The regulatory landscape for precision oncology in the United States is complicated, 2 with multiple governmental regulatory agencies with different scopes of 3 jurisdiction. Several regulatory proposals have been introduced since the Food and 4
Drug Administration released a draft guidance to regulate laboratory-developed 5 tests in 2014. Key aspects of the most recent proposals and discussion of central 6 arguments related to the regulation of precision oncology laboratory tests provides 7
insight to stakeholders for future discussions related to regulation of laboratory 8 tests. 9 Manufacturers can then sell their products to laboratories, who wish to perform that 32 testing. Testing kits which are cleared or approved by the FDA are regulated under 33 previous approaches to regulation included 3 categories of tests (low, moderate, 103 and high), the VALID Act of 2020 only has 2 categories of low-and high-risk. Tests 104 in the low-risk categorization would be allowed to be developed and used for 105 patient care through individual submission to FDA or use of the precertification 106 pathway. Tests that were considered to be in the high-risk category would not be 107 eligible for using the precertification pathway and would require the test to be 108 submitted to the FDA via a pathway similar to the current the premarket approval 109 (PMA) pathway. Given that many current molecular oncology LDTs are used to 110 select therapy regimens or could be used to decide prophylactic surgeries, most of 111 these tests are expected to be classified in the high-risk category, requiring a time-112 consuming and expensive PMA, were VALID to be come law. While there is the 113 provision for high-risk tests to use "mitigating measures" that would allow a 114 different regulatory pathway, it is unclear how this might work in practice, and none 115
of the examples cited in the legislation reference professional practice or expertise. 116
The proposed precertification is similar in concept to some existing programs, 117 including the conditional approval process utilized by the New York State 118 Department of Health (NYDOH) 13 , but uses a technology classification system to 119 allow laboratories or manufacturers to develop within a certain scope of expertise. 120
The technological categories have underlying scientific principles that are 121 considered generally similar by the FDA. The technology categories are clot 122 detection, colorimetric, enzymatic, fluorometry, immunoassay, mass 123 spectrometry/chromatography, microbial culture, nephlometric/turbidimetric, next 124 generation sequencing (NGS), non-NGS nucleic acid analysis, slide-based technology, 125 and spectroscopy. The Valid Act of 2020 stipulates that laboratories would become 126 precertified for a specific technology by submitting an initial assay through the 127 stand-alone pathway, and if successful would obtain a multi-year permission to 128 develop and modify tests within that technology class. At the end of a certification 129 term, the lab could submit a new assay for review and could receive an extension of 130 the precertification. While tests developed in the precertification window would 131 not need to be submitted for review, documentation would have to be maintained 132 for inspection by FDA or 3 rd -party reviewers. 133
A key provision of VALID is the extensive grandfathering provision that is included 135 in the legislation where tests that are available before the legislation enactment can 136 continue to be offered after the law is in effect. This grandfathering was included to 137 prevent the sudden loss of laboratory tests as the law is enacted. A key aspect of 138 this grandfathering is that tests cannot be modified after VALID becomes law, and 139 the FDA has the authority to order any test off the market if they choose.. Act. These two legislative bills are indicative of the extreme differences that people, 147 companies, and institutions have taken on the issue of regulation of laboratory 148 services and the methods that are used to provide data to inform patient care. The 149 key regulatory prosals and legislation are presented in Table 1 19 . Given the costs associated with 204 obtaining FDA approval for laboratory tests, there will be significant costs that 205 laboratories will have to bear under the VALID proposal, both in terms of submitting 206 tests for consideration of precertification and in maintaining that certification. In 207 addition, tests that are in the high-risk classification will be less likely to be 208 laboratory developed and will either need a commercial solution or require referral 209 to an outside laboratory. 210 211 A concern that has been repeatedly raised by the FDA and other groups is that the 212 nature of LDTs has changed over the past decades. Where LDTs were once mostly 213 performed in hospital laboratories for local patients, in the present day, LDTs are 214 often performed in central laboratories that are removed from the site of patient 215 care. These labs can fall into several general categories: reference laboratories for 216 hospital systems, regional reference laboratories, national reference laboratories, 217 and commercial, for-profit entities. While these laboratories are all likely to adhere 218 to high standards and perform analytically sound tests, the change of LDTs from a 219 primarily local to a regional or national scale has been suggested by the FDA to be a 220 rationale for no longer applying enforcement discretion. Although not explicitly 221 stated in the FDA's statements, is the potential for decreased patient safety, not due 222 to the type of test performed (LDT vs. FDA cleared/Approved), but due to decreased 223 interaction of the laboratory experts with the team caring for individual patients. 224
