Animal immunization merges with innovative technologies: A new paradigm shift in antibody discovery.

Animal-derived antibody sources, particularly, transgenic mice that are engineered with human immunoglobulin loci, along with advanced antibody generation technology platforms have facilitated the discoveries of human antibody therapeutics. For example, isolation of antigen-specific B cells, microfluidics, and next-generation sequencing have emerged as powerful tools for identifying and developing monoclonal antibodies (mAbs). These technologies enable not only antibody drug discovery but also lead to the understanding of B cell biology, immune mechanisms and immunogenetics of antibodies. In this perspective article, we discuss the scientific merits of animal immunization combined with advanced methods for antibody generation as compared to animal-free alternatives through in-vitro-generated antibody libraries. The knowledge gained from animal-derived antibodies concerning the recombinational diversity, somatic hypermutation patterns, and physiochemical properties is found more valuable and prerequisite for developing in vitro libraries, as well as artificial intelligence/machine learning methods to discover safe and effective mAbs.

A few ethical issues in translational research for medicinal products discovery and development.

The results obtained with basic research showing significant therapeutic promise are often not translated into clinical applications. The purpose of translational research is to favour the transition of basic research to application at the patient's bedside, and from here to routine clinical practice (without excluding the opposite pathway, in which the evidence generated by clinical practice helps to guide research). Although translational research can provide patients with valuable therapeutic resources, it is not risk-free. The most significant ethical issues in translational research on medicinal products derive from the risk of the intention to shorten the timeframes for the application of the results of the research making the scientific methods adopted and the regulatory requisites to be satisfied along the long path from the bench to the patient's bedside less rigorous. This is also relevant during pandemics when shortening the timeline from basic research to bedside is even more crucial. It is therefore necessary to establish defined and agreed requisites in order to guarantee the ethicality of translational research, by promoting the good of individuals and minimising the risks.

Ethical Challenges in Biomarker-Driven Drug Development.

The increasing importance of biomarkers-as drivers of research and drug development activity, surrogate outcomes in clinical trials, and the centerpiece of precision medicine-raises many new ethical challenges. In what follows, I briefly review some of the major ethical challenges and debates already identified in the literature, and then describe a new ethical challenge that arises from the abstract nature of biomarker hypotheses.

Psychedelic Drugs as Therapeutics: No Illusions About the Challenges.

Interest in the potential therapeutic benefits of psychedelic agents has recently increased. In addition to psilocybin, a wide variety of agents with psychedelic properties have been proposed and partially tested. However, the challenges of obtaining approval to market a restricted psychotomimetic agent are formidable.

A Community Perspective on the Inclusion of Pregnant Women in Tuberculosis Drug Trials.

Affecting both mother and the existing pregnancy, tuberculosis (TB) increases the likelihood of poor birth outcomes. Despite substantial clinical need for TB prevention and treatment, pregnant women remain neglected by research initiatives. As members of 3 community advisory boards that provide input into TB drug trials, we offer a community perspective on the inclusion of pregnant women in TB drug research and discuss (1) our perspective on the risk/benefit tradeoff of including pregnant women in research to address different forms of TB; (2) recent examples of progress in this area; (3) lessons learned from the human immunodeficiency virus research field, where pregnant women have enjoyed better-although imperfect-representation in research; and (4) recommendations for different stakeholders, including researchers, regulatory authorities, ethics committees, and policymakers.

Ethical Conduct of Research in Children: Pediatricians and Their IRB (Part 1 of 2).

As human experimentation continues to grow into an ever more complex and sophisticated endeavor, the relevant ethical and regulatory structures become more intricate. When pediatricians and general practitioners are invited by pharmaceutical companies to enroll their offices in a clinical trial or a multicenter observational study or when they develop their own research questions, they frequently find themselves at a loss in the human research environment. The legal and regulatory complexity may have an unintended deterring effect at a time when office-based high quality pediatric research is urgently needed to support evidence-based medicine. Unfortunately, in many instances, unaware practitioners become involved in low-risk research activities without knowing it and become entangled in legal, auditing, and compliance procedures. This paper, written in 2 parts, aims at providing a general guidance on the principles that regulate human research with a focus on pediatrics. Part 1 discusses the history, the legal framework, and the consent process and highlights some practical aspects of initial protocol submission, continued review, and institutional review board determinations with the main focus on multicenter clinical trials (industry-sponsored research). Part 2 focuses on pediatric research regulation, also known as subpart-D, and minimal risk research, which encompasses many research activities aimed at addressing questions that may emerge in pediatricians' practices (investigator-initiated research).

Ethical challenges in developing drugs for psychiatric disorders.

