Search

Aims: Information on breastfeeding and safety of biologics in infants is lacking due to difficulties in case collection. We evaluated methods for determining the concentration of biologics in breast milk using a dry filter method that can simplify the collection, storage and transport of breast milk. Methods: To generate dried filter paper (DFP) samples, approximately 30 μL of breast milk was placed onto a Whatman 903 card and punched out. After extraction, the supernatant was measured using an enzyme‐linked immunosorbent assay. Three concentrations of each drug were prepared in liquid breast milk (LBM) and DFP samples to determine their stability up to 28 days after storage at 2–8°C or −20°C for LBM and 25 ± 5°C for DFP. LBM and DFP samples were also provided by nursing mothers using biologics during lactation, and drug concentrations in both samples were compared. The agreement between the two measurement methods was confirmed by Bland–Altman analysis. Results: Breast milk was provided by 12 mothers who used biologics (tocilizumab, abatacept, etanercept, golimumab, sarilumab and belimumab). The coefficients of variation for within‐run and between‐run precision for the six drugs were within 15% for both LBM and DFP, and accuracy was within 90%–110% of the quality controls. After 28 days, concentrations remained at more than 90%. The difference between the values obtained by each method was within the acceptable range of error (−12.1 to +16.6 ng/mL). Conclusions: A method for determining the concentration of biologics using DFP is expected to help improve pharmacotherapy for lactating women. [ABSTRACT FROM AUTHOR]

Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behaviour in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease‐ and/or target organ‐specific examples. Identifying and testing PD targets and effects in special populations, and application of age‐ and/or population‐specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques such as preclinical models to study therapeutic strategies, and shift from sequential enrolment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD‐related as well as drug safety‐related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development. [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]

Improved global access to novel age‐appropriate formulations for paediatric subsets, either of new chemical entities or existing drugs, is a priority to ensure that medicines meet the needs of these patients. However, despite regulatory incentives, the introduction to the market of paediatric formulations still lags behind adult products. This is mainly caused by additional complexities associated with the development of acceptable age‐appropriate paediatric medicines. This position paper recommends the use of a paediatric Quality Target Product Profile as an efficient tool to facilitate early planning and decision making across all teams involved in paediatric formulation development during the children‐centric formulation design for new chemical entities, or to repurpose/reformulate off‐patent drugs. Essential key attributes of a paediatric formulation are suggested and described. Moreover, greater collaboration between formulation experts and clinical colleagues, including healthcare professionals, is advocated to lead to safe and effective, age‐appropriate medicinal products. Acceptability testing should be a secondary endpoint in paediatric clinical trials to ensure postmarketing adherence is not compromised by a lack of acceptability. Not knowing the indications and the related age groups and potential dosing regimens early enough is still a major hurdle for efficient paediatric formulation development; however, the proposed paediatric Quality Target Product Profile could be a valuable collaborative tool for planning and decision making to expedite paediatric product development, particularly for those with limited experience in developing a paediatric product. [ABSTRACT FROM AUTHOR]

The safety and efficacy of pharmacotherapy in children, particularly preterms, neonates and infants, is limited by a paucity of good‐quality data from prospective clinical drug trials. A specific challenge is the establishment of valid biomarkers. OMICs technologies may support these efforts by complementary information about targeted and nontargeted molecules through systematic characterization and quantitation of biological samples. OMICs technologies comprise at least genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiomics in addition to the patient's phenotype. OMICs technologies are in part hypothesis‐generating, allowing an in depth understanding of disease pathophysiology and pharmacological mechanisms. Application of OMICs technologies in paediatrics faces major challenges before routine adoption. First, developmental processes need to be considered, including a subdivision into specific age groups as developmental changes clearly impact OMICs data. Second, compared to the adult population, the number of patients is limited as are the type and amount of necessary biomaterial, especially in neonates and preterms. Thus, advanced trial designs and biostatistical methods, noninvasive biomarkers, innovative biobanking concepts including data and samples from healthy children, as well as analytical approaches (eg liquid biopsies) should be addressed to overcome these obstacles. The ultimate goal is to link OMICs technologies with innovative analysis tools, such as artificial intelligence at an early stage. The use of OMICs data based on a feasible approach will contribute to the identification complex phenotypes and subpopulations of patients to improve the development of medicines for children with potential economic advantages. [ABSTRACT FROM AUTHOR]

Older people are often affected by impaired organ and bodily functions resulting in multimorbidity and polypharmacy, turning them into the main user group of many medicines. Very often, medicines have not specifically been developed for older people, causing practical medication problems for them like limited availability of easy to swallow formulations, easy to open packaging and dosing instructions for enteral administration. In 2020, the European Medicines Agency (EMA) published a reflection paper 'Pharmaceutical development of medicines for use in the older population', which discusses how the emerging needs of an ageing European population can be addressed by medicines regulation. The paper intends to help industry to better consider the needs of older people during pharmaceutical/clinical medicines development by summarising data on the most relevant topics, providing early suggestions on how to move forward and prompting expert discussions and studies into knowledge gaps. Topics include patient acceptability, (dis)advantages of an administration route, formulation, dosage form, packaging, dosing device and user instruction. While the paper is directed at older people and the pharmaceutical industry, the reflections are also relevant to younger patients with similar disease‐related needs and of value to other stakeholders parties, e.g., healthcare professionals, academics, patients and caregivers, as the paper makes clear what can be expected from industry and where collaborative work is needed. This commentary provides an overview of the different steps in the development of the reflection paper, discusses points considered most controversial and/or subject to (multidisciplinary) expert discussions and indicates their value for real world clinical practice. [ABSTRACT FROM AUTHOR]

