Regulation of Personal Genomics Again Questioned With FDA’s Warning Letter to 23andMe

The warning letter the U.S. Food and Drug Administration (FDA) sent to 23and-Me (Mountain View, Calif.) has reignited a fierce debate pitting the merits of FDA regulation of personal genomics tests against individuals’ rights to explore the data stored in their own DNA.

In the Nov. 22 warning letter, the FDA demands that 23andMe “immediately discontinue marketing” its saliva collection kit and Personal Genome Service (PGS), which it launched back in 2007. The FDA contends that the PGS is a medical device that is being marketed without clearance or approval. This reaffirms the FDA’s 2010 position that personal genomic tests are medical devices and not laboratory-developed tests.

The FDA calls the PGS a class III medical device, which carries the greatest associated risk and requires premarket approval. The letter argues that PGS “is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or function of the body.” Specifically, the FDA calls out as “particularly concerning” the company’s online marketing of “PGS for providing ‘health reports on 254 diseases and conditions,’ including categories such as ‘carrier status,’ ‘health risks,’ and ‘drug response,’ and specifically as a ‘first step in prevention’ that enables users to ‘take steps toward mitigating serious diseases’ such as diabetes, coronary heart disease, and breast cancer.”

The FDA cites results on disease risk and drug response (specifically BRCA-related genetic risk and drug responses to warfarin sensitivity, clopidogrel response, and 5-fluorouracil toxicity) because of the “potential health consequences that could result from false positive or false negative assessments for high-risk indications such as these.”

A Question of Intention
“Intended” might be the pivotal word in determining the FDA’s jurisdiction in regulating personal genomics, should jurisdiction become a matter in litigation. The FDA says that most of the intended uses for PGS listed on the 23andMe Web site have “grown over time” without premarket approval or de novo classification, “as FDA has explained . . . on numerous occasions.”

According to the description of services in the terms of service on 23andMe’s Web site, “23and-Me Services are for research, informational, and educational use only” and “the services are not intended to be used by the customer for any diagnostic purpose.” However, the company’s Web site and marketing campaign directly contradict these stated terms. One could also argue that CLIA designation of 23andMe’s laboratory also suggests it was designed “for the purpose of providing information for the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health of, human beings,” as stated in CLIA registration.

“To what extent should parties (e.g., 23andMe and its users) be permitted to determine their own contractual terms, including waivers of regulatory or statutory protections specifically involving an individual’s health decisions?” asks Jennifer Wagner, J.D., Ph.D., a postdoctoral trainee at University of Pennsylvania’s Center for the Integration of Genetic Healthcare Technologies in a contributing Genomics Law Report blog post. “The medicalization of our genomes and obstacles to access to and sharing of that information are contrary to numerous human rights principles.”

Wagner says that controversy surrounding regulation of personal genomic tests is part of a larger trend toward democratization of health care, with individuals (including research participants, patients, and customers) wanting access to their own and shared data.

“We don’t have an issue with people getting their own DNA data,” Alberto Gutierrez, director of the FDA’s Office of In Vitro Diagnostics and Radiological Health, told Bloomberg. “We just have concerns with how it’s being interpreted.”

“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,” explained the FDA in its letter to the company, questioning the validity of the results returned.

This contention is also the basis of a class-action suit filed Nov. 27 in the Southern District Court of California. The plaintiffs allege that “23andMe, Inc. (‘Defendant’) falsely and misleadingly advertises their Saliva Collection Kit/Personal Genome Service (‘PGS’) as providing ‘health reports on 240+ conditions and traits,’ ‘drug response,’ ‘carrier status,’ among other things, when there is no analytical or clinical validation for the PGS for its advertised uses.” The suit  calls for monetary damages, including a full refund to purchasers of PGS, if the class-action status is certified by the court.

In response to the warning letter and suit, 23andMe CEO Anne Wojcicki wrote in a Dec. 5 blogpost, “We also want to make clear that we stand behind the data we have generated for customers. Our lab partner adheres to strict quality standards . . .  known as CLIA. These are the same standards used in the majority of other health and disease-related tests. We decided several years ago to comply with CLIA guidelines to be consistent with other types of laboratory testing and to assure customers about the quality of data.”

Speculation abounds as to whether the company’s lack of communication was an oversight (the company’s general counsel reportedly left the company this past summer) or a strategic move to steer the discussion away from the FDA. In this scenario, a court may ultimately determine the FDA’s role in regulating direct-to-consumer (DTC) personal genomic products as medical devices.

Fueling speculation was a Nov. 26 blog post by Wojcicki: “This is new territory for both 23andMe and the FDA. This makes the regulatory process with the FDA important because the work we are doing with the agency will help lay the groundwork for what other companies in this new industry do in the future.”

Implications
The fundamental issue remains: Is the rigor of FDA approval necessary for personal genomics tests? And at the heart of that question is whether or not consumers are utilizing the information in an actionable manner, beyond satiating curiosity.

“If the FDA indeed insists on making 23andMe prove beyond doubt the validity of every single correlation, no genetic-testing service will be able to economically deliver medically relevant genetic information directly to consumers,” writes science commentator David Dobbs in the New Yorker. “It will destroy the industry and leave medical genetics in the hands of a medical establishment that has already failed to give people an easy way to obtain and use the elemental information in their own spit.”

