At the end of 2015 the FDA released a whitepaper supporting their intention to overhaul the regulation of laboratory developed tests (LDTs) in 2016. These are tests that doctors use to determine the risk of a patient developing a disease or to determine the appropriate treatment to administer to a patient. While FDA-approved diagnostic tests do exist, many labs in the US can and do make and use their own tests, and these tests that are designed, developed and manufactured in a single laboratory are what the FDA plan to increase regulation of.
The FDA has held the authority to regulate LDTs along with all other in vitro diagnostics, since 1976, but they have typically exercised discretion and not required that all labs developing tests seek FDA approval. Instead, these labs and tests are currently regulated by the Centres of Medicare and Medicaid Services by the 1988 Clinical Laboratory Improvement Amendments (CLIA).
The CLIA regulations determine whether the tests are being performed correctly, but do not assess whether the tests themselves are clinically valid, in terms of providing patients with accurate information about their condition. The FDA have shown concern for a number of years now over the state of LDTs, which increasingly rely on complex technology and are being produced and used in larger numbers, meaning an increased risk to patients and users of these tests.
To support their claims that the current system of regulation is not sufficient, in November 2015, the FDA released a whitepaper “The Public Health Evidence for FDA Oversight of Laboratory Developed Tests: 20 Case Studies (link is external)”. This report details 20 different case studies of LDTs that were shown to have the potential to have caused harm to patients without FDA intervention, or have actually caused harm to patients through their use in labs across the US.
Some of the case studies included in the report provided an exceptionally high rate of false positive results. One example cited by the FDA of an assay producing false positive diagnoses is for Lyme disease, the treatment of which involves IV antibiotics for 2-4 weeks. Both a dot blot test analysing the urine antigens of patients with suspected Lyme disease and an assay analysing blood markers were shown by independent evaluation to give false positive results. Apart from causing unnecessary distress and treatment for falsely diagnosed patients, a false positive assay result like this delays an accurate diagnosis of a patient’s true condition and increases the risk of developing antibiotic-resistant organisms.
In other cases the tests gave rise to false negative results and some were found to assess irrelevant markers to the condition being analysed, which prevent efficient and accurate treatment of a patient’s condition,.
Also included in this report were estimates of the costs endured due to the failing of some of these assays. The cost to society for each case of falsely diagnosed Lyme disease is estimated at $1,226. For the CARE clinics Autism Biomarker Test, which the FDA says that the biomarkers analysed are unproven in relation to autism and the treatments recommended by this test irrelevant to the condition, the report estimates the public health cost of this failed test at $66.1 million.
The use of Affimer proteins in diagnostic tests could offer increased performance to many different diagnostic platforms. Affimer binders can be generated to theoretically any target. Target specificity is ensured by the introduction of competition of similar molecules during Affimer protein development and batch-to-batch stability is assured, giving confidence in the ongoing performance of an assay. Affimer proteins are stable and fully functional on solid supports and have been shown to be very robust, withstanding temperatures up to 80°C and pH from 2-14, so their performance will not be affected by the assay environment. Building this kind of technology into diagnostic tests cold offer the reproducibility and specificity that is missing in many of the assays illustrated in the FDA’s report.
The FDA have released a draft guidance setting out how they plan to regulate these tests. These guidelines would not apply to all tests. Those that the FDA consider low-risk, those that diagnose rare diseases and those that have no FDA-approved equivalent would still fall under the enforcement discretion of the FDA. But the rest of the labs producing diagnostic tests would need to submit data to the FDA to prove their tests’ validity.
While some welcome the enhanced regulation of the FDA and believe it will increase patient safety, others claim that it will deter researchers from developing new tests and prevent them from adjusting the tests quickly for new uses. The FDA intends to phase in the new regulations over a nine year period, beginning this year, and so it will be interesting to see how many assays survive.