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Wiley Launches Paper Mill Detection Tool after Losing Millions Due to Fraudulent Journal Submissions

Groups representing academic publishers are taking steps to combat paper mills that write the papers and then sell authorship spots

Clinical laboratory professionals rely on peer-reviewed research to keep up with the latest findings in pathology, laboratory medicine, and other medical fields. They should thus be interested in new efforts to combat the presence of “research paper mills,” defined as “profit oriented, unofficial, and potentially illegal organizations that produce and sell fraudulent manuscripts that seem to resemble genuine research,” according to the Committee on Publication Ethics (COPE), a non-profit organization representing stakeholders in academic publishing.

“They may also handle the administration of submitting the article to journals for review and sell authorship to researchers once the article is accepted for publication,” the COPE website states.

In a recent example of how paper mills impact scholarly research, multinational publishing company John Wiley and Sons (Wiley) announced in The Scholarly Kitchen last year that it had retracted more than 1,700 papers published in journals from the company’s Hindawi subsidiary, which specializes in open-access academic publishing.

“Often journals will invite contributions to a special issue on a specific topic and this provides an opening for paper mills to submit often many publications to the same issue,” explained a June 2022 research report from the COPE and the International Association of Scientific Technical and Medical Publishers (STM).

“In Hindawi’s case, this is a direct result of sophisticated paper mill activity,” wrote Jay Flynn, Wiley’s Executive Vice President and General Manager, Research, in a Scholarly Kitchen guest post. “The extent to which our processes and systems were breached required an end-to-end review of every step in the peer review and publishing process.”

In addition, journal indexer Clarivate removed 19 Hindawi journals from its Web of Science list in March 2023, due to problems with their editorial quality, Retraction Watch reported.

Hindawi later shut down four of the journals, which had been “heavily compromised by paper mills,” according to a blog post from the publisher.

Wiley also announced at that time that it would temporarily pause Hindawi’s special issues publishing program due to compromised articles, according to a press release.

“We urgently need a collaborative, forward-looking and thoughtful approach to journal security to stop bad actors from further abusing the industry’s systems, journals, and the communities we serve,” wrote Jay Flynn (above), Wiley EVP and General Manager, Research and Learning, in an article he penned for The Scholarly Kitchen. “We’re committed to addressing the challenge presented by paper mills and academic fraud head on, and we invite our publishing peers, and the many organizations that work alongside us, to join us in this endeavor.” Clinical laboratory leaders understand the critical need for accurate medical research papers. (Photo copyright: The Scholarly Kitchen.)

Using AI to Detect Paper Mill Submissions

Wiley acquired Hindawi in 2021 in a deal valued at $298 million, according to a press release, but the subsidiary has since become a financial drain for the company.

The journals earn their revenue by charging fees to authors. But in fiscal year 2024, which began last fall, “Wiley expects $35-40 million in lost revenue from Hindawi as it works to turn around journals with issues and retract articles,” Retraction Watch reported, citing an earnings call.

Wiley also revealed that it would stop using the Hindawi brand name and bring the subsidiary’s remaining journals under its own umbrella by the middle of 2024.

To combat the problem, Wiley announced it would launch an artificial intelligence (AI)-based service called Papermill Detection in partnership with Sage Publishing and the Institute of Electrical and Electronics Engineers (IEEE).

The service will incorporate tools to detect signs that submissions originated from paper mills, including similarities with “known papermill hallmarks” and use of “tortured phrases” indicating that passages were translated by AI-based language models, according to a press release.

These tools include:

  • Papermill Similarity Detection: Checks for known papermill hallmarks and compares content against existing papermills papers.
  • Problematic Phrase Recognition: Flags unusual alternatives to established terms.
  • Unusual Publication Behavior Detection: Identifies irregular publishing patterns by paper authors.
  • Researcher Identity Verification: Helps detect potential bad actors.
  • Gen-AI Generated Content Detection: Identifies potential misuse of generative AI.
  • Journal Scope Checker: Analyzes the article’s relevance to the journal.

The company said that the new service will be available through Research Exchange, Wiley’s manuscript submission platform, as early as next year.

Other Efforts to Spot Paper Mill Submissions

Previously, STM announced the launch of the STM Integrity Hub, with a mission “to equip the scholarly communication community with data, intelligence, and technology to protect research integrity,” Program Director Joris van Rossum, PhD, told The Scholarly Kitchen.

