How 23andMe used rigorous clinical trials to win a landmark FDA authorization
When the Human Genome Project (HGP) was declared a fait accompli in 2003, after 13 years of international collaborative work and a great deal of government funding, it heralded the beginning of a new era in genetics-driven medicine. Much of what is happening now in personalized medicine, especially oncology, is based on genomic framework established at the end of the 20th century.
But there’s another side to the story: Consumers now have access to their own genetic information and have become empowered to learn about their ancestry, and in some cases, their genetic proclivities. Since 2007, 23andMe, a privately held personal genomics and biotechnology company based in Mountain View, CA, has been offering direct-to-consumer (DTC) consumer genetic testing.
According to 23andMe, the company boasts “over 800,000 genotyped customers.” Here’s how it works: Customers order a DNA test online and send it back with a saliva sample. Then, DNA analysts in the 23andMe lab use a chip consisting of a fully customized probe to detect genetic variations.
This service has been popular not only among customers, but also among healthcare practitioners like Dr. Barry Mennen, a Washington, D.C.-based practicing physician.
Physician, heal thyself
In fact, Dr. Mennen finds the test so useful that he has used it to test himself. He explains, “Picking an example from my own 23andMe analysis done about six years ago, my risk for age-related macular degeneration is 8.6% compared to an average risk of 6.5%, yielding an increased risk of 1.3 times normal for me," said Mennen in an interview with BioPharma Dive. "Is this relevant? Is there any change I should make because of this? No. This result is meaningless; however, for a common type of glaucoma, my risk was 3x normal (2.2% vs. 0.7%). Slightly more relevant, so what did I do? Well, I hadn't seen my ophthalmologist in about three years, so this spurred me to visit her in order to get a baseline pressure done in my eyes."
For roughly six years, 23andMe made it possible for physicians like Dr. Mennen, as well as consumers, to order information not only about ancestry, but also about carrier status, health risks, drug-response proclivities, and other health-related information. Using its flagship Personal Genome Service (PGS), 23andMe’s genetic analysts were able to provide direct feedback to consumers about their health-related genetic risks and overall profile. The idea was that this knowledge could help an individual consumer take steps to modify certain risk factors while taking control of his or her own health.
The FDA steps in
And then came the FDA. On November 22, 2013, the agency came down hard on 23andMe with a warning letter notifying the company that it was in violation of FDA regulations for marketing the 23andMe Saliva Collection Test and the PGS without marketing clearance.
According to the FDA, 23andMe was using the PGS, technically a medical device, to provide reports on 254 health conditions—and that most of these conditions fall under the rubric of medical diseases. The agency also noted that it had conducted 14 face-to-face and teleconference meetings with 23andMe, on top of exchanging numerous emails, with the goal of helping the company come into compliance. What's more, the FDA worked with 23andMe to address some of the outstanding issues related to the company's 510(k) submissions—without a fully satisfactory outcome. The result: The FDA ordered 23andMe to stop marketing the PGS.
A first step—and a victory
Fast-forward 15 months. Last week, the FDA issued its first approval to 23andMe for a carrier-status use—specifically a genetic test for Bloom Syndrome, a serious, rare genetic disorder which mainly affects Ashkenazi Jews and can lead to stunted growth and cancer risk. The indication specifies that the test should only be used for postnatal carrier screening in adults of reproductive age—and 23andMe is required to provide information to those who take the test about how to access a board-certified clinical molecular geneticist for appropriate counseling.
It was a good-news day in Mountain View. On the company blog, 23andMe’s CEO, Anne Wojcicki, wrote: "This is an important first step in fulfilling our commitment to return genetic health reports to consumers in the US."
"This is also the first-time the FDA has granted authorization to market a direct-to-consumer genetic test, and it gives 23andMe a regulatory framework for future submissions," she added. "While this authorization is for a single carrier status test only, we are committed to providing US customers with health information once more tests have been through this process and we have a more comprehensive product offering."
A rigorous clinical trial program
The FDA approval was underscored by a rigorous clinical trial program in which 23andMe performed two separate studies to test the accuracy of the company's test in detecting Bloom Syndrome—including one with 70 unique samples and another with 105 unique samples. In addition, 23andMe conducted a usability study with 302 people inexperienced with the 23andMe process which found that the average consumer can understand the test instructions. Finally, the company expanded the usability study to include a total of 667 individuals representing a cross-section of the U.S. population in terms of age, gender, race, and education.
The reaction to the FDA's position shift has been mainly positive. "With this ruling, the FDA is putting a toe in the water in the area of personal genomic testing with the Bloom Syndrome decision, and they say that will indeed open up more carrier state tests for the direct-to-consumer market," said Mennen.
"This area, known as carrier-state investigation, is not controversial and has been done for years looking for errors of inborn metabolism, certain neurodegenerative diseases, and others. However, with the involvement of 23andMe, this has been removed from the physician’s office and is between a commercial entity and the consumer. This is excellent and will help prevent cases of devastating diseases such as Bloom Syndrome."
In one important way, 23andMe’s victory was a victory for all companies that market carrier-status genetic tests. Prior to this decision, the PGS was considered a class III medical device, which required pre-marketing approval in addition to 510(k) clearance. However, along with the FDA’s approval of the Bloom Syndrome test came a new status for all carrier-status tests—class II—meaning that 510(k) clearance and de novo classification is required, but not premarketing authorization.
Is FDA oversight of these types of tests really necessary? Dr. Mennen thinks so. When asked, he said, "I believe that FDA oversight is necessary to make sure that the claims are validated—so that marketers don’t go beyond the data. Also, patients need to understand that they need healthcare practitioners to help them interpret the data."
Dr. Mennen notes that in his experience working with 23andMe, the company "has acted in a very responsible and transparent manner."
"I greatly look forward to future developments in the area as private enterprise, clinical research and appropriate regulatory oversight come together leading us all to better outcomes," said Mennen.
CORRECTION: An earlier version of this story contained a typo regarding the FDA's reclassification to class II. It has been corrected.