For almost 40 years the FDA has regulated in vitro diagnostics (IVDs) as medical devices. An IVD is a reagent, instrument, or system that is intended for the diagnosis of a disease or other condition, including the determination of the state of a patient’s health, “in order to cure, mitigate, treat, or prevent” a disease or a complication.[ii] These products are intended for use in collecting, preparing and examining samples from patients, such as nucleic acid. For example, one of the more well-known IVDs is the assay for HER2 expression levels. HER2 is a gene that is amplified in 20% of breast cancer patients, and it is those particular patients—and not others— who can benefit from treatment with Herceptin.[iii]
Historically, the agency distinguished between commercially-available IVDs and Laboratory Developed Tests, or “LTDs,” which were tests that were designed, manufactured, and used within a single laboratory for clinical purposes.[iv] In 1976, the volume of LTDs was small. The treating physicians who interpreted the results were in the same institutions as the laboratory personnel who performed the assays. And the LTDs were often similar to standard IVDs, including components that were otherwise approved for clinical use, and/or were intended to diagnose a rare disease.[v] Because the potential impact on the public was small, the FDA exercised enforcement discretion when it came to LTDs. It appears that is about to change. The FDA issued draft guidance for LTDs on Sept. 30th.
Today the molecular diagnostics landscape looks entirely different than it did in the mid-1970s. Using a next generation sequencing platform, an individual’s entire genome can be sequenced in a day or two, in theory for $1000.[vi] PCR technology has advanced to the point where the lower limit of detection of a target sequence is in the range of 0.25 pg/µl, which is 1/24th the amount of DNA in a single human cell.[vii] Finding a needle in a haystack is now possible. Moreover, genetic differences between individuals can be examined by simultaneously querying 23 different genetic markers; with appropriate resources, this can even be done on a global scale.[viii]
In light of these technological advances, it is no surprise that LTDs are performed at a much higher volume than they used to be. Many are much more complex than any assay that existed in 1976, relying on automated interpretation, multiple signals and/or algorithms to generate a result. They may also be performed using reagents or equipment that has not been approved for clinical use. They are often performed by a completely different entity than the institution that is providing patient care.[ix] And—increasingly—they are used to inform critical treatment decisions.[x] Many therapies can only be prescribed for patients with certain genotypes,[xi] and additional assays are being sought to improve the safety and effectiveness of existing therapies, or to assist in monitoring patients’ responses to treatment.[xii] There is also value in being able to determine who won’t respond to treatment. Currently, roughly 40-50% of patients with arthritis, asthma, depression, or diabetes do not respond to the first line of treatment because of genetic variations.[xiii]
The FDA’s draft guidance recognizes that there is a wide range of risks associated with existing LTDs, and proposes a risk-based approach to regulatory enforcement.[xiv] It will continue to exercise discretion when the risk to the public is low. For example, it will exercise its discretion regarding LTDs used for forensic purposes, and for LTDs used in advance of transplantation procedures, so long as the tests are performed in certain, Clinical Laboratory Improvement Amendments (CLIA) certified laboratories.[xv]
The agency will also exercise enforcement discretion for premarket review and quality systems requirements for: (1) low-risk LTDs (Class I) devices; (2) “traditional” LTDs;[xvi] (3) LTDs for rare diseases (< 4,000 incidences per year); or (4) LTDs for unmet needs, where no FDA-approved option is available. For LTDs in these categories, the FDA will enforce the requirements for registering and listing the assay, and for reporting adverse events.[xvii]
Likewise, in other instances, the regulations for registering, listing and reporting will also be enforced, but so will premarket review requirements. For high-risk LTDs, premarket requirements will be enforced beginning 12 months after the guidance is finalized, with a four-year phase-in period. The assays that fall into this category are those with the same intended use as a companion diagnostic, which is a test that provides information essential for the safe and effective use of a corresponding therapy.[xviii] This category also includes LTDs with the same intended use as a Class III medical device, and LTDs for determining the safety or efficacy of blood or blood products.[xix] Premarket review requirements for moderate-risk LTDs will begin after the high-risk tests have been addressed.[xx]
The American Clinical Laboratory Association (ACLA) opposes FDA regulation, arguing that LTDs are “know-how,” not physical articles, and that the FDA has exceeded its statutory authority.[xxi] In the ACLA’s view, any FDA regulation is duplicative of regulations already in place by the Centers for Medicare and Medicaid Services (CMS) under CLIA.[xxii]
While the FDA acknowledges that CLIA regulations ensure high quality laboratory standards, there are significant concerns that are not addressed.[xxiii] Specifically, CLIA regulations do not ensure safety and effectiveness of the LDT prior to commercial launch. They do not require that adverse events be reported, or that unsafe devices be removed from the market. They assess how well an assay is performed, but not how well it was designed or manufactured. And they do not require informed consent from patients who participate in clinical studies designed to investigate the diagnostic, apart from any corresponding therapy.[xxiv]
The comment period on the draft guidance begins on Oct. 3rd. As personalized medicine is big business,[xxv] significant input from all stakeholders should be expected. Stay tuned.
 Sharon Roberg-Perez is a principal at Robins, Kaplan, Miller & Ciresi L.L.P. in Minneapolis. Her practice focuses on biotechnology and medical device patent litigation and enforcement. Prior to her legal career, Ms. Roberg-Perez earned her Ph.D. from the Massachusetts Institute of Technology, and did postdoctoral work at Caltech. Ms. Roberg-Perez is licensed to practice before the United States Patent & Trademark Office.
[viii] Purps, J. et al., A global analysis of Y-chromosomal haplotype diversity for 23 STR loci (Sept. 2014) Forensic Sci Int Genet. Sep 2014; 12(100): 12–23.
[ix] Draft Guidance at 7-8.
[xi] Supra n. 3, The Case for Personalized Medicine at 9-10, 42-60.
[xiii] Supra n. 4, The Case for Personalized Medicine at 9.
[xiv] Draft Guidance at 8.
[xvi] A “traditional” LTD is one that is designed, manufactured and used by a single laboratory that is in the same facility within which patients are both diagnosed and treated. The assay itself should be comprised of approved components, and be performed by qualified professionals, without the need for automated instrumentation or software for interpretation. Id. at 21.
[xxv] In the last four years, one in five original, new molecules approved by the FDA has been a targeted therapy, with “substantial benefits in [a] smaller, molecularly defined, pharmacologically relevant subset of patients.” Pacanoski, MA et al., Next-Generation Medicines: Past Regulatory Experience and Considerations for the Future, Clinical Pharmacology & Therapeutics 95(3): 247-249 at 247 (March 2014). The molecular diagnostics market is a multi-billion dollar market because being able to identify that subset of patients is key. Wattpad, Market Growth – Worldwide Molecular Diagnostics Market 2014 to 20120 (last accessed Sept. 30, 2014) (http://www.wattpad.com/54193039-market-growth-worldwide-molecular-diagnostics); DeciBio, Clinical Diagnostics (last accessed Sept. 30, 2014) (http://decibio.com/clinical-diagnostics.php).
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