A Bayesian pharmacokinetics integrated phase I-II design to optimize dose-schedule regimes.

The schedule of administering a drug has profound impact on the toxicity and efficacy profiles of the drug through changing its pharmacokinetics (PK). PK is an innate and indispensable component of the dose-schedule optimization. Motivated by this, we propose a Bayesian PK integrated dose-schedule finding (PKIDS) design to identify the optimal dose-schedule regime by integrating PK, toxicity, and efficacy data. Based on the causal pathway that dose and schedule affect PK, which in turn affects efficacy and toxicity, we jointly model the three endpoints by first specifying a Bayesian hierarchical model for the marginal distribution of the longitudinal dose-concentration process. Conditional on the drug concentration in plasma, we jointly model toxicity and efficacy as a function of the concentration. We quantify the risk-benefit of regimes using utility-continuously updating the estimates of PK, toxicity, and efficacy based on interim data-and make adaptive decisions to assign new patients to appropriate dose-schedule regimes via adaptive randomization. The simulation study shows that the PKIDS design has desirable operating characteristics.

ESR Essentials: basic physics of MR safety-practice recommendations by the European Society for Magnetic Resonance in Medicine and Biology.

OBJECTIVES: The use of magnetic resonance imaging (MRI) is safe from a long-term perspective since there are no known cumulative risks for patients or personnel. However, the technique comes with several acute risks associated with the powerful electromagnetic fields that are necessary to produce medical images. These risks include, among other things, a projectile hazard, loud noise, and the risk of heating. Safe use of MRI requires knowledge about the different hazards related to MRI and organizational structured work including the implementation of routines describing a safe workflow from the referral of a patient to the signed report. In this article, the risks associated with MRI are described along with suggestions for how each risk can be minimized or eliminated. CONCLUSION: The aim of this article is to provide support for the development of, and compliance with, MRI safety routines, and to work with the technique in a safe way. The scope of this treatise does not cover specific details of implant safety, however, the physical principles described can be applied to the risk assessment of implants. KEY POINTS: Establish whether any MR contraindications apply to the patient. Evaluate means to deal with identified risks for both patients and personnel. It is imperative to always perform and document a risk-benefit assessment.

Design and sample size determination for multiple-dose randomized phase II trials for dose optimization.

The U.S. Food and Drug Administration (FDA) has launched Project Optimus to shift dose selection from the maximum tolerated dose (MTD) to the dose that produces the optimal risk-benefit tradeoff. One approach highlighted in the FDA's guidance involves conducting a randomized phase II trial following the completion of a phase I trial, where multiple doses (typically including the MTD and one or two doses lower than the MTD) are compared to identify the optimal dose that maximizes the benefit-risk tradeoff. This article focuses on the design of such a multiple-dose randomized trial, specifically the determination of the sample size. We generalized the standard definitions of type I error and power to accommodate the unique characteristics of dose optimization and derived a decision rule along with an algorithm to determine the optimal sample size. The resulting design is referred to as MERIT (Multiple-dosE RandomIzed Trial design for dose optimization based on toxicity and efficacy). Simulation studies demonstrate that MERIT has desirable operating characteristics, and a sample size between 20 and 40 per dosage arm often offers reasonable power and type I errors to ensure patient safety and benefit. To facilitate the implementation of the MERIT design, we provide software, available at https://www.trialdesign.org.

Challenges Addressing Lung Cancer Screening for Patients With Multimorbidity in Primary Care: A Qualitative Study.

PURPOSE: Many individuals who are eligible for lung cancer screening have comorbid conditions complicating their shared decision-making conversations with physicians. The goal of our study was to better understand how primary care physicians (PCPs) factor comorbidities into their evaluation of the risks and benefits of lung cancer screening and into their shared decision-making conversations with patients. METHODS: We conducted semistructured interviews by videoconference with 15 PCPs to assess the extent of shared decision-making practices and explore their understanding of the intersection of comorbidities and lung cancer screening, and how that understanding informed their clinical approach to this population. RESULTS: We identified 3 themes. The first theme was whether to discuss or not to discuss lung cancer screening. PCPs described taking additional steps for individuals with complex comorbidities to decide whether to initiate this discussion and used subjective clinical judgment to decide whether the conversation would be productive and beneficial. PCPs made mental assessments that factored in the patient's health, life expectancy, quality of life, and access to support systems. The second theme was that shared decision making is not a simple discussion. When PCPs did initiate discussions about lung cancer screening, although some believed they could provide objective information, others struggled with personal biases. The third theme was that ultimately, the decision to be screened was up to the patient. Patients had the final say, even if their decision was discordant with the PCP's advice. CONCLUSIONS: Shared decision-making conversations about lung cancer screening differed substantially from the standard for patients with complex comorbidities. Future research should include efforts to characterize the risks and benefits of LCS in patients with comorbidities to inform guidelines and clinical application.

