It looks increasingly likely that FDA will play a larger role in genetic test oversight, though policymakers may soon have to decide just how much more the agency can and should do.

"There is a major gap in the oversight of genetic tests when it comes to the evaluation of clinical validity. ... A truck can drive through that hole," says Reed V. Tuckson, M.D., chief of medical affairs at UnitedHealth Group and chair of a Department of Health and Human Services advisory panel tasked with drafting a better model for genetic test oversight. "We find that to be unacceptable and it needs to be fixed."

Industry and government agency reps are calling for FDA review of all diagnostic tests, including those developed by laboratories, and their proposals are increasingly attracting attention. Currently FDA does not regulate most lab-developed tests, or LDTs, sold as diagnostic services. The agency consistently regulates in vitro diagnostic test kits, sold as packaged products.

At a Feb. 12-13 meeting of the HHS Secretary's Advisory Committee on Genetics, Health and Society (SACGHS) in Washington, D.C., the committee led by Tuckson said it will recommend to HHS that all lab tests be "addressed," if not necessarily regulated, by FDA to ensure safety and effectiveness and utilize FDA's experience in evaluating diagnostics.

FDA Willing To Take On More, But Not All, Tests

"I believe that FDA does have the authority to regulate all of these tests," said Steve Gutman, director of FDA's Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), though he does not believe the agency has enough resources to match the task.

"I certainly don't want all of these tests because it's not possible," he noted at the SACGHS meeting. "But I do think the high-risk tests belong at FDA."

Last March, SACGHS was commissioned by HHS Secretary Michael Leavitt to draft a plan to address observed gaps in genetic test oversight that could lead to harms. A draft of the report and its accompanying recommendations was released for public comment Nov. 5 (¹ [A#01330490006], p. 10). The committee received 64 sets of comments on the draft report, 12 of them from the diagnostics industry.

Many commenters advanced the notion that genetic tests are no different than other laboratory tests in terms of oversight.

As SACGHS finalized its 16 main recommendations, which it plans to send to the HHS secretary by Feb. 29, members struggled to define FDA's proper role in lab-developed test oversight.

Genetic and other tests are currently subject to a mix of FDA regulations, CMS oversight under the 1988 Clinical Laboratory Improvement Amendments (CLIA), state laws and professional society-established standards.

CLIA requires biennial surveys of higher-complexity laboratories plus proficiency testing (PT) to evaluate the quality of lab testing, though not the clinical efficacy of each specific test.

The SACGHS draft report notes that most labs skirt CMS' testing requirements and that CLIA lacks FDA's postmarket vigilance and adverse event reporting mechanisms.

"We think FDA is best equipped to look at clinical validity," AdvaMed VP-Technology and Regulatory Affairs Khatereh Calleja said in an interview. "They have a long history of looking at the higher-risk tests and assuring the safety and effectiveness of devices."

Calleja added, "I think SACGHS recognizes that both agencies play a critical role, but the hard question will be to make a final determination of how this is all going to play out."

Labs Oppose Broader FDA Oversight

FDA has already taken a proactive role in increasing its oversight of a small subset of lab-developed tests with its contested draft guidance on in vitro diagnostic multivariate index assays (IVDMIAs) (² Also see "Lab Stakeholders Still Oppose FDA’s Multivariate Assay Policy" - Medtech Insight, 3 September, 2007., p. 7).

"We've actually cleared only one IVDMIA," Gutman notes. "We respected the fact that it was a very complex device. ... It was a very unusual submission, and it shows, I think, the flexibility of our review process."

FDA's attempts, however, have drawn backlash from labs and others who instead advocate for expanded oversight through CLIA reforms, such as education and training, higher-quality CLIA inspections and additional resources to access controls and standards.

"It is quite frankly infeasible for many LDTs to go through the exact same process an IVD [kit] might go through," said Mara Aspinall, president of Genzyme's genetics unit, which sells genetic test services out of its high-complexity CLIA-certified laboratory.

The College of American Pathologists and Association of Pathology Chairs also oppose a separate role for FDA in LDT regulation. They say smaller labs, for instance, will be hard-pressed to comply with FDA's unfamiliar review system.

But OIVD's Gutman says FDA has ample educational processes in place for newcomers - submission workshops, outreach at professional associations, and the pre-IDE process for those not familiar with the review program.

"Quality is quality, so if small labs are doing a good job now then they will not have difficulty complying," Gutman told "The Gray Sheet."

Also, there are "several dozen guidance documents" on FDA's premarket program and more than 80 Clinical and Laboratory Standards Institute standards, he says, "many of which are already geared toward laboratories rather than manufacturers."

Public/Private Group Could Risk-Stratify Tests

Ultimately, most of the committee supported FDA review of all genetic tests, but admitted that such a scheme was not realistic due to resource constraints.

