FDA Draft Guidance on Drug-Drug Interaction Assessment for Therapeutic Proteins

On August 10, 2020, FDA issued draft guidance on Drug-Drug Interaction Assessment for Therapeutic Proteins.  The draft provides a systematic, risk-based approach to help sponsors of investigational new drug applications and applicants of biologic license applications determine the need for drug-drug interaction (DDI) studies for a therapeutic protein.  FDA explains that even though the guidance is directed to therapeutic proteins, general concepts could be applicable to other biological products, including cellular and gene therapies. 

When evaluating the potential for DDIs, the guidance recommends sponsors consider the mechanisms for potential DDIs between therapeutic proteins or between a therapeutic protein and small molecules.  The draft then provides several examples of the types of situations in which an assessment of the DDI potential of a therapeutic protein may be warranted.  For example, the guidance notes that therapeutic proteins that are proinflammatory cytokines (e.g., peginterferon) can cause downregulation of cytochrome P450 (CYP) enzymes, increasing exposure levels to drugs that pass through this metabolic pathway.  Conversely, therapeutic proteins that reduce cytokine levels can boost CYP expression and reduce exposure for drugs that are CYP substrates.  In either case, the draft recommends that sponsors should evaluate the need for DDI studies to further inform the labeling for such therapeutic proteins, which should include a description of study results and any clinical actions. 

The draft notes that if the sponsor believes the potential for clinically significant DDI is low, a sponsor may not need to include potential DDIs in labeling language as long as they can provide an adequate justification to FDA.  Alternatively, the sponsor may conduct a DDI study in the relevant indicated population to further inform labeling. 

The draft also discusses antibody-drug conjugates and instructs how to evaluate the systemic exposure of the small molecule drug component of the conjugate. 

The guidance then highlights various types of DDI assessments and includes study design considerations for in vitro and animal studies, clinical studies, population pharmacokinetic modeling (nested DDI studies), and physiologically based pharmacokinetic modeling, recommending a systematic, science-driven approach to evaluating the DDI potential of therapeutic proteins. 

Lastly, the draft includes labeling recommendations for DDIs and directs sponsors to previously issued FDA guidance. 

Readers are encouraged to read the draft guidance, also available on FDA’s website.