The impact of anti-malarial markets on artemisinin resistance: perspectives from Burkina Faso.

BACKGROUND: Widespread artemisinin resistance in Africa could be catastrophic when drawing parallels with the failure of chloroquine in the 1970s and 1980s. This article explores the role of anti-malarial market characteristics in the emergence and spread of arteminisin resistance in African countries, drawing on perspectives from Burkina Faso. METHODS: Data were collected through in-depth interviews and focus group discussions. A representative sample of national policy makers, regulators, public and private sector wholesalers, retailers, clinicians, nurses, and community members were purposively sampled. Additional information was also sought via review of policy publications and grey literature on anti-malarial policies and deployment practices in Burkina Faso. RESULTS: Thirty seven in-depth interviews and 6 focus group discussions were conducted. The study reveals that the current operational mode of anti-malarial drug markets in Burkina Faso promotes arteminisin resistance emergence and spread. The factors are mainly related to the artemisinin-based combination therapy (ACT) supply chain, to ACT quality, ACT prescription monitoring and to ACT access and misuse by patients. CONCLUSION: Study findings highlight the urgent requirement to reform current characteristics of the anti-malarial drug market in order to delay the emergence and spread of artemisinin resistance in Burkina Faso. Four recommendations for public policy emerged during data analysis: (1) Address the suboptimal prescription of anti-malarial drugs, (2) Apply laws that prohibit the sale of anti-malarials without prescription, (3) Restrict the availability of street drugs, (4) Sensitize the population on the value of compliance regarding correct acquisition and intake of anti-malarials. Funding systems for anti-malarial drugs in terms of availability and accessibility must also be stabilized.

Exploring the feasibility of introducing triple artemisinin-based combination therapy in the malaria treatment policy in Vietnam.

BACKGROUND: This study investigates the processes regarding changing malaria treatment policies in Vietnam. Moreover, it explores the feasibility of introducing triple artemisinin-based combination therapy (TACT) in Vietnam to support the national malaria control and elimination plan. METHODS: Data were collected via 12 in-depth interviews with key stakeholders, combined with a review of policy documents. RESULTS: TACT is considered as a useful backup strategy in case future treatment failures with current artemisinin-based combination therapy (ACT) would occur. Moreover, TACT is also considered as a promising strategy to prevent the re-establishment of malaria. However, regulatory procedures and implementation timelines for TACT were expected to be lengthy. Therefore, strategies to engage national decision-makers, regulators, and suppliers should be initiated soon, stipulating the benefits of TACT deployment. In Vietnam, a procedure to apply for an import permit without registration that has previously been applied to the introduction of artesunate-pyronaridine was proposed to accelerate the introduction of TACT. Global-level support through the World Health Organization recommendations and prequalification were considered critical for supporting the introduction of TACT in Vietnam. CONCLUSIONS: Appropriate approach strategies and early stakeholder engagement will be needed to accelerate the introduction of TACT in Vietnam.

Strategies for deploying triple artemisinin-based combination therapy in the Greater Mekong Subregion.

BACKGROUND: This is a qualitative study to identify implementation challenges for deploying triple artemisinin-based combination therapy (TACT) in the Greater Mekong Subregion (GMS) of Southeast Asia and to explore strategies to overcome these challenges. METHODS: In-depth interviews were conducted in three countries that have repeatedly been confronted with ACT failures: Cambodia, Vietnam, and Lao PDR. Thirty-nine key stakeholders in the healthcare systems in these countries were interviewed. One participatory workshop was conducted in Cambodia, where scenarios for potential TACT deployment were discussed. RESULTS: The results section is organized around four strategic themes that emerged from the data: policy support, data and evidence, logistics and operation, and downstream engagement. The study revealed that countries in the GMS currently rely on ACT to eliminate Plasmodium falciparum malaria by 2025. TACT is, however, considered to be a useful backup strategy in case of future treatment failures and to prevent the re-establishment of malaria. The study showed that a major challenge ahead is to engage decision makers and healthcare providers into deploying TACT, given the low case incidence of falciparum malaria in the GMS. Interview respondents were also skeptical whether healthcare providers would be willing to engage in new therapies for a disease they hardly encounter anymore. Hence, elaborate information dissemination strategies were considered appropriate and these strategies should especially target village malaria workers. Respondents proposed several regulatory and programmatic strategies to anticipate the formation of TACT markets in the GMS. These strategies include early dossier submission to streamline regulatory procedures, early stakeholder engagement strategies to shorten implementation timelines, and inclusion of TACT as second-line therapy to accelerate their introduction in case they are urgently needed. CONCLUSIONS: This paper presents a qualitative study to identify implementation challenges for deploying TACT in the GMS and to explore strategies to overcome these challenges. The findings could benefit researchers and decision makers in strategizing towards potential future deployment of TACT in the GMS to combat artemisinin and partner drug resistance.

