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Facing FDA Warning Letter and Lawsuit, Can 23andMe Stay True to its DTC Credo in 15 days?

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For the time being, 23andMe's web-based genotyping service remains up and accessible to its 500,000 customers. Meanwhile, the firm is working against a 15-day clock to provide the US Food and Drug Administration the necessary information that will enable the firm maintain its direct-to-consumer genetic testing business in some form.

In a Nov. 22 warning letter, signed by Alberto Gutierrez, director of FDA's Office of In Vitro Diagnostics and Radiological Health, the agency asked 23andMe to "immediately discontinue marketing" its Personal Genome Service "until such time as it receives FDA marketing authorization for the device." FDA's action against the Google-backed, Mountain View, Calif.-based firm has ignited a public outcry, with customers petitioning the government to allow 23andMe to maintain its business and one California woman filing a class action lawsuit against the company and asking for her money back.

Two groups have submitted petitions to We the People and to Change.org seeking to collect 100,000 and 10,000 signatures, respectively. The petition on We the People, from a group that identifies itself as "the healthcare consumers of America," has collected more than 3,000 signatures on its bid to have the Obama administration overrule the FDA's action against 23andMe. TechFreedom.org's petition in Change.org has amassed over 4,000 signatures urging the FDA to focus on physician and patient education about the benefits and limits of genetic testing instead of banning direct access.

Meanwhile, 23andMe customer and San Diego resident Lisa Casey has filed a class action lawsuit charging that the firm is falsely advertising the health impact and usefulness of its Personal Genome Service, which gauges genetic mutations associated with hundreds of conditions, traits, ancestry, and drug response. "There is no analytical or clinical validation for the PGS for its advertised uses," the lawsuit states. 23andMe "uses the information it collects from the DNA tests consumers pay to take to generate databases and statistical information that it then markets to other sources and the scientific community in general, even though the test results are meaningless." Casey believes there are thousands of others who are dissatisfied with 23andMe's offerings and is asking the company to return the $99 they each paid for the service.

Direct-to-consumer genetic testing firms, since they first launched several years ago, have been a source of controversy among consumers, researchers, and regulatory authorities. There are those that believe that people have a right to their genomic information without the interference of a doctor or a government agency, and 23andMe is playing an important role by facilitating such access. There are others, though, who point out that 23andMe isn't just providing people with access to their raw genomic data, but interpreting what the data means for their health based on evolving science and without input from medical professionals.

With other prominent health-oriented DTC genetic testing companies like Navigenics and Decode Genetics being swallowed up by other firms and no longer offering DTC services, 23andMe has for some time been the only option for people who wished to know about their genetic predisposition for diseases and their likelihood for responding to various drugs without having to visit their doctors for a prescription. But even this may not be available for much longer, since the FDA seems to be fed up with 23andMe's failure to communicate with the agency, and remains unconvinced by data the firm has submitted on the clinical and analytical validity of its genetic tests.

It's clear from the FDA's warning letter that the agency and 23andMe have had extensive interactions – 14 meetings, hundreds of emails, and dozens of written exchanges – about its Personal Genome Service since 2009. "Even after these many interactions with 23andMe, we still do not have any assurance that the firm has analytically or clinically validated the PGS for its intended uses, which have expanded from the uses that the firm identified in its submissions," the FDA states in its letter.

23andMe to date has submitted 510(k) applications for its testing service, one in July and another in September of 2012. However, the FDA complains in its letter that the firm hasn't responded since May of this year to many requests for additional information about its 510(k)s. After receiving no answer from the company following two letters, the agency now considers 23andMe's applications withdrawn.

"Despite numerous requests, the company has failed to submit the information requested by the FDA, putting consumers at risk of receiving inaccurate information that could result in delayed or inappropriate medical care," an agency spokesperson said. "The lack of any response from 23andMe, even after their submissions were automatically withdrawn, and their continuing to offer the tests, was the primary event that triggered the FDA letter."

No 'enforcement discretion' for DTC testing

FDA's objection to DTC marketing of genetic tests started some time ago, when the agency sent a round of letters to a handful of DTC firms in 2010, include 23andMe. At the time, the agency informed the companies that it considered these types of tests medical devices, which require regulatory clearance or approval. After a contentious public meeting, a testy congressional hearing, and an undercover Government Accountability Office investigation that concluded these firms were making misleading claims, the nascent DTC genetic testing market for medical conditions essentially disappeared — except for 23andMe.

