Why Does Big Pharma Support LDT Regulation?

by Jondavid Klipp | Aug 21, 2024 | Lab Developed Tests (LDT), FDA

Why Does Big Pharma Support LDT Regulation?

Friends of Cancer Research (FOCR-Washington, DC) has been a steadfast advocate for FDA regulation of LDTs (both the VALID Act and the FDA’s final rule). FOCR contends that FDA regulation will reduce variability in diagnostic tests used to identify cancer patients who are most likely to benefit from cancer therapy.

The nonprofit FOCR has a mission “to accelerate policy change, support groundbreaking science, and deliver new therapies to patients quickly and safely.” A Laboratory Economics’ analysis of FOCR’s Form 990 tax statements shows that it gets most of its funding from major pharmaceutical companies.

Twelve pharmaceutical companies and their trade organization, the Pharmaceutical Research & Manufacturing Assn. (PhRMA), contributed a total of $2.9 million to FOCR in 2021, according to FOCR’s latest publicly available Form 990 tax statement. This accounted for 58% of the total contributions and grants received by FOCR in 2021.

Over the three-year period (2019-2021), the biggest contributors to FOCR have included BristolMyers ($1.2 million), Merck ($986,500) and Astra Zeneca ($850,075). PhRMA also contributed $430,000.

The pharmaceutical companies supporting FOCR are developing expensive oncology drugs targeted at cancer patients with specific genetic mutations. For example, in November 2023, the FDA approved Bristol-Myers’ Augtyro to treat adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer. The wholesale price for Augtyro is $29,000 per month/$348,000 per year. There is no FDA-cleared test to detect ROS1 rearrangements for selecting patients for treatment with Augtyro. LDT test panels for ROS1 include LungOI (PLA 0414U; Medicare rate: $706) performed by the Imagene Lab (Phoenix, AZ).

Laboratory Economics thinks that big pharma may be concerned that some LDTs have erroneously high cut-off values—the benchmarks that determine a positive or negative test result—that can limit patient access to cancer drugs.

FOCR President Jeff Allen, PhD, gave testimony on LDTs before the U.S. House of Representatives’ Committee on Energy and Commerce, Subcommittee on Health on March 21, 2024. Allen said that FDA regulation of LDTs was necessary to “Establish uniform performance standards, regulatory processes, and transparency for all diagnostic tests to ensure accuracy of results.”

How to Keep Your Existing LDTs on the Market

by Jondavid Klipp | Jul 11, 2024 | Lab Developed Tests (LDT), AI, CMS, Digital Pathology

How to Keep Your Existing LDTs on the Market

Labs have some tough decisions to make now that the FDA has issued a final rule giving it authority to regulate LDTs. Labs offering LDTs prior to publication of the final rule on May 6 have three choices: 1) comply with the new FDA regs and keep their LDTs on inhouse test menus; 2) switch to an FDA-cleared test kit (if available); or 3) ignore the FDA regs and risk potential enforcement actions and fines. For expert advice on option 1 from regulatory attorney Christine Bump.

Christine Bump, a regulatory attorney at Penn Avenue Law & Policy (Washington, DC), has been guiding laboratories and test manufacturers through the FDA’s premarket clearance process and post market compliance requirements for 20 years. Below we summarize Bump’s
advice for keeping existing LDTs on the market.

FDA Stage 1 requirements for currently marketed LDTs
Nearly all LDTs, including currently marketed LDTs (prior to May 6, 2024), “unmet need” LDTs performed by “integrated” health systems and NYS CLEP-approved tests, must meet Stage 1 requirements by May 6, 2025.

Stage 1 includes FDA Medical Device Reporting (MDR), which will require laboratories to report adverse events for any LDT that they perform. Under FDA’s regulations, an adverse event is any event that reasonably suggests that a device has or may have caused or contributed to a death or serious injury, or would be likely to cause or contribute to a death or serious injury if the event happens again. An adverse event report would therefore be required for an incorrect test result that has, may, or could cause such consequences. The incorrect test result could be caused by instrument malfunctions as well as mislabeled or contaminated specimens.

An adverse event report must generally be reported to the FDA within 30 days after the lab became aware of the error. The regulations require specific information be included in the report, and labs will also need to file\ a report that describes what corrective action they took, or if they chose to remove that LDT from their test menu.

An adverse event report could prompt the FDA to ask follow-up questions or schedule an on-site inspection.

The FDA is especially sensitive to incorrect test results that delayed patient treatment or caused
unnecessary treatment (or had the potential to do so).

