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FDA's Genomic Biomarker Qualification Guidance Lays Out Submissions Plan for Sponsors

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By Turna Ray

The US Food and Drug Administration has released a guidance outlining the data submission process that biopharmaceutical companies can follow to establish the reliability of genomic markers they intend to use in clinical trials in order to gain greater insights into the drugs they are developing.

In the guidance, released earlier this month, the FDA provided recommendations for how and in what contexts drug developers can submit data to "qualify" genomic biomarkers they will then use to stratify patients in a drug trial, determine the dose a drug may be administered in, and gain insights into drug-related adverse events.

"Qualification is a conclusion that, within the stated context of use, the results of assessment with a biomarker can be relied upon to adequately reflect a biological process, response, or event, and support use of the biomarker during drug or biotechnology product development, ranging from discovery through postapproval," the FDA explains in the guidance. The guidance does not discuss the specific evidentiary standards that a biomarker must meet in order to be qualified by regulatory authorities.

According to Marc Walton, FDA's associate director for translational medicine, the agency views biomarkers as a type of drug development tool. "Drug development tools are intended for use in aiding development programs for new therapies, but not focused on use in clinical practice after the drug has been approved," Walton told PGx Reporter. "Drug development tools may make drug development programs more efficient or more successful."

Furthermore, the requirements for getting a biomarker qualified is separate from the evidentiary criteria a sponsor must meet in order to get a biomarker included in the label of a personalized medicine product. "Personalized medicine will also need new biomarkers to take full advantage of the potential," Walton said. "However, biomarkers intended to be recommended in labeling will need evaluation in ways that are beyond what qualification is intended to facilitate."

While a personalized therapy that depends on a biomarker may have previously been qualified in the context of another drug development program, the FDA views the biomarker qualification as a separate process from validating a test that will gauge a particular biomarker and pick out best responders for a drug. "Note that biomarkers that are part of personalized medicine will often require a companion diagnostic device to measure that biomarker," Walton said. "FDA has recently issued draft guidance on companion diagnostic policy, and that guidance can be consulted as well for an understanding of that circumstance."

The FDA's draft guidance on companion diagnostics development was released last month and is open for public comments (PGx Reporter 07/13/2011).

The FDA developed this latest biomarker qualification guidance with the Efficacy Working Group of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. When drug developers want to file an application for biomarker qualification, they will be able to file the same common application across ICH regions. Through this harmonized process, the FDA is hoping to "foster consistency of applications," facilitate "easy review and exchange of assessments" by regulatory authorities across different regions, and reduce the burden on sponsors.

The agency notes in the guidance that principles in the current document evolved through its experience with sponsors that have previously qualified biomarkers as part of their drug development programs. In an interview with PGx Reporter earlier this year, Issam Zineh, associate director of genomics at the Office of Clinical Pharmacology in FDA's Center for Drug Evaluation and Research, said that the agency has seen an increase in the number of biomarker qualification applications to CDER in past years. In 2008, there was one biomarker qualification submission, whereas in 2009 and 2010, there were four and six such applications, respectively (PGx Reporter 01/05/2011).

Another way for drug developers to get input from the agency on biomarkers is through its Voluntary Exploratory Data Submissions program, an effort that is intended to facilitate non-regulatory discussions between sponsors and the agency. Zineh previously said that biomarker qualification submissions typically come from consortia, and VXDS submissions tend to come from individual companies or scientists. Since the VXDS and biomarker qualification pathways serve different purposes, the agency wants to "encourage a healthy balance of both types of submissions," Zineh said.

This biomarker qualification guidance comes as sponsors appear to be getting more comfortable including genomic data in their regulatory submissions for drugs. According to FDA's estimates there were 60 submissions containing genomic data in 2008, 140 such submissions in 2009, and 210 submissions in 2010. Although the number of qualified biomarker applications and the amount of genomic data submitted as part of regulatory filings seems to be on the rise, the FDA believes that the pace of validating biomarkers also needs to increase.

In a July report discussing CDER's science and research gaps, the FDA acknowledged that it needs to improve its understanding of biomarkers to foster greater advances in personalized medicine. "We need to improve our understanding of the safety and efficacy of pharmacotherapy as it applies to individual patients and patient subsets," the agency states in the report (PGx Reporter 07/27/2011). The latest guidance is meant to not only facilitate the incorporation of valid biomarkers into drug development, but the streamlined process will also improve understanding of genomic markers across multiple regulatory agencies.

Submission Guidelines

A submission for biomarker qualification can include data on a single or multiple markers, and the markers may be submitted as part of the development program for a single drug or intended to be used as part of ongoing research for a class of drugs or across multiple drug classes. Although the guidance is focused on genomic markers, sponsors can also use the principles outlined in the document to submit data on proteomic, imaging, and other types of non-genomic markers used in drug development.

"We regard the Drug Development Tool biomarker as the information that is used as the decision-driving factor in a drug development program. If there are a number of genes (or blood biomarkers, or other types) that must be measured and used in a combination manner to provide a single package of information, then all the elements of that combination make up the biomarker," FDA's Walton explained in an e-mail. "We would work with the submitter to qualify the combination, as it is likely in that situation that each individual piece of the combination is not adequate to enable drug development decisions, and would not be suitable for qualification."

The guidance describes the variety of purposes for which a qualified biomarker may be used, including study subject selection in a clinical trial; disease prognosis; assessing the mechanism of action of a drug in terms of efficacy or toxicity; dose optimization; drug response monitoring; predicting drug efficacy; and minimizing drug-related adverse reactions.

The agency recommends that sponsors simultaneously submit their biomarker qualification applications across regulatory regions. Once a marker is qualified under a specific context, other sponsors using that marker in the same context as part of their new drug applications, biologics license applications, and marketing authorization applications don't have to re-qualify the marker. "It would be appropriate to simply provide a copy of the assessment report of the authority in the NDA/BLA/MAA or other relevant regulatory procedure," the FDA notes in the guidance.

According to the guidance, in order to qualify a biomarker, sponsors should submit non-clinical and clinical data on the biomarker, analytical validation data on the assay used to gauge the genomic markers, and the characteristics of the drug that the markers are associated with. In their application, sponsors should describe the biomarker (i.e. SNPs, copy number variations, gene expression signatures), discuss the markers' association in the disease setting, discuss the strengths and limitations of the submitted biomarker information, and provide a rationale for using a biomarker in the development program for a particular drug.

In the case of composite markers, "the process through which these [markers] were selected should be defined," the FDA states in the guidance.

Finally, sponsors should also discuss in their application the context in which they intend to use a genomic biomarker or multiple markers. "The context of use can be limited to use in drug or biotechnology product development," the FDA states. "It is expected that a biomarker proposed for qualification would facilitate drug or biotechnology product development program(s) or drug or biotechnology product use and could offer an improvement over currently available biomarkers for safety or efficacy endpoint assessments."


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