When any tests are performed in centralized laboratories with limited access to 226 clinical records, there is a higher risk of making pre-analytical, post-analytical, and 227 cognitive errors that can impact patient care. In addition, incentives such as the 228 payment structure of the laboratory can incentivize behaviors that are divergent 229 from the best interest of patients and the health system. Many decentralized 230 laboratories use a fee-for-service payment model which has been suggested to 231 increase overutilization 20, 21 , and can potentially lead to situations where analytical 232 and clinical validity claims may overreach the available data 22 . Analyses have 233 suggested that laboratory testing done remotely from the patient may lead to 234 increases in cost, turnaround time, duplicative orders, unnecessary studies, and 235 increased errors 23, 24 . Ironically, the addition of additional and costly regulations 236 under VALID may actually drive further consolidation of the centralization model of 237 laboratory testing, which could lead to additional errors as previously described. As 238 complex testing is removed from regional and academic centers and concentrated in 239 centralized laboratories, the ability of laboratory medicine experts to interact with 240 their patient-facing colleagues is likely to decrease, resulting in further degradation 241 in care. 242
In contrast, integration of laboratory medicine experts in the clinical care team has 244 been suggested to improve diagnostic yield, especially in the setting of complex and 245 nuanced laboratory data, and the potential benefits of integration with clinical 246 details to improve diagnostic yield, have been proposed as a valuable service for 247 pathologists 25 that can provide insight to the clinical care teams. As precision oncology has become more reliant on numerous biomarkers and mutations to direct 249 treatment, systematic studies have demonstrated that interpretations of results may 250 benefit from expert consultation 26 , which may not be available when the testing is 251 performed remotely. While it is true that the type and complexity of tests that have 252 been developed as LDTs has changed, the more critical aspect that has changed is 253 the decentralization of care that has simultaneously occurred, and that is an aspect 254 of medical practice that cannot be regulated by the FDA. 255 256
A commonly cited rationale for the need to regulate LDTs is the need to ensure that 259 results are equivalent between assays, especially in the area of oncology tests that 260 are used to direct oncologic decision-making and treatments. While the rhetoric is 261 often that the accuracy of LDTs is not known, there are many studies and programs 262 in place that laboratories use to evaluate the performance of their LDTs and 263 manufactured kits, with proficiency testing and comparative studies being key tools. 264
Many published scientific studies have demonstrated good equivalence between 265 molecular oncology tests, both LDTs and FDA approved [27] [28] [29] [30] [31] [32] , including studies 266 examining assessment of important recurrent oncologic mutations that are 267 frequently assessed in proficiency testing. It is also critical to remember that even 268 when the same test is used to assess identical samples, but in different labs, there 269 will be slight differences in performance due to statistical factors 33 . There are 270 publications citing disagreement between specific laboratory methods, but 271 investigation of the methods and biology relevant to specific comparisons often 272 reveal that the apparent differences may actually be do to biological phenomena 34,35 , 273 or specific disease biology [36] [37] [38] address new problems as they emerge. These common practices of comparisons of 294 different laboratories using blinded, standardized materials demonstrates the 295 analytical accuracy of the methods and provides a mechanism for identifying 296 laboratories and tests that are not preforming up to the standard, and offer a route 297 to problem resolution. The participation in proficiency testing programs is another 298 mitigating measure that allows for continuous quality improvement and should also 299 be considered in any regulatory scheme. 300 301
