Leveling the playing field: bringing development of biomarkers and molecular diagnostics up to the standards for drug development

Abstract

Molecular diagnostics are becoming increasingly important in clinical research to stratify or identify molecularly profiled patient cohorts for targeted therapies, to modify the dose of a therapeutic, and to assess early response to therapy or monitor patients. Molecular diagnostics can also be used to identify the pharmacogenetic risk of adverse drug reactions. The articles in this CCR Focus section on molecular diagnosis describe the development and use of markers to guide medical decisions regarding cancer patients. They define sources of preanalytic variability that need to be minimized, as well as the regulatory and financial challenges involved in developing diagnostics and integrating them into clinical practice. They also outline a National Cancer Institute program to assist diagnostic development. Molecular diagnostic clinical tests require rigor in their development and clinical validation, with sensitivity, specificity, and validity comparable to those required for the development of therapeutics. These diagnostics must be offered at a realistic cost that reflects both their clinical value and the costs associated with their development. When genome-sequencing technologies move into the clinic, they must be integrated with and traceable to current technology because they may identify more efficient and accurate approaches to drug development. In addition, regulators may define progressive drug approval for companion diagnostics that requires further evidence regarding efficacy and safety before full approval can be achieved. One way to accomplish this is to emphasize phase IV postmarketing, hypothesis-driven clinical trials with biological characterization that would permit an accurate definition of the association of low-prevalence gene alterations with toxicity or response in large cohorts.

Figure 1. The Types of Markers and Phases of Clinical Trials

There are five types of markers in clinical research as diagrammed within the context of the Phase of clinical trial in which they are used. Pharmacokinetic and Pharmacodynamic markers are used as Research Assays and generally not for medical decision-making in patients on the trial. In contrast, the other three markers (Prognostic, Predictive, and Pharmacogenetic) often are used for medical decision-making and therefore need to be performed in a CLIA-certified laboratory. In addition, these markers if used for medical decision-making also are likely to require a FDA pre-Investigational Drug Exemption (pre-IDE) review. Please see text for further descriptions of the types of markers and phases of trials as well as the CLIA and FDA requirements.

Figure 2. The Flow of Marker Development

As documented in this manuscript, markers that are candidates for molecular diagnostics come from multiple sources that include TARGET, TCGA, as well as independent investigators who use various approaches to analyze aspects of biology. As these markers enter into the clinical research space they must undergo the process of analytical validation as well as use in clinical trials. Once these diagnostics have been identified as successful prognostic, predictive or pharmacogenomic markers they may be used in clinical practice if reviewed positively by the FDA, CMS or other payors.