Unraveling the autoimmune translational research process layer by layer

Abstract

Autoimmune diseases have a complex etiology and despite great progress having been made in our comprehension of these disorders, there has been limited success in the development of approved medications based on these insights. Development of drugs and strategies for application in translational research and medicine are hampered by an inadequate molecular definition of the human autoimmune phenotype and the organizational models that are necessary to clarify this definition.

Figure 1

Yearly therapeutic approval of drugs and biologics by the FDA between 2006 and 2011. New molecular entities and biological license applications approved by the FDA’s Center for Drug Evaluation and Research (CDER) and biological products approved by the Center for Biologics Evaluation and Research (CBER) are shown relative to the approval of drugs related to autoimmunity (approved by CBER or CDER) for each year. The approval numbers were retrieved from the FDA’s drug approval databases (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Reports.ReportsMenu; http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/BiologicalApprovalsbyYear/default.htm) and references 49–53. New molecular entities are shown in light blue, biological license applications are shown in dark blue, approved biological products are shown in gray, and approved drugs and biologics related to autoimmunity are shown in light purple. IV, intravenous; SQ, subcutaneous; PID, primary immune deficiency; RA, rheumatoid arthritis; MS, multiple sclerosis.

Figure 2

Operational challenges for translational research and medicine. Adapted from references 7, 12, 39 and 54 and the Harvard Catalyst website. Translational research is defined based on the operational hurdles that must be overcome (top). These layers include: T0, the fundamental studies and applied research that define cellular mechanisms, their relationship to disease and, consequently, the identification of therapeutic targets and methods of treatment (new molecular entities); T1, first phase 1 studies in humans that aim to define proof of mechanism and proof of concept; T2, phase 2 and 3 clinical trials that are necessary for the approval of a therapeutic agent for clinical use; T3, phase 4 clinical trials that are associated with optimizing the therapeutic use of an agent in clinical practice; and T4, the outcome or comparative effectiveness research that serves to determine the ultimate utility and cost effectiveness of an agent relative to others currently in use. Critical path research (red), as defined by the FDA, or the valley of death, as defined by the pharmaceutical industry, comprises research related to the T0, T1 and T2 stages. Each of these activities possesses many overlapping sets of challenges, as listed in the gray box.

Figure 3

Tissue banks in autoimmunity-related translational research. It is crucial to classify autoimmune diseases based on molecular pathways to improve the ability to predict disease course (through surrogate markers) and better link therapeutic agents to specific subsets of molecularly defined patients. This classification will require more human experimentation as well as mechanisms to support this process through development of standardized methods of tissue acquisition, archiving, sequential high-throughput molecular analyses and ongoing phenotypic data acquisition (preferentially through linkage to an electronic medical record (EMR)) to allow for the bioinformatic testing of relevant hypotheses, as summarized in the schematic diagram.

Figure 4

An organizational model for translational research and medicine in autoimmunity: the Biomedical Research Centre (BRC) at Guy’s and St. Thomas’ Hospital and King’s College London. The BRC, as part of the Experimental Medicine Hub at Guy’s Hospital, is a ‘one-stop shop’ for translational research. It stretches over nearly 10,000 m of dedicated clinical research space. The top floor contains key administrative functions that bring together hospital research and developmental functions, university functions, a joint clinical trials office, meeting space and a desk area for the faculty of translational medicine. A dedicated purpose-built clinical research facility containing a good manufacturing practice (GMP) facility, an immune monitoring facility, a procedure room and a tissue processing laboratory is located one floor below along with a commercial phase 1 clinical trials unit. Other floors are occupied by a GMP pharmacy, a stem cell laboratory and a genomics core. GSTFT R&D, Guy’s and St Thomas’ NHS Foundation Trust research and development; JCTO, joint clinical trials office; NIHR,, National Institute for Health research; CLRN, comprehensive local research network; PCRN, primary care research network; RDS, research design services; ES, embryonic stem.