Requirements for generic anti-epileptic medicines: a regulatory perspective

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The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-threat agents, and photoactivatable platinum(IV) complexes. Nanoparticles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations, including supramolecular self-assembled structures, proteins, peptides, metal–organic frameworks, and coordination polymers, will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also will reflect our optimism that the next generation of approved platinum cancer drugs is about to arrive.National Cancer Institute (U.S.) (CA034992

Effect of social defeat in a territorial bird (Parus major) selected for different coping styles

We addressed the questions (i) whether a social defeat triggers similar autonomic and behavioral responses in birds as is known from mammals and (ii) whether individuals that differ in coping style differ in their reaction to a social defeat. Adult captive male great tits (Parus major) from either of two different selection lines for coping style were used to test the effect of social defeat by an aggressive resident male conspecific on subsequent social and nonsocial behaviour, body temperature, breath rate and body mass. These parameters were measured 1 day before (baseline), immediately after and at Days 1 to 3 and 6 after the social interaction took place (Day 0). Social defeat decreased social exploration and increased body temperature substantially for at least 1 day in all birds. Breath rate and body mass were not affected. Birds belonging to the more aggressive and bolder line showed impairment in activity immediately after the social defeat. This is to our knowledge the first report showing that psychosocial stress in birds can have a similar impact as in rodents, but with a shorter recovery time. This might be due to species-specific differences in sensitivity to social stress, or to differences in the way social stress was induced. [KEYWORDS: social defeat; stress; great tit; body temperature; breath rate; activity; coping Male great tits; individual-differences; stress; rats; behavior; fever; hyperthermia; consequences; domesticus; dominance]

When to trust our learners?: Clinical teachers' perceptions of decision variables in the entrustment process

INTRODUCTION: Clinical training programs increasingly use entrustable professional activities (EPAs) as focus of assessment. However, questions remain about which information should ground decisions to trust learners. This qualitative study aimed to identify decision variables in the workplace that clinical teachers find relevant in the elaboration of the entrustment decision processes. The findings can substantiate entrustment decision-making in the clinical workplace. METHODS: Focus groups were conducted with medical and veterinary clinical teachers, using the structured consensus method of the Nominal Group Technique to generate decision variables. A ranking was made based on a relevance score assigned by the clinical teachers to the different decision variables. Field notes, audio recordings and flip chart lists were analyzed and subsequently translated and, as a form of axial coding, merged into one list, combining the decision variables that were similar in their meaning. RESULTS: A list of 11 and 17 decision variables were acknowledged as relevant by the medical and veterinary teacher groups, respectively. The focus groups yielded 21 unique decision variables that were considered relevant to inform readiness to perform a clinical task on a designated level of supervision. The decision variables consisted of skills, generic qualities, characteristics, previous performance or other information. We were able to group the decision variables into five categories: ability, humility, integrity, reliability and adequate exposure. DISCUSSION: To entrust a learner to perform a task at a specific level of supervision, a supervisor needs information to support such a judgement. This trust cannot be credited on a single case at a single moment of assessment, but requires different variables and multiple sources of information. This study provides an overview of decision variables giving evidence to justify the multifactorial process of making an entrustment decision

When to trust our learners? : Clinical teachers' perceptions of decision variables in the entrustment process

INTRODUCTION: Clinical training programs increasingly use entrustable professional activities (EPAs) as focus of assessment. However, questions remain about which information should ground decisions to trust learners. This qualitative study aimed to identify decision variables in the workplace that clinical teachers find relevant in the elaboration of the entrustment decision processes. The findings can substantiate entrustment decision-making in the clinical workplace. METHODS: Focus groups were conducted with medical and veterinary clinical teachers, using the structured consensus method of the Nominal Group Technique to generate decision variables. A ranking was made based on a relevance score assigned by the clinical teachers to the different decision variables. Field notes, audio recordings and flip chart lists were analyzed and subsequently translated and, as a form of axial coding, merged into one list, combining the decision variables that were similar in their meaning. RESULTS: A list of 11 and 17 decision variables were acknowledged as relevant by the medical and veterinary teacher groups, respectively. The focus groups yielded 21 unique decision variables that were considered relevant to inform readiness to perform a clinical task on a designated level of supervision. The decision variables consisted of skills, generic qualities, characteristics, previous performance or other information. We were able to group the decision variables into five categories: ability, humility, integrity, reliability and adequate exposure. DISCUSSION: To entrust a learner to perform a task at a specific level of supervision, a supervisor needs information to support such a judgement. This trust cannot be credited on a single case at a single moment of assessment, but requires different variables and multiple sources of information. This study provides an overview of decision variables giving evidence to justify the multifactorial process of making an entrustment decision

Am I ready for it? Students’ perceptions of meaningful feedback on entrustable professional activities

