The 06 August 2012 announcement by researchers from Boston’s Brigham and Women’s Hospital reporting the identification of a blood biomarker that could lead to earlier diagnoses and perhaps an actual treatment for amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, was of great interest to me. First, my brother-in-law, at the peak of his very active life (58 years old), was diagnosed with ALS. Twelve months later he was confined to a wheelchair and eight months after that he died because his diaphragm no longer functioned. Second, I had always envisioned biomarkers as a valuable tool for clinical research, offering significant improvement over observational endpoints necessary for many disease indications, and I wondered how successful biomarker research had become.
Not all news for biomarkers has been positive. In July 2011, the New York Times ran a series on biomarkers following a scandal at Duke University. Because of inadequate research, the entire science of biomarkers was called into question. It is extremely difficult to find patterns in genes, molecules, or proteins with significant meaning, independently confirm them, and then use them in a significant way. In addition because the FDA does not require it and there is not as great a reward for companies for tests based on biomarkers as there are for new drugs, there is still not a great emphasis on finding new biomarkers. However, most agree that when drugs are matched with specific patient populations using clinical biomarkers (e.g., genetic variations) that are predictive of drug response, the therapeutic value to the patient is significantly increased. This is of great value to companies facing ever increasing costs associated with drug development because the appropriate population of patients can be identified that will get the most benefit from the drug. Oncology researchers have been leaders in the field and identified both genetic and proteomic biomarkers used in drug development to predict patient’s responses to a treatment.
The search for biomarkers is generally different for each biomarker. In the case of the ALS biomarker, mice genetically predisposed to ALS showed that changes to the immune system led to damage in the brain of the mice. Once they confirmed that identical changes occurred in patients with ALS, they had their biomarker – activated monocytes. The FDA has long been interested in fostering the identification and development of biomarkers. A biomarker qualification program was established to support the work of CBER, CDER, CDRH and National Center for Toxicological Research in developing biomarkers with external researchers. The Interdisciplinary Pharmacogenomic Review Group program provided a formal process to guide the development and evaluation of biomarkers for use in the regulatory process.
Goals of the biomarker qualification program included:
- Provide a framework for scientific development and regulatory acceptance of biomarkers for use in drug development
- Facilitate integration of qualified biomarkers in the regulatory review process
- Encourage the identification of new and emerging biomarkers for evaluation and utilization in regulatory decision-making
- Support outreach to relevant external stakeholders to foster biomarker development
The December 2011 Draft Guidance for Industry Use of Histology in Biomarker Qualification Studies defines a biological marker or biomarker as a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or biological responses to a therapeutic intervention. A biomarker can include physiologic, pathologic, or anatomic characteristics or measurements that relate to some aspect of a normal or abnormal biologic function. Biomarkers include measurements that suggest the etiology of, the susceptibility to, the prognosis of, or the progression of disease; measurements related to the mechanism of response to treatments; and actual clinical responses to therapeutic interventions. In the 2010 Evaluation of Biomarkers and Surrogate Endpoints in Chronic Diseases from the Institute of Medicine (IOM) of the National Academies, the IOM was asked by the FDA to review the evaluation process for biomarkers and make recommendations. Highlights of their recommendations were that for biomarkers with regulatory impact, the FDA should convene expert panels; initial evaluation of analytical validation and qualification should be separate from a particular context of use; and the expert panels should reevaluate analytical validation, qualification, and utilization on a continual and case-by-case basis. They further recommended that the FDA should use the same degree of scientific rigor for evaluation of biomarkers across regulatory areas (i.e., drugs, medical devices, biologics, or foods and dietary supplements) irrespective of their proposed use.
One of the biggest challenges facing researchers and clinicians in the field of biomarkers is developing a better understandings of the pathophysiology of disease. With a better understanding, the failure of novel therapies could be reduced significantly by discovering new biomarkers. A 2007 article in the AAPS Journal estimated the total number of biomarkers of interest at about 1,133,000, yet there are relatively few FDA-approved drugs with pharmacogenomic information in their labels. The clinical need is ever increasing to identify potential drug targets and biomarkers in disease pathways.
- FDASIA, Part 1: The “UFAs” (ask-cato.com)
- FDASIA, Part 2: Pediatric Drugs and Devices and Medical Device Regulatory Improvements (ask-cato.com)
- FDASIA, Part 3: Generating Antibiotic Incentives Now (GAIN) and Drug Approval and Patient Access Changes (ask-cato.com)
- FDASIA, Part 4: Drug Supply Chain, Drug Shortages, and Other Provisions (ask-cato.com)
- New Provisions in the FDA Safety and Innovation Act (aka PDUFA V) (ask-cato.com)