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FDA Issues Draft Guidelines on Qualifying Biomarkers to Speed Rx Development

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Originally published Oct. 29.

By Turna Ray

The US Food and Drug Administration this week released a draft guidance outlining how pharmaceutical researchers can qualify biomarkers to streamline the drug development process.

The draft document, titled "Qualification Process for Drug Development Tools," lays out the process by which industry can receive FDA's go-ahead for biomarkers, including pharmacogenomic markers, for use in a specific context. After getting these biomarkers "qualified" by the FDA, industry can use these markers in a similar context in multiple drug trials, drug classes, or clinical disorders, without having to repeatedly seek the agency's approval.

In addition to biomarkers, the guidance includes patient-reported outcome instruments in the category of drug-development tools, or DDTs. "Once a DDT is qualified for a specific context of use, industry can use the DDT for the qualified purpose during drug development, and CDER reviewers can be confident in applying the DDT for the qualified use without the need to reconfirm the DDT’s utility," the guidance states.

Stakeholders have 90 days to comment on the draft guidance.

In the guidance, the agency identifies possible types of DDT biomarkers that assess various biological characteristics, including "genetic composition, receptor expression patterns, radiographic or other imaging-based measurements, blood composition measurements (e.g., serum enzyme levels, prostate specific antigen), electrocardiographic parameters, or organ function (e.g., creatinine clearance, pulmonary function tests, cardiac ejection fraction)."

Although the draft guidance doesn't mention specific pharmacogenomic markers, the agency does lay out the context in which genomic markers can be qualified.

"In some circumstances, a biomarker may identify a patient population subgroup that becomes the focus of clinical trials," the FDA notes in the document. For example, prognostic biomarkers can identify patients at a higher risk of a disease and therefore well suited to enter a clinical trial for a drug. Or a predictive biomarker can identify which patients are most likely to benefit or see fewer adverse reactions from a drug based on its mechanism of action.

"There are also cases where a biomarker, in the setting of a particular disease and the currently available therapies, can identify a subgroup for whom there is no available therapy and in whom clinical trials can most rapidly evaluate the potential benefit of a new therapy," the FDA notes.

It will be seldom that surrogate markers, "intended to substitute for a clinical efficacy endpoint," are qualified through this process. "Because there is substantial risk of adversely affecting the public health if a biomarker is falsely accepted as a surrogate endpoint, robust scientific evidence is needed to justify qualification of a biomarker for broad use as a surrogate endpoint," the agency noted. "Qualification of a biomarker as a surrogate endpoint is likely to occur much less often than qualification of biomarkers for other uses."

The guidance document, however, specifically differentiates the qualification process for biomarkers from devices used in clinical trials to study the impact of those qualified biomarkers in disease progression or drug response.

"Biomarkers being considered for qualification are intended to be conceptually independent of the specific device performing the measurement. Any device that reliably and accurately measures the biomarker is expected to yield the same results," the FDA specified in the guidance. "While a biomarker cannot become qualified without a reliable means to measure the biomarker, FDA clearance of a measurement device does not imply that the biomarker has been demonstrated to have a qualified use in drug development and evaluation. Data from studies designed to achieve that objective will be needed to establish qualification."

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By the same reasoning, FDA qualification of a biomarker does not mean that the device used to qualify it has been granted marketing approval. "The commercial marketing for clinical use of the device requires submission to, and review by, [FDA's Center for Devices and Radiological Health]," the guidance states. "We anticipate that devices intended for use in patient management will have appropriate CDRH review."

Given "the substantial work needed to achieve qualification," the agency encourages those interested in qualifying DDTs to form collaborative groups. In the area of pharmacogenomics, groups like the Pharmacogenomics Knowledge Base, the International Serious Adverse Event Consortium, and the NIH's Biomarkers Consortium — groups that are conducting studies to investigate the impact of certain gene markers on diseases and drug response or teams that have already gathered substantial data on the impact of genomic markers on drug response in published literature — would likely have the resources to participate in the DDT qualification process.

An agency spokesperson told PGx Reporter that the FDA would list qualified biomarkers on its website.

Qualification Process

Those interested in qualifying a biomarker must submit a letter of intent proposing the context of use, critical appraisal of the data and methods, plans for future studies, and justification for why the biomarker should be qualified as a drug-development tool in the proposed context.

The FDA's Center for Drug Evaluation and Research will review the letter of intent and decide whether to take the biomarker through its review and qualification process. If the FDA decides to go forward with the qualification process, then the "DDT submitters" will meet with a Qualification Review Team, comprising CDER staff, to determine knowledge gaps, data requirements, and the submitter's goals.

At this stage, "the Voluntary Exploratory Data Submission mechanism may be valuable to submitters during early DDT development for biomarker DDTs," the guidance advises.

The FDA launched the VXDS program several years ago to encourage sponsors to share genomics data with the agency without any regulatory repercussions (PGx Reporter 11/29/06). According to agency officials, since 2008, submissions to the VXDS program have grown 250 percent.

If CDER denies the biomarker qualification request, then submitters will receive communication from the FDA as to why this decision was made and what alternative options are.

For submitters whose requests are accepted, after meeting with a review team, they will begin to gather the necessary data needed for qualification. The draft guidance provides an example of the data points a biomarker qualification briefing document should include.

In this briefing document, submitters should discuss the proposed context or intended use of the biomarker in question, as well as "unresolved issues" that pose a barrier to qualification of the marker. Furthermore, at this stage, the FDA also asks the submitter to define the biomarker. For example, for genomic markers, the submitter should discuss if it’s a SNP, a copy number variant, or a differential gene expression signature, the guidance informs.

The FDA defines "the qualified context of use" as the "boundaries within which the available data adequately justify use" of the biomarker. The agency recognizes that a particular biomarker has uses beyond those stated in an application for qualification, and as such advises submitters to work with the QRT to submit additional data on expanded uses of the marker as it becomes available.

"The QRT will review the qualification package, discuss the project at internal meetings, and arrive at a QRT recommendation on the qualification decision," the draft guidance notes. "In the case of complex or controversial DDT development programs, CDER may choose to hold public discussions."

Finally, the reviews are distributed to participating CDER offices for discussion and qualification. If the review process results in a CDER decision to qualify the biomarker, the division will issue a Statement of Qualification summarizing its determination, which will be issued as a draft guidance.

"Once a DDT is qualified for a specific use, the context of use may become modified or expanded over time as additional data are collected, submitted, and analyzed," the FDA added, as a caveat. "Alternatively, if the growing body of scientific evidence no longer supports the context of use, the DDT qualification may be withdrawn."

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