS) assess what matters most to patients, how much, and what tradeoffs patients are willing to make. IMI PREFER was a six-year European public-private partnership under the Innovative Medicines Initiative that developed recommendations on how to assess and use PPS in medical product decision-making, including in the regulatory evaluation of medicinal products. This paper aims to summarize findings and recommendations from IMI PREFER regarding i) PPS applications in regulatory evaluation, ii) when and how to consult with regulators on PPS, iii) how to reflect PPS in regulatory communication and iv) barriers and open questions for PPS in regulatory decision-making. Methods: PREFER performed six literature reviews, 143 interviews and eight focus group discussions with regulators, patient representatives, industry representatives, Health Technology Assessment bodies, payers, academics, and clinicians between October 2016 and May 2022. Results: i) With respect to PPS applications, prior to the conduct of clinical trials of medicinal products, PPS could inform regulators' understanding of patients' unmet needs and relevant endpoints during horizon scanning activities and scientific advice. During the evaluation of a marketing authorization application, PPS could inform: a) the assessment of whether a product meets an unmet need, b) whether patient-relevant clinical trial endpoints and outcomes were studied, c) the understanding of patient-relevant effect sizes and acceptable trade-offs, and d) the identification of key (un-)favorable effects and uncertainties. ii) With respect to consulting with regulators on PPS, PPS researchers should ideally have early discussions with regulators (e.g., during scientific advice) on the PPS design and research questions. iii) Regarding external PPS communication, PPS could be reflected in the assessment report and product information (e.g., the European Public Assessment Report and the Summary of Product Characteristics). iv) Barriers relevant to the use of PPS in regulatory evaluation include a lack of PPS use cases and demonstrated impact on regulatory decision-making, and need for (financial) incentives, guidance and quality criteria for implementing PPS results in regulatory decision-making. Open questions concerning regulatory PPS use include: a) should a product independent broad approach to the design of PPS be taken and/or a product-specific one, b) who should optimally be financing, designing, conducting, and coordinating PPS, c) when (within and/or outside clinical trials) to perform PPS, and d) how can PPS use best be operationalized in regulatory decisions. Conclusion: PPS have high potential to inform regulators on key unmet needs, endpoints, benefits, and risks that matter most to patients and their acceptable trade-offs. Regulatory guidelines, templates and checklists, together with incentives are needed to foster structural and transparent PPS submission and evaluation in regulatory decision-making. More PPS case studies should be conducted and submitted for regulatory assessment to enable regulatory discussion and increase regulators' experience with PPS implementation and communication in regulatory evaluations. [ABSTRACT FROM AUTHOR]

BACKGROUND: Shared decision-making is mandated for patients receiving primary prevention implantable cardioverter defibrillators (ICDs). Less attention has been paid to generator exchange decisions, although at the time of generator exchange, patients' risk of sudden cardiac death, risk of procedural complications, quality of life, or prognosis may have changed. This study was designed to explore how patients make ICD generator exchange decisions. METHODS: Emory Healthcare patients with primary prevention ICDs implanted from 2013 to 2021 were recruited to complete in-depth interviews exploring perspectives regarding generator exchanges. Interviews were conducted in 2021. Transcribed interviews were qualitatively coded using multilevel template analytic methods. To investigate benefit thresholds for pursuing generator exchanges, patients were presented standard-gamble type hypothetical scenarios where their ICD battery was depleted but their 5-year risk of sudden cardiac death at that time varied (10%, 5%, and 1%). RESULTS: Fifty patients were interviewed; 18 had a prior generator exchange, 16 had received ICD therapy, and 17 had improved left ventricular ejection fraction. As sudden cardiac death risk decreased from 10% to 5% to 1%, the number of participants willing to undergo a generator exchange decreased from 48 to 42 to 33, respectively. Responses suggest that doctor's recommendations are likely to substantially impact patients' decision-making. Other drivers of decision-making included past experiences with ICD therapy and device implantation, as well as risk aversion. Therapeutic inertia and misconceptions about ICD therapy were common and represent substantive barriers to effective shared decision-making in this context. CONCLUSIONS: Strong defaults may exist to continue therapy and exchange ICD generators. Updated risk stratification may facilitate shared decision-making and reduce generator exchanges in very low-risk patients, especially if these interventions are directed toward clinicians. Interventions targeting phenomena such as therapeutic inertia may be more impactful and warrant exploration in randomized trials. [ABSTRACT FROM AUTHOR]

Abstract Objective A multicriteria decision analysis (MCDA) model was used to evaluate the benefits and risks of traditional Chinese medicine preparations of sinomenine alone or in combination with conventional drugs in the treatment of rheumatoid arthritis (RA) and to provide a basis for the rational clinical application of sinomenine. Methods A study search was performed using six major databases, and Review Manager 5.3 was used for data analysis. Then, an MCDA model evaluation system was established for the treatment of RA with sinomenine preparations, and the benefit values, risk values, and total benefit-risk values of sinomenine preparations alone or in combination with conventional drugs were calculated using Hiview 3.2 software. Finally, Monte Carlo simulations were performed using Crystal Ball embedded in Excel software to calculate the 95% confidence intervals (95% CI), and the probability of the differences between the 2 drug regimens was determined to optimize the evaluation results. Results Forty-four randomized controlled trials (RCTs) were included. Quantitative assessment of the MCDA model showed that the sinomenine preparation alone offered less benefits than when combined with conventional drugs with a benefit difference of 20 (95% CI 3.06, 35.71). However, the risk of the combination was significantly lower with a risk difference of 13(95% CI -10.26, 27.52). The total value of the benefit-risk of sinomenine alone and in combination with conventional drugs was 46 and 53 at 60% and 40% of the benefit-risk ratio of the two dosing regimens, respectively, with a difference of 7 (95% CI -4.26, 22.12). The probability that the comprehensive score of the combined regimen is greater than that of sinomenine alone is 90.1%, and the evaluation was steady. Conclusion The benefit-risk of the combined application regimen of sinomenine is greater than that of sinomenine alone.

Rice arsenic (As) contamination and its consumption poses a significant health threat to humans. The present study focuses on the contribution of arsenic, micronutrients, and associated benefit-risk assessment through cooked rice from rural (exposed and control) and urban (apparently control) populations. The mean decreased percentages of As from uncooked to cooked rice for exposed (Gaighata), apparently control (Kolkata), and control (Pingla) areas are 73.8, 78.5, and 61.3%, respectively. The margin of exposure through cooked rice (MoEcooked rice) < 1 signifies the existence of health risk for all the studied exposed and control age groups. The respective contributions of iAs (inorganic arsenic) in uncooked and cooked rice are nearly 96.6, 94.7, and 100% and 92.2, 90.2, and 94.2% from exposed, apparently control, and control areas. LCR analysis for the exposed, apparently control, and control populations (adult male: 2.1 × 10–3, 2.8 × 10–4, 4.7 × 10–4; adult female: 1.9 × 10–3, 2.1 × 10–4, 4.4 × 10–4; and children: 5.8 × 10–4, 4.9 × 10–5, 1.1 × 10–4) through cooked rice is higher than the recommended value, i.e., 1 × 10–6, respectively, whereas HQ > 1 has been observed for all age groups from the exposed area and adult male group from the control area. Adults and children from rural area showed that ingestion rate (IR) and concentration are the respective influencing factors towards cooked rice As, whereas IR is solely responsible for all age groups from urban area. A vital suggestion is to reduce the IR of cooked rice for control population to avoid the As-induced health risks. The average intake (μg/day) of micronutrients is in the order of Zn > Se for all the studied populations and Se intake is lower for the exposed population (53.9) compared to the apparently control (140) and control (208) populations. Benefit-risk assessment supported that the Se-rich values in cooked rice are effective in avoiding the toxic effect and potential risk from the associated metal (As). [ABSTRACT FROM AUTHOR]

