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FDA Update to Erbitux, Vectibix Labels Encourages Rx/Dx Co-development, Industry Expert Says

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By Turna Ray

Despite the US Food and Drug Administration having used retrospective data from sponsors in updating labeling for colorectal cancer drugs Vectibix and Erbitux with pharmacogenomics data, the protracted nature of the regulatory process has, if anything, further encouraged pharma companies to embark on prospective studies where drug/diagnostic combination products are developed simultaneously, according to an industry insider.

BMS and Amgen both issued statements this week announcing that the FDA had updated the "indication and usage" section of the labels of Amgen's Vectibix and ImClone/BMS' Erbitux to note that "retrospective analyses of metastatic colorectal cancer trials have not shown a treatment benefit for the EGFR inhibitors in patients whose tumors had KRAS mutations in codon 12 or 13," and that the use of the drugs is not recommended for the treatment of colorectal cancer patients with these mutations.

In order to make the labeling change, the agency reviewed retrospective data from seven clinical trials, two involving Vectibix and five with Erbitux. These trials are listed in the new labeling. The acceptance of retrospective data in making the labeling change is significant for drug developers and diagnostics firms, since prospective clinical trials are more expensive and take longer to conduct.

Nevertheless, the agency's use of retrospective data in its relabeling decision "is certainly going to be very much the exception, rather than the rule," DxS CEO Stephen Little told Pharmacogenomics Reporter this week. UK-based DxS markets a KRAS Mutation Test kit in Europe. While DxS' test kit is being reviewed by the FDA for regulatory approval, it is being sold through Exiqon as a laboratory-developed test.

DxS officials have previously indicated that pending FDA's labeling update it could not fully market the test in the US as a companion diagnostic. Little could not provide a timeframe for when DxS expects to hear from FDA regarding its pre-market approval application for the companion diagnostic.

"In the retrospective data submitted, samples had been banked and there was good information from other studies to suggest that [the labeling update] was a worthwhile thing to do," Little said. "But in general, what we're seeing is that a lot more companies are now thinking about this well in advance. I think right now there may be one or two opportunities for retrospective changes, but in general that's not the ideal way to manage the process."

This labeling update has been a long time coming. The FDA's decision comes more than a year after European regulators narrowed the indication for the two drugs based on KRAS mutation testing, and several months after US professional societies, such as the American Society of Clinical Oncology and the National Comprehensive Cancer Network, recommended that doctors test all metastatic colorectal cancer patients for KRAS variants prior to treatment with an anti-EGFR antibody therapy.

In the US, the labeling changes took longer as the FDA struggled with whether or not to accept retrospective clinical trial data from sponsors for pharmacogenomic assessments. In an effort to understand the circumstances under which the FDA would accept retrospective data to narrow the indication of a drug for a particular subpopulation, the agency convened an advisory committee meeting last fall to discuss Amgen and BMS/ImClone's submissions for the labeling changes [see PGx Reporter 12-17-2008].

In its briefing materials to the advisory committee, the FDA made clear that it discourages sponsors from conducting 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."

In response to the agency's concerns, members of the expert panel urged the FDA to maintain "common sense" evidentiary criteria. Committee members generally agreed that when considering retrospective data on genetically targeted treatments, the FDA should validate that the assay was used to adequately define the subpopulation; ensure that tumor samples used in the study represent the disease state of the patients in the trial; and require sponsors to replicate retrospective findings in a prospective trial.

In statements to Pharmacogenomics Reporter, both Amgen and BMS said that the FDA did not require additional prospective clinical trials as a condition for the labeling update.

However, Amgen is investigating the clinical utility of KRAS testing to predict response to Vectibix in the combination chemotherapy setting in two prospective Phase III clinical trials in mCRC patients. Trial results are slated for release in the third quarter of this year.

According to an Amgen spokesperson, the company undertook these prospective trials after consulting with the FDA, but the trial was not mandated by the agency.

The FDA approved Erbitux (cetuximab) in 2004 and Vectibix (panitumumab) in 2006. The labeling changes are specific to the use of KRAS as a biomarker for Vectibix and Erbitux as monotherapy treatments for metastatic colorectal cancer.

Encouraging Rx/Dx Co-Development

"Our expectation is that what this decision will encourage drug companies to do is think about their companion diagnostic strategies a lot earlier in the process," Little said. "This could lead to more partnerships and collaborations, whereby the diagnostic and drug are approved at the same time, so you don't get this hiatus between approval of the drug and approval of the diagnostic."