In 2023, the group announced that the hub would integrate Papermill Alarm from Clear Skies, a paper mill detection tool launched in 2022 with a focus on cancer research. It uses a “traffic-light rating system for research papers,” according to a press release.

In an announcement about the launch of Wiley’s Papermill Detection service, Retraction Watch suggested that one key to addressing the problem would be to reduce incentives for authors to use paper mills. Those incentives boil down to the pressure placed on many scientists, clinicians, and students to publish manuscripts, according to the research report from STM and COPE.

In one common scenario, the report noted, a paper mill will submit a staff-written paper to multiple journals. If the paper is accepted, the company will list it on a website and offer authorship spaces for sale.

“If a published paper is challenged, the ‘author’ may sometimes back down and ask for the paper to be retracted because of data problems, or they may try to provide additional supporting information including a supporting letter from their institution which is also a fake,” the report noted.

All of this serves as a warning to pathologists and clinical laboratory professionals to carefully evaluate the sources of medical journals publishing studies that feature results on areas of healthcare and lab medicine research that are of interest.

—Stephen Beale

Related Information:

Potential “Paper Mills” and What to Do about Them: A Publisher’s Perspective

Up to One in Seven Submissions to Hundreds of Wiley Journals Flagged by New Paper Mill Tool

Guest Post: Addressing Paper Mills and a Way Forward for Journal Security

Paper Mills Research Report from COPE and STM

Wiley Paused Hindawi Special Issues amid Quality Problems, Lost $9 Million in Revenue

‘The Situation Has Become Appalling’: Fake Scientific Papers Push Research Credibility to Crisis Point

Publisher Retracts More than a Dozen Papers at Once for Likely Paper Mill Activity

STM Integrity Hub Incorporates Clear Skies’ Papermill Alarm Screening Tool

The New STM Integrity Hub

Upholding Research Integrity in the Age of AI

Laboratory Leaders at 2024 Annual Executive War College Discuss Critical Challenges Facing Clinical Laboratory and Pathology Managers for 2024 and Beyond

Trifecta of forces at work that will affect the clinical laboratory and pathology industries have been described as a ‘perfect storm’ requiring lab and practice managers to be well informed

Digital pathology, artificial intelligence (AI) in healthcare, and the perfect storm of changing federal regulations, took centerstage at the 29th Executive War College on Diagnostics, Clinical Laboratory, and Pathology Management in New Orleans this week, where more than 1,000 clinical laboratory and pathology leaders convened over three days.

This was the largest number of people ever onsite for what has become the world’s largest event focused exclusively on lab management topics and solutions. Perhaps the highlight of the week was the federal Food and Drug Administration’s (FDA’s) announcement of its final rule on Laboratory Developed Tests (LDTs). Overall, the conference featured more than 120 speakers, many of them national thought leaders on the topic of clinical lab and pathology management. More than 65% of the audience onsite were executive level lab managers.

 “The level of interest in the annual Executive War College is testimony to the ongoing need for dynamic, engaging, and highly relevant conference events,” said Robert Michel (above), Editor-in-Chief of Dark Daily and its sister publication The Dark Report, and founder of the Executive War College. “These in-person gatherings present great opportunities for clinical laboratory and pathology managers and leaders to network and speak with people they otherwise might not meet.” (Photo copyright: Dark Intelligence Group.)

Demonstrating Clinical Value

For those who missed the action onsite, the following is a synopsis of the highlights this week.

Lâle White, Executive Chair and CEO of XiFin, spoke about the future of clinical laboratory testing and the factors reshaping the industry. There are multiple dynamics impacting healthcare economics and outcomes—namely rising costs, decreasing reimbursements, and the move to a more consumer-focused healthcare. But it is up to labs, she said, to ensure their services are not simply viewed as a commodity.

“Laboratory diagnostics have the potential to change the economics of healthcare by really gaining efficiencies,” she noted. “And it’s up to labs to demonstrate clinical value by helping physicians manage two key diagnostic decision points—what tests to order, and what to do with the results.”

But even as labs find ways to increase the value offered to clinicians, there are other disruptive factors in play. Consumer-oriented tech companies such as Google, Apple, and Amazon are democratizing access to patient data in unforeseen ways, and Medicare Advantage plans are changing the way claims are processed and paid.