Unlike its competitors, who in the face of regulatory pressure quickly shifted their marketing strategy to physicians, 23andMe fought to keep its direct-to-consumer philosophy during public hearings and before Congress. Last year, even after 23andMe filed its first 510(k) application for its service with the FDA, the firm's Chief Legal Officer Ashley Gould assured that nothing would hinder customers' ability to directly access their genetic information.

Based on the latest warning letter, however, FDA's issue with 23andMe seems not so much that the company performs genetic testing in a lab without its blessing, but that consumers can go online and order tests for serious health-related conditions without a doctor's prescription. The DTC model, in particular, factors heavily in the agency's estimation of the risk 23andMe's testing service poses to patients.

Historically, the agency has practiced enforcement discretion over laboratory-developed tests, leaving oversight responsibilities to the Centers for Medicare & Medicaid Services, under the Clinical Laboratory Improvement Amendments. In recent years, as LDTs have become more widely available and broadly marketed, the agency has said it plans to bring LDTs under its regulatory purview and develop risk-based guidelines to ensure that tests developed at a single laboratory are safe and effective.

23andMe currently performs genetic testing in a CLIA-certified lab, and so the firm's tests fall in the LDT category. Some industry observers believe that FDA's regulatory stance on LDTs is inextricably tied to its ability to regulate DTC genetic testing. "At its core this is part of the CLIA/LDT versus FDA/IVD debate," Avi Kulkarni, a partner at consulting firm Booz & Company with expertise in the diagnostics industry, said in an e-mail.

Indeed, the high-risk tests that the agency expresses concern about in its warning letter to 23andMe – BRCA mutation testing for breast and ovarian cancer risk and pharmacogenetic testing for prescription drugs such as warfarin, clopidogrel, and 5-FU – are also available as LDTs from a number of other labs without FDA approval. The difference is these LDTs must be ordered by a physician.

The American Clinical Laboratory Association is a group representing the interests of the lab industry that has been staunchly against FDA regulation of LDTs. But the group has distanced itself from the DTC genetic testing providers, such as 23andMe, even though 23andMe is also providing LDTs. "With respect to the direct-to-consumer labs … we don't welcome them as ACLA members," ACLA President Alan Mertz told PGx Reporter in an interview in June.

"We actually agree with FDA, and we sent a letter to the agency … saying that we felt DTC genomics tests were higher risk because they were ordered without a physician and without the physician getting results," Mertz said. "This is not really an issue of whether the spit kit is a component, and therefore any tests that have components that are regulated are medical devices. The issue is DTC. The whole issue there is how they're ordered and also how they're marketed."

Ron Rogers, spokesperson for leading BRCA mutation testing provider Myriad Genetics, told PGx Reporter that direct-to-consumer availability of such testing has resulted in a lot of confusion among consumers. Myriad's BRACAnalysis for assessing hereditary risk for breast and ovarian cancer is a lab-developed test performed in a CLIA certified lab, but it doesn't have FDA approval or clearance. In two decades of marketing BRACAnalysis to doctors, however, Myriad has tested more than a million women and has amassed the largest database on mutations implicated with disease.

Meanwhile, in 2009, 23andMe began reporting three of the most common BRCA mutations associated with increased breast and ovarian cancer risk in women of Ashkenazi Jewish ancestry. Consumers must read educational material about the markers on the firm's website and unlock their results should they decide to view them, and 23andMe informs customers that there are many other mutations associated with breast and ovarian cancer risk than the ones reported by the company.

"We've actually had some of their customers come to us for BRCA testing and say that they thought that 23andMe was offering a more comprehensive test than they actually were," said Rogers. "That firm only tests for 0.02 percent of relevant bases that are important for gauging hereditary breast and ovarian cancer risk."

While the FDA has said it is also developing risk-based guidelines for its oversight of LDTs, as far as the agency is concerned, direct-to-consumer genetic testing is a different ball of wax. "The FDA has not exercised enforcement discretion over direct-to-consumer testing, whether the test was manufactured by a traditional IVD manufacturer, or whether it was created in a single laboratory to be performed at that single laboratory," an agency spokesperson told PGx Reporter.

The FDA recently issued a final guidance on research-use and investigational-use labeled tests and components, but hasn't issued broader guidance on LDTs yet (see related story, in this issue). As such, the agency is continuing to practice enforcement discretion over LDTs.

