There is considerable public interest in using biomarkers (measurements of substances present in the body or physical health parameters such as blood pressure or changes in pupil size) as a way to diagnose disease and evaluate medical product safety in clinical trials. This interest has only increased with the development of improved tools and techniques for genetic screening, and there are a number of papers published each year describing new tests as possible biomarkers. However, there has been less progress in qualifying new biomarkers for use in the clinic. During the qualification process, data is collected and used to establish the actual value of the biomarker as a guide for decisions about patient treatment or health. A qualified biomarker has been shown to produce specific and actionable information about the body system it is measuring. This means physicians and companies developing medical products may use the qualified biomarker with confidence to make treatment decisions and clinical trial measurements. Biomarker measurements may be used to assess patient safety or efficacy as well as determine how well patients will respond to particular treatments.

The FDA recognized the gap in moving new biomarkers into clinical use and set up the Biomarker Qualification Program as a way to facilitate the development process. There are 3 stages of submission under the program:

1. The Letter of Intent – indicating a group’s intent to develop a biomarker
2. The Qualification Plan – the plan for qualification of the biomarker
3. The Full Qualification Package – the complete submission package for qualification approval

For each submission stage, the agency will publicly post a set of information about the submission, including its formal decision on the stage, at its submissions website.

The Kidney Safety Biomarker package offers a good example of how the program works. The purpose of the biomarker is improving the assessment of potential injury to the kidney during Phase 1 clinical trials (where an investigational new drug is dosed in normal healthy volunteers to determine how it behaves in a human body). The proposed biomarker is a weighted composite measure of 6 separate proteins measured in urine samples. It’s called the PFC index after the 2 groups who proposed the biomarker (PSTC/FNIH; see the package for the expanded version of their complex name). There are currently no measures of small changes to the kidney’s renal tubule system; changes in the existing measurements (creatinine clearance, BUN, and urinary protein) are not sensitive to small changes. The submission has shown that increases in the level of 6 separate biological substances are correlated with subtle kidney damage detectable in preclinical pathology studies and could offer an early signal of kidney damage in humans. By using an analytical method with the appropriate robustness, sensitivity, and specificity, drug may also find the individual protein measures add value in assessing differences between dosing groups in a clinical trial.

The qualification process takes time (the Kidney Biomarker submission was made in August, 2015, and was approved in July, 2018) and the approval may be for limited use (the Kidney Biomarker review document contains cautions about using the biomarker package beyond phase 1 trials and with test methods that have insufficient lower limits of detection, among other caveats). This work is a process, however; the same group received approval to use these same 6 measurements for preclinical drug safety evaluations in 2009, and I anticipate they will continue to expand the range of qualified uses in the future.

Text Copyright © 2018 Katrina Rogers