The Office of Management and Budget (OMB) concluded its review of the final rule on April 22. Former FDA commissioner Scott Gottlieb, MD, and other regulatory experts expect the White House to send the final rule to Congress as early as late April and no later than May 22.
On Tuesday morning, Lâle White, executive chair and CEO of San Diego’s XiFin, Inc., will present a keynote on new regulations and diagnostics players that are “poised to reshape lab testing.” Her presentation is followed by a general session on Clinical Laboratory Improvement Amendments (CLIA) regulations featuring Salerno Reynolds, PhD., acting director at the U.S. Centers for Disease Control and Prevention (CDC) Center for Laboratory Systems and Response.
Robert Michel, Editor-in-Chief of The Dark Report will wrap day one with a general session on the regulatory trifecta coming soon to all labs, from LDT to CLIA to private payers’ policies for genetic claims.
Innovation in the spotlight
“It’s a rich mix of expert speakers, lab leaders who are doing innovative things in their own organizations, along with the consultants and the lab vendors who are pushing the front edge of laboratory management, operations, and clinical service delivery,” says Michel, who each year creates the agenda for EWC.
Several sessions, master classes, and speakers will look to the future with discussions about how healthcare data drives innovations in diagnostics and patient care, digital pathology adoption around the world, and hot topics such as artificial intelligence (AI), big data and precision medicine.
Panels offer a variety of viewpoints
“One valuable benefit of participating at the Executive War College is the various panel discussions,” Michel says. “Each panel brings together national experts in a specific area of the laboratory profession. As an example, our lab legal panel this year brings together four prominent and experienced attorneys who share opinions, insights, and commentary about relevant issues in compliance, regulations, and contractual issues with health plans and others.”
This allows attendees to experience a breadth of opinions from multiple respected experts in this area, he adds.
For example, a digital pathology panel will bring together representatives from labs, service providers, and the consultants that are helping labs implement digital pathology. The session will be especially helpful to labs that are deciding when to acquire digital pathology tools and how to deploy them effectively to improve diagnostic accuracy, Michel says.
And a managed care panel will feature executives from some of the nation’s biggest health plans—the ones that sit on the other side of the table from labs—to provide insights and guidance on how labs can work more effectively with them.
Networking opportunities abound
The event is about much more than politics and policy, however. There’s also a distinct social aspect.
“Everyone is welcome, and everyone appreciates the camaraderie, so don’t be shy about going up and introducing yourself to someone. The quality of the crowd is top-notch, yet I’ve always experienced a willingness for those of us who have been to this rodeo to always be welcoming,” she notes.
Michel agrees. “One of the special benefits of participation at the EWC is the superb networking interactions and collaboration that takes place,” he says.
“From the first moments that attendees walk into our opening reception on Monday night until the close of the optional workshops on Thursday, one can see a rich exchange happening amongst circles of attendees. Introductions are being made. Connections are developing into business opportunities. The sum of an attendee’s experience at the Executive War College is to gain as much knowledge from the networking and collaboration as they do from the sessions.”
Tim Stenzel, MD, PhD, will discuss what clinical laboratories need to know about the draft LDT rule, FDA memo on assay reclassification, and ISO-13485 harmonization
Many clinical laboratories anxiously await a final rule from the US Food and Drug Administration (FDA) that is expected to establish federal policies under which the agency will regulate laboratory developed tests (LDTs). The agency released a proposed rule on Oct. 3, 2023, setting a Dec. 4 deadline for submission of comments. The White House’s Office of Management and Budget received a draft of the final rule less than three months later on March 1, 2024.
“Given how fast it moved through HHS, the final [rule] is likely pretty close” to the draft version, wrote former FDA commissioner Scott Gottlieb, MD, in a post on LinkedIn. Gottlieb and other regulatory experts expect the White House to submit the final rule to Congress no later than May 22, and perhaps as soon as this month.