Increased global longevity requires a re‐evaluation of current structures in society to adapt to the consequential demographic shift. As (very) old people are prone to impaired human organ and body functions resulting in, for example, multimorbidity, polypharmacy, hospitalisation and problems in medication management, it is increasingly acknowledged that re‐evaluations should include the suitability of pharmaceutical patient care as one of the cornerstones of public health. Following the 2011 European Medicines Agency (EMA) Geriatric Strategy, in 2017 the EMA published the draft "Reflection paper on the pharmaceutical development of medicines for use in the older population". The draft paper was opened for public consultation and specific attention and feedback (either supportive or with a proposal for revision) was asked on three design aspects: tablet breaking, drug administration through enteral feeding tubes and medication management. Following publication, the draft paper was presented at two public conferences attended by participants from different disciplines. This manuscript is intended to draw the attention of different stakeholder parties to the urgent need to collaborate on the emerging issues arising from increasing longevity and multimorbidity, and especially those associated with pharmaceutical patient care and drug product design, including the need for collaborative research into existing or emerging knowledge gaps. The manuscript focuses on the three aforementioned aspects of pharmaceutical development (tablet breaking, drug administration through enteral feeding tubes and medication management) as these highly relate to medication safety and efficacy and constitute persistent and typical challenges for older people, caregivers and healthcare professionals in daily clinical practice. [ABSTRACT FROM AUTHOR]

Adopted guidelines reflect a harmonised European approach to a specific scientific issue and should reflect the most recent scientific knowledge. However, whilst EU regulations are mandatory for all member states and EU directives must be followed by national laws in line with the directive, EMA guidelines do not have legal force and alternative approaches may be taken, but these obviously require more justification. This new series of the BJCP, developed in collaboration with the EMA, aims to address this issue by providing an annotated version of some relevant EMA guidelines and regulatory documents by experts. Hopefully, this will help in promoting their diffusion and in opening a forum for discussion with our readers. [ABSTRACT FROM AUTHOR]

Measurement of pre‐dose tacrolimus concentrations, also referred to as trough concentrations or C0 (in this paper the term C0 will be used), is the most frequently used parameter for therapeutic drug monitoring in patients after solid organ transplantation. C0 is relatively easy to obtain, and can be combined with other lab tests. C0 monitoring is convenient for patient and hospital staff. Adjusting the dose based on C0 assumes that the C0 has a good correlation with the overall exposure to the drug, as reflected in the area under concentration—time curve (AUC).However, C0 may not be the panacea it is suggested to be, and there are patients who may benefit from additional measurements to more precisely assess drug exposure. Especially in patients with a low C0/dose ratio, the peak tacrolimus concentrations after oral administration may be unexpectedly high, resulting in toxicity and (as has been shown already) in poor long‐term graft survival. At the other extreme, patients who only need a very low dose to reach target C0 may have a low peak and also a low AUC and may be underexposed.In this paper, the limitations of C0 will be discussed, and the type of studies needed to provide the evidence for implementation of more sophisticated therapeutic drug monitoring. The paper focuses on treatment of adult kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Opioid use disorder (OUD) and chronic pain are commonly co‐occurring disorders which can exacerbate each other. Sex/gender differences have been shown in aspects of the clinical course and biological underpinnings of both OUD and chronic pain. The purpose of this scoping review is to summarize literature which has addressed sex/gender differences in relation to the confluence of OUD and chronic pain. This review focused on peer‐reviewed journal articles with human subjects and addressing (a) opioid misuse, chronic opioid use or opioid use disorder (OUD), (b) chronic or persistent pain and (c) sex/gender differences in relation to OUD and/or chronic pain. Of the 146 papers identified by the search strategy, 30 met the criteria for inclusion. Charting focused on a priori themes of chronic pain, opioid misuse/OUD and sex/gender in sample, predictor and outcome variables, and key study findings. The majority of research identified was cross‐sectional in nature, and sex/gender differences and treatment effects were largely included as post‐hoc analyses. Together, the results of this early work align with higher prevalence for OUD in men/males and chronic pain in women/females, while adding critical information with respect to potential sex/gender differences in the development and treatment of their co‐occurrence across a range of biological and psychosocial factors. Findings underline the importance of considering sex and gender in the intersection of the development and treatment of OUD and chronic pain. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Previous systematic reviews suggest that deprescribing may improve survival, particularly in frail older people. Evidence is rapidly accumulating, suggesting a need for an updated review of the literature.We updated a 2016 systematic review and meta‐analysis to include studies published from inception to 26 April 2024 from specified databases. Studies in which older people had at least one medication deprescribed were included and grouped by study designs and targeted medications. The risk of bias was assessed using the Cochrane tool and the Newcastle‐Ottawa tool. Odds ratios (OR) or mean differences were calculated as the effect measures using either the Mantel–Haenszel or generic inverse‐variance method with fixed‐ or random‐effects meta‐analyses. The primary outcome was mortality. Secondary outcomes were adverse drug withdrawal events, physical health, cognitive function, quality of life and effect on medication regimen. Subgroup analyses were performed based on age and intervention types.A total of 259 studies (reported in 286 papers) were included in this updated review. Deprescribing polypharmacy did not result in a significant reduction in mortality in both randomized (OR 0.96, 95% confidence interval [CI] 0.84–1.09) and non‐randomized studies (OR 0.70, 95% CI 0.36–1.38). Further subgroup analyses of randomized studies on deprescribing polypharmacy demonstrated a significant reduction in mortality in the young old (aged 65–79) (OR 0.71, 95% CI 0.51–0.99) and when patient‐specific interventions were applied (OR 0.79, 95% CI 0.63–0.99).Deprescribing can be achieved with potentially important benefits in terms of improved survival, particularly when patient‐specific interventions are applied and initiated early in the young old. [ABSTRACT FROM AUTHOR]

