The recent controversy surrounding the clinical use of a proteomic test for the early detection of ovarian cancer has underscored the regulatory gaps for an emerging breed of laboratory tests, and it is raising questions about how best to balance the interests of patients who want access to cutting edge diagnostics with the need to ensure the efficacy and appropriate use of new technology.
The science behind the test, called OvaCheck, was developed by research scientists Emanuel Petricoin, Ph.D., from the U.S. Food and Drug Administration and Lance Liotta, M.D., Ph.D., of the National Institutes of Health, in conjunction with Correlogic Systems in Bethesda, Md., which owns the patent. The test uses mass spectroscopy to look for a protein pattern, or "fingerprint," in blood samples that the group reported is indicative of ovarian cancer.
Designed for women at high risk for ovarian cancer, the screening test is being hailed for its pioneering use of protein patterns and its potential to detect the disease in an early stage. But praise has been tempered with criticism, and last month, shortly after one of the two laboratories licensed to perform the test dropped marketing materials for the testwhich is not yet on the marketunder the hotel doors of attendees at a Society of Gynecologic Oncologists (SGO) conference, the FDA stepped into the gathering storm.
In a February 18 letter addressed to Peter Levine, president and chief executive officer of Correlogic Systems, FDA official Steven Gutman, M.D., said the agency was aware the company was "contemplating or has begun the commercial distribution" of the test. He invited Levine to a meeting "to discuss the nature and appropriate regulatory status of your technology, and the least burdensome ways that Correlogic Systems may fulfill any premarket review requirements that may apply."
Levine said he was surprised by the letter, which "showed up out of the clear blue," and he did not know what it meant for the regulatory status of the test. He stressed that although one of the laboratories had jumped the gun on the distribution of marketing materials without his knowledge, OvaCheck would not be available until the companies completed their validation process.
"This process is being driven by the science, not by the calendar," Levine said. Correlogic Systems makes the software that analyzes the blood samples and has licensed two laboratories to conduct the tests: Quest Diagnostics and Laboratory Corporation of America (LabCorp), the latter of which was responsible for the marketing drop at the SGO meeting. (FDAs Gutman subsequently sent Quest and LabCorp letters on March 2 stating, "Because the nature of this test is not clear from the materials we have reviewed, we are uncertain if your ovarian cancer offering will be subject to regulation only by [the Centers for Medicare and Medicaid Services], under the Clinical Laboratory Improvement Amendments of 1988 (CLIA), or whether it may also require premarket review by FDA under the Federal Food, Drug, and Cosmetic Act.")
Prior to receiving Gutmans letter, Levine said he had assumed that OvaCheck would be exempt from FDA review under a test designation called "home brew," which gives certain laboratories that conduct their own in-house test a reprieve from the agencys premarket approval process. The agency imposes some standards on the components of certain home brew tests, namely those using "analyte-specific reagents," but exerts no oversight authority relative to the test itself.
Home brew tests are regulated instead under the general requirements of CLIA (see Box, p. 501), and although the designation is widely viewed as necessary and appropriate for getting new diagnostics to market, it leaves in regulatory limbo a pipeline of genomic and proteomic tests that are under development, for which there is no specific oversight.
"The regulatory gap is a huge concern," said Leigh Anderson, Ph.D., founder and chief executive officer of the Plasma Proteome Institute. "The issue is balancing the safety and reliability of information with getting medical advances on the market."
In the case of OvaCheck, the FDA "is in new territory," Anderson said. The agency has never before seen a "multiplex test" in which more than one protein is used as a marker.
Whereas OvaCheck is in the eye of the storm, a less noticed test, representing an early application of applied genomics to the prediction of breast cancer recurrence, has recently appeared on the market without FDA review.
The test, dubbed OncotypeDX, was developed by Genomic Health in Redwood City, Calif., and a research team headed by Norman Wolmark, M.D., chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP) and chairman of the department of human oncology at Allegheny General Hospital in Pittsburgh.
The test uses a 21-gene expression profile to identify women who are likely to experience a recurrence of breast cancer. OncotypeDX is targeted to the segment of breast cancer patients who are node-negative, have been treated with tamoxifen, and are hormone receptor-positive. The test was developed from three clinical trials and validated in a study using 668 specimens.
OncotypeDX "will enable a more rational decision to be made relative to subsequent and additional treatment," Wolmark said. It is far more accurate and reproducible than traditional parameters used to make treatment decisions, namely a patients age, tumor size, and tissue grade, he added. "It is the first step in proof of the principle that we can use gene profiles to provide more accurate information over and above the criteria that are currently in clinical use," he said.
He declined to call the test a "breakthrough," instead referring to it as a "step in the right direction." Data on the test were presented at a conference last December, and the group plans to publish the data in the near future.
OncotypeDX was CLIA-approved January 16, said Kathleen Rinehart, spokeswoman for Genomic Health. Genomic Health is focusing its early marketing efforts on several large cancer centers. The company "has taken the established path for licensure and would welcome the opportunity to work with FDA if it chooses to get more involved in this area," she added.
FDA officials did not return phone calls for this article, and it is unclear whether or when the agency may assume a more authoritative role in the oversight of genomic and proteomic testing.
In the meantime, a greater concern than regulatory review is the ability to review data demonstrating the efficacy of these tests, said Debbie Saslow, Ph.D., director of breast and gynecologic cancer at the American Cancer Society. "Sometimes the FDA review process can be time-consuming and expensive and can lead to delays that can potentially delay benefit to patients," she said. "We wouldnt want an across the board decision or position on that. The big issue is, can we see the data."
OvaCheck developers so far have not published data validating their initial findings, which appeared in a February 2002 issue of the Lancet, and absent such data, the test is not market ready, critics say.
Eleftherios P. Diamandis, M.D., head of clinical biochemistry at Mount Sinai Hospital and professor and head of clinical biochemistry at the University of Toronto, extends his concern about OvaCheck validation tests to the underlying technology.
"This is a kind of black-box technology," which raises scientific questions about methodology, he said. The results have not been reproduced, and the test needs to be controlled for potentially confounding factors such as age, race, nutritional status, drugs, and the number of times a sample was frozen, Diamandis said.
"The technology is exciting and promising, but there are no peer-reviewed publications that discuss the sensitivity and specificity [of the test using this new platform], and there are no outcomes [from] clinical trials to say that indeed it does what they say it does," said Beth Karlan, M.D., director of gynecologic oncology at Cedars-Sinai Medical Center in Los Angeles and president-elect of the SGO.
Karlan is concerned about a direct-to-consumer marketing campaign for OvaCheck that will not be backed by sufficient data for the public to understand its application or for the medical community to know how best to act on the results. She said she hopes to see "more work validating this tests effectiveness before offering it to the public." The SGO issued a February 7 statement calling for additional research.
Saslow said that the 5% false-positive rate of a similar test, initially reported in 2002, is also a concern. "Even a 1% [false-positive rate] for ovarian cancer is considered high," she said, because among the general population, and even among those deemed at high risk, a relatively small segment of women will get the disease. Clinicians argue that even a low false-positive rate will translate to large numbers of women erroneously diagnosed, and those patients may undergo further testing and possibly unnecessary surgical procedures.
Levine said that the criticism of OvaCheck is premature. The company is working on validation tests and will take "all steps necessary to ensure everything works properly" before OvaCheck is brought to market. More than 1,000 samples have been collected so far, and when the data are ready they will be shared through a peer-reviewed journal or other venue. In the meantime, critics should waylay judgments about the test, Levine said.
"You cant offer an opinion until you see the data," he added.
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