September 2010
Feature Story

Anne Paxton

Laboratory-developed tests (LDTs) haven’t been tarnished by scandal, and discussion of tighter Food and Drug Administration regulation of the tests informally known as “homebrew” has simmered quietly for years, with many proposals floated and not much action taken. But this year, Walgreens’ short-lived plan to offer genetic testing direct to consumers at 6,000 of its drugstores, and shocking findings of a federal undercover probe of companies offering genetic profiles to consumers, have altered the landscape. They’ve helped push the LDT regulatory debate to more of a rolling boil.

“The FDA had been rather quiescent on this issue,” says Gail H. Vance, MD, a CAP governor who has led CAP discussions with the FDA over LDTs. But once the press took up the Walgreens story, suddenly LDTs moved up the agenda. “The FDA moved with lightning speed—as quickly as if it were a pandemic.”

The majority of genetic tests, in fact, are LDTs, and many direct-to-consumer tests are considered LDTs, Dr. Vance says. So it may not have been coincidence that, only a few weeks after Walgreens decided to drop its genetic testing plan, the FDA issued a June notice in the Federal Register saying that due to “public health concerns ... it is time to reconsider its policy of enforcement discretion over LDTs.” When the agency then brought laboratory industry and medical groups to testify at a July hearing on the subject of LDT regulation, discussion of direct-to-consumer testing was prominently included.

“The direct-to-consumer testing [DTC] was what really got their attention,” says Association for Molecular Pathology president Karen P. Mann, MD, PhD. “They felt if it is being marketed as giving medical information, in that case it’s medical testing and they should have oversight.” Although the agency has said it will not take action rapidly, “they did express at the meeting they consider there is a difference between an in-hospital lab, where there is lots of interaction with clinicians and complete access to the clinical history of the patient, and testing more in a vacuum as with DTCs where there isn’t any sort of interaction.”

“I think they resolved that they were going to get involved, but how they were going to get involved was not absolutely clear,” says Dr. Vance, who is professor of pathology and genetics at Indiana University School of Medicine and director of the IU Genetic Testing Laboratories

The comment period on LDT regulation was supposed to close Aug. 15, but prompted by requests, the FDA extended it to Sept. 15. The agency said a commenter asserted that “the initial time period was insufficient to respond fully to FDA’s specific requests for comments and to allow potential respondents to thoroughly evaluate and address pertinent issues,” before the FDA phases in a regulatory framework.

The LDT regulatory process has unfolded as the agency prepares to release a rewrite of its 510(k) regulations for clearance of medical devices. “I think there is a connection,” says Dr. Vance. “Because the fact is the 510(k) process has come under criticism.” The Institute of Medicine has been studying 510(k)s and the FDA had to provide information for that review. “So I think that spurred some of their decisionmaking—whether or not they decide to change the 510(k) process to include LDTs.”

She points to another significant development: a key article that appeared in the New England Journal of Medicine by FDA commissioner Margaret Hamburg, MD, and National Institutes of Health director Francis Collins MD, PhD, about the role of genetic variance in diagnosing and treating disease (2010;363:301–304). In it, these federal officials said the FDA intends to revise its therapeutic and diagnostic test review process to meet some of the issues associated with the sorts of genetic tests that are already being used to diagnose subsets of patients and to direct treatments.

Many of these so-called personalized medicine drugs need a test to go before the FDA to prove they can discriminate the marker before they can get approved, Dr. Vance says. “So I think this linking of diagnostics to drugs is another element spurring the debate—because LDTs would be part of the companion diagnostics discussion,” Dr. Vance says.

All of this activity has highlighted what has been a continuing concern: the inconsistent oversight of LDTs, she notes. “The example I would use are the companies Agendia and Genomic Health.” Agendia has a 70-gene expression array, MammaPrint, that assesses risk of breast cancer metastasis, which it submitted to the FDA and which was approved, while Genomic Health offers a 21-gene PCR test, Oncotype DX, which quantifies likelihood of breast cancer recurrence and which is not approved.

Traditionally, LDTs have been developed not to be manufactured or sold to other labs but as a service to patients and their physicians. “So the Oncotype DX test was coming under the radar. In essence, we now have biotechnology firms posing as labs,” Dr. Vance says. And that, she adds, has stretched the category of LDTs beyond the point where the FDA’s enforcement discretion is up to the job.

In a related development, in June the FDA decided to abandon a three-year-long policy development process to regulate IVDMIAs (in vitro diagnostic multivariate index assays), the lab-developed multiplex tests that employ mathematical algorithms to assess molecular-based risk for disease or response to a drug. After two draft guidances, the entire project was scrapped. Now, Dr. Vance says, “what you’ll probably see is they will classify these IVDMIAs as a group of tests over which the FDA will have oversight.”