Objective: Patients have unique insights and are (in-)directly affected by each decision taken throughout the life cycle of medicinal products. Patient preference studies (PPS) assess what matters most to patients, how much, and what trade-offs patients are willing to make. IMI PREFER was a six-year European public-private partnership under the Innovative Medicines Initiative that developed recommendations on how to assess and use PPS in medical product decision-making, including in the regulatory evaluation of medicinal products. This paper aims to summarize findings and recommendations from IMI PREFER regarding i) PPS applications in regulatory evaluation, ii) when and how to consult with regulators on PPS, iii) how to reflect PPS in regulatory communication and iv) barriers and open questions for PPS in regulatory decision-making.Methods: PREFER performed six literature reviews, 143 interviews and eight focus group discussions with regulators, patient representatives, industry representatives, Health Technology Assessment bodies, payers, academics, and clincians between October 2016 and May 2022.Results: i) With respect to PPS applications, prior to the conduct of clinical trials of medicinal products, PPS could inform regulators’ understanding of patients’ unmet needs and relevant endpoints during horizon scanning activities and scientific advice. During the evaluation of a marketing authorization application, PPS could inform: a) the assessment of whether a product meets an unmet need, b) whether patient-relevant clinical trial endpoints and outcomes were studied, c) the understanding of patient-relevant effect sizes and acceptable trade-offs, and d) the identification of key (un-)favorable effects and uncertainties. ii) With respect to consulting with regulators on PPS, PPS researchers should ideally have early discussions with regulators (e.g., during scientific advice) on the PPS design and research questions. iii) Regarding external PPS communication, PPS could be reflected in the assessment report and product information (e.g., the European Public Assessment Report and the Summary of Product Characteristics). iv) Barriers relevant to the use of PPS in regulatory evaluation include a lack of PPS use cases and demonstrated impact on regulatory decision-making, and need for (financial) incentives, guidance and quality criteria for implementing PPS results in regulatory decision-making. Open questions concerning regulatory PPS use include: a) should a product independent broad approach to the design of PPS be taken and/or a product-specific one, b) who should optimally be financing, designing, conducting, and coordinating PPS, c) when (within and/or outside clinical trials) to perform PPS, and d) how can PPS use best be operationalized in regulatory decisions.Conclusion: PPS have high potential to inform regulators on key unmet needs, endpoints, benefits, and risks that matter most to patients and their acceptable trade-offs. Regulatory guidelines, templates and checklists, together with incentives are needed to foster structural and transparent PPS submission and evaluation in regulatory decision-making. More PPS case studies should be conducted and submitted for regulatory assessment to enable regulatory discussion and increase regulators’ experience with PPS implementation and communication in regulatory evaluations.

Benefit-risk assessment is commonly conducted by drug and medical device developers and regulators, to evaluate and communicate issues around benefit-risk balance of medical products. Quantitative benefit-risk assessment (qBRA) is a set of techniques that incorporate explicit outcome weighting within a formal analysis to evaluate the benefit-risk balance. This report describes emerging good practices for the 5 main steps of developing qBRAs based on the multicriteria decision analysis process. First, research question formulation needs to identify the needs of decision makers and requirements for preference data and specify the role of external experts. Second, the formal analysis model should be developed by selecting benefit and safety endpoints while eliminating double counting and considering attribute value dependence. Third, preference elicitation method needs to be chosen, attributes framed appropriately within the elicitation instrument, and quality of the data should be evaluated. Fourth, analysis may need to normalize the preference weights, base-case and sensitivity analyses should be conducted, and the effect of preference heterogeneity analyzed. Finally, results should be communicated efficiently to decision makers and other stakeholders. In addition to detailed recommendations, we provide a checklist for reporting qBRAs developed through a Delphi process conducted with 34 experts. • This report presents current expert consensus in emerging good practice for developing methodologically rigorous and fit-for-purpose quantitative benefit-risk assessments, together with a checklist to support their reporting. • We provide detailed recommendations on each of the 5 main steps of quantitative benefit-risk assessments: formulating the research question, choosing appropriate analysis models, evaluating the attribute sets and diagnosing any potential violations of model assumptions, choosing the appropriate methods to elicit the required preference weights, and communicating the results effectively. • For preference elicitation, we provide an overview of the 3 methods that are appropriate for eliciting outcome weighting: discrete choice experiments, threshold technique, and swing weighting. [ABSTRACT FROM AUTHOR]

Worldwide medical device regulatory authorities increasingly rely on the benefit-risk ratio for decision-making. However, current benefit-risk assessment (BRA) methods are mostly descriptive, not quantitative. We aimed to summarize the regulatory requirements of BRA, discuss the feasibility of adopting multiple criteria decision analysis (MCDA), and explore factors for optimizing the MCDA for quantitative BRA of devices. Regulatory organizations emphasize BRA in their guidance, and some recommend user-friendly worksheets to conduct qualitative/descriptive BRA. The MCDA is considered one of the most useful and relevant quantitative BRA methods by pharmaceutical regulatory agencies and the industry; the International Society for Pharmacoeconomics and Outcomes Research summarized the principles and good practice guidance of MCDA. We recommend optimizing the MCDA by considering the following unique characteristics of the device BRA: using data from state of the art as a control and clinical data from post-market surveillance and literature; considering the device's diverse characteristics when selecting controls; assigning weight according to type, magnitude/severity, and duration of benefits and risks; and including physician and patient opinions in the MCDA. This article is the first to explore using MCDA for device BRA and might lead to a novel quantitative BRA method for devices. Worldwide regulatory organizations for medical devices emphasize benefit–risk assessment (BRA) in their guidance and recommend qualitative or descriptive BRA approaches. However, no guidance has described any quantitative BRA method for medical devices. The multiple criteria decision analysis (MCDA) method is considered the most useful and relevant quantitative BRA method for drugs by pharmaceutical regulatory agencies and industries. The principles of MCDA are described by the International Society for Pharmacoeconomics and Outcomes Research and lead to emerging good practice guidance on the implementation of MCDA to support healthcare decision-making. To optimize the MCDA method for the quantitative BRA of medical devices, we recommend considering the unique characteristics thereof; including using data from SOTA as a control; using additional clinical data from post-market surveillance and literature; considering the device's diverse characteristics when selecting a control; assigning weight according to the type, magnitude/severity, and duration of benefits and risks; and including both physician and patient opinions in the MCDA method. The medical device industry and device regulatory organizations could benefit from this article. A quantitative BRA tool can be developed based on our findings and can be used by agencies and companies to monitor the safety and effectiveness of medical devices throughout their life cycle. Future research should focus on developing these theoretical considerations into a user-friendly tool for the quantitative BRA of devices and the validation of such tools using different types of devices. [ABSTRACT FROM AUTHOR]

