There was no particular incident that tipped the scales on in vitro diagnostic multivariate index assays (IVDMIAs) at the FDA. It may have been more like the proverbial straws on a camel’s back. The FDA would not comment at press time since it was in the middle of reviewing the issue, but there are some clues as to the agency’s motivation.

“At one roundtable meeting about 3 years ago, [the FDA] did bring up a particular microarray,” says Elissa Passiment, EdM, CLS(NCA), executive vice president of the American Society for Clinical Laboratory Science (ASCLS). “They could not see how a laboratorian would be able to interpret the results without relying on the manufacturer, and they were uncomfortable that the test may not have had a good method of validation. Their concern was that the test represented a new methodology—they didn’t want to stifle innovation but they wanted to assure validity.”

As the FDA explains in its “Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays,” the FDA realized that it was not regulating IVDMIAs through other means. It states, “FDA believed it was regulating the primary ingredients of most in-house tests because it was regulating the common elements of in-house tests, including most ASRs, general purpose reagents, general purpose laboratory equipment, other laboratory instrumentation, and control. IVDMIAs include elements … that are not among these primary ingredients of in-house tests and that, therefore, raise safety and effectiveness concerns.”1

The organization hasn’t, however, created new regulations, or even initiated a rule-making process. Technically, the guidance is not legally enforceable, but since it represents the FDA’s thoughts on the matter, affected parties are taking the guidance seriously, and it could become official some day, particularly as the market continues to grow and more tests are approved. Some companies have chosen to seek voluntary clearance.

MammaPrint from Agendia, Amsterdam, The Netherlands, is the first test to be approved as an IVDMIA. eXagenBC from eXagen Diagnostics Inc, Albuquerque, NM, is expected to be the next; the company submitted its FDA application in April.

IVDMIAs are expected to increase rapidly over the next decade. The market has grown quickly even in the past 3 years. One expert estimates that more than 200 assays that are potentially MIAs are currently in late stages of development. Subsequently, when the FDA published its guidance in September 2006 and asked for comments, the industry responded.

Organizations such as the American Clinical Laboratory Association (ACLA) and the Coalition for 21st Century Medicine submitted letters and attended the public meeting in February. Some believe the guidance presents more problems than solutions; others find it workable, but no one thinks it’s perfect.

Defining IVDMIAs

One of the main issues is how to define IVDMIAs. In its guidance, the FDA states that this category includes “test systems that employ data, derived in part from one or more in vitro assays, and an algorithm that usually, but not necessarily, runs on software to generate a result that diagnoses a disease or condition, or is used in the cure, mitigation, treatment, or prevention of disease.”1 It states three criteria meant to distinguish the assays from other laboratory-developed tests: the use of clinical data, an algorithm, and a result that requires the test developer’s help to interpret.

Because the FDA definition is so specific, some think it is adequate. “If the FDA asked for only one or two of its criteria, it would start getting into laboratory-developed tests,” Passiment says. “But by requiring all three the tests are characterized pretty well.”

Some, however, think this definition has the potential to include well- established tests. Alan Mertz, president of the ACLA, suggests the FDA’s definition could cover routine tests such as prothrombin time/INRs, 24-hour urine analytes, and HIV and hepatitis genotyping, even if that was not the FDA’s intent.

“I think you get universal agreement, including the FDA, that what was put in the September draft guidance was not clear,” says Paul Radensky, a partner with McDermott, Will and Emery LLP, Miami, and spokesperson for the Coalition for 21st Century Medicine. How do you determine when a test has been well established, he asks, and who is the arbiter of that?

“As long as there is an inherently subjective standard, there will be a lot of unpredictability,” Radensky says, “and there will remain uncertainty into the future. ‘We’ll know it when we see it’ is not helpful.”

