FDA Announces Availability of a Public Docket, “Framework for Assessment of Drug-Drug Interactions for Therapeutic Proteins”

On May 10, 2018, the U.S. Food and Drug Administration (FDA) announced the availability of a public docket entitled “Framework for Assessment of Drug-Drug Interactions for Therapeutic Proteins” to assist with its development of a policy/guidance document on the assessment of drug-drug interactions (DDIs) for therapeutic proteins (TPs). Concurrent use of more than one prescription drug is common. Taking more than one drug at a time can result in drug-drug interactions (DDIs) which can result in toxicities or loss of efficacy. It is impractical to evaluate the impact of every possible drug combination. Therefore, FDA follows a systematic risk-based approach for DDI assessment.

Two draft guidance documents intended to assist drug developers in the planning and evaluation of DDI potential during drug development were published in October 2017 (In vitro and In vivo DDI) to replace the 2012 draft guidance entitled “Drug Interaction Studies—Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations”. These guidance documents focus on enzyme and transporter based DDIs. However, they did not include discussion on TPs. 

The 2012 guidance recommended DDI assessment for TPs in three scenarios: (1) for cytokine or cytokine modulators; (2) for a known or suspected mechanism for DDI not related to effects on CYP enzymes or transporters; or (3) when a TP is used in combination with another drug. The agency is currently revisiting the framework outlined in the draft 2012 DDI guidance to offer timely and actionable information pertaining to DDIs for TPs and is seeking public input to assist in updating or creating a new framework.

Interested persons are invited to provide detailed information and comments on the approach to DDI assessment for TPs. FDA is particularly interested in responses to the following overarching questions and will consider all information and comments submitted: 

1. In what scenarios/circumstances and for which classes of therapeutic proteins should DDI assessment be performed? Please provide rationale for your suggestions including available data and scientific principles to inform the considerations.
2. For circumstances when DDI assessments are necessary:

• What types of assessments can be useful (e.g., in vitro, dedicated clinical studies, population pharmacokinetics (PK), physiologically-based PK modeling (PBPK))? Please discuss challenges and limitations with each type of assessment and, as necessary, present discussions by classes of TP.
• What are the study design considerations (e.g., population, analytes) for the types of assessments discussed in bullet 2a above? Please describe the rationale for any design considerations proposed.