Redefining Human Data

Reynolds Salerno, PhD, Director of the Division of Laboratory Services for the federal Centers for Disease Control and Prevention (CDC) provided an update on the agency’s top priorities for 2024.

Clinical labs are fundamental components of the public health infrastructure. So, the CDC plans on focusing on delivering high-quality laboratory science, supported by reliable diagnostics and informatics for disease outbreaks and exposures, and engaging with public and private sector partners.

Salerno is an active member of the Clinical Laboratory Improvement Act Committee (CLIAC), which has been working on a number of initiatives, including revisions to the Clinical Laboratory Improvement Act (CLIA) that would change the definition of “materials derived from the human body” to include data derived from human specimens such as medical imaging, genetic sequences, etc.

New Molecular Testing Codes

The history of MolDX and Z-Codes were the topics discussed by Gabriel Bien-Willner, MD, PhD, Chief Medical Officer for healthcare claims and transaction processing company Palmetto GBA. Molecular testing is highly complex, and the lack of well-defined billing codes and standardization makes it difficult to know if a given test is reasonable and necessary.

Z-Codes were established to clarify what molecular testing was performed—and why—prompting payers to require both Z-Codes and Current Procedural Terminology (CPT) codes when processing molecular test claims. Medicare’s MolDX program further streamlines the claims process by utilizing expertise in the molecular diagnostics space to help payers develop coverage policies and reimbursement for these tests.

FDA Final Rule on LDT Regulation

Timothy Stenzel, MD, PhD, CEO of Grey Haven Consulting and former director of the FDA’s Office of In Vitro Diagnostics reviewed the latest updates from the FDA’s Final Rule on LDT (laboratory developed test) regulation. Prior to the FDA releasing its final rule, some experts suggested that the new regulations could result in up to 90% of labs discontinuing their LDT programs, impacting innovation, and patient care.

However, the final rule on LDTs is very different from the original proposed rule which created controversy. The final rule actually lowers the regulatory burden to the point that some labs may not have to submit their LDTs at all. The FDA is reviewing dozens of multi-cancer detection assays, some of which have launched clinically as LDTs. The agency is likely to approve those that accurately detect cancers for which there is no formal screening program.

Stenzel explained the FDA’s plan to down-classify most in vitro diagnostic tests, changing them from Class III to Class II, and exempting more than 1,000 assays from FDA review. He also discussed the highlights of the Quality Management System Regulation (QMSR). Launched in January, the QMSR bought FDA requirements in line with ISO 13485, making compliance easier for medical device manufacturers and test developers working internationally.

Looming Perfect Storm of Regulatory Changes

To close out Day 1, Michel took to the stage again with a warning to clinical laboratories about the looming “Perfect Storm” trifecta—the final FDA ruling on LDTs, Z-Code requirements for genetic testing, and updates to CLIA ’92 that could result in patient data being considered a specimen.

Laboratory leaders must think strategically if their labs are to survive the fallout, because the financial stress felt by labs in recent years will only be exacerbated by macroeconomic trends such as:

  • Staff shortages,
  • Rising costs,
  • Decreasing and delayed reimbursements, and
  • Tightening supply chains.

Lab administrators looking for ways to remain profitable and prosperous should look beyond the transactional Clinical Lab 1.0 fee-for-service model and adopt Clinical Lab 2.0, which embraces HEDIS (Healthcare Effectiveness Data and Information Set) scores and STAR ratings to offer more value to Medicare Advantage and other payers.

Wednesday’s General Session agenda was packed with information about the rise of artificial intelligence, big data, and precision medicine in healthcare. Taking centerstage on the program’s final day was Michael Simpson, President and CEO of Clinisys. Simpson gave a global perspective on healthcare data as the new driver of innovation in diagnostics and patient care.

Michel closed the conference on Wednesday by recapping many of these highlights, and then inviting his audience to the 30th annual Executive War College Diagnostics, Clinical Laboratory, and Pathology Management conference to be held on April 29-30, 2025, here at the Hyatt Regency New Orleans. Register now to attend this critical gathering.