Stenzel, who retired from the FDA last year, emphasized that he was not speaking on behalf of the federal agency and that he adheres to all FDA confidentiality requirements. He formed a new company—Grey Haven LLC—through which he is accepting speaking engagements in what he describes as a public service.
“I’m taking a wait and see approach,” said Tim Stenzel, MD, PhD (above), former director of the FDA’s Office of In Vitro Diagnostics, in an interview with Dark Daily. “The rule is not finalized. The FDA received thousands of comments. It’s my impression that the FDA takes those comments seriously. Until the rule is published, we don’t know what it will say, so I don’t think it does any good to make assumptions.” Clinical laboratory leaders will have an opportunity to learn how to prepare for FDA regulation of LDTs directly from Stenzel at the upcoming Executive War College in May. (Photo copyright: LinkedIn.)
FDA’s History of LDT Regulation
Prior to his five-year stint at the agency, Stenzel held high-level positions at diagnostics manufacturers Invivoscribe, Quidel Corporation, Asuragen, and Abbott Laboratories. He also directed the clinical molecular diagnostics laboratory at Duke University Medical Center in North Carolina. In the latter role, during the late 1990s, he oversaw development of numerous LDTs, he said.
The FDA, he observed, has long taken the position that it has authority to regulate LDTs. However, since the 1970s, after Congress passed the Medical Device Amendments to the federal Food, Drug, and Cosmetic Act, the agency has generally exercised “enforcement discretion,” he said, in which it declined to regulate most of these tests.
At the time, “many LDTs were lower risk, small volume, and used for specialized needs of a local patient population,” the agency stated in a press release announcing the proposed rule. “Since then, due to changes in business practices and increasing ability to ship patient specimens across the country quickly, many LDTs are now used more widely, for a larger and more diverse population, with large laboratories accepting specimens from across the country.”
Clinical Labs Need a Plan for Submission of LDTs to FDA
The FDA proposed the new rule after Congress failed to vote on the VALID Act (Verifying Accurate Leading-edge IVCT Development Act of 2021), which would have established a statutory framework for FDA oversight of LDTs. Citing public comments from FDA officials, Stenzel believes the agency would have preferred the legislative approach. But when that failed, “they thought they needed to act, which left them with the rulemaking path,” he said.
The new rule, as proposed, would phase out enforcement discretion in five stages over four years, he noted. Labs would have to begin submitting high-risk tests for premarket review about three-and-a-half years from publication of the final rule, but not before Oct. 1, 2027. Premarket review requirements for moderate- or low-risk tests would follow about six months later.
While he suggested a “wait and see” approach to the final rule, he advises labs that might be affected to develop a plan for dealing with it.
Potential Lawsuits
Stenzel also noted the likelihood of litigation in which labs or other stakeholders will seek to block implementation of the rule. “It’s a fairly widespread belief that there will be a lawsuit or lawsuits that will take this issue through the courts,” he said. “That could take several years. There is no guarantee that the courts will ultimately side with the FDA.”
He acknowledged that it is a controversial issue among clinical laboratories. Many labs have voiced opposition to the rule as well as the Valid Act.
Currently in retirement, Stenzel says he is making himself available as a resource through public speaking for laboratory professionals and other test developers who are seeking insights about the agency.
“The potential value that I bring is recent experience with the FDA and with stakeholders both inside and outside the FDA,” he said, adding that during his presentations he likes “to leave plenty of time for open-ended questions.”
In the case of his talks at the Executive War College, Stenzel said he anticipates “a robust conversation.”
He also expects to address other FDA-related issues, including:
A recent memo in which the agency said it would begin reclassifying most high-risk In Vitro Diagnostic (IVD) tests—those in class III (high risk)—into class II (moderate to high risk).
The emergence of multi-cancer detection (MCD) tests, which he described as a “hot topic in the LDT world.” The FDA has not yet approved any MCD tests, but some are available as LDTs.
A new voluntary pilot program in which the FDA will evaluate LDTs in situations where the agency has approved a treatment but has not authorized a corresponding companion diagnostic.