Preferred Islet Delivery Device Characteristics and Implantation Strategies of Patients With Type 1 Diabetes.

Islet delivery devices (IDDs) offer potential benefits for islet transplantation and stem cell-based replacement in type 1 diabetes. Little is known about patient preferences regarding islet delivery device characteristics and implantation strategies. Patient preferences for IDDs and implantation strategies remain understudied. We invited patients, parents and caregivers to fill in an online questionnaire regarding IDDs. An online survey gathered responses from 809 type 1 diabetes patients and 47 caregivers. We also assessed diabetes distress in a subgroup of 412 patients. A significant majority (97%) expressed willingness to receive an IDD. Preferred IDD attributes included a 3.5 cm diameter for 37.7% of respondents, while when provided with all options, 30.4% found dimensions unimportant. Respondents were open to approximately 4 implants, each with a 5 cm incision. Many favored a device functioning for 12 months (33.4%) or 24 months (24.8%). Younger participants (16-30) were more inclined to accept a 6 months functional duration (p < 0.001). Functional duration outweighed implant quantity and size (p < 0.001) in device importance. This emphasizes patients' willingness to accommodate burdens related to IDD features and implantation methods, crucial for designing future beta cell replacement strategies.

Expert perspectives on the introduction of Triple Artemisinin-based Combination Therapies (TACTs) in Southeast Asia: a Delphi study.

BACKGROUND: Triple Artemisinin-based Combination Therapies (TACTs) are being developed as a response to artemisinin and partner drug resistance in Southeast Asia. However, the desirability, timing and practical feasibility of introducing TACTs in Southeast Asia is subject to debate. This study systematically assesses perspectives of malaria experts towards the introduction of TACTs as first-line treatment for uncomplicated falciparum malaria in Southeast Asia. METHODS: A two-round Delphi study was conducted. In the first round, 53 malaria experts answered open-ended questions on what they consider the most important advantages, disadvantages, and implementation barriers for introducing TACTs in Southeast Asia. In the second round, the expert panel rated the relevance of each statement on a 5-point Likert scale. RESULTS: Malaria experts identified 15 advantages, 15 disadvantages and 13 implementation barriers for introducing TACTs in Southeast Asia in the first round of data collection. In the second round, consensus was reached on 13 advantages (8 perceived as relevant, 5 as not-relevant), 12 disadvantages (10 relevant, 2 not-relevant), and 13 implementation barriers (all relevant). Advantages attributed highest relevance related to the clinical and epidemiological rationale of introducing TACTs. Disadvantages attributed highest relevance related to increased side-effects, unavailability of fixed-dose TACTs, and potential cost increases. Implementation barriers attributed highest relevance related to obtaining timely regulatory approval, timely availability of fixed-dose TACTs, and generating global policy support for introducing TACTs. CONCLUSIONS: The study provides a structured oversight of malaria experts' perceptions on the major advantages, disadvantages and implementation challenges for introducing TACTs in Southeast Asia, over current practices of rotating ACTs when treatment failure is observed. The findings can benefit strategic decision making in the battle against drug-resistant malaria.