While resolution of the broader regulatory questions will likely be a lengthy process, what are the immediate implications of the warning letter both for 23andMe and for the personal genomics industry?

“The company seems headed for serious regulatory trouble. It has three options: stop marketing the PGS kit, cooperate with the FDA in the hope of getting approval, or forge ahead without approval and challenge the FDA’s authority in court,” says John Conley, of counsel to Robinson, Bradshaw & Hinson. “The second approach could have a happy ending, but it’s clear from the letter that the agency doesn’t trust 23andMe. The approval process is long and complex under any circumstances, and likely to be even more so in this case. The third is the nuclear option. At best, it will take a long time, and I think at this point that the courts would be likely to come down on the FDA’s side.”

Conley, also a law professor at the University of North Carolina, Chapel Hill, adds that if 23andMe doesn’t stop marketing the PGS kit without obtaining approval, the FDA could impose administrative sanctions, including impounding 23andMe’s stock of PGS kits. Again, this could move the battle to the courts if appealed by 23andMe, or the FDA could go directly to court to seek an injunction.

With 23andMe’s former competitors deCode and Navigenics essentially out of the personal genomics business, are there broader implications of the warning letter?

“Google money can keep 23andMe alive indefinitely, but I’m extremely skeptical that this market has a future. Who are the customers?” asks Conley in a Genomics Law Report blog post. “There is undoubtedly a hard core of genetic hobbyists, but 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 health or reproductive decisions?”

Experts say it is interesting to note that the FDA kept the warning letter limited to the facts of this case and did not make statements against the entire DTC genomic testing industry.

“The current letter to 23andMe does not make a blanket claim that DTC tests cannot or will not be cleared for marketing,” explains Conley and “stops short of broad new legal pronouncements.”

Conley adds, though, that while “some of the FDA’s claims about risk also seem a bit overwrought” he bets that if the case moves into a legal venue, “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.”

Takeaway: While 23andMe’s strategy for moving forward with its PGS is still unknown, the FDA’s warning letter did not in theory limit the DTC industry if it can prove the validity of its products.

Side Bar Box:

A Failure to Communicate

Among the more startling elements of the warning letter were the details of 23andMe’s failure to maintain communication with the FDA. A seemingly frustrated FDA says that as a result of 23andMe’s failure to submit “adequate information” in response to the agency’s “detailed feedback,” the FDA considers company’s previous 510(k) submissions “withdrawn.”

There is significant speculation as to why in light of “14 face-to-face and teleconference meetings, hundreds of e-mail exchanges, and dozens of written communications” which included potential classifications and regulatory pathways (including reasonable submission timelines), statistical advice, and potential risk mitigation strategies, the company neglected to act.

“Months after you submitted your 510(k)s and more than five years after you began marketing, you still had not completed some of the studies and had not even started other studies necessary to support a marketing submission . . . [and] now eleven months later, and you have yet to provide FDA with any new information about these tests.” Despite a complete lack of communication with the FDA since May, 23andMe has “initiated new marketing campaigns, including television commercials that, together with an increasing list of indications, show that you plan to expand the PGS’s uses and consumer base” without approval.

In a statement, 23andMe said, “We recognize that we have not met the FDA’s expectations regarding timeline and communication regarding our submission. Our relationship with the FDA is extremely important to us and we are committed to fully engaging with them to address their concerns.”

Side Bar Box:
Gentle Labs Launches Exome Sequencing to Consumers

Gentle Labs (Leuven, Belgium) launched a $1,990 personal exome test at the end of November for customers worldwide. The test focuses on carrier screening for 1,700 genetic conditions, but unlike other DTC offerings, results are reported by a contracted medical geneticist to either the patient or the patient’s doctor. This strategy, Jennifer Wagner, J.D., Ph.D., from University of Pennsylvania’s Center for the Integration of Genetic Healthcare Technologies says, could be “a potentially valuable self-policing alternative to governmental oversight by ensuring that those providing genetic/omic services for a fee (regardless of setting) are using reasonable methods and judgment and receiving adequate continuing education.”

Gentle Labs says it screens not only for conditions for parents-to-be, but also personal genetic risks like breast and colon cancer, heart disease, and pharmacogenomic markers. Once ordered by consumers, kits are mailed to their homes and saliva samples are shipped back for analysis. All lab work is outsourced to the CLIA-certified next-generation sequencing lab at Otogenetics (Norcross, Ga.). The test is based on 50x whole-exome sequencing, enabling screening for “very rare” disease-causing markers, Gentle says.

Unlike other DTC firms, Gentle contracts with medical geneticists through the multinational firm Royal Doctors to communicate results either to the patient or a doctor of the patient’s choosing. After results have been reported in six weeks, iPad and Web apps are available for clients to explore more about their genetic findings. Reports use illustrated, color-coded diagrams and maps to make results easily comprehendible.

“We are confident that genetic tests will be breaking out of their niche consisting of genetics enthusiasts and will become mainstream,” Peter Schols, Gentle’s CEO, tells DTET. “We think we are ready for this challenge: with more markers than any other company, with genetic counseling included in the package and with great apps to explore results, we can offer the best possible experience in personal genomics.”

Gentle is in talks with private insurers to establish reimbursement coverage. Schols says that the company just completed its seed round of financing and in the future the company not only plans to expand its testing services, but also plans to engage academic partners in genetic research on cancer susceptibility, autoimmune conditions, and eye diseases, once the company’s user base is large enough.

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