Laboratory Corporation of America has decided to stop marketing its OvaSure ovarian cancer detection test after a warning letter it received last month from the US Food and Drug Administration said the test is “misbranded” because certain parts of the assay were not developed by the company.
In an Oct. 20 letter from LabCorp’s General Counsel F. Samuel Eberts to Steven Gutman, director of FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety, LabCorp noted that it would stop marketing OvaSure on Oct. 24. In the letter, the company also disagreed with the FDA that it needed the agency’s approval to launch the test, and requested a meeting to discuss the matter.
LabCorp refused to comment on any aspect of the ongoing regulatory tussle concerning the ovarian cancer test.
The row began Aug. 7 when the FDA sent LabCorp its first letter, a cautionary note informing the firm that the lab-developed OvaSure test was insufficiently validated. LabCorp met with the FDA on Sept. 5 to discuss this issue. Then, on Sept. 29, the agency sent LabCorp a second letter, this time warning that OvaSure is not within the scope of laboratory-developed tests over which the agency has traditionally exercised enforcement discretion.
Although LabCorp stopped marketing the test last week, the company responded to the warning letter by questioning whether LabCorp’s “interactions with Yale University provide FDA any basis for exercising jurisdiction over the test.”
LabCorp in June launched the six-biomarker OvaSure as a laboratory-developed test under the Clinical Laboratories Improvement Act. It was codeveloped with researchers at Yale University School of Medicine.
Based on information collected by the FDA and data provided by the company at the Sept. 5 meeting, OIVD determined that OvaSure is a test “designed, developed, and validated by investigators at Yale University and not LabCorp,” and that the instructions for use and the performance characteristics for the test were developed by Yale investigators. This discrepancy apparently convinced the FDA that OvaSure was not entirely a laboratory-developed test regulated under CLIA, but a medical device requiring FDA clearance.
However, in its response to the FDA, LabCorp maintained that although it had licensed certain aspects of the technology from Yale, the company essentially developed OvaSure.
“LabCorp has licensed intellectual property from Yale University; we did not purchase any products or materials from Yale. Yale’s role in LabCorp’s test is limited to licensing to LabCorp certain intellectual property,” LabCorp said in its letter. “Yale has no control, contractual or otherwise, to influence the development, methodology, validation, performance characteristics, use, distribution or any other aspects of LabCorp’s testing service.”
Yale researchers were not immediately available to comment for this article. It remains unclear which specific components of OvaSure were developed by Yale and LabCorp.
In clinical studies that led to the development of OvaSure, Yale investigators used protein arrays to identify six candidate biomarkers to assess early-stage ovarian cancer in high-risk women, including leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factory, and CA-125. These biomarkers were incorporated into a multiplex immunoassay.
LabCorp decided to begin offering its test after Yale collaborators published results of a Phase II study that indicated the test had 95.3 percent sensitivity and 99.4 percent specificity. The Yale researchers are currently conducting a Phase III trial for the test and expect to publish its results by the end of the year.
However, in its Aug. 7 letter, the FDA suggested that it was perhaps premature to launch the test based on Phase II data.
“We are deeply concerned that the unprecedented position FDA has advanced in its Warning Letter will limit the dissemination of information and expertise, and will stifle the ability of laboratories to provide innovative diagnostic tests.”
“We note that this research was carried out, and performance derived, on two populations that are strongly clinically biased for being healthy and normal, and for having already experienced ovarian cancer,” the FDA noted in the letter. “Based on the available information, we do not believe the scientific community would consider the reported study sufficient to establish performance characteristics of a test in ‘high risk women who might have ovarian cancer’, i.e., in a clinical setting, as claimed in your intended use and promotional materials.”
LabCorp has maintained since that letter that by selling the test as a CLIA-certified diagnostic it has jumped through the appropriate regulatory hoops.
“The OvaSure test meets all applicable CLIA regulatory requirements. LabCorp bears full responsibility under CLIA for the performance of its tests, including OvaSure, and independently validates its tests on an ongoing basis,” the company stated in its Oct. 20 response. “The testing service developed by LabCorp and all subsequent changes to standard operating procedures for OvaSure were rigorously validated pursuant to CLIA requirements.
“LabCorp does not agree with the assertion in the [FDA’s Sept. 29] Warning Letter that OvaSure is a medical device subject to regulation under the Federal Food, Drug, and Cosmetic Act. As we have previously stated, we believe that laboratory developed assays are not medical devices within the meaning of the FDC Act and that they are not subject to regulation as medical devices.”
The apparent confusion regarding the status of OvaSure arises out of the two-pronged regulatory pathway currently available to laboratory test developers interested in bringing a commercial assay to market.
Although the FDA has long held that it has jurisdiction to regulate all laboratory-developed tests, it has historically practiced “enforcement discretion” over such tests, leaving them under the purview of the Centers of Medicare and Medicaid Services under CLIA. Last year, however, the FDA released a draft guidance explaining its intent to regulate in vitro diagnostic multivariate index assays, a subset of algorithm-driven laboratory developed tests.
FDA’s warning letter to LabCorp makes no reference to IVDMIAs, which further confounds the agency’s evolving stance on regulation of LDTs. The agency has yet to issue a final guidance on the matter.
Meanwhile, LabCorp asserted in its Oct. 20 response to FDA’s warning letter that the agency’s action against the company threatens to stifle the development of diagnostic tests.
“Cooperative agreements between laboratories and academic researchers are prevalent. Many tests currently offered by laboratories were initially developed by academic research centers; these tests rely heavily on the research performed by leaders in their respective disciplines,” LabCorp said in the letter. “Licensing agreements permit this research to be translated into innovative diagnostic test services, while providing academic centers with critical funding to continue their groundbreaking research.”
When FDA issued Exact Sciences a similar warning letter notifying the company that the homebrew stool-based colorectal cancer assay it was developing with LabCorp required pre-market approval, several industry insiders noted at the time that as the FDA’s regulatory approach toward LDTs changes, and diagnostic tests become more technologically complex, companies will need to proceed with caution when entering into diagnostic development collaborations [see PGx Reporter 03-05-2008].
A year ago, FDA warned Exact Sciences that its PreGen-Plus assay was “adulterated” and “misbranded,” since the test was “designed, developed, validated, and marketed by Exact rather than a test that was developed and validated by LabCorp.” [see PGx Reporter 01-23-2008].
Although LabCorp developed OvaSure with an academic institution and was developing PreGen-Plus with a diagnostic firm, both instances illustrate the difficulty of collaboratively developing LDTs in the current regulatory landscape.
“Restricting the ability of laboratories to utilize information and knowledge generated by academic researchers will have a negative impact on the availability of diagnostic tests that offer substantial healthcare benefits to patients and healthcare professionals,” the company told FDA. “We are deeply concerned that the unprecedented position FDA has advanced in its Warning Letter will limit the dissemination of information and expertise, and will stifle the ability of laboratories to provide innovative diagnostic tests.”