Implementation of artificial intelligence (AI) applications in radiology: hindering and facilitating factors.

OBJECTIVE: The objective was to identify barriers and facilitators to the implementation of artificial intelligence (AI) applications in clinical radiology in The Netherlands. MATERIALS AND METHODS: Using an embedded multiple case study, an exploratory, qualitative research design was followed. Data collection consisted of 24 semi-structured interviews from seven Dutch hospitals. The analysis of barriers and facilitators was guided by the recently published Non-adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework for new medical technologies in healthcare organizations. RESULTS: Among the most important facilitating factors for implementation were the following: (i) pressure for cost containment in the Dutch healthcare system, (ii) high expectations of AI's potential added value, (iii) presence of hospital-wide innovation strategies, and (iv) presence of a "local champion." Among the most prominent hindering factors were the following: (i) inconsistent technical performance of AI applications, (ii) unstructured implementation processes, (iii) uncertain added value for clinical practice of AI applications, and (iv) large variance in acceptance and trust of direct (the radiologists) and indirect (the referring clinicians) adopters. CONCLUSION: In order for AI applications to contribute to the improvement of the quality and efficiency of clinical radiology, implementation processes need to be carried out in a structured manner, thereby providing evidence on the clinical added value of AI applications. KEY POINTS: • Successful implementation of AI in radiology requires collaboration between radiologists and referring clinicians. • Implementation of AI in radiology is facilitated by the presence of a local champion. • Evidence on the clinical added value of AI in radiology is needed for successful implementation.

Exploring health practitioners' acceptability of a prospective semi-quantitative pfHRP2 device to define severe malaria in the Democratic Republic of Congo.

BACKGROUND: A rapid diagnostic tool is being developed to discern severely ill children with severe malaria from children who are ill with alternative febrile diseases but have coincidental peripheral blood parasitaemia. The device semi-quantitatively measures plasma pfHRP2 and has the potential to reduce mortality in children with severe febrile illnesses by improving diagnosis. The aim of this study is to identify contributing and inhibiting factors that affect healthcare practitioners' acceptability of this prospective diagnostic device in a high malaria transmission setting in the Democratic Republic of Congo. METHODS: Data were collected qualitatively by conducting semi-structured interviews with a purposeful sample of health professionals in Kinshasa, capital of Democratic Republic of Congo. In total, 11 interviews were held with professionals at four different institutes. RESULTS: Four key findings emerged: (1) Congolese practitioners perceive the semi-quantitative pfHRP2 device as a welcome intervention as they recognize the limited reliability of their current diagnostic and therapeutic approaches to severe febrile illnesses; (2) compatibility of the semi-quantitative pfHRP2 device with clinical equipment and competences of Congolese health practitioners is considered to be limited, especially in rural settings; (3) a formal training programme is crucial for correct understanding and application of the semi-quantitative pfHRP2 device; and, (4) provision of evidence to practitioners, and support from health authorities would be important to establish confidence in the semi-quantitative pfHRP2 device. CONCLUSIONS: Congolese practitioners perceive the prospective semi-quantitative pfHRP2 device as a welcome addition to their clinical equipment. The device could improve current diagnostic work-up of severe febrile illness, which might consequently improve treatment choices. However, despite this recognized potential, several hurdles and drivers need to be taken into account when implementing this device in DR Congo.

An analysis of marketing authorisation applications via the mutual recognition and decentralised procedures in Europe.

