FDA Issues a Warning Letter to LabCorp Regarding The Illegal Marketing of The OvaSure™ Test

On September 29, 2008, the U.S. Food and Drug Administration (FDA) Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), Center for Devices and Radiological Health, issued a warning letter (FDA Warning Letter) to the Chief Executive Officer of the Laboratory Corporation of America (LabCorp) regarding the illegal marketing of the OvaSure™ ovarian cancer early detection diagnostic test. …Steven Gutman, M.D., M.B.A., the OIVD Director, informed David P. King, President and Chief Executive Officer of LabCorp, that his company was in serious violation of the Food, Drug, and Cosmetic Act (FDCA) involving the illegal marketing of the OvaSureTM test and asked that the violations be promptly corrected to avoid initiation of regulatory action by the FDA.

On September 29, 2008, the U.S. Food and Drug Administration (FDA), Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), Center for Devices and Radiological Health, issued a warning letter (the FDA Warning Letter) to the Chief Executive Officer of the Laboratory Corporation of America (LabCorp) regarding the illegal marketing of the OvaSure™ ovarian cancer early detection diagnostic test.

In the September 29th FDA Warning Letter, Steven Gutman, M.D., M.B.A., the OIVD Director, informed David P. King, President and Chief Executive Officer of LabCorp, that his company was in serious violation of the Food, Drug, and Cosmetic Act (FDCA) involving the illegal marketing of the OvaSureTM test and asked that the violations be promptly corrected to avoid initiation of regulatory action by the FDA. The FDA Warning Letter was issued to LapCorp after review of information obtained from LabCorp’s website including a press release and a technical bulletin, as well as information provided by LabCorp in a face-to-face meeting with the FDA on September 5, 2008.

The FDA Warning Letter to LapCorp states that the OvaSure™ test is a “device” under the FDCA because it is intended for use in the diagnosis of disease or other conditions, or in the cure, treatment, prevention, or mitigation of disease. Once classified as a “device” under the FDCA (assuming non-applicability of select exemption criteria), LapCorp is required by law to obtain marketing approval or clearance for the OvaSure™ test from the FDA prior to its sale to the public. This FDA finding, in theory, helps protect the public health by ensuring that new devices are shown to be both safe and effective or substantially equivalent to other devices already legally marketed in this country for which approval is not required.

Based upon OIVD’s findings, the FDA concluded that LapCorp did not obtain FDA marketing approval or clearance for the OvaSure™ test and is in violation of Federal law. Specifically, the FDA describes LapCorp’s violations of, and the required corrective action under, the FDCA as follows:

“… The device [i.e., OvaSure™] is adulterated under section 501(f)(1)(B) of the [Food, Drug, and Cosmetic] Act, 21 U.S.C. 351(f)(1)(B), because you do not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. 360e(a), or an approved application for an investigational device exemption (IDE) under section 520(g) of the Act, 21 U.S.C. 360j(g). The device is also misbranded under section 502(o) [of] the Act, 21 U.S.C. 352(o), because you did not notify the agency [i.e., the FDA] of your intent to introduce the device into commercial distribution, as required by section 510(k) of the Act, 21 U.S.C. 360(k). For a product requiring premarket approval before marketing, the notification required by section 510(k) of the act is deemed to be satisfied when a premarket approval application (PMA) is pending before the agency. 21 CFR §807.81(b). …

… You should take prompt action to correct these violations. Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties.”

The FDA Warning Letter provides LapCorp with 15 working days to correct its violations under the FDCA as noted above, and to explain how such violations will be prevented in the future. The FDA requests LapCorp to notify the agency if such corrective action cannot be taken within the specified 15 working day time frame.

Libby’s H*O*P*E*™ covered the initial marketing release of LabCorp’s OvaSure™ test and the FDA’s initial inquiry into the clinical validation support underlying the marketing of that test on June 23, 2008 and August 23, 2008, respectively.

Source: FDA Issued a Warning Letter to the CEO of LabCorp Regarding The Illegal Marketing of The OvaSureTM Test, Office of In Vitro Diagnostic Device Evaluation and Safety, Center for Devices and Radiological Health, Food and Drug Administration. September 29, 2008.

Lost In Translation? FDA Believes That LabCorp’s Ovarian Cancer Early Detection Test (OvaSure) Lacks Adequate Clinical Validation

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
Via FedEx

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.

Sincerely yours,

/S/

Steven I. Gutman, M.D., M.B.A.
Office Director
Office of In Vitro Diagnostic Device Evaluation and Safety
Center for Devices and Radiological Health

Comments:

  • 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.

Sources:

Updates:

  • 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.