Stepping back for good reasons: a reappraisal of the DF-1 connector for defibrillator leads.

The DF-4 defibrillator standard has been rapidly adopted due to its convenience at implantation. There are however trade-offs compared to the traditional DF-1 standard that are underappreciated. This viewpoint outlines the advantages and limitations of current defibrillator lead standards that should be kept in mind, as they impact the options that are available to deal with issues that may arise.

How glaucoma patients balance between the advantages and disadvantages of acceptance to the recommended treatment regimen in real-life: Perspectives from a middle-income country.

PURPOSE: Patients with primary open-angle glaucoma (POAG) are required to take long-term treatments with topical medications to halt disease progression. This cross-sectional survey aimed to describe the level of acceptance of Brazilian patients toward the long-term treatment with eyedrops and to find possible correlates of high acceptance. METHODS: POAG patients were recruited from the Glaucoma Service-Santa Casa of Sao Paulo, Sao Paulo, Brazil. Clinical and demographic data were retrieved from participants' electronic records. All patients answered the ACCEPT© questionnaire. This is a generic patient-reported outcome questionnaire specifically developed to assess patients' acceptance of long-term medications and not adherence. Summed scores and those for each domain were calculated to range from 0 to 100 with a higher score indicating greater acceptance. RESULTS: The sample comprised 96 patients with POAG. The mean age was 63.2 ± 8.9 years; 48 were male and 48 female; 55 (57.3%) were white, 36 (37.5%) African-Brazilian, and 5 (5.2%) were of mixed color; most patients (97.9%) had less than high school degree and all had a family income

Risk-benefit trade-offs and precision utilities in phase I-II clinical trials.

BACKGROUND: Identifying optimal doses in early-phase clinical trials is critically important. Therapies administered at doses that are either unsafe or biologically ineffective are unlikely to be successful in subsequent clinical trials or to obtain regulatory approval. Identifying appropriate doses for new agents is a complex process that involves balancing the risks and benefits of outcomes such as biological efficacy, toxicity, and patient quality of life. PURPOSE: While conventional phase I trials rely solely on toxicity to determine doses, phase I-II trials explicitly account for both efficacy and toxicity, which enables them to identify doses that provide the most favorable risk-benefit trade-offs. It is also important to account for patient covariates, since one-size-fits-all treatment decisions are likely to be suboptimal within subgroups determined by prognostic variables or biomarkers. Notably, the selection of estimands can influence our conclusions based on the prognostic subgroup studied. For example, assuming monotonicity of the probability of response, higher treatment doses may yield more pronounced efficacy in favorable prognosis compared to poor prognosis subgroups when the estimand is mean or median survival. Conversely, when the estimand is the 3-month survival probability, higher treatment doses produce more pronounced efficacy in poor prognosis compared to favorable prognosis subgroups. METHODS AND CONCLUSIONS: Herein, we first describe why it is essential to consider clinical practice when designing a clinical trial and outline a stepwise process for doing this. We then review a precision phase I-II design based on utilities tailored to prognostic subgroups that characterize efficacy-toxicity risk-benefit trade-offs. The design chooses each patient's dose to optimize their expected utility and allows patients in different prognostic subgroups to have different optimal doses. We illustrate the design with a dose-finding trial of a new therapeutic agent for metastatic clear cell renal cell carcinoma.

Which Benefits Can Justify Risks in Research?

Research ethics committees (RECs) evaluate whether the risk-benefit ratio of a study is acceptable. Decentralized clinical trials (DCTs) are a novel approach for conducting clinical trials that potentially bring important benefits for research, including several collateral benefits. The position of collateral benefits in risk-benefit assessments is currently unclear. DCTs raise therefore questions about how these benefits should be assessed. This paper aims to reconsider the different types of research benefits, and their position in risk-benefit assessments. We first propose a categorization of research benefits, based on the types of benefits that can be distinguished from the literature and ethical guidelines. Secondly, we will reconsider the position of collateral benefits. We argue that these benefits are not fundamentally different from other benefits of research and can therefore be included in risk-benefit assessments of DCTs.

