The pharmaceutical industry is in the midst of a productivity crisis and rates of translation from bench to bedside are dismal. Patients are being let down by the current system of drug discovery; of the several 1000 diseases that affect humans, only a minority have any approved treatments and many of these cause adverse reactions in humans. A predominant reason for the poor rate of translation from bench to bedside is generally held to be the failure of preclinical animal models to predict clinical efficacy and safety. Attempts to explain this failure have focused on problems of internal validity in preclinical animal studies (e.g. poor study design, lack of measures to control bias). However there has been less discussion of another key factor that influences translation, namely the external validity of preclinical animal models. External validity is the extent to which research findings derived in one setting, population or species can be reliably applied to other settings, populations and species. This paper argues that the reliable translation of findings from animals to humans will only occur if preclinical animal studies are both internally and externally valid. We review several key aspects that impact external validity in preclinical animal research, including unrepresentative animal samples, the inability of animal models to mimic the complexity of human conditions, the poor applicability of animal models to clinical settings and animal–human species differences. We suggest that while some problems of external validity can be overcome by improving animal models, the problem of species differences can never be overcome and will always undermine external validity and the reliable translation of preclinical findings to humans. We conclude that preclinical animal models can never be fully valid due to the uncertainties introduced by species differences. We suggest that even if the next several decades were spent improving the internal and external validity of animal models, the clinical relevance of those models would, in the end, only improve to some extent. This is because species differences would continue to make extrapolation from animals to humans unreliable. We suggest that to improve clinical translation and ultimately benefit patients, research should focus instead on human-relevant research methods and technologies.

Objectives Although sex and relationship education (SRE) represents a key strand in policies to safeguard young people and improve their sexual health, it currently lacks statutory status, government guidance is outdated and a third of UK schools has poor-quality SRE. We aimed to investigate whether current provision meets young people's needs. Design Synthesis of qualitative studies of young people's views of their school-based SRE. Setting Eligible studies originated from the UK, Ireland, the USA, Australia, New Zealand, Canada, Japan, Iran, Brazil and Sweden. Participants Studies of students aged 4–19 in full-time education, young adults ≤19 (not necessarily in full-time education) or adults ≤25 if recalling their experiences of school-based SRE. Results –69 publications were identified, with 55 remaining after quality appraisal (representing 48 studies). The synthesis found that although sex is a potent and potentially embarrassing topic, schools appear reluctant to acknowledge this and attempt to teach SRE in the same way as other subjects. Young people report feeling vulnerable in SRE, with young men anxious to conceal sexual ignorance and young women risking sexual harassment if they participate. Schools appear to have difficulty accepting that some young people are sexually active, leading to SRE that is out of touch with many young people's lives. Young people report that SRE can be negative, gendered and heterosexist. They expressed dislike of their own teachers delivering SRE due to blurred boundaries, lack of anonymity, embarrassment and poor training. Conclusions SRE should be ‘sex-positive’ and delivered by experts who maintain clear boundaries with students. Schools should acknowledge that sex is a special subject with unique challenges, as well as the fact and range of young people's sexual activity, otherwise young people will continue to disengage from SRE and opportunities for safeguarding and improving their sexual health will be reduced.