PURPOSE: The aim of this study is to provide a comprehensive overview of the outcomes of marketing authorisation applications via the mutual recognition and decentralised procedures (MRP/DCP) and assess determinants of licensing failure during CMDh referral procedures. METHODS: All MRP/DCP procedures to the Co-ordination group for Mutual recognition and Decentralised procedures-human (CMDh) during the period from January 2006 to December 2013 were analysed. Reasons for starting referral procedures were scored. In addition, a survey under pharmaceutical companies was performed to estimate the frequency of licensing failure prior to CMDh referrals. RESULTS: During the study period, 10392 MRP/DCP procedures were finalized. Three hundred seventy-seven (3.6%) resulted in a referral procedure, of which 70 (19%) resulted in licensing failure, defined as refusal or withdrawal of the application. The frequency of CMDh referrals decreased from 14.5% in 2006 to 1.6% in 2013. Of all referrals, 272 (72%) were resolved through consensus within the CMDh, the remaining 105 (28%) were resolved at the level of the CHMP. Most referrals were started because of objections raised about the clinical development program. Study design issues and objections about the demonstration of equivalence were most likely to result in licensing failure. An estimated 11% of all MRP/DCP procedures resulted in licensing failure prior to CMDh referral. CONCLUSION: Whereas the absolute number of MRP/DCP procedures resulting in a referral has reduced substantially over the past years, no specific time trend could be observed regarding the frequency of referrals resulting in licensing failure. Increased knowledge at the level of companies and regulators has reduced the frequency of late-stage failure of marketing applications via the MRP/DCP.

Toward Responsible Artificial Intelligence in Long-Term Care: A Scoping Review on Practical Approaches.

BACKGROUND AND OBJECTIVES: Artificial intelligence (AI) is widely positioned to become a key element of intelligent technologies used in the long-term care (LTC) for older adults. The increasing relevance and adoption of AI has encouraged debate over the societal and ethical implications of introducing and scaling AI. This scoping review investigates how the design and implementation of AI technologies in LTC is addressed responsibly: so-called responsible innovation (RI). RESEARCH DESIGN AND METHODS: We conducted a systematic literature search in 5 electronic databases using concepts related to LTC, AI, and RI. We then performed a descriptive and thematic analysis to map the key concepts, types of evidence, and gaps in the literature. RESULTS: After reviewing 3,339 papers, 25 papers were identified that met our inclusion criteria. From this literature, we extracted 3 overarching themes: user-oriented AI innovation; framing AI as a solution to RI issues; and context-sensitivity. Our results provide an overview of measures taken and recommendations provided to address responsible AI innovation in LTC. DISCUSSION AND IMPLICATIONS: The review underlines the importance of the context of use when addressing responsible AI innovation in LTC. However, limited empirical evidence actually details how responsible AI innovation is addressed in context. Therefore, we recommend expanding empirical studies on RI at the level of specific AI technologies and their local contexts of use. Also, we call for more specific frameworks for responsible AI innovation in LTC to flexibly guide researchers and innovators. Future frameworks should clearly distinguish between RI processes and outcomes.

Translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system active drugs.

The primary purpose of this study was to assess the translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system (CNS) active drugs. As a part of this, IBs were reviewed on reporting quality. Investigator's Brochures (IBs) of studies performed at the Centre for Human Drug Research (CHDR) reporting statistically significant results of CNS activity related to the drug's mechanism of action were included. The quality of IBs was assessed based on the presence of a rationale for the chosen animal model, completeness of pharmacokinetic (PK) results in reporting and internal validity information of the preclinical evidence. The IB-derisk tool was used to generate preclinical and early clinical data overviews data. For each compound, the overlap between pharmacologically active dose ranges and well-tolerated levels was calculated for three pharmacokinetic (PK) parameters: human equivalent dose (HED), maximum plasma concentration (Cmax) and area under the curve (AUC). Twenty-five IBs were included. In general, the quality of reporting in IBs was assessed as poor. About a third of studies did not explore the entire concentration-effect curve (pre)clinically. Single dose tolerability ranges were most accurately predicted by Cmax. Human equivalent dose and AUC were the best predictors of pharmacologically active ranges. Tolerable and pharmacologically active dose ranges in healthy volunteers can be reasonably well predicted from preclinical data with the IB-derisk tool. The translatability of preclinical studies can be improved by applying a higher reporting standard in IBs including comparable PK measurements across all preclinical and clinical studies.

Impact of the new European Union In Vitro Diagnostics Regulation on the practice of hospital diagnostic laboratories.