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Objective: A multicriteria decision analysis (MCDA) model was used to evaluate the benefits and risks of traditional Chinese medicine preparations of sinomenine alone or in combination with conventional drugs in the treatment of rheumatoid arthritis (RA) and to provide a basis for the rational clinical application of sinomenine. Methods: A study search was performed using six major databases, and Review Manager 5.3 was used for data analysis. Then, an MCDA model evaluation system was established for the treatment of RA with sinomenine preparations, and the benefit values, risk values, and total benefit-risk values of sinomenine preparations alone or in combination with conventional drugs were calculated using Hiview 3.2 software. Finally, Monte Carlo simulations were performed using Crystal Ball embedded in Excel software to calculate the 95% confidence intervals (95% CI), and the probability of the differences between the 2 drug regimens was determined to optimize the evaluation results. Results: Forty-four randomized controlled trials (RCTs) were included. Quantitative assessment of the MCDA model showed that the sinomenine preparation alone offered less benefits than when combined with conventional drugs with a benefit difference of 20 (95% CI 3.06, 35.71). However, the risk of the combination was significantly lower with a risk difference of 13(95% CI -10.26, 27.52). The total value of the benefit-risk of sinomenine alone and in combination with conventional drugs was 46 and 53 at 60% and 40% of the benefit-risk ratio of the two dosing regimens, respectively, with a difference of 7 (95% CI -4.26, 22.12). The probability that the comprehensive score of the combined regimen is greater than that of sinomenine alone is 90.1%, and the evaluation was steady. Conclusion: The benefit-risk of the combined application regimen of sinomenine is greater than that of sinomenine alone. [ABSTRACT FROM AUTHOR]

Children frequently respond differently to therapies compared to adults. Differences also exist between paediatric age groups for pharmacokinetics and pharmacodynamics in both efficacy and safety. Paediatric pharmacovigilance requires an understanding of the unique aspects of children with regard to, for example, drug response, growth and development, clinical presentation of adverse drug reactions (ADRs), how they can be detected and population‐specific factors (e.g., more frequent use of off‐label/unlicensed drugs). In recognition of these challenges, a group of experts has been formed in the context of the conect4children (c4c) project to support paediatric drug development. This expert group collaborated to develop methodological considerations for paediatric drug safety and pharmacovigilance throughout the life‐cycle of medicinal products which are described in this article. These considerations include practical points to consider for the development of the paediatric section of the risk management plan (RMP), safety in paediatric protocol development, safety data collection and analysis. Furthermore, they describe the specific details of post‐marketing pharmacovigilance in children using, for example, spontaneous reports, electronic health care records, registries and record‐linkage, as well as the use of paediatric pharmacoepidemiology studies for risk characterisation. Next the details of the assessment of benefit–risk and challenges related to medicinal product formulation in the context of a Paediatric Investigation Plan (PIP) are presented. Finally, practical issues in paediatric signal detection and evaluation are included. This paper provides practical points to consider for paediatric pharmacovigilance throughout the life‐cycle of medicinal products for RMPs, protocol development, safety data collection and analysis and PIPs. [ABSTRACT FROM AUTHOR]

Introduction: Lifelong Antiretroviral Therapy (ARVT) in patients with Human Immunodeficiency Virus (HIV) infection damages cochlea. Hearing Loss (HL) has been reported with lamivudine therapy in both HIV and/or Hepatitis B Virus (HBV) infections. Hence, the benefit of lamivudine therapy in individuals affected by these infections and risk of development of HL needs to be studied to make an adequate benefit-risk assessment. Aim: To evaluate the relationship of hearing impairment in patients treated with lamivudine and diagnosed with either HIV or HBV infection. Materials and Methods: The present study is a systematic review in which English-language publications that assessed HL in patients who are on lamivudine drug therapy were included. The types of studies included were: prospective studies, retrospective studies, case reports and case series. A comprehensive database search (PubMed, PubMed Central, Cochrane review, Google scholar and Embase) was conducted to identify the relevant literature published on HL and were searched for keywords related to lamivudine and HL- 'lamivudine and hearing loss', 'lamivudine and deafness', 'lamivudine and hypoacusis', 'lamivudine and hearing impairment' and 'lamivudine and ototoxicity' for searching the data. The publications were independently reviewed and assessed for study quality and the data (title, author, year of publication, study design, study setting, population characteristics) extraction was done. Results: Out of 1,778 publications found at the initial stage, nine were included in the systematic review and quantitative metaanalysis. The majority (4/9) were cross-sectional studies. The prevalence of hearing impairment defined as per the protocol was 41% (total population 1,548). The I2 statistic was used to test statistical heterogeneity, with values of >50% representing important heterogeneity, then a random-effects model was used to perform the meta-analysis. A subgroup analysis was performed for the age group =18 years and >18 years. All analyses were conducted using the R software version 4.1.0. It was found that most of the studies (8/9) suffered moderateserious overall risk across all the domains of ROBINS-1 tool. Conclusion: This study showed a positive association of HL with lamivudine in patients with HIV infection. [ABSTRACT FROM AUTHOR]

Introduction: Lifelong Antiretroviral Therapy (ARVT) in patients with Human Immunodeficiency Virus (HIV) infection damages cochlea. Hearing Loss (HL) has been reported with lamivudine therapy in both HIV and/or Hepatitis B Virus (HBV) infections. Hence, the benefit of lamivudine therapy in individuals affected by these infections and risk of development of HL needs to be studied to make an adequate benefit-risk assessment. Aim: To evaluate the relationship of hearing impairment in patients treated with lamivudine and diagnosed with either HIV or HBV infection. Materials and Methods: The present study is a systematic review in which English-language publications that assessed HL in patients who are on lamivudine drug therapy were included. The types of studies included were: prospective studies, retrospective studies, case reports and case series. A comprehensive database search (PubMed, PubMed Central, Cochrane review, Google scholar and Embase) was conducted to identify the relevant literature published on HL and were searched for keywords related to lamivudine and HL- ‘lamivudine and hearing loss’, ‘lamivudine and deafness’, ‘lamivudine and hypoacusis’, ‘lamivudine and hearing impairment’ and ’lamivudine and ototoxicity’ for searching the data. The publications were independently reviewed and assessed for study quality and the data (title, author, year of publication, study design, study setting, population characteristics) extraction was done. Results: Out of 1,778 publications found at the initial stage, nine were included in the systematic review and quantitative meta-analysis. The majority (4/9) were cross-sectional studies. The prevalence of hearing impairment defined as per the protocol was 41% (total population 1,548). The I2 statistic was used to test statistical heterogeneity, with values of >50% representing important heterogeneity, then a random-effects model was used to perform the meta-analysis. A subgroup analysis was performed for the age group ≤18 years and >18 years. All analyses were conducted using the R software version 4.1.0. It was found that most of the studies (8/9) suffered moderate-serious overall risk across all the domains of ROBINS-1 tool. Conclusion: This study showed a positive association of HL with lamivudine in patients with HIV infection.