An FDA effort to harmonize ISO 13485—a set of international standards governing development of medical devices and diagnostics—with the agency’s own quality system regulations. Compliance with the ISO standards is necessary to market products in many countries outside the US, particularly in Europe, Stenzel noted. Harmonization will simplify product development, he said, because manufacturers won’t have to follow two or more sets of rules.
To learn how to prepare for the FDA’s future regulation of LDTs, clinical laboratory and pathology group managers would be wise to attend Stenzel’s presentations at this year’s Executive War College. Visit here to learn more and to secure your seat in New Orleans.
Forces in play will directly impact the operations and financial stability of many of the nation’s clinical laboratories
With significant regulatory changes expected in the next 18 to 24 months, experts are predicting a “Perfect Storm” for managers of clinical laboratories and pathology practices.
Currently looming are changes to critical regulations in two regulatory areas that will affect hospitals and medical laboratories. One regulatory change is unfolding with the US Food and Drug Administration (FDA) and the other regulatory effort centers around efforts to update the Clinical Laboratory Improvement Amendments of 1988 (CLIA).
The major FDA changes involve the soon-to-be-published Final Rule on Laboratory Developed Tests (LDTs), which is currently causing its own individual storm within healthcare and will likely lead to lawsuits, according to the FDA Law Blog.
In a similar fashion—and being managed under the federal Centers for Medicare and Medicaid Services (CMS)—are the changes to CLIA rules that are expected to be the most significant since 2003.
The final element of the “Perfect Storm” of changes coming to the lab industry is the increased use by private payers of Z-Codes for genetic test claims.
In his general keynote, Robert L. Michel, Dark Daily’s Editor-in-Chief and creator of the 29th Executive War College on Diagnostics, Clinical Laboratory, and Pathology Management, will set the stage by introducing a session titled, “Regulatory Trifecta Coming Soon to All Labs! Anticipating the Federal LDT Rule, Revisions to CLIA Regulations, and Private Payers’ Z-Code Policies for Genetic Claims.”
“There are an unprecedented set of regulatory challenges all smashing into each other and the time is now to start preparing for the coming storm,” says Robert L. Michel (above), Dark Daily’s Editor-in-Chief and creator of the 29th Executive War College on Diagnostics, Clinical Laboratory, and Pathology Management, a national conference on lab management taking place April 30-May 1, 2024, at the Hyatt in New Orleans. (Photo copyright: The Dark Intelligence Group.)
Coming Trifecta of Disruptive Forces to Clinical Laboratory, Anatomic Pathology
The upcoming changes, Michel notes, have the potential to cause major disruptions at hospitals and clinical laboratories nationwide.
“Importantly, this perfect storm—which I like to describe as a Trifecta because these three disruptive forces that will affect how labs will conduct business—is not yet on the radar screen of most lab administrators, executives, and pathologists,” he says.
Because of that, several sessions at this year’s Executive War College conference, now in its 29th year, will offer information designed to give attendees a better understanding of how to manage what’s coming for their labs and anatomic pathology practices.
“This regulatory trifecta consists of three elements,” adds Michel, who is also Editor-in-Chief of Dark Daily’s sister publication The Dark Report, a business intelligence service for senior level executives in the clinical laboratory and pathology industry, as well in companies that offer solutions to labs and pathology groups.
According to Michel, that trifecta includes the following:
Element 1
FDA’s Draft LDT Rule
FDA’s LDT rule is currently the headline story in the lab industry. Speaking about this development and two other FDA initiatives involving diagnostics at the upcoming Executive War College will be pathologist Tim Stenzel, MD, PhD, former director of the FDA’s Office of In Vitro Diagnostics. It’s expected that the final rule on LDTs could be published by the end of April.
Stenzel will also discuss harmonization of ISO 13485 Medical Devices and the FDA’s recent memo on reclassifying most high-risk in vitro diagnostics to moderate-risk to ease the regulatory burden on companies seeking agency review of their diagnostic assays.
