A new risk-based approach for genetic test regulation in the US

By Philippa Brice

12 August 2014


US regulator the Food and Drug Administration (FDA) has issued advance notification of proposed changes to their oversight of laboratory tests, which will apply broadly to genetic tests.

The draft guidance, Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs), sets out a risk-based system consistent with that already in place for in vitro diagnostic devices (IVDs). An LDT is defined as an IVD intended for clinical use that is designed, manufactured and used within a single laboratory.

The FDA says the planned changes are due to the changing testing environment, including the increasing use of diagnostic tests ‘in guiding critical clinical management decisions for high-risk diseases and conditions, particularly in the context of personalized medicine’. They also note that many LDTs are now used in laboratories independent of the healthcare delivery body that will act on results, may utilise components not approved for clinical applications, and often involve highly complex algorithms or other interpretative software.

Filling the regulatory gaps

Gaps in the current regulatory system are said to include no requirement to report adverse events, require informed consent from validation study participants or assess manufacturing quality. The FDA is particularly concerned by the lack of requirement to demonstrate clinical validity (the ability for a diagnostic to measure or detect the clinical condition or risk being evaluated), only analytical validity, i.e. whether the test accurately detects what it claims to detect. This is held to represent a risk to patients where LDTs are being used to make ‘critical clinical decisions’ -that is, diagnosis or treatment. Concern is also expressed that neither health professionals nor patients may be aware that the LDT is not FDA approved and that their analytical and clinical validity have not been evaluated.

Evaluating the risk of diagnostic genetic tests

To assess the risk posed by an LDT, the FDA proposes to consider factors including:

  • whether it is intended for use in high risk diseases or patient populations
  • whether it is intended for screening or diagnosis
  • the nature of the clinical decision that will be made  based on the test result
  • whether other information will contribute to the clinical decision
  • alternative diagnostic and treatment options available
  • potential consequences of erroneous results

The regulator will then impose regulatory requirements on most LDTs for clinical applications, the exceptions being certain LDTs used to assess blood or tissue transplant compatibility. This will include registration, listing and adverse event reporting for low-risk LDTs and others that are for rare-diseases or currently unmet needs. For other high and moderate risk LDTs, the FDA will additionally enforce regulatory requirements for premarket review and quality evaluation. Overall, these measures are intended to create ‘reasonable, predictable, and consistent regulatory policy for assuring the safety and effectiveness of LDTs’.

Importantly, the FDA singles out three categories of LDT that it thinks likely to fall into the high risk category:

  1. Companion diagnostics – LDTs that claim to inform therapy selection of therapy, patient population, or dose that are not included in the therapeutic product labelling.
  2. Screening devices for serious diseases intended for use in asymptomatic patients with no other available diagnostic options
  3. Diagnostic devices for certain infectious diseases with high-risk intended use e.g. monitoring viral infections in immunocompromised patients.

Striking the right balance

The FDA has set out a sensible, balanced approach in their proposed regulatory changes for the US health system. In particular, they recognise the rapidly evolving environment for genetic and other forms of diagnostic testing and the need to respond to these changes, and are also able to make rational distinctions between low, moderate and high risk test applications.

This is entirely consistent with the comprehensive ACCE framework for genetic test evaluation, which considers a test as the application of an assay for a defined purpose in a specific population and takes into account analytical and clinical validity, as well as clinical utility and associated ethical, legal and social issues. The latter are not regulatory issues, but rather additional considerations that may also be required by those who decide on the funding and provision of genetic tests. This framework is central to the UK Genetic Testing Network evaluation process for NHS LDTs for inherited diseases.

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