DENTAL, ORAL AND CRANIOFACIAL TISSUE REGENERATION CONSORTIUM (DOCTRC)
The National Institute of Dental and Craniofacial Research (NIDCR) is firmly committed to facilitating clinical translation of the most promising scientific and technological advances in tissue engineering and regenerative medicine (TE/RM) to safely and effectively regenerate and reconstruct dental, oral and craniofacial (DOC) tissues. Toward achieving this goal, NIDCR will establish a multidisciplinary DOC Tissue Regeneration Consortium (DOCTRC) that will conduct pre-clinical studies leading to the submission of Investigational New Drug (IND)/Investigational Device Exemption (IDE) applications to the U.S. Food and Drug Administration (FDA) to develop safe, predictive and effective clinical strategies for regeneration of functional tissues of the human DOC complex, including vascularized and innervated craniofacial bone and musculoskeletal complex, periodontium, tooth, cartilage, salivary gland and temporomandibular joint (TMJ). The DOCTRC will be built through a three-stage process. This FOA will support activities in the first stage, the opportunity to plan for Resource Centers (RCs), which will be the foundation for the DOCTRC. The overall outcome of the DOCTRC effort will be the development of TE/RM products, including combination products, based on cells, biologics and/or devices and associated protocols ready for the initiation of clinical trials.
To meet the demands of the accelerated translational timeline of this effort, the DOCTRC will employ those TE/RM tools and strategies that have been tested previously in small or large animal models, and have already demonstrated significant translational potential and readiness to advance through the translational pipeline.
The three stages of DOCTRC effort are outlined below:
- Stage 1, Planning Stage (solicited through this FOA): This stage will be implemented under an R34 Planning Grant funding mechanism to provide up to one year of support to develop an overall vision, roadmap, organizational structure and operational procedures for centralized RCs. The goal of stage 1 will be to develop detailed plans for establishing interactive interdisciplinary teams of biologists, bioengineers, clinicians and other technical experts to function as RCs. While participation of the academic clinicians is welcomed, inclusion of the practicing clinicians involved in everyday patient care is required for building a successful RC infrastructure. Industry expertise may also be added to the RC teams, as needed.
- Stage 2, Resource Centers Stage: Following the completion of the R34 planning stage, awardees will be able to compete for the establishment of the RCs in stage 2 through a second FOA. The duration of stage 2 will be three years. On the basis of peer-review assessment and programmatic considerations, NIDCR will select 1-3 most meritorious teams from stage 1 to establish the centralized RCs. The goals of the RCs will be to 1) develop a robust infrastructure to deliver uniform high-quality technical support and research capacities for pre-clinical studies and 2) organize, recruit and integrate several Interdisciplinary Translational Project (ITP) teams into the RC. Each of these ITP teams will have identified and developed a specific TE/RM approach for regeneration of a functional DOC tissue that synergizes with the expertise of the RC. In order to effectively support the ITPs, the RCs will improve, optimize, validate and standardize tools and technologies for DOC tissue regeneration in the following areas: (i) cells and biomaterials; (ii) disease and injury -relevant large animal models; (iii) functional assays and endpoints; and (iv) interactions with the FDA. To successfully compete for inclusion in the final stage of DOCTRC, the RCs and the ITP teams must establish productive collaborations by the completion of the RC development stage, and demonstrate their capacity to collectively advance the most likely to succeed tissue engineering/regenerative medicine (TE/RM) products through the translational pipeline. Productive collaborations between different RCs in the areas of complementary expertise will be highly encouraged.
- Stage 3, Consortium Stage: The RCs and their ITP teams will compete for the final stage through a third FOA to establish DOCTRC. The duration of stage 3 will be four to five years. The ITP teams will utilize resources developed by the RCs during stage 2, and will work in continuous close collaboration with the RCs while seeking advice from the FDA in advancing specific TE/RM clinical applications. The DOCTRC will complete validation, manufacturing, and preclinical testing of the most likely to succeed TE/RM products and will develop INDs/IDEs for submission to FDA. The outcome of the DOCTRC will be TE/RM products and associated protocols ready for initiation of Phase I clinical trials.