Salerno will also cover the CDC’s efforts to foster closer connections with clinical labs and their local public health laboratories, as well as the expanding menu of services for labs that his department now offers.
Element 3
Private Payer Use of Z-Codes for Test Claims
On the third development—increased use by private payers of Z-Codes for genetic test claims—the speaker will be pathologist Gabriel Bien-Willner, MD, PhD. He is the Medical Director of the MolDX program at Palmetto GBA, a Medicare Administrative Contractor (MAC). It is the MolDX program that oversees the issuance of Z-Codes for molecular and diagnostic tests.
UnitedHealthcare (UHC) was first to issue such a Z-Code policy last year, although it has delayed implementation several times. Other major payers are watching to see if UHC succeeds with this requirement, Michel says.
Other Critical Topics to be Covered at EWC
In addition to these need-to-know regulatory topics, Michel says that this year’s Executive War College will present almost 100 sessions and include 148 speakers. Some of the other topics on the agenda in New Orleans include the following and more:
Standardizing automation, analyzers, and tests across 25 lab sites.
Effective ways to attract, hire, and retain top-performing pathologists.
Leveraging your lab’s managed care contracts to increase covered tests.
“Our agenda is filled with the topics that are critically important to senior managers when it comes to managing their labs and anatomic pathology practices,” Michel notes.
“Every laboratory in the United States should recognize these three powerful developments are all in play at the same time and each will have direct impact on the clinical and financial performance of our nation’s labs,” Michel says. “For that reason, every lab should have one or more of their leadership team present at this year’s Executive War College to understand the implications of these developments.”
Visit here to learn more about the 29th Executive War College conference taking place in New Orleans.
New non-invasive test could replace traditional painful spinal taps and clinical laboratory fluid analysis for diagnosis of Parkinson’s disease
Scientists at AXIM Biotechnologies of San Diego have added another specimen that can be collected non-invasively for rapid, point-of-care clinical laboratory testing. This time it is tears, and the diagnostic test is for Parkinson’s disease (PD).
The new assay measures abnormal alpha-synuclein (a-synuclein), a protein that is a biomarker for Parkinson’s, according to an AXIM news release which also said the test is the first rapid test for PD.
“The revolutionary nature of AXIM’s new test is that it is non-invasive, inexpensive, and it can be performed at a point of care. It does not require a lumbar puncture, freezing, or sending samples to a lab. AXIM’s assay uses a tiny tear drop versus a spinal tap to collect the fluid sample and the test can be run at a doctor’s office with quantitative results delivered from a reader in less than 10 minutes,” the news release notes.
“Furthermore, emerging evidence shows that a-synuclein assays have the potential to differentiate people with PD from healthy controls, enabling the potential for early identification of at-risk groups,” the news release continues. “These findings suggest a crucial role for a-synuclein in therapeutic development, both in identifying pathologically defined subgroups of people with Parkinson’s disease and establishing biomarker-defined at-risk cohorts.”
This is just the latest example of a disease biomarker that can be collected noninvasively. Other such biomarkers Dark Daily has covered include:
“With this new assay, AXIM has immediately become a stakeholder in the Parkinson’s disease community, and through this breakthrough, we are making possible new paradigms for better clinical care, including earlier screening and diagnosis, targeted treatments, and faster, cheaper drug development,” said John Huemoeller, CEO, AXIM (above), in a news release. Patients benefit from non-invasive clinical laboratory testing. (Photo copyright: AXIM Biotechnologies.)
Fast POC Test versus Schirmer Strip
AXIM said it moved forward with its novel a-synuclein test propelled by earlier tear-related research that found “a-synuclein in its aggregated form can be detected in tears,” Inside Precision Medicine reported.
