Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment.

New approach methodologies (NAMs) based on human biology enable the assessment of adverse biological effects of pharmaceuticals and other chemicals. Currently, however, it is unclear how NAMs should be used during drug development to improve human safety evaluation. A series of 5 workshops with 13 international experts (regulators, preclinical scientists, and NAMs developers) was conducted to identify feasible NAMs and to discuss how to exploit them in specific safety assessment contexts. Participants generated four "maps" of how NAMs can be exploited in the safety assessment of the liver, respiratory, cardiovascular, and central nervous systems. Each map shows relevant endpoints measured and tools used (e.g., cells, assays, platforms), and highlights gaps where further development and validation of NAMs remains necessary. Each map addresses the fundamental scientific requirements for the safety assessment of that organ system, providing users with guidance on the selection of appropriate NAMs. In addition to generating the maps, participants offered suggestions for encouraging greater NAM adoption within drug development and their inclusion in regulatory guidelines. A specific recommendation was that pharmaceutical companies should be more transparent about how they use NAMs in-house. As well as giving guidance for the four organ systems, the maps provide a template that could be used for additional organ safety testing contexts. Moreover, their conversion to an interactive format would enable users to drill down to the detail necessary to answer specific scientific and regulatory questions.

The impact of conducting preclinical systematic reviews on researchers and their research: A mixed method case study.

BACKGROUND: Systematic reviews (SRs) are cornerstones of evidence-based medicine and have contributed significantly to breakthroughs since the 1980's. However, preclinical SRs remain relatively rare despite their many advantages. Since 2011 the Dutch health funding organisation (ZonMw) has run a grant scheme dedicated to promoting the training, coaching and conduct of preclinical SRs. Our study focuses on this funding scheme to investigate the relevance, effects and benefits of conducting preclinical SRs on researchers and their research. METHODS: We recruited researchers who attended funded preclinical SR workshops and who conducted, are still conducting, or prematurely stopped a SR with funded coaching. We gathered data using online questionnaires followed by semi-structured interviews. Both aimed to explore the impact of conducting a SR on researchers' subsequent work, attitudes, and views about their research field. Data-analysis was performed using Excel and ATLAS.ti. RESULTS: Conducting preclinical SRs had two distinct types of impact. First, the researchers acquired new skills and insights, leading to a change in mindset regarding the quality of animal research. This was mainly seen in the way participants planned, conducted and reported their subsequent animal studies, which were more transparent and of a higher quality than their previous work. Second, participants were eager to share their newly acquired knowledge within their laboratories and to advocate for change within their research teams and fields of interest. In particular, they emphasised the need for preclinical SRs and improved experimental design within preclinical research, promoting these through education and published opinion papers. CONCLUSION: Being trained and coached in the conduct of preclinical SRs appears to be a contributing factor to many beneficial changes which will impact the quality of preclinical research in the long-term. Our findings suggest that this ZonMw funding scheme is helpful in improving the quality and transparency of preclinical research. Similar funding schemes should be encouraged, preferably by a broader group of funders or financers, in the future.

Performance of preclinical models in predicting drug-induced liver injury in humans: a systematic review.

Drug-induced liver injury (DILI) causes one in three market withdrawals due to adverse drug reactions, causing preventable human suffering and massive financial loss. We applied evidence-based methods to investigate the role of preclinical studies in predicting human DILI using two anti-diabetic drugs from the same class, but with different toxicological profiles: troglitazone (withdrawn from US market due to DILI) and rosiglitazone (remains on US market). Evidence Stream 1: A systematic literature review of in vivo studies on rosiglitazone or troglitazone was conducted (PROSPERO registration CRD42018112353). Evidence Stream 2: in vitro data on troglitazone and rosiglitazone were retrieved from the US EPA ToxCast database. Evidence Stream 3: troglitazone- and rosiglitazone-related DILI cases were retrieved from WHO Vigibase. All three evidence stream analyses were conducted according to evidence-based methodologies and performed according to pre-registered protocols. Evidence Stream 1: 9288 references were identified, with 42 studies included in analysis. No reported biomarker for either drug indicated a strong hazard signal in either preclinical animal or human studies. All included studies had substantial limitations, resulting in "low" or "very low" certainty in findings. Evidence Stream 2: Troglitazone was active in twice as many in vitro assays (129) as rosiglitazone (60), indicating a strong signal for more off-target effects. Evidence Stream 3: We observed a fivefold difference in both all adverse events and liver-related adverse events reported, and an eightfold difference in fatalities for troglitazone, compared to rosiglitazone. In summary, published animal and human trials failed to predict troglitazone's potential to cause severe liver injury in a wider patient population, while in vitro data showed marked differences in the two drugs' off-target activities, offering a new paradigm for reducing drug attrition in late development and in the market. This investigation concludes that death and disability due to adverse drug reactions may be prevented if mechanistic information is deployed at early stages of drug development by pharmaceutical companies and is considered by regulators as a part of regulatory submissions.