Background: This study identifies populations who may benefit most from expanded cancer screening.Methods: Two American Cancer Society prospective cohort studies, Cancer Prevention Study-II Nutrition Cohort and Cancer Prevention Study-3, were used to identify the risk factors associated with a > 2% absolute risk of any cancer within 5 years. In total, 429,991 participants with no prior personal history of cancer were followed for cancer for up to 5 years. Multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for association. By using these hazard ratios, individualized coherent absolute risk estimation was used to calculate absolute risks by age.Results: Overall, 15,226 invasive cancers were diagnosed among participants within 5 years of enrollment. The multivariable-adjusted relative risk of any cancer was strongest for current smokers compared with never-smokers. In men, alcohol intake, family history of cancer, red meat consumption, and physical inactivity were also associated with risk (p < .05). In women, body mass index, type 2 diabetes, hysterectomy, parity, family history of cancer, hypertension, tubal ligation, and physical inactivity were associated (p < .05). The absolute 5-year risk exceeded 2% among nearly all participants older than 50 years and among some participants younger than 50 years, including current or former smokers (<30 years since quitting) and long-term nonsmokers with a body mass index >25 kg/m2 or a first-degree family history of cancer. The absolute 5-year risk was as high as 29% in men and 25% in women.Conclusions: Older age and smoking were the two most important risk factors associated with the relative and absolute 5-year risk of developing any cancer. [ABSTRACT FROM AUTHOR]

Objective: Demonstrate how benefit‐risk profiles of systemic treatments for moderate‐to‐severe osteoarthritis (OA) can be compared using a quantitative approach accounting for patient preference. Study design and setting: This study used a multimethod benefit‐risk modelling approach to quantifiably compare treatments of moderate‐to‐severe OA. In total four treatments and placebo were compared. Comparisons were based on four attributes identified as most important to patients. Patient Global Assessment of Osteoarthritis was included as a favourable effect. Unfavourable effects, or risks, included opioid dependence, nonfatal myocardial infarction and rapidly progressive OA leading to total joint replacement. Clinical data from randomized clinical trials, a meta‐analysis of opioid dependence and a long‐term study of celecoxib were mapped into value functions and weighted with patient preferences from a discrete choice experiment. Results: Lower‐dose NGFi had the highest weighted net benefit‐risk score (0.901), followed by higher‐dose NGFi (0.889) and NSAIDs (0.852), and the lowest score was for opioids (0.762). Lower‐dose NGFi was the highest‐ranked treatment option even when assuming a low incidence (0.34% instead of 4.7%) of opioid dependence (ie, opioid benefit‐risk score 808) and accounting for both the uncertainty in clinical effect estimates (first rank probability 46% vs 20% for NSAIDs) and imprecision in patient preference estimates (predicted choice probability 0.26, 95% confidence interval [CI] 0.25‐0.28 vs 0.21, 95% CI 0.19‐0.23 for NSAIDs). Conclusion: The multimethod approach to quantitative benefit‐risk modelling allowed the interpretation of clinical data from the patient perspective while accounting for uncertainties in the clinical effect estimates and imprecision in patient preferences. [ABSTRACT FROM AUTHOR]

• When considering high intensity focused ultrasound (HIFU) ablation therapies, patients marginally prioritized urinary incontinence (UI) over prostate biopsy outcomes, and erectile dysfunction (ED) was the least important outcome. • Patients are willing to accept increased risk of ED or UI to obtain an increased chance of favorable biopsy outcome. • Results from this study may help inform development and evaluation of future HIFU ablation therapies. Food and Drug Administration must make decisions about emerging high intensity focused ultrasound (HIFU) devices that may lack relevant clinical oncologic data but present with known side effects. This study aims to capture patients' perspective by quantifying their preferences regarding the available benefit and important side effects associated with HIFU for localized prostate cancer. Preferences for HIFU outcomes were examined using a discrete choice experiment survey. Participants were asked to choose a preferred treatment option in 9 choice questions. Each included a pair of hypothetical treatment profiles that have similar attributes/outcomes with varying levels. Outcomes included prostate biopsy outcome and treatment-related risks of erectile dysfunction (ED) and urinary incontinence (UI). We calculated the maximum risk of side effect patients were willing to tolerate in exchange for increased benefit. Preferences were further explored via clinical and demographic data. About 223 subjects with a mean age of 64.8 years completed the survey. Respondents were willing to accept a 1.51%-point increase in new ED risk for a 1%-point increase in favorable biopsy outcome. They were also willing to accept a 0.93%-point increase in new UI risk for a 1%-point increase in biopsy outcome. Subjects who perceived their cancer to be more aggressive had higher risk tolerance for UI. Younger men were willing to tolerate less ED risk than older men. Respondents with greater than college level of education had a lower risk tolerance for ED or UI. Results may inform development and regulatory evaluation for future HIFU ablation devices by providing supplemental information from the patient perspective. Emerging high intensity focused ultrasound devices may lack relevant clinical oncologic data but present with known side effects. A discrete choice experiment showed that patients with localized prostate cancer were willing to accept increased treatment-related risk of erectile dysfunction or urinary incontinence to obtain increased chance of favorable biopsy outcome. Results may inform development and evaluation of future HIFU therapies. [ABSTRACT FROM AUTHOR]

A persisting problem in the clinical operative routine is surgery-associated venous thromboembolisms with the possible complications. The competent and reliably realized prophylaxis of thromboembolism is part of the original and elementary tasks of the surgeon, both the operator as well as the clinically active physician. Many preventive approaches were developed and established in the daily management but a residual risk for development of thrombosis still remains. Under this aspect a search was carried out particularly with respect to scientific literature with review and guideline character on the topic of risk stratification, prophylactic procedures in general and for specific indications. [ABSTRACT FROM AUTHOR]

Abstract: Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results. [ABSTRACT FROM AUTHOR]

Aquatic products contain both beneficial substances such as polyunsaturated fatty acids and harmful compounds such as methylmercury, and their combined health effects should be assessed at a common end point for a rational analysis. We used a risk–benefit model to assess net IQ point gain from consumption of Chinese mitten crabs (Eriocheir sinensis) from Jiangsu Province. Levels of methylmercury in the edible parts of the crabs ranged from 0.79 to 69.47 μg/kg (mean: 26.88 ± 15.09 μg/kg). Levels of methylmercury did not differ by sampling location. In aquaculture experiments, we simulated artificial pond farming using either iced trash fish or formulated feed. Crabs fed iced trash fish contained 28.72 ± 2.30 mg/g of eicosapentaenoic acid and docosahexaenoic acid and crabs fed formulated feed contained 19.64 ± 3.62 mg/g of eicosapentaenoic acid and docosahexaenoic acid. Model calculations estimated a gain of 7.52 IQ points from consumption of crabs fed formulated feed and 11.00 IQ points from consumption of crabs fed iced trash fish. They are all above the maximum theoretical IQ point gain value. Chinese mitten crab is a kind of high-quality food which is beneficial to the neural development of infants. Our findings may assist in improving crab farming methods and consumption patterns, accelerating the sustainable development of the Chinese mitten crab industry. [ABSTRACT FROM AUTHOR]

