The U.S. Food and Drug Administration (FDA) sent a letter to the Laboratory Corporation of America (LabCorp) on August 7, 2008, stating that it believes the Yale ovarian cancer early detection test (marketed by LabCorp under the name OvaSure™) ” … has not received adequate clinical validation, and may harm the public health.” In that letter, the FDA invites LabCorp to discuss all validation studies that support the marketing of the OvaSure™ test.
The U.S. Food and Drug Administration (FDA) sent a letter to the Laboratory Corporation of America (LabCorp) on August 7, 2008, stating that it believes the Yale ovarian cancer early detection test (marketed by LabCorp under the name OvaSure™) “… has not received adequate clinical validation, and may harm the public health.” In the letter, the FDA invites LabCorp to discuss all validation studies that support the marketing of the OvaSure™ test. The August 7 FDA letter appears to reflect a previously announced, yet controversial, change in FDA policy. Libby’s H*O*P*E*™ reported previously on the development of the Yale ovarian cancer early detection test [March 14, 2008], and LabCorp’s subsequent market release of that test under the name OvaSure™ [June 23, 2008].
On August 19, 2008, the Oncology STAT™ news service reported that the August 7 FDA letter was posted on the website of the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) on August 15, but was removed from the site a few days later. On August 22, 2008, we identified the “cached” copy of the August 7 FDA letter on the OIVD website. The August 7 FDA letter is provided below in its entirety.
The August 7 FDA letter was issued by OIVD and informs LabCorp that “[i]t appears that you are marketing the Ovasure™ Test with performance characteristics (specifically, 95.3% sensitivity and 99.4% specificity) that are identical to those reported in a research study published by Visintin, I. et al., in the February 15 edition of Clinical Cancer Research (Visintin, I. et al., Clin Cancer Res. 2008 Feb 15;14(4):1065-72.).” The OIVD Director, Steven Gutman, M.D., M.B.A., states that the Visintin, I. et. al ” … 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.” Based upon this rationale, the OIVD concludes that it does 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.”
Historical FDA Policy Regarding Laboratory-Developed (“Home Brew”) Tests
Based upon historical FDA policy, LapCorp would not be required to obtain FDA premarket or postmarket approval for the OvaSure™ test because the early detection test would be categorized as a “laboratory-developed test” (also referred to as a “home brew” test) under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). In general, the CLIA establishes quality standards for all laboratory testing to ensure the accuracy, reliability and timeliness of patient test results regardless of where the test is performed.
Prior to 2006, the FDA did not exercise its authority to regulate home brew tests, which are developed by a laboratory for in-house use as a test service. The reasons are likely twofold. First, the FDA believed that the regulatory oversight exercised by the Centers for Medicare & Medicaid Services (CMS) with respect to the laboratories (under CMS jurisdiction pursuant to CLIA), ensured that such laboratories were competent to properly manufacture and use home brew tests without additional FDA intervention. Second, the FDA possessed regulatory authority to review the primary ingredients or components in the home-brew tests (known as “analyte specific reagents” (ASRs)), and did not believe that further test regulation was necessary.
Announcement of FDA Policy Change For Select In Vitro Diagnostic Assays
In 2006, and again in 2007, the FDA issued draft guidance (entitled, Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays) in which, for the first time, the agency exercised its authority to regulate select in vitro diagnostic multivariate index assays (“IVDMIAs”) that are developed and manufactured by clinical laboratories for their own use (i.e., laboratory-developed tests/home brew tests). An IVDMIA is a diagnostic laboratory assay or test that utilizes mathematical formulae to interpret genetic and protein data required for the generation of information used to make critical diagnosis and treatment decisions for patients. IVDMIAs, for FDA regulatory purposes, are classified as medical devices under the Federal Food, Drug & Cosmetic Act (FDCA), and therefore, can be subject to premarket and postmarket regulation. IVDMIAs developed and manufactured by commercial, non-laboratory-based companies are currently regulated by the FDA. The majority of IVDMIAs, however, are developed and manufactured by laboratories for their own use as home brew tests.
Under the FDA draft guidance, home brew IVDMIAs would in many cases require 510(k) pre-market clearance or Pre-Market Approval (PMA). In addition, these same IVDMIAs would have to comply with “device” post-market manufacturing and reporting requirements. The August 7 FDA letter does not state that a 510(k) pre-market clearance or Pre-Market Approval is required; rather OIVD invites LabCorp to discuss any “validation strategies” undertaken beyond the research results reported by Visintin, I. et. al. LabCorp is not the only company affected by the FDA policy change. The FDA also used its change in regulatory policy to prevent Correlogic Systems, Inc. from marketing its ovarian cancer early detection test, known as OvaCheck®, without prior FDA approval. Arguably, the FDA is placing the OvaSure™ and OvaCheck® ovarian cancer early detection tests on equal regulatory footing.
Ever-Increasing Sophistication of Genetic and Proteomic Assay Technology
The emergence and increased use of IVDMIAs using novel technology (e.g., proteomics) as an integral part of patient diagnosis and treatment, and their direct advertisement to consumers, may have influenced the FDA to conclude more recently that the current level of oversight with respect to genetic and proteomic testing by laboratories was inadequate. Assuming the FDA position is correct, inadequate federal oversight could lead to significant issues related to the quality and validity of IVDMIAs.