But that research used what AXIM called the “outdated” Schirmer Strip method to collect tears. The technique involves freezing tear samples at -80 degrees Celsius (-112 Fahrenheit), then sending them to a clinical laboratory for centrifugation for 30 minutes; quantifying tear protein content with a bicinchoninic acid assay, and detecting a-synuclein using a plate reader, AXIM explained.
Alternatively, AXIM says its new test may be performed in doctors’ offices and offers “quantitative results delivered from a reader in less than 10 minutes.”
“Our proven expertise in developing tear-based diagnostic tests has led to the development of this test in record speed, and I’m extremely proud of our scientific team for their ability to expand our science to focus on such an important focus area as Parkinson’s,” said John Huemoeller, CEO, AXIM in the news release.
“This is just the beginning for AXIM in this arena,” he added. “But I am convinced when pharmaceutical companies, foundations, and neurologists see how our solution can better help diagnose Parkinson’s disease in such an expedited and affordable way, we will be at the forefront of PD research, enabling both researchers and clinicians a brand-new tool in the fight against PD.”
One of those tests was “a lateral flow diagnostic for point-of-care use that measures the level of lactoferrin proteins in tear fluid, which work to protect the surface of the eye. … Axim said that low lactoferrin levels have also been linked to Parkinson’s disease and that the assay can be used alongside its alpha-synuclein test,” Fierce Biotech noted.
“It made sense to try and look at the proteinaceous [consisting of or containing protein] constituents of tear fluid,” Lew told Neurology Live. “Tear fluid is easy to collect. It’s noninvasive, inexpensive. It’s not like when you do a lumbar puncture, which is a much more involved ordeal. There’s risk of contamination with blood (saliva is dirty) issues with blood and collection. [Tear fluid analysis] is much safer and less expensive to do.”
In Biomarkers in Medicine, Lew et al noted why tears make good biomarkers for Parkinson’s disease, including “the interconnections between the ocular [eye] surface system and neurons affected in Parkinson’s disease.”
The researchers also highlighted “recent data on the identification of tear biomarkers including oligomeric α-synuclein, associated with neuronal degeneration in PD, in tears of PD patients” and discussed “possible sources for its release into tears.”
Future Clinical Laboratory Testing for Parkinson’s
Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s. It affects nearly one million people in the US. About 1.2 million people may have it by 2030, according to the Parkinson’s Foundation.
Thus, an accurate, inexpensive, non-invasive diagnostic test that can be performed at the point of care, and which returns clinical laboratory test results in less than 10 minutes, will be a boon to physicians who treat PD patients worldwide.
Clinical laboratory managers and pathologists may want to follow AXIM’s future research to see when the diagnostic test may become available for clinical use.
Immunotherapy device could also enable clinical laboratories to receive in vivo biomarker data wirelessly
Researchers from Rice University in Houston and seven other states in the US are working on a new oncotherapy sense-and-respond implant that could dramatically improve cancer outcomes. Called Targeted Hybrid Oncotherapeutic Regulation (THOR), the technology is intended primarily for the delivery of therapeutic drugs by monitoring specific cancer biomarkers in vivo.
Through a $45 million federal grant from the Advanced Research Projects Agency for Health (ARPA-H), the researchers set out to develop an immunotherapy implantable device that monitors a patient’s cancer and adjusts antibody treatment dosages in real time in response to the biomarkers it measures.
It’s not a far stretch to envision future versions of the THOR platform also being used diagnostically to measure biomarker data and transmit it wirelessly to clinical laboratories and anatomic pathologists.
ARPH-A is a federal funding agency that was established in 2022 to support the development of high-impact research to drive biomedical and health breakthroughs. THOR is the second program to receive funding under its inaugural Open Broad Agency Announcement solicitation for research proposals.
“By integrating a self-regulated circuit, the THOR technology can adjust the dose of immunotherapy reagents based on a patient’s responses,” said Weiyi Peng, MD, PhD (above), Assistant Professor of Biology and Biochemistry at the University of Houston and co-principal investigator on the research, in a UH press release. “With this new feature, THOR is expected to achieve better efficacy and minimize immune-related toxicity. We hope this personalized immunotherapy will revolutionize treatments for patients with peritoneal cancers that affect the liver, lungs, and other organs.” If anatomic pathologists and clinical laboratories could receive biometric data from the THOR device, that would be a boon to cancer diagnostics. (Photo copyright: University of Houston.)
