A Study of Subgroup Analysis and Precision Medicine in Recent NDA/BLA Submissions

Authors:: Poster Author(s)

Tang, Linli, FDA/CDER (Student); McCabe, Megan, FDA/CDER (Student); Collins, Sylva, FDA/CDER (Mentor); Nie, Lei, FDA/CDER (Mentor)

Center:: Contributing Office

Center for Drug Evaluation and Research

Abstract

Poster Abstract

Objectives

In clinical research, the safety and efficacy of an experimental treatment is usually assessed by the average treatment effect in the entire patient population. However, in large clinical trials, actual safety and efficacy might vary across patient subpopulations due to differences in some patient characteristics. Since the 1980’s, FDA has encouraged and discussed subgroup analyses in various guidance documents. As a result, in the past decades, the drug development process has been improved by the prospect of striking a delicate balance between assessing both average treatment effect and individual treatment effect. The primary objective of this project was to summarize the usages and provide examples of subgroup analysis and precision medicine in recent years to assess the impact of the regulation of subgroup analysis and precision medicine on New Drug Applications (NDA) and Biologics License Applications (BLA). Additionally, this study highlights key issues related to subgroup analyses using examples of improper or misleading subgroup analysis and discusses considerations for including subgroup analyses and precision medicine concepts in the drug development process.

Methods

For each topic of interest within the field of subgroup analysis and precision medicine, we firstly used Mercado Search 360 to conduct two searches: (1) search of sponsor submissions and (2) search of FDA reviews and communications. Search results were narrowed down to NDAs and BLAs with FDA received date falling between May 31, 2011 to May 31, 2021, and the sponsor submissions were restricted to reports of efficacy and safety from controlled clinical studies. Filtering of search results was conducted using filters in Mercado Search 360 and SAS. In addition, we dealt with multiple search results for a given NDA or BLA by prioritizing review of the clinical study report or protocol, which are the most relevant documents. Search results were reviewed to answer some important questions about each application, such as the motivation for the subgroup analyses, how subgroup analyses were performed, and whether any decisions were made based on subgroup analysis results.

Results

Many aspects of precision medicine have been embedded in drug development, including frequentist and Bayesian subgroup analysis, enrichment designs, biomarker, subgroup identification, and tissue-agnostic trials. Specifically, subgroup analyses are common practice and some of them have impacted regulatory decisions as they revealed efficacy and safety concerns in some subpopulations. Biomarker research is greatly facilitating precision medicine. Enrichment designs have been used in various pivotal trials conducted to provide substantial evidence of safety and efficacy. Since the first tissue agnostic approval was made in May 2017, more tissue agnostic trials have been proposed and conducted. Subgroup identification has been utilized in several NDA/BLA submissions to identify subpopulations that will benefit more from treatment. Improper subgroup analysis has been conducted and some subgroup analyses could be misreported and misinterpreted.

Conclusions

Drug development has been gradually enhanced by incorporating precision medicine elements into clinical trials. Subgroup analysis and biomarker research have emerged as important drug development tools. There have been instances in which subgroup analysis results may have impacted regulatory decisions. Subgroup identification and tissue-agnostic trials may further facilitate the development of precision medicine.