Stage 1 also requires labs to maintain complaint files for each LDT they offer, including the date the complaint was received; the name, address, and phone number of the complainant; the nature and details of the complaint; any corrective action taken, etc. Specific records and reports
must also be maintained and submitted regarding corrections and removals of tests, including for
repairs, adjustments, relabeling, etc.

FDA Stage 2 requirements for currently marketed LDTs
Once again, Stage 2 requirements apply to nearly all LDTs and become effective May 6, 2026.

Stage 2 requires each laboratory to be registered with the FDA and list all of the LDTs they perform.

Stage 2 also requires labs to submit labeling for each LDT they offer. Labeling includes test performance information and a summary of supporting validation. As part of its review of labeling, the FDA plans to look closely at claims of superior performance and whether those claims are adequately substantiated. This includes any test claims made on a lab’s website, brochures or by sales reps.

Labeling information is typically included as a package insert or affixed to test kit box for FDA-cleared or approved IVD tests. However, since LDTs are not distributed in boxed test kits, it is unclear exactly where the label for an LDT will need to be placed. Labels might be required on the LDT test requisition form, but this hasn’t been confirmed yet. We’re waiting for the FDA to issue more guidance on label requirements.

FDA Stage 3 requirements for currently marketed LDTs

By May 6, 2027, currently marketed as well as “unmet need” LDTs developed and used within “integrated” health systems need to be in compliance with the records requirements of the quality system regulation. These records relate to the device master record, the device history record, and the quality system record. (Note: Complaint file record requirements are already covered under Stage 1.)

The device master records must include information about device specifications, production process specifications, quality assurance procedures and specifications, packaging and labeling specifications, and procedures and methods for installation, maintenance, and servicing.

The device history records must include information about the dates and quantity manufactured, the quantity released for distribution, acceptance records, information to identify each production unit and device identifiers.

Labs must have the required information compiled, documented, and in a records system that is accessible and readily available to FDA investigators during inspections.

FDA On-site Inspections
All registered lab facilities performing LDTs are subject to scheduled on-site inspections by the FDA every two years. FDA inspections are completely different than and are independent of CMS CLIA and CAP inspections. FDA inspectors will be focused on reviewing LDT test records and files. However, the reality is that the FDA already lacks the resources to perform regularly scheduled on-site inspections of existing test kit manufacturers. The agency may have difficulty keeping up with the thousands of new lab facilities that fall under its purview as a result of its final rule.

FDA Finalizes LDT Regulation; Partial “Grandfather” Exemptions for Existing LDTs

by Jondavid Klipp | May 14, 2024 | FDA, Lab Developed Tests (LDT), Laboratory Regulations

FDA Finalizes LDT Regulation; Partial “Grandfather” Exemptions for Existing LDTs

Although less severe than the FDA’s initial proposed regulations, the Final Rule (published May 6) will add a new complex layer of bureaucracy for labs offering laboratory-developed tests (LDTs). LDTs on the market prior to May 6 will not have to go through the full FDA application and clearance process. However, labs will need to develop quality system complaint files, registration, labeling, etc. for each LDT they currently offer. New LDTs will ultimately need to go through the full FDA application and
clearance process.

Jonathan Genzen, MD, PhD, Chief Medical Officer and Senior Director of Governmental Affairs at ARUP Laboratories (Salt Lake City, UT), has been closely following the FDA’s movement toward regulating laboratory developed tests. Below we summarize Dr. Genzen’s perspectives on the Final Rule with an emphasis on what it means for currently marketed LDTs.

What are the Stage 1 requirements for “grandfathered” LDTs under the Final Rule?

These tests are not fully “grandfathered” under the Final Rule, as certain FDA oversight requirements still apply.

Currently marketed LDTs (on the market prior to May 6, 2024) will need to comply with FDA Medical Device Reporting (MDR) regulations. This includes reporting certain device-related adverse events and product problems to the FDA, as well as correction and removal reporting requirements.

Currently marketed LDTs will also need to comply with one of the Stage 3 quality system requirements (Complaint Files — 21 C.F.R. 820.198). Laboratories will be required to establish and maintain procedures for receiving, reviewing, and evaluating complaints for their LDTs.

The Stage 1 requirements will need to be met by May 6, 2025.

What are the Stage 2 requirements for “grandfathered” LDTs under the Final Rule?