—Leslie Williams

Related Information:

Executive War College: The Ultimate Event for Helping Solve Your Diagnostics, Clinical Lab and Pathology Management Challenges

Labs Should Prepare for Arrival of ‘Perfect Storm’

Executive War College 2025 Registration

Big Industry Changes in Focus at the Annual Executive War College

FDA announces final rule on Lab-Developed Tests LDTs) as Clinical Lab Leaders Meet in New Orleans

Regulatory changes were the talk of the 29th Annual Executive War College, with attendees buzzing about Monday’s  US Food and Drug Administration (FDA) announcement that it had finalized the rule on laboratory developed tests (LDTs). The timing was perfect at the first full day of the New Orleans event, which is focused on diagnostics, clinical laboratory, and pathology management, and featured a bevy of experts to walk the audience through the current state of the regulatory landscape.

“The timing of EWC with the release of this policy couldn’t be better,” CEO and founder of Momentum Consulting Valerie Palmieri told Dark Daily in an interview at Monday night’s opening reception. “It’s a great conference to not only catch up with colleagues but really hear and have those difficult discussions about where we are today, where we’re going, and where we need to be.”

Final LDT rule ‘radically’ different than draft

Tim Stenzel, MD, PhD, former director of the FDA’s Office of In Vitro Diagnostics called the finalized rule “radically different” from the proposed rule. In some ways it is less complex: “The bar is lower,” he said, noting that he was voicing his personal views and not those of the federal agency. “I was convinced that there would be lawsuits, but I’m now not sure if that’s advisable.”

Still, laboratory teams will have to parse the more than 500-page document to determine how the final rule relates to their specific circumstances. After that, it won’t be as challenging, Stenzel said.

His advice: First, read the rule. Second, reach out to FDA for help—he’s sure, he said, that the office is geared up to respond to a “ton of questions” about the implications for individual labs and are standing by to answer emails from labs. And, he added in a discussion session, emailing the agency is free.

The final rule will be in force 60 days after it’s published. Stenzel provided a timeline for some of the milestones:

1 Year: Comply with MD(AE) reporting and reporting of corrections and removals.

2 Years: Comply with labeling, registration and listing, and investigational use requirements.

3 Years: QS records and, in some cases, design controls and purchasing controls.

3.5 Years: Comply with high risk (class III) premarket review requirements.

4 Years: Comply with moderate and low-risk premarket review requirements.

 Lâle White, Executive Chair and CEO of XiFin, Inc.

Big changes bring big opportunities

Executive Chair and CEO of XiFin, Inc. Lâle White welcomed the audience with a morning keynote entitled “Big Changes in Healthcare” on new regulations and diagnostics players poised to reshape lab testing.

The diagnostics business is in constant flux, she noted, from payer requirements to greater regulatory and compliance burdens on labs. Other factors include the growing senior population and increasingly complex health conditions, rising costs throughout the healthcare ecosystem, falling funding and reimbursement, and staffing shortages.

As for the economic challenges, consumers are increasingly making decisions based on cost, convenience and quality. The population is shifting to Medicare advantage, which is more cost effective. But changes to the star ratings system will mean lower pay for payer organizations. Those companies will, in turn, mitigate their losses by making changes to pre-authorizations and tightening denials, even for clean claims.

Still, White said, more money isn’t the answer.

White urged the audience to use technology, including artificial intelligence and advances in genetic testing, to manage these and other industry changes.

“We need to optimize the tests we order,” she said. “And if we did that, lab diagnostics really has the potential to change the economics of health and improve outcomes.”

The FDA, Stenzel added, is “very interested” in stimulating innovation, building on the laboratory industry’s success in responding swiftly to the COVID pandemic and outbreaks of Monkey Pox, for example.

CDC: Laboratories on the front line of readiness

The pre-lunch events also included an update on the Centers for Disease Control and Prevention’s Clinical Laboratory Improvement Amendments (CLIA) regulations for clinical laboratories, featuring Reynolds Salerno, director of the division of laboratory systems at the CDC.

He shared lessons learned from recent public health emergencies, talked about CDC’s efforts to engage with clinical labs to improve future public health readiness and response and provided an overview of the CDC’s first laboratory-specific center.

“Laboratories are fundamental to public health,” he said. The industry is on the “front lines” when it comes to identifying threats, responding to them, and preparing for future responses.

Robert Michel, Editor-in-Chief of The Dark Report wrapped up the day’s regulatory discussions with a general session on the “regulatory trifecta” that includes the LDT final rule, CLIA regulations, and private payers’ policies for genetic claims.

