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How Dx-Development Collaboration Between LabCorp and Yale Yielded FDA Intervention

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Laboratory Corporation of America has decided to stop marketing an ovarian cancer-detection test it co-developed with Yale University researchers after a US Food and Drug Administration warning letter said the test is “misbranded” because certain parts of the assay were developed by Yale investigators and not the company.
 
According to LabCorp, however, Yale’s only involvement in the test was that it licensed the underlying intellectual property to LabCorp, and the school has not influenced any other aspects of LabCorp’s testing service.
 
As such, the company claims that its interactions with the university do not allow the FDA to exercise jurisdiction over the test, and that the agency’s actions may set a precedent that could stifle development of innovative diagnostics based on university research.
 
The blood-based diagnostic, which is currently in Phase III clinical trials, is based on the multiplexed detection of six protein biomarkers discovered by a team led by Gil Mor, an associate professor of reproductive sciences at the Yale School of Medicine, and colleagues.
 
In 2006, LabCorp exclusively licensed the biomarker panel and testing method with the goal of using it to develop a diagnostic for epithelial ovarian cancer. Under that agreement, Yale received an undisclosed signing fee, and is slated to receive undisclosed milestone payments and royalties on future products.
 
LabCorp has been selling the six-biomarker test since June under the brand name OvaSure as a laboratory-developed test under the Clinical Laboratories Improvement Act, which offers certified high-complexity testing laboratories such as LabCorp a quicker and less-stringent path to market for certain types of diagnostic tests than obtaining FDA pre-market approval.
 
However, CLIA regulations state that such a test must be developed and validated in the lab that performs, markets, or sells it. The FDA has apparently taken issue with exactly how much of the OvaSure test Yale developed.
 
The row began Aug. 7 when the FDA sent LabCorp its first letter, a cautionary note informing the firm that the homebrew OvaSure was insufficiently validated. LabCorp met with the FDA on Sept. 5 to discuss the 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.
 
The FDA wrote in the letter that based on information it collected and data provided by LabCorp at the Sept. 5 meeting, the agency’s Office of In Vitro Diagnostic Device Evaluation and Safety 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.
 
LabCorp has declined to comment on any aspect of this ongoing regulatory tussle.
 
However, in an Oct. 20 letter from LabCorp’s General Counsel Samuel Eberts to Steven Gutman, director of FDA’s OIVD, LabCorp noted that it would stop marketing OvaSure on Oct. 24, which it has. 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.
 
In its letter to OIVD, LabCorp also questioned whether its interactions with Yale provide FDA “any basis for exercising jurisdiction over the test.” The company maintained that although it had licensed certain aspects of the technology from Yale, it alone 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.”
 

“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 health care benefits to patients and health care professionals.”

Yale researchers involved with the test’s development were not immediately available to comment for this article. A spokesperson from Yale’s Office of Cooperative Research, which was responsible for brokering licensing deals and sponsored research with LabCorp, declined to comment, saying the matter was an issue between LabCorp and the FDA.
 
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 in February 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 (see BTW, 2/27/2008).
 
However, in its Aug. 7 letter, the FDA suggested that it was perhaps premature to launch the test based on Phase II data.
 
“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.”
 
In its response to the FDA, LabCorp maintained that by selling the test as a CLIA-certified diagnostic it has satisfied the agency’s regulatory requirements.
 
“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 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.
 
LabCorp further asserts 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 based on university research.
 
“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,” the company added. “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 health care benefits to patients and health care professionals.”
 
At least one comparable case of a company and academic institution partnering to develop and market CLIA-approved diagnostic test is that of Rosetta Genomics, Columbia University Medical College, and the University of California-Irvine School of Medicine.
 
In April, Rosetta said that it inked agreements with CLIA-certified laboratories at CUMC and UC-Irvine to distribute the company’s first microRNA-based cancer diagnostics (see BTW, 4/23/2008).
 
Specifically, Rosetta said at the time that it had submitted for approval to the New York State Department of Health its first test, which is designed to distinguish squamous from non-squamous non-small cell lung cancer. If approved, the test, developed by Columbia University Medical College, would be sold nationwide through CUMC’s CLIA-certified High-Complexity Molecular Pathology Laboratory.
 
In addition, Rosetta said it tapped the UC-Irvine School of Medicine CLIA lab to develop and validate the same lung cancer test, as well as tests to distinguish mesothelioma from adenocarcinoma and to identify cancers of unknown primary origin.
 
Although there are some similarities to the LabCorp-Yale relationship, a major difference is that in the Rosetta case, the technology licensing occurred in the reverse direction: instead of a university licensing IP to a company to develop and market a test around it, Rosetta licensed discoveries it made (and some that it licensed from other academic institutions) to CUMC and UC-Irvine, which are taking on the task of developing and validating tests based on Rosetta’s discoveries.
 
At the time, Ronen Tamir, executive vice president for marketing and communications at Rosetta, told BTW that “basically the test belongs to [CUMC MPL] from a CLIA point of view. The CLIA regulation states very clearly that the test has to be developed and validated in the lab that is going to perform it, market it, and sell it.”
 
— A version of this story appeared in Pharmacogenomics Reporter, a Biotech Transfer Week sister publication. Ben Butkus, of BTW, contributed to this article.

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