Are Animal Models Needed to Discover, Develop and Test Pharmaceutical Drugs for Humans in the 21st Century?

Despite many decades of research, much of which has focused on studies in animals, we humans continue to suffer from multiple diseases for which there are no cures or treatments [...].

Can prospective systematic reviews of animal studies improve clinical translation?

Systematic reviews are powerful tools with the potential to generate high quality evidence. Their application to animal studies has been instrumental in exposing the poor quality of these studies, as well as a catalyst for improvements in study design, conduct and reporting. It has been suggested that prospective systematic reviews of animal studies (i.e. systematic reviews conducted prior to clinical trials) would allow scrutiny of the preclinical evidence, providing valuable information on safety and efficacy, and helping to determine whether clinical trials should proceed. However, while prospective systematic reviews allow valuable scrutiny of the preclinical animal data, they are not necessarily able to reliably predict the safety and efficacy of an intervention when trialled in humans. Consequently, they may not reliably safeguard humans participating in clinical trials and might potentially result in lost opportunities for beneficial clinical treatments. Furthermore, animal and human studies are often conducted concurrently, which not only makes prospective systematic reviews of animal studies impossible, but suggests that animal studies do not inform human studies in the manner presumed. We suggest that this points to a confused attitude regarding animal studies, whereby tradition demands that they precede human studies but practice indicates that their findings are often ignored. We argue that it is time to assess the relative contributions of animal and human research in order to better understand how clinical knowledge is actually produced.

Are researchers moving away from animal models as a result of poor clinical translation in the field of stroke? An analysis of opinion papers.

OBJECTIVES: Despite decades of research using animals to develop pharmaceutical treatments for patients who have had a stroke, few therapeutic options exist. The vast majority of interventions successful in preclinical animal studies have turned out to have no efficacy in humans or to be harmful to humans. In view of this, we explore whether there is evidence of a move away from animal models in this field. METHODS: We used an innovative methodology, the analysis of opinion papers. Although we took a systematic approach to literature searching and data extraction, this is not a systematic review because the study involves the synthesis of opinions, not research evidence. Data were extracted from retrieved papers in chronological order and analysed qualitatively and descriptively. RESULTS: Eighty eligible papers, published between 1979 and 2018, were identified. Most authors were from academic departments of neurology, neuroscience or stroke research. Authors agreed that translational stroke research was in crisis. They held diverse views about the causes of this crisis, most of which did not fundamentally challenge the use of animal models. Some, however, attributed the translational crisis to animal-human species differences and one to a lack of human in vitro models. Most of the proposed solutions involved fine-tuning animal models, but authors disagreed about whether such modifications would improve translation. A minority suggested using human in vitro methods alongside animal models. One proposed focusing only on human in vitro methods. CONCLUSION: Despite recognising that animal models have been unsuccessful in the field of stroke, most researchers exhibited a strong resistance to relinquishing them. Nevertheless, there is an emerging challenge to the use of animal models, in the form of human-focused in vitro approaches. For the sake of stroke patients there is an urgent need to revitalise translational stroke research and explore the evidence for these new approaches.

Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail.

BACKGROUND: 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. REVIEW OF PROBLEMS OF EXTERNAL VALIDITY: 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. CONCLUSION: 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.

Retrospective harm benefit analysis of pre-clinical animal research for six treatment interventions.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

What is best practice in sex and relationship education? A synthesis of evidence, including stakeholders' views.

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.

