Study Population Recommendations in Product-Specific Guidances for In Vivo Bioequivalence Studies of Kinase Inhibitors

Authors:: Poster Author(s)

Cheng, Yijie, FDA/CDER (Student); Yang, Wen Cheng, FDA/CDER (Mentor); Ren, Ping, FDA/CDER; Chan, Theresa, FDA/CDER; Shon, Jihong, FDA/CDER; Gong, Xiajing, FDA/CDER; Boyce, Heather, FDA/CDER; Frost, Mitchell, FDA/CDER; Kim, Myong-Jin, FDA/CDER; Zhang, Yi, FDA/CDER

Center:: Contributing Office

Center for Drug Evaluation and Research

Abstract

Poster Abstract

Background

Kinase Inhibitors (KIs) are a class of small molecules targeting on the cell proliferation signaling cascade for the treatment of solid tumors and blood cancers. Since the Agency's approval of the first KI, imatinib mesylate capsules, in 2001, 64 KI drugs in immediate release dosage forms have been approved. Subsequently, product-specific guidances (PSGs) for 46 KI drugs have been published to facilitate the generic drug development. In general, bioequivalence (BE) studies are recommended to be conducted in general population or healthy subjects but a few PSGs recommend BE studies in patients with indicated diseases. One of the major challenges in developing PSGs for these KI drugs is to recommend appropriate study population for BE studies to avoid potential safety risk in study subjects. This involves comprehensive assessment of adverse events and potential safety concerns caused by KI drugs.

Objectives

By systemically collecting and summarizing the rationale of study population recommendations in BE studies on KI drugs, this research project is intended to explore the index of alert elements on the selection of patients as study population for BE studies during PSG development for KI drugs.

Methods

Among the PSGs published for 46 KI drugs, we studied first 20 KI drugs [selected based on the alphabetical order of the drug substance name] by collecting information from PSG reviews, clinical safety consult responses, and the reference listed drug (RLD) labeling. First, we classified these KI drugs based on their mechanisms of action. Second, we extracted the adverse events (such as cytotoxicity and carcinogenicity) among each classes of KI drugs. Third, we summarized the rationale for the selection of patients as the recommended study population.

Preliminary Results

Among them, 15 drugs are tyrosine kinase inhibitors, and five drugs are serine/threonine kinase inhibitors. The PSGs recommend general population as the study population for 17 KI drugs; the PSGs recommends patients as the study population for the remaining three KI drugs. The PSGs for eight out of 17 KI drugs recommend general population containing additional exclusion conditions that include subjects with history of serious retinopathy, renal dysfunction, hepatic dysfunction, uncontrolled hypertension, uncontrolled dyslipidemia, and at risk of QT prolongation or Torsades de pointes. Based upon three KI drugs in which patients are recommended for BE studies, we found that certain significant adverse events such as QT prolongation risk, arrythmia, gastrointestinal perforation, and cytotoxic agents with carcinogenic potentials have led to recommend patients as the appropriate study subjects.

Conclusion

Based upon the limited preliminary data, the recommendation of patients as the appropriate study population mainly depends on the severity and tolerance of serious adverse events caused by the administration of KI drugs in order to prevent potential health risk to study subjects.