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DTC Genomics Gets Time Before FDA as Agency Considers Regulatory Strategy

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By Turna Ray

HYATTSVILLE, Md. — Genomic information marketed directly to consumers poses different risks to the public than over-the-counter tests for pregnancy or cholesterol, agreed a panel of experts convened by the US Food and Drug Administration this week to gather input on DTC genomic testing firms. As such, the panel recommended that health regulators will likely need a system to establish the clinical validity of gene markers used by DTC genomics firms to assess consumers' response to drugs and predisposition to diseases.

During the latter part of a two-day meeting to discuss FDA's stated intent to regulate laboratory-developed tests, the agency heard from DTC genomics firms, patient advocacy organizations, and policy groups on how it should proceed in overseeing the rapidly growing consumer genomics industry. Most speakers agreed that the FDA should bring consistency to DTC genomic risk interpretations, and promulgate standard practices for the industry developed either by an expert advisory panel or a third-party standard-setting body.

The meeting comes a month after the FDA sent untitled letters requesting meetings with several consumer genomics firms and one instrument vendor. In those letters, the agency informed some of the firms that their gene scans were not LDTs and were therefore subject to premarket review (PGx Reporter 06/16/10).

FDA's regulatory action over the consumer genomics industry has come at a time when a debate is raging about the level of access the general public should have to genomic data. The fact that DTC firms are offering services that assess consumers' predisposition to serious illnesses — such as ovarian cancer and Alzheimer's disease — without physician involvement is of particular concern to detractors of the industry. Critics have noted that clinically unvalidated genetic information garnered through DTC firms could lead consumers to take unnecessary or wrong action that is harmful to their health.

Meanwhile, supporters of the DTC model maintain that people are capable of understanding genomic data as well as, if not better than, many doctors, and should have unfettered access to their genomic information, without the "paternalistic" intervention of regulators and physicians.

To discuss these perspectives, FDA convened a panel of commentators — including Vance Vanier, CEO of Navigenics; Sue Friedman, founder of Facing Our Risk of Cancer Empowered; Anne Willey, director of the Office of Laboratory Policy and Planning at the New York State Department of Health; Wayne Rosenkrans, president of the Personalized Medicine Coalition; and Susanne Haga, assistant research professor at the Duke Institute for Genome Sciences and Policy.

Muin Khoury, director of the Office of Public Health Genomics at the Centers for Disease Control and Prevention and moderator of the panel, questioned whether experts thought DTC gene scans should fall under FDA's LDT regulatory framework or if such tests are significantly different to warrant a separate regulatory strategy.

Willey pointed out that at-home test kits for pregnancy or high cholesterol are based on relatively simple technology, and were only marketed as over-the-counter products after regulatory authorities established them to be safe for home use. Not only do these over-the-counter LDTs have standards for quality and manufacturing in place, but consumers often use them upon the advice of a doctor, as is the case with cholesterol testing, or with physician follow-up, as in the case of pregnancy tests.

In comparison, Willey observed, a DTC genetic testing firm often serves as a marketing intermediary between consumers and the laboratory performing genomic analysis, and as such is not overseen by health regulators. While the laboratories that conduct genetic analyses may be regulated by the Centers for Medicare & Medicaid Services under CLIA, the DTC firms are not.

The NYDoH subjects DTC firms to the same certification requirements as labs performing the tests, including an assessment of the clinical and analytical validity of markers tested, even if they outsource the genetic analysis to outside laboratories. According to Willey, who has guided several DTC genomics firms through NYDoH's stringent certification requirements, state health regulators look at the specific gene markers that these companies test for and clear only those that the published literature has shown to be clinically robust.

In New York, where Navigenics received a license to market to physicians but not directly to consumers, the company does not test for all the gene markers available through its Health Compass service, according to Willey, who offered up the NYDoH's strategy as a blueprint for the FDA going forward.

"We're really dealing with an emerging field," said PMC's Rosenkrans. "There's a clear need for standards," he acknowledged, putting forth the proposal that perhaps an independent third party might do the job.

