Finding Biomarkers With Clinical Benefit And FDA Appeal For Neurodegenerative Diseases

By Life Science Leader Editorial Staff

A biomarker is an objective sign of a medical state that can be assessed precisely to provide patient data during clinical trials. According to the National Institutes of Health (NIH), biomarkers are “characteristics that are measured and evaluated as indicators of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”¹ Examples include everything from blood pressure to elaborate laboratory assessments. In the case of devastating neurodegenerative diseases like Alzheimer’s and amyotrophic lateral sclerosis (ALS), sponsors are striving to identify treatments for these indications as swiftly and effectively as possible to help restore or maintain cognitive function in patients. By identifying effective biomarkers that will be supported by the FDA, sponsors increase their chances of designing a successful trial protocol, gaining FDA approval, and delivering their drugs to patients.

The Obstacles Surrounding Biomarker Selection

Currently, there are very few biomarkers for neurodegenerative diseases that are truly validated and accepted by regulatory agencies. This is why securing the FDA’s buy-in for a biomarker early in development is critical. However, depending on the biomarker and its benefits to the patient, there may be associated difficulties. Consider the controversy surrounding aducanumab. Aducanumab is a recently approved Alzheimer’s drug that clears the plaque of amyloid deposits that have built up in the brain of people diagnosed with Alzheimer’s.² It has been theorized that this plaque buildup interferes with the brain function of Alzheimer’s patients, thus there has been a push to design and manufacture drugs to prevent or clear the buildup and, hopefully, improve cognitive function for patients. However, at present, there is no firm evidence to prove that clearing amyloid plaque deposits will reduce cognitive decline.²

Throughout its clinical trial, aducanumab demonstrated a significant reduction in amyloid deposit buildup, and ultimately, it received Accelerated Approval from the FDA to treat Alzheimer’s patients. The question was, did removing these amyloid deposits translate into clinical function and benefit for the patient? Many in the medical community believe this drug did not demonstrate enough clinical benefit for Accelerated Approval.² Ultimately, sponsors might have an effective biomarker that can be measured as such, but that impact must be translated into a benefit for the participant, and what translates as beneficial is variable across the industry. 

Selecting Biomarkers With The FDA In Mind

To use biomarkers effectively, their function in the trial must be well-defined. Overall, the FDA recognizes the significant role that biomarkers play in determining the effectiveness of therapeutics as well as their usage to marry clinical and non-clinical data.³ Biomarkers can lead to improved therapeutic understanding and safer experiences for patients. The FDA and NIH developed a resource, titled Biomarkers, Endpoints, and Other Tools, to provide guidance for sponsors on how to effectively improve the use of biomarkers.³ While some biomarkers are already validated by the FDA for drug development, a biomarker doesn’t have to be qualified to be used in a clinical trial. The biomarker data will be reviewed on a case-by-case basis based on a drug’s application and intended usage. To help ensure thoughtful biomarker usage, consider scheduling an early meeting with the regulatory division you will be working with to receive any biomarker-specific advice and context you might need for successful development.⁴ From there, continue to engage with regulatory authorities to keep biomarker usage aligned with their expectations.

Setting An Effective Biomarker Plan

Many of the drugs designated as “reasonably likely to yield a clinical benefit” have been granted Accelerated Approval with respect to biomarkers. This has led to significant debate within the industry. Biomarkers can be an effective mechanism for determining a drug’s viability if they are implemented via a collaborative effort to determine what is acceptable and most efficient, as well as demonstrative of clinical benefit to the patient.

For more information about designing clinical trial protocols, watch the recent Clinical Leader Live event Trial Protocol Design Do’s and Don’ts.

References:

1. Selleck, M. J., Senthil, M., & Wall, N. R. (2017). Making Meaningful Clinical Use of Biomarkers. Biomarker insights, 12, 1177271917715236. https://doi.org/10.1177/1177271917715236
2. Lang, K. (2023, January 11). Aducanumab debate: Expert views on Biogen’s alzheimer drug. Medical News Today. https://www.medicalnewstoday.com/articles/progress-and-controversy-in-alzheimers-research-aducanumabs-fda-approval
3. Commissioner, O. of the. (2022, September 6). Biomarkers. U.S. Food and Drug Administration. https://www.fda.gov/science-research/focus-areas-regulatory-science-report/focus-area-biomarkers
4. Center for Drug Evaluation and Research. (2021, July 7). About biomarkers and qualification. U.S. Food and Drug Administration. https://www.fda.gov/drugs/biomarker-qualification-program/about-biomarkers-and-qualification