In solid organ transplantation (SOT), biologicals such as recombinant therapeutic proteins, monoclonal antibodies, fusion proteins and conjugates are increasingly used for immunosuppression, desensitization, ABO (blood group) incompatibility, antibody‐mediated rejections and atypical haemolytic uremic syndrome. In this paper, we review the medical evidence available for biologicals used in SOT and the potential for improvement by the application of therapeutic drug monitoring (TDM) and model‐informed precision dosing. Biologicals are used for off‐label indications within the field of SOT, building on the experience from their use on labelled indications. Dosing is currently mostly standard, and experience vs. effect and toxicity is limited. Pharmacokinetic characteristics of these large, partly also immunogenic molecules differ from those of traditional small molecules. Individualization by concentration measurements and modelling has mostly been proof‐of‐concept or feasibility studies that lack the power to provide evidence for improvement in clinical outcome. For some drugs such as alemtuzumab, eculizumab, rituximab, tocilizumab and belatacept, studies have demonstrated significant interindividual variability in pharmacokinetics. Variability in absorption from subcutaneous administration may increase interindividual variability. There is also an economic aspect of appropriate dosing that needs to be pursued. Available assays and models to refine interpretation are in place, but trials of adequate size to document the usefulness of TDM and MIPD are scarce. Collaboration within the TDM community seems mandatory to establish studies of sufficient strength to provide evidence for the use of biologicals that are currently used off‐label in SOT and furthermore to identify the settings where TDM may be beneficial. [ABSTRACT FROM AUTHOR]

Aims: The global older population is growing rapidly, and the rise in polypharmacy has increased potentially inappropriate medication (PIM) encounters. PIMs pose health risks, but detecting them automatically in large medical databases is complex. This review aimed to uncover PIM prevalence in individuals aged 65 years or older using health databases and emphasized the risk of underestimating PIM prevalence due to underutilization of detection tools. Methods: This study conducted a broad search on the Medline database to identify articles about the prevalence of PIMs in older adults using various databases. Articles published between January 2010 and June 2023 were included, and specific criteria were applied for study selection. Two literature reviews conducted before our study period were integrated to obtain a perspective from the 1990s to the present day. The selected papers were analysed for variables including database type, screening method, adaptations and PIM prevalence. The study categorized databases and original screening tools for clarity, examined adaptations and assessed concordance among different screening methods. Results: This study encompassed 48 manuscripts, covering 58 sample evaluations. The mean prevalence of PIMs within the general population aged over 65 years was 27.8%. Relevant heterogeneity emerged in both the utilized databases and the detection methods. Adaptation of original screening tools was observed in 86.2% (50/58) of cases. Half of the original screening tools used for assessing PIMs belonged to the simple category. About a third of the studies employed less than half of the original criteria after adaptation. Only three studies used over 75% of the original criteria and more than 50 criteria. Conclusions: This extensive review highlights PIM prevalence among the older adults, emphasizing method intricacies and the potential for underestimation due to data limitations and algorithm adjustments. The findings call for enhanced methodologies, transparent algorithms and a deeper understanding of intricate rules' impact on public health implications. [ABSTRACT FROM AUTHOR]

The Cochrane Library published a systematic review of interventions for paracetamol overdose in 2018.8 The conclusion begins: 'These results highlight the paucity of randomised clinical trials comparing different interventions for paracetamol overdose and their routes of administration and the low or very low level quality of the evidence that is available'. Disproportionate effect on child admissions of the change in Medicines and Healthcare Products Regulatory Agency guidance for management of paracetamol poisoning: an analysis of hospital admissions for paracetamol overdose in England and Scotland. Keywords: poisoning; research; toxicology EN poisoning research toxicology 56 57 2 02/01/22 20220101 NES 220101 Clinical Toxicology is one of the core sub-specialities of Clinical Pharmacology and Therapeutics. [Extracted from the article]

A recent article in the British Journal of Clinical Pharmacology discusses a method developed by Saito et al. to measure the concentrations of biologic agents in dried milk spots. The study provides insights into the pharmacokinetic properties of these agents and offers clinically important information for their safe use. However, the authors suggest that additional data on analyte stability in the filter paper and the integrity of the analytes extracted from breast milk are needed. They also question the conclusions drawn from the study and recommend further evaluation of the effects of variability in dried spots and the need for separate analysis for each drug. Overall, more validation and evaluation are required before applying this method in clinical trials or practice. [Extracted from the article]

Cytomegalovirus (CMV) infection frequently occurs after solid organ transplantation and is associated with an increased morbidity and mortality. Fortunately, the development of valganciclovir prophylaxis has lowered the incidence of CMV infection and its complications in immunosuppressed solid organ transplant recipients. However, breakthrough infections during valganciclovir prophylaxis and late CMV infection after cessation of valganciclovir prophylaxis still occur with the current prophylactic strategy. Additionally, valganciclovir resistance has emerged among CMV strains, which complicates the treatment of CMV infections. Furthermore, the use of valganciclovir is associated with myelotoxicity, which can lead to the premature withdrawal of prophylaxis. It is important to address these current issues in order to improve the standard care after solid organ transplantation. This paper will therefore discuss the clinical practice of valganciclovir prophylaxis, elaborate on its issues and suggest how to improve the current prophylactic strategy with a possible role for therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

I read with interest the paper entitled I The impact of tacrolimus exposure on extra-renal adverse effects in adult renal transplant recipients i that was published in the I Journal i (2019, Vol 85, pp. 516-529). Patients receiving tacrolimus have their doses individualized (based upon tacrolimus trough concentration) and this (at least partially) I normalizes i exposure to account for differences in patient factors. [Extracted from the article]

To examine how countries differ in attitudes to adverse drug reactions by examining published scientific papers.We searched Ovid EMBASE for publications indexed by the category′therapeutic agents′, and the subcategory′adverse effects′, by country for 43 countries.We counted 1 810 202 papers world-wide regarding therapeutic agents during 14 years, of which 195 154 (10.8%) were included in the adverse effects subcategory. There were substantial differences between countries, not explained by population, economic variation, overall publication rate on therapeutic agents, or the presence of large indigenous pharmaceutical companies.Many local cultural factors influence the ratio of papers on adverse reactions to all drug effects, so it may be difficult to improve their recognition and reporting by international efforts. [ABSTRACT FROM AUTHOR]

