Translating Biomarker Discovery into Companion Diagnostics through Validation and Regulatory Consideration - Genomic Biomarkers for Pharmaceutical Development - page 176

pertaining to signal leak between wells. Studies must be designed to demonstrate a lack of
bleed over of signal from well to well if previous instrument validation parameters do not
address this.
7.4.3.12 Limiting Factors
The limiting factors category is a general summary of the performance weaknesses of the
companion diagnostic assay identified throughout the discovery and validation of the biomarker
and assay. Limiting factor analysis identifies key components of the assay and how variations
in these components affect potential impact. These issues should be identified, and appropriate
mitigation strategies provided for each risk. Comprehensive review of these limiting factors and
recognition of appropriate mitigation strategies will be necessary to achieve a full validation.
7.4.4 Clinical Validation
The clinical validation of the companion diagnostic device is the process by which the pre-
dictive ability of the device is assessed in the context of a pivotal therapeutic product trial.
The topic of how to properly design a pivotal clinical study utilizing a potential companion
diagnostic device is a separate topic that is not covered in this chapter. However, ideally the
analytically validated market-ready device should be utilized in the enrollment of the pivotal
trial to ensure confidence in the call and its predictive ability.
7.5 CONCLUSIONS
Although the process of migrating an assay from a research setting through validation and
ultimately clinical implementation can be quite cumbersome, having an awareness of time-
sensitive deliverables, and adherence to the guidance provided by the FDA can greatly miti-
gate potential bottlenecks. Understanding the role of the regulatory authority is critical to the
development process, as this is the ultimate device filing decision enabling the use of an assay
in a clinical testing environment as a companion diagnostic. The topics presented in this chap-
ter have provided the framework for navigating this process; however, it is a case-by-case sce-
nario to successfully apply the process to each assay on an individual basis, primarily due to
the variability in the technical nature of assays. As the feedback from the regulatory agency
is crucial to the ultimate approval of the test, it will be important to continually monitor the
rationale of the appropriate regulatory authority. While the current methods being utilized in
the diagnostic space can be molded to fit this framework, as technical methods such as deep
sequencing are applied in the diagnostics space, there will likely be an evolution in analytical
processes to accommodate these technical advances.
References
[1] US Department of Health and Human Services, Food and Drug Administration, Center for Devices and
Radiological Health, Office of In vitro Diagnostic Device Evaluation and Safety, Center for Biological Evaluation
and Research. 'Draft Guidance for Industry and Food and Drug Administration Staff: In vitro Companion
Diagnostic Devices.' Retrieved from < http: // www.fda.gov / MedicalDevices / DeviceRegulationandGuidance /
GuidanceDocuments / ucm262292.htm > ; 2011 [accessed December 2012].