Materializing research promises: opportunities,priorities and conflicts in translational medicine

There is considerable evidence that the translation rate of major basic science promises to clinical applications has been inefficient and disappointing. The deficiencies of translational science have often been proposed as an explanation for this failure. An alternative explanation is that until recently basic science advances have made oversimplified assumptions that have not matched the true etiological complexity of most common diseases; while clinical science has suffered from poor research practices, overt biases and conflicts of interest. The advent of molecular medicine and the recasting of clinical science along the principles of evidence-based medicine provide a better environment where translational research may now materialize its goals. At the same time, priority issues need to be addressed in order to exploit the new opportunities. Translational research should focus on diseases with global impact, if true progress is to be made against human suffering. The health outcomes of interest for translational efforts need to be carefully defined and a balance must be struck between the subjective needs of healthcare consumers and objective health outcomes. Development of more simple, practical and safer interventions may be as important a target for translational research as the development of cures for diseases where no effective interventions are available at all. Moreover, while the role of the industry is catalytic in translating research advances to licensed interventions, academic independence needs to be sustained and strengthened at a global level. Conflicts of interest may stifle translational research efforts internationally. The profit motive is unlikely to be sufficient alone to advance biomedical research towards genuine progress.     

Translational medicine: science or wishful thinking?

"Translational medicine" as a fashionable term is being increasingly used to describe the wish of biomedical researchers to ultimately help patients. Despite increased efforts and investments into R&D, the output of novel medicines has been declining dramatically over the past years. Improvement of translation is thought to become a remedy as one of the reasons for this widening gap between input and output is the difficult transition between preclinical ("basic") and clinical stages in the R&D process. Animal experiments, test tube analyses and early human trials do simply not reflect the patient situation well enough to reliably predict efficacy and safety of a novel compound or device. This goal, however, can only be achieved if the translational processes are scientifically backed up by robust methods some of which still need to be developed. This mainly relates to biomarker development and predictivity assessment, biostatistical methods, smart and accelerated early human study designs and decision algorithms among other features. It is therefore claimed that a new science needs to be developed called 'translational science in medicine'.     

Translational Medicine - doing it backwards

In recent years the concept of "translational medicine" has been advanced in an attempt to catalyze the medical applications of basic biomedical research. However, there has been little discussion about the readiness of scientists themselves to respond to what we believe is a required new approach to scientific discovery if this new concept is to bear fruit. The present paradigm of hypothesis-driven research poorly suits the needs of biomedical research unless efforts are spent in identifying clinically relevant hypotheses. The dominant funding system favors hypotheses born from model systems and not humans, bypassing the Baconian principle of relevant observations and experimentation before hypotheses. Here, we argue that that this attitude has born two unfortunate results: lack of sufficient rigor in selecting hypotheses relevant to human disease and limitations of most clinical studies to certain outcome parameters rather than expanding knowledge of human pathophysiology; an illogical approach to translational medicine. If we wish to remain true to our responsibility and duty of performing research relevant to human disease, we must begin to think about fundamental new approaches.     

Translating rare-disease therapies into improved care for patients and families: what are the right outcomes,designs, and engagement approaches in health-systems research?

There is a need for research to understand and improve health systems for rare diseases in order to ensure that new, efficacious therapies developed through basic and early translational science lead to real benefits for patients. Such research must (i) focus on appropriate patient-oriented outcomes, (ii) include robust study designs that can accommodate real-world decision priorities, and (iii) involve effective stakeholder-engagement strategies. For transformative therapies, study outcomes will need to shift toward longer-term goals in recognition of success in preventing catastrophic outcomes. For incremental therapies, outcomes should be selected in recognition of the impact of care on quality of life for patients and families. To generate new evidence, we suggest that hybrid study designs integrating elements of practice-based observational research and pragmatic trials hold the most promise for addressing priorities such as minimizing bias, accounting for cointerventions, identifying long-term impacts, and considering clinical heterogeneity. To effectively engage with stakeholders, a knowledge exchange infrastructure is needed to foster collaboration among patients with rare diseases and their families, health-care providers, researchers, and policy decision makers. A key priority for these groups must be collaboration toward a shared understanding of the outcomes that are of most relevance to the facilitation of patient-centered care.     