The Medicines and Healthcare products Regulatory Agency was established in April 2003 by the merger of the Medicines Control Agency (MCA) and the Medical Devices Agency (MDA). This paper describes the scientific and organizational basis for the merger and describes the various challenges facing this new Agency. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion In this reflection paper, the authors, based on their experience as teachers and students of the courses of Pharmacology at the University of Bologna, reflect on their specific roles towards innovation in the teaching of Clinical Pharmacology.Strengths, weaknesses and challenges are presented as identified during the teaching and learning experience in the currently evolving medical degree programmes of the University in light of current trends in medical education.Keeping in mind the identified challenges together with the features proposed for the model prescriber (knowledgeable, contemporary, communicative and safe), we indicate some ways to improve the students' experience and make sure they develop up‐to‐date skills in Clinical Pharmacology taking advantage of recent ongoing collaborations at European level. International collaboration is indeed necessary to adequately address the current challenges of teaching clinical pharmacology.Our shared conclusion is that empowering students with a scientifically sound method to retrieve relevant information and developing their skills to communicate in an interprofessional and, wherever possible, international environment is the key to prepare future prescribers and, ultimately, to improve patient safety. [ABSTRACT FROM AUTHOR]

This paper aims to explore the possibility of employing large language models (LLMs) – a type of artificial intelligence (AI) – in clinical pharmacology, with a focus on its possible misuse in bioweapon development. Additionally, ethical considerations, legislation and potential risk reduction measures are analysed. The existing literature is reviewed to investigate the potential misuse of AI and LLMs in bioweapon creation. The search includes articles from PubMed, Scopus and Web of Science Core Collection that were identified using a specific protocol. To explore the regulatory landscape, the OECD.ai platform was used. The review highlights the dual‐use vulnerability of AI and LLMs, with a focus on bioweapon development. Subsequently, a case study is used to illustrate the potential of AI manipulation resulting in harmful substance synthesis. Existing regulations inadequately address the ethical concerns tied to AI and LLMs. Mitigation measures are proposed, including technical solutions (explainable AI), establishing ethical guidelines through collaborative efforts, and implementing policy changes to create a comprehensive regulatory framework. The integration of AI and LLMs into clinical pharmacology presents invaluable opportunities, while also introducing significant ethical and safety considerations. Addressing the dual‐use nature of AI requires robust regulations, as well as adopting a strategic approach grounded in technical solutions and ethical values following the principles of transparency, accountability and safety. Additionally, AI's potential role in developing countermeasures against novel hazardous substances is underscored. By adopting a proactive approach, the potential benefits of AI and LLMs can be fully harnessed while minimizing the associated risks. [ABSTRACT FROM AUTHOR]

Aims: A key reason for the failure of antituberculosis (anti‐TB) treatment is missed doses (instances where medication is not taken). Adverse drug reactions (ADRs) are 1 cause of missed doses, but the global evidence, their relative contribution to missed doses vs. other causes, the patterns of missed doses due to ADRs and the specific ADRs associated with missed doses have not been appraised. We sought to address these questions through a scoping review. Methods: MEDLINE, Embase and Web of Science were searched on 3 November 2021 using terms around active TB, missed doses and treatment challenges. Studies reporting both ADR and missed dose data were examined (PROSPERO: CRD42022295209). Results: Searches identified 108 eligible studies: 88/108 (81%) studies associated ADRs with an increase in missed doses; 33/61 (54%) studies documenting the reasons for missed doses gave ADRs as a primary reason. No studies examined patterns of missed doses due to ADRs; 41/108 (38%) studies examined associations between 68 types of ADR (across 15 organ systems) and missed doses. Nuance around ADR‐missed doses relations regarding drug susceptibility testing profile and whether the missed doses originated from the patient, healthcare professionals, or both were found. Conclusion: There is extensive evidence that ADRs are a key driver for missed doses of anti‐TB treatment. Some papers examined specific ADRs and none evaluated the patterns of missed doses due to ADRs, demonstrating a knowledge deficit. Knowing why doses both are and are not missed is essential in providing targeted interventions to improve treatment outcomes. [ABSTRACT FROM AUTHOR]

Chemodenervation with botulinum neurotoxin type A (BoNTA) is the preferred method for focal spasticity management among various treatment options. While BoNTA injection is considered safe, its widespread use and increasing evidence raise safety concerns. In this paper, we present a patient with central pontine myelinolysis, a rare disease, who developed acute respiratory distress syndrome on the third day after BoNTA application to the spastic gastrocnemius muscle group and required intubation in the intensive care unit due to this complication. To our knowledge, this is the first case reported in the literature to develop an acute pulmonary complication after BoNTA injection into spastic lower extremity muscles. [ABSTRACT FROM AUTHOR]

The sources of bias in medication adherence research have not been comprehensively explored. We aimed to identify biases expected to affect adherence research and to develop a framework for mapping these onto the phases of adherence (initiation, implementation and discontinuation). A literature search was conducted, key papers were reviewed and a Catalogue of Bias was consulted. The specific biases related to adherence measurement and metrics were mapped onto the phases of adherence using a tabular matrix. Twenty‐three biases were identified, of which 11 were specifically relevant to adherence measures and metrics. The mapping framework showed differences in the numbers and types of biases associated with each measure and metric while highlighting those common to many adherence study designs (e.g., unacceptability bias and apprehension bias). The framework will inform the design of adherence studies and the development of risk of bias tools for adherence research. [ABSTRACT FROM AUTHOR]

The British Journal of Clinical Pharmacology highlights several papers in its latest issue. One paper discusses the updated EMA guideline on medicinal products containing genetically modified cells. Two other papers focus on adherence, with one reporting that research underestimates non-adherence and the other suggesting that patient-reported daily doses can improve estimates of adherence. The issue also includes a study on the use of artificial intelligence in pharmacovigilance and a report on high-fidelity simulation medical education training in acute clinical toxicology. Lastly, a study from South Africa examines determinants of early changes in serum creatinine in individuals starting antiretroviral therapy for HIV. [Extracted from the article]

Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well‐designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state‐of‐the‐art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science. [ABSTRACT FROM AUTHOR]