Aims: Cancer drugs are increasingly approved through expedited regulatory pathways including the European conditional marketing authorization (CMA). Whether, when taking CMA post‐approval confirmatory trials into account, the level of evidence and clinical benefit between CMA and standard approved (SMA) drugs differs remains unknown. Methods: We identified all CMA cancer indications converted to SMA in 2006–2020 and compared these to similar SMA indications with regard to pivotal trial and CMA post‐approval confirmatory trial design, outcomes and demonstrated clinical benefit (per the European Society for Medical Oncology Magnitude of Clinical Benefit Scale). We tested for differences in clinical benefit and whether substantial clinical benefit was demonstrated. To account for the clinical benefit of unconverted CMA indications, we performed sensitivity analyses. Results: We included 15 SMA and 15 converted CMA cancer indications (17 remained unconverted). Approval of 11 SMA (73%) and four CMA indications (27%) was supported by a controlled trial. Improved overall survival (OS) was demonstrated for four SMA indications (27%). Improved quality of life (QoL) was demonstrated for three SMA (20%) and one CMA indication(s) (7%). Of subsequent CMA post‐approval confirmatory trials, 11 were controlled (79%), one demonstrated improved OS (7%) and five improved QoL (36%). After conversion, CMA indications were associated with similar clinical benefit (P =.31) and substantial clinical benefit as SMA indications (risk ratio 1.4, 95% confidence interval 0.57–3.4). Conclusion: While CMA cancer indications are initially associated with less comprehensive evidence than SMA indications, levels of evidence and clinical benefit are similar after conversion from CMA to SMA. [ABSTRACT FROM AUTHOR]

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Introduction: Poor indexing and inconsistent use of terms and keywords may prevent efficient retrieval of studies on the patient-based benefit-risk assessment (BRA) of medicines. We aimed to develop and validate an objectively derived content search strategy containing generic search terms that can be adapted for any search for evidence on patient-based BRA of medicines for any therapeutic area. Methods: We used a robust multistep process to develop and validate the content search strategy: (1) we developed a bank of search terms derived from screening studies on patient-based BRA of medicines in various therapeutic areas, (2) we refined the proposed content search strategy through an iterative process of testing sensitivity and precision of search terms, and (3) we validated the final search strategy in PubMed by firstly using multiple sclerosis as a case condition and secondly computing its relative performance versus a published systematic review on patient-based BRA of medicines in rheumatoid arthritis. Results: We conceptualized a final search strategy to retrieve studies on patient-based BRA containing generic search terms grouped into two domains, namely the patient and the BRA of medicines (sensitivity 84%, specificity 99.4%, precision 20.7%). The relative performance of the content search strategy was 85.7% compared with a search from a published systematic review of patient preferences in the treatment of rheumatoid arthritis. We also developed a more extended filter, with a relative performance of 93.3% when compared with a search from a published systematic review of patient preferences in lung cancer. [ABSTRACT FROM AUTHOR]

Introduction: Peripheral neuropathic pain (PNP) is difficult to treat. Several oral drugs are recommended as first-line treatments. Nevertheless, many patients cannot obtain sufficient pain relief or do not tolerate systemically active treatments. Topical treatments, with a lower risk of systemic side effects such as lidocaine 700 mg medicated plaster, are also recommended in treatment guidelines. This analysis compares the benefit–risk balance of topical 700 mg lidocaine medicated plaster with the benefit–risk balance of oral pregabalin administration for the treatment of PNP following current recommendations on benefit–risk assessment (BRA) methodology. Methods: The Benefit–Risk Action Team (BRAT) framework was used as structured approach. Selection of key benefits and risks was supported by a patient survey. Published randomized controlled clinical trials were the main source to identify data related to key benefits and risks. The outcome of randomized clinical trials was compared with real-world evidence (RWE) data for consistency. Results: Identified key benefits were pain reduction and improvement in quality of life. Key risks identified were application site reactions, dizziness, confusion, weight gain, peripheral edema, and blurred vision. Overall, there was similarity in key benefits between the comparators; however, a clear advantage regarding key risks in favor of lidocaine 700 mg medicated plaster was observed. This observation was consistent across data from a direct comparison trial, randomized placebo-controlled trials, as well as data from RWE studies. The low number of randomized controlled trials for lidocaine 700 mg medicated plaster was the main limitation. Conclusion: Guided by the opinion of patients regarding key benefits and risks deemed important for treatments of peripheral neuropathic pain, our analysis showed that lidocaine 700 mg medicated plaster has a more favorable benefit–risk balance compared to pregabalin (300 and 600 mg daily). [ABSTRACT FROM AUTHOR]

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease requiring long-term treatment. Upadacitinib (UPA), a Janus kinase (JAK) inhibitor, is a new treatment for RA. The benefit–risk profile of a medication is best understood by evaluating the number needed to treat (NNT) and the number needed to harm (NNH). This analysis evaluated the comparative risk–benefit of UPA versus adalimumab (ADA). Methods: Post-hoc analyses were performed using data from the SELECT-COMPARE trial of UPA versus placebo (PBO) and UPA versus ADA among patients with active RA who remained on stable methotrexate (MTX) treatment and had an inadequate response; patients who failed to achieve response were rescued by predefined criteria—PBO or ADA switch to UPA, and UPA switch to ADA (all patients on PBO were switched to UPA at week 26). This analysis assessed efficacy and adverse events of special interest (AESIs) at week 26, 48, and 156 (3 years). NNT and NNH (95% confidence intervals) values were calculated between UPA versus ADA for all time points, and between UPA versus PBO for week 26. NNT and NNH values were applied to a hypothetical cohort of 100 patients to estimate the comparative efficacy and safety profiles. Results: UPA consistently showed greater efficacy than ADA, as evidenced by NNT values < 10 for achievement of Disease Activity Score in 28 joints based on C-reactive protein (DAS28-CRP) of < 2.6 and ≤ 3.2, respectively, and functional improvement. Based on indices for disease assessment other than the DAS28-CRP, remission outcomes were higher with UPA versus ADA over 26 weeks (NNTs: 7–12), 48 weeks (NNTs: 9–16), and 156 weeks (NNTs: 9–15). With the exception of herpes zoster, other AESIs demonstrated a similar risk with UPA versus ADA. Conclusion: In patients with active RA despite MTX use, UPA demonstrated an incremental achievement of clinical outcomes compared to ADA together with a similar profile of AESIs with ADA (with the exception of herpes zoster). [ABSTRACT FROM AUTHOR]

Background: To help navigate the complex treatment landscape of ulcerative colitis (UC), we quantified the benefit-risk trade-offs that patients were willing to make when choosing treatment., Methods: Patients completed an online discrete choice experiment. Eligible patients had a UC diagnosis for ≥6 months, were aged ≥18 years, and resided in France, Germany, Italy, Spain, or the UK. Patients chose between 2 hypothetical treatments set up to ensure trade-offs were made. Clinical trial data, literature review, and patient interviews identified treatment attributes. Relative attribute importance (RAI) scores and maximum acceptable risks were generated. A patient-centric benefit-risk assessment of 200 mg of filgotinib was conducted as an example to show how measured trade-offs can be used., Results: Overall, 631 patients participated; patients had a mean age of 42.2 years and were predominantly male (75.3%). Achieving and maintaining clinical remission was the most important factor for patients (RAI 32.4%); to achieve this, patients were willing to accept slightly higher risks of blood clots, serious infections, and malignancies compared with lower risk treatment profiles. Patients also valued the convenience of oral treatments, avoiding steroids, and the ability to attend school/work. The patient-centric benefit-risk assessment suggested patients are significantly more likely to prefer Janus kinase 1 preferential inhibitor filgotinib over placebo., Conclusions: Achieving clinical remission was the highest treatment priority for patients. To attain this, patients were willing to accept some slightly higher risk treatment profiles. Patient choices in the benefit-risk assessment suggested patients were significantly more likely to prefer filgotinib over placebo., (© 2024 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

