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FDA Cancer Drug Meeting Could Provide Insight into Agency's Rx/Dx Position

NEW YORK (GenomeWeb News) - The US Food and Drug Administration’s Oncologic Drugs Advisory Committee will meet Tuesday in Gaithersburg, Md., to discuss the validity of conducting retrospective clinical trials to define the genetic subpopulation for two metastatic colorectal cancer drugs, Amgen’s Vectibix and ImClone/Bristol-Myers Squibb Erbitux. 
The meeting could result in the FDA providing further clarity to pharmacogenomics companies on the agency’s position regarding Rx/Dx co-development.
“The committee should discuss the conditions, if any, where a prospective/retrospective clinical study design may provide evidence for treatment effects that are limited (or restricted) to biomarker classified subpopulation, thereby being judged as evidence of a predictive biomarker,” the FDA said in briefing documents posted ahead of the meeting.
In addition, the committee will consider what level of reproducibility to demand from sponsors upon the acceptance of a non-randomized, retrospective trial. “That is, can one single large prospective/retrospective trial serve as the basis for label consideration or is an independent prospectively randomized controlled trial needed to replicate the finding?,” FDA asks.
During the meeting, the independent committee of experts will discuss the validity of retrospective trials in determining the safety and efficacy of drug/diagnostic combination products, specifically with regard to cetuximab (Erbitux) and panitumumab (Vectibix). The makers of these two anti-epidermal growth factor receptor drugs, ImClone and Amgen, have submitted retrospective analyses in an effort to establish the drugs’ increased efficacy in a subpopulation of metastatic colorectal cancer patients with a wild-type version of the KRAS gene.
On the one hand, the FDA makes clear in its briefing documents that it discourages retrospective genomic biomarker assessments, since such trials involve the “re-analysis of a ‘failed’ clinical trial in which efficacy is purported to be established in a subset defined by a genomic biomarker/patient characteristics without consideration of multiplicity (i.e., data dredging), substantial missing data, and poorly characterized assays.”
Ideally, the agency notes its preference that sponsors simultaneously conduct prospective analysis of the clinical studies to establish the efficacy of the drug and gauge the prognostic and predictive value of the genomic biomarker with a “well-characterized” assay.
However, the agency also acknowledges that in cases where scientific advancements have uncovered a genetic association after a drug has gone to market, simultaneous Rx/Dx co-development may not be possible. The FDA approved Erbitux in 2004 and Vectibix in 2006. 
The acceptance within the scientific community of KRAS as a predictive marker of response to EGFR-inhibiting treatments in metastatic colorectal cancer came in the years following approval of these drugs.
The KRAS gene is mutated in between 35 percent and 45 percent of metastatic CRC patients. Studies have shown that KRAS testing can better define which CRC patients will benefit from treatment with EGFR-inhibiting monoclonal antibodies, such as Vectibix and Erbitux.
At the American Society of Clinical Oncology’s annual meeting this June, Eric Van Cutsem, a professor at the University Hospital Gasthuisberg in Leuven, Belgium, and colleagues presented data from a large, multinational prospective clinical trial showing that metastatic colorectal cancer patients who carry the wild-type version of the KRAS gene are much more likely than patients with the mutated form of the gene to benefit from the monoclonal antibody Erbitux.
The National Comprehensive Cancer Network in November recommended that cancer doctors determine the status of the KRAS gene either of a primary tumor or a metastasizing site as part of a pre-treatment work-up for colon cancer patients.
Across the pond, the European Medicines Agency recommends doctors establish patients’ KRAS status before prescribing Vectibix and Erbitux. The FDA has so far held off on issuing similar recommendations indicating that it is awaiting prospective trial data.
Noting that “the widespread publication and presentation of the retrospective KRAS analyses have resulted in practice changes in the community, thus, a prospectively designed trial may no longer be feasible,” the FDA agreed to accept retrospective analysis if certain conditions were met.
Both sponsors have submitted two retrospective trials from large randomized trials. In convening a meeting of expert advisors to discuss the strengths and weaknesses of Amgen’s and ImClone’s retrospective study designs, the FDA will further flesh out its policy for Rx/Dx co-development.
The agency issued a white paper on Rx/Dx codevelopment in 2005. Since then, FDA has discussed issuing formal guidance on the topic but has yet to do so. However, at a recent meeting on personalized medicine in Boston, Lawrence Lesko, director of FDA’s Office of Clinical Pharmacology, announced that the FDA had convened a multi-center and multi-disciplinary working group to advance the stalled document. 
Several diagnostic firms, including Althea Diagnostics, Laboratory Corporation of America, ViennaLab/Oasis Diagnostics, and Caris Diagnostics offer KRAS testing in the US. Many believe it would likely help drive physician adoption and reimbursement efforts if the FDA updates the label of Erbitux and Vectibix with information on KRAS testing.

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