Regulatory certainty has been stated as a key component to encouraging innovation 303 in the realm of laboratory testing. This argument is often framed in as regulatory 304 certainty provides a financial incentive for investing in innovation, which focuses on 305 the financial and business aspects of laboratory testing, but neglects the medical 306 needs that often drive test development. Regulatory certainty has been present for 307 manufactured kits for many years, but the long developmental timeline for many 308 assays has led to assays being obsolete when they finally become availble 31 , which 309 can be problematic if the state of scientific and medical understanding change in the 310 intervening years. In order to decide to undertake long regulatory approval 311 processes, entities must have not only the resources to undertake the process, but 312 will also need to have a return on investment in order to proceed. In contrast, many 313
LDTs are developed to assess a specific medical or operational need that is not 314 possible of practical to address by alterative means. Having a regulatory framework 315 that allows for both scenarios will allow for patients to have the maximum access to 316 important diagnostic tests. Many manufacturers and regulators have stated that a single regulatory pathway is the most appropriate and efficient approach, but that 318 view focuses on the needs of those constituencies, but neglects other considerations. 319 A chief concern is the reality that most laboratories are responsible for managing 320 thousands of tests that are required for patient care, while manufacturers and 321 specialty laboratories generally have a limited portfolio of tests that they maintain. While data have demonstrated that precision oncology assays have excellent 365 accuracy and concordance, the concern that disparate assays should be able to be 366 accurately evaluated during development is a valid. Rather than a rigid regulatory 367 construct, this specific concern can be addressed through establishment 368 professional practice guidelines and recommendations, and though development of 369 standards that can be used for assay development and quality control 49,50 for 370 established biomarkers. As scientific knowledge and medical understanding are 371 constantly evolving, the role of professionals is critical to investigate and 372 understand the technical, biological, and medical variables that impact laboratory 373 tests, and that will require deep involvement and expertise. Such resources are 374 especially important in the setting of precision oncology as some highly-actionable 375 alterations are also extremely rare and difficult to detect by many technologies [51] [52] [53] . 376
When such standards are in available and routinely used, the risk that an incorrect 377 result will be generated in the analytical process decreases. Similarly, tests that use 378
proprietary algorithms or artificial intelligence should have a higher level of 379 scrutiny because the ability to compare individual tests using a standard material 380 may not be appropriate. Development of physical and performance standards by 381 professional societies should be leveraged to allow for test development and 382 comparison. Utilizing professional societies will allow for integration of the most 383 recent scientific and medical findings, is potentially more nimble than a process 384 embedded in a federal agency. 385
Patients expect that the assay that is being used to provide information to care for 389 them is the most up to date method possible, as such, tests must be able to updated 390 as necessary to maintain their performance and relevance. For manufacturers and 391 commercial laboratories, a precertification pathway as delineated in VALID may be 392 a sensible approach for precision oncology applications, if such tests can be assigned 393 an appropriate risk classification. With regards to laboratories that are closely 394 associated with physicians providing patient care, a more flexible approach akin to 395 that currently under CLIA provides an optimal balance between the ability of 396 laboratory medicine physicians to practice medicine, protect patients, provide 397 relevant laboratory results, and regulatory burden. The regulatory environment of precision oncology tests in the US is complex, and 402 multiple legislative proposals to update the regulatory environment have been 403 introduced. As discussions around laboratory regulation proceed, careful 404 consideration of the risks, benefits, and costs of various regulatory approaches must 405 be considered. In order to deliver the most appropriate care to patients in difficult 406 circumstances, broader evaluation of the implications of test regulation should be 407 contemplated. Many assertions and assumptions have been made as to why 408 additional regulation of laboratory tests is required, but the likely effects of that regulation on patient care have not been evaluated with regards patients and the 410 full spectrum of stakeholders. Identifying tools that can be leveraged to improve 411 laboratory test quality may offer many benefits that do not necessarily require a 412 burdensome regulatory framework. 413