Medical Nanotechnology

Nanotechnology, the science of creating structures, devices, and systems with a length scale of approximately 1-100 nanometers, is poised to have a revolutionary effect on biomedical research and clinical science. By operating at the same scale as most biomacromolecules, nanoscale devices can afford a detailed view of the molecules and events that drive cellular systems and that lie at the heart of disease, and thus, nanotechnology can impact the drug discovery, development, and clinical testing of novel pharmaceuticals. Already, nanoscale drug delivery vehicles are in clinical use, but those successes represent just one way in which nanotechnology will prove useful. One promising nanoscale technology under development may provide real-time, in vivo measurements of apoptosis, and thus may afford an early signal of therapeutic efficacy, both in human clinical trials and in preclinical screening. Microfluidic systems, built of nanoscale components, can enable a host of rapid, massively parallel, high-throughput screening systems, while nanoscale sensors in a wide variety of formats are ready to provide multiplexed biochemical and genetic measurements in living systems. These advances could be utilized to shave time and expense from multiple stages of the drug discovery and development effort.     

Facilitating biomedical researchers’ interrogation of electronic health record data: Ideas from outside of biomedical informatics

Electronic health records (EHR) are a vital data resource for research uses, including cohort identification, phenotyping, pharmacovigilance, and public health surveillance. To realize the promise of EHR data for accelerating clinical research, it is imperative to enable efficient and autonomous EHR data interrogation by end users such as biomedical researchers. This paper surveys state-of-art approaches and key methodological considerations to this purpose. We adapted a previously published conceptual framework for interactive information retrieval, which defines three entities: user, channel, and source, by elaborating on channels for query formulation in the context of facilitating end users to interrogate EHR data. We show the current progress in biomedical informatics mainly lies in support for query execution and information modeling, primarily due to emphases on infrastructure development for data integration and data access via self-service query tools, but has neglected user support needed during iteratively query formulation processes, which can be costly and error-prone. In contrast, the information science literature has offered elaborate theories and methods for user modeling and query formulation support. The two bodies of literature are complementary, implying opportunities for cross-disciplinary idea exchange. On this basis, we outline the directions for future informatics research to improve our understanding of user needs and requirements for facilitating autonomous interrogation of EHR data by biomedical researchers. We suggest that cross-disciplinary translational research between biomedical informatics and information science can benefit our research in facilitating efficient data access in life sciences.     

The Microbe Farms: Microbial Biorepositories in Clinical Microbiology

Biorepositories aim to acquire, authenticate, preserve, develop, and distribute biological specimens, along with information, technology, intellectual property, and standards for the advancement and application of scientific knowledge. Biorepositories are critical components of modern healthcare, as they provide resources to advance translational biomedical research, navigation through the FDA process for in vitro devices, verification and validation of diagnostic methods, and personalized medicine. In order to fully realize the opportunities that biorepositories offer to medicine, laboratories must be able to guarantee high-quality biospecimens, associated information, and a system able to respond to the needs of method verification, quality control, or the requests of scientific colleagues. A biorepository requires funding resources and space, which are often difficult to find within existing health care resources, yet health care may benefit most from the resources biorepositories provide. It is crucial that institutions be able to recognize these issues and start preparing and releasing adequate resources to support the development of biorepositories with a common goal to improve health care by increasing the quality of biomedical research and diagnostic test development. The future of biorepositories depends on the development of more evidence-based practices in both the research and clinical settings. As the field matures, educating a new generation of biospecimen/biobanking scientists will be an important need.     

Disclosure of clinical trial results when product development is abandoned

Currently, sponsors are not required to report the outcomes of clinical research on drugs or devices that do not lead to an approved product. Consequently, the public cannot benefit from scientific information derived from all failed or abandoned drugs and devices. Provisions in the U.S. Food and Drug Administration Amendments Act of 2007 provide an opportunity for the Department of Health and Human Services to rectify this situation. By reporting the results of clinical trials of abandoned products in a publicly accessible database and in the peer-reviewed journal literature, sponsors would satisfy a core ethical obligation of clinical research and enhance translational science.     