Having gone through the protracted process of garnering regulatory clearance for a companion diagnostic for drugs already on the market, DxS officials have previously indicated that their focus going forward will be to engage in projects in which the drug and diagnostic are being developed in parallel.

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The lengthy FDA regulatory process even impacted drug sales for the pharma companies involved. Earlier this year, both BMS and Amgen acknowledged that the lack of clear guidance from the FDA regarding KRAS testing had negatively affected the sales of the drugs [see PGx Reporter 02-04-2009].

Although the labeling update will cut into Amgen and BMS/ImClone's market share for Vectibix and Erbitux, it is good news for KRAS test developers.

According to Little, sales for the company's TheraScreen KRAS test in Europe have "taken off." From 2007 to 2008, the company's revenues grew four-fold, and Little expects sales to double this year. Specifically, "the adoption rate for the KRAS test has been phenomenal," mainly because the "drug industry is pushing it," Little previously told Pharmacogenomics Reporter [see PGx Reporter 03-04-2009].

Conditions for Retrospective Data

Other than to say that the FDA did not require additional prospective trials, BMS and Amgen did not provide further comment on the discussions with the FDA that led to the labeling update based on retrospective analyses.

And while FDA's labeling update using retrospective data may be the exception, the FDA's December 2008 Oncologics Drugs Advisory Committee (ODAC) meeting — where the clinical utility of the KRAS gene as a predictive biomarker in colorectal cancer patients treated with Vectibix and Erbitux was discussed — offers a window into the various considerations that led to the agency's decision.

In briefing documents, FDA states that it agreed to accept the retrospective data from the BMS/ImClone and Amgen under the following conditions: the trials must be adequate and well-controlled; the sample size must be sufficiently large to ensure randomization; tumor tissue must be obtained in more than 95 percent of registered study participants and an evaluable result must be available for greater than 90 percent of study subjects; the assay must be reviewed and validated by the FDA; genetic analyses must be performed according to a qualified assay methods by blinded investigators; and sponsors and the FDA must create an analytical plan to test hypotheses for updating labels and making promotional claims.

Derek Raghavan, director of the Cleveland Clinic Taussig Cancer Center and an ODAC consultant, pointed out during the December ODAC meeting that while retrospective studies were not a substitute for well-powered prospective trials, the agency needed "common sense" rules for looking at retrospective data on biomarker assessments.

During the meeting, most participants agreed that any retrospective study submitted to the FDA should be randomized, blinded, and have appropriate statistical power and control multiplicity.

Another major focus of the discussions involved how tumor samples collected during the original study should be used in retrospective trials. Committee members agreed that it is critical that the samples represent the patient's disease state at the time of the study, since the patient's disease state could change between the time of the original study and subsequent retrospective analyses.

According to Amgen, in its retrospective analyses, the large majority of specimens available were from the primary tumor. "For KRAS assessment, we believe this is reasonable, since the KRAS alteration occurs early in CRC pathogenesis, and there is a high concordance in KRAS status between primary and metastatic tumors," the Amgen spokesperson told Pharmacogenomics Reporter. "For other biomarkers, in each individual case it will be important to determine if the marker should optimally be assessed on primary or metastatic lesions."

BMS did not provide any comment regarding sample acquisition in retrospective trials.

For the labeling change, ImClone submitted five retrospective studies and Amgen provided two studies to the FDA. However, only one of the Vectibix studies (no. 408) and two of Erbitux's submissions (CRYSTAL and NCIC-017) reached their primary efficacy endpoints.

ODAC members debated during the meeting whether to accept retrospective analysis if the primary study failed to reach its efficacy endpoint. Ultimately, it seems the FDA concluded that retrospective biomarker analysis was not impacted by whether the original study met the primary endpoint. The new labels list all seven trials under the "Clinical Studies" section.

During the meeting, Richard Simon, an ODAC consultant and chief of the National Cancer Institute's Biometric Research Branch, advised FDA to look at whether a sponsor conducted "a focused analysis and accrued enough patients that test positive and negative for the biomarker, and [had] a test that is analytically validated on archived tissue."

With the labeling update from the FDA and anticipating a positive decision from the agency regarding its KRAS mutation test kit, DxS will likely be ramping up its marketing efforts for the companion diagnostic. DxS has an exclusive global distribution agreement with Roche Diagnostics for the distribution of the TheraScreen: K-RAS Mutation kit [see PGx Reporter 06-04-2008].

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