Many promising scientific and technological advances have emerged from the investment that NIDCR and NIH have made in TE/RM over the years. These include scaffolds that can guide functional maturation of the engineered constructs in vitro and facilitate tissue regeneration in vivo. Such scaffolds can be designed to deliver active biomolecules to cells, degrade at a pre-determined rate, control inflammatory responses, and exhibit many other useful characteristics. Further, substantial progress has been made in isolation and characterization of DOC tissue-specific stem and progenitor cells, functional assays have been developed for testing safety and efficacy of TE/RM products, and new cell and tissue tracking and imaging modalities have been derived to monitor tissue regeneration in vivo. Despite this progress, only a few TE/RM-based prospective therapies for DOC and other tissues have reached the stage of clinical trials.
NIDCR carried out a comprehensive analysis of the nature of obstacles interfering with TE/RM translation, and on the basis of this analysis, developed a plan to establish the translation-targeted DOCTRC. One of the key features to ensure the success of DOCTRC in advancing TE/RM products to the clinic will be a strong alignment between the clinical needs for DOC tissue regeneration and the available TE/RM tools and technologies that have sufficiently matured in discovery research. Achieving this alignment will require robust interdisciplinary partnerships among practicing clinicians, biologists, bioengineers, regulatory experts and other technical professionals. In this partnership, the clinicians will define the areas of clinical needs and will establish product design criteria, and on the basis of these recommendations, the technical and regulatory experts of the DOCTRC will develop specific products and technical strategies to meet these needs.
Given a multitude of the available TE/RM-based biomaterials, scaffolds, cell sources, functional assays, and animal models, a preparatory stage will be required before specific products and protocols can be advanced through the translational pipeline for preclinical testing. Specifically, it will be necessary to conduct side-by-side quantitative comparisons, and to standardize, optimize and validate the available materials, cells and protocols in DOC disease and injury -relevant large animal models with respect to their safety, efficacy, and other functional outcome parameters. The outcome of this effort will be the identification of those candidates that are most likely to succeed in clinical settings. Moreover, effective scale up, Good Manufacturing Practices (GMP) protocols and Standard Operating Procedures (SOPs) will need to be developed before the products can be effectively advanced toward clinical trials. The DOCTRC will systematically address these issues during its two initial stages while the third stage will focus on advancing the most-likely to succeed products and protocols toward Phase I clinical trials.
This FOA encourages applications for Planning Grants (R34) from interdisciplinary groups of investigators to propose plans for establishing the RCs. x. Prior involvement in advancing TE/RM products and technologies to clinical trials is highly desired. Other types of technical expertise can be added, as needed. Multiple Program Director/Principle Investigator (multi-PD/PI) applications are strongly encouraged.
This FOA is designed to support the development of the overall vision, roadmap, organizational structure and operational procedures of the RCs, as well as to define specific approaches and practices that will be employed by the RCs. This FOA is not designed to support the collection of preliminary data or to conduct pilot studies to support a rationale for the RCs.
Examples of the activities supported by this FOA include, but are not limited to the following:
- Outlining scientific, technical, manufacturing and regulatory issues to be addressed by the RC for advancing DOC TE/RM products and protocols toward clinical trials.
- Planning the structure, the composition and other characteristics of the RC, such as focus areas, specific types of expertise to be included and other capabilities. This plan should describe how the proposed RC structure would insure a broad coverage of clinical needs.
- Outlining the dynamics of interdisciplinary collaborative interactions among the different members of the RC team with a particular emphasis on the interactions among clinical, technical and regulatory experts.
- Planning specific strategies to be employed for quantitative side-by-side comparisons, standardization and functional validation of different biomaterials, cell sources and other components of TE/RM products to allow selection of the candidates that have high probability to succeed in the translational pipeline.
- Defining functional assays, specific metrics and endpoints to be used in side-by-side comparisons, standardization and validation of the TE/RM products.
- Defining protocols and an organizational framework for selecting TE/RM candidate products that have a high probability to succeed in translational pipeline.
- Defining animal models, particularly large DOC disease and injury -relevant animal models to be used for testing the efficacy of the TE/RM products. If new models are proposed, specific approaches for the development and validation of these models should be described.
- Outlining potential strategies for scaling up and GMP manufacturing of the TE/RM products.
- Defining specific milestones and timelines for the RC’s productivity and output.
- Outlining possible alternative strategies to be used for overcoming technical, organizational and other types of obstacles encountered during RC development.
- Planning and development of training materials, Standard Operating Procedures, and management protocols for the RC staff.
- Outlining product development plans for IND/IDE submissions to the FDA.