U.S. and European regulations expect qualification of biomarkers for clinical use to be a multi-stage process that incrementally broadens a marker's application.

This approach will allow drug companies to benefit from a biomarker even as they accumulate data to demonstrate clinical utility, FDA's Federico Goodsaid, associate director for genomics in CDER's Office of Translational Sciences, and Marisa Papaluca of EMA point out in the May 10 issue of Nature Biotechnology.

Seeking the ultimate goal, such as clinical qualification, in a single application "is not only time-consuming but also unlikely to encourage the investment needed to generate data for biomarker qualification," they say.

To enable a faster return on investment, the regulators suggest that an effective qualification process must allow approval of intermediate uses that "fit into and benefit the drug development process."

That was the route taken by the Predictive Safety Testing Consortium for seven nephrotoxicity biomarkers. Those markers are qualified by FDA and EMA for preclinical drug testing, and can be utilized in clinical studies only after a case-by-case review by regulators (¹ Also see "Nephrotoxicity Biomarker Prepares For Clinic After FDA Blesses Animal Test" - Pink Sheet, 2 June, 2008.).

PSTC, a group with 16 corporate members that was formed under the auspices of the Critical Path Institute, now is developing studies to support qualification of the nephrotoxicity biomarkers for clinical use without the need for agency approval of each application. That would simplify their use and ease the review burden for the agencies. FDA is currently assessing a number of requests for their clinical use.

"Context Of Use" Governs Qualification

Providing insight into regulators' expectations for biomarker submissions, Goodsaid and Papaluca predict that qualification is likely if data support a specific "context of use."

The most difficult part of the process will be defining incremental contexts of use and the corresponding evidence to support that use, they contend.

Context of use is more than the general and specific application and implementation of a biomarker, the regulators explain. The context also includes the critical factors that define where a biomarker is to be used and how information gained by measuring the biomarker is to be integrated into drug development and regulatory review, they say.

The initial proposal, they stress, "should project a significant improvement over currently available biomarkers and/or endpoints."

In putting an application together, Goodsaid and Papluca note that the context of use drives data requirements and the initial proposal must be supported by data available in the initial application stage or expected to be available throughout data evaluation.

The submission structure should be flexible enough to deal with the specific requirements for each biomarker context, the regulators suggest, noting that the format may vary significantly with the context in which the biomarker is used and with the specificities of each biomarker.

Qualification Pipeline Fills As FDA Drafts Guidance

The Goodsaid/Papaluca article accompanies a series of papers that discuss the nephrotoxicity biomarker submission, a trial run for FDA's biomarker qualification process (² Also see "Nephrotoxicity Biomarkers To Be Test Run For FDA Qualification Program" - Pink Sheet, 9 July, 2007.).

Eleven other biomarker submissions are now in the pipeline at FDA. These involve efficacy as well as safety biomarkers, applications in the non-clinical and clinical spaces, and genomic, proteomic and imaging platforms, the agency says.

The proposed safety biomarkers are for measuring adverse effects on the kidney, liver and skeletal muscle; the proposed efficacy biomarkers are in oncology and infectious disease.

Even as FDA reviews those proposals, it is drafting guidance on the qualification process for drug development tools that FDA Commissioner Margaret Hamburg says will give sponsors a clearer picture of the criteria that FDA will use to assess biomarkers (³ Also see "FDA Prepares To Issue Draft Biomarker Qualifications Guidance" - Pink Sheet, 8 March, 2010.). The document will cover the qualification not only of biomarkers, but also of patient-reported outcome instruments. It is expected to be available for public comment this summer.

FDA and EMA shared scientific review discussions of the nephrotoxicity submission, but reached their qualification conclusions independently. They are working to simplify preparation of submissions when qualification is sought from several agencies. That effort includes an International Conference on Harmonization working group, which is developing guidelines on defining the context of use and integrating submission structure and data formats. The ICH E16 document will be issued this year.

Next Step For Nephrotoxicity Biomarkers

Studies being developed by PSTC to support qualification of the nephrotoxicity biomarkers for clinical use are described in a Nature Biotechnology paper by Frank Dieterle, Novartis, et al.

An observational longitudinal study, with six to 13 months of follow-up, will assess intrasubject and intersubject variability in baseline biomarker levels. The study will involve well-characterized age- and gender-matched healthy volunteers and ambulatory patients with underlying conditions known to predispose them to drug-induced nephrotoxicity, Dieterle says. A subset of patients with currently active chronic kidney injury from a variety of causes will be included for comparative analysis.

The goal is to obtain data relating to biomarker baseline values and natural longitudinal variance of biomarkers within different subject populations.

The consortium and regulators also have discussed the optimal design of studies involving patients receiving approved drugs with known nephrotoxicity, such as intravenous contrast medium, gentamicin and cisplatin.

PSTC expects these studies to be initiated in parallel with clinical assay development and validation. By validating biomarker thresholds in different studies, sponsors can obtain evidence to support general use of the biomarker signals across a range of patient populations and drug exposures, the group notes.

A key issue in designing the studies is the poor sensitivity and specificity of the currently accepted gold standard - serum creatinine - as a marker of acute kidney injury, Dieterle points out. As a result, discussion has focused on the definition of acute kidney injury, the need to collect data from other traditional renal injury markers and the meaning and interpretation of an elevation in the new biomarkers that occurs in the absence of an increase in SCr.

PSTC also is collaborating on pre-clinical safety biomarkers with regard to carcinogenicity, liver, muscle and vascular injury and expects to make several additional submissions to FDA by early 2011 or sooner.

NIH is also hoping to work with industry on a research network focused on liver injury (see ⁴ Also see "AstraZeneca Funds NIH Network Studying Drug-Induced Liver Injuries" - Pink Sheet, 14 June, 2010.).

- Cathy Dombrowski ( ⁵ c.dombrowski@elsevier.com )

Biomarker Qualification Should Be Multi-Step Process, Regulators Say

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