Though Ciphergen missed its self-imposed deadline of disclosing a diagnostic collaboration before the end of June, the company's track record of careful biomarker validation and its expertise in manufacturing SELDI instruments and chips may help it to score such a deal with Quest Diagnostics.
The deal, if it materializes, may also be a significant step in the development and eventual use of proteomic biomarkers as tools for molecular diagnostics and even pharmacogenomics-based drug discovery. The timing of Quest's negotiations with Ciphergen, together with its existing alliance with Correlogic Systems, also come at a time when the US Food and Drug Administration has become "open-minded" to the idea of reviewing protein-biomarker data [see sidebar].
Ciphergen said last week in an SEC filing that the company is "in discussions" with Quest for a potential diagnostics alliance but that "the nature of the potential alliance, including the financial and business terms, have not yet been agreed to and there can be no assurance that an alliance will be completed between the two parties."
Though Quest has licensed for commercialization the OvaCheck ovarian cancer test developed by Ciphergen rival Correlogic Systems (see ProteoMonitor 6/17/2005), and has even made an equity investment in the protein biomarker shop as early as last month, a deal with Ciphergen, which has been developing its own ovarian cancer test, could complement Correlogic's test, according to at least one person familiar with both technology.
"In trying to launch [OvaCheck] too early, [Correlogic] really did a faux pas. It hurt the whole clinical proteomics industry. It destroyed the credibility and left a really bad taste in the mouth of all the players. I think Ciphergen learned a lesson from this, and they have been doing a very good job at validating their tests."
Correlogic has expertise in proteomics software and strength in product development and commercialization, but in the past the company has not been thorough in validating its preliminary results. When the company originally tried to launch OvaCheck three years ago in collaboration with Quest and LabCorp, it did so without carefully validating its preliminary results. Correlogic's credibility was later bruised when it was later shown that the test's specificity was not high enough.
"In trying to launch [OvaCheck] too early, they really did a faux pas," said Jorge Leon, president and founder of molecular diagnostics-focused consulting company Leomics Associates. "It hurt the whole clinical proteomics industry. It destroyed the credibility and left a really bad taste in the mouth of all the players. I think Ciphergen learned a lesson from this, and they have been doing a very good job at validating their tests."
From Leon's perspective, a collaboration between Quest, Correlogic, and Ciphegen "could certainly work" because the companies each bring different areas of expertise.
"Certainly, [Ciphergen and Quest] are two formidable partners," Leon, a former vice president of applied genomics for Quest, told Pharmacogenomics Reporter's sister publication ProteoMonitor this week. "Ciphergen is a leader in proteomics, in quality control and validation. Quest is a leader in test development and commercialization. Together, probably they can do something."
If Quest decides to partner with Ciphergen and integrate its technology with the OvaCheck test, one of the main challenges it will face will be deciding which product will serve as the platform for an ovarian cancer diagnostic. Correlogic's OvaCheck is based on a proteomic pattern created by five proteins that have not been identified, while Ciphergen's test is based on a panel of three protein biomarkers that have been identified and characterized (see PM 5/13/2005).
Correlogic launched a two-year validation study for its OvaCheck test last June (see PM 6/25/2004). The study is based on an initial study led by proteomic pioneers Lance Liotta and Emanuel Petricoin. The study, which involved 50 women with ovarian cancer and 66 controls and women with non-malignant disorders, showed that the proteomic pattern was able to discriminate ovarian cancer with 100 percent sensitivity and 95 percent specificity.
Ciphergen, on the other hand, last fall began validating its ovarian cancer test based on three protein biomarkers in a study involving 1,500 samples. Preliminary analysis of 436 samples in the validation study showed the biomarker panel combined with CA 125, the existing ovarian cancer biomarker used in hospitals and clinics, scored between .88 and .91 out of a perfect score of one, in terms of specificity and sensitivity (see PM 11/5/2004)
According to Andrew Berchuck, a professor of gynecological oncology at Duke University, both Ciphergen and Correlogic's ovarian cancer test have a long way to go before they can be used to screen for early stage ovarian cancer. In order for a test to give 10 false positive results for every true positive, it would have to have a specificity of 99.5 percent. Given that the consequence of a positive test result could be surgery, it is critical that specificity be at or above that level, Berchuck stressed.