LabCorp Announces Availability of Ovarian Cancer Blood Test To Assess The Presence of Early Stage Ovarian Cancer

“Laboratory Corporation of America® Holdings is now offering OvaSure™, an Ovarian Cancer Screening test to assess the presence of early stage ovarian cancer in high-risk women. In a recent study of high risk and average risk subjects, this blood test, using six biomarkers and research conducted at Yale University School of Medicine, was shown to discriminate between disease-free women and ovarian cancer patients (stage I-IV) with high specificity (99.4%) and sensitivity (95.3%). Additional studies performed at Yale University School of Medicine demonstrate comparable findings.”

On March 14, 2008, the H*O*P*E*™ weblog reported that a new blood test developed by the Yale University School of Medicine detected early stage ovarian cancer with 99% accuracy in Phase II clinical trial testing. To review the March 14 H*O*P*E*™ weblog post, click here. In 2006, Laboratory Corporation of America (Lab Corp) obtained licensing rights to the ovarian cancer early detection blood test, known as OvaSure™, from Yale. Today, Lab. Corp. announced in a press release that it is making the OvaSure™ blood test immediately available nationwide to women who are at high risk of developing ovarian cancer in the future. The relevant portion of the Lab Corp. press release dated June 23, 2007 is set forth below.

LabCorp Announces Availability of OvaSure™

Burlington, NC, June 23, 2008 – Laboratory Corporation of America® Holdings (LabCorp®) (NYSE: LH) is now offering OvaSure™, an Ovarian Cancer Screening test to assess the presence of early stage ovarian cancer in high-risk women. In a recent study of high risk and average risk subjects, this blood test, using six biomarkers and research conducted at Yale University School of Medicine, was shown to discriminate between disease-free women and ovarian cancer patients (stage I-IV) with high specificity (99.4%) and sensitivity (95.3%). Additional studies performed at Yale University School of Medicine demonstrate comparable findings.

‘LabCorp is pleased to offer for high-risk women the OvaSure test to enhance the potential of detecting and treating ovarian cancer in its early or localized stage when the likelihood of survival is greatest,’ said Myla P. Lai-Goldman, M.D., Executive Vice President, Chief Medical Officer of LabCorp. ‘OvaSure is a significant addition to LabCorp’s family of proteomic tests, and a major component of LabCorp’s strategy to bring the latest in diagnostic technology to women’s healthcare.’

It has been estimated that for the year 2008, 21,650 women will be newly diagnosed with ovarian cancer. It has been further estimated that 15,520 women will die from the disease in 2008. Despite being one-eighth as common as breast cancer, it is three times more lethal. If ovarian cancer is diagnosed and treated at the localized stage, the 5-year survival rate is 92%; unfortunately, only 19% of all cases are found at the localized stage. Most women have their ovarian cancer detected at the regional or distant stage when the 5-year survival rates are 71% and 30% respectively.

‘I am pleased that this test is available to help physicians detect and treat ovarian cancer in its earliest stages,’ said Gil Mor, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale and a member of Yale Cancer Center. ‘Our team is proud that our research may help play a role in higher survival rates for women with this disease.’”

[Quoted Source: LabCorp Announces Availability of OvaSure™ , Laboratory Corporation of America Press Release dated June 23, 2008.]

Comment**: Although additional Phase III clinical trial testing with a larger patient population is required, the OvaSure™ blood test may represent the “gold standard” for early stage ovarian cancer detection in the near future. The immediate availability of the OvaSure™ blood test for use by women who are at high risk for developing ovarian cancer could save lives by catching ovarian cancer in its earliest stages, thereby making treatment of the disease highly effective. To view the ABCNews.com news report regarding the Yale ovarian cancer screening blood test that aired on April 21, 2008, click here.

**As of August 21, 2008, the amended OvaSure™ test “use” information provides, among other things, that a woman who has had both ovaries removed (i.e., a bilateral oophorectomy) should not use the test. Accordingly, it appears that the OvaSure™ test cannot be used by a “high-risk” woman to screen for an ovarian cancer recurrence, if she had both ovaries removed as part of her first line treatment following initial diagnosis of the disease.

OvaSure™ Information: The OvaSure™ blood test is now available nationwide through LabCorp. If you want to review OvaSure™ blood test information on the LabCorp. website, click here (then click on the letter “O” located on the upper left side panel keyboard and scroll down until you find the three OvaSure™ blood test information entries). It is our understanding that the OvaSure™ test cost approximately (U.S.)$225 and test results are available within five business days.

OvaSure™ Use (updated 8/21/08): “The OvaSureTM assay may be used as a tool to identify high-risk women who might have ovarian carcinoma. OvaSureTM is not indicated for a patient who is currently undergoing chemotherapy, who has had both ovaries removed, who is pregnant, or who is lactating. About 10% of women with benign ovarian masses (including cysts) may have positive results by this test.”

