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  1. News & Events for Human Drugs

From our perspective: Clinical biomarker qualification

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Shashi Amur, Ph.D., Scientific Coordinator for CDER’s Biomarker Qualification Program shares her perspective on CDER’s first clinical biomarker qualification, and the need for more high-quality drug development tools.

Shashi Amur

Biomarkers in drug development

Let me begin with the definition of a biomarker: a biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or biological responses to a therapeutic intervention. An example that is familiar to many people is the use of blood glucose levels to measure the effectiveness of a diabetes medication. In this case, glucose is the biomarker.

Biomarkers can be employed in many different aspects of drug discovery and development and also in the health care setting. Biomarker research can increase our understanding of the molecular underpinnings of a disease process, and this in turn can result in discovery of novel drug targets. A greater understanding of the disease process could also lead to biomarker-based enrichment strategies that enroll patients more likely to respond an investigational treatment in clinical trials. For example, human epidermal growth factor receptor 2 (HER2) is overexpressed in a subset of breast cancer patients who have a poor prognosis. This molecule has been used as a biomarker to identify patients who overexpress HER2 and thus are more likely to respond to monoclonal antibody treatments that block the HER2 protein.

In addition to influencing clinical trial design, biomarkers are also used in drug development for a variety of purposes including monitoring drug safety in preclinical or clinical studies, and identifying the optimal dose of a therapeutic. Clinical biomarkers are also useful in health care practice for the diagnosis and monitoring of a disease, or for identifying patients at risk for a serious adverse event or those who may be more likely to benefit from a drug treatment.

Biomarker qualification

There are multiple pathways for biomarker acceptance and integration into drug development. Traditionally, biomarker acceptance has been achieved through submission of biomarker data in Investigational New Drug, New Drug or Biologics License applications. The challenge with this approach is that the supporting biomarker data is retained with the regulatory submission. To make drug development tools publicly available and subsequently expedite drug development and regulatory review, CDER established qualification pathways for biomarkers, clinical outcome assessments and animal models under the Animal Rule, as part of FDA’s Critical Path Initiative.

Qualification is a conclusion that within the stated context of use, a biomarker can be relied upon to have a specific interpretation and application in drug development and regulatory review. Once qualified, the biomarker can be used for the specific context of use in regulatory submissions without having to reconsider and reconfirm its suitability. From FDA’s perspective, qualification eliminates the need for repeated evaluations of similar supporting data.

CDER’s Biomarker Qualification Program

There are three stages in the biomarker qualification process: initiation, consultation and advice, and review. Following initiation, a biomarker qualification review team is formed of reviewers with the appropriate expertise from various FDA offices. The team provides advice throughout biomarker development by reviewing submissions and providing feedback to the submitters. In the final stage, the team reviews the full qualification package and develops qualification recommendations. Qualification recommendations for the biomarker are published as draft guidance in the Federal Register.

To date, the Biomarker Qualification Program (BQP) has received 23 biomarker submissions; two biomarkers in the review stage and 21 in various stages of consultation and advice. Previously, CDER qualified three sets of nonclinical safety biomarkers; two sets for drug-induced kidney toxicity and one set of for drug-induced cardiac toxicity. Recently, we qualified the first clinical biomarker for use in drug development.

CDER’s first clinical biomarker qualification

Galactomannan is the first clinical biomarker that has been qualified through our program. The Mycoses Study group, a partnership with many academic and industry members, developed the galactomannan biomarker for use in studies of invasive aspergillosis (IA) and submitted it to our BQP for review and qualification.

Aspergillus is a type of fungus that commonly affects the lungs. In patients with a weakened immune system, the infection can be invasive, spreading beyond the lungs, and become life-threatening. Galactomannan is a molecule found in the cell walls of the organism, and is released in the course of fungal growth. As a clinical biomarker, galactomannan is qualified to be the sole criterion for classifying patients with probable IA.

The context of use for this biomarker is the identification of a subset of patients with probable IA in patients who have hematologic malignancies or were recipients of hematopoietic stem cell transplants and also have clinical and radiologic features consistent with invasive fungal infection. This context of use may be expanded to additional patient populations if we receive follow-up submissions that demonstrate the usefulness of galactomannan in these groups.

Potential impact of the galactomannan qualification

Patients with IA were previously diagnosed based on microbiology cultures alone or together with histopathologic, microscopic, or radiologic test results. All of these tests, alone or in combination, have sensitivity or specificity issues, and may take a long time to produce results. Due to the high morbidity and mortality of this disease and the challenges of earlier diagnostic methods, it was often too late to enroll patients with IA in a clinical trial.

Measurement of galactomannan is more sensitive than other methods currently in use, and as noted in our qualification draft guidance, it can replace all other diagnostic criteria used to select the specified patient subpopulation for these clinical trials. It is hoped that this qualification will help streamline the identification of patients with probable IA for enrollment in clinical trials and improve the development process for IA drugs.

The horizon for CDER’s BQP

Many stakeholders share the hope that increased availability of qualified biomarkers will facilitate innovation in drug development and view biomarker development and qualification as a collaborative undertaking necessitating input from experts across the research and development landscape. We are reaching out to a wide array of individuals with scientific, clinical and toxicological expertise to identify biomarkers that are needed to improve drug development.

In 2013, we convened a workshop with Howard Hughes Medical Institute to discuss potential use cases for biomarkers. This year, a meeting hosted by the Engelberg Center for Health Care Reform and convened by the Brookings Institution and FDA was held to help advance the use of biomarkers in drug and biologic product development. Next year, another workshop planned by the University of Maryland’s Center of Excellence in Regulatory Science and Innovation (M-CERSI), will discuss evidentiary considerations for safety biomarkers and for patient selection biomarkers.

The BQP will continue to work with our colleagues in academia, industry and other government and regulatory agencies to develop evidentiary standards and facilitate biomarker development and qualification.


Dr. Amur has worked at FDA for nearly 10 years, first as a Senior Genomics reviewer in the Office of Clinical Pharmacology and then as the Biomarker Qualification Scientific Coordinator in the Office of Translational Sciences. Dr. Amur is currently the Chair of the Pharmacogenomics Focus Group at the American Association of Pharmaceutical Scientists (AAPS). Dr. Amur received her Ph.D. in biochemistry from Indian Institute of Science, India and completed post-doctoral fellowships at Temple University and at UCLA. Prior to working at FDA, Dr. Amur held positions at Specialty Laboratories, Applied Biosystems, and Immune Tolerance Network and Neotropix, Inc.


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