FDA finalizes drug-drug interaction guidance for therapeutic proteins
The US Food and Drug Administration (FDA) on Friday issued a final guidance to assist sponsors in determining whether to conduct drug-drug interaction studies for therapeutic proteins for investigational new drug applications (INDs) and biologics license applications (BLAs).The guidance, which was jointly issued by the Center for Drug Evaluation and Resarch (CDER) and the Center for Biologics Evaluation and Research (CBER), contains minor revisions from an earlier draft issued in August 2020. (RELATED: FDA guides drug-drug interaction studies for therapeutic proteins, Regulatory Focus 10 August 2020).
The agency announced that “with the continued market growth and increased clinical use of therapeutic proteins, it is important to understand the nature of and the potential for drug-drug interactions (DDIs) with these products.”
Therapeutic proteins include purified monoclonal antibodies, cytokines and enzymes. FDA notes vaccines, allergenic products and cellular and gene therapy products are outside the scope of the guidance, though many of the general principles can be applied to these products.
The finalized version deletes a section on DDI studies for anti-body drug conjugates (ADC); instead FDA refers sponsors to a February 2022 draft guidance on clinical pharmacology considerations for ADCs, where this information is addressed. (RELATED: FDA issues clinical pharmacology draft guidance for antibody-drug conjugates, Regulatory Focus 8 February 2022).
In their comments, the Biotechnology Innovation Organization (BIO) and Pfizer had requested more information on ADC DDI studies.
The final version also clarifies that review divisions should be consulted if sponsors determine that the DDI potential of a therapeutic protein is low and provide a justification for not conducting these studies.
The revision includes a new section recommending physiologically based (PBPK) modeling studies in evaluating the DDI potential of a therapeutic protein. Such modeling “has a potential role in understanding the underlying mechanism of a DDI.” Sponsors were advised to consult its 2018 guidance on PBPK modeling for more information. (RELATED: Updates: FDA Finalizes Guidance on Physiologically Based Pharmacokinetic Analyses, Regulatory Focus, 4 September 2018).
Cases where DDIs are necessary
The guidance highlights cases in which assessing DDIs are necessary for certain therapeutic proteins, such as proinflammatory cytokines, including peginterferon. The guidance states that peginterferon can “downregulate the expression of cytochrome P450 (CYP) enzymes (e.g., blinatumab), thereby decreasing the metabolism of drugs that are CYP substrates and increasing their exposure levels.”
Sponsors should conduct DDIs for therapeutic proteins that are not considered proinflammatory cytokines, such as therapeutic proteins that affect human physiological processes such as glucagon-like peptide-1 (GLP-1) receptor agonists. These include dulaglutide and albiglutide, which cause gastric emptying and “change the pharmacokinetic profiles of co-administered drugs.”
The guidance also covers the different types of DDI assessments, such as in vitro and animal studies, dedicated clinical studies, population pharmacokinetic (PK) modeling or nested DDI studies and other modeling approaches such as physiologically based PK (PBPK) modeling studies.
Industry largely expressed support of the draft guidance. In its comments, BIO said that “the opportunity for sponsors to consider the specifics of their therapeutic proteins in the context of specific indications and concomitant medications and propose a fit-for-purpose development strategy in consultation with the Agency is appreciated. In addition, the recognition of the potential contribution and value of model-based analyses, such as PBPK modeling, affords additional tools to interrogate the potential for DDIs and make informed decisions or scientific justifications.”
Merck said that “this is an important guidance, which describes FDA’s thinking and the scientific evidence for/around testing and labeling for drug-drug interactions. In general, we concur with the guidance.”
Pfizer also backed the guidance during the consultation period. “We commend the Agency for its timely and helpful guidance for sponsors to assess drug-drug interactions for therapeutic proteins, and we appreciate the opportunity to comment on this important resource,” the company wrote.
Final guidance, Notice
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