OvaSure™ Limitations (updated 8/21/08) : “Pregnant women or women who are lactating should not be screened by the assay because it may lead to false-positive results. A Calculated Risk Index of 0.50 or greater indicates a positive reading, which is suggestive of ovarian cancer (possible presence of disease). In a clinical study (see Journal Abstract below) across all disease stages, the six-marker panel composed of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA-125 demonstrated a sensitivity of 95.3% and a specificity of 99.4% in detecting disease. Greater than 99% sensitivity (119 of 120) was shown in late-stage disease (stage III and stage IV). In early stage disease (stage I and stage II), the assay demonstrated a sensitivity of 91.6%, providing a significant improvement over CA-125 alone (less than 60% of stage I and stage II combined) for ovarian cancer detection. All positive readings should be retested on a new sample drawn at least three weeks after the original sample was collected. Patients with positive results confirmed by retesting on a second sample should be followed by a women’s health specialist who may order additional evaluations, such as sensitive imaging. Components used in this test are labeled as research purposes only. The performance characteristics of this product have not been established by the assay manufacturer. Results should not be used as a diagnosis for ovarian cancer without confirmation of the diagnosis by another medically established diagnostic product or procedure.”

OvaSure™ Journal Abstracts and Full Text Studies:

Updates:

  • July 2, 2008: The Society of Gynecologic Oncologists (SGO) issued a statement regarding the Labcorp OvaSure™ test. The SGO statement, dated July 2, 2008, is quoted below in its entirety.

“July 2, 2008

Society of Gynecologic Oncologists
Statement Regarding OvaSureTM

The Society of Gynecologic Oncologists (SGO) recognizes the need for accurate early detection biomarkers for ovarian cancer. For this reason, SGO reviewed the literature regarding OvaSure, a serum-based diagnostic test for ovarian cancer.

After reviewing OvaSure’s materials, it is our opinion that additional research is needed to validate the test’s effectiveness before offering it to women outside of the context of a research study conducted with appropriate informed consent under the auspices of an institutional review board.

SGO is committed to actively following and contributing to this vitally important research. As physicians who care only for women with gynecologic cancers, our hope is that these cancers can either be prevented or detected early. Because no currently available test has been shown to reliably detect ovarian cancer in its earliest and most curable stages, we will await the results of further clinical validation of OvaSure with great interest.”

The SGO is a national medical specialty organization of physician-surgeons who are trained in the comprehensive management of women with malignancies of the reproductive tract. The purpose of the SGO is to improve the care of women with gynecologic cancers by encouraging research and disseminating knowledge to raise the standards of practice in the prevention and treatment of gynecologic malignancies, in cooperation with other organizations interested in women’s health care, oncology and related fields.

Quoted Update Source: Society of Gynecologic Oncologists Statement Regarding OvaSure™, Society of Gynecologic Oncologists, July 2, 2008 (Adobe Reader PDF document).

Other Update Sources: Fast Facts: Background on The Society of Gynecologic Oncologists, Society of Gynecologic Oncologists Press Kit, undated.

“AM Nick is a Fellow in the Department of Gynecologic Oncology, and AK Sood is the Bettyann Asche-Murray Distinguished Professor in the Department of Gynecologic Oncology and in the Department of Cancer Biology, both at the University of Texas MD Anderson Cancer Center, Houston, TX, USA.

In order to overcome the significant mortality associated with ovarian cancer, a highly sensitive and specific screening test is urgently needed. CA125 is used to assess response to chemotherapy, detect recurrence, and distinguish malignant from benign disease; however, this marker is elevated in only 50-60% of stage I ovarian cancers, making it inadequate for early detection of malignancy. In this Practice Point, we discuss Visintin et al.‘s attempt to validate a novel multiplex assay that uses a panel of six serum biomarkers-leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA125 [medical abstract & full text of Visintin et. al. study provided above]. The study included 362 healthy controls and 156 patients with newly diagnosed ovarian cancer. The final model yielded 95.3% sensitivity, 99.4% specificity, a positive predictive value of 99.3% and a negative predictive value of 99.2%. These results indicate potential utility of this assay for early detection of ovarian cancer, although further validation is needed in a sample set representative of the general population.”

  • August 21, 2008: The Labcorp information with respect to the OvaSure™ test was recently modified. Despite that fact that the test was made available for “high-risk” women, it cannot be used by women who have had both ovaries removed. Consequently, it appears that a woman who had both ovaries removed (i.e., bilateral oophorectomy) after an initial diagnosis of ovarian cancer, cannot use the OvaSure™ test to screen for a potential recurrence of the disease in the future.