On September 20th, 2016, the Senate Health, Education, Labor and Pensions Committee convened a hearing to discuss laboratory testing the in the era of precision medicine. The hearing took place amid an ongoing debate over the proper regulatory framework for laboratory-developed tests (LDTs). LDTs are in vitro diagnostic tests (IVDs) that are made and performed within a single laboratory. They differ from IVDs that are manufactured and sold as diagnostic kits, which are performed at many labs that did not originate the test. The regulation of laboratory-developed tests was the source of a draft FDA guidance document proposing that FDA take over regulation of LDTs from the existing framework overseen by the Centers for Medicare and Medicaid Services (CMS), authorized by the Clinical Laboratory Improvement Amendments (CLIA).

Four witnesses were invited to participate in the hearing:

• David S. Klimstra, MD, Attending Pathologist at Memorial Sloan Kettering Cancer Center (opening statement)
• Brad Spring, Vice President, Regulatory Affairs and Compliance, BD Life Sciences (opening statement)
• Jeff Allen, PhD, President and CEO, Friends of Cancer Research (opening statement)
• Karen L. Kaul, MD, PhD, Chair, Department Of Pathology And Laboratory Medicine, Duckworth Family Chair, North Shore University Health System (opening statement)

The Chair and Vice-chair of the committee began with opening statements, followed by opening statements from each of the witnesses.

Senator Lamar Alexander (R-TN), Chair of the committee, began by expressing his concern about the FDA’s capacity to regulate LDTs in a timely manner. He pointed to a recently cited figure that there are currently 60,000 LDTs being used by laboratories in the US, and asked how the FDA would be able to examine approval applications for all of them without significantly delaying patient access.

Senator Patty Murray (D-WA), Vice-chair of the committee, shared her view that lack of FDA oversight of LDTs has led to a regulatory gap that could put patients at risk, citing a recent safety memo put out by FDA regarding ovarian cancer screening tests saying that such tests are unreliable and not currently under FDA regulation. She added her desire to see a regulatory framework where the accuracy and reliability of all tests is guaranteed.

The witnesses then provided opening statements. Dr. Klimstra shared the views of a clinical pathologist at a leading cancer center. He argued that the addition of FDA oversight to his practice would put significant financial strain on its ability to provide its current level of services to patients. Mr. Spring shared the views of a member of the diagnostics industry; as a manufacturer of diagnostic kits, Mr. Spring pointed to the differences in rigor between FDA and CLIA oversight, arguing that all tests should be subject to equally stringent regulations, regardless of where they are conducted. Dr. Allen shared the views of a patient advocacy organization, arguing that the current divided system of oversight puts patients at risk and does not guarantee that tests measuring the same markers produce equivalent results. Finally, Dr. Kaul, like Dr. Klimstra, shared the views of a practicing clinical pathologist at an academic research center, pointing out cases where LDTs were developed far earlier than FDA-approved tests.

Opening statements were followed by a period of question and answer.

Chairman Alexander (R-TN) asked what the consequences would be for patients if LDTs are regulated in the same manner as kits. According to his information, he noted there are 60,000 tests. Will the FDA regulate all those? Dr. Klimstra replied that it is doubtful the FDA would regulate all of the tests the Senator mentioned, but did not suggest it would be significantly less than the total amount.  Chairman Alexander then asked what would happen to labs that offer many LDTs. Dr. Klimstra replied that his lab would be forced out of business if it were required to submit for approval all of its LDTs.  Chairman Alexander then brought up the presence of NY state regulation. He asked if FDA began implementing its guidance, it would amount to triple oversight of MSKCC. Dr. Klimstra agreed with this statement.

Chairman Alexander then asked Dr. Kaul what the consequences would be of FDA oversight on her lab, to which she responded that the lab would have to stop offering tests, and patients would not get the care they needed. Chairman Alexander concluded his time by commenting that it doesn’t make much sense to solve the problem by slowing down the use of LDTs; our goal is to speed up the development of tests so that institutions can use the tests while patients are still alive.

Vice-chair Murray (D-WA) asked how do we know that claims made by labs are supported by strong scientific evidence? Dr. Allen replied that we don’t know what the evidence is, particularly for tests targeted at emerging markers.  She then asked Dr. Klimstra, do patients in other states have the same assurance of patients in New York, to which he replied no. She then asked Mr. Spring what did he need to demonstrate to FDA for approval of his tests? Mr. Spring replied that the majority of tests go through analytic validity testing; then they do some clinical testing at tissue banks. Senator Murray then asked Dr. Kaul what safeguards are in place to ensure that the results in her lab would match Dr. Klimstra’s lab. Dr. Kaul replied that the CLIA validation process requires that labs take their tests through the same quality assessment as FDA; tests are reviewed when lab inspectors drop in unannounced to look at validation data and if they’re not happy with it they can’t offer the testing. She noted, however, that it could be done more proactively, implying that CLIA oversight does not guarantee pre-market testing. CAP is the purveyor of proficiency testing, where they send unknown samples to labs and publish data supporting the fact that tests are comparable to other labs; not much variation; we can see how the results stack up against kits. Finally, Dr. Kaul added that screening tests such as the ovarian cancer detection test mentioned are different than the tests she was talking about.