Antibody Therapy on Demand
Omid Veiseh, PhD, Associate Professor of Bioengineering at Rice University and principal investigator on the project, described the THOR device as a “living drug factory” inside the body. The device is a rod-like gadget that contains onboard electronics and a wireless rechargeable battery. It is three inches long and has a miniaturized bioreactor that contains human epithelial cells that have been engineered to produce immune modulating therapies.
“Instead of tethering patients to hospital beds, IV bags, and external monitors, we’ll use a minimally invasive procedure to implant a small device that continuously monitors their cancer and adjusts their immunotherapy dose in real time,” said Veiseh in a Rice University press release. “This kind of ‘closed-loop therapy’ has been used for managing diabetes, where you have a glucose monitor that continuously talks to an insulin pump.
But for cancer immunotherapy, it’s revolutionary.”
The team believes the THOR device will have the ability to monitor biomarkers and produce an antibody on demand that will trigger the immune system to fight cancer locally. They hope the sensor within THOR will be able to monitor biomarkers of toxicity for the purpose of fine-tuning therapies to a patient immediately in response to signals from a tumor.
“Today, cancer is treated a bit like a static disease, which it’s not,” Veiseh said. “Clinicians administer a therapy and then wait four to six weeks to do radiological measurements to see if the therapy is working. You lose quite a lot of time if it’s not the right therapy. The tumor may have evolved into a more aggressive form.”
The THOR device lasts 60 days and can be removed after that time. It is designed to educate the immune system to recognize a cancer and prevent it from recurring. If the cancer is not fully eradicated after the first implantation, the patient can be implanted with THOR again.
Use of AI in THOR Therapy
The researchers plan to spend the next two and a half years building prototypes of the THOR device, testing them in rodents, and refining the list of biomarkers to be utilized in the device. Then, they intend to take an additional year to establish protocols for the US Food and Drug Administration’s (FDA) good manufacturing practices requirements, and to test the final prototype on large animals. The researchers estimate the first human clinical trials for the device will begin in about four years.
“The first clinical trial will focus on refractory recurrent ovarian cancer, and the benefit of that is that we have an ongoing trial for ovarian cancer with our encapsulated cytokine ‘drug factory’ technology,” said Veiseh in the UH press release.
The group is starting with ovarian cancer because research in this area is lacking and it will provide the opportunity for THOR to activate the immune system against ovarian cancer, which is typically challenging to fight with immunotherapy approaches. If successful in ovarian cancer, the researchers hope to test THOR in other cancers that metastasize within the abdomen, such as:
All control and decision-making will initially be performed by a healthcare provider based on signals transmitted by THOR using a computer or smartphone. However, Veiseh sees the device ultimately being powered by artificial intelligence (AI) algorithms that could independently make therapeutic decisions.
“As we treat more and more patients [with THOR], the devices are going to learn what type of biomarker readout better predicts efficacy and toxicity and make adjustments based on that,” he predicted. “Between the information you have from the first patient versus the millionth patient you treat, the algorithm is just going to get better and better.”
Moving Forward
In addition to UH and Rice University, scientists working on the project come from several institutions, including:
More research and clinical trials are needed before THOR can be used in the clinical treatment of cancer patients. If the device reaches the commercialization stage, Veiseh plans to either form a new company or license the technology to an existing company for further development.
“We know that the further we advance it in terms of getting that human data, the more likely it is that this could then be transferred to another entity,” he told Precision Medicine Online.
Pathologists and clinical laboratories will want to monitor the progress of the THOR technology’s ability to sense changes in cancer biomarkers and deliver controlled dosages of antibiotic treatments.