Background Receiving feedback while in the clinical workplace is probably the most frequently voiced desire of students. In clinical learning environments, providing and seeking performance-relevant information is often difficult for both supervisors and students. The use of entrustable professional activities (EPAs) can help to improve stu-dent assessment within competency-based education. This study aimed to illustrate what students' perceptions are of meaningful feedback viewed as conducive in preparing for performing EPA unsupervised. Methods In a qualitative multicentre study we explored stu-dents' perceptions on meaningful feedback related to EPAs in the clinical workplace. Focus groups were conducted in three different healthcare institutes. Based on concepts from the literature, the transcripts were coded, iteratively reduced and displayed. Results Participants' preferences regarding meaningful feedback on EPAs were quite similar, irrespective of their institution or type of clerkship. Participants explicitly men-tioned that feedback on EPAs could come from a variety of sources. Feedback must come from a credible, trustworthy Electronic supplementary material The online version of this article (doi: 10.1007/s40037-017-0361-1) contains supplementary material, which is available to authorized users. supervisor who knows the student well, be delivered in a safe environment and stress both strengths and points for improvement. The feedback should be provided immedi-ately after the observed activity and include instructions for follow-up. Students would appreciate feedback that refers to their ability to act unsupervised. Conclusion There is abundant literature on how feedback should be provided, and what factors influence how feed-back is sought by students. This study showed that students who are training to perform an EPA unsupervised have clear ideas about how, when and from whom feedback should be delivered. What this paper adds To enhance the educational environment in the workplace, meaningful feedback and valid assessment of students are required. As the literature shows, it is difficult to success-fully apply workplace-based assessments in clinical prac-tice. The use of entrustable professional activities (EPAs) can help to improve student assessment within competency-based education. However, there still is little evidence about what students perceive as useful information to prepare for performing an EPA with less than full supervision. This study aimed to illustrate what students' perceptions are of meaningful feedback viewed as conducive to prepare for the performance of an EPA unsupervised Am I ready for it? Students' perceptions of meaningful feedback on entrustable professional activitie

Bidirectional learning opportunities: how GP-supervisors and trainees exchange knowledge

Introduction: Workplace-based learning conversations can be a good opportunity for supervisors and trainees to learn from each other. When both professionals discuss their specific knowledge openly with each other, learning conversations may be a useful educational tool, for instance for learning how to apply evidence-based medicine (EBM) in the workplace. We do, however, need a better understanding of how the exchange of knowledge provides opportunities for such bidirectional learning. The aim of this study was therefore to analyse how trainees and supervisors currently handle bidirectional learning opportunities by describing in detail how supervisors respond to knowledge expressed by trainees during a learning conversation. Method: We video-recorded learning conversations between supervisors and trainees in general practice (GP). Within these learning conversations, EBM discussions on medical topics were selected and transcribed. We then identified, analysed using Conversation Analysis (CA) and categorised each expression of knowledge by the trainee and the supervisor's subsequent response. Results: We found that when a trainee expresses knowledge during the learning conversation, supervisors either (a) refute the expressed knowledge, (b) immediately suggest an alternative or (c) pose (additional) questions. These responses have consequences for the learning opportunities of both trainee and supervisor: it is only when supervisors pose further questions that trainees are encouraged to elaborate on their knowledge, leading to a bidirectional learning opportunity. Discussion: Improving EBM learning opportunities for both supervisors and trainees requires more than simply instructing trainees to express knowledge-based—for instance—on recent evidence more often. Inflexible institutional roles related to historical claims of supervisors’ epistemic authority hamper bidirectional learning. Posing open questions during learning conversations enhances the flexibility of institutional roles while also creating bidirectional learning opportunities

The Global Bioequivalence Harmonisation Initiative (GBHI): Report of the fifth international EUFEPS/AAPS conference

The series of conferences of the Global Bioequivalence Harmonisation Initiative (GBHI) was started in 2015 by the European Federation for Pharmaceutical Sciences (EUFEPS). All GBHI meetings so far were co-organised together with the American Association of Pharmaceutical Scientists (AAPS). Beginning with the 3rd workshop US-FDA joined as co-sponsor – to support global harmonisation of regulatory recommendations for bioequivalence (BE) assessment. At the 5th GBHI conference, the following BE topics were intensively discussed, and the following main conclusions were drawn: (1) Statistical considerations for BE assessment in specific situations covering scaling approaches for highly variable drug (HVD) products, two-stage adaptive design and opportunities of modelling and simulation to support BE: even though special BE study concepts like adaptive designs are not often used in practise so far, a majority of the workshop participants were in favour of a more frequent application of such approaches. The regulatory conditions relevant in this context need further concretisation and harmonisation between the regions. Moreover, modelling and simulation were considered as a promising and evolving approach, also for BE development programmes. (2) Fed versus fasting conditions in BE trials: Findings that BE between generic products could be confirmed only after fasted administration but failed under fed conditions seem more an exception than the rule. Obviously, BCS class IV compounds are most problematic in this context. Differences in critical excipients such as surfactants or pH-modifiers may be relevant reasons for different sensitivity for interactions in fasted versus fed conditions. Consequently, such deviations in composition of generic preparations should be avoided. Moreover, confirmation of BE may be generally difficult comparing different dosage forms, such like capsules versus tablets, especially in fed state. (3) BE assessment of locally acting drug products applied topically to the skin: Appropriateness and potential benefit of in-vitro tests as alternatives to clinical efficacy studies have been comprehensively discussed. In addition to the already well-established in-vitro release and permeation tests, other techniques were suggested, e. g., Raman spectroscopy or dermal open flow microperfusion. Validation of those methods is challenging and, despite significant progress already achieved during previous years, more research is needed before they may be fully accepted for regulatory purposes. (4) BE evaluation of narrow therapeutic index (NTI) drugs: The discrepancies amongst regulatory agencies in necessity of tighter BE acceptance ranges, the recommendations for inclusion of peak and total drug exposure into BE assessment with more restrictive criteria and the importance of comparison of the product-related within subject variability for NTI drugs were debated. Arguments in favour and against the different approaches were presented and discussed but need further consideration before harmonisation can be achieved. The highly interactive meeting and extensive exchange between regulators and scientists from industry and academia resulted in useful progress in open BE issues and supported the goal of science-driven harmonisation