Objectives Sex and relationship education (SRE) is regarded as vital to improving young people’s sexual health, but a third of schools in England lacks good SRE and government guidance is outdated. We aimed to identify what makes SRE programmes effective, acceptable, sustainable and capable of faithful implementation. Design This is a synthesis of findings from five research packages that we conducted (practitioner interviews, case study investigation, National Survey of Sexual Attitudes and Lifestyles, review of reviews and qualitative synthesis). We also gained feedback on our research from stakeholder consultations. Settings Primary research and stakeholder consultations were conducted in the UK. Secondary research draws on studies worldwide. Results Our findings indicate that school-based SRE and school-linked sexual health services can be effective at improving sexual health. We found professional consensus that good programmes start in primary school. Professionals and young people agreed that good programmes are age-appropriate, interactive and take place in a safe environment. Some young women reported preferring single-sex classes, but young men appeared to want mixed classes. Young people and professionals agreed that SRE should take a ‘life skills’ approach and not focus on abstinence. Young people advocated a ‘sex-positive’ approach but reported this was lacking. Young people and professionals agreed that SRE should discuss risks, but young people indicated that approaches to risk need revising. Professionals felt teachers should be involved in SRE delivery, but many young people reported disliking having their teachers deliver SRE and we found that key messages could become lost when interpreted by teachers. The divergence between young people and professionals was echoed by stakeholders. We developed criteria for best practice based on the evidence. Conclusions We identified key features of effective and acceptable SRE. Our best practice criteria can be used to evaluate existing programmes, contribute to the development of new programmes and inform consultations around statutory SRE.

The idea of synthesising theory is receiving attention within public health as part of a drive to design theoretically informed interventions. Theory synthesis is not a new idea, however, having been debated by sociologists for several decades. We consider the various methodological approaches to theory synthesis and test the feasibility of one such approach by synthesising a small number of sociological theories relevant to health related risk-taking. The synthesis consisted of three stages: (i) synthesis preparation, wherein parts of relevant theories were extracted and summarised; (ii) synthesis which involved comparing theories for points of convergence and divergence and bringing together those points that converge; and (iii) synthesis refinement whereby the synthesis was interrogated for further theoretical insights. Our synthesis suggests that serious and sustained risk-taking is associated with social isolation, liminality and a person's position in relation to the dominant social group. We reflect upon the methodological and philosophical issues raised by the practice of theory synthesis, concluding that it has the potential to reinvigorate theory and make it more robust and accessible for practical application.

The harm benefit analysis (HBA) is the cornerstone of animal research regulation and is considered to be a key ethical safeguard for animals. The HBA involves weighing the anticipated benefits of animal research against its predicted harms to animals but there are doubts about how objective and accountable this process is. i. To explore the harms to animals involved in pre-clinical animal studies and to assess these against the benefits for humans accruing from these studies; ii. To test the feasibility of conducting this type of retrospective HBA. Data on harms were systematically extracted from a sample of pre-clinical animal studies whose clinical relevance had already been investigated by comparing systematic reviews of the animal studies with systematic reviews of human studies for the same interventions (antifibrinolytics for haemorrhage, bisphosphonates for osteoporosis, corticosteroids for brain injury, Tirilazad for stroke, antenatal corticosteroids for neonatal respiratory distress and thrombolytics for stroke). Clinical relevance was also explored in terms of current clinical practice. Harms were categorised for severity using an expert panel. The quality of the research and its impact were considered. Bateson’s Cube was used to conduct the HBA. The most common assessment of animal harms by the expert panel was ‘severe’. Reported use of analgesia was rare and some animals (including most neonates) endured significant procedures with no, or only light, anaesthesia reported. Some animals suffered iatrogenic harms. Many were kept alive for long periods post-experimentally but only 1% of studies reported post-operative care. A third of studies reported that some animals died prior to endpoints. All the studies were of poor quality. Having weighed the actual harms to animals against the actual clinical benefits accruing from these studies, and taking into account the quality of the research and its impact, less than 7% of the studies were permissible according to Bateson’s Cube: only the moderate bisphosphonate studies appeared to minimise harms to animals whilst being associated with benefit for humans. This is the first time the accountability of the HBA has been systematically explored across a range of pre-clinical animal studies. The regulatory systems in place when these studies were conducted failed to safeguard animals from severe suffering or to ensure that only beneficial, scientifically rigorous research was conducted. Our findings indicate a pressing need to: i. review regulations, particularly those that permit animals to suffer severe harms; ii. reform the processes of prospectively assessing pre-clinical animal studies to make them fit for purpose; and iii. systematically evaluate the benefits of pre-clinical animal research to permit a more realistic assessment of its likely future benefits.