• Gender-neutral HPV vaccination is increasingly introduced and recently in France. • HPV vaccination has proven effective against anogenital warts and anal cancers in men. • In France, HPV vaccination for girls was statistically associated with GBS. • Quantifying benefits and risks is novel and needed for communication. • Monte-Carlo simulations allows accurate assessment including uncertainty. The burden of human papillomavirus (HPV) infection can be substantially reduced through vaccination of girls, and gender-neutral policies are being adopted in many countries to accelerate disease control among women and expand direct benefits to men. Clinical direct benefit of boys HPV vaccination has been established for ano-genital warts and anal cancer. HPV vaccines are considered safe, but an association with Guillain-Barre syndrome has been found in French reimbursement and hospital discharge data. We conducted a Monte-Carlo simulation assuming a stable French population of 11- to 14-year-old boys, adult men and men having sex with men. We modelled and quantified the mid-term benefits as the annually prevented ano-genital warts among the 8.72 M men aged 15–35 years and the long-term benefits as the annually prevented anal cancer cases among the 17.4 M men aged 25–65 years. We also estimated the number of Guillain-Barre syndrome cases hypothetically induced by vaccination. With a vaccine coverage of 30%, an annual number of 9310 (95% uncertainty interval [7050–11,200]) first ano-genital warts episodes among the 8.72 M men aged 15–35 years are prevented. According to more or less optimistic hypotheses on the proportion of HPV cancers covered by the vaccine, between 15.1 [11.7–17.7] and 19.2 [15.0–22.6] cases of anal cancer among the 17.4 M men aged 25–65 years would be annually avoided. Among men having sex with men, the corresponding figures were 1907 (1944–2291) for ano-genital warts and between 2.0 [0.23–4.5] and 2.6 [0.29–5.7] for anal cancer. Among 11- to 14-year-old boys, 0.82 (0.15–2.3) Guillain-Barre syndrome cases would be induced annually. A long-term program of HPV vaccination among boys in France would avoid substantially more cancer cases than hypothetically induce Guillain-Barre syndrome cases, in the general and specifically the homosexual population. Additional benefits may arise with the possible vaccine protection against oro-laryngeal and –pharyngeal cancer. [ABSTRACT FROM AUTHOR]

Introduction: Poor indexing and inconsistent use of terms and keywords may prevent efficient retrieval of studies on the patient-based benefit-risk assessment (BRA) of medicines. We aimed to develop and validate an objectively derived content search strategy containing generic search terms that can be adapted for any search for evidence on patient-based BRA of medicines for any therapeutic area. Methods: We used a robust multistep process to develop and validate the content search strategy: (1) we developed a bank of search terms derived from screening studies on patient-based BRA of medicines in various therapeutic areas, (2) we refined the proposed content search strategy through an iterative process of testing sensitivity and precision of search terms, and (3) we validated the final search strategy in PubMed by firstly using multiple sclerosis as a case condition and secondly computing its relative performance versus a published systematic review on patient-based BRA of medicines in rheumatoid arthritis. Results: We conceptualized a final search strategy to retrieve studies on patient-based BRA containing generic search terms grouped into two domains, namely the patient and the BRA of medicines (sensitivity 84%, specificity 99.4%, precision 20.7%). The relative performance of the content search strategy was 85.7% compared with a search from a published systematic review of patient preferences in the treatment of rheumatoid arthritis. We also developed a more extended filter, with a relative performance of 93.3% when compared with a search from a published systematic review of patient preferences in lung cancer.

The study aimed to quantify the excess risk of interaction between high free sugars (sugars) intake and lack of exposure to water fluoridation on child dental caries. Data from the Australian National Child Oral Health Study, a population-based survey of 24,664 children aged 5 to 14 y, were collected using parental questionnaires and oral epidemiological examinations by trained examiners. Information on socioeconomic status, dental health behaviors, and dental service use was used as covariates. The number of servings of sugars-containing foods and drinks consumed in a usual day was assessed as the main exposure, categorized into 5 groups. Residential history was used to calculate lifetime exposure to fluoridated water (LEFW), categorized as low (<25%), medium (25% to <75%), or high (75%–100%). Caries prevalence (dmfs/DMFS >0) and experience (dmfs/DMFS) in the primary (ages 5–10 y) and permanent (ages 8–14 y) dentitions were the main dependent variables. The association of sugars intake and LEFW with each outcome was estimated in multivariable log-Poisson regression models with robust standard error estimation, adjusted for covariates. The relative excess risk due to interaction (RERI) between sugars intake and LEFW was estimated. Strong positive gradients in all outcomes were observed across sugars intake groups. Relative to the lowest intake group, the 3 highest intake groups had significantly higher adjusted prevalence ratios for having caries and higher adjusted mean ratios of caries experience in both dentitions, after controlling for all covariates. LEFW strongly and consistently attenuated the effects of all levels of sugars intake on the outcomes. RERI estimates indicated that a combination of lack of exposure to fluoridated water and high sugars intake resulted in greater excess risk of primary and permanent caries than if there was no interaction. Evidently, children with high sugars intakes and low exposure to water fluoridation are at disproportionately higher risk of dental caries. [ABSTRACT FROM AUTHOR]

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Abstract Background Health risks linked with dioxin in fish remain a complex policy issue. Fatty Baltic fish contain persistent pollutants, but they are otherwise healthy food. We studied the health benefits and risks associated with Baltic herring and salmon in four countries to identify critical uncertainties and to facilitate an evidence-based discussion. Methods We performed an online survey investigating consumers’ fish consumption and its motivation in Denmark, Estonia, Finland, and Sweden. Dioxin and methylmercury concentrations were estimated based on Finnish studies. Exposure-response functions for several health endpoints were evaluated and quantified based on the scientific literature. We also quantified the infertility risk of men based on a recent European risk assessment estimating childhood dioxin exposure and its effect on sperm concentration later in life. Results Baltic herring and salmon contain omega-3 fatty acids and vitamin D, and the beneficial impact of these fishes on cardiovascular diseases, mortality, and the risk of depression and cancer clearly outweighs risks of dioxins and methylmercury in people older than 45 years of age and in young men. Young women may expose their children to pollutants during pregnancy and breast feeding. This study suggests that even in this critical subgroup, the risks are small and the health benefits are greater than or at least similar to the health risks. Value of information analysis demonstrated that the remaining scientific uncertainties are not large. In contrast, there are several critical uncertainties that are inherently value judgements, such as whether exceeding the tolerable weekly intake is an adverse outcome as such; and whether or not subgroup-specific restrictions are problematic. Conclusions The potential health risks attributable to dioxins in Baltic fish have more than halved in the past 10 years. The new risk assessment issued by the European Food Safety Authority clearly increases the fraction of the population exceeding the tolerable dioxin intake, but nonetheless, quantitative estimates of net health impacts change only marginally. Increased use of small herring (which have less pollutants) is a no-regret option. A more relevant value-based policy discussion rather than research is needed to clarify official recommendations related to dioxins in fish.

