Objective
The overall objective of this proposal is to continue the ongoing work of T1DC, to expand its value to the T1D community, and to increase the efficiency in which the consortium can operate. T1DC is a public-private partnership that aims to provide a neutral pre-competitive space for those with an interest in developing new products for people living with T1D, including the biopharmaceutical industry, academic and clinical researchers, patient-advocacy organizations, philanthropic organizations, and regulators. T1DC leverages the expertise of the T1D community and its data, analytics, and regulatory knowledge to identify unmet needs in T1D product development and develop regulatory-grade solutions that overcome these barriers.
The overall objective of this proposal is to continue the work initiated through TOMI-T1D under the umbrella of the T1DC, as the T1DC New Onset T1D Workstream. This workstream will continue and build upon the achievements to date of TOMI-T1D, seeking to obtain formal regulatory endorsement of the under-development New Onset T1D Clinical Trial Simulation Platform and to continue analysis of the aggregated individual-level database to identify new potential outcome markers that enable clinical trials of shortened duration.
The New Onset T1D Clinical Trial Simulation Platform will provide sponsors with a powerful tool to optimize the design of clinical trials for disease-modifying therapies (i.e., those intended to prevent or delay the destruction of beta cells) for individuals with new-onset T1D. The platform will allow sponsors to assess the results of simulated virtual trials with user-specified design considerations, including a) patient populations, for example baseline age and sex or other identified relevant factors, b) trial size, duration, and assessment frequency, c) estimated drug effects, and d) additional factors identified as relevant during the model-building process. Simulated trials can be re-run with modifications to trial design parameters as necessary by the trial sponsor to identify the overall trial design that best meets the needs of the sponsors.
The overall objective of the additional analyses that will be performed on the TOMI-T1D database are to identify new or existing outcome measures and composite measures that could allow for shorter clinical trials, especially when considering early Phase 2 clinical trials. If possible, in order to identify measures that can reliably determine clinical benefit to patients in as little as 3-6 months with reasonably sized trials, sponsors can make go/no-go decisions regarding a potential therapeutic sooner. In turn, this would enable sponsors to appropriately re-allocate resources to other potential therapies or initiate pivotal registration studies earlier with higher confidence. Importantly, including the T1D community, especially the regulators, in these analyses ensures the community can collectively agree on appropriate trial endpoints.
Finally, an important objective of this effort is to leverage the aggregated database to further ongoing conversations with regulators regarding the acceptance of new endpoints or surrogate endpoints, determined to be clinically meaningful to patients, which could help streamline pivotal Phase 3 studies. This objective includes the pursuit of C-peptide as a surrogate, or reasonably likely surrogate endpoint, for use in new-onset T1D studies.
Background Rationale
There are currently no disease-modifying therapies available for use in T1D. As the global incidence and prevalence of T1D rises, there is a growing unmet medical need for new therapies that target the underlying disease process. Despite several recent successes, product development in T1D remains costly, lengthy, and high-risk for product developers. When also considering the relatively small target population (compared to other chronic autoimmune diseases like rheumatoid arthritis), many product developers have turned attention and resources towards other areas of unmet need. To ensure new products become available for patients at risk for, or currently living with T1D, the community must collaborate to improve the efficiency and likelihood of success of new product development in T1D.
Recognizing these challenges, C-Path joined in collaboration with Cardiff University, the University of Colorado, the University of Alberta, and JDRF in 2019 to launch the Trial Outcome Markers Initiative in T1D (TOMI-T1D). The overall goal of TOMI was to leverage the clinical expertise of leading academic and clinical researchers from around the globe, industry perspectives from key drug development partners, and C-Path’s regulatory knowledge and data collaboration experience to develop a large, aggregated database of new onset T1D trials. This database would be used to the develop and support regulatory endorsement of a novel drug development tool that could improve trial design in new-onset T1D trials and support additional analyses of high scientific and regulatory interest to advance the field.
The TOMI effort has made substantial progress since its inception, aggregating 24 clinical trial and observation studies, initiating the regulatory review process for a new-onset T1D Clinical Trial Simulation Platform, and producing important early scientific learnings through database analysis. TOMI-T1D has established a large stakeholder group, with regular meetings consisting of academic and industry stakeholders and data contributors.
