In 2002, Correlogic Systems nudged bioinformatics toward the clinical realm by licensing its proteomics analysis software to two commercial laboratories for development of an ovarian cancer diagnostic test. But a recent letter from the US Food and Drug Administration indicates that Correlogic — and other companies hoping to develop bioinformatics-driven diagnostic methods — may have to jump through a few more regulatory hoops than originally expected to bring such a test to market.
On Feb. 18, the FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety issued a letter inviting Correlogic’s CEO Peter Levine “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.”
According to the letter, Correlogic’s technology appears to fall under the FDA’s definition of a medical device — meaning that it may require premarket approval — but the agency has “no record that such a test has been the subject of premarket review by FDA.”
FDA officials declined to comment on the letter, and a Correlogic spokesperson said only that “we have not had the meeting with the FDA yet, but we will meet with them and we are happy to do so.”
But happiness is not the usual consequence for the recipients of letters like this one — at least not in the short term. The FDA letter “could have a dramatic effect on Correlogic’s plans,” said Alan Kusinitz, managing partner at SoftwareCPR, an FDA software regulation firm. If the FDA determines that Correlogic’s technology is indeed a medical device representing a new technology for cancer detection, “then the company would be subject to a potentially lengthy premarket review of their safety and effectiveness data, and inspection for compliance with other medical device regulations,” Kusinitz said. In a best-case scenario — in which the company would already have data from clinical trials studies, outcome data, design control information for the software, validation documentation, and other required information — such a process could take six months or more, he said. If that documentation is not in place, the approval process could take years.
Still in Development
Neither Quest Diagnostics nor Laboratory Corporation of America — the two labs that licensed Correlogic’s algorithms — has yet made the diagnostic commercially available, but Pam Sherry, a senior vice president for LabCorp, told BioInform’s sister publication ProteoMonitor that “as of a couple of days ago” the company had planned to roll out a test “on or around April 1.” Sherry declined to comment on the letter and its potential impact on those rollout plans.
Gary Samuels, a spokesperson for Quest Diagnostics, also declined to comment on the letter, and said that because the company is still evaluating the technology, a decision has not yet been made about whether an ovarian cancer test based on Correlogic’s technology “will be available ever” through Quest. He said that each of the three involved companies — Correlogic, LabCorp, and Quest — was independently conducting validation tests now on a “large collection” of specimens, and that initial analysis has already been completed on 750 specimens from high-risk women provided by the NCI-sponsored National Ovarian Cancer Early Detection program. “This test doesn’t exist — we’re speculating about how a test might work if it’s ever offered,” Samuels said.
In November 2002, Correlogic signed an agreement with Quest and LabCorp for the development of a “homebrew” ovarian cancer test based on its KDE (Knowledge Discovery Engine) pattern-recognition software, which is able to classify protein expression patterns derived from mass spectrometry experiments. The homebrew designation often serves as a regulatory shortcut for diagnostics: While tests that are marketed directly to hospitals or physicians must endure a lengthy premarket approval process, homebrew tests offered as a service by approved clinical laboratories are very lightly regulated. In the case of the Correlogic diagnostic test, LabCorp and Quest would presumably run the mass spec experiments on blood samples sent to their labs and use the Correlogic software to analyze the data.
Is Software a Medical Device?
It appears that the FDA directed its letter only to Correlogic, and not to LabCorp or Quest, because the software itself qualifies as the diagnostic device. The agency defines a medical device as “any instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part or accessory, which is intended for use in the diagnosis of disease or other conditions.” According to Suzan Onel, an attorney who specializes in premarket submissions at the law firm of Kirkpatrick & Lockhart, “If this product is specifically intended for the diagnosis of cancer, [the FDA has] a strong argument that this software is a medical device.”
Onel said that the FDA’s approval requirements for software associated with medical devices can vary widely, but the agency tends to grow concerned “whenever there’s the possibility of a decision being made based on the reliance on software as opposed to professional medical intervention … whenever there could be a situation where the software program would be doing the diagnosis.” In this case, she said, the FDA may want to know whether Correlogic intends to confirm the software analysis with another method or rely solely on its pattern recognition approach. If it’s the latter case, “they could be much more likely to take a more cautious posture and say, ‘This is a medical device in and of itself.’” In other situations, she said, the agency often allows the software manufacturer “to stay on the sidelines, and focuses on the company that’s actually putting together the diagnostic.” The bottom line, Onel said, is that the FDA has the flexibility in its statutes and regulations “to decide how wide or how narrow they want to make that circle.”
As to whether the method could escape regulation as a medical device under the homebrew classification, Onel noted that “the agency would have to agree that it’s a homebrew.”
Kusinitz said that if the FDA deems Correlogic to be a medical device manufacturer, “then there are many requirements for medical device manufacturers that don’t apply to, say, research … even if they’re a software shop. The key is what the software does, and if it meets the definition of a medical device, then they are subject to [the FDA’s requirements.]” In addition to submitting a premarket submission for the device, Correlogic will have to prove that it is in compliance with the FDA’s other regulations for quality systems, submit adverse event reports, and carry out “a pretty rigorous set of requirements that strictly research groups are not familiar with,” he said.
In a related precedent, the FDA sent a similar letter to Roche Molecular Diagnostics last July, and followed up in October with a letter explaining that Roche’s AmpliChip, a diagnostic microarray based on the Affymetrix GeneChip platform, did not qualify as an analyte-specific reagent, a type of homebrew technology. In the October letter, Gutman said that the chip’s intended use was “of substantial importance in preventing impairment of human health” and therefore was not exempt from premarket notification requirements according to FDA guidelines.
Roche has since decided not to market the test as a homebrew, but will continue to provide it as a research product for use by pharmaceutical companies in clinical trials.
It’s still unclear what kind of impact the FDA’s interest in Correlogic’s technology will have on the fledging company’s plans, but news of the agency’s letter hasn’t dampened the spirits of other bioinformatics companies looking to market similar tools. Eclipse Diagnostics, a Large Scale Biology spin-off, is also preparing a software-based diagnostic test for ovarian cancer using proteomics data. John Rakitan, senior vice president and general manager of Eclipse, told BioInform that the company read the FDA letter to Correlogic with “great interest,” but interpreted it as an effort by the agency to be “helpful.” In terms of the opportunities for commercializing its own software-based diagnostic, “the landscape hasn’t changed based on this letter,” he said.
Navigating the FDA Regulatory Landscape: a Guide to Some Key Documents
- FDA’s 1998 Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices: http://www.fda.gov/cdrh/ode/software.pdf
- FDA’s 2002 General Principles of Software Validation: http://www.fda.gov/cdrh/comp/guidance/938.html.
- Onel, Suzan. ‘FDA Regulation of Medical Device Software: A Delicate Balancing Act,’ The Journal of BioLaw and Business, Vol. 6  24-29]: http://www.biolawbusiness.com/vol6num4.asp#five (subscription required)
- FDA letter to Correlogic Systems, Feb. 18, 2004: http://www.fda.gov/cdrh/oivd/letters/021804-correlogic.html
- FDA letter to Roche Molecular Diagnostics, Oct. 29, 2003: http://www.fda.gov/cdrh/oivd/amplichip.html
- FDA letter to Roche Molecular Diagnostics, July 8, 2003: http://www.fda.gov/cdrh/oivd/letter-roche2.html