OBJECTIVES: The In Vitro Diagnostics Regulation 2017/746 (IVDR) coming into force from May 2022, creates the first European regulatory recognition for biomarker tests linked to medicinal products, so-called companion diagnostics (CDx). Since the introduction of the IVDR is associated with uncertainties about its impact on hospital practice, it is urgent and valuable to investigate how and why CDx are currently used in hospital practice, which factors influence the choice for applying in-house or commercial CDx, and what the expectations are about how the IVDR may affect current practice. METHODS: We investigated these questions using an interview-based approach and focused on 15 hospital laboratories in the Netherlands, including 7 academic and 8 general hospitals. All types of CDx were considered relevant for this research, including both genetic and protein-based biomarkers. RESULTS: Factors found included: costs and convenience, complexity of application, and compatibility with existing workflows. Next to in-house and commercial CDx, hospital laboratories addressed compatibility by tweaking existing CDx. CONCLUSION: Although increased quality of CDx is welcomed, worries toward increased costs and administrative work, and decreased quality were expressed. Further, the IVDR might also hinder using optimized in-house and tweaked CDx. Additionally, increased administrative burden could decrease innovativeness toward CDx.

The impact of patient advocacy: the case of innovative breast cancer drug reimbursement.

Current research into patient advocacy focuses on attempts of patient groups to mobilise resources and to influence researchers, pharmaceutical companies and policy-makers. This paper adopts a 'framing political opportunities' approach to draw attention to other kinds of advocacy strategies. In a case study of breast cancer patient advocacy of Herceptin reimbursement, it is shown how patient groups tried to gain access to policy-making by means of three different opportunity-framing strategies. Articulation aims at creating awareness through public-agenda building. Negotiation aims at frame alignment between interdependent stakeholders by arranging meetings. Politicisation is a strategy to influence the agendas of political arenas. Patient organisations succeeded in creating awareness and support, which had a considerable impact on other stakeholders. These impacts in turn aided the politicisation of the issue. However, the final impact on reimbursement procedures was only partially achieved due to depoliticising counterstrategies based on persistent ideas buttressing a particular division of responsibilities in the organisation of healthcare. According to these ideas cost control in healthcare is a medical responsibility, not a political one.

Market Formation in a Global Health Transition.

Transition studies have started to focus on market formation in innovation systems. This article investigates market formation in a global health transition that was instigated by drug-resistant malaria. We explore how markets for Artemisinin-based Combination Therapies (ACT) in the Greater Mekong Subregion (GMS) were formed at multiple geographical scales and locations. The study reveals the role of public institutes, academia and partnerships in early innovation system development. It demonstrates how transnational organizations created a supportive global landscape for ACT development and deployment. It then reveals how these advancements led to the formation of public-sector and private-sector ACT markets in the GMS. We illustrate how market formation activities took place on global, national and local scales and how structural couplings enabled the functioning of this global innovation system. The lessons learned are particularly relevant now that drug-resistant malaria has once more emerged in the GMS, urgently calling for new therapies and associated end-user markets.

Tradition, not science, is the basis of animal model selection in translational and applied research.

National and international laws and regulations exist to protect animals used for scientific purposes in translational and applied research, which includes drug development. However, multiple animal models are available for each disease. We evaluated the argumentation behind the selection of a specific animal model using thematic content analysis in project applications issued in 2017-2019 in the Netherlands. In total, 125 animal models for translational and applied research from 110 project applications were assessed. Explanations to select a specific model included: the model's availability (79%); the availability of expertise (62%); and the model showing similar disease pathology/symptoms (59%) to humans. Therefore, current selection of a specific animal model seems to be based on tradition rather than its potential predictive value for clinical outcome. The applicants' explanations for the implementation of the 3R prin­ciples (replacement, reduction and refinement) as to the animal model were unspecific. Replacement was achieved by using data from prior in vitro studies, reduction by optimal experimental design and statistics, and refinement by reducing discomfort. Additionally, due to the stated need for a test model with high complexity (47%) and intactness (30%), the full replacement of animal models with alternative (non-live animal) approaches was thought unachievable. Without a clear, systematic and transparent justification for the selection of a specific animal model, the likelihood of poorly trans­latable research remains. It is not only up to the researcher to demonstrate this, as ethical committees and funding bodies can provide positive stimuli to drive this change.