Aims: Sewage treatment effluent with pharmaceutical residues is discharged into surface waters, raising societal concerns. The aim of this paper is to describe the Dutch chain approach on medicinal residues in water that has been implemented by the Dutch government. We show how stakeholders from both the health and water sectors have got actively involved. Within this chain approach, source measures as well as end‐of‐pipe measures are identified and, where feasible and effective, implemented. Methods: Descriptive paper on the Dutch chain approach. Results: Getting the water and health care sectors to talk with each other instead of about each other was the key accomplishment. Comprehension of each other's viewpoints, terminology, policy goals and span of control, was pivotal in setting shared goals, creating perspective about possible measures and actually taking (joint) action. Together, stakeholders agreed to act within their own possibilities, without pointing at others, and to focus on pragmatic measures. In this article, we provide examples of measures taken, pilot projects performed, and of measures that were not implemented. Besides this, we discuss the most important barriers encountered during this process and how they were overcome. Conclusion: The issue of pharmaceuticals in the environment is a wicked problem, which makes it necessary to work together with many stakeholders on possible solutions, avoiding paralysis by complexity. Most importantly, stakeholders need to invest in mutual understanding, keep an open communication, and feel invited to bring in solutions for their part of the chain. [ABSTRACT FROM AUTHOR]

Aim: Pharmacokinetics have historically been assessed using drug concentration data obtained via blood draws and bench‐top analysis. The cumbersome nature of these typically constrains studies to at most a dozen concentration measurements per dosing event. This, in turn, limits our statistical power in the detection of hours‐scale, time‐varying physiological processes. Given the recent advent of in vivo electrochemical aptamer‐based (EAB) sensors, however, we can now obtain hundreds of concentration measurements per administration. Our aim in this paper was to assess the ability of these time‐dense datasets to describe time‐varying pharmacokinetic models with good statistical significance. Methods: We used seconds‐resolved measurements of plasma tobramycin concentrations in rats to statistically compare traditional one‐ and two‐compartmental pharmacokinetic models to new models in which the proportional relationship between a drug's plasma concentration and its elimination rate varies in response to changing kidney function. Results: We found that a modified one‐compartment model in which the proportionality between the plasma concentration of tobramycin and its elimination rate falls reciprocally with time either meets or is preferred over the standard two‐compartment pharmacokinetic model for half of the datasets characterized. When we reduced the impact of the drug's rapid distribution phase on the model, this one‐compartment, time‐varying model was statistically preferred over the standard one‐compartment model for 80% of our datasets. Conclusions: Our results highlight both the impact that simple physiological changes (such as varying kidney function) can have on drug pharmacokinetics and the ability of high‐time resolution EAB sensor measurements to identify such impacts. [ABSTRACT FROM AUTHOR]

Pharmacovigilance studies based on spontaneous reporting systems use disproportionality analysis methods to identify drug‐event combinations with higher‐than‐expected reporting. Enhanced reporting is deemed as a proxy for a detected signal and is used to generate drug safety hypotheses, which can then be tested in pharmacoepidemiologic studies or randomized controlled trials. Higher‐than‐expected reporting means that the reporting rate of a drug‐event combination of interest is disproportionately higher than the rate in a specific comparator or reference set. Currently, it is unclear which comparator is the most appropriate for use in pharmacovigilance. Moreover, it is also unclear how the selection of a comparator may affect the directionality of the various reporting and other biases. This paper reviews commonly used comparators chosen for signal detection studies (active comparator, class‐exclusion comparator, and full data reference set). We give an overview of the advantages and disadvantages of each method based on examples from the literature. We also touch upon the challenges related to the derivation of general recommendations for the selection of comparators when mining spontaneous reports for pharmacovigilance. [ABSTRACT FROM AUTHOR]

Upscaling of medication adherence interventions to routine care is still challenging. This realist theory‐inspired review aimed to assess which intervention aspects are potentially important for the scalability of effective cardiovascular disease (CVD) medication adherence interventions and how they are reported in effectiveness studies. A total of 4097 articles from four databases were screened of which ultimately 31 studies were included. Relevant information on scalability was extracted using a theoretic framework based on the scalability assessment tool used in the QUALIDEC study for the following domains: (i) innovation, (ii) implementers and patients, (iii) adopting organizations and health system, and (iv) socio‐political context. Extracted articles were analysed for themes and chains of inference, which were grouped based on commonality and source of evidence to form new hypotheses. Six different domains relevant for scalability of adherence interventions were identified: (1) Complexity of the intervention; (2) training; (3) customization of the intervention; (4) drivers of the intervention; (5) technical interventions; and (6) stakeholder involvement. These six domains might be useful for the development of more scalable interventions by bridging the gap between research and practice. Data relevant for scalability is not well reported on in effectiveness trials for CVD medication adherence interventions and only limited data on scalability has been published in additional papers. We believe the adoption and reach of effective CVD medication adherence interventions will improve with increased awareness for the necessity of scalability in all phases of intervention development. [ABSTRACT FROM AUTHOR]

Aims: The Care Home Independent Pharmacist Prescriber Study (CHIPPS) process evaluation hypothesized that contextual factors influenced the likelihood of deprescribing by pharmacist-independent prescribers. The aim of this paper is to test this hypothesis. Methods: From CHIPPS study data, medications deprescribed totalled 284 for 370 residents in UK care homes. Regression analysis was used to describe the relationship between the number of medicines stopped and contextual factors (number of residents cared for, pharmacist employment within associated medical practice, previous care home experience, hours active within trial, years’ experience as a pharmacist and as a prescriber). Results: Number of residents and pharmacist-independent prescriber employment within a medical practice were positive predictors of deprescribing. Conclusion: Previous experiences were not related to deprescribing likelihood. Increasing the number of residents increases the opportunity for deprescribing and therefore this relationship is intuitive. The location within a medical practice is an interesting finding that requires further exploration to understand its exact nature. [ABSTRACT FROM AUTHOR]