The FDA’s re-positioning on these several fronts happens to fit in beautifully with the structure that the CAP formally proposed last fall to regulate LDTs, Dr. Vance says. The model would set up three tiers of risk—low, moderate, and high—and establish FDA authority only over the high-risk tests. Those would include both the IVDMIAs, such as Oncotype DX, and tests performed in a single lab that lack transparency of performance—for example, tests for which no proficiency testing is performed because PT is not available. The FDA would review the high-risk tests before they could be used clinically, while the laboratory’s accreditor would review moderate-risk tests.

“The FDA is very receptive to a tiered approach,” Dr. Vance notes. Based on meetings with the FDA, she believes the agency is also open to a third-party public-private partnership to regulate LDTs—in part because of the resources that would be needed to regulate so many LDTs. “We’ve said we can really help you because we’re in the labs, and we’re constantly monitoring these tests. They’ll probably warm up to the issue, but I can’t say they’re there yet.”

The NEJM article did hint at additional resources for translational science, she says, though whether there are resources for the agencies themselves for oversight specifically was not indicated. “I don’t know how broad the definition of translational or regulatory science may be.”

A concern of the CAP is that potential LDT regulation would disadvantage hospital labs and academic centers that are already regulated under CLIA. “If the FDA claims oversight over all LDTs,” Dr. Vance says, “then those labs will be subject to dual regulatory oversight and would have to respond to CMS’ CLIA oversight as well as FDA, whereas manufacturers only need to respond to FDA.”

The CMS and the FDA should partner with one another on regulating LDTs, in Dr. Vance’s opinion. The chasm is the clinical validity component, because the CMS doesn’t want to head any further down that road. But the FDA and the CMS will need to work cooperatively to come to some resolution on principles of clinical validation, she predicts, and the College is continuing to work on the basic elements. She predicts, too, there will be a rule on LDTs and a component of that for direct-to-consumer tests. “You’re probably not going to see Walgreens sales,” she adds.

When the FDA hearing was announced on relatively short notice, many organizations scrambled to present data, Dr. Vance says, “and I’m using the word ‘scrambled,’ because they didn’t necessarily have a clearly outlined program in hand.” When the CAP came to the hearing, “we had already been to the FDA twice, and we came with a proposal in hand, and the agency asked us to float this proposal publicly and see what people had to say.” While the CAP may not win acceptance for what it’s proposing, “CAP has been determined. We’ve allocated resources for this and put in hundreds of hours on this LDT proposal because it’s the right thing to do. I do think our proposal has influenced their thinking, and I think what we’re offering is a solution that may in part be utilized.”

Several factors have led to the new push to regulate LDTs, says Frank Cockerill III, MD, the Ann and Leo Markin professor and chair of pathology and president and CEO of Mayo Medical Laboratories at Mayo Clinic, Rochester, Minn. “Certainly FDA has had statutory authority for many years. And some time back, Genentech and AdvaMed sent citizens’ petitions to the FDA with concern about adequate validation of some LDTs in the U.S.” However, he believes it was not only the Walgreens plan but also a report by the Government Accountability Office, which was released shortly afterward, that roused the FDA to action. “The GAO report was profoundly devastating in what it uncovered about certain direct-to-consumer labs,” he says.

Presented at a House of Representatives hearing July 22, the report is titled “Direct-to-Consumer Genetic Tests: Misleading Test Results Are Further Complicated by Deceptive Marketing and Other Questionable Practices.” It strongly bolsters the case for more effective FDA regulation of direct-to-consumer testing, Dr. Cockerill says.

The GAO used five undercover agents, and sent two samples from each person to four different companies—one specimen containing factual information about the donor, the other containing fictitious information. For prices ranging from $299 to $999, the companies produced DNA-based disease predictions that varied widely for the same person. For example, a 48-year-old male was told his risk of developing prostate cancer was average in two tests, below average in another, and above average in the fourth. Experts consulted by the GAO agreed that consumers should not rely on the results of any direct-to-consumer genetic tests at this time.

“The information provided to these patients was all over the map: ‘You don’t have a risk for this cancer.’ ‘You have a high risk for this cancer,’” Dr. Cockerill says. “We don’t know exactly what type of testing was being performed. We do know that some of these laboratories were sequencing significant portions of the human genome using next-generation sequencing. Unfortunately, the analytical and clinical validation of this type of testing still may not be there and ready for prime time in the clinical lab.”

A recent report from his group at Mayo demonstrated difficulties with agreement of genomic sequencing results among different sequencing platforms (Hoppman-Chaney, et al. Clin Chem. 2010;56:1297–1306). Implicit for test development, he says, is the certainty that the results generated are reliable and reproducible and of clinical relevance. “The same goes for next-generation sequencing in its current state, which, if I were sitting at the FDA, I would be concerned about.”

The College’s three-tiered proposed LDT regulatory model seems to be winning support from several sides, but the position of the Association for Molecular Pathology differs somewhat from the CAP’s. “We agree there are some tests that require more oversight. The kind of tests I’m thinking of are those that have non-transparent algorithms, where it’s very hard to assess in an independent fashion exactly how good the test is,” says Dr. Mann, who is director of molecular hematopathology at Emory University Hospital, Atlanta.