Analytic and heuristic process for prudent antimicrobial use in animals: What are triggers and how do they work?

The over and misuse of antimicrobials in animal agriculture causes a prevailing crisis for humans, animals, and the environment. From the One Health approach perspective, the formation process of adopting prudent antimicrobial use (AMU), once established, can be used to mitigate this crisis. The study aimed to determine the analytic-based and heuristic-based process that evoked prudent AMU among animal farmers by synthesis of stimulus-organism-response framework and dual-system theory and to explore gender differences on risk-benefit trade-offs. A structural equation model was employed to test the proposed hypotheses with field survey data from 1100 small-scale farmers. The results reveal that for the analytic-based process, social influence, antimicrobial-related threats, and self-efficacy are all salient stimuli having indirect effects on intention via the two organisms of perceived risks and perceived benefits. For heuristic-based process, farmers' altruistic value orientations are positively associated with intention. An interesting fact is that threat awareness has two opposite effects on intention, namely, the suppression effect and the enhancement effect. Moreover, the negative effect of perceived risks on intention is greater among female farmers, compared to male counterparts. These findings provide valuable insights for the forming of theory-based intervention strategies to perfect China's national action plan.

The lesser of two evils: Assessing the public acceptance of AI thermal facial recognition during the COVID-19 crisis.

AI thermal facial recognition (AITFR) has been rapidly applied globally in the fight against Coronavirus disease 2019 (COVID-19). However, AITFR has also been accompanied by a controversy regarding whether the public accepts it. Therefore, it is necessary to assess the acceptance of AITFR during the COVID-19 crisis. Drawing upon the theory of acceptable risk and Siegrist's causal model of public acceptance (PA), we built a combined psychological model that included the perceived severity of COVID-19 (PSC) to describe the influencing factors and pathways of AITFR acceptance. This model was verified through a survey conducted in Xi'an City, Shaanxi Province, China, which collected 754 valid questionnaires. The results show that (1) COVID-19 provides various application scenarios for AI-related technologies. However, the respondents' trust in AITFR was found to be very low. Additionally, the public appeared concerned about the privacy disclosure issue and the accuracy of the AITFR algorithm. (2) The PSC, social trust (ST), and perceived benefit (PB) were found to directly affect AITFR acceptance. (3) The PSC was found to have a significant positive effect on perceived risk (PR). PR was found to have no significant effect on PA, which is inconsistent with the findings of previous studies. (4) The PB were found to be a stronger mediator of the indirect effect of the PSC on ST induced by AITFR acceptance.

PKBOIN-12: A Bayesian Optimal Interval Phase I/II Design Incorporating Pharmacokinetics Outcomes to Find the Optimal Biological Dose.

Immunotherapies and targeted therapies have gained popularity due to their promising therapeutic effects across multiple treatment areas. The focus of early phase dose-finding clinical trials has shifted from finding the maximum tolerated dose (MTD) to identifying the optimal biological dose (OBD), which aims to balance the toxicity and efficacy outcomes, thus optimizing the risk-benefit trade-off. These trials often collect multiple pharmacokinetics (PK) outcomes to assess drug exposure, which has shown correlations with toxicity and efficacy outcomes but has not been utilized in the current dose-finding designs for OBD selection. Moreover, PK outcomes are usually available within days after initial treatment, much faster than toxicity and efficacy outcomes. To bridge this gap, we introduce the innovative model-assisted PKBOIN-12 design, which enhances BOIN12 by integrating PK information into both the dose-finding algorithm and the final OBD determination process. We further extend PKBOIN-12 to TITE-PKBOIN-12 to address the challenges of late-onset toxicity and efficacy outcomes. Simulation results demonstrate that PKBOIN-12 more effectively identifies the OBD and allocates a greater number of patients to it than BOIN12. Additionally, PKBOIN-12 decreases the probability of selecting inefficacious doses as the OBD by excluding those with low drug exposure. Comprehensive simulation studies and sensitivity analysis confirm the robustness of both PKBOIN-12 and TITE-PKBOIN-12 in various scenarios.

[Pregnancy and breastfeeding in women with multiple sclerosis]. / Schwangerschaft und Stillzeit bei Frauen mit Multipler Sklerose.