The overall goal of the proposed research is to continue the work initiated through TOMI with added operational efficiency, by aligning TOMI-T1D and the T1DC. This funding would support the launch of a new T1DC workstream, focusing on improving product development for new-onset T1D and building upon the ongoing work of TOMI-T1D.
Description of Project
The Critical Path Institute (C-Path) proposes to continue and expand ongoing efforts to facilitate the development, regulatory approval, and dissemination of regulatory science solutions that inform medical product development in type 1 diabetes (T1D). C-Path's current collaborations with the T1D community include product developers, patient advocacy organizations, philanthropic organizations, clinical and academic researchers, and regulatory agencies. These groups work together in the pre-competitive space provided by C-Path to advance the development of medical products for T1D. By obtaining regulatory endorsement of the specific tools generated through these collaborations, medical product developers, researchers, and regulatory agencies are aligned on the appropriate use of the tool, and all have confidence to implement the tool in the development and review of new therapeutics. Tools and analyses developed or conducted by the consortium are made publicly available, ensuring the entire community benefits from this work.
In July 2022, the T1DC restructured the consortium to establish a new ‘hub and spoke’ model to be better positioned to identify and meet the most pressing needs identified by the community. The restructured consortium launched with the T1DC Core (‘hub’) and the T1D Prevention Workstream (the first ‘spoke’).
The current proposal would support the launch of a new T1DC workstream, the New Onset T1D Workstream, focusing on improving product development for new-onset T1D and building upon the ongoing work of TOMI-T1D. The overall goal of TOMI-T1D was to leverage the clinical expertise of leading academic and clinical researchers from around the globe, industry perspectives from key drug development partners, and C-Path’s regulatory knowledge and data collaboration experience to develop a large, aggregated database of new onset T1D trials. This database would be used to develop new regulatory science solutions and support regulatory endorsement of these solutions by the major regulatory Agencies (i.e., the US Food and Drug Administration [FDA] and the European Medicines Agency [EMA]). Specifically, TOMI-T1D is developing a novel new-onset T1D Clinical Trial Simulation Tool, pursuing the acceptability of C-peptide as a surrogate or reasonably likely surrogate endpoint, and exploring additional early-phase exploratory composite endpoints as of a novel drug development tools/solutions that could improve trial design in new-onset T1D trials. The aggregated TOMI-T1D database will also be used to and support additional analyses of high scientific and regulatory interest to advance the field. The TOMI-T1D effort has made substantial progress since its inception, aggregating 24 clinical trial and observation studies, initiating the regulatory review process for a new-onset T1D Clinical Trial Simulation Platform, and has begun to produce important early scientific learnings through database analysis. Analysis of the database will be based on high-priority research areas, identified through consistent and regular feedback from TOMI-T1D’s and T1DC’s stakeholder group, comprised of academic, clinical, industry, and regulator stakeholders.
Continuing the work of TOMI-T1D under the T1DC will allow for increased operational efficiency, and as an established public-private partnership with the FDA, will facilitate increased engagement and involvement from the US regulators.
Anticipated Outcome
The anticipated outcomes of this effort are as follows:
1) Establishment of the New Onset T1D Workstream, under the Type 1 Diabetes Consortium focused on new onset T1D
2) Expansion of the existing curated, standardized, and integrated patient-level database of longitudinal observational studies and clinical trials in T1D prevention by acquiring and aggregating additional studies of interest
3) Development of a new onset T1D clinical trial simulation tool
4) Achievement of regulatory endorsement of the new onset T1D clinical trial simulation tool through appropriate regulatory review pathways at FDA and EMA
5) Development and public release of a user-friendly graphical user interface to allow product developers and regulators to implement the tool into the design and review of new onset T1D clinical trials
6) Analysis and publication of endpoints or composite measures that could facilitate shorter early phase clinical studies
7) Analysis of aggregated database and appropriate regulatory engagement to advance the role of C-peptide as an endpoint or surrogate endpoint for new onset T1D studies.
Relevance to T1D
The overall goal of this work is to facilitate the development of new products for individuals currently living with T1D by leveraging the resources, data, and expertise of the entire T1D community through a pre-competitive public private partnership. This effort will apply the foundations of excellence in data science, quantitative modeling, and regulatory science of the Critical Path Institute to the T1D community and expand upon work already completed by TOMI-T1D.