PET Drug Development
1. Favorable PET Drug Development Considerations
Whether a drug is developed with commercial intent or not, PET or non-PET, the human administration of an unapproved drug requires the filing of an IND with FDA by the sponsor. More than any other type of drugs, the development of PET Drugs is facilitated by the fact that extremely low mass doses (mg or nM) are being administered to patients, typically raising few to no acute safety concerns. By default, PET products almost always fall under the microdosing regulatory framework[i]. This provides 2 immediate opportunities that the FDA considers underutilized by sponsors:
If the drug is FDA approved for another indication, its safety profile is already documented and it is possible to move to First-in-Human (FIH) sooner than usual. Specifically, it is possible to study the drug potential in vivo for reaching specific target(s) for a new indication through PET imaging studies conducted under a Radioactive Drug Research Committee (RDRC)[ii] oversight – instead of filing an IND and seeking FDA oversight. On behalf of FDA, an RDRC ensures that the sponsor is adhering to ethical and regulated standards of clinical conduct, so long as the scope of clinical research is not drug safety and efficacy, and is limited instead to study drug body distribution and elimination (ADME/PK scope). A successful RDRC outcome could lead to the opening of an IND for safety and efficacy studies towards NDA/BAL approval.
If the new PET drug (NCE) is from a chemical family with sufficient established knowledge to estimate patient safety risks, then the filing of an exploratory IND (eIND)[iii] is a faster route to FIH use, often involving little to no new animal safety data. However, the purpose of an eIND should be similar to the RDRC; once tissue/target specificity has been established, the eIND should be closed and a new IND opened for subsequent human trials (i.e. formal Phase 1-2).
Because radiopharmaceuticals often address life threatening disease states with very limited alternative medical modalities, PET drug may be prone to distribution under an Expanded Access program[iv] run under an IND (either a stand-alone IND or a protocol within an existing IND), as long as the prospective drug Indication under the Expanded Access is being pursued formally under an IND. Allowing use of an unapproved product outside of the clinical program can complicate the approval process of a new drug, however it may not carry the same level of risk for radiopharmaceuticals due to a generally favorable risk/benefit ratio to patients.
2. Early first in human (FIH) access
Developing upfront a granular formal target product profile (TPP) is one of the best ways to identify the minimum scientific package that will support FIH. It is also the best tool to track progress and articulate risk profile with regulatory agencies.
Since PET drugs involve microdosing[v], the scientific evidence provided by sponsors can be reduced and rely heavily on in vitro tissue affinity studies (supporting pharmacological classification and receptor specificity), as well as in vivo animal (typically rodent) imaging studies that provide core elements of drug distribution and target organ selectivity. When the chemical family is known (e.g. similar drugs approved), sponsors may consider the filing of an exploratory IND (eIND) with proper scientific justification of risk in order to move to FIH (“Phase 0”) using limited pre-clinical information.
The chemistry (CMC) requirements should be phase-appropriate and rely on scientific soundness and adequate physicochemical characterization instead of extensive validation[vi]. Product release will reflect the short shelf life, especially regarding microbiological testing[vii].
3. PET Drugs Clinical Development Standards
PET drugs are included in the broader guidance on contrast imaging agents[viii]. They require similar demonstration of safety and efficacy as conditions of approval by various regulatory agencies within the ICH territories. However, the clinical trials programs are facilitated by the fact that a PET drug efficacy is established based on imaging outcome, which tends to require fewer patients than therapeutic trials. In addition, the safety profile typically shows very low levels of drug related acute side effects. The FDA encourages sponsors of therapeutic drugs to discuss the timing and staging of any associated new “companion” PET drug in order to ensure the availability of both agents to patients.
[iii] https://www.fda.gov/files/Guidance-to-Industry-and-Reviewers---Exploratory-IND-Studies-%28PDF%29.pdf