–Gienna Shaw

From Regulations to Innovations: Annual Executive War College Convenes in New Orleans

29th Conference Features Information on What Clinical Lab Leaders Need to Know About a ‘Perfect Storm’ of New Compliance Challenges

There are signs that the US Food and Drug Administration (FDA) is poised to release the final rule on laboratory developed tests (LDTs)—perhaps even during the 29th annual Executive War College on Diagnostic, Clinical Laboratory, and Pathology Management, which kicks off in New Orleans this week.

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.

Either way, Tim Stenzel, MD, PhD, former director of the FDA’s Office of In Vitro Diagnostics, and other regulatory experts will be on hand at Executive War College (EWC) to walk attendees through what promises to be a “perfect storm of clinical lab and pathology practice regulatory changes.” Stenzel is scheduled to speak about the LDT rule during three sessions with fellow panelists on Day 1.

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.

“This is a friendly tribe,” Vicki DiFrancesco, a US HealthTek advisory board member who first attended EWC more than two decades ago, wrote in a recent post.

“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.”

–Gienna Shaw

Former FDA Director to Speak at Executive War College on FDA’s Coming Regulation of Laboratory Developed Tests

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.

But what will the final rule look like? Tim Stenzel, MD, PhD, former director of the FDA’s Office of In Vitro Diagnostics, suggests that it is too soon to tell.

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.”

In “Perfect Storm of Clinical Lab and Pathology Practice Regulatory Changes to Be Featured in Discussions at 29th Annual Executive War College,” Dark Daily covers how the forces in play will directly impact the operations and financial stability of many of the nation’s clinical laboratories.

Stenzel is scheduled to speak about the LDT rule during three sessions at the upcoming Executive War College on Diagnostic, Clinical Laboratory, and Pathology Management conference taking place on April 30-May 1 in New Orleans.

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.

—Stephen Beale

Related Information:

FDA Proposes Rule Aimed at Helping to Ensure Safety and Effectiveness of Laboratory Developed Tests

Proposed Rule Webinar: Medical Devices; Laboratory Developed Tests (webinar transcript)

Proposed Rule Webinar: Medical Devices; Laboratory Developed Tests (slides)

FDA Proposed Rule on Medical Devices; Laboratory Developed Tests

CDRH Announces Intent to Initiate the Reclassification Process for Most High Risk IVDs

Questions and Answers about Multi-Cancer Detection Tests Oncology Drug Products Used with Certain In Vitro Diagnostics Pilot Program

Swiss Research Study into Long COVID Promises New Diagnostic and Therapeutic Possibilities

New biomarker may lead to new clinical laboratory testing and treatments for long COVID

Researchers studying long COVID at the University Hospital of Zurich (UZH) and the Swiss Institute of Bioinformatics (SIB), both in Switzerland, have discovered a protein biomarker in blood that indicates a component of the body’s innate immune system—called the complement system—remains active in some individuals long after the infection has run its course. The scientists are hopeful that further studies may provide clinical laboratories with a definitive test for long COVID, and pharma companies with a path to develop therapeutic drugs to treat it.

Ever since the COVID-19 pandemic began, a subset of the population worldwide continues to experience lingering symptoms even after the acute phase of the illness has passed. Patients with long COVID experience symptoms for weeks, even months after the initial viral infection has subsided. And because these symptoms can resemble other illnesses, long COVID is difficult to diagnose. 

This new biomarker may lead to new clinical laboratory diagnostic blood tests for long COVID, and to a greater understanding of why long COVID affects some patients and not others.

The Swiss scientists published their findings in the journal Science titled, “Persistent Complement Dysregulation with Signs of Thromboinflammation in Active Long COVID.”

“Those long COVID patients used to be like you and me, totally integrated [into] society with a job, social life, and private life,” infectious disease specialist Michelè van Vugt, MD (above), Senior Fellow and Professor at Amsterdam Institute for Global Health and Development (AIGHD), told Medical News Today. “After their COVID infection, for some of them, nothing was left because of their extreme fatigue. And this happened not only in one patient but many more—too many for only [a] psychological cause.” Clinical laboratories continue to perform tests on patients experiencing symptoms of COVID-19 even after the acute illness has passed. (Photo copyright: AIGHD.)

Role of the Complement System

To complete their study, the Swiss scientists monitored 113 patients who were confirmed through a reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) test to have COVID-19. The study also included 39 healthy control patients who were not infected.