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that is essential for pyrimidine de novo synthesis. Rapidly growing cancer cells and replicating viruses are dependent on host cell nucleotides, the precursors of which are provided by DHODH. Hence, DHODH becomes an ideal target for pharmacological intervention. RP7214 is a potent and selective inhibitor of human DHODH and has shown antiviral and antileukaemic activity in preclinical studies. This paper describes the phase I study that evaluated the safety and pharmacokinetics of single and multiple ascending doses (SAD and MAD) and the food effect of RP7214 in healthy volunteers (HVs). The study was a randomized, double‐blind, placebo‐controlled trial of single dose (100, 200 and 400 mg QD), multiple doses (200 and 400 mg BID for 7 days) and a food effect study at a single dose of 200 mg. A total of 18, 12 and 12 HVs were enrolled in the SAD, MAD and food effect parts of the study, respectively. RP7214 was well tolerated at all dose levels. There were 20 treatment‐emergent adverse events (TEAEs) reported, out of which most were mild to moderate in severity while three TEAEs were grade ≥3. RP7214 showed accumulation on multiple dosing. Steady‐state concentrations were reached within about 3‐6 days. The mean plasma half‐life at steady‐state was 12.8 hours (9.9‐15.3). Food did not impact the absorption of RP7214. Inhibition of DHODH, as evidenced by increased dihydroorotate levels, was observed, confirming target engagement. The high systemic exposure with a favourable safety profile shows potential for the development of RP7214 in SARS‐CoV‐2 and acute myeloid leukaemia (NCT04680429). [ABSTRACT FROM AUTHOR]

Drug transporters such as P-glycoprotein (P-gp) modulate intestinal drug absorption.[2] If P-gp expression is enhanced (e.g. after repetitive intake of rifampicin or rifabutin), absorption is lowered. Dolutegravir, drug-drug interactions, P-glycoprotein (P-gp), population pharmacokinetics, physiology-based pharmacokinetics, rifabutin Keywords: dolutegravir; drug-drug interactions; P-glycoprotein (P-gp); physiology-based pharmacokinetics; population pharmacokinetics; rifabutin EN dolutegravir drug-drug interactions P-glycoprotein (P-gp) physiology-based pharmacokinetics population pharmacokinetics rifabutin 2329 2331 3 06/20/23 20230701 NES 230701 We read with great interest the recent paper by Kawuma and co-workers[1] which we consider an excellent contribution to a topic of high clinical relevance. [Extracted from the article]

Pharmacogenomics (PGx) relates to the study of genetic factors determining variability in drug response. Implementing PGx testing in paediatric patients can enhance drug safety, helping to improve drug efficacy or reduce the risk of toxicity. Despite its clinical relevance, the implementation of PGx testing in paediatric practice to date has been variable and limited. As with most paediatric pharmacological studies, there are well‐recognised barriers to obtaining high‐quality PGx evidence, particularly when patient numbers may be small, and off‐label or unlicensed prescribing remains widespread. Furthermore, trials enrolling small numbers of children can rarely, in isolation, provide sufficient PGx evidence to change clinical practice, so extrapolation from larger PGx studies in adult patients, where scientifically sound, is essential. This review paper discusses the relevance of PGx to paediatrics and considers implementation strategies from a child health perspective. Examples are provided from Canada, the Netherlands and the UK, with consideration of the different healthcare systems and their distinct approaches to implementation, followed by future recommendations based on these cumulative experiences. Improving the evidence base demonstrating the clinical utility and cost‐effectiveness of paediatric PGx testing will be critical to drive implementation forwards. International, interdisciplinary collaborations will enhance paediatric data collation, interpretation and evidence curation, while also supporting dedicated paediatric PGx educational initiatives. PGx consortia and paediatric clinical research networks will continue to play a central role in the streamlined development of effective PGx implementation strategies to help optimise paediatric pharmacotherapy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "The haemodynamic effects of intravenous paracetamol (acetaminophen) in healthy volunteers: a double-blind, randomized, triple crossover trial" by E. Chiam and others, citing discrepancies in haemodynamic effects of mannitol and saline.

The British Journal of Clinical Pharmacology's latest issue highlights include a Themed Issue on Drug Safety, which emphasizes the importance of investigating and limiting side effects while maintaining efficacy. The journal also features two papers on adherence, discussing the potential use of model-based TDM for optimizing antihypertensive drugs and the adverse consequences of undiagnosed nonadherence in Randomized Controlled Trials. The author concludes by wishing readers a safe and enjoyable summer. [Extracted from the article]

Aim: The aim of this study was to examine the cooccurrence of heightened media attention after the publication of a paper by Skovlund et al in September 2016 on the link between hormonal contraception and depression or mood on adverse drug reaction (ADR) reports in the UK. Methods: A quantitative analysis of relevant newspaper articles published between January 2014 and December 2017 was performed, as well as a content analysis. ADR reports were collected from the Medicines and Healthcare Products Regulatory Agency website and via a Freedom of Information request. A quantitative analysis was performed on ADR reports of hormonal contraceptives for all ADRs and for depressed mood disorders and disturbances. Results: The publication of the Skovlund et al paper did not lead to a peak in relevant newspaper articles, but there was a change in the content of the newspaper articles, which focussed more on the link between hormonal contraceptives and depression or mood. There was an overall increase in ADR reports by women relating to hormonal contraceptives between 2016 and 2017, and for combined contraceptives this was due to an increase in ADR reports of depressed mood disorders and disturbances. Conclusions: The content of media attention appears to affect ADR reporting by women for combined contraceptives. In general, patients report the majority of depressed mood disorders and disturbances ADRs as opposed to health professionals, who report other ADRs. Care providers can anticipate the effect of heightened media attention and help patients when they experience these ADRs. [ABSTRACT FROM AUTHOR]

