key: cord-339122-7vvqtk84
authors: Deb, Chaarushena; Moneer, Osman; Nicholson Price, W
title: Covid-19, Single-Sourced Diagnostic Tests, and Innovation Policy
date: 2020-07-07
journal: J Law Biosci
DOI: 10.1093/jlb/lsaa053
sha: 
doc_id: 339122
cord_uid: 7vvqtk84

The United States’ disastrous response to the onset of the Covid-19 pandemic has arisen in large part by an utter failure to provide adequate diagnostic tests for the presence of SARS-CoV-2. The Centers for Disease Control were the sole testing source authorized by the Food and Drug Administration, and when the CDC failed to provide reliable tests in sufficient volume, it took weeks for other providers to be approved and to ramp up testing. Revised policies should decrease the likelihood of sole-sourcing tests in pandemic contexts, which results in a fragile system. The pandemic sole-sourcing failure, however, not only accelerated the pandemic, but also provides lessons for innovation policy about diagnostic testing more generally. Sole-sourcing hurts clinical practice by limiting confirmatory testing and systemic robustness, whether in a pandemic or in regular practice. We thus argue against relying too heavily on exclusivity-creating patents as innovation incentive for diagnostic tests—including the proposed Coons-Tillis patent reform bill which would increase patentability for many such tests. Instead, we propose the use of reformed reimbursement to create better incentives for diagnostic test innovation. In both pandemics and elsewhere, single-sourcing creates too great a point of failure, but targeted innovation policy can help

At the heart of the United States' disastrous response to the Covid-19 pandemic is a failure of diagnostic testing. That something so fundamental to medical care could be so botched evokes incredulity. From primary care offices to critical care settings, every patient encounter begins with a diagnostic workup. Diagnostic testing tools are key parts of the physician's toolkit, and confirmatory testing is essential. But in the greatest public health challenge of the 21st century, the failures of diagnostic testing have been laid entirely bare.

The story of this failure in diagnostic testing has been told in detail and will be unpacked for years to come. Briefly, the U.S. pandemic response lacked high quality diagnostics, failed to deliver tests in sufficient quantity, and was too slow in deploying developed tests when initially needed. 1 This lack of appropriate testing resulted in inaccurate patient identification and poor epidemiological characterization of viral spread. 2 From there, the errors further multiplied and rendered the rest of the governmental pandemic response similarly sluggish and ineffective.

This article seeks to highlight an implication of the failure that applies broadly to diagnostic testing in general: the problems inherent in relying on a sole source for a diagnostic test. Though we focus on the question of single-sourcing in this exploration, we do not claim this factor as the only failure characterizing U.S. Covid-19 testing policy. 3 Beyond single-sourcing, the FDA stumbled through a series of missteps around its application of Emergency Use Authorization (EUA) strictures and its issuance of EUAs. 4 Nationwide testing further suffered from the CDC's initial promotion of stringent criteria (e.g., travel history, symptom severity, etc.) to determine whether patients should even be allowed to receive tests. The constellation of these factors resulted in fewer patients being tested and rapid spread of the virus. 5 On the other end of the spectrum, the FDA's antibody-testing policy was likely too lax for SARS-CoV-2 serology tests (designed to determine viral antibody presence in blood), leading to too many poor-quality marketed tests that could lead individuals to falsely believe they were immune to COVID-19. 6 The test generated a high proportion of false positives due to initial development with faulty reagents. 10 Beyond quality control issues, the diagnostic test further suffered from a slow reporting of results as clinicians had to send samples back to labs beyond the clinical practice setting for analysis. 11 These shortcomings exacerbated the pandemic's toll by preventing quick containment of the virus.

Crisis may have been averted had there been any alternatives to the CDC's test, but under the FDA's restrictions, there were no other approved tests available to perform any confirmatory testing and receive second opinions. Labs were left to sit powerless until other tests were at long-last approved. This de facto diagnostic test monopoly proved critical and pushed back pandemic control efforts by several weeks. 12 Even after the FDA permitted other labs to conduct testing, they were all required to follow the CDC's chemical formulation. 13 Non-CDC labs all required the same reagents, effectively rendering the additional approvals useless because the small reagent manufacturer could not keep up with the instantaneous jump in demand. The approval of several competing tests earlier in the pandemic response that are not chemically identical, such as the Roche SARS-CoV-2 test, 14 could have also alleviated some of the initial supply chain pressure and underscores the need to prevent monopoly testing. Of course, single-sourcing does not always lead to problems; the SARS-CoV-2 test adopted by the World Health Organization has worked well in the countries that used it. 15 But single-sourcing sharply raises the possibility of problems leading to catastrophic failure down the line.

