The root causes of pharmacodynamic assay failure.
Robust pharmacodynamic assay results are valuable for informing go/no-go decisions about continued development of new anti-cancer agents and for identifying combinations of targeted agents, but often pharmacodynamic results are too incomplete or variable to fulfill this role. Our experience suggests that variable reagent and specimen quality are two major contributors to this problem. Minimizing all potential sources of variability in procedures for specimen collection, processing, and assay measurements is essential for meaningful comparison of pharmacodynamic biomarkers across sample time points. This is especially true in the evaluation of pre- and post-dose tumor biopsies, which suffer from high levels of tumor insufficiency due to variations in biopsy collection techniques and significant specimen heterogeneity within and across patients. Developing methods to assess heterogeneous biopsies is necessary in order to evaluate a majority of tumor biopsies collected for pharmacodynamic biomarker studies. Improved collection devices and standardization of methods are being sought in order to improve the tumor content and quality of tumor biopsies. In terms of reagent variability, we have found that stringent initial reagent qualification and quality control of R&D-grade reagents is critical to minimize lot-to-lot variability and prevent assay failures, especially for clinical pharmacodynamic questions, which often demand assay performance that meets or exceeds clinical diagnostic assay standards. Rigorous reagent specifications and use of appropriate assay quality control methodologies help to ensure consistency between assay runs, laboratories and trials to provide much needed pharmacodynamic insights into the activity of investigational agents.
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD. Electronic address: Katherine.FerryGalow@nih.gov.
Katherine V
KV
Ferry-Galow
Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, Rockville, MD.
Hala R
HR
Makhlouf
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
Deborah F
DF
Wilsker
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
Scott M
SM
Lawrence
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
Thomas D
TD
Pfister
MedImmune LLC, Gaithersburg, MD.
Allison M
AM
Marrero
Johns Hopkins School of Medicine, Department of Pharmacology and Molecular Sciences, Baltimore, MD.
Kristina M
KM
Bigelow
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
William H
WH
Yutzy
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
Jiuping J
JJ
Ji
Pathology/Histotechnology Laboratory, Animal Sciences Program, Leidos Biomedical Research, Frederick National Laboratories, Frederick, MD.
Donna O
DO
Butcher
Pathology/Histotechnology Laboratory, Animal Sciences Program, Leidos Biomedical Research, Frederick National Laboratories, Frederick, MD.
Brad A
BA
Gouker
Stanford University School of Medicine, Department of Oncology, Stanford, CA.
Shivaani
S
Kummar
NCI/DCTD-Early Clinical Trials Development Program, Bethesda, MD.
Alice P
AP
Chen
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
Robert J
RJ
Kinders
Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
Ralph E
RE
Parchment
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.
James H
JH
Doroshow
D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001706:Biopsy; D006801:Humans; D007202:Indicators and Reagents; D009369:Neoplasms / Q000473:pathology; D015203:Reproducibility of Results; D013048:Specimen Handling / Q000379:methods* / Q000592:standards
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007202:Indicators and Reagents
Assay quality control; Reagent qualification; Tumor biopsy