FDA Regulation Defines Business Strategy in Direct-to-Consumer Genetic Testing

October 30, 2017
Contributed by: Lindsey Jones

Why do consumers seek direct-to-consumer (DTC) genetic testing?

Consumers purchase services that sequence and analyze portions of their DNA to understand their risk for familial cancer, plan a safer pregnancy, optimize diet and fitness routines, and satisfy their curiosity about the secrets of their genome and ancestry. The diversifying reasons for consumer interest in DTC genetic testing are estimated to increase its global market value to $350 million by 2022.

With such a valuable market at stake, regulation of DTC genetic testing by the US Food and Drug Administration (FDA) has been under intent surveillance by the biotech industry, healthcare providers, and consumers alike.

The FDA has been regulating medical devices since 1976 when Congress passed the Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act. A medical device is defined as anything that can be used to diagnose, cure, treat, mitigate, or prevent disease, including an instrument, reagent, or “similar or related article.” In vitro genetic tests are therefore considered medical devices.

The FDA regulates both genetic tests that are ordered from and performed at home (DTC) and those that are ordered from and performed in a healthcare setting or laboratory (a laboratory-developed test, or LDT). These two types of tests require different levels of FDA regulation.

LDTs are ordered by a physician, developed by and performed in a single laboratory, are not sold to other laboratories, and are not marketed to consumers. In theory, this reduces the risk of misunderstanding the results and the possibility of erroneous health-related decision-making by the consumer.

On the other hand, DTC tests must pass a higher regulatory bar and demonstrate that they clearly and safely relay information to consumers in the absence of a medical professional. DTC tests do not provide an “informed intermediary” such as a physician or trained expert to explain results, reduce stress, and discuss follow-up options, while physician-delivered reports from LDTs do.

Before the FDA began regulating DTC tests, consumers were purchasing these tests to learn about their risk for Parkinson’s disease, how they might respond to certain types of drugs, if they were likely to develop Alzheimer’s disease, their ancestry, and more. Many of these results were diagnostic in nature, which prompted the FDA to intervene.

FDA crackdown on DTC testing

The FDA watchfully waited as DTC genetic testing companies developed products. The FDA assessed the potential risks and impacts of the products on the consumer, and did not regulate the conduct of DTC genetic testing companies until the companies brought products to market that could be classified as medical devices.

In May 2010, the FDA notified Pathway Genomics that their product was a medical device, and therefore needed FDA approval. In June 2010, the FDA followed by sending warnings to four additional DTC genetic testing companies: 23andMe, deCODE Genetics, Inc., Navigenics, Inc., and Knome, Inc.

When these companies were notified of the FDA approval requirement for their genetic tests, they were all marketing similar at-home saliva collection kits that were used for DNA analysis and the generation of personal health reports. These reports included information that could be used to diagnose disease, screen for carrier status of inherited disease, assess cancer risk, and in the case of Pathway Genomics and 23andMe, predict response to certain drugs.

These five companies pursued very different paths to profitability after their FDA warning.

Knome was acquired by Tute Genomics in 2015, but continued to market genome services under its own name. On September 13, 2016, Knome advertised a Kickstarter campaign for DTC whole genome and whole exome sequencing services. On September 15, they pulled the campaign after receiving a warning letter from the FDA that expressed concern over their DTC marketing. A month after this FDA warning, Tute accepted an offer for acquisition by PierianDx, which offers clinically-oriented next-generation sequencing services to medical centers. After the acquisition, no products were produced under the Knome or Tute names.

Navigenics continued to sell DTC genetic testing until it was acquired by Life Technologies in 2012, when it ceased producing consumer-facing products. Thermo Fisher Scientific acquired Life Technologies in 2014.

deCODE Genetics sold its deCODEme personalized genome service until the company was purchased by Amgen in 2012. deCODE still exists as a privately-held company, but now only performs genomics research on Icelandic volunteer participants.

Only 23andMe and Pathway Genomics have stayed in the DTC genetic testing space, and they have done so through different approaches.

A pivot to remain profitable


23andMe, which started selling its Personal Genome Service in 2007, continued to sell DTC tests after their first FDA warning in 2010. Ultimately, this led to the company being banned from providing any health-related genetic testing services in November 2013.

During this ban, 23andMe was still able to provide users with ancestry data and uninterpreted genomic data, but this change in service attracted fewer new users.

Despite this reduction in user growth, 23andMe genotyped its millionth person in June 2015. With 85% of its customers consenting for their de-identified genotypic and phenotypic data to be used for research, 23andMe has amassed a massive, profitable data repository that facilitates internal research and industry partnerships. In 2013, 23andMe announced its first industry partnership with Pfizer to study the genetic basis of disease in 23andMe’s data.