As the classification of mental disorders advances towards a disease model as promoted by the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC), there is hope that a more thorough neurobiological understanding of mental illness may allow clinicians and researchers to determine treatment efficacy with less diagnostic variability. This paradigm shift has presented a variety of ethical issues to be considered in the development of psychiatric drugs. These challenges are not limited to informed consent practices, industry funding, and placebo use. The consideration for alternative research models and quality of research design also present ethical challenges in the development of psychiatric drugs. The imperatives to create valid and sound research that justify the human time, cost, risk and use of limited resources must also be considered. Clinical innovation, and consideration for special populations are also important aspects to take into account. Based on the breadth of these ethical concerns, it is particularly important that scientific questions regarding the development of psychiatric drugs be answered collaboratively by a variety of stakeholders. As the field expands, new ethical considerations will be raised with increased focus on genetic markers, personalized medicine, patient-centered outcomes research, and tension over funding. We suggest that innovation in trial design is necessary to better reflect practices in clinical settings and that there must be an emphasized focus on expanding the transparency of consent processes, regard for suicidality, and care in working with special populations to support the goal of developing sound psychiatric drug therapies.

Why cure, why now?

Combination antiretroviral therapy (cART) is highly effective at preventing morbidity and mortality due to infection with human immunodeficiency virus (HIV), but does not eradicate the virus. Consequently, cART must be administered life-long. Recent progress has stimulated research towards a cure of HIV infection. Approaches under investigation include hematopoietic stem cell transplantation, latency reactivating agents, immune based therapies, and cell-based therapies. Each of these approaches carries potential risks that must be weighed against the availability of safe and effective cART. Balancing the risks and benefits of this research poses unique challenges to potential study participants, clinicians and investigators.

ReRouting biomedical innovation: observations from a mapping of the alternative research and development (R&D) landscape.

In recent years, the world has witnessed the tragic outcomes of multiple global health crises. From Ebola to high prices to antibiotic resistance, these events highlight the fundamental constraints of the current biomedical research and development (R&D) system in responding to patient needs globally.To mitigate this lack of responsiveness, over 100 self-identified "alternative" R&D initiatives, have emerged in the past 15 years. To begin to make sense of this panoply of initiatives working to overcome the constraints of the current system, UAEM began an extensive, though not comprehensive, mapping of the alternative biomedical R&D landscape. We developed a two phase approach: (1) an investigation, via the RE:Route Mapping, of both existing and proposed initiatives that claim to offer an alternative approach to R&D, and (2) evaluation of those initiatives to determine which are in fact achieving increased access to and innovation in medicines. Through phase 1, the RE:Route Mapping, we examined 81 initiatives that claim to redress the inequity perpetuated by the current system via one of five commonly recognized mechanisms necessary for truly alternative R&D.Preliminary analysis of phase 1 provides the following conclusions: 1. No initiative presents a completely alternative model of biomedical R&D. 2. The majority of initiatives focus on developing incentives for drug discovery. 3. The majority of initiatives focus on rare diseases or diseases of the poor and marginalized. 4. There is an increasing emphasis on the use of push, pull, pool, collaboration and open mechanisms alongside the concept of delinkage in alternative R&D. 5. There is a trend towards public funding and launching of initiatives by the Global South. Given the RE:Route Mapping's inevitable limitations and the assumptions made in its methodology, it is not intended to be the final word on a constantly evolving and complex field; however, its findings are significant. The Mapping's value lies in its timely and unique insight into the importance of ongoing efforts to develop a new global framework for biomedical R&D. As we progress to phase 2, an evaluation tool for initiatives focused on identifying which approaches have truly achieved increased innovation and access for patients, we aim to demonstrate that there are a handful of initiatives which represent some, but not all, of the building blocks for a new approach to R&D.Through this mapping and our forthcoming evaluation, UAEM aims to initiate an evidence-based conversation around a truly alternative biomedical R&D model that serves people rather than profits.

The multifactorial role of the 3Rs in shifting the harm-benefit analysis in animal models of disease.

Ethics on animal use in science in Western society is based on utilitarianism, weighing the harms and benefits to the animals involved against those of the intended human beneficiaries. The 3Rs concept (Replacement, Reduction, Refinement) is both a robust framework for minimizing animal use and suffering (addressing the harms to animals) and a means of supporting high quality science and translation (addressing the benefits). The ambiguity of basic research performed early in the research continuum can sometimes make harm-benefit analysis more difficult since anticipated benefit is often an incremental contribution to a field of knowledge. On the other hand, benefit is much more evident in translational research aimed at developing treatments for direct application in humans or animals suffering from disease. Though benefit may be easier to define, it should certainly not be considered automatic. Issues related to model validity seriously compromise experiments and have been implicated as a major impediment in translation, especially in complex disease models where harms to animals can be intensified. Increased investment and activity in the 3Rs is delivering new research models, tools and approaches with reduced reliance on animal use, improved animal welfare, and improved scientific and predictive value.

