C3 Submits Comments to the FDA’s Oncology Drug Advisory Committee

The Food and Drug Administration’s (FDA) Oncology Drug Advisory Committee (ODAC) is meeting today to discuss whether the labels for Erbitux (cetuximab) and Vectibix (panitumumab) should include a mention of KRAS testing. The discussion at the meeting will have implications for future development of companion diagnostics. C3 President Carlea Bauman will be testifying during the public comment section:

Comments submitted to Food and Drug Administration Oncology Drug Advisory Committee (ODAC) meeting on December 16, 2008

C3: Colorectal Cancer Coalition is a nonprofit, nonpartisan advocacy organization committed to winning the fight against colon and rectal cancer through research, empowerment and access.

C3 believes in fully disclosing sources of financial support. C3 receives funding from both Bristol Myers Squibb and Amgen in the form of charitable donations. Additionally, in 2008, C3 received a charitable grant from Caris Diagnostics, a company that tests colorectal cancer tumors for the KRAS mutation. None of these companies nor any of our other corporate supporters has influenced our comments on this issue.

On page three of the FDA Briefing Document, FDA listed the requirements they laid for submission of KRAS data.

In theory, these are good requirements and could be applied to both KRAS and future biomarkers and companion diagnostics.

However, we feel that the requirements fail to take into account the fact that there are many approved drugs on the market. As we speak, researchers are mining banked tissues, looking for markers that will help target those drugs most effectively. Some of that research may yield gems that will help patients avoid toxicity, or increase likelihood of benefit from treatment. However, while current and ongoing trials routinely bank high proportions of tissue, past trials did not. Thus, a requirement that tissue be available from 90-95 percent of participants in a single trial means that tissue from past trials will be largely useless for submissions.

In this era of personalized medicine, C3 strongly believes that we must be cautious about one-size-fits-all requirements. We believe that tissue and assay requirements vary, and that the following types of questions should be considered:

• What do we know about the biomarker? Are the results consistent with what we know about the mechanism of action? Do we know what percentage of patients in the general population have this biomarker?

• What do we know about the assay? Does the assay involve new technology? Are the assay results subjective, such as in a gene expression test, or are they objective, such as in a gene mutation test? Do they require “black box” calculations such as OncotypeDX?

• Are the clinical results consistent across analyses of multiple datasets?

• What is the strength of the clinical impact on patients? Do patients with a specific biomarker respond more to a specific drug? Less? Not at all?

With respect to KRAS, getting hold of 95 percent of the tissue across the spectrum of trials is not possible. However:

• The tissues that have been analyzed show a consistent breakdown of about two to one between wild-type and mutant patients, which is consistent with the occurrence of the historical mutation rate in colorectal cancer. The suspected mechanism of action is consistent with lack of response in the KRAS-mutant population.

• The results hold true across trials, regardless of phase, assay or laboratory.

• The assay results are black and white, and gene mutation tests are not a new technology.

• KRAS-mutant patients get no benefit from cetuximab or panitumumab. This has been shown in multiple analyses. And in OPUS, KRAS-mutant patients who received cetuximab did worse.

With respect to the KRAS issue, we have reviewed the analyses, spoken with researchers and looked at positions taken by the National Comprehensive Cancer Network and the College of American Pathology. As a result, we strongly urge ODAC to recommend a label modification for KRAS to provide some mention of these research findings in the label – perhaps something as simple as “Research indicates that patients with KRAS-mutant tumors do not benefit from treatment with this class of drugs.”

In addition, the KRAS story illustrates the problem with “one-size-fits-all” requirements for companion diagnostics. We urge ODAC to recommend that for the future, FDA develop requirements that fit with the reality of the research environment and the wide variability of markers and assays. At the end of the day, a flexible approach will facilitate the development of assays that allow patients to benefit from the reality of personalized medicine.

Carlea Bauman, President

For additional information, see:
• Briefing documents from FDA, Amgen and ImClone
• C3 information on KRAS