Currently marketed LDTs will need to comply with FDA registration, listing, labeling, and investigational use requirements by May 6, 2026. The most complex of these requirements is labeling. It appears that all LDTs eligible under the currently marketed enforcement discretion policy will need to meet full FDA labeling requirements for IVDs. This will be a complex task to conduct retrospectively, as labeling requirements are extensive and will need to be completed within two years to remain in compliance with the Final Rule.

Which anatomic pathology services are covered under the Final Rule for LDTs?

From my interpretation, with the exception of manual staining and manual immunohistochemistry (“1976-type” LDTs), the Final Rule doesn’t distinguish between AP and CP testing. The Final Rule appears to apply to all LDTs, with the exception of manual interpretation of the final slides by a pathologist. This means that currently performed anatomic pathology LDTs, including non-manual IHC staining, are now subject to FDA oversight.

What happens when an existing LDT is modified?
The moment a currently marketed test has a modification considered to be significant by the FDA (and they provide representative examples in the Final Rule), then the LDT would be subject to additional QS requirements including design controls, purchasing controls, acceptance activities, corrective and preventive action (CAPA), and records requirements. Such modifications to existing LDTs will also require a premarket submission to the FDA.

Over time, I anticipate that many routine test modifications, including sample type changes and automation of manual assays on liquid handlers, will now necessitate FDA submissions. And I suspect that the FDA is underestimating the number of tests that will ultimately need to go through premarket review, as well as the financial impact to the clinical laboratory community.

Is the NYS CLEP less expensive and a quicker process than FDA review?

I believe that LDT submission and review under the NYS Clinical Laboratory Evaluation Program (CLEP) – which oversees clinical laboratory testing for NY patients – is available only to NYS-accredited labs. NY clinical laboratory accreditation is likely not a practical option for most laboratories that do not intend to perform testing on NY patients. The NY CLEP performs outstanding, high-quality work, and they will need to share their perspective on how the program should or should not be used in the context of the FDA’s Final Rule.

Is a lawsuit challenging FDA’s authority to regulate LDTs likely?
I believe that litigation is very likely. The FDA’s language in the Final Rule regarding “illegality” (page 30) makes this even more likely in my opinion. If not following the FDA’s new framework for LDTs is deemed illegal—even if it compromises the ability to care for patients (e.g. emergency validations for clinically urgent testing in acute settings) – then the lab industry has been backed into a corner and judicial review could be the only remaining remedy.

FDA Final LDT Rule Could be Published Soon

by Jondavid Klipp | Mar 18, 2024 | CLFS, ACLA, FDA, Lab Developed Tests (LDT)

FDA Final LDT Rule Could be Published Soon

On March 1, the FDA submitted its final rule for LDT regulation to
the White House’s Office of Information and Regulatory Affairs
(OIRA). This is a perfunctory last step before the final rule is published
in the Federal Register. This could occur as soon as April 1. This will be
the most impactful new regulatory change for laboratories since PAMA
completely overhauled the Medicare CLFS in 2018.

FDA FINAL LDT RULE COULD BE PUBLISHED SOON

OIRA (pronounced “oh-eye-rah”) is a statutory part of the Office of Management and Budget within the Executive Office of the President. OIRA is responsible for reviewing all federal regulations (i.e., the Executive Branch’s administrative actions) to ensure they meet all statutory requirements. OIRA is currently headed by Richard Revesz, Administrator, who was appointed by President Biden and confirmed by the U.S. Senate in late 2022.

“OIRA reviewed the proposed rule in record time, so it is reasonable to expect that the review of the final rule will not be protracted. I would not be surprised if OIRA completes its review in 30 days and FDA publishes the final rule in the federal register in the first week of April,” according to attorney Sheila Walcoff, Chief Executive at the IVD consulting firm Goldbug Strategies (Gaithersburg, MD).

Typically, a final rule will specify an effective date of 30 or 60 days after the publication date, adds Walcoff.

Once a final rule is published it will be difficult to overturn.

Last Chance to Sway OIRA Against Regulation

OIRA staff held nine teleconferences with organizations advocating both for and against FDA LDT regulation last year. OIRA is next scheduled to meet with The Association for Diagnostics and Laboratory Medicine (ADLM — formerly AACC) on March 18. ADLM, which represents approximately 8,000 members, including clinical labs and IVD manufacturers, has steadfastly
opposed FDA regulation of LDTs. This could be the last chance that the lab industry has to sway OIRA against rubber-stamping the final rule.