Pragmatic randomized trials in drug development pose new ethical questions: a systematic review.

Implementation of pragmatic design elements in drug development could bridge the evidence gap that currently exists between the knowledge we have regarding the efficacy of a drug versus its true, comparative effectiveness in real life. We performed a review of the literature to identify the ethical challenges thus far related to pragmatic trials. The three central ethical questions identified for pragmatic trials are: (i) what level of oversight should pragmatic trials require; (ii) do randomized patients face additional risks; and (iii) is a waiver of informed consent ethically defensible? Despite the fact all reviewed publications dealt with post-launch pragmatic trials, these results could serve as an important starting point for conceptualizing which challenges could potentially arise in the pre-launch setting.

Lessons learned in pediatric clinical research to evaluate safe and effective use of drugs in pregnancy.

Children and pregnant women are vulnerable populations lacking clinical data to guide drug dosing. For children, over the past 15 years, the knowledge gap in pharmacokinetic, safety, and efficacy data has been narrowed as a result of the use of innovative clinical trial designs, minimal risk research methods, increased understanding of developmental pharmacology, multidisciplinary research teams, increased clinical pharmacology expertise and training, collaborative research networks, and critical legislative changes. This progress has not been observed to a similar degree for pregnant women. These two populations, however, share similar drug development challenges and, therefore, lessons learned in pediatric clinical trials can be leveraged to advance drug development in pregnant women.

"With human health it's a global thing": Canadian perspectives on ethics in the global governance of an influenza pandemic.

We live in an era where our health is linked to that of others across the globe, and nothing brings this home better than the specter of a pandemic. This paper explores the findings of town hall meetings associated with the Canadian Program of Research on Ethics in a Pandemic (CanPREP), in which focus groups met to discuss issues related to the global governance of an influenza pandemic. Two competing discourses were found to be at work: the first was based upon an economic rationality and the second upon a humanitarian rationality. The implications for public support and the long-term sustainability of new global norms, networks, and regulations in global public health are discussed.

Opportunities and challenges provided by cloud repositories for bioinformatics-enabled drug discovery.

Healthcare-related bioinformatics databases are increasingly offering the possibility to maintain, organize, and distribute DNA sequencing data. Different national and international institutions are currently hosting such databases that offer researchers website platforms where they can obtain sequencing data on which they can perform different types of analysis. Until recently, this process remained mostly one-dimensional, with most analysis concentrated on a limited amount of data. However, newer genome sequencing technology is producing a huge amount of data that current computer facilities are unable to handle. An alternative approach has been to start adopting cloud computing services for combining the information embedded in genomic and model system biology data, patient healthcare records, and clinical trials' data. In this new technological paradigm, researchers use virtual space and computing power from existing commercial or not-for-profit cloud service providers to access, store, and analyze data via different application programming interfaces. Cloud services are an alternative to the need of larger data storage; however, they raise different ethical, legal, and social issues. The purpose of this Commentary is to summarize how cloud computing can contribute to bioinformatics-based drug discovery and to highlight some of the outstanding legal, ethical, and social issues that are inherent in the use of cloud services.

Needs-driven versus market-driven pharmaceutical innovation: the consortium for the development of a new medicine against malaria in Brazil.

The prevailing model for encouraging innovation based on patents and market-oriented raises at least two economic and ethical issues: it imposes barriers on individuals and developing countries governments' access to medicines by defining prices that do not match their income, and the unavailability of new or appropriate products to address the health problems of these populations. In the last decade, this scenario has undergone some changes due to the emergence of new actors, the contribution of aid resources, the introduction to the market of new products against neglected diseases, the development of new governmental healthcare policies and research programs, etc. One example of such initiatives is the Fixed-Dose Artesunate Combination Therapy (FACT) project consortium, which brought together institutions with different natures from both the North and the South, for the development of two antimalarial fixed-dose combinations recommended by the WHO - artesunate-amodiaquine (ASAQ) and artesunate-mefloquine (ASMQ). This paper proposes to describe and analyze the ASMQ consortium, which is the result of a new pharmaceutical development approach, based on a different paradigm - needs-driven instead of market-driven -, collaborative, with strategic participation of institutions from the South, funded by alternative resources (public and philanthropic). Thus, it represents an interesting object of study for bioethical debates on intellectual property and innovation, and its analysis is justified in light of the current debate on ways of stimulating needs-driven pharmaceutical innovation.