Science Policy For All

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Regulating laboratory tests for accuracy and patient safety

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By: Cheryl Jacobs Smith, PhD

On June 13, 2013, the Supreme Court ruled that Myriad Genetics did not own the sole rights to the genetic testing of genes involved in breast cancer susceptibility, BRCA1 and/or BRCA2 (1). Therefore, diagnostic companies and academic institutions could then create their own diagnostic tests surrounding BRCA1 and BRCA2. However, since the ruling, as more and more companies and academic centers are taking advantage of the “open market” on diagnostic tests, a question arises: Are all of these diagnostic tests appropriate for the clinic and safe for patient use?

The Food and Drug Administration (FDA) would certainly say no. In a document issued on October 3, 2014, the FDA outlined a draft guidance addressing gaps and areas of improvement related to the regulatory oversight of diagnostic tests (2). In the draft guidance, the FDA emphasized that the subset of in vitro diagnostic devices (IVDs) referred to as laboratory developed tests (LDTs), should have additional regulatory oversight to assure their safety and efficacy. Some recommendations include: adverse event reporting, an option to remove unsafe LDTs, critical evaluation of clinical validity and reproducibility of LDTs, and structured guidelines for informed consent.

Since 1976, the Medical Device Amendments (MDA), which amended the Federal Food, Drug, and Cosmetic Act (the FD&C Act), established a rubric for the regulation of medical devices intended for human use (3)(4). It was amended to make explicit that the act include IVDs, and thus, LDTs. The definition of an IVD applies equally whether it is manufactured by conventional manufacturers or by individual laboratories. However, since the implementation of the MDA of 1976, the FDA has enforced applicable provisions with respect to LDTs under the FD&C Act at the manufacturer’s discretion. Thus, enforcement discretion for LDTs developed as a matter of general practice rather than by law.

The Centers for Medicare and Medicaid Services (CMS) has regulated LDTs (with research LDTs exempt) since 1988 under the Clinical Laboratory Improvement Amendments (CLIA—42 U.S.C. 263a) (5). Although all clinical laboratories must be properly certified to receive Medicare or Medicaid payments, CLIA has no direct responsibilities to either Medicare or Medicaid. CLIA governs the accreditation, inspection, and certification process for laboratories. However, the statutes of CLIA do not evaluate test validity prior to marketing, nor do they assess the clinical validity of a LDT. This regulatory gray area poses a couple of questions: Can the LDTs actually identify the biological events that the manufacturers claim? And, if so, with what accuracy in the tested population? These are very important questions when the result of a particular test could determine medical treatment. Therefore, although CLIA oversight is important, it alone does not ensure that LDTs are properly designed, appropriately manufactured, and are safe and effective for patient use. With the large regulatory gaps that still exist in the LDT market, how is it that this has gone on for so long without being addressed?

Initially, when LDTs were used to measure blood type or one or two biological markers at a time, CLIA accreditation was sufficient. However, due to changes in the complexity and use of LDTs, and with the advent of complex algorithms accompanied by computational analysis, CLIA requirements alone have become inadequate. Learning this information may make consumers uneasy to have any sort of test done by a medical office in the near future. Yet, is the current state of affairs of LDTs this dire?

I have been fortunate to witness the process by which an LDT is developed. From what I observed, the process appeared highly regimented, rigorous, and repeated to ensure accuracy and specificity of both the test and the instrument running the test. The diagnostic laboratory was not only CLIA-certified but was also certified by the College of American Pathologists (CAP) Laboratory Accreditation Program that “[…] test disciplines with the most scientifically rigorous customized checklist requirements.” (6) Under CAP-certification, laboratories must maintain the accuracy of test results and ensure accurate patient diagnosis, as well as have mechanisms in place to correct cited deficiencies. In that setting, the manufactured LDTs met the CLIA and CAP-certification requirements and included data on LDT specificity, accuracy, and clinical validity to discern between various biological conditions. Consequently, for this laboratory and others with CLIA and CAP-certification, additional oversight by the FDA could prove to be redundant and burdensome slowing down LDT production and availability, in turn potentially negatively impacting patient care. However, not every laboratory that manufactures LDTs conforms to this high level of scientific and medical integrity. Therefore, how can LDTs be regulated so that consumers can be confident in the methodology and reliability of LDTs without stifling LDT production and innovation?

The FDA proposes to amend the regulations surrounding LDTs by implementing a risk-based approach toward oversight of LDTs. Similar to how other medical devices are categorized into risk classes (I-III with I being the lowest risk and III the highest risk), LDTs would be classified based on risk to the patient and/or user and receive appropriate regulations commensurate to the risk level. With the exception of some LDTs solely used for forensic purposes and those used in CLIA-certified, high-complexity histocompatibility laboratories, those laboratories with high, moderate, and low risk LDTs would be required to enforce applicable regulatory requirements that include registration and listing, adverse event reporting, pre-market review, and quality system requirements. If the FDA guidelines become regulatory law for LDTs, patients would gain a comprehensive database of reliable LDTs increasing patient flexibility with whom they choose to do the LDTs and perhaps reduce costs if saturated markets are filled with reliable LDTs rather than a mixture of quality. Additionally, LDT manufacturers would be able to scrutinize tests more comprehensively instead of relying on word-of-mouth or anecdotal evidence to improve unreliable tests.

The suggested increased regulation of LDTs by the FDA may seem burdensome but would achieve a more comprehensive manner to regulate and equalize the validity of LDTs on the market. If anything, it would be helpful to have LDT pre- and post-market evaluations standardized as these measures uncover important medical device mishaps that frequently save patients from unnecessary harm or distress (7). The Diagnostic Test Working Group (DTWG), an independent group consisting of representatives from diagnostic manufacturers and clinical laboratories, suggested adopting some, but not all, of the FDA’s recommendations. Most importantly, the group stressed that this new legislation should require LDT manufacturers to register the LDT with the FDA but that additional oversight concerning sensitivity, specificity, and validity should be applied to LDTs only in the high risk class. Furthermore, DTWG suggested that the FDA should create an additional center for LDTs (8). The later should be seriously considered as FDA is excellent in drafting regulatory frameworks that ensure patient safety, but frankly lack the money and thus, people power to execute its regulations effectively. New LDT regulation may be needed, but without increasing the FDA’s budget to allow swift and effective execution of the FDA’s recommendations, this LDT legislation could ultimately just be black ink on white paper.


Written by sciencepolicyforall

June 10, 2015 at 9:00 am

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