The field of Industrial and Organizational Psychology: An early example of translational research

The purpose of this article was to introduce the discipline of Industrial and Organizational (I/O) Psychology and discuss its connection with translational research. I/O Psychology is dedicated to improving the lives of people at work, and maintaining the communication between science and practice has been key to the success of that endeavor. A discussion on some of the more heavily researched I/O topics is presented, along with a discussion on the application of I/O in the form of organizational interventions. It is hoped that this article will contribute to the current discussion on translational research among the biomedical and biobehavioral fields and also be used as a resource for those seeking to improve the functioning of their organizations.     

Adherence to biomedical HIV prevention methods: Considerations drawn from HIV treatment adherence research

Biomedical approaches to HIV prevention (eg, microbicides, antiretroviral preexposure prophylaxis) are undergoing clinical trials to test their efficacy. One key consideration emerging from completed trials is the critical role of adherence to the investigational product. Suboptimal product adherence may compromise clinical trial results and ultimately undermine the effectiveness of biomedical prevention methods in any future real-world use. Efforts to strengthen biomedical HIV prevention product adherence can benefit from existing research methodologies, findings, and interventions developed for adherence to HIV treatment. Research on treatment adherence is most relevant to medication-based biomedical prevention strategies, such as antiretroviral preexposure prophylaxis and acyclovir for herpes simplex virus-2. Three areas where HIV treatment adherence literature can inform research on such biomedical prevention strategies are 1) specialized methods for assessing medication adherence, 2) research findings emphasizing social context as an adherence determinant, and 3) promising behavioral interventions to improve adherence.     

A network perspective on unraveling the role of TRP channels in biology and disease

Transient receptor potential (TRP) channels are a large family of non-selective cation channels that mediate numerous physiological and pathophysiological processes; however, still largely unknown are the underlying molecular mechanisms. With data generated on an unprecedented scale, network-based approaches have been revolutionizing the way in which we understand biology and disease, discover disease genes, and develop therapeutic strategies. These circumstances have created opportunities to encounter TRP channel research to data-intensive science. In this review, we provide an introduction of network-based approaches in biomedical science, describe the current state of TRP channel network biology, and discuss the future direction of TRP channel research. Network perspective will facilitate the discovery of latent roles and underlying mechanisms of TRP channels in biology and disease.     

The current state of implementation science in genomic medicine: opportunities for improvement

PurposeThe objective of this study was to identify trends and gaps in the field of implementation science in genomic medicine.MethodsWe conducted a literature review using the Centers for Disease Control and Prevention’s Public Health Genomics Knowledge Base to examine the current literature in the field of implementation science in genomic medicine. We selected original research articles based on specific inclusion criteria and then abstracted information about study design, genomic medicine, and implementation outcomes. Data were aggregated, and trends and gaps in the literature were discussed.ResultsOur final review encompassed 283 articles published in 2014, the majority of which described uptake (35.7%, n = 101) and preferences (36.4%, n = 103) regarding genomic technologies, particularly oncology (35%, n = 99). Key study design elements, such as racial/ethnic composition of study populations, were underreported in studies. Few studies incorporated implementation science theoretical frameworks, sustainability measures, or capacity building.ConclusionAlthough genomic discovery provides the potential for population health benefit, the current knowledge base around implementation to turn this promise into a reality is severely limited. Current gaps in the literature demonstrate a need to apply implementation science principles to genomic medicine in order to deliver on the promise of precision medicine.Genet Med advance online publication 12 January 2017     

Ex Vivo Metrics™, a preclinical tool in new drug development

Among the challenges facing translational medicine today is the need for greater productivity and safety during the drug development process. To meet this need, practitioners of translational medicine are developing new technologies that can facilitate decision making during the early stages of drug discovery and clinical development. Ex Vivo Metrics™ is an emerging technology that addresses this need by using intact human organs ethically donated for research. After hypothermic storage, the organs are reanimated by blood perfusion, providing physiologically and biochemically stable preparations. In terms of emulating human exposure to drugs, Ex Vivo Metrics is the closest biological system available for clinical trials. Early application of this tool for evaluating drug targeting, efficacy, and toxicity could result in better selection among promising drug candidates, greater drug productivity, and increased safety.     