Among friends: a qualitative exploration of the role of peers in young people's alcohol use using Bourdieu's concepts of habitus, field and capital.

Drinking is viewed by young people as a predominantly social activity which provides an opportunity for entertainment and bonding with friends. Using Bourdieu's concepts of habitus, field and capital, this article explores young people's attitudes and beliefs around alcohol use, influences on behaviour, and the role of peers, with a view to informing the development of preventive interventions. Semi-structured interviews were conducted with 28 young people aged 18-20 in the south west of England. We describe how friends were integral in drinking experiences, and drinking with friends was equated with fun and enjoyment. In this way, the desire for social and symbolic capital appeared to be a key motivator for adolescent drinking. Critically, however, wider cultural norms played the predominant role in shaping behaviour, via the internalisation of widely accepted practice and the subsequent externalisation of norms through the habitus. Applying Bourdieu's theory suggests that population-level interventions that regulate alcohol consumption, and thus disrupt the field, are likely to facilitate behaviour change among young people by driving a response in habitus.

What do young people think about their school-based sex and relationship education? A qualitative synthesis of young people's views and experiences.

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.

Developing a Collaborative Agenda for Humanities and Social Scientific Research on Laboratory Animal Science and Welfare.

Improving laboratory animal science and welfare requires both new scientific research and insights from research in the humanities and social sciences. Whilst scientific research provides evidence to replace, reduce and refine procedures involving laboratory animals (the '3Rs'), work in the humanities and social sciences can help understand the social, economic and cultural processes that enhance or impede humane ways of knowing and working with laboratory animals. However, communication across these disciplinary perspectives is currently limited, and they design research programmes, generate results, engage users, and seek to influence policy in different ways. To facilitate dialogue and future research at this interface, we convened an interdisciplinary group of 45 life scientists, social scientists, humanities scholars, non-governmental organisations and policy-makers to generate a collaborative research agenda. This drew on methods employed by other agenda-setting exercises in science policy, using a collaborative and deliberative approach for the identification of research priorities. Participants were recruited from across the community, invited to submit research questions and vote on their priorities. They then met at an interactive workshop in the UK, discussed all 136 questions submitted, and collectively defined the 30 most important issues for the group. The output is a collaborative future agenda for research in the humanities and social sciences on laboratory animal science and welfare. The questions indicate a demand for new research in the humanities and social sciences to inform emerging discussions and priorities on the governance and practice of laboratory animal research, including on issues around: international harmonisation, openness and public engagement, 'cultures of care', harm-benefit analysis and the future of the 3Rs. The process outlined below underlines the value of interdisciplinary exchange for improving communication across different research cultures and identifies ways of enhancing the effectiveness of future research at the interface between the humanities, social sciences, science and science policy.

Transparency and public involvement in animal research.

To be legitimate, research needs to be ethical, methodologically sound, of sufficient value to justify public expenditure and be transparent. Animal research has always been contested on ethical grounds, but there is now mounting evidence of poor scientific method, and growing doubts about its clinical value. So what of transparency? Here we examine the increasing focus on openness within animal research in the UK, analysing recent developments within the Home Office and within the main group representing the interests of the sector, Understanding Animal Research. We argue that, while important steps are being taken toward greater transparency, the legitimacy of animal research continues to be undermined by selective openness. We propose that openness could be increased through public involvement, and that this would bring about much needed improvements in animal research, as it has done in clinical research.

Locating and applying sociological theories of risk-taking to develop public health interventions for adolescents.

Sociological theories seldom inform public health interventions at the community level. The reasons for this are unclear but may include difficulties in finding, understanding or operationalising theories. We conducted a study to explore the feasibility of locating sociological theories within a specific field of public health, adolescent risk-taking, and to consider their potential for practical application. We identified a range of sociological theories. These explained risk-taking: (i) as being due to lack of social integration; (ii) as a consequence of isolation from mainstream society; (iii) as a rite of passage; (iv) as a response to social constraints; (v) as resistance; (vi) as an aspect of adolescent development; (vii) by the theory of the 'habitus'; (viii) by situated rationality and social action theories; and (ix) as social practice. We consider these theories in terms of their potential to inform public health interventions for young people.

Exploring the feasibility of theory synthesis: a worked example in the field of health related risk-taking.

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.