Rationale: In the IMPACT (Informing the Pathway of COPD Treatment) trial, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy reduced exacerbation risk versus FF/VI and UMEC/VI and mortality risk versus UMEC/VI. However, pneumonia incidence was higher in the inhaled corticosteroid (FF)-containing arms, raising questions about the relative benefit of exacerbation reduction compared with the increased risk of pneumonia.Objectives: Determine benefit-risk of the three treatments by evaluating time-to-first and rates of composite exacerbation or pneumonia outcomes.Methods: We evaluated time-to-first (prespecified) and rates (post hoc) of investigator-reported pneumonia, serious pneumonia leading to hospitalization or death, and the composite endpoints of 1) moderate (required antibiotics/corticosteroids)/severe (hospitalized) exacerbation or pneumonia and 2) severe exacerbation or serious (hospitalized) pneumonia. Analyses were repeated for radiographically confirmed pneumonia (post hoc).Results: Moderate/severe exacerbations occurred in 47%, 49%, and 50% of patients randomized to FF/UMEC/VI, FF/VI and UMEC/VI, and pneumonias in 8%, 7%, and 5%, respectively. FF/UMEC/VI reduced the risk of combined moderate/severe exacerbation or pneumonia (time-to-first) versus FF/VI (hazard ratio, 0.87 [95% confidence interval (CI), 0.82-0.92]) and UMEC/VI (0.87 [0.81-0.94]), as well as the risk of combined severe exacerbation or serious pneumonia versus UMEC/VI (0.83 [0.72-0.96]). FF/UMEC/VI reduced the rate of combined moderate/severe exacerbation or pneumonia (rate ratio, 0.78 [0.72-0.84]) and combined severe exacerbation or serious pneumonia (rate ratio, 0.76 [0.65-0.89]) versus UMEC/VI. Results were similar for radiographically confirmed pneumonia endpoints.Conclusions: Despite higher incidence of pneumonia in FF-containing arms, these composite exacerbation/pneumonia outcomes support a favorable benefit-risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations. [ABSTRACT FROM AUTHOR]

Background: The potential value of patient preference studies has been recognized in clinical individual treatment decision-making between clinicians and patients, as well as in upstream drug decision-making. Drug developers, regulators, reimbursement and Health Technology Assessment (HTA) bodies are exploring how the use of patient preference studies could inform drug development, regulatory benefit risk-assessment and reimbursement decisions respectively. Understanding patient preferences may be especially valuable in decisions regarding Non-Small Cell Lung Cancer (NSCLC) treatment options, where a variety of treatment options with different characteristics raise uncertainty about which features are most important to NSCLC patients. As part of the Innovative Medicines Initiative PREFER project, this qualitative study aimed to identify patient-relevant lung cancer treatment characteristics.Methods: This study consisted of a scoping literature review and four focus group discussions, 2 in Italy and 2 in Belgium, with a total of 24 NSCLC patients (Stages III-IV). The focus group discussions sought to identify which treatment characteristics patients find most relevant. The discussions were analyzed thematically using a thematic inductive analysis.Results: Patients highlighted themes reflecting: 1) positive effects or expected gains from treatment such as greater life expectancy and maintenance of daily functioning, 2) negative effects or adverse events related to therapy that negatively impact patients’ daily functioning such as fatigue and 3) uncertainty regarding the duration and type of treatment effects. These overarching themes were consistent among patients from Belgium and Italy, suggesting that treatment aspects related to efficacy and safety as well as the psychological impact of lung cancer treatment are common areas of concern for patients, regardless of cultural background or country.Discussion: Our findings illustrate the value of using qualitative methods with patients to identify preferred treatment characteristics for advanced lung cancer. These could inform a subsequent quantitative preference survey that assesses patient trade-offs regarding treatment options.

We propose a comprehensive analysis of existing concepts of AI coming from different disciplines: Psychology and engineering tackle the notion of intelligence, while ethics and law intend to regulate AI innovations. The aim is to identify shared notions or discrepancies to consider for qualifying AI systems. Relevant concepts are integrated into a matrix intended to help defining more precisely when and how computing tools (programs or devices) may be qualified as AI while highlighting critical features to serve a specific technical, ethical and legal assessment of challenges in AI development. Some adaptations of existing notions of AI characteristics are proposed. The matrix is a risk-based conceptual model designed to allow an empirical, flexible and scalable qualification of AI technologies in the perspective of benefit-risk assessment practices, technological monitoring and regulatory compliance: it offers a structured reflection tool for stakeholders in AI development that are engaged in responsible research and innovation. [ABSTRACT FROM AUTHOR]

The recent benefit–risk framework (BRF) developed by the Food and Drug Administration (FDA) is intended to improve the clarity and consistency in communicating the reasoning behind the FDA's decisions, acting as an important advancement in US drug regulation. In the PDUFA VI implementation plan, the FDA states that it will continue to explore more structured or quantitative decision analysis approaches; however, it restricts their use within the current BRF that is purely qualitative. By contrast, European regulators and researchers have been long exploring the use of quantitative decision analysis approaches for evaluating drug benefit–risk balance. In this paper, we show how quantitative modelling, backed by decision theory, could complement and extend the FDA's BRF to better support the appraisal of evidence and improve decision outcomes. After providing relevant scientific definitions for benefit–risk assessment and describing the FDA and European Medicines Agency (EMA) frameworks, we explain the components of and differences between qualitative and quantitative approaches. We present lessons learned from the EMA experience with the use of quantitative modelling and we provide evidence of its benefits, illustrated by a real case study that helped to resolve differences of judgements among EMA regulators. [ABSTRACT FROM AUTHOR]

Network Meta-analysis and multi-criteria decision analysis(MCDA) model were performed to evaluate the benefit-risk of Compound Cantharis Capsules, Huisheng Oral Solution, and Jinlong Capsules in the adjuvant treatment of primary liver cancer(PLC). The randomized controlled trial(RCT) of Compound Cantharis Capsules, Huisheng Oral Solution, and Jinlong Capsules in treating PLC were retrieved from CNKI, Wanfang, VIP, Web of Science, PubMed, and Cochrane Library. R 4.2 was employed to conduct a network Meta-analysis, on the basis of which the effect values of the three medicines were obtained by indirect comparison. MCDA was performed to establish the value tree based on the benefit-risk indexes. Hiview 3.2 was used to calculate the benefit values, risk values, and benefit-risk values of the three medicines in treating PLC, and a sensitivity analysis was carried out to evaluate the robustness of the results. Oracle Crystal Ball 11.1 was employed to optimize the evaluation results by Monte Carlo simulation. A total of 39 RCTs were included. The results showed that Compound Cantharis Capsules, Huisheng Oral Solution, and Jinlong Capsules combined with transcatheter arterial chemoembolization(TACE) had the benefit values of 45, 51 and 45, the risk values of 59, 47, and 41, and the benefit-risk values of 52, 49, and 43, respectively. The benefit-risk differences and [95%CI] of Compound Cantharis Capsules vs Huisheng Oral Solution, Compound Cantharis Capsules vs Jinlong Capsules, and Huisheng Oral Solution vs Jinlong Capsules were 3.00[-13.09, 21.82], 9.00[-4.39, 24.62], and 6.00[-8.84, 20.28], respectively. Based on the results of MCDA, Huisheng Oral Solution, Jinlong Capsules, and Compound Cantharis Capsules combined with TACE had the greatest benefit, the greatest risk, and the best overall benefit, respectively. Considering the efficacy and safety, the priority of the three oral Chinese patent medicines combined with TACE for treating PLC followed the trend of Compound Cantharis Capsules, Huisheng Oral Solution, and Jinlong Capsules.

