The Testing of the Tests

The diagnostic testing business is taking off, moving into genetic testing and more direct-to-consumer (DTC) marketing, and raising red flags all over. Congress is investigating charges that consumer test kits are unreliable or outright fraudulent. FDA is concerned that inaccurate test results could alarm patients or camouflage real health problems. It is looking to regulate these products more aggressively to protect public health, but faces opposition from diagnostic lab operators and marketers of laboratory-developed tests (LDTs). A real concern is that too-heavy regulation could discourage development of new tests vital to personalized medicine. Pharma companies are watching closely to see how these issues may impact drug-diagnostic co-development and medical product marketing.

The LDT debate hit the headlines in May when Walgreens announced plans to sell Pathway Genomics' genetic test kit in its stores. Pathway's kits, as well as others, many sold over the Internet, collect a saliva sample from the customer and then analyze it for a range of DNA characteristics. The test marketers claim the information can reveal a person's predisposition for certain diseases, such as Alzheimer's or cancer, and assess response to specific medicines and treatments. But the regulators and health professionals fear that faulty findings may lead to unnecessary and inappropriate care.

Jill Wechsler

FDA advised Pathway that its test first must be evaluated and approved for market, and Walgreens cancelled the deal. Soon after, FDA sent similar letters to other leading consumer genetic testing companies—deCODE Genetics, 23andMe, Navigenics, Illumina, and Knome. The firms maintain that FDA review is not appropriate for LDTs, but some have welcomed the move as a way to expand product acceptance and use.

Meanwhile, the House Energy and Commerce Committee stepped up its ongoing investigation of genetic testing and held a hearing in July on test kit quality and marketing. The highlight was a Government Accountability Office (GAO) report on a "secret shopper" exercise that produced varying health reports from 10 tests based on DNA samples from five real and fictitious donors. The results are of "little or no practical use," GAO stated, and may even smack of deceptive marketing. At the hearing, Jeffrey Shuren, director of the Center for Devices and Radiological Health (CDRH), made a strong case for FDA oversight of genetic testing, advising that FDA plans to develop a draft oversight framework that could be phased in over time, based on a test's level of risk.

Tricky Rules

A murky, bifurcated regulatory regime for test laboratories makes LDT monitoring a tricky issue. FDA regulates as medical devices the equipment used in test laboratories and certain consumer test kits, such as home pregnancy tests and glucose monitors; the Centers for Medicare and Medicaid Services monitors and certifies test labs under the Clinical Laboratory Improvement Amendments (CLIA) of 1988. FDA has maintained a hands-off approach to LTDs developed and used within labs. However, the proliferation of more complex tests marketed directly to consumers is prompting a new look, particularly at companies using the LTD label to avoid FDA oversight. Moreover, manufacturers of those commercial tests that FDA reviews complain that the LDT loophole creates an unlevel playing field.

These issues were discussed at a two-day FDA public meeting in July on options for LDT regulation. Staffers from CDRH's Office of InVitro Diagnostics (OIVD) summarized FDA's history with LDTs and its efforts to ensure the quality of test components as more complex products have emerged. While the genetic tests marketed a few years ago emphasized "nutritional" analysis and were considered fringe products, DTC genetic tests today claim to predict risk for disease. Elizabeth Mansfield, OIVD director of personalized medicine, noted that LDTs have evolved to be more like commercial diagnostics, and that the public needs greater assurance that the tests are reliable, that design and software is validated, and that the products are safe and effective.

Representatives of clinical laboratories insisted that CLIA provides effective oversight of their operations, and that they don't want that to change. LDT manufacturers agreed that FDA regulation is not needed and warned it would stymie innovation and experimentation. Everyone urged a clear pathway for small volume tests, particularly those that diagnose rare diseases. FDA officials acknowledged that flexibility is needed to spur development of innovative diagnostics for unmet needs, and the importance of achieving balance between ensuring the accuracy and reliability of diagnostics, and encouraging labs to invest in new assays. Diagnostics are the "linchpin of personalized care," Mansfield commented.

Key to Personalized Medicine

The importance of diagnostics for turning genomic discoveries into useful treatments was articulated in a July 22 New England Journal of Medicine article by FDA commissioner Margaret Hamburg and National Institutes of Health (NIH) director Francis Collins. Researchers have discovered hundreds of genes with variations that may contribute to human illness, they note, but these require accurate diagnostics to identify patients who can benefit from targeted therapies. Because many therapeutic decisions currently rely on diagnostics that have not been reviewed for accuracy and reliability by FDA, Hamburg and Collins warn that these can produce results that are "quite challenging to interpret" and can shape important medical decisions, such as removing a woman's ovaries.

FDA thus seeks "an efficient review process that produces diagnostic-therapeutic approaches that clinicians can rely on" and which encourages manufacturer investment in test validation.

FDA will work to ensure the quality of key diagnostic tests, say Hamburg and Collins, to better protect patients and to encourage personalized medicine that "will lead to real health improvements."

At a seminar sponsored by the Food and Drug Law Institute (FDLI), Mansfield emphasized that "the book is not written" on how FDA will revise its regulatory approach. She also observed that tests sold directly to consumers are poor candidates for minimal enforcement because there is no physician intermediary to oversee use and results.

A first step is for FDA to develop a registration and listing system to find out what tests are out there and who is making them; a voluntary genetic test registry established by NIH may be a starting point. FDA further seeks to formulate an appropriate risk stratification system, with clear exceptions for diagnostics for rare disease and emergency situations (such as infectious disease outbreaks). Mansfield explained that FDA's concept of risk classification is closely linked to a product's intended use and risk to a patient of an undetected incorrect result. FDA resources also are a concern, as LDT oversight involves some 10,000 products, many more than the number of IVDs FDA monitors.

Of importance to pharma marketers is how much the DTC element is driving FDA regulation of LDTs, observed attorney Daniel Vorhaus at the FDLI seminar. FDA has been examining a host of issues related to genetic testing for some time, he noted, but more active consumer marketing is shaping the broader LTD discussion. Vorhaus acknowledged concerns that without a physician intermediary, there may be a greater potential for LTDs to mislead individuals, but questioned whether such harms actually arise from these tests.

There seems to be agreement on the need for standards for calculating and reporting risks to consumers and on enforcing truth-in-advertising rules. But Mansfield also detects "a lot of fear" that LDT regulation will disrupt laboratory testing and hinder innovation. And whatever FDA does, the FDLI panel predicted, it will generate a lot of "interesting" lawsuits on all sides.

Jill Wechsler is Pharmaceutical Executive's Washington correspondent. She can be reached at jwechsler@advanstar.com