Ethical, Regulatory and Market related aspects of Deploying Triple Artemisinin-Based Combination Therapies for Malaria treatment in Africa: A study protocol.

Introduction: According to the World Malaria Report 2019, Africa accounts for 94% of the global malaria deaths. While malaria prevalence and mortality have declined over the years, recent reports suggest that these gains may stand the risk of being reversed if resistance to Artemisinin Combination Therapies (ACTs) spreads from Southeast Asia to Africa. Efforts are being made to develop new treatments that will address the looming threat of ACT resistance, including the development of triple artemisinin combination therapies (TACTs). The proposed study seeks to explore the views of stakeholders on the key ethical, regulatory and market-related issues that should be considered in the potential introduction of triple artemisinin combination therapies (TACTs) in Africa. Methods: The study employed qualitative research methods involving in-depth interviews and focus group discussions (FGDs) with stakeholders, who will be directly affected by the potential deployment of triple artemisinin combination treatments, as regulators, suppliers and end-users. Participants will be purposively selected and will include national regulatory authorities, national malaria control programs, clinicians, distributors and retailers as well as community members in selected districts in Burkina Faso and Nigeria. Discussion: The proposed study is unique in being one of the first studies that seeks to understand the ethical, social, regulatory and market position issues prior to the development of a prospective antimalarial medicine.

To what extent are the antimalarial markets in African countries ready for a transition to triple artemisinin-based combination therapies?

INTRODUCTION: Triple artemisinin-based combination therapies (TACTs) are being developed as a response to artemisinin and partner drug resistance in the treatment of falciparum malaria in Southeast Asia. In African countries, where current artemisinin-based combination therapies (ACTs) are still effective, TACTs have the potential to benefit the larger community and future patients by mitigating the risk of drug resistance. This study explores the extent to which the antimalarial drug markets in African countries are ready for a transition to TACTs. METHODS: A qualitative study was conducted in Nigeria and Burkina Faso and comprised in-depth interviews (n = 68) and focus group discussions (n = 11) with key actor groups in the innovation system of antimalarial therapies. RESULTS: Evidence of ACT failure in African countries and explicit support for TACTs by the World Health Organization (WHO) and international funders were perceived important determinants for the market prospects of TACTs in Nigeria and Burkina Faso. At the country level, slow regulatory and implementation procedures were identified as potential barriers towards rapid TACTs deployment. Integrating TACTs in public sector distribution channels was considered relatively straightforward. More challenges were expected for integrating TACTs in private sector distribution channels, which are characterized by patient demand and profit motives. Finally, several affordability and acceptability issues were raised for which ACTs were suggested as a benchmark. CONCLUSION: The market prospects of TACTs in Nigeria and Burkina Faso will depend on the demonstration of the added value of TACTs over ACTs, their advocacy by the WHO, the inclusion of TACTs in financial and regulatory arrangements, and their alignment with current distribution and deployment practices. Further clinical, health-economic and feasibility studies are required to inform decision makers about the broader implications of a transition to TACTs in African counties. The recent reporting of artemisinin resistance and ACT failure in Africa might change important determinants of the market readiness for TACTs.

Levelling the Translational Gap for Animal to Human Efficacy Data.