Consumer genomics firms have long acknowledged they would prefer federal guidance for the nascent industry rather than navigating conflicting state regulations on DTC genomic testing. In fact, 23andMe formally solicited help from FDA Commissioner Margaret Hamburg and NIH Director Francis Collins — two leaders who have promised to join their agencies in advancing personalized medicine — in aligning industry standards that would reduce divergence in reporting genetic risk scores (PGx Reporter 07/07/10).

Public presenters and the panel also discussed privacy protections and transparency issues related to new consumer-driven research models advanced by DTC genomics firms. Speakers agreed that within these emerging research models, DTC firms should be open about the risks associated with participating in their studies.

Guidance Welcome

In 2009, 23andMe, Decode, and Navigenics voluntarily published a consensus document outlining technical standards that they planned to uphold in their tests, such as the accuracy of the DNA chips they use, their methodology for characterizing individual risk, and criteria for determining which SNPs to include in their analysis. However, at the time, experts held that more work needed to be done in this regard, particularly with regard to clinical validation.

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At this week's meeting, speakers suggested that FDA enlist the help of third parties to set standards for establishing clinical validity in the consumer genomics industry. Some entities that fit the bill are the National Institute for Standards and Technology and United States Diagnostics Standards, the independent certification body for laboratory and pathology diagnostics recently launched by former Critical Path Institute Chief Scientific Officer Jeffrey Cossman.

Patient advocates have expressed concern that DTC services are putting too much emphasis on the role of gene mutations in health, without factoring in the impact of environment, ethnicity, and other traits. For example, Adele Schneider of the Albert Einstein Medical Center took issued with DTC firms' methods of Tay Sachs screening, a genetic disease particularly prevalent among Ashkenazi Jews that is best tested for with a combination of an enzyme assay and a DNA test.

While consumer genomics firms test for mutations in the HEXA gene which causes Tay Sachs disease, these firms do not measure their customers' level of the hexosaminidase A enzyme. As such, customers of DTC genomics services, particularly those of Ashkenazi Jewish descent, may be told they are not carriers of the gene mutation, even though they may still be affected by Tay Sachs, Schneider pointed out.

Other areas that need FDA's attention are risk classifications for consumer genomics products, which would require the agency to gather empirical data on how consumers understand and use genomic information. Navigenics' Vanier noted that Eric Topol, director of the Scripps Translational Science Institute, will soon release preliminary results from a study supporting the view that genomic information does not have negative psychological effects on consumers.

"There's a small body of emerging data showing that people feel empowered by their genomic data," Vanier said. The study led by Topol was launched two years ago, when Scripps Translational Research Institute, Navigenics, Affymetrix, and Microsoft partnered to conduct a 20-year study to determine the long-term behavioral impact of personal genetic testing. Under the program, as many as 10,000 Scripps Health system employees, family members, and friends are being offered genetic scans through Navigenics (PGx Reporter 10/15/08).

While one study might suggest that consumers can benefit from genomic information, the Government Accountability Office has been investigating the harms experienced by customers of DTC genomics firms.

In the meeting materials posted for a congressional hearing that will be held later this week on the consumer genomics industry, the House Committee on Energy & Commerce said that it had asked the GAO to investigate the rapidly growing industry, since the committee was concerned that "consumer fraud in this area is on the rise." As a result, the GAO's Forensic Audit and Special Investigations Unit investigated four genetic testing companies: Pathway Genomics, Navigenics, 23andMe, and Decode Genetics. GAO is slated to present its findings to the committee on July 22.

At FDA's public meeting, David Becker, chief scientific officer of Pathway Genomics, acknowledged that the risk to consumers increases when DTC firms provide information about genes linked to drug response. Pathway's attempt to move its gene scan service to retail pharmacies ultimately spurred FDA to issue letters to several industry players requesting further information on their services (PGx Reporter 05/13/10).

Becker recommended that a new regulatory paradigm for the industry should require firms to garner accreditation from the College of American Pathologists and participate in the National Institutes of Health's genetic testing registry. "This will give FDA a chance to collect data" on how genomic data provided by DTC genomics services impacts consumers, he said.

