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by William Nowatzke

Bill NowatzkeThe term biomarker means many things to many people, depending on your role as a pharmaceutical scientist. With respect to the drug development world, biomarkers have traditionally been used to evaluate the efficacy of therapeutic intervention. Examples of biomarkers include physiological measurements (blood pressure, body mass index) and imaging tools (MRI, echocardiography). This discussion focuses on biomarkers (proteins, hormones) that are quantitatively measured in biological samples.

For example, cholesterol is a biomarker that can be used to estimate the efficacy of cholesterol-lowering therapeutics. When an individual ingests a statin, specific enzyme activities in the liver are changed to decrease the production of cholesterol. LDL cholesterol may be decreased by 20 – 60%! This type of biomarker is referred to as pharmacodynamic (PD) biomarker. PD biomarkers are valued because they may provide evidence of a candidate drug’s efficacy and proof of mechanism very early in the drug development program, thus permitting the internal prioritization of specific programs.

In addition to PD biomarkers, analytes in biological fluids are measured for diagnostic purposes. Examples include determining the presence/absence of disease, defining prescription dosages, and determining the likely hood that an individual will respond to a specific therapeutic (personalized medicine / companion diagnostic). For example, HER-2/neu (ERBB2) diagnostic testing is used to predict 5-year disease-free and overall survival in patients with breast cancer, assess eligibility for trastuzumab (Herceptin) treatment, assist in dose selection for certain drugs, and predict response to drug therapies.

Biomarkers only add value to a study if the data generated are correct. Research-quality commercial assay kits may be purchased to ‘measure’ nearly any analyte desired. And in the rare event that a commercial kit is not available, vendors offer tens of thousands of analyte specific antibodies, which can be used to develop a biomarker immunoassay or enrich samples for LC-MS determinations.

Unfortunately, the data generated from these processes are not always useful. Frustrated executives are often dumfounded by study data that is not supported by press releases suggesting that biomarker ‘X’ is the latest and greatest tool to deliver a slam dunk data set for investors and stock holders. Although the biomarker may indeed be informative, often the data is useless due to either preanalytical (stability, adhesion to the collection device) or analytical (poor precision, linearity) issues that have not been thoroughly investigated.

The FDA recognizes that biomarker data that is submitted to support a drug label is critical and must be of the highest quality possible. With the release of the September 2013 revised Guidance on Bioanalytical Method Validation, the FDA has included biomarkers as a class of analytes that must undergo a formal method validation. The successful AAPS workshop Quantitative Bioanalytical Methods Validation and Implementation was held last December to discuss the revised document.

With the release of the draft guidance, the bioanalytical community has a glimpse of possible future regulatory expectations from the FDA. These requirements will present significant challenges to laboratories generating biomarker data with the intended use of supporting marketed drug label claims.

The AAPS National Biotechnology Conference (NBC) Is recognized internationally as the premiere professional conference for pharmaceutical scientists engaged in biotechnology activities, and the tagline for this year’s conference is “Advancing Health Through Innovations in Biotherapeutics”. The May 19-21 conference is organized into four program themes including “Biomarkers and PK/PD”. As a consequence, there is extensive programming geared toward biomarkers and drug development, including:

  • AAPS Workshop on Method Development, Validation, and Trouble Shooting of Ligand Binding Assays in the Regulated Environment (Sunday, May 18)
  • 2014 AAPS Distinction in Biomarker Research Award (Opening Plenary, May 19)
  • Understanding Covariates Impacting PK/PD of Monoclonal Antibodies: Implications in Clinical Practice and Management (May 19)
  • Analytical and Clinical Validation of Pharmacodynamic Biomarkers (May 19)
  • David and Goliath: Pediatric Pharmacokinetics of Small Molecules versus Biologics (May 20)
  • Best Practices for Conveying Exploratory Biomarker Data to FDA (May 20)
  • Validation of Cell-Based Assays for Implementation in Regulatory Environments Suitable for Drug Development (May 20)
  • Disconnect Between PK and PD: Challenges and Strategies (May 21)
  • Methods for Visualising and Quantifying Biodistribution of Large Molecules (May 21)
  • How Effective Biomarker Identification and Implementation Can Impact Patient Outcome (May 21)
  • Small Ions, Large Antibodies, and Everything in between: Real-Time, Target-Site Monitoring with Open Flow Microperfusion (May 21)
  • The hot topic session Validation of Quantitative Biomarker Assays to Meet FDA Regulatory Expectations (May 21)
  • Integrated Approaches Using PK/PD/Ig/TOX for Biologics Development (May 21)
  • Tissue Bioanalysis of Biotherapeutics and PK/PD Data Interpretation: Challenges and Breakthroughs (May 21)

NBC offers excellent opportunities to hear internationally recognized key opinion leaders discuss the current practices and future changes to consider when generating biomarker and diagnostic data to support regulated drug development programs!

William Nowatzke, Ph.D., is the Sr. Director of Commercial Operations at Radix BioSolutions. He has 15 years of academic/industry/CRO experience supporting preclinical/clinical trials/postmarketing surveillance for pharmaceutical drug development programs.