The British Journal of Clinical Pharmacology's March issue highlights the incorporation of Artificial Intelligence (AI) into clinical pharmacology research, education, patient care, drug development, and dissemination. The issue also features papers on the side effects of drugs, including sex differences in serious adverse drug reactions, predicting adverse drug reactions in neonates, and a program for reporting adverse drug reactions in children and young adults. Additionally, the issue discusses inappropriate prescribing, standardization in pharmacovigilance efforts for pregnancy and breastfeeding, and the effects of isotretinoin on metabolizing enzymes. The author encourages readers to explore the editorial and all the papers on AI and clinical pharmacology. [Extracted from the article]

The British Journal of Clinical Pharmacology's February issue highlights several research papers on various topics. One study focuses on a potential treatment for autoimmune diseases using a novel C‐X‐C chemokine receptor 3 antagonist. Another paper examines the absorption, distribution, metabolism, and elimination of a cholesterol 24‐hydroxylase inhibitor for the treatment of seizures. Additionally, the issue includes critical evaluations of evidence from clinical studies, such as the use of oral gonadotrophin releasing hormone antagonists for uterine fibroids and the establishment of a children's Drugs and Therapeutics Committee. The issue also discusses the United Kingdom Prescribing Safety Assessment, which assesses the competence of physicians to prescribe medications. Overall, this issue offers valuable insights for clinical pharmacologists. [Extracted from the article]

Describes a method of therapeutic drug monitoring of antiepileptic drugs (AED) in blood spots dried on filter paper in outpatient settings. Correlation of AED concentrations in serum and whole blood; Quantification of AED.

Aims: The aim of this paper is to assess recent developments in non‐medical tramadol use, tramadol use disorder, illegal procurement and deaths. Methods: This study used repeated cross‐sectional analysis of data collected nationwide from 2013 to 2018. Analysis was conducted through multisource monitoring of the French Addictovigilance Network of: (1) validated reports of high‐risk tramadol use, (2) record systems collecting information from toxicology experts investigating analgesic‐related deaths (DTA) and deaths related to substance abuse (DRAMES), and pharmacists for forged prescriptions (OSIAP), and (3) survey of drug users, with investigation of patterns of use while visiting addiction‐specialised institutions (OPPIDUM). Results: Despite a plateauing level of tramadol exposure in the French population, the proportion of tramadol reports increased 1.7‐fold (187 cases in 2018, 3.2% (95% confidence interval [CI]: 2.74–3.63%), versus 1.9% (95% CI: 1.49–2.42% in 2013). Trends were similar in OSIAP: 11.9% of forged prescriptions in 2018 (95% CI: 10.56–13.45%); 1.7‐fold increase; in OPPIDUM: 0.76% (95% CI: 0.55–1.02); 2.2‐fold increase; and DRAMES: 3.2% of drug abuse‐related deaths in 2018 (95% CI: 1.89–5.16) versus 1.7% in 2013 (95% CI: 0.65–3.84). Tramadol was the primary opioid in analgesic‐related deaths in DTA (45% in 2018). Two profiles of high‐risk tramadol users were identified: (1) patients treated for pain or with tramadol persistence when pain disappeared (mainly women; mean age 44 years), and (2) individuals with non‐medical use for psychoactive effects (mainly men; mean age 36 years). Conclusion: The triangulation of the data obtained through addictovigilance monitoring evidenced a recent increase in high‐risk tramadol use. These findings have a practical impact on the limitation of the maximal duration of tramadol prescriptions. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to evaluate the analgesic effectiveness and adverse reactions of ketorolac in comparison with other drugs when administered postoperatively after third molar surgery. Methods: PubMed and Google Scholar were utilized to search for articles comparing the efficacy and safety of ketorolac and other analgesic agents after third molar surgery. Data from papers with a lower risk of bias were recorded. The overall evaluation of analgesia onset, general and subgroup evaluation of the number of patients requiring rescue analgesic medication, general and subgroup assessment of the study medication (satisfaction on the study drugs), and the overall estimation of adverse effects were performed using the Review Manager Software 5.3 to analyse the data and obtain the meta‐analysis plot. Results: The subgroup evaluation of the study medication showed that patients who received ketorolac 30 mg were more satisfied than those who were given parecoxib 1 mg (odds ratio [OR] = 8.57, 95% confidence interval [CI] = 3.66–20.08, P =.00001), parecoxib 2 mg (OR = 7.17, 95% CI = 2.88–17.86, P =.0001), parecoxib 5 mg (OR = 3.03, 95% CI = 1.69–5.41, P =.0002), and parecoxib 10 mg (OR = 2.42, 95% CI = 1.36–4.32, P =.003). Moreover, patients who received ketorolac reported fewer adverse reactions compared with those who had received opioid analgesics (OR = 0.14, 95% CI = 0.32–1.76, P =.0001). Conclusions: The data from this study demonstrates that the postoperative administration of ketorolac 30 mg presents better results on patient satisfaction when compared to parecoxib 1 mg to 10 mg, and presents a similar satisfaction to parecoxib 20 mg following third molar removal. [ABSTRACT FROM AUTHOR]

This review provides tools to consider the inclusion of healthy volunteers (HVs) in first‐in‐human (FIH) oncology clinical trials with small molecules, including targeted and immunomodulatory agents, a strategy that was not envisioned with classic chemotherapy. To enable an FIH oncology trial in HVs compared to cancer patients (CPs), a robust nonclinical package must be generated, which includes toxicokinetic and pharmacokinetic studies, as well as more extensive safety pharmacology, toxicology and genotoxicity studies. This strategy could provide an early clinical characterization of the pharmacokinetic parameters and clinical safety profile in the absence of comorbidities and concomitant medication. It also avoids the ethical issue of administrating subtherapeutic doses to CPs, and could potentially help to accelerate the timelines of clinical drug development for patient care. That being said, stakeholders involved in these studies need to proceed with caution, fully understand the regulatory guidance and thoroughly evaluate the benefits and risks. This paper serves to address the regulatory guidance and other considerations needed when using healthy volunteers in early oncology trials. [ABSTRACT FROM AUTHOR]