"23andMe's actions to date suggest that they think that the FDA's big brother approach to enforcement discretion that seems to disregard CLIA regulations in this instance is not legally enforceable," Kulkarni said. "And it is my personal opinion that the FDA is not necessarily going to win this fight, not unless they can get Congress to redraw the lines separating CLIA and FDA more carefully."

23andMe's options

23andMe declined to comment for this article. In a letter to customers, CEO Anne Wojcicki acknowledged that the firm had fallen behind schedule in responding to the agency's requests. Creating a pathway through which a DTC genetic testing service can garner regulatory clearance for hundreds of tests is "new territory" for the firm and the agency, said Wojcicki. Before the brouhaha with the FDA, Wojcicki was featured on the November cover of Fast Company and dubbed "the most daring CEO in America."

Now that the FDA has laid down an ultimatum – respond to its data requests within 15 days or face penalties – 23andMe may be forced to bend its steely resolve to maintain direct access for its customers. "The agency is committed to working with 23andMe to ensure that the appropriate information is submitted that may eventually lead to a clearance or approval," the FDA spokesperson said. "Until that time, FDA has requested that 23andMe cease offering their Personal Genome Service test."

Lakshman Ramamurthy, former senior reviewer and policy advisor at FDA's diagnostics division, noted that 23andMe has a very complex and large regulatory package that they would have to submit to the agency. He suspects that the communications between 23andMe and the FDA broke down because the company probably didn't like what they were hearing from the agency about what they would have to submit.

"It's a very long list of demands they have to meet," said Ramamurthy, director of the regulatory and policy practice at Avalere Health, an advisory firm focused on healthcare business strategy and policy. Noting that the FDA in its warning letter expressed concern about tests it classified as high risk to consumers when given in a DTC setting, Ramamurthy predicted that 23andMe will probably try to negotiate with the agency to try to identify the types of tests it can continue to provide directly to its customers. "They may choose to mask the results from the high risk analytes … in the hopes that they can provide other types of information," he said.

For example, the agency hasn't cracked down on companies, such as National Geographic and Gene by Gene, that provide direct-to-consumer genetic testing for mapping ancestry and genealogy. Furthermore, the agency doesn't seem to mind if companies report to customers their raw genomic data without interpretation.

"What we learned [through discussion with the agency] is that the FDA doesn't want companies saying anything about a likely medical condition, unless the company is a doctor," Bennett Greenspan, Gene by Gene managing partner and CEO of subsidiary FamilyTreeDNA, has previously told PGx Reporter. "The agency wants all that information explained by an MD. We found that the only caveat was that if you didn't explain anything, then they recognized that it's your personal DNA and if you want to look at it for your own personal research purpose, that's not within the FDA's purview." In addition to ancestry testing services, Gene by Gene earlier this year launched a DTC sequencing service that provides consumers with raw data from whole-genome sequencing and exome sequencing analysis, intended for research use.

In its regulatory strategy with the FDA, 23andMe may be able to draw some lessons from Illumina's recent success in garnering clearance for its MiSeqDx next-generation sequencing platform, reagents kit, and cystic fibrosis tests. Ramamurthy pointed out that only a few days before the FDA warned 23andMe, the agency cleared for marketing Illumina's MiSeqDx tests and platform. "That platform is also capable of looking at scores of genetic markers," he noted. "And at the minimum the FDA found the analytical validity of the platform to be reproducible … and so, one approach for 23andMe would be to at least demonstrate analytical validity for its test platform."

While 23andMe conducts the necessary validity studies for the FDA, another option may be to shift marketing to doctors. "Direct-to-consumer testing is something where the FDA sees that there is no buffer between the results being generated and the consumer acting on that information," Ramamurthy said.

After the agency initially took issue with DTC firms, 23andMe competitors at the time, Navigenics and Decode, continued to offer their genetic testing services for some time through physicians. "Even in a direct-to-physician model, I think the agency might ask to see that 23andMe's panel has produced reproducible and accurate testing," Ramamurthy said. "I don't think switching to a direct-to-physician model would absolve the company from proving analytical and clinical validity of its tests."

Moreover, that option would be inconsistent with 23andMe's credo that people should have unfettered access to genetic data. A direct-to-physician strategy would also turn off customers who have purchased tests from the company to circumvent the medical community they believe is paternalistic and too slow to embrace technological advances.

"The FDA seems to think that Americans can't be trusted with more information about their potential health risks because some people might make rash decisions with it. But banning personal genomics isn’t the answer," TechFreedom, a non-profit that promotes technological progress and individual choice, states in its Change.org petition. "23andMe is simply doing what the Internet does best: Forcing old dogs to learn new tricks."

