On November 14, 2013, the Food and Drug Administration (“FDA”) issued a draft guidance document – “Draft Guidance for Industry, Tool Developers, and Food and Drug Administrative Staff”  (“Draft Guidance”) reporting a voluntary process for the qualification of medical device development tools (MDDT) used in device development and evaluation programs in the Center for Devices and Radiological Health (CDRH). The qualification process is proposed to facilitate the development and timely evaluation of innovative medical devices by providing a more efficient and predictable means for collecting the necessary information to make regulatory assessments. The Draft Guidance is noted to apply to therapeutic and diagnostic devices and specifically includes biomarker tools, that are key to some personalized medicine diagnostics. This post will review key concepts of the Draft Guidance that are relevant to biomarkers and biomarker tools.

Medical Device Development Tool

A Medical Device Development Tool or “MDDT” is defined as “a scientifically validated tool – a clinical outcome assessment (e.g. patient-reported or clinician-reported rating scales), a test used to detect or measure a biomarker (e.g. assay for a chemical analyte or medical imaging method), or non-clinical assessment method or model (e.g. in vitro, animal or computational model) – that aids device development and regulatory evaluation.”  “Context of use” refers to the use parameters for which the MDDT has been validated. This use is defined in part by the device or product area in which the MDDT can be qualified, the stage of device development, and the specific role of the MDDT. Once an MDDT is qualified for a specific context of use, the Draft Guidance notes that the FDA’s expectation is that it can be used by any medical device developer for that context of use. CDRH reviewers should accept the MDDT for the qualified context of use without the need to reconfirm the suitability of the MDDT. The Draft Guidance makes it clear, however, that the existence of a qualified MDDT does not convey a requirement that the tool must be used during the device development or regulatory evaluation process. However, other scientifically valid tools or approaches may also be used.

Biomarkers and Biomarker Tests

A biomarker test is one of the three recognized type of MDDTs. For the purpose of the Draft Guidance, a “biomarker test” or “BT” is a test or instrument (e.g. an in vitro/laboratory test or medical imaging method) or other objective measurement method used to detect or measure a biomarker. A “biomarker” is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or responses to a therapeutic intervention.  The Draft Guidance notes that MDDTs need not be FDA cleared or approved products. However, when an MDDT test is used in a clinical trial as a companion diagnostic, in that it is essential for the safe and effective use of a corresponding developed therapeutic product, it must comply with applicable investigational use requirements.

The Draft Guidance indicates that the CDRH intends for qualified BTs to be relied upon to support device-related regulatory decision-making for the defined context of use. For example, they may be used to select patients for inclusion in a device clinical trial, to monitor treatment response, to predict or identify safety problems related to treatment with a medical device, or to identify patients who are or are not candidates for certain forms of therapy.

When considering BTs for qualification, the Draft Guidance notes that CDRH will assess both the strength of evidence supporting the biomarker for the specified context of use, as well as the validity of the test instrument and/or methodology to measure the biomarker. In qualifying a BT, the Draft Guidance indicates that the FDA will accept the strength of evidence supporting the biomarker for the specified context of use. For subsequent BTs seeking qualification for similar contexts of use, the developer must only demonstrate the validity of the test instrument and/or methodology to measure that same biomarker. The amount and type of new evidence needed to support qualification of a BT depends on whether there is any test or instrument for measurement of the biomarker that is already FDA cleared or approved for clinical use through premarket review, and if so, whether the proposed context of use for the BT is consistent with the indication for use of the cleared or approved product. If there is no corresponding FDA cleared or approved device to qualify a BT, test validity (e.g., precision and accuracy) should be demonstrated in the proposed context of use. In contrast, MDDT qualification proposals involving an FDA cleared or approved test or involving biomarkers for which FDA has established the analytical performance criteria necessary for measurement for the specified context of use, the developer can make use of existing data that support the analytical validity of the test, so long as the MDDT submitter is legally authorized to do so.

The Draft Guidance notes that the processes and criteria for qualification of a BT as an MDDT remain distinct from requirements for pre-market product review, even when the products (biomarker test for use in device development and legally marketed medical device), the objects of the product (biomarker and analyte) and inferences drawn (biology and clinical significance) are similar or identical.

The procedures and qualifications for MDDT qualification are outlined in detail in the Draft Guidance, available here. Comments and suggestions regarding the draft Guidance must be provided within 90 days of publication in the Federal Register of the notice announcing the availability of the draft Guidance. Written comments should be submitted to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. Electronic comments should be submitted to www.regulations.gov.