Additionally, 23andMe used this opportunity to open a therapeutics division. This division aims to mine existing 23andMe user data to identify drug targets for disease treatment and develop drugs for current and future targets.

23andMe worked to comply with the FDA, which resulted in an approval to market a DTC carrier test for Bloom’s Syndrome in February 2013. This ruling demonstrated an important proof of concept: 23andMe was able to accurately and reliably detect a rare Bloom’s syndrome variant in nearly 200 samples in two laboratories. Additionally, 23andMe clearly labeled their home testing kits as non-diagnostic, proved that customers were able to understand how to provide a sample for the DNA test, and showed that users could understand the meaning of their results.

Most importantly, the FDA used this opportunity to establish clear guidelines for DTC autosomal recessive carrier status testing. These guidelines make it easy for companies to add autosomal recessive carrier status tests to their portfolio when using FDA-approved sample collection and processing devices. In October 2015, 23andMe added additional carrier status reports to its genome service.

In April 2017, 23andMe had its greatest FDA success when it earned approval to market ten genetic health risk (GHR) reports. These reports give users an approximate genetic risk for developing a disease, but do not diagnose a lifetime risk of disease. FDA-approved GHR reports may influence minor lifestyle changes, but are not allowed to influence a treatment.

The FDA announced that these tests were backed by strong evidence in the scientific literature and that they met the FDA’s newly established criteria for accuracy, reliability, and clinical evidence during the de novo premarket review process. The FDA plans to exempt future 23andMe GHR tests from premarket review, as long as the test does not yield results that may be “the sole basis” for a major treatment decision.

Despite 23andMe’s regulatory struggles with the FDA, they persevered and were instrumental in establishing the regulation of the DTC genetic testing marketplace. In doing so, they have positioned themselves to be a lasting power in DTC genetic testing.

Their regulatory successes have paved the way for speedier approvals for other genetic testing companies. A fruitful partnership with Pfizer has yielded studies on lupus, inflammatory bowel disease, major depressive disorders, and bipolar disorders. Pfizer’s success with 23andMe data has encouraged others to seek partnerships with 23andMe for data usage. As a result, 23andMe’s therapeutics division has additional genetic mutations to investigate for pharmaceutical targeting.

Pathway Genomics

Pathway Genomics had a plan to market their Genetic Health Report through Walgreens in 2010, but that plan quickly fell apart after the warning letter from the FDA. As a result, Pathway Genomics split their genetic testing into two different categories: those that contain health-related information, and those that do not.

Their health-related tests, like a hereditary cancer panel, a weight loss program guided by DNA, and carrier status reports, were developed by Pathway Genomics to be performed in a laboratory upon the referral of a physician, which categorizes them as an LDT.

Pathway Genomics’ LDTs are still subject to FDA approval but are less strictly regulated than their DTC products. While the health-related tests are advertised to consumers, they still require the order of a physician, and the results are delivered by a health professional.

Pathway Genomics also offers DTC genetic tests that do not contain possibly actionable health data. These tests provide insights into fitness parameters and skin qualities, and can be ordered on the Internet by the consumer without physician referral.

Moving their genetic tests to a physician-ordered and physician-delivered model allows Pathway Genomics to test for genetic variants with medically significant outcomes, such as those associated with forms of hereditary cancer, because a physician can guide the consumer through the results and discuss future actions.

In addition to changing the regulatory designation of some tests, Pathway Genomics partnered with IBM in 2014 to work on a consumer-facing mobile app, later named OME, to help users understand and interact with their personal genomic information. OME is still not available to consumers but promises to integrate artificial intelligence with genomic data to help consumers act on their personal genomic information.

Even though Pathway Genomics significantly changed their business strategy by moving many of their DTC tests to physician-ordered LDTs, they received a second warning from the FDA about a new DTC liquid biopsy cancer detection test in September 2015. The device was not registered with the FDA, and the FDA had concerns that it was a high-risk test that lacked proper clinical validation. Pathway Genomics subsequently pulled it from the market.

Current landscape of DTC genetic testing

While 23andMe and Pathway Genomics have remained strong players in the DTC genetic testing field, other companies offering unique approaches to personalized genomics have sprung up in the wake of regulatory shake-ups.

Ancestry and aging

There are many companies on the market that provide ancestry information, or the geographical origins of one’s DNA. These companies, like Ancestry.com, Inc. ($ACOM), MyHeritage, and Family Tree DNA ($GENE), are unregulated by the FDA.