Berin Szoka, president of TechFreedom and a 23andMe customer, wrote the petition based on his own experience discussing genetic testing with his doctor. The organization believes that instead of restricting 23andMe from offering genetic testing directly to its customers, the agency should educate doctors about the risk and benefits of such testing. "Those of us who have already used the site know the real problem is that doctors themselves are behind the curve," TechFreedom says in the petition. "The only profession slower to change how they do things than doctors is bureaucrats."

So, if 23andMe were to change its marketing strategy and began selling its tests only to doctors, that wouldn't please TechFreedom at all. "Our point is that 23andMe is providing a much-needed catalyst for change in the medical profession: Getting patients to make the first move," Szoka told PGx Reporter over e-mail.

Having spent some time at the FDA, Ramamurthy is rather amused by the argument that regulation of DTC genetics firms is paternalistic. "If I were to follow that logic, I would say drawing yellow lines on highways is paternalistic. I would think having speed limits is paternalistic," he quipped. "I find the argument about paternalism really disingenuous, unless we live in a free-for-all."

Dissatisfied customer

TechFreedom still needs more than 5,000 supporters on its petition to reach its 10,000-signature target and the We the People petition is more than 96,000 signatures shy of reaching its goal. Szoka doesn't believe that petitions alone will spur the FDA to change its course with regard to 23andMe. "Government agencies rarely reverse course unless sued," he said.

All this may end in a legal tussle. Lawyer John Conley of Robinson, Bradshaw & Hinson wrote recently in a blog post that if 23andMe doesn't address the FDA's concerns within 15 days, then the agency can impound the firm's PGS kits. 23andMe could appeal this in court, and then the court would have to address the question of whether the agency has the authority to regulate DTC testing. The FDA could also go to court to seek an injunction against the firm.

Of course, 23andMe could "forge ahead without approval and challenge the FDA’s authority in court," wrote Conley. "Personally, I’m rooting for 23andMe," he added. "But legally, if things go that route, I think the FDA would prevail. I think the courts would ultimately accept the FDA's determination that DTC test kits are medical devices that it has the power to regulate."

At the moment, the only entity being sued is 23andMe, by a dissatisfied customer.

In the class action lawsuit filed in Southern California federal district court, plaintiff Casey alleges that 23andMe is misleading customers by claiming in advertising that its genetic testing service can be a reliable health aid, when in fact the test has not been analytically or clinically validated. 23andMe "has reaped the profit involved in marketing seemingly useful and reliable PGS health services while simultaneously failing to provide proof of the validity of such marketing claims to FDA in violation of the [Federal Food, Drug and Cosmetic Act]," the lawsuit states.

Although Casey believes there are thousands of 23andMe customers who share her view and want their $99 back, it's hard to know at this point how strong her case is. "Who are the customers?" Conley posited in his blog post. Beyond the dedicated genetic hobbyists, "how many people can there be who (1) know enough to seek out a genetic testing product, but (2) know so little that they’d rely on a cheap and vastly underpredictive consumer product to make heath or reproductive decisions?"

In the time that PGx Reporter has reported on DTC genetic testing, 23andMe's customer base has been mostly highly educated, financially well off people, many of them genomics researchers or experts in other scientific disciplines. This is not to say that 23andMe doesn't have customers like Karen Durrett, a stay-at-home mom of three from Georgia with no formal science education, who bought a test from the firm in 2008 after seeing the company featured on Oprah.

Durrett found out through 23andMe that she had a heightened risk for breast cancer. This, in addition to the knowledge that there was a history of cancer in her family, allowed Durrett to make decisions that led to the early identification of her own breast cancer. Hoping to attract more customers like Durrett, 23andMe dropped the price of its service last year from $299 to $99.

However, not every 23andMe customer will receive reports that are directly useful for their health like Durrett did. And 23andMe isn't promising that, at least not in the fine print. The company's terms of service, to which customers have to agree to before buying its tests, states in plain language that the results it reports are for research and informational use only and not meant as medical advice. "While we measure many hundreds of thousands of data points from your DNA, only a small percentage of them are known to be related to human traits or health conditions," the company says in the terms of service.

Furthermore, the company notifies customers that they might learn things about their health that they don't anticipate and they shouldn't change any behaviors based solely on 23andMe's reports. "You should not assume that any information we may be able to provide to you, whether now or as genetic research advances, will be welcome or positive," 23andMe says.

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