The problems with single-sourcing, though, are not limited to pandemics. Diagnostic tests are crucial to quotidian clinical practice. And within that practice, the abilities to access high-quality diagnostics rapidly and to perform confirmatory testing are crucial. Single-sourcing diagnostic tests jeopardizes the ability to confirm test results, but also may impact innovative efforts to develop new

diagnostics based on old tools, supply robustness, and cost-effective development. 16 An appropriate model for diagnostic testing development, including innovation incentives, should go beyond simply discouraging test monopolies and promoting confirmatory testing, by also allowing for low R&D costs for test development and yielding fast delivery of high quality tests-preventing the errors highlighted in the Covid-19 testing response from occurring in both emergency and non-emergency situations.

Unfortunately, policy efforts ongoing since before the pandemic are pointing exactly the wrong direction. After an eight-year stretch of unpatentability for certain diagnostics, efforts are afoot to change the law: Recent legislative action would allow such tests to be patented again, 17 raising concerns about limitations on initial use and confirmatory testing. 18

In this paper, we first consider how to address the problems with single-sourcing diagnostic tests in emergency medical contexts like the ongoing Covid-19 pandemic. We then turn to applying those lessons for standard diagnostic test development, in particular considering how we can create adequate incentives for development without relying on a problematic single-source or quasimonopoly model.

The key diagnostic testing roadblock during the Covid-19 pandemic response in the U.S. appears to have been the FDA's decision to permit only the CDC to offer diagnostic testing for SARS-CoV-2. Without approval to test, none of the many other potential testing providers could offer confirmatory testing when the CDC's test offered ambiguous results, provide testing to make up for the CDC's breathtaking shortfall in testing volume, or offer innovative advances on the basic test to improve the substantial time required to get results back from the CDC. 19 Though the FDA

ultimately did relax its regulatory structure in approving diagnostic tests, 20 the policy-driven delay had profound consequences.

Accordingly, the most straightforward intervention would involve updates to the FDA's emergency use authorization process. The 2013 Pandemic and All-Hazards Preparedness Reauthorization Act (PAHPRA) passed under the Obama administration contemplated a pandemic, but focused primarily on streamlining the administrative process necessary for the FDA to start issuing "Emergency Use Authorizations" (EUA) of unapproved medical countermeasures (MCM) and expanding the emergency uses of already FDA-approved MCMs. 21 We suggest updating the EUA model so that safety and efficacy of novel diagnostic tests can be established as quickly as possible. Thus, in order to facilitate early deployment of multiple tests in a pandemic scenario, we suggest considering whether the EUA model be updated to: (1) streamline the EUA application process, perhaps through an alternative, temporary route administered through CMS, a regulatory body that CLIA-approved labs are already familiar with, (2) make the regulatory regime more flexible, such that a more lenient structure can be quickly put in place to combat the early stages of an epidemic, and (3) initially institute a limited liability model that would incentivize labs, like those at Stanford and the University of Washington, to begin using their test if they have good scientific data backing their safety and efficacy, especially if EUA processing delays are expected. An absence of any regulatory oversight brings its own problems-witness antibody testing-but overly tight entry rules can also be disastrous. FDA eventually adopted a more lenient policy incorporating some of these points, but the delay was costly. Perhaps most significantly, therefore, we think it important for FDA to consider the potential danger of single-sourcing when shaping its early pandemic responses to avoid a situation like that faced in early 2020. We recognize these changes are not a panaceasome labs lacked CLIA approval, creating a parallel barrier to testing-but think they deserve careful consideration.

