Information on FDA review of geroscience-related IND applications
There has been increasing research attention to the concept of geroscience, which focuses on the role of aging mechanisms in age-related diseases. A central geroscience premise is that drugs or other interventions targeted at such mechanisms have the potential to prevent or treat multiple aging-related conditions. Many investigators have expressed interest in Food and Drug Administration (FDA) policies and practices that may relate to geroscience-related drug development.
Development or repurposing of such drugs will generally require FDA review of Investigational New Drug (IND) applications. However, certain types of studies may not require IND applications, as described in FDA’s 2013 Guidance: Investigational New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND.
FDA provides a wide range of public information and opportunities for discussion with sponsors of geroscience-related drug development programs. In early stages of planning and development of potential drug development programs, sponsors’ consideration of pertinent FDA Guidances and other public information may be useful. See Search for FDA Guidance Documents.
Sponsors may discuss their drug development programs with FDA staff through a variety of Formal Meetings. Pre-IND meetings can serve the purpose of discussing broad outlines of the IND development.
Critical Path Innovation Meetings provide another avenue through which sponsors can have a non-binding scientific dialog with FDA on the broad outlines and potential strategies of their drug development programs.
Prior to meeting(s) with FDA, applicants/sponsors should develop a detailed document describing their development program as much as possible, including issues such as safe dosing regimen, proof of concept, intended population, and potential indication. This document should be submitted to FDA for review prior to the meeting. Sponsors may wish to submit a Target Product Profile which describes the goals of their drug development program and specific studies intended to support their potential labeling concepts, to FDA staff.
Development or repurposing of geroscience-related drugs may raise novel issues, including:
Defining indication and context of use
Since aging mechanisms that may contribute to disease are present in the general population, a drug favorably affecting such mechanisms might conceivably be proposed for very widespread use. However, heterogeneity within the population may produce substantial individual differences in the drug’s balance of risks versus benefits. The breadth and depth of evidence for safety and efficacy across population and disease subgroups that would be required to support a claim for the drug’s proposed indication(s) and context of use will be an important consideration in geroscience-related drug development programs.
Use of multiple, composite, or global outcomes as a basis for claims
Given the premise of aging mechanisms’ effects on multiple outcomes, a sponsor might choose to propose a claim based on effects on multiple individual outcomes, a composite incorporating multiple individual outcomes, or a global outcome (e.g., all-cause mortality or physical disability) using a measure that is influenced by multiple conditions. For more information on pertinent FDA public information related to challenges that need to be addressed in regard to use of multiple outcomes, see Multiple Endpoints in Clinical Trials Guidance for Industry.
Sponsors considering a claim of effects on multiple outcomes, a composite outcome, or a global outcome for a drug are encouraged to discuss with FDA the evidentiary criteria that would be applied to assess such a proposed claim, and the design of the clinical trial(s) needed to provide such evidence. In addition, if individual outcomes that the sponsor wishes to include in such a claim span the scope of more than one division or office within the Center for Drug Evaluation and Research, discussions at preliminary meetings (e.g., the pre-IND meeting) should include designation of the appropriate division(s)/office(s) that will review the application or the review strategy for the application.
Roles of biomarkers and surrogate endpoints
Aging mechanisms that operate over the lifespan may produce their clinical effects only after decades. Hence, a very long duration may be required to assess clinical benefits and risks of some interventions that modulate such mechanisms. This has generated interest in developing and validating biomarkers that could be measured after shorter intervention periods and used as surrogate endpoints to predict future clinical effects.
FDA has accepted effects on a limited number of surrogate endpoints as a basis for claims, based on specific criteria. These criteria and related information are presented in FDA’s Surrogate Endpoint Resources for Drug and Biologic Development.
FDA will consider requests for accelerated approval based on evidence that the proposed surrogate or intermediate clinical endpoint is reasonably likely to predict clinical benefit. Policies regarding such requests, and requirements for evidence and confirmatory studies are described in FDA’s information on Accelerated Approval. FDA also recognizes the value of biomarkers as drug development tools to assess additional considerations besides prediction of clinical outcomes. These include indicators of individuals’ risk or prognosis for proposed clinical endpoints, measures of target engagement and biologic responses to the drug under consideration, and indicators of safety issues. Such biomarkers may have valuable roles in geroscience-related drug development and individual applications. FDA has a process for evaluating and qualifying biomarkers and their proposed contexts of use. This process and related information is described in FDA’s CDER Biomarker Qualification Program.
Regarding such considerations for geroscience-related trials, it is important to stress the benefits of discussions with FDA early in drug development. Although FDA public documents provide valuable general information, sponsors’ dialog with FDA and understanding of FDA perspectives on the specific features of their potential drug development program are likely to be crucial for preparing a well-developed plan that addresses FDA’s regulatory criteria and concerns.