The COVID‐19 pandemic has driven an unprecedented level of global activity in drug discovery and clinical development for effective therapeutics targeting the coronavirus disease. There are currently 744 therapeutics being tested in 2879 clinical trials globally. Almost 90% of these clinical trials are focused on monotherapies. Combination therapies are the mainstay of antiviral therapeutics to increase the potency of the individual compounds and to combat the rapid evolution of resistance, although combination therapies have inherently complex clinical and regulatory development challenges. Increased understanding of the SARS‐CoV‐2 lifecycle and COVID‐19 pathology provides a scientific rationale for evaluating the effectiveness of different combinations. In this paper, we provide an overview of the current clinical trial landscape for combination therapeutics targeting COVID‐19 through weekly scanning of national and international clinical trial registries. Our analysis delves specifically into dual combination therapies in what can be defined as "pivotal clinical trials" (active, randomised, controlled and at least phase II), with a focus on new and repurposed therapeutic candidates that have shown positive signals and/or been granted authorisation for emergency use based on positive efficacy and safety data. [ABSTRACT FROM AUTHOR]

Quantitative systems pharmacology (QSP) is a relatively new discipline within modelling and simulation that has gained wide attention over the past few years. The application of QSP models spans drug‐target identification and validation, through all drug development phases as well as clinical applications. Due to their detailed mechanistic nature, QSP models are capable of extrapolating knowledge to predict outcomes in scenarios that have not been tested experimentally, making them an important resource in experimental and clinical pharmacology. However, these models are complicated to work with due to their size and inherent complexity. This makes many applications of QSP models for simulation, parameter estimation and trial design computationally intractable. A number of techniques have been developed to simplify QSP models into smaller models that are more amenable to further analyses while retaining their accurate predictive capabilities. Different simplification techniques have different strengths and weaknesses and hence different utilities. Understanding the utilities of different methods is essential for selection of the best method for a particular situation. In this paper, we have created an overall framework for model simplification techniques that allows a natural categorisation of methods based on their utility. We provide a brief description of the concept underpinning the different methods and example applications. A summary of the utilities of methods is intended to provide a guide to modellers in their model endeavours to simplify these complicated models. [ABSTRACT FROM AUTHOR]

While the main burden may lie with our colleagues teaching epidemiology and scientific methodology, we should make sure our students leave their pharmacology course prepared to read and appraise papers on drugs. It is worth noting that the risk was present not just in prescribing potentially ineffective treatment; the ensuing shortage also affected patients taking hydroxychloroquine for other conditions who had trouble filling their prescriptions. TEACHING (CLINICAL) PHARMACOLOGY While the focus of our curriculum is currently on the development of novel drugs, it may be worthwhile to include more examples of drug repurposing and the resulting research and ethical questions concerning off-label use of old drugs in a different new settings and populations. [Extracted from the article]

The British Journal of Clinical Pharmacology has published its June issue, which includes a range of articles on various topics. One article discusses the development of a method for extracting information on drug-health food product interactions using language processing techniques. Another article explores the risk/benefit ratio of different medications, such as potentially inappropriate medications for newly treated patients with type 2 diabetes and the risk of delirium after sedation with propofol or midazolam in intensive care units. Additionally, the issue features papers on ADME and pharmacokinetics. Readers can access the full articles through the provided links. [Extracted from the article]

The article titled "The association between proton pump inhibitor use and systemic anti-tumour therapy on survival outcomes in patients with advanced non-small cell lung cancer: A systematic review and meta-analysis" by Na Wei, Bin Zheng, Wancai Que, Jin Zhang, and Maobai Liu has issued a correction regarding the use of "Begger's test" in the statistical analysis and publication bias sections. The correct term should be "Begg's test." The authors assure readers that these corrections do not significantly affect the overall findings and conclusions of the paper. They apologize for any confusion caused and appreciate the opportunity to rectify the errors. [Extracted from the article]

Capacity building programmes for African regulators should link education, training and research with career development in an approach that combines an academic base and experiential learning aligned within a competency framework. A regulatory ecosystem that engages with a broad range of stakeholders will mean that expertise in the ever‐expanding field of regulatory science filters into teaching and research in a symbiotic way. In this way capacity development interventions will be a collaborative approach between the learning context (academic and training institutions) and the performance context (regulatory agencies and industry), which will ultimately best serve the patients. Monitoring and evaluation of capacity development interventions will be essential to show value of investments and ultimately guide continued funding and sustainability. This paper reviews the skills and human capacity gaps, reports on regulatory assessment pathways used in Ghana, South Africa and Zimbabwe and outlines a staged tactical approach for Africa that builds on previous efforts to strengthen African regulatory ecosystems. [ABSTRACT FROM AUTHOR]

Under‐representation of people with dementia in clinical research remains a significant obstacle to develop evidence‐based practice guidelines and recommendation for dementia care and slows down the development of disease‐modifying pharmacological interventions. This is partly due to the ethical challenges and complexities of recruiting people with dementia for clinical trials. The traditional approach adopted by research ethics committees and regulatory bodies has been to protect people with dementia as a vulnerable population from harms of participating in research. There are concerns that this approach is unduly rigid, precludes the conduct of necessary research, and has exclusionary, paternalistic and discriminatory ramifications. As such, there are increasing calls to shift to a new hybrid facilitative/protective approach. This paper identifies 4 strategies to operationalise the facilitative/protective approach in the context of dementia research. These are: (i) embedding dementia research in clinical care; (ii) increasing the recruitment of people at preclinical stages of dementia; (iii) streamlined proxy consent procedures; and (iv) advance research consent. I note that all 4 strategies hold the promise of facilitating the recruitment of people with dementia in clinical research. Nonetheless, they give rise to a diverse range of new ethical concerns and issues. This necessitates further scholarly work to explore possible ways to address the ethical concerns and issues arisen by the uptake of protective/facilitative approach. In particular, further research is necessary to clarify, to what extent, the said strategies ameliorate or increase the vulnerability of people with dementia. [ABSTRACT FROM AUTHOR]