The researchers examined 6,596 proteins in 268 blood samples collected when the sick patients were at an acute stage of the virus, and then again six months after the infection. They found that 40 of the patients who were sick with COVID-19 eventually developed symptoms of long COVID. Those 40 patients all had a group of proteins in their blood showing that the complement system of their immune system was still elevated even after recovering from the virus.

“Complement is an arm of the immune system that ‘complements’ the action of the other arms,” Amesh Adalja, MD, Adjunct Assistant Professor at Johns Hopkins Bloomberg School of Public Health, told Prevention, “Activities that it performs range from literally attacking the cell membranes of a pathogen to summoning the cells of other immune systems to the site of infection.”

In addition to helping bodies heal from injury and illness, the complement immune system also activates inflammation in the body—and if the complement system is activated for too long the patient is at risk for autoimmune disease and other inflammatory conditions.

This inflammation may cause microclots in patients. “These can block the blood vessels and lead to damage … That can cause premature cardiac events, dementia, respiratory failure, and renal failure,” infectious disease specialist Thomas Russo, MD, SUNY Distinguished Professor, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, told Prevention.

Brain Fog

To make matters worse for long COVID patients, a recent study published in Nature Neuroscience titled, “Blood-Brain Barrier Disruption and Sustained Systemic Inflammation in Individuals with Long COVID-Associated Cognitive Impairment,” found that nearly 50% of people who experience long COVID also experience a condition called Brain Fog (aka, mental fog or clouding of consciousness.)

Conducted by genetic scientists at Trinity College Dublin and St. James’ Hospital in Dublin, Ireland, the study “analyzed blood samples—specifically, serum and plasma—from 76 patients who were hospitalized with COVID-19 in March or April 2020, along with those from 25 people taken before the pandemic. The researchers discovered that people who said they had brain fog had higher levels of a protein in their blood called S100β [a calcium-binding protein] than people who didn’t have brain fog,” Prevention reported.

“S100β is made by cells in the brain and isn’t normally found in the blood. That suggests that the patients had a breakdown in the blood-brain barrier, which blocks certain substances from getting to the brain and spinal cord, the researchers noted,” Prevention reported.

“The scientists then did MRI scans with dye of 22 people with long COVID (11 of them who reported having brain fog), along with 10 people who recovered from COVID-19. They found that long COVID patients who had brain fog had signs of a leaky blood-brain barrier,” Prevention noted.

“This leakiness likely disrupts the integrity of neurons in the brain by shifting the delicate balance of materials moving into and out of the brain,” Matthew Campbell, PhD, Professor and Head of Genetics at Trinity College Dublin, told Prevention.

Interactions with Other Viruses

According to Medical News Today, the Swiss study results also suggest that long COVID symptoms could appear because of the reactivation of a previous herpesvirus infection. The patients in the study showed increased antibodies against cytomegalovirus, a virus that half of all Americans have contracted by age 40.

The link between long COVID and these other viruses could be key to developing treatment for those suffering with both illnesses. The antiviral treatments used for the herpesvirus could potentially help treat long COVID symptoms as well, according to Medical News Today.

“Millions of people across the planet have long COVID or will develop it,” Thomas Russo MD, Professor and Chief of Infectious Disease at the University at Buffalo in New York, told Prevention. “It’s going to be the next major phase of this pandemic. If we don’t learn to diagnose and manage this, we are going to have many people with complications that impact their lives for the long term.”

Long COVID won’t be going away any time soon, much like the COVID-19 coronavirus. But these two studies may lead to more effective clinical laboratory testing, diagnoses, and treatments for millions of people suffering from the debilitating condition.

—Ashley Croce

Related Information:

New Study Finds Potential Cause of Long COVID Symptoms—Experts Explain

Persistent Complement Dysregulation with Signs of Thromboinflammation in Active Long COVID

CDC: Long COVID or Post-COVID Conditions

Long COVID: Major Findings, Mechanisms and Recommendations

Long COVID Explanation in New Study Possibly Paves Way for Tests and Treatments

Scientists May Have Discovered Reason for Long COVID Brain Fog—Here’s Why It Matters

Blood–Brain Barrier Disruption and Sustained Systemic Inflammation in Individuals with Long COVID-Associated Cognitive Impairment

Could New Clues on How Long COVID Affects Immune System Lead to Treatment?

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