LabCorp Amendment of OvaSure™ “Use” Information
LabCorp recently amended its intended use and promotional materials to provide that the OvaSure™ test cannot be used by a woman who has had both ovaries removed (i.e., a woman who previously had a bilateral oophorectomy). Specifically, LabCorp intends that the OvaSure™ test be used to identify a woman who is at “high-risk” for ovarian cancer; however, an ovarian cancer survivor who is currently in remission, cannot use the OvaSure™ test to screen for a recurrence of the disease if her ovaries were removed as part of her first-line treatment after the initial ovarian cancer diagnosis. CLICK HERE to view Libby’s H*O*P*E* post (with updates) dated June 23, 2008, regarding the OvaSure™ test use and limitation information as amended.
Letter to the President and Chief Executive Officer of LabCorp
August 7, 2008
David P. King
President and Chief Executive Officer
Laboratory Corporation of America
430 South Spring Street
Burlington, North Carolina 27215
Dear Mr. King:
It has come to our attention that you are currently marketing the OvaSure™ Yale Ovarian Cancer Test, also advertised as the OvaSure™ For Women at High-Risk for Ovarian Cancer, and OvaSure™ For Women at High-Risk for Ovarian Cancer, (Serial Monitor), (collectively referred to hereafter as the OvaSure™ Test) which is intended to be used as a tool to identify high-risk women who might have ovarian carcinoma. It appears that you are marketing the OvaSure™ Test with performance characteristics (specifically, 95.3% sensitivity and 99.4% specificity) that are identical to those reported in a research study published by Visintin, I., et al., in the February 15 edition of Clinical Cancer Research (Visintin, I. et al., Clin Cancer Res. 2008 Feb 15;14(4):1065-72.). 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. 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.
Based on our review of your promotional materials and the research publication cited above, we believe you are offering a high risk test that has not received adequate clinical validation, and may harm the public health. We would like to discuss with you your offer of this test, and any validation strategies you have undertaken beyond those reported in the publication cited above.
We look forward to discussing this with you, and are committed to working with you as we strive to protect the public health without unnecessarily imposing regulatory burdens on the marketing of products of potential clinical importance.
Steven I. Gutman, M.D., M.B.A.
Office of In Vitro Diagnostic Device Evaluation and Safety
Center for Devices and Radiological Health
- The corporate and governmental intrigue surrounding the FDA regulatory issues with respect to the OvaSure™ and OvaCheck® ovarian cancer early detection tests would make for a thrilling Hollywood screenplay, except for the catastrophic fact that approximately 15,000 U.S. women die annually from ovarian cancer due to the lack of a reliable early detection test. Because of the latter, approximately 80 percent of women are not diagnosed until they are in advance stages of the disease.
- The FDA’s current – and still evolving – policy signals a strong possibility that previously unregulated diagnostics could require FDA approval or clearance prior to marketing as well as being subject to other medical device requirements under the FDCA.
- It is critical for the FDA to take whatever action is necessary to protect U.S. public health. It is also essential that ovarian cancer survivors, clinicians and all affected corporate entities receive clear, consistent regulatory guidance and prompt action from the FDA with respect to this potential life-saving matter.
- FDA Questions LabCorp in Its Ovarian Cancer Test Service, OncologySTAT™ News, Week in Review, Issue 33, Aug. 22, 2008 (reprinting article by D. Filmore, The Pink Sheet Daily, Aug. 19, 2008).
- Draft Guidance for Industry,Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays, July 26, 2007 (Adobe Reader PDF doc.)
- Office of In Vitro Diagnostic Device Evaluation & Safety, Centers For Devices and Radiological Health, U.S. Food & Drug Administration (online).
- Clinical Laboratory Improvement Amendments (CLIA) (online), Centers for Medicare & Medicaid Services, U.S. Department of Health & Human Services.
- CLIA-Clinical Laboratory Improvement Amendments (online), Center For Devices and Radiological Health, U.S. Food & Drug Administration
- Clinical Proteomics Advances as Vermillion, LabCorp, Correlogic Prep For Market, by Bernadette Toner, ProteoMonitor, June 26, 2008 (online version)
- Recent U.S. Regulatory Developments Herald Increasing FDA Regulation of Laboratory-Developed Diagnostic Tests and Services, by Jane E. Baluss, The Pulse publication, Foley & Lardner LLP, October 5, 2007.
- Significant extension of FDA regulatory oversight over certain “home brew” laboratory tests, by Jill Alvarez & Teresa Kelto, FDA Alert (a publication of Nixon Peabody LLP), Sept. 25, 2006.
- August 25, 2008: Cancer Test For Women Raises Hope, and Concern, by Andrew Pollack, Health Section (online edition), The New York Times, Aug. 25, 2008 (Aug. 26, p. F1. NY print edition).
- September 9, 2008: The FDA recently reposted on its website, a copy of the August 7th letter to the President and Chief Executive Officer of LabCorp regarding OvaSure™. To view a copy of the letter, CLICK HERE.
- October 8, 2008: FDA Issues A Warning Letter to LabCorp Regarding The Illegal Marketing of the OvaSure™ Test, by Paul Cacciatore, Libby’s H*O*P*E*, Oct. 8, 2008.