David Babaian, JD, LLM

by David Babaian

Genetic Health Risk Assessment Approvals Get an FDA Makeover

This year, emerging technologies have given way to innovative regulatory paradigms that aim to strike a balance between consumer autonomy and consumer protections. Equilibrium is often elusive, but regulators have been active in attempting to achieve it.

In a recent example, the FDA indicated in November 2017 its intent to allow exemption of certain genotyping systems from premarket notification under specified conditions. In an announcement, Commissioner Scott Gottlieb recognized individuals’ increasing engagement in their own healthcare and interest in genetic risk profiles, but warned of the risks of making health decisions on incomplete or even erroneous information without consulting a healthcare professional.


How Did These Changes Come About?

Generally, the FDA permits certain regulated devices to come to market based on a reasonable assurance of safety and effectiveness, as established by similar, previously approved predicates.

Over time, amendments to the FD&C Act (the “Act”) have enabled de novo classification. Ultimately, if the device has not been previously classified and the FDA designates it class III, or if the manufacturer concludes there is no legally marketed device upon which to base a determination of substantial equivalence, a request may be made for a classification under section 513(f)(2) of the Act.

When FDA classifies a device into class I or II via the de novo process, the device may then serve as a predicate for future devices of that type. As a result, other device sponsors do not have to submit a de novo request or premarket approval request in order to market a substantially equivalent device.

The FDA may go further and exempt a class II device from the premarket notification requirements if it determines that such notification is unnecessary to provide reasonable assurance of safety and effectiveness of the device.

Generally, the following factors determine whether premarket notification is necessary at all for class II devices.

  • The device does not have a significant history of false or misleading claims or of risks associated with inherent characteristics of the device
  • Characteristics of the device necessary for its safe and effective performance are well established
  • Changes in the device that could affect safety and effectiveness will either (a) be readily detectable by users by visual examination or other means such as routine testing, before causing harm, or (b) not materially increase the risk of injury, incorrect diagnosis, or ineffective treatment
  • Any changes to the device would not be likely to result in a change in the device’s classification


Improved Access to Genetic Health Systems?

As a kind of prelude, in 2015, the FDA permitted marketing of the first direct-to-consumer (DTC) genetic carrier screening test—a class II device that received de novo classification—for Bloom syndrome, designated an Autosomal Recessive Carrier Screening Gene Mutation Detection System.  The final notification of exemption from premarket notification for this type of device was likewise published in November 2017.

Also in 2017, the Agency classified a Personal Genome Service Test and dubbed the device type, a Genetic Health Risk Assessment System (GHRAS), defined as “a qualitative, in vitro molecular diagnostic system used for detecting variants in genomic DNA isolated from human specimens that provides information about users’ genetic risk of developing a disease….”

The FDA identified the following risks deserving of general and special controls for this type of device.

  • Incorrect understanding of the device and test system
  • Incorrect test results (false positives; false negatives)
  • Incorrect interpretation of test results

The special controls to mitigate these identified risks of the class II device include required disclamatory statements on the labeling, pre-purchase page, and test report.

Illustratively, users must be informed in plain language of the limitations (the test uses a specific variant, not the user’s whole genetic profile, and it doesn’t account for other risk factors) and the risks of GHRAS and genetic testing. They must also be told that it is normal to feel anxious, and if they do, they should speak to a healthcare professional. Users should be told how to find a genetic counselor and other resources, among other notices.

The label and test report for healthcare professionals must include links to technical information, as well as statements to the effect that the tests aren’t intended for diagnosis, but rather for making lifestyle choices.

Among other restrictions on the use of GHRAS, when the test results may reveal a life-threatening or irreversibly debilitating disease or condition for which there are few or no options to prevent, treat, or cure the disease, user opt-in is required for each such condition.

Importantly for device manufacturers, the GHRAS must use a sample collection device that is FDA-cleared, -approved, or -classified as 510(k) exempt, with an indication for in vitro diagnostic use in over-the-counter DNA testing.  Any changes to the device that could significantly affect safety or effectiveness require new data or information in support of such changes must be posted.


A New Paradigm for Approval of Genetic Health Risk Assessments

The FDA indeed took the class II de novo classification of GHRAS a step further in November by exempting all such devices from premarket notification, albeit with a significant caveat in this instance: the exemption is limited to a GHRAS that has received a first-time FDA marketing authorization.

Dr. Gottlieb extolled the merits of the new paradigm explaining, “If and when finalized, manufacturers of these types of tests would have to come to the FDA for a one-time review to ensure that they meet the FDA’s requirements, after which they may enter the market with new GHR tests without further review.”

He specifically referred to the special controls for these tests issued in the de novo classification order, which outline requirements for assuring the tests’ precision, reliability, and clinical relevance. Perhaps seeking to allay fears concerning deregulation, these special controls describe the type of studies and data—including user comprehension evidence—required to demonstrate performance and usability of these genetic tests, within the greater context of the new “firm-based” approach.

The FDA is accepting comments on the GHRAS exemption until January 8, 2018.