The failure of diagnostic testing during the U.S. response to the Covid-19 pandemic provides a warning and a lesson for policy surrounding diagnostic tests more generally. Good policy for diagnostic testing in non-emergent times requires both protecting clinician access to diagnostic testing and creating appropriate incentives to support diagnostic test development. An incentive model for diagnostic tests should thus focus on three main aims: (i) promote the typical use case for tests, including allowing physicians to obtain second opinions, (ii) minimize the cost of research and development, and (iii) ensure rapid deployment of safe and effective tests. The third and especially the first of these aims are hindered by single-sourcing. And thus any sort of incentive model that relies on granting market exclusivity -such as the traditional patent system, FDA approval exclusivity, or trade secret protection -raises the same sorts of issues, if on a smaller scale, as those grimly demonstrated by the failure of U.S. SARS-CoV-2 testing at the onset of the Covid-19 pandemic, which ultimately resulted in the loss of many lives. 30 By preventing access to second opinions or incentivizing fast, but ultimately ineffective science, we risk putting patients in harm's way. 31 A better incentive system would allow for an increased number of players in the market, all vying to be the best diagnostic for each indication. Such a system would promote diagnostic creation and implementation that mirrors actual diagnostic usage.

We first summarize (A) a recent history of diagnostic test patentability, since patents have both created incentives but hampered access and clinical practice; (B) describe current efforts to increase diagnostic test patents; and then (C) propose improved reimbursement mechanisms as a solution to the balancing act of managing appropriate economic incentives and allowing for optimal clinical practice during non-emergent conditions. 

Diagnostic testing patentability has once again entered public debate, this time in Congress rather than the courts. In the summer of 2019, Senators Thom Tillis (R-N.C.) and Chris Coons (D-Del.) proposed draft legislation to modify existing patent law, rendering many diagnostic tests patentable. 35 The proposal no longer considers "abstract ideas," "laws of nature," or "natural phenomena" to be exceptions to patent eligibility, explicitly overturning the three Supreme Court decisions. 36 Under the proposal, courts would no longer be able to invalidate patents because they cover underlying biological relationships-precisely the stuff of diagnostic tests. 37

The desire to incentivize diagnostic test development through exclusivity rights granted by patents drives the biotech industry's support of the bill. 38 While single gene patents are unlikely to reemerge due to the critical patent requirement of novelty-the human genome has been sequenced many times over, so genes are unlikely to be patentably "new"-patenting in other areas of molecular diagnostics (e.g., polygenic risk scoring or autoantibody detection) remains a concern. 39 32 Robert 

Although the pandemic has sidelined unrelated legislative efforts, there remains interest in revising patent law. If the Tillis-Coons bill passes, we may see a return to the pre-Mayo era in which certain diagnostic tests existed as patent-protected monopolies, making it hard to verify quality or to obtain confirmatory tests. 40 Outside the pandemic's recent horrifying exemplar, confirmatory tests have been stymied by patent-based single-sourcing in the past. For instance, until 2009 PGxHealth was the sole provider of genetic testing services for Long QT Syndrome (LQTS). 41 Independent assessment by clinicians suggested discrepancies in test accuracy and quality. 42 A competing diagnostic test could have allowed clinicians to discover these shortcomings and further validate false negatives. 43 Good clinical practice also requires the availability of multiple diagnostic test options, including ideally by alternate test providers, as physicians frequently rely on second opinions to choose the best care for their patients. Previous studies exploring the practice of second opinions in diagnostics have suggested that the ability to verify the results of an initial diagnosis may lead to a change in diagnosis or treatment. 44 Before the Supreme Court intervened, Myriad's exclusivity for BRCA1/2 genetic variant testing prevented precisely this ability. 45

The Tillis-Coons bill relies on patents to provide an incentive in the form of market exclusivity, but exclusivity is especially problematic for diagnostic tests. (There are other problems with relying on patents to drive biomedical innovation, especially in relation to equity, but we do not focus on those challenges here). 46 Though patent holders may not always exercise their monopoly rights, the danger lies in their potential to do so.

Instead, we should create incentives for diagnostic test development by leveraging non-patent policy levers. A more effective incentive system would allow an increased number of players in the market, all vying to be the most accurate and cost-effective test for each indication. Such a system would promote diagnostic creation and implementation that mirrors actual physician usage. 