Expected Legal Challenge

A final rule is almost guaranteed to trigger a lawsuit from lab trade groups, which will argue that the FDA does not have the authority to regulate LDTs.
The American Clinical Laboratory Assn. (ACLA — Washington, DC) seems to be gearing up for a lawsuit to the impending final rule. In a statement, ACLA President Susan Van Meter said:

ACLA has significant concerns about the legality and impact of FDA unilaterally imposing an ill-fitting medical device scheme on laboratory-developed testing services, which are professional services and not medical products. Should the agency promulgate a final rule, ACLA will assess its options at that time; but we continue to urge the agency to withdraw the proposed rule and reengage on advancing appropriate legislation.

Could a New Trump Administration Put the Kibosh on LDT Regulation?

As a component of OMB, OIRA is part of the Executive Office of the President and helps ensure that covered agencies’ rules reflect the President’s policies and priorities.

The FDA is moving quickly because the national election in November could result in a new administration opposed to LDT regulation. A new President could, immediately upon taking office, prevent a proposed rule from being finalized, according to long-time lab regulation expert Dennis
Weissman (Falls Church, VA).

However, Weissman says that changing or canceling a final rule is much more difficult. Once a federal rule has been finalized a new administration would be required to undergo the formal rulemaking process (i.e., opportunity for public comment on a proposal followed by final rule) to change or repeal all or part of a final rule.

In addition to this administrative action, Congress could also take legislative action to overturn a final rule, notes Weissman.

FDA Won’t Extend Comment Period on LDT Regs

by Jondavid Klipp | Nov 14, 2023 | ACLA, CAP, FDA, Lab Developed Tests (LDT)

FDA Won’t Extend Comment Period on LDT Regs

The FDA has announced that its standard 60-day comment period for its proposed regulation of laboratory-developed test (LDTs) will not be extended past December 4. Several trade groups, including CAP and ACLA, had requested to stretch the comment period to 120 days. An extension would have potentially delayed implementation of the rule while giving Congress more time to pass LDT reform legislation. The FDA has indicated that a final rule could be published as early as April 1, 2024.

The FDA estimates that there are approximately 12,000 U.S. labs performing high-complexity testing and that 10% of these are marketing LDTs. These 1,200 labs are currently offering 80,400 LDTs and 7,776 new LDTs are coming to the market each year. The FDA estimates that labs will generate $28.6 billion of revenue from LDTs in 2023.

One of the biggest concerns is the FDA’s capacity to review and process as many as 80,000+ LDT applications over the next few years. For example, the FDA gave marketing authorization to a grand total of only 765 medical devices, including lab tests, in 2022, according to the FDA’s Center for Devices and Radiological Health 2022 Annual Report. The FDA’s ability to process tens of thousands of LDT applications in a timely manner, even with the help of third-party reviewers, is doubtful.

During an October 24 call with investors, Jim Davis, Chief Executive of Quest Diagnostics, said that Quest agrees with the long-standing assertion of the American Clinical Laboratory Assn. (ACLA), “that the FDA does not have the statutory authority to unilaterally regulate LDTs under its existing medical device authority.” Davis noted that by volume, LDTs account for less than 10% of Quest’s overall testing business. Quest performs the majority of its LDT testing at three ISO-certified labs, including San Juan Capistrano, CA; Chantilly, VA; and Lewisville, TX.

On an October 26 conference call, Labcorp CEO Adam Schechter said that LDTs account for less than 5% of Labcorp’s volume and less than 10% of its testing revenue. “If you look at the rigor that we go through with our laboratory-developed tests, we think we do the vast majority of what they [FDA] would be asking for anyway.” Schechter said FDA regulation could have unintended consequences. LDTs “are sometimes the most important test for new specialty areas. And getting those tests to patients quickly is what’s most important.”

One group in favor of LDT regulation is AdvaMed (Washington, DC), whose members include Abbott, BD, Bio-Rad Laboratories, bioMerieux, Hologic, Illumina and Roche. “We like the rule….This is really about making sure there’s a level playing field when you’re talking about diagnostics tests and having everything go through a similar pathway,” said AdvaMed CEO Scott Whitaker at an October 10 press conference. “Either you raise the regulatory standard, or you lower the regulatory standard, but you do it across the board without stifling innovation,” he said.

The last major effort by the FDA to formally regulate LDTs came in October 2014, when the agency issued draft guidance. But after collecting comments and facing two years of stiff opposition, the agency chose not to issue final guidance. One of the strongest critics was ACLA, which challenged the FDA’s authority over the tests by filing a citizen petition and making clear its intent to sue if necessary.