Finally, the agency will also need to figure out which government entity will keep an eye on the marketing claims DTC firms make. While the Federal Trade Commission has said it is looking into marketing claims made by DTC genomics firms, Rosenkrans pointed out that FDA's Division of Drug Marketing, Advertising and Communication, which currently oversees marketing by pharmaceutical companies, may also be able to take on this responsibility.

Consumer-Driven Research Concerns

During the meeting, 23andMe founder Anne Wojcicki told FDA that the firm, which operates on a consumer-driven research model, believes that everyone should have access to their genomic information. Not only that, but "we want our customers to feel like research participants and not research subjects," Wojcicki said.

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Last month, the company published the first genome-wide association findings based on self-reported data from its customers, and Wojcicki at the meeting said that 23andMe will conduct and publish other studies on Parkinson's and other diseases.

In 23andMe's first study published in PLoS Genetics, researchers from 23andMe and Columbia University analyzed data from more than 9,000 customers and were able to verify previously reported associations for five traits and identified new SNPs linked to four of the traits, including hair curl, freckling, sneezing in response to light, and the ability to detect asparagus metabolite odors in urine. However, according to an editorial about 23andMe's paper published in the same journal, publication of the study was held up due to the editors seeking insight on "ethical review, consent, and data access.

"The editors of PLoS Genetics decided to proceed after satisfying ourselves on two major points, namely that the participants were not coerced to participate in the study in any way, and they were clearly aware that their samples would be used for genetic research," wrote Greg Gibson and Gregory Copenhaver in the editorial.

After the PLoS Genetics paper and editorial were published, 23andMe garnered institutional review board approval for genomic studies conducted by the company using customer data, and updated its research consent procedures by giving customers more say in how their genomic data was used in research. Before this update to its policies, when customers purchased a 23andMe gene scan, they automatically gave consent to the company to use their data in internal research, as well as research with third parties (PGx Reporter 07/14/10).

Still, there are aspects of 23andMe's research policies that concern industry observers.

At the FDA public meeting, Jeremy Gruber, president for the Council for Responsible Genetics, pointed out that 23andMe's updated consent policies still allow the company to use patients' initial agreement to participate in research as a blanket permission to use their data for multiple studies, even with undisclosed third parties.

As part of its new consent policies, 23andMe informs customers that its studies will not "cover potentially sensitive topics" such as sexual orientation, illicit drug use or other illegal behavior, or HIV/AIDS status. If 23andMe conducts future studies on such controversial topics, the company promises to seek separate approval from its customers for these projects. Furthermore, in the event 23andMe collaborates with other companies or research groups to conduct studies, these outside entities have access to customers' de-identified, pooled genomic data.

But deidentification of genetic samples is not fail-proof, a risk that the company acknowledges and tells its customers up front before they make a decision to participate in research.

Gruber suggested FDA come up with standards for storing patient samples and for deindentification of data. He further urged the agency to demand more transparency from consumer genomics firms about their financial relationships with other commercial and research entities.

During the panel discussion, most of the invited speakers agreed that patient-driven research was a viable model in the era of Internet-driven social media sites like Facebook and Twitter. "The research paradigm is changing," Rosenkrans said, adding that the use of social media to recruit study participants or gather patient-reported outcomes for treatments is on its way to ending the "tyranny of the randomized-controlled trial." RCT is the long-accepted gold standard for conducting studies in the traditional research paradigm.

More important than the design of a particular study, "the main thing is to make sure patients understand what they're getting into," Duke's Haga asserted.

In this regard, the lack of patient and physician education were highlighted as areas of significant concern, which both the DTC genomics industry, patient groups, professional societies, and the FDA will need to address with the growing incorporation of genomics into healthcare.

According to Ashley Gould, general counsel to 23andMe, the company offers free services to many doctors in an effort to familiarize the physician community with genomic risk information. Furthermore, Balaji Srinivasan, chief technology officer at Counsyl – a company offering preimplantation screening for genetic diseases that initially marketed its tests DTC but recently shifted its business model to provide its saliva collection kits through physicians – recommended DTC firms follow the example of George Church's Personal Genome Project, which requires people interested in participating in the whole genome sequencing project to pass a literacy exam on scientific, social, and ethical topics related to genomic testing.

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