Use of 55 PET radiotracers under approval of a Radioactive Drug Research Committee (RDRC)

In the US, EU and elsewhere, basic clinical research studies with positron emission tomography (PET) radiotracers that are generally recognized as safe and effective (GRASE) can often be conducted under institutional approval. For example, in the United States, such research is conducted under the oversight of a Radioactive Drug Research Committee (RDRC) as long as certain requirements are met. Firstly, the research must be for basic science and cannot be intended for immediate therapeutic or diagnostic purposes, or to determine the safety and effectiveness of the PET radiotracer. Secondly, the PET radiotracer must be generally recognized as safe and effective. Specifically, the mass dose to be administered must not cause any clinically detectable pharmacological effect in humans, and the radiation dose to be administered must be the smallest dose practical to perform the study and not exceed regulatory dose limits within a 1-year period. In our experience, the main barrier to using a PET radiotracer under RDRC approval is accessing the required information about mass and radioactive dosing.

Results

The University of Michigan (UM) has a long history of using PET radiotracers in clinical research studies. Herein we provide dosing information for 55 radiotracers that will enable other PET Centers to use them under the approval of their own RDRC committees.

Conclusions

The data provided herein will streamline future RDRC approval, and facilitate further basic science investigation of 55 PET radiotracers that target functionally relevant biomarkers in high impact disease states.

Background

Human use of positron emission tomography (PET) radiotracers in a given country (or member states in the case of the European Union) is required to be conducted under appropriate governmental oversight (Schwarz and Decristoforo 2019; Schwarz et al. 2019). In this paper, we focus upon clinical use of PET radiotracers in the United States, which is regulated by the Food and Drug Administration (FDA) (VanBrocklin 2008; Harapanhalli 2010; Schwarz et al. 2014). However, we expect the regulatory concepts described herein to also hold true in other locations, particularly in light of recent efforts to harmonize PET regulations around the world (Schwarz et al. 2019).

In the US, clinical use of PET radiotracers is conducted under the umbrella of an FDA-approved New Drug Application (NDA) or, in the case of generic PET radiotracers, an Abbreviated New Drug Application (ANDA). Human research is also conducted under governance of the FDA, via three major pathways: i) the Investigational New Drug application (IND), ii) an exploratory IND (eIND), or iii) under the oversight of a Radioactive Drug Research Committee (RDRC) (Suleiman et al. 2006; FDA Guidance for Industry and Researchers: The Radioactive Drug Research Committee: Human Research without an Investigational New Drug Application 2010; Carpenter Jr et al. 2009; Mosessian et al. 2014). The necessary path to approval is dictated by parameters outlined below, as well as the stated purpose of the research in question (Fig. 1).

figure 1

While the IND and eIND represent the most common pathways to FDA approval for first-in-man studies, some of the requirements (e.g., costly toxicology in two species for an IND) represent significant hurdles to overcome in the application process. One notable solution, as described by Mosessian et al., is to divide labor and preparation for different components of the application between different cores and facilities at a given institution (Mosessian et al. 2014). In contrast, conducting human PET research under RDRC oversight represents a relatively efficient and cost effective path to FDA approval. The concept of the RDRC was introduced in 1975, and committees are charged by the FDA with the responsibility of overseeing PET research at the institutional level. RDRC committees are comprised of at least 5 members and are required to include people with the following expertise:

In order for a given PET imaging study to be conducted under RDRC approval, the proposed research must meet the following criteria (as described comprehensively in 21 CFR 361.1):