Quest will not care in the end which company or analyte its labs will use — the company will only care about which product delivers the best clinical result, Leon noted.
"Companies like Quest and LabCorp are at the end of the food chain," Leon said. "They are the ones that deliver the services that give doctors the answer. The doctors and Quest do not care which company or analyte they use. They care about the best result and choosing the most sensitive and specific clinical product."
Representatives for Quest did not return a telephone seeking comment. A spokeswoman for Correlogic declined to comment for this article, saying that, because a deal between Ciphergen and Quest has not yet been reached, it is company policy not to discuss hypothetical scenarios.
According to Correlogic's web site, the FDA is "currently reviewing the appropriate regulatory path" for the OvaCheck test. "If the FDA agrees that OvaCheck may be offered as a laboratory developed test, regulated under the Clinical Laboratory Improvement Act, the test can be available shortly after such a regulatory determination.
"If however, the FDA requires a full regulatory submission prior to introduction of the test, it will be many months or longer in order to meet such a demand. Discussions with the FDA have been ongoing during the past year and we hope to have a determination in the near future," according to the web site.
Gail Page, president of Ciphergen's diagnostic division, said late last year that the FDA has been pleased with the cross-sectional representation of samples in studies using the SELDI technology to find and validate biomarkers, and with the agency's comfort with data produced by Ciphergen-using scientists may help in ultimately getting biomarkers approved.
"[The FDA] was relieved that we don't just feed in samples and out comes the data," Page to ProteoMonitor in October 2004. "They were pleased with our cross-validation and they loved the fact that we identified the proteins."
The FDA's Perspective
From the FDA's perspective, proteomic biomarkers are "not going to be different from any [genomic] diagnostic that has been approved or that is in approval, or can be approved," according to Felix Frueh, associate director of CDER and head of the FDA's Interdisciplinary Pharmacogenomics Research Group [see accompanying interview]. "The nature of the biomarker is different, but the fact is we're not approving or disapproving based on what the biomarker is as a protein or a gene, or blood pressure.
"We are basing our decision on the usefulness of the biomarker, regardless of its nature," Frueh added. "It's analytical performance and clinical performance and clinical usefulness. It just seems that … the field is heating up rapidly, and developments can be seen very quickly. Perhaps also from a regulatory perspective, we are going to see submissions in that area."
Frueh also said that more companies have been filing proteomic biomarkers with the FDA, specifically in the pre-investigational new drug application phase at the FDA's Center for Devices and Radiological Health. "What we have seen at CDRH is predominantly genomics. But we're starting to see proteomics as well," Frueh told Pharmacogenomics Reporter. "I wouldn't know the ratio, but it's twice genomics to proteomics at this time. I'm talking the new kind of proteomics, like mass-spec tests, not ELISA tests."
Frueh said that proteomic biomarkers may have a home in the Voluntary Genomic Data Submission pathway, which is part of the agency's pharmacogenomics data-submission guidance.
"If you read the guidance, and if you were to exchange the word 'pharmacogenomics' with 'proteomics,' a lot of what's written in the [pharmacogenomics] guidance holds true," Frueh said. "In other words, the decision trees and the validity of biomarkers that now would be proteomic rather than genomics biomarkers would hold up.
"There is no reason why there shouldn't be any difference," he added. "Take that further to the [VGDS guidance], I don't see a reason why voluntary submissions for proteomics could or should be any different than they are for genomics. In other words — and we've been talking about this — you could imagine some kind of process where you exchange 'G' with 'X,' so it would not be a VGDS but rather VXDS, and that 'X' could stand for … 'Exploratory.'
"What we have created with the pathway for voluntary genomic submission is a pathway not necessarily only for genomic data, but for all exploratory early-stage research-type data."
Asked if the FDA has received proteomic biomarker data as part of the VGDS pathway, Frueh said: "No, we have not. We have been contacted several times for request about whether or not we accept them. What we've gotten so far really wasn't at the stage that we thought would warrant a submission at this point. But we definitely are open-minded."