In its letter to the FDA, the ACLA notes that it “was informed by FDA officials that it was not their intent to include such well-established tests within the scope of the Draft Guidance, and FDA requested our assistance in clarifying and narrowing the definition of IVDMIAs to conform to its intended application.”2

The ACLA responded suggesting that the FDA narrow the definition to include new test systems that meet the FDA criteria and “present significant safety and effectiveness risks not present in test systems that have become the standard of care.”2

Exclusionary criteria should include low-risk consequences of invalid or inaccurate test results, independent verification, support of clinical validity in peer-reviewed literature, transparent algorithms, interpretation support for clinicians, support in clinical guidelines, established use, CPT code assignments, and/or payer recognition.2 “There needs to be a grandfather clause for tests already in use,” says Mertz.

The First Official IVDMIA

MammaPrint  IVDMIA
The MammaPrint is the first IVDMIA to receive clearance from the FDA.

Though not technically the first in vitro diagnostic multivariate index assay (IVDMIA), MammaPrint from Agendia, Amsterdam, The Netherlands, was the first to be cleared by the FDA as an IVDMIA—and it was done voluntarily.

“We felt it was clear that the FDA would sooner or later step in and regulate this market,” says Rene Bernards, Agendia’s chief scientific officer. “So the company made a proactive move and hired a quality manager in October 2003.”

Agendia worked closely with the FDA since the product represented a new type of test, and previous criteria for clearance had not been established; the FDA’s draft guidance on IVDMIAs was not released until September 2006. The FDA did not require a premarket approval for MammaPrint; instead it granted the test de novo 510(k) status, which applies to low-risk devices with no predicate device. The process took a little bit longer than the typical 510(k) process and required more data, but the test is now established as a predicate device for future breast cancer products of this nature.

MammaPrint predicts the risk of metastasis in breast cancer patients using DNA microarrays. The gene-profiling test uses messenger RNA (mRNA) to perform triplicate gene expression measurements and duplicate sample measurements to provide consistency and confidence with the results. Agendia runs the test, with a turnaround of about 10 days. MammaPrint was cleared by the FDA in February.

Assuring Quality of IVDMIAs

Existing IVDMIAs have been regulated under a variety of requirements, including those of CLIA, state regulations, and other accrediting organizations such as The Joint Commission, CAP, and COLA. The tests are often high-complexity and laboratory developed.

“Currently, laboratories or researchers who develop IVDMIAs test them internally, often on their own specimens and within their own laboratory procedures, which are governed by CLIA. Offered under the umbrella of home brews, it is a self-policing situation,” says eXagen’s Popper.

This, however, does not mean poor quality. Popper notes that OncotypeDX from Genomic Health Inc, Redwood City, Calif, is a research-developed assay performed in a CLIA-approved laboratory. Though it lacks FDA clearance, the company has published supporting data in peer-reviewed literature.

Unfortunately, even published data can be suspect, particularly if it appears in questionable journals. The big question for some, therefore, is how to assure the quality of these tests with FDA oversight.

“If a lab brings these tests onboard, it has to rely on the manufacturer and its suggested QC to do the in-house quality control,” Passiment says, “but there is no way to validate the software, so there is no way to know if the results you are putting out there really mean anything.”

The other big question is whether the FDA recommendations laid out in the draft guidance will actually improve test quality. Some think it is tough to say. “It’s not clear from testing itself that falling under compliance with two different regulatory systems with different purposes will actually improve quality,” says Radensky.

He suggests that new FDA regulations may actually produce some conflicts. For instance, CLIA test reporting requires laboratories to provide updated information relevant for treating physicians who interpret the test as well as consultants to help interpret the data in the context of the patient. “These requirements are different than what the FDA would consider for labeling and promotion,” Radensky says.

But others think the guidance lays a good foundation for an area where a lack of oversight exists. “The FDA’s recommendations do need to be expanded, explained, and clarified,” Passiment says, “but they are a good start.”

Clearing IVDMIAs

According to Popper, FDA recommendations establish a level playing field, subjecting all data to the same scrutiny that has held up well for other types of assays. Companies and laboratories developing these types of tests will need to integrate FDA clearance into product planning and time lines, but will not necessarily have to alter their processes. In some cases, the FDA will require data that would have been collected for internal validation anyway.