Dendritic Cell Therapy of High-Grade Gliomas

The prognosis of patients with malignant glioma is poor in spite of multimodal treatment approaches consisting of neurosurgery, radiochemotherapy and maintenance chemotherapy. Among innovative treatment strategies like targeted therapy, antiangiogenesis and gene therapy approaches, immunotherapy emerges as a meaningful and feasible treatment approach for inducing long-term survival in at least a subpopulation of these patients. Setting up immunotherapy for an inherent immunosuppressive tumor located in an immune-privileged environment requires integration of a lot of scientific input and knowledge of both tumor immunology and neuro-oncology. The field of immunotherapy is moving into the direction of active specific immunotherapy using autologous dendritic cells (DCs) as vehicle for immunization. In the translational research program of the authors, the whole cascade from bench to bed to bench of active specific immunotherapy for malignant glioma is covered, including proof of principle experiments to demonstrate immunogenicity of patient-derived mature DCs loaded with autologous tumor lysate, preclinical in vivo experiments in a murine orthotopic glioma model, early phase I/II clinical trials for relapsing patients, a phase II trial for patients with newly diagnosed glioblastoma (GBM) for whom immunotherapy is integrated in the current multimodal treatment, and laboratory analyses of patient samples. The strategies and results of this program are discussed in the light of the internationally available scientific literature in this fast-moving field of basic science and translational clinical research.     

Getting the word out: Teaching middle-school children about cardiovascular disease

Cardiovascular disease (CVD) has roots in childhood. Because CVD begins early, a clear strong case for early education focused on CVD primary prevention exists. Scientists are not traditionally involved in disseminating health knowledge into public education. Similarly, public school teachers typically do not have access to biomedical research that may increase their students' health science literacy. One way to bridge the “cultural” gap between researchers and school teachers is to form science–education partnerships. For such partnerships to be successful, teams of scientists and teachers must “translate” biomedical research into plain language appropriate for students. In this work, we briefly review the need for improving health literacy, especially through school-based programs, and describe work with one model scientist–teacher partnership, the Teacher Enrichment Initiatives. Examples of cardiovascular research “translated” into plain language lessons for middle-school students are provided and practical considerations for researchers pursuing a science–education partnership are delineated.     

Desiderata for ontologies to be used in semantic annotation of biomedical documents

A wealth of knowledge valuable to the translational research scientist is contained within the vast biomedical literature, but this knowledge is typically in the form of natural language. Sophisticated natural-language-processing systems are needed to translate text into unambiguous formal representations grounded in high-quality consensus ontologies, and these systems in turn rely on gold-standard corpora of annotated documents for training and testing. To this end, we are constructing the Colorado Richly Annotated Full-Text (CRAFT) Corpus, a collection of 97 full-text biomedical journal articles that are being manually annotated with the entire sets of terms from select vocabularies, predominantly from the Open Biomedical Ontologies (OBO) library. Our efforts in building this corpus has illuminated infelicities of these ontologies with respect to the semantic annotation of biomedical documents, and we propose desiderata whose implementation could substantially improve their utility in this task; these include the integration of overlapping terms across OBOs, the resolution of OBO-specific ambiguities, the integration of the BFO with the OBOs and the use of mid-level ontologies, the inclusion of noncanonical instances, and the expansion of relations and realizable entities.     

Inventors as investigators: the ethics of patents in clinical trials.

CONTEXT: The Bayh-Dole Act and renewed emphasis on translational research have stimulated patenting activities at universities. PURPOSE: To examine how different institutions manage possible patent-related conflicts of interest in human subjects research, and to provide an ethical analysis and recommendations. METHOD: Policies of nine major professional organizations, 13 of the largest recipients of federal biomedical funding in the United States and Canada, and 17 biomedical journals were canvassed. Disagreements in policies were used as the basis for analyzing the ethics of inventorship in clinical trials. RESULTS: Policies varied along three lines. First, some policies did not define patent inventorship as a potential conflict of interest. Second, some of those that did define it as such used licensing as a trigger for conflict of interest management. Third, several policies imposed presumptive restrictions on an investigator's participation in a trial involving his or her invention. CONCLUSIONS: The author defends on ethical grounds restrictive policies on patent holding in clinical trials and rejects objections to restrictive policies. The author recommends five policies: (1) any related patent holding should always be disclosed to IRBs and research subjects, (2) investigators who hold conflicting patents should be presumptively barred from certain activities in a study, (3) institutional interests in patents should be managed and disclosed to research subjects, (4) IRBs should also be informed of an investigator's filed (not just held) patents on an experimental agent, and (5) the stringency of policies should be adjusted according to a patent's earning potential and the risk associated with a study.