The diagnosis of multiple sclerosis (MS) in women of reproductive age is associated with many uncertainties regarding childbearing and lactation. Pregnancies of MS patients are not usually considered high-risk pregnancies per se. The likelihood of pregnancy complications or adverse pregnancy outcomes is not increased by the disease; however, a careful planning of pregnancy is important in order to choose the treatment option with the greatest benefit for the mother and the least possible risk for the baby. For highly active courses of the disease, anti-CD20 antibodies, cladribine, or continued administration of natalizumab show the best data. Patients with MS can be supported in their desire to breastfeed. If women have had a very active disease course, it is recommended that treatment should be started as soon as possible postpartum. Interferon-beta preparations, glatiramer acetate and ofatumumab are also approved for use during breastfeeding but off-label breastfeeding is also possible with other monoclonal antibodies.

Orthodontic treatment protocol versus Peer Assessment Rating: Assessing the quality of orthodontic treatment.

OBJECTIVE: To apply the Peer Assessment Rating (PAR) to cases that have been assessed by the NHS Business Service Authority (NHSBSA) using the orthodontic treatment protocol (OTO), then compare the NHSBSA outcome assessment with weighted (W) and unweighted (U) PAR scores. DESIGN: Cross-sectional study. SETTING: UK. CASES: Anonymised orthodontic cases submitted to the NHSBSA. METHODS: A sample of 30 reports from 2021/2022 were randomly selected to include different standard of treatment grades. The records were de-identified and the pre- and post-treatment study models were PAR scored by a calibrated assessor. RESULTS: The mean percentage change in PAR was higher in cases from green reports (W: 78%; U: 79%) than amber (W: 68%; U: 67%) and red reports (W: 65%; U: 65%). Alignment and poor buccal segment interdigitation were the most reported concerns for cases included in the red and amber graded reports. A residual increased overjet was the most common occlusal feature leading to PAR scores not being more than 70% improved. Only slight agreement was shown between OTP and PAR using the kappa statistic, and the chi-square statistical test found that outcome measures are statistically significantly different. CONCLUSION: There are fundamental differences between OTP and PAR, and general agreement between them has not been demonstrated. The NHSBSA Report provides a more critical outcome assessment than PAR, identifying elements that are not assessed or measured by the PAR index.

From "exceptional ethics" to public health ethics. Patients and proxies facing COVID-19. Ethics and public health during COVID-19 / D'une « éthique d'exception ¼ à une éthique de la santé publique. Patients et proches face à la COVID-19. Éthique et santé publique en temps de COVID-19.

The study aimed to elicit the perception and ethical considerations of patients and proxies with respect both to the individual medical decisions and public health decisions made during the COVID-19 crisis. It used a qualitative, multi-center study based on semi-directive interviews, conducted by an interdisciplinary team. The analysis was conducted using a thematic analysis approach and an ethical framework. Three themes emerged from the analysis: 1) patients, unlike proxies, did not complain about their diminished role in the decision-making process. Both highlighted the importance of "basic care" as opposed to a technical approach to treatment; 2) despite the transparency of the information process, a deep "crisis of trust" has developed between citizens and public authorities; 3) although both patients and proxies accepted the limitations of personal liberties imposed in the name of public health, they argued that these limitations should respect certain boundaries, both temporal and spacial. Above all, they should not affect basic affective human relationships, even if such boundaries are a factor in an increased risk of infection. The study showed that there is a need to reconsider the definition and the main principles of public health ethics, namely transparency and proportionality.

L'étude vise à analyser la perception que les patients et les proches de patients pris en charge pendant la crise de la COVID-19, ont pu avoir de leur prise en charge, et leurs réflexions éthiques sur la place et la définition de la santé publique. L'étude a utilisé une méthode qualitative et multicentrique. Les entretiens semi-directifs ont été conduits par une équipe pluridisciplinaire et analysés avec une approche thématique et une grille de lecture éthique à partir des principes de l'éthique biomédicale. Trois thèmes ont émergé : 1) Les patients ont exprimé peu de revendications de participer aux décisions médicales les concernant, contrairement aux proches qui se sont sentis exclus de leur rôle. Tous ont mis l'accent sur l'importance des soins de base par rapport aux soins techniques ; 2) La gestion de la crise n'est pas jugée sévèrement, mais une crise de confiance importante a été mise en évidence, malgré la « transparence ¼ affichée de l'information ; 3) les contraintes collectives ont été largement acceptées au nom de la solidarité, mais on a jugé qu'elles doivent avoir des limites (temporelle et spatiales). Surtout, elles ne doivent pas empêcher des relations humaines simples et essentielles. L'étude met en évidence qu'il est nécessaire de développer une réflexion nouvelle autour de l'éthique de la santé publique : il convient de questionner les principes de « transparence ¼ et de « proportionnalité ¼ et d'adopter une définition de « santé publique ¼ plus large que la minimisation du risque infectieux.