Senator Burr (R-NC) commented that he was bewildered by the discussion up to this point. He argued that if we identify the marker earlier we have more time to optimize treatment. Isn’t our responsibility to do what’s in best interest of patients, he asked, regardless of territorial battles we engage in in DC? He specifically asked the witnesses, is there anyone who believes that FDA architecture exists to handle an approval three years from now? Mr. Spring replied that FDA needs to change but they’ve shown proactivity in issuing guidances. Dr. Klimstra added that FDA needs to consider the vast array of tests that will be subject to its guidance, particularly it needs to treat differently tests that cannot be validated by other laboratories. Dr. Allen added that the key thing he looks for is safe and clinically valid tests. He added that he does not mistrust the pathologists interpreting the test results, but wants to make sure the tools they use are roughly equivalent to one another. Burr concluded with a warning that FDA may not have the requisite expertise to deal with the pace of technological advances, and that the committee needs to keep in mind the current architecture of the agency to deal with this issue.

Senator Baldwin (D-WI) asked if patients know that some of the tests they are given are not FDA approved. Dr. Allen replied that patients likely do not know the approval status of the tests they receive, nor should they be expected to. Senator Baldwin then asked Dr. Klimstra what is the key difference between New York and other states’ regulation of LDTs. Dr. Klimstra noted that New York requires pre-market clearance of tests; other states do not.

Senator Hatch (R-UT) commented on the emergency preparedness of labs in the presence of Zika and H1N1 threats, as well as the barriers to speedy test development associated with the FDA’s Emergency Use Authorization (EUA) program. He then asked Dr. Kaul to comment on this topic. She replied that labs need reference material, and argued for helping labs gain quality reference material to show they can meet quality targets before having a test go to patients. She noted a pilot program by Tapestry currently ongoing to test this approach. Senator Hatch then asked if it would be wise to delay the final guidance. Dr. Klimstra replied yes, it’s a complex issue that requires more time; all available options and ramifications of choices should be considered; the current review process would not be adequate to meet the needs of all the applications.

Senator Bennet (D-CO) asked each witness to tell the committee what the key takeaways from the hearing ought to be. Dr. Klimstra said to keep in mind the ramifications; don’t inadvertently delay patient access to valuable testing. Mr. Spring and Dr. Allen reiterated that all tests ought to follow the same regulatory framework for consistency and reliability. Dr. Kaul argued for expanded CLIA oversight, saying that FDA will present considerable challenges in terms of time and expense; she noted as part of CLIA expansion should be pre-market approval. Senator Bennet then asked Dr. Allen to discuss how FDA regulation of LDTs would affect the breakthrough therapies program. Dr. Allen replied that the use of molecular diagnostics is critical to the breakthrough program; 18 of 48 drugs had a test associated with their use; and with breakthrough, the underlying standard for the drug does not change, it’s the flexibility and collaboration with drug sponsors. He noted that we have a similar opportunity on the testing side to ensure that development of a test is not the rate limiting step in getting approval.

Senator Cassidy (R-LA) began his line of questioning by asking Dr. Klimstra to discuss the system of oversight in NY. During the exchange, it was noted that Dr. Klimstra’s lab has an established relationship with New York regulators that allows it to go through regulatory approval in a matter of weeks, something that less prestigious institutions do not benefit from. It also got pointed out that New York has an added level of oversight over CLIA, requiring pre-market approval of tests. Senator Cassidy then asked Dr. Allen to explain a finding in a recently published paper that 27% of LDTs were available before the availability of an FDA-approved version. Dr. Allen pointed out that there is nothing requiring labs from submitting for FDA approval, and the voluntary nature of the process leads to delays in FDA submissions. Senator Cassidy then asked Dr. Kaul about a “crowdsource” approach to LDT oversight in which labs collaborate with one another, sharing data in order to compare test results and validate each other’s tests. Dr. Kaul noted that this is already ongoing: they publish data and present it at meetings where people can pick it apart; however, she said they do need to tidy up quality standards and process for pre-review.

Chairman Alexander then began a second line of questioning, asking other witnesses to comment on the proposal Senator Cassidy had just raised, about labs collaborating to validate one another’s tests. Dr. Allen noted that FDA has been touching on these issues as well in recently released guidance on the subject of genomic sequencing platforms, and it would be a worthy exercise to apply such a collaborative system of checks and balances on older tests as well. Chairman Alexander also asked Dr. Allen to respond to the argument that FDA cannot possibly handle the influx of 60,000 new applications for approval, nor can labs meet the financial burden of regulatory filing. Dr. Allen said that we should start with the highest risk tests; also mentioning that the tests that do the same thing don’t need to go through full PMA.

The discussion earlier had to do with genomic screening, but a similar pathway could be developed for older tests; could they show that they are analytically equivalent to tests that have already demonstrated clinically validity. Chairman Alexander then raised the possibility of starting from scratch, noting the deficiencies in both FDA and CLIA oversight. Dr. Klimstra seemed open to the notion of starting from scratch; Dr. Allen and Mr. Spring advocated for FDA oversight; Dr. Kaul advocated for expanded CLIA oversight.

Senator Warren (D-MA) raised the issue of variability between tests that claim to measure the same thing. Dr. Allen noted that there are processes that can be put in place to allow tests that demonstrate analytical validity to not have to start from scratch if clinical validity has already been established. Senator Warren concluded from this that the committee has identified a clear problem: variability across tests and across regulatory standards. It’s up to the committee, she said to come up with way to hammer out a way to resolve the issue.

The hearing adjourned at noon.