But the AMP does have concerns about the three-tiered model the CAP is proposing. “We have pretty good consensus on the highest-risk tier. It’s the two lower ones that concern us, because it’s very hard to definitively break tests out into low and moderate risk—one reason being that something low risk in one clinical situation would be high risk in another. So if you’re confirming some sort of inherited genetic condition in adults, it’s very different from prenatal testing, because the consequences would be different in the two settings,” Dr. Mann says.

The AMP also expresses reservations about another organization that would have further oversight over the clinical laboratory. “Our position is we have considerable oversight already. The reality is that with the current FDA process, to get a 510(k) through the FDA and approved is a major undertaking,” Dr. Mann points out. “So a relatively low-volume test, from the manufacturer’s point of view, is not worth their time.” She adds: “That is at least in part the reason we don’t have an FDA-approved test currently for BCR-ABL monitoring, to assess treatment of patients with chronic myeloid leukemia.”

“We do have a number of LDTs developed within our own labs,” Dr. Cockerill says. “Mayo Medical Laboratories is one of the largest providers of esoteric tests in the country,” and it performs these tests for 4,000 clients around the world. He believes that the FDA wants to move toward using a more standardized approach to LDTs in place of discretionary enforcement.

“And from our perspective, that’s okay,” he says. But Mayo is concerned that the approach the FDA takes not be over-reaching and be implemented in a way that does not stifle innovation. “Regulation should be cost-effective so labs can afford to provide a wide range of LDTs for patients, as we’ve done at Mayo for many years. It should allow for qualification of some tests that are ‘orphans,’” owing to very small disease burden and subsequent low test volumes. Large clinical trials are not feasible for these tests. “At Mayo, we provide many of these orphan tests, which are expensive to perform, have little or no margin, and therefore are not feasible to set up at many laboratories.” Finally, Dr. Cockerill says, additional regulation by the FDA should not duplicate the requirements of other agencies that regulate laboratory testing.

Some commenters have said it would help if the FDA shifted its emphasis to include assessing clinical utility of tests, rather than simply clinical validity. But “I’m just not sure that’s part of their mandate,” Dr. Mann says. “Patient safety is more what they are focusing on; they don’t want you to be doing a test that’s clinically invalid and would cause you to change treatment.”

The FDA has been working on a revision of the 510(k) rules for some time, Dr. Mann says, and she believes it could possibly include down-classification of some IVDs, but details are not yet available. “The rewrite probably wouldn’t directly relate to oversight for LDTs—except that if they make it easier for companies to get FDA-approved kits, there will be some areas where people will switch from using LDTs to using FDA-approved kits.”

To some degree, diagnostics manufacturers are competitively and philosophically pitted against each other on the issue of LDT regulation. But many charge that the degree of flexibility inherent in enforcement discretion has created an unlevel playing field—one they’d like to see evened out. Most manufacturers are supportive of stricter, more consistent FDA regulation. Agendia, for example, strongly backs Genentech’s petition for regulation and was actively involved in developing the now-shelved IVDMIA guidelines, says Bernhard Sixt, PhD, Agendia’s CEO and co-founder.

At the FDA hearing, Dr. Sixt notes, there was considerable talk about the possibility of innovation being stifled if FDA regulation is required. “But I really strongly disagree, because there are significant funds available for doing real innovation if you look at the biotechnology model. I think innovation will definitely be driven by regulation.”

Agendia’s MammaPrint test for breast cancer went through the FDA approval process before it was marketed, he says. While Oncotype DX was marketed earlier even though it was technically an LDT, “we were doing things according to the book. We wanted to make sure everything was safe and reliable and validated before we pressed a commercial effort.” The company also offers the TargetPrint test, an LDT of quantitative gene expression of ER, PR, and HER2/neu, which physicians order along with MammaPrint. Since March of this year, and still at no charge, physicians can also order BluePrint with MammaPrint to get more information about biological subtypes.

The United States is Agendia’s chief market, but the company also operates in Europe where self-regulation is more the rule. However, Dr. Sixt says, “we believe the regulator is not here to tell you what to do but check if you did what you’re supposed to do. Therefore, we were not afraid of going to the U.S. because it very much asks for the things a company needs to do before commercializing a test anyway.” Agendia is supportive of the CAP’s three-tiered regulatory model, he says.

Pathology groups hope that in whatever regulatory model it outlines, the FDA stays cognizant of the enormous role LDTs play in providing critical diagnostic information. “The important thing to remember is that LDTs are performed throughout the laboratory,” Dr. Mann says. “They’re not just molecular tests. The majority of immunohistochemistry stains are LDTs. Our flow cytometry tests for leukemia and lymphoma phenotyping are all LDTs. There are a huge number of LDTs that are part of routine medical care. It‘s not just cutting-edge or new tests; it’s bread and butter. And I think the FDA knows this. They have no interest in bringing health care to a halt.”