Increasing reimbursement rates to reflect the expected value of diagnostic tests could help. Public and private insurance providers use the Current Procedural Terminology (CPT) system to determine the level of reimbursement warranted by new diagnostics. 47 The CPT system, in which diagnostics are often treated as commodities, is based on cost and procedure instead of the diagnostic's value. 48 To incentivize diagnostic development without creating monopolies, health insurance reimbursement strategies should be updated to provide a monetary reward for the potentially substantial cost-savings and health improvements of diagnostics.

For administrative simplicity, the CPT shoehorns new tests into established reimbursement categories ("codes") that have established prices, generally evaluating new diagnostics only in comparison to existing diagnostics. 49 New tests found analogous to old tests may be "cross-walked" to the old test's price, even if the new test is far more effective-and provides much more value. 50 In December of 2019, 70% of new diagnostics were cross-walked. 51 Completely novel tests with no adequate comparison may require new pricing determinations that can take years to implement. 52 Thus, new diagnostics face relatively cheap prices that may not offset research and development costs, decreasing incentives to create new tests. In an attempt to promote value-based pricing, some diagnostic test manufacturers have opted for a "miscellaneous" CPT code. 53 Such coding requires an assignment of value from each payer, which effectively bypasses traditional cost-based pricing but represents a logistical nightmare that dissuades most manufacturers.

Effective diagnostic tests, however, can shift healthcare spending from therapeutic to preventative care, promote precision medicines responding specifically to a patient's disease state, lower physician trial and error, and reduce hospital stays 54 -all of which reduce health-care system costs and improve patient care. Shifting to a reimbursement model that recognizes these substantial savings could properly incentivize diagnostic tests' true value.

CMS has recently acquired a new set of tools that may facilitate a leadership role in reimbursement model changes. The Clinical Laboratory Fee Schedule underwent a major overhaul as part of the Protecting Access to Medicare Act of 2014 (PAMA). Though the system had not been updated in three decades, many cumbersome but necessary changes, such as a national fee schedule and private market data collection, were implemented in order to save Medicare nearly $4 billion over 10 years. 55 While there are likely to be bureaucratic challenges to implementing value-based reimbursement for diagnostics via CMS, some of the provisions of the new PAMA Fee Schedule, such as the shift to

national pricing, could ease simpler regulatory updates rather than a complete overhaul of the Fee Schedule and thus make change easier.

To be sure, some diagnostics will recommend more expensive care; getting the incentives right across the board will be complicated, but reimbursement is a better and more nuanced tool than bringing back broad patent exclusivity. 56 We recognize reimbursement will not create a complete incentive regime, and may need supplementing with grants or prizes. 57 And in some instances, patents will still be present, especially for more technically complex diagnostics. 58 But as a general level, reimbursement policy reform shows substantial potential for creating incentives without relying on single-sourcing.

SARS-CoV-2 did not create new problems in biomedical innovation; instead, it dramatically exposed underlying issues, including in the development and deployment of diagnostic tests. In particular, single-sourcing, whether through regulatory restrictions or patent quasi-monopolies, may seem like an attractive way to centralize control and to create incentives. But for diagnostic tests which rely on confirmatory testing, innovative improvements, and robust access to supply, single-sourcing creates a host of serious problems. Creating the right incentives demands careful attention to these problems, and ideally structuring a regime that avoids them. Reimbursement, especially structured through public involvement, provides a promising option for such a regime. Both to avoid future pandemic-related disasters and to improve the normal practice of medicine, it is worth rethinking how we drive and shape the development of diagnostic tests.

2019 ICD-10-PCS Conversion Table (ZIP)" hyperlink; then select "icd10pcs_conversion_table.xlsx" file) (last visited Apr

Office of the Inspector General Health and Human Services, HHS OIG Data Brief Medicare Payments for Clincial Diagnostic Laboratory Test in 2015: Year 2 of Baseline Data

 REV. 1115REV. (2015. 58 We acknowledge the existence of the rare cases in which early patent protection may be necessary to secure enough resources for development, most famously theorized by Edmund W. Kitch in The Nature and Function of the Patent System, 20 J.L. & ECON 265, (1977) (discussing the "prospect theory" of patents). The judicious use of grants and prizes may minimize the number of such cases.