Reports of a reproducibility crisis combined with a high attrition rate in the pharmaceutical industry have put animal research increasingly under scrutiny in the past decade. Many researchers and the general public now question whether there is still a justification for conducting animal studies. While criticism of the current modus operandi in preclinical research is certainly warranted, the data on which these discussions are based are often unreliable. Several initiatives to address the internal validity and reporting quality of animal studies (e.g., Animals in Research: Reporting In Vivo Experiments (ARRIVE) and Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (PREPARE) guidelines) have been introduced but seldom implemented. As for external validity, progress has been virtually absent. Nonetheless, the selection of optimal animal models of disease may prevent the conducting of clinical trials, based on unreliable preclinical data. Here, we discuss three contributions to tackle the evaluation of the predictive value of animal models of disease themselves. First, we developed the Framework to Identify Models of Disease (FIMD), the first step to standardise the assessment, validation and comparison of disease models. FIMD allows the identification of which aspects of the human disease are replicated in the animals, facilitating the selection of disease models more likely to predict human response. Second, we show an example of how systematic reviews and meta-analyses can provide another strategy to discriminate between disease models quantitatively. Third, we explore whether external validity is a factor in animal model selection in the Investigator's Brochure (IB), and we use the IB-derisk tool to integrate preclinical pharmacokinetic and pharmacodynamic data in early clinical development. Through these contributions, we show how we can address external validity to evaluate the translatability and scientific value of animal models in drug development. However, while these methods have potential, it is the extent of their adoption by the scientific community that will define their impact. By promoting and adopting high quality study design and reporting, as well as a thorough assessment of the translatability of drug efficacy of animal models of disease, we will have robust data to challenge and improve the current animal research paradigm.

Comparison of drug efficacy in two animal models of type 2 diabetes: A systematic review and meta-analysis.

Previous qualitative research has suggested there are only minor differences between the db/db mouse and the Zucker Diabetic Fatty (ZDF) rat, both animal models of type 2 diabetes. However, it is not known whether these models are also comparable regarding drug response in quantitative terms (effect size). To investigate the extent of these differences, we conducted a systematic review and meta-analysis of approved drugs in these models. We searched on PubMed and Embase on July 3, 2019 for studies including either model, a monotherapy arm with an EMA/FDA approved drug for the treatment of type 2 diabetes, HbA1c assessment and a control group. Studies aimed at diabetes prevention or with surgical interventions were excluded. We calculated the Standardised Mean Difference (SMD) to compare effect sizes (HbA1c reduction) per drug and drug class across models. We included a risk of bias assessment for all included publications. A total of 121 publications met our inclusion criteria. For drugs with more than two comparisons, both models predicted the direction of the effect regarding HbA1c levels. There were no differences between the db/db mouse and ZDF rat, except for exenatide (P = 0.02) and GLP-1 agonists (P = 0.03) in which a larger effect size was calculated in the ZDF rat. Our results indicate the differences between the db/db mouse and ZDF rat are not relevant for preliminary efficacy testing. This methodology can be used to further differentiate between animal models used for the same indication, facilitating the selection of models more likely to predict human response.

Correction: A standardised framework to identify optimal animal models for efficacy assessment in drug development.

[This corrects the article DOI: 10.1371/journal.pone.0218014.].

Are some animal models more equal than others? A case study on the translational value of animal models of efficacy for Alzheimer's disease.

Clinical trial failures (>99%) in Alzheimer's disease are in stark contrast to positive efficacy data in animals. We evaluated the correlation between animal and clinical efficacy outcomes (cognition) in Alzheimer's disease using data from registered drugs as well as interventions tested in phase II or III clinical trials for Alzheimer's disease. We identified 20 interventions, which were tested in 208 animal studies in 63 different animal models. Clinical outcome was correlated with animal results in 58% of cases. But, individual animal models showed divergent results across interventions, individual interventions showed divergent results across animal models, and animal model outcomes were determined with 16 different methods. This result is unsurprising due to poor external validity (what do we model) of the animal models. Although the animal models all share Alzheimer's disease symptoms, none represents the whole syndrome. Investigators did not motivate why one model was chosen over another, and did not consider the ways the disease phenomena were generated (spontaneous, (experimentally) induced or by genetic modification), or the species characteristics, which determine the outcomes. The explanation for the lack of correlation between animal and human outcomes can be manifold: the pathogenesis of Alzheimer's disease is not reflected in the animal model or the outcomes are not comparable. Our conclusion is that currently no animal models exist which are predictive for the efficacy of interventions for Alzheimer's disease.