Approval of novel biomarkers: FDA's perspective and major requests

Abstract

FDA has been regulating diagnostic tests (including biomarkers) since passage of the Medical Device Amendments of 1976. Although always of interest as diagnostic tools, biomarkers (particularly genetic/genomic) have become of increased interest because of their potential impact on the development and personalized use of drugs. Unfortunately, there seem to be uncertainties among translational researchers as to the specifi c analytical and clinical measurement criteria needed for the approval of these novel biomarkers. This meeting presentation describes the current FDA perspective and major requirements and data for the validation/approval of an in vitro diagnostic device (IVD) based on a biomarker. The approval process for an IVD based on a biomarker used in the identifi cation of a disease or condition (diagnosing, screening, monitoring) is well established, and is essentially identical to the process to generate suffi cient analytical and clinical data for the approval of regular diagnostic devices. On the contrary, approvals for IVDs based on biomarker which may be designed to evaluate the effi cacy or answer safety questions for new drug entities are less streamlined. The clinical studies are more complex, resulting in higher ethical standards, increased costs and requiring complex statistical evaluation. There is a small but growing literature on new models for co-development of drugs and diagnostics which will be discussed. Regulators like the FDA develop and bring a fl exible regulatory toolbox to the table and are committed to assuring that scientifi c and regulatory thresholds are tempered to assure rapid access to new technologies while protecting public health.

An agenda for UK clinical pharmacology: Monitoring drug therapy

“…While the role of biomarkers as surrogates for clinical outcomes during drug development has been widely promoted by the USA's Food and Drug Administration (FDA) during the past decade, it is still uncertain whether practical management of patients has much benefited from such developments [26]. Monitoring tests are considered by the authorities as a business mainly related to diagnostic tests and their approval is disconnected from drug innovation [27]. Pharmacogenetic tests today represent a noteworthy exception.…”

Companion Diagnostics and the Drug–Diagnostic Codevelopment Model

“…The ability to discriminate between test‐positive and test‐negative results at a given cut‐off value will not only depend on the analytical performance of the assay but just as much on the strength of the clinical response to treatment with the targeted drug in the individual patients. The clinical cut‐off value must be established prior to the conduct of the pivotal clinical drug/diagnostic studies in phase III, which are to provide the final evidence of safety and efficacy of the drug as well as a clinical validation of the CoDx assay [FDA, ; Scherf et al., ]. If a cut‐off value cannot be established, often due to a weak correlation between the assay result and clinical outcome, it will be problematic to continue into phase III at this point, and the consequence is likely to be a no‐go decision for this combination of drug and diagnostic [Winther and Jørgensen, ].…”

“…The reason for this is mainly to be found in the design of the clinical trials that have evaluated the clinical utility of the different HER2 tests. In order to generate this type of information, both test‐positive and test‐negative subgroups of patients need to be included in the clinical trials that evaluate the drug–diagnostic combination [FDA, ; Scherf et al., ; Winther and Jørgensen, ]. As for the HER2 assays, it is not likely that we will gain access to this type of information, mainly due to ethical reasons, but it is important that the new drug–diagnostic combinations under development take these aspects into consideration when the designs of the clinical trials are decided [Jørgensen et al., ].…”

Targeted and Untargeted Proteomics Approaches in Biomarker Development

“…While qualification is not a required step in order to use a biomarker in drug development, qualification through the FDA Biomarker Qualification Program means that a biomarker has been demonstrated to be useful within a specified context of use (e.g., to support a specified manner of interpretation in drug development). Further specific analytical and clinical measurement criteria must be met to obtain FDA approval of a specific diagnostic test in the form of a device or an in vitro diagnostic . Many reviews have therefore considered what makes a “good” biomarker in the hope of guiding translational research …”