TeloYears offers to measure consumers’ telomere length to determine their “cellular age,” which aims to provide information about aging and healthy habits. Because this test is not diagnostic, it is not regulated by the FDA.

DNA product marketplace

Helix, a spinoff of Illumina and a relative newcomer to the space, has a very novel take on DTC genetic testing. Helix sells next-generation sequencing and storage of a customer’s DNA, but does not provide any direct analysis. Instead, Helix has partnered with many companies to provide a wide variety of DNA-powered services to their customers, without the need for re-sequencing for each service added.

Some services available for purchase through Helix’s DNA product marketplace are for serious health conditions, like inherited diabetes and cholesterol tests through Admera Health, or carrier screening through Sema4. Other tests provide ancestry information from National Geographic, or food sensitivity testing with EverlyWell. Any test with medical implications is done upon physician order and with accessibility to genetic counselors. The partner company, not Helix, manages FDA compliance.

Helix may interest new types of customers in genetic testing through partners like Vinome, which curates wine for clients based on their DNA and taste preferences, and Dot One which designs personalized art and textiles based on a person’s unique DNA sequences.

Helix has many partnerships pending with well-known organizations like the Mayo Clinic, and other DTC genetic testing companies, like Invitae. Owning all of that genomic data will provide a rich research resource for Helix as their customer base grows.

Advertised to consumers, ordered by physicians

Genetic testing companies in the health, family planning, and cancer spaces are currently employing an interesting business model; they market their services to consumers, but require a physician to order and deliver the tests results. As such, they are not true DTC companies, but sell LDTs that are still regulated by the FDA.

Counsyl offers carrier status reports, prenatal screening, and hereditary cancer tests, all provided with a physician’s order and access to genetic counselors. Counsyl has never executed a DTC approach.

Color Genomics provides physician-ordered hereditary cancer testing with genetic counseling.

Veritas Genetics is one of a few companies that currently advertise whole-genome sequencing. They are the first to offer the sub-$1000 genome, at $999. Veritas also offers targeted cancer, carrier status, prenatal, and pediatric tests. All of their products require physician approval.

Invitae ($NVTA), founded in 2010, had an initial public offering in 2015 and is positioning itself to be a major player in the field. Invitae offers whole exome sequencing, hereditary cancer risk analysis, gene panels for specific concerns like cardiac health, and broader screening for multiple diseases. All of Invitae’s products require a physician referral and include genetic counseling.

Invitae has expanded its operations into the fertility market. They recently acquired Good Start Genetics, which specializes in pre-implantation and carrier status diagnostics, and CombiMatrix, which provides prenatal diagnostics, pediatric disorders, and miscarriage analysis. Invitae is poised to take advantage of a specialized market with its pregnancy-associated tests.

How will the FDA continue to regulate DTC genetic testing?

As the body of scientific literature supporting the genetic basis of disease grows, the FDA will need to dynamically evaluate its regulation of DTC tests. The determination of how risky particular information may be to a consumer, and if a certain genetic mutation is considered diagnostic or not, will likely change.

Currently, there is a spectrum of low-risk/non-diagnostic to high-risk/diagnostic genetic testing.

Genetically determining that a woman is at high risk for breast cancer may lead her to prophylactically remove her breasts and ovaries, which is a clear example of a diagnostic genetic test that may lead to a significant medical intervention. But what level of medical intervention determines if a test is diagnostic?

The FDA has not explicitly stated how it determines if a medical device is diagnostic. This broad categorization of “diagnostic” allows the FDA to protect consumers from risky products and testing as it sees fit.

However, as consumer scientific literacy improves, medical technologies evolve, and as do-it-yourself tools become available online, consumers are able to glean more from their uninterpreted genomic data than ever before. How long will it be before all consumers of DTC genetic testing can mine their genomes on their own?

The FDA is entering a new era of regulation as whole genome sequencing becomes more accessible to consumers. Because a large portion of the human genome has yet to be decoded, the level of “diagnostic” information it contains, and therefore how the dissemination of that information to consumers should be controlled, is unclear.

Successful DTC genetic testing companies must not only work within the FDA’s current regulatory framework but also be poised to quickly move into new markets as new types of genomic information are determined to be useful to consumers and as the criteria of what is considered “diagnostic” by the FDA continues to evolve.

 Lindsey Jones is a Science Communications Fellow at BCBA,f a fifth-year Biomedical Sciences PhD student at UCSF and studies brain tumor genetics.