Narrow Therapeutic Index Drugs: FDA Experience, Views, and Operations

The U.S. Food and Drug Administration (FDA) has defined narrow therapeutic index (NTI) drugs as “those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life‐threatening or result in persistent or significant disability or incapacity.” FDA has undertaken efforts to develop NTI assessment criteria and enhance public confidence in generic NTI drugs through public workshops, research, and post‐marketing surveillance. In 2015, FDA formed the NTI Drug Working Group to develop a consistent approach to identify NTI drugs and resolve NTI‐related scientific and regulatory issues in a transparent and collaborative manner. One key objective of the NTI Drug Working Group is to evaluate potential NTI drugs based on five general characteristics of NTI drugs as highlighted in the case example for theophylline drug products. As of January 5, 2024, there are 33 drug products, with 14 distinct active ingredients, specified as NTI drugs in their respective product‐specific guidances (PSGs) for generic drug development. Future collaborative efforts with other agencies to harmonize the terms and definitions for NTI drugs may help enhance clarity and consistency during the drug development and the regulatory review process.