In the guidance document, the FDA states that it is seeking the least burdensome approach to quality assurance, a point it expressed to the ASCLS at the roundtable discussion 3 years ago. But some fear that any FDA involvement will result in a burden that will, at best, slow development and, at its worst, will hamper innovation.

“The FDA realizes it is placing a regulatory hurdle on the path of development, but at the same time is trying to be as helpful as it can,” Popper says. “I don’t think its involvement will slow down innovation, but it may delay the time to commercialization by about 6 to 12 months.”

Popper speaks from experience: eXagen has been working with the FDA over the past 2 years to obtain clearance for its breast cancer prognostic marker assay, eXagenBC. “We met with the FDA on three occasions, and they were very helpful from a study design perspective and making clear what they wanted,” he says.

Others, however, think the draft guidance has already impacted development negatively. The uncertainty alone can be enough to kill a project, turning away investors who do not want to take on the risk of unknown regulatory hurdles, which can result in longer time frames and greater cost.

One source who requested anonymity stated that most MIA companies typically spend from $40 million to $70 million developing an assay under the current rule, but that the FDA recommendations would increase that expense two or three times. In addition, the effort and time required to gather the necessary data and complete the paperwork would create additional obstacles.

For larger manufacturers, these burdens may not hinder development. Indeed, many manufacturers support the guidance, saying it evens the market and places the same requirements on all developers. Laboratories, however, may have a harder time. Many are not used to the FDA process nor do they have the resources to handle the extra paperwork and process. The volume generated by many of these tests would not cover the expense, making the pursuit impractical if not completely unattainable.

Passiment suggests that the effort will depend on the researcher. “At the February testimony, some scientists said they would stop their research, but others said it would merely slow them down,” she says. “Many are driven by their mission to serve the greater good.”

The Future of IVDMIAs

Of course, the FDA is also driven by this mission, and regulation can bring additional benefits besides quality. Passiment suggests that oversight will eliminate questionable tests that are skating by under the ASR rule, while raising confidence in those that obtain clearance. Tests that obtain clearance can be used in laboratories outside of the original developer.

“This level of regulation brings tests into the realm of the hospital,” says Popper. “With validated tests in-house, a hospital doesn’t have to divide a specimen into multiple pieces to send off to other laboratories.”

The actual validation need not burden test developers, either. “You’ve got to prove that the test works whether you submit the information to the FDA or not,” Popper says. She acknowledges that the FDA will require diverse data gathered from at least three or four sites on enough patients to determine a statistically significant difference between high- and low-risk patients.” “You should want to do this anyway,” she says.

“Want to” and “have to,” however, are two different things—what the FDA decides to do next will affect the regulatory status of IVDMIAs and whether organizations will want or need to obtain clearance. Currently, the agency is reviewing industry responses and formulating its response.

Many hope the FDA will decide to change course and pursue a more formal rule-making process. Mertz, who attended a recent presentation of Steven Gutman, MD, director of the FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety of the Center for Devices and Radiological Health, suspects the agency may produce another draft guidance.

More information on in vitro diagnostics.

Whatever the FDA decides, Passiment says she hopes the agency shares its reasoning, because without formal rule-making, the FDA does not have to explain itself. The agency also does not have to allow a transition period, though many hope it will do this, too, if the FDA recommends clearance, which seems likely. Even if the FDA does not step in, it is possible that Congress will. New bills addressing health care have been introduced and are in the works; the scales have been tipped.


  1. Center for Devices and Radiological Health (CDRH). Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays. U.S. FDA, Department of Health and Human Services. Available at [removed][removed]www.fda.gov/cdrh/oivd/guidance/1610.pdf[/removed][/removed]. Accessed on June 11, 2007.
  2. American Clinical Laboratory Association. Public Comment In Vitro Diagnostic Multivariate Index Assays. ACLA. February 8, 2007. Available at [removed]www.clinical-labs.org/documents/IVDMIAcommentsfinal.pdf[/removed]. Accessed on June 11, 2007.

Renee Diiulio is a contributing writer to CLP.