"All this parsing is just code for: real-world constraints make it difficult to implement," said committee member James P. Evans, M.D., a genetics and medicine professor at UNC Chapel Hill.

Ex officio committee member Muin J. Khoury, M.D., director of the national office of public health genomics at the Centers for Disease Control and Prevention, said because he considers FDA's oversight system the gold standard, any alternative system for LDTs must be equally rigorous.

"The committee can ... describe what the ideal is, which is truth in advertisement, minimum standards of clinical validity, analytical validity and quality control," Khoury said. "Clinical utility is tough. But you need a threshold below which stuff just shouldn't be going to the market."

At the end of the day, SACGHS recommended that HHS form and fund a public/private stakeholder group to decide how to risk-stratify tests, drawing on new or existing regulatory models, such as New York State's lab oversight system. The stakeholder group should also try to eliminate duplicative oversight procedures, SACGHS says.

Gutman says the trouble with a two-tiered risk-assessment system, one for IVD kits and another for LDTs, is that it "wouldn't create parity and it might create confusion and chaos, or an incentive for everyone to make LDTs."

"Since we do have a risk-based program that we've been operating for 32 years now, it would be our preference not to scrap that and start with a new risk-based program," he said.

AdvaMed Proposes New Oversight System

AdvaMed, which represents a number of IVD test kit makers, has long pushed for a more level playing field, calling for a consistent, across-the-board regulatory threshold for both LDTs and IVD kits (³ Also see "IVD Manufacturers, Labs Should Be Subject To Same Standards – AdvaMed" - Medtech Insight, 30 August, 2004., p. 5).

The device trade group presented SACGHS with an alternative oversight model, which it says will make better use of FDA resources by requiring the most premarket data for the highest-risk tests.

In AdvaMed's proposal, FDA oversees safety and effectiveness of all diagnostic tests, including LDTs, using a risk-based approach, and all clinical labs are subject to CLIA requirements and quality standards.

"AdvaMed has a point," Gutman said. "A lab test is a lab test. If I'm a patient ... I want someone to be responsible for it working." FDA says it is currently weighing AdvaMed's proposal and several others.

FDA oversight should focus on risk of harm to patients, "not only on new technology or the novelty of the analyte," Robert Di Tullio, cochair of AdvaMed's diagnostics task force, commented before the HHS advisory panel.

Low-risk or well-standardized tests should be exempt from premarket review, or subject only to labeling review of performance claims, the trade group says. Tests for rare diseases or seldom used tests should also be allowed to skirt some premarket requirements.

AdvaMed proposes that FDA and CMS harmonize their regulatory requirements for all diagnostic tests and leverage each other's standards and resources for oversight of LDTs.

FDA, CLIA Regs Can Be Harmonized - Gutman

Gutman notes that FDA's Quality System Regulations (QSRs) and CLIA's requirements are more similar than many think.

"We're cognizant of the fact that there are QSR and CLIA differences," Gutman said, but added, "I view that actually as a red herring. I actually think there have been more similarities than differences, and the differences just need to be explained in a user-friendly way."

Both sets of regs require test makers to maintain controlled operational environments, establish quality control and quality assurance systems and have well-documented standard operating procedures, Gutman said. The differences lie mostly in design control requirements and the way corrective and preventive action is performed.

"FDA is committed to developing guidance and working with CLIA to try to avoid duplicative regulation," Gutman said.

HHS Panel Calls For More PT, Mandatory Registry

Currently, CLIA requires that all non-waived tests undergo some form of performance assessment, but only 83 specific analytes are required to undergo proficiency testing, the most rigorous form of assessment.

SACGHS recommends CMS require proficiency testing for all non-waived tests for which methods and products to perform such testing are available. Tests without PT products available would undergo an alternative assessment method as required by CLIA regulations. Meanwhile HHS should fund studies of other assessment methods and promote the development of new PT products, SACGHS says.

"We could look at all of the PT needs across the country, not just genetic testing," said Judith Yost, director of CMS' division of laboratory services.

"You can get to the personnel requirements through professional standards; you can get to quality control. There is a CDC group that is working on genetic testing quality control, and those recommendations can go into our guidance to laboratories," she said. "And, believe me, anytime we put something in there, people do it."

CMS Says It Will Crack Down On Uncertified Labs

In addition, the HHS advisors urged CMS to more strongly sanction labs that perform tests without CLIA certification. Currently, CMS cannot take action against uncertified labs, and instead reports them to the HHS Inspector General.

Yost says the agency has successfully dealt with violators by sending "a rather unfriendly" letter, but could certainly use more authority. She says CLIA technically has authority over all entities that meet the statutory definition of a lab.

After submitting its specific recommendations to Secretary Leavitt this month, SACGHS plans to finalize a more detailed report on genetic test oversight by April 30.

- Jessica Bylander (j.bylander@elsevier.com)

FDA Genetic Test Oversight Is On The Rise, But How Far Can It Go?

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