With limited understanding of most new biotechnologies, how do citizens form their opinion and what factors influence their attitudes about these innovations? In this study, we use gene drive biotechnology in agricultural pest management as an example and theoretically propose that given low levels of knowledge and awareness, citizens' acceptance of, or opposition to, gene drive is significantly shaped by two predisposition factors: individuals' general orientation toward science and technology, and their specific benefit-risk assessment frame. Empirically, we employ data collected from a recent US nationally representative public opinion survey (N = 1220) and conduct statistical analyses to test the hypotheses derived from our theoretical expectations. Our statistical analyses, based on various model specifications and controlling for individual-level covariates and state-fixed effects, show that citizens with a more favorable general orientation toward science and technology are more likely to accept gene drive. Our data analyses also demonstrate that citizens' specific gene drive assessment frame-consisting of a potential benefit dimension and a potential risk dimension, significantly shapes their attitudes as well-specifically, people emphasizing more on the benefit dimension are more likely to accept gene drive, whereas those who place more importance on the risk dimension tend to oppose it. We discuss contributions of our study and make suggestions for future research in the conclusion., (© 2023 Society for Risk Analysis.)

Abstract Background/Objectives: The US Food and Drug Administration (FDA) is responsible for assessing safety (risks) and effectiveness (benefits) of new drug products using the data provided in a Sponsor’s new drug product marketing application before they can be marketed. The FDA forms cross-disciplinary review teams to conduct these assessments. Recently, the FDA began implementing more interdisciplinary approaches to its assessments, reducing redundancy in review processes and documentation by increasing team integration around review issues. Methods: Through a phenomenological descriptive comparative case study, the impact of FDA’s new interdisciplinary approach on review team integration was compared with its traditional multidisciplinary review approach. Results: We identified collaborative integration occurring in one FDA review team using the new interdisciplinary review and another team using the traditional review and then modeled and analyzed the collaborative, cross-disciplinary integration in each case using an input-process-output (IPO) model drawn from the Science-of-Team-Science (SciTS). Conclusion: This study provides a systematic method for understanding and visualizing integration in each type of review previously and presently used at FDA and illustrates how the new interdisciplinary approach can ensure more integration than more traditional approaches previously used. In addition, our study suggests that an IPO model of integration can characterize how effectively FDA review teams are integrating around issues and assist in the evaluation of differences in integration between FDA’s new interdisciplinary review and the existing multidisciplinary approach. The approach used here is a new application of SciTS scholarship in a unique sector, and it also serves as an example for measuring review team effectiveness.

Objectives: Inclusion of patient preference (PP) data in decision making has been largely discussed in recent years. Healthcare decision makers—regulatory and health technology assessment (HTA)—are more and more conscious of the need for a patient-centered approach to decide on optimal allocation of scarce money, time, and technological resources. This literature review aims to examine the use of and recommendations for the integration of PP in decision making.Methods: A literature search was conducted through PubMed/Medline in May 2019 to identify publications on PP studies used to inform benefit–risk assessments (BRAs) and HTAs and patient-centered projects and guidelines related to the inclusion of PPs in health policy decision making. After title and abstract screening and full-text review, selected publications were analyzed to retrieve data related to the collection, use, and/or submission of PPs informing BRA or HTA as well as attempts and initiatives in recommendations for PPs integration in decision-making processes.Results: Forty-nine articles were included: 24 attempts and pilot project discussions and 25 PP elicitation studies. Quantitative approaches, particularly discrete choice experiments, were the most used (24 quantitative elicitation studies and 1 qualitative study). The objective of assessing PPs was to prioritize outcome-specific information, to value important treatment characteristics, to provide patient-focused benefit–risk trade-offs, and to appraise the patients' willingness to pay for new technologies. Moreover, attempts and pilot projects to integrate PPs in BRAs and HTAs were identified at the European level and across countries, but no clear recommendations have been issued yet. No less than seven public and/or private initiatives have been undertaken by governmental agencies and independent organizations to set guidance targeting improvement of patients' involvement in decision making.Conclusion: Despite the initiatives undertaken, the pace of progress remains slow. The use of PPs remains poorly implemented, and evidence of proper use of these data in decision making is lacking. Guidelines and recommendations formalizing the purpose of collecting PPs, what methodology should be adopted and how, and who should be responsible for generating these data throughout the decision-making processes are needed to improve and empower integration of PPs in BRA and HTA.

The pace of innovation is accelerating, and so medicines regulators need to actively innovate regulatory science to protect human and animal health. This requires consideration and consultation across all stakeholder groups. To this end, the European Medicines Agency worked with stakeholders to draft its Regulatory Science Strategy to 2025 and launched it for public consultation. The responses to this consultation were analyzed qualitatively, using framework analysis and quantitatively, to derive stakeholders' aggregate scores for the proposed recommendations. This paper provides a comprehensive resource of stakeholder positions on key regulatory science topics of the coming 5 years. These stakeholder positions have implications for the development and regulatory approval of both human and veterinary medicines.

BackgroundNational regulatory authorities (NRAs) make the decision to register a medicine based on an assessment of its benefits and risks and publicly available assessment reports are used as a tool to communicate the basis for the decision. The Universal Methodology for Benefit-Risk Assessment (UMBRA) has also been used to effectively communicate the basis of regulatory decisions. Many NRAs in emerging markets place reliance on the public assessment reports (PARs) of reference agencies to inform about their own regulatory decisions. However, PAR users often criticise the redacted nature of PARs and may be challenged in identifying key benefits and risks, value judgements, and benefit-risk (BR) trade-offs.MethodsPARs for ertugliflozin l-pyroglutamic acid, erenumab, and durvalumab published by regulatory bodies in Australia, Europe, Canada, and the United States were compared with the validated UMBRA Benefit-Risk Template to evaluate the BR decision documentation. Published validation of UMBRA included report of a consortium of four regulatory authorities in Australia, Canada, Switzerland, and Singapore indicating that their clinical assessment templates were modified to align with the UMBRA approach. A focus group discussed the use of PARs as potential knowledge management tools for stakeholder understanding of regulatory decision making. The South African Health Product Regulatory Authority (SAHPRA) approach to document and communicate the BR decisions was evaluated.ResultsResults indicate key elements to include in the PARs including regulatory history, an effects table and a record of the strengths and uncertainties for each benefit and risk. Focus group participants agreed that a harmonised PAR template would support improved regulatory decision-making transparency. SAHPRA communication of BR decisions could be improved through the use of the UMBRA BR Template as a guidance for BR assessment and the basis of the South Africa public assessment report format.ConclusionSAHPRA's use of a structured template that supports transparent and quality decision making could have a major impact in ensuring consistency in the BR assessment of new medicines. The implementation of this effective approach for communicating BR decisions will advance agency goals of being a trusted, responsive, accountable regulatory body in which all healthcare stakeholders may rely on with confidence.