Challenge Inoculum for Hepatitis C Virus Controlled Human Infection Model.

For any controlled human infection model (CHIM), a safe, standardized, and biologically relevant challenge inoculum is necessary. For hepatitis C virus (HCV) CHIM, we propose that human-derived high-titer inocula of several viral genotypes with extensive virologic, serologic, and molecular characterizations should be the most appropriate approach. These inocula should first be tested in human volunteers in a step-wise manner to ensure safety, reproducibility, and curability prior to using them for testing the efficacy of candidate vaccines.

Comparative Risk of Serious Infections With Biologic Agents and Oral Small Molecules in Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Safety is a key consideration when choosing advanced therapies (biologic agents and oral small-molecule inhibitors/modulators) in patients with inflammatory bowel diseases (IBDs). We performed a systematic review and meta-analysis comparing the risk of serious infections with advanced therapies in active comparator studies. METHODS: Through a systematic search until February 28, 2022, we included 20 head-to-head studies comparing risk of serious infections with tumor necrosis factor α (TNFα) antagonists, vedolizumab, ustekinumab, tofacitinib, filgotinib, and ozanimod in patients with IBD. We performed random-effects meta-analysis comparing different advanced therapies. RESULTS: No significant difference was observed in the risk of serious infections between vedolizumab vs TNFα antagonists in all patients with IBD (17 cohorts: odds ratio [OR], 0.84; 95% CI, 0.68-1.04), with moderate heterogeneity (I2 = 37%); on subgroup analysis, vedolizumab was associated with a lower risk of serious infections in patients with ulcerative colitis (11 cohorts: OR, 0.68; 95% CI, 0.56-0.83; I2 = 0%), but not in Crohn's disease (CD) (9 cohorts: OR, 1.03; 95% CI, 0.78-1.35; I2 = 42%). Age, sex, prior biologic exposure, and use of biologic monotherapy did not influence this association. In patients with CD, ustekinumab was associated with a lower risk of serious infections vs TNFα antagonists (3 cohorts: OR, 0.49; 95% CI, 0.25-0.93; I2 = 16%) and vs vedolizumab (3 cohorts: OR, 0.40; 95% CI, 0.17-0.93; I2 = 67%). Few studies compared other advanced therapies. CONCLUSIONS: Vedolizumab may offer net benefit over TNFα antagonists in patients with ulcerative colitis, but not in CD. Ustekinumab may offer net benefit over TNFα antagonists and vedolizumab in patients with CD.

Comparative short-term safety and efficacy of hypnotics: A quantitative risk-benefit analysis.

Several professional societies have provided recommendations for prescribing medications for insomnia. None has provided an integrative analysis that concurrently quantifies safety and efficacy (e.g., risk-benefit ratios). This represents an important gap for informing clinician decision-making. Accordingly, the aim of the present review is to provide such an analysis for five classes of sleep-promoting medications. Adverse event data values were extracted from the most recent FDA-approved package inserts and converted to an integer before being placebo-adjusted and standardized as a rate per 1000 (AEr). Efficacy data, pre-to-post self-reported data for active and placebo conditions were acquired from pivotal trials identified in "white papers" and systematic reviews/meta-analyses. Weighted effect sizes were calculated for subjective sleep latency, wake time after sleep onset and total sleep time, and then were averaged by medication class for each sleep continuity variable. Overall efficacy was represented by a single variable, SWT (sleep latency + wake time after sleep onset + total sleep time). Risk-benefit was represented using a simple ratio value. For safety, it was found that melatonin receptor agonists had the lowest adverse event rate (AEr = 43.1), and non-benzodiazepine benzodiazepine receptor agonists had the highest rate (AEr = 255.0). For efficacy, it was found that the pre-to-post placebo adjusted effect sizes were largest for benzodiazepines (effect size = 1.94) and smallest for melatonin receptor agonists (effect size = 0.109). For risk-benefit, histamine antagonist had the most favourable profile (risk-benefit = 69.5), while melatonin receptor agonist had the least favourable profile (risk-benefit = 395.7). Overall, the combined metric for risk-benefit suggests that treatment with a histamine antagonist is optimal and potentially represents the best first-line therapy for the medical management of insomnia.

