IVD Genetic Testing Direct to Consumer (DTC) FDA Approval: Case Study

Jun 29, 2016 | News

The area of genetic testing has expanded significantly in recent years with more types of testing becoming available for both clinical and non-clinical applications. The AMA states there are more than two thousand genetic tests available to aid in the diagnosis and treatment of more than one thousand different diseases

Clinical genetic testing can consist of diagnostic and predictive medicine which identifies whether an individual has a certain genetic disease or an increased risk for a particular disease. Pharmacogenomics evaluates an individual's genetic makeup to determine whether a drug is suitable for a particular patient and whole-genome and whole-exome sequencing examines the entire genome or exome to discover genetic alterations that may be the cause of disease. Genetic testing can include breast, ovarian, and prostate cancer; Crohn’s disease, deafness, Huntington’s disease, sickle cell anemia, and cystic fibrosis to name a few.  Non-clinical genetic testing is also performed to determine characteristics such as ancestry and paternity.

Most genetic testing is available only through a healthcare provider; however the emerging field of direct-to-consumer (DTC) testing provides the possibility of obtaining test results directly from a company without the involvement of a healthcare provider or genetic counselors.

The FDA considers in-vitro diagnostic products (IVD), a regulated medical device. They are intended for use in the diagnosis of disease or other conditions through the collection, preparation, and examination of specimens taken from the human body. An IVD that is intended for clinical use and designed, manufactured and used within a single laboratory is considered a laboratory developed test (LDT). The FDA has identified a genetic test as a type of IVD.

The FDA has become aware of the DTC genetic testing field. On July 22, 2010 Jeff Shulman FDA Director, Center for Devices and Radiological Health appeared before the Subcommittee on Oversight and Investigations to address genetic testing and the consequences to the public. In this meeting he stated the following:

“….although FDA has the authority to regulate LDTs, FDA has generally exercised enforcement discretion since the device law was passed in 1976. At that time tests made by laboratories were generally low-risk diagnostic tools or relatively simple, well-understood tests that diagnosed rare diseases and conditions, and which were more dependent on expert interpretation…The nature of laboratory-developed tests has changed over the last 30 years, but most dramatically in the last few years.”

In comments specific to genetic tests being sold directly to consumers (DTC) Dr. Shulman stated:

“In particular, some companies are making claims about high-risk medical indications, such as determining the risk for cancer or the likelihood of responding to a specific drug. Moreover, in many cases the link between the genetic results and the risk of developing a disease or responding/not responding to a drug has not been well-established…Marketing genetic tests directly to consumers can increase the risk of a test because a patient may make a decision that adversely affects their health, such as stopping or changing the dose of a medication or continuing an unhealthy lifestyle, without the intervention of a learned intermediary. The risk points up the importance of ensuring that consumers are also provided accurate, complete, and understandable information about the limitations of test results they are obtaining.”

In a further effort to provide guidance on the agency’s views related to LDT and DTC the FDA published a draft guidance Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) on 10/3/14. This guidance document reinforces the FDA position regarding LDT and genetic tests intended for DTC by stating the following:

“Due to changes in the complexity and use of LDTs and the associated increased risks, as described above, FDA believes the policy of general enforcement discretion towards LDTs is no longer appropriate…The FDA generally does not exercise enforcement discretion for direct-to-consumer (DTC) tests regardless of whether they meet the definition of an LDT provided in this guidance.”

Over this time period the FDA has sent numerous warning letters to companies notifying them they are in violation of these IVD medical device requirements. One company that received an FDA warning letter was 23andMe, Inc. from Mountain View, CA. In that warning letter dated 11/22/13, the FDA stated the company was marketing the 23andMe Saliva Collection Kit and Personal Genome Service (PGS) for indications including assessments for BRCA-related genetic risk and drug responses (e.g., warfarin sensitivity, clopidogrel response, and 5-fluorouracil toxicity) without marketing clearance or approval and the device was therefore adulterated and misbranded and in violation of the Federal Food, Drug and Cosmetic Act.

Regulatory Pathway

After receiving the warning letter from the FDA, 23andMe, Inc. submitted to the agency a direct de novo application for the company’s Personal Genome Service (PGS) Carrier Screening Test for Bloom Syndrome device indicated for the detection of the BLMAsh variant in the BLM gene from saliva collected using an FDA-cleared collection device (Oragene DX model OGD-500.001). This test can be used to determine carrier status for Bloom syndrome, but cannot determine if a person has two copies of the BLMAsh variant. The test is most relevant for individuals of Ashkenazi Jewish descent intended to be sold over-the-counter or DTC and stated there is no legally marketed device on which to base a determination of substantial equivalence.

Devices of a new type that the FDA has not previously classified and therefore do not have a predicate device are “automatically” or “statutorily” classified as a class III device. A direct de novo submission is a petition made to the FDA when a company believes its device is appropriate for classification into Class I or Class II.

A de novo submission includes information and evidence regarding the safety and effectiveness of the device and establishes the risk profile of the device demonstrating that general controls needed to design, develop and manufacture the device are appropriate. This information includes a thorough device description, device classification summary, supporting protocols and/or data, risk and mitigation information, and device labeling.

The FDA agreed with the company’s de novo petition and responded through FDA reclassification order letter DEN140044 finalized on 10/1/15 stating the following:

“FDA concludes that this device, and substantially equivalent devices of this generic type, should be classified into Class II. This order, therefore, classifies the 23andMe PGS Carrier Screening Test for Bloom Syndrome, and substantially equivalent devices of this generic type, into Class II under the generic name, Autosomal recessive carrier screening gene mutation detection system…FDA believes premarket notification is not necessary to provide reasonable assurance of the safety and effectiveness of the device type and, therefore, is planning to exempt the device from the premarket notification requirements of the FD&C Act.”

The 23andMe, Inc. device is required to be compliant with general controls which are required of all medical devices and includes adulteration, misbranding, device registration and listing, and GMP compliance. In addition to the general controls, the autosomal recessive carrier screening gene mutation detection system is also subject to special controls which include:

  • Providing information on how to obtain a board-certified clinical molecular geneticist or equivalent for pre- and post-test counseling
  • use of a FDA cleared or exempt collection device with an indication for in vitro diagnostic use in DNA testing
  • providing information on the device labeling including warnings and limitation statements
  • the need to meet certain performance specifications
  • limited distribution of the device to the manufacturer, the manufacturer’s subsidiaries, and laboratories regulated under the Clinical Laboratory Improvement Amendments


After receiving an FDA warning letter 23andMe, Inc. submitted to the FDA a direct de novo application stating there is no legally marketed device on which to base a determination of substantial equivalence and petitioned the agency for it not to be classified as a Class III device. The FDA agreed with this de novo application and determined the 23andMe, Inc. device is a Class II exempt device.

The FDA believes the devices does not exceed the threshold of requiring a premarket submission but that special controls are required to ensure the safety and efficacy of the device. This decision indicates the FDA gave this submission a thorough and even review and, considering the number of genetic tests available, sets a precedent for manufacturers of devices with similar risk profiles in the emerging field of DTC that they may also be successful through the de novo route without the considerable time and expense of a premarket approval (PMA), therefore avoiding an FDA warning letter. Also, devices equivalent to the Autosomal recessive carrier screening gene mutation detection system would be considered exempt from premarket notification requirements.