DROID: dose-ranging approach to optimizing dose in oncology drug development.

In the era of targeted therapy, there has been increasing concern about the development of oncology drugs based on the "more is better" paradigm, developed decades ago for chemotherapy. Recently, the US Food and Drug Administration (FDA) initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. To accommodate this paradigm shifting, we propose a dose-ranging approach to optimizing dose (DROID) for oncology trials with targeted drugs. DROID leverages the well-established dose-ranging study framework, which has been routinely used to develop non-oncology drugs for decades, and bridges it with established oncology dose-finding designs to optimize the dose of oncology drugs. DROID consists of two seamlessly connected stages. In the first stage, patients are sequentially enrolled and adaptively assigned to investigational doses to establish the therapeutic dose range (TDR), defined as the range of doses with acceptable toxicity and efficacy profiles, and the recommended phase 2 dose set (RP2S). In the second stage, patients are randomized to the doses in RP2S to assess the dose-response relationship and identify the optimal dose. The simulation study shows that DROID substantially outperforms the conventional approach, providing a new paradigm to efficiently optimize the dose of targeted oncology drugs. DROID aligns with the approach of a randomized, parallel dose-response trial design recommended by the FDA in the Guidance on Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases.

Impact of correlations between prioritized outcomes on the net benefit and its estimate by generalized pairwise comparisons.

Benefit-risk balance is gaining interest in clinical trials. For the comprehensive assessment of benefits and risks, generalized pairwise comparisons are increasingly used to estimate the net benefit based on multiple prioritized outcomes. Although previous research has demonstrated that the correlations between the outcomes impact the net benefit and its estimate, the direction and magnitude of this impact remain unclear. In this study, we investigated the impact of correlations between two binary or Gaussian variables on the true net benefit values via theoretical and numerical analyses. We also explored the impact of correlations between survival and categorical variables on the net benefit estimates based on four existing methods (Gehan, Péron, Gehan with correction, and Péron with correction) in the presence of right censoring via simulation and application to actual oncology clinical trial data. Our theoretical and numerical analyses revealed that the true net benefit values were impacted by the correlations in various directions depending on the outcome distributions. With binary endpoints, this direction was governed by a simple rule with a threshold of 50% for a favorable outcome. Our simulation showed that the net benefit estimates based on Gehan's or Péron's scoring rule could be substantially biased in the presence of right censoring, and that the direction and magnitude of this bias were associated with the outcome correlations. The recently proposed correction method greatly reduced this bias, even in the presence of strong outcome correlations. The impact of correlations should be carefully considered when interpreting the net benefit and its estimate.

Preclinical efficacy in investigator's brochures: Stakeholders' views on measures to improve completeness and robustness.

AIMS: Research ethics committees and regulatory agencies assess whether the benefits of a proposed early-stage clinical trial outweigh the risks based on preclinical studies reported in investigator's brochures (IBs). Recent studies have indicated that the reporting of preclinical evidence presented in IBs does not enable proper risk-benefit assessment. We interviewed different stakeholders (regulators, research ethics committee members, preclinical and clinical researchers, ethicists, and metaresearchers) about their views on measures to increase the completeness and robustness of preclinical evidence reporting in IBs. METHODS: This study was preregistered (https://osf.io/nvzwy/). We used purposive sampling and invited stakeholders to participate in an online semistructured interview between March and June 2021. Themes were derived using inductive content analysis. We used a strengths, weaknesses, opportunities and threats matrix to categorize our findings. RESULTS: Twenty-seven international stakeholders participated. The interviewees pointed to several strengths and opportunities to improve completeness and robustness, mainly more transparent and systematic justifications for the included studies. However, weaknesses and threats were mentioned that could undermine efforts to enable a more thorough assessment: The interviewees stressed that current review practices are sufficient to ensure the safe conduct of first-in-human trials. They feared that changes to the IB structure or review process could overburden stakeholders and slow drug development. CONCLUSION: In principle, more robust decision-making processes align with the interests of all stakeholders and with many current initiatives to increase the translatability of preclinical research and limit uninformative or ill-justified trials early in the development process. Further research should investigate measures that could be implemented to benefit all stakeholders.