Chat GPT Faces the 2022, 400-page VALID ACT

Chat GPT wasn't around in 2022, but the 400-page VALID ACT was, and for a while, VALID had some momentum in Congress.

See a May 2022 article where authors Boiani and Robertson at Epstein Becker Green note that a version of VALID was attached to FDA user fee legislation:

https://natlawreview.com/article/valid-act-senate-action-brings-fda-regulation-ldts-closer-to-fruition

That article links to a still-up 400 page VALID version.

https://www.help.senate.gov/imo/media/doc/FDASLA%20Discussion%20Draft%20May%2017%202022.pdf

CHAT GPT wasn't around in 2022 to read VALID ACT, but it is now.  See below.

As a bonus, in closing I asked Chat GPT to also compare the 400 page VALID ACT and the 160 page FDA LDT rule.

Robots work to compare VALID and LDT RULE. Results below.

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Summarize the VALID ACT.

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The VALID Act (Verifying Accurate Leading-edge IVCT Development Act) of 2022, included but not finalized as part of the FDASLA Act, represents a landmark effort to establish comprehensive regulatory oversight for laboratory-developed tests (LDTs). 

Traditionally, LDTs have been regulated under the Clinical Laboratory Improvement Amendments (CLIA), which focus on the laboratories performing the tests rather than the tests themselves. Had it passed, this act aimed to bring these tests under the regulatory purview of the Food and Drug Administration (FDA), establishing a risk-based framework for their evaluation and oversight.

Key Provisions of the VALID Act:

1. Risk-Based Framework: The VALID Act proposes a regulatory structure that categorizes in vitro clinical tests (IVCTs) based on the potential risk they pose to patients. This framework allows the FDA to apply different levels of scrutiny and oversight depending on the risk associated with each test. High-risk tests, which are more likely to impact patient outcomes if inaccurate, will undergo more rigorous review processes, while lower-risk tests may be subject to less stringent requirements. This tiered approach ensures that the regulatory burden is proportional to the potential risk, promoting patient safety without stifling innovation.

2. Pre-Market Review and Technology Certification: The act introduces the concept of a pre-market review for higher-risk tests, requiring manufacturers to submit data demonstrating the safety and efficacy of their tests before they can be marketed. In addition to this, the VALID Act also proposes a technology certification process. Laboratories that meet certain criteria and demonstrate consistent quality and reliability in their testing processes can receive certification. This certification allows them to develop and modify tests without seeking FDA approval for each individual test, provided they adhere to the certification standards. This approach aims to strike a balance between ensuring test quality and fostering innovation.

3. Transitional Provisions and Implementation: Recognizing the complexity and scope of these new regulations, the VALID Act includes provisions for a phased implementation. This transition period allows laboratories and manufacturers time to adapt to the new requirements. It includes clear guidelines and timelines for compliance, ensuring that the industry can move towards these new standards in a structured manner. The act also establishes an emergency use authorization (EUA) pathway for IVCTs, similar to the EUA process used during the COVID-19 pandemic. This allows for the rapid deployment of tests in public health emergencies, ensuring timely access to critical diagnostic tools.

4. FDA Oversight and Enforcement: The VALID Act grants the FDA enhanced authority to oversee the development, marketing, and use of IVCTs. This includes the ability to inspect facilities, review test data, and take enforcement actions against laboratories and manufacturers that fail to comply with the regulatory requirements. The act also emphasizes post-market surveillance, requiring manufacturers to monitor the performance of their tests and report adverse events. This ensures that any issues with test accuracy or reliability are promptly identified and addressed.

5. Resources and Funding: To support the implementation and enforcement of these new regulations, the VALID Act outlines the need for additional resources. This includes the establishment of user fees, similar to those used in other areas of FDA oversight, to fund the review and regulation of IVCTs. These fees will provide the FDA with the necessary funding to carry out its expanded responsibilities under the act, including conducting pre-market reviews, inspecting facilities, and overseeing post-market surveillance.

Implications for the Industry:

The VALID Act marks a significant shift in the regulation of laboratory-developed tests. By bringing LDTs under FDA oversight and establishing a risk-based framework, the act aims to ensure that all tests used in patient care meet consistent standards of quality and reliability. This has important implications for both patients and the healthcare industry. For patients, it promises more reliable and accurate diagnostic tests, which are crucial for guiding treatment decisions. For laboratories and test developers, it introduces new regulatory requirements and potential challenges, but also offers opportunities for innovation through the technology certification pathway.

In summary, the VALID Act seeks to modernize the regulatory landscape for laboratory-developed tests, providing a structured, risk-based approach to ensure test quality and patient safety while fostering innovation in diagnostic testing. This legislation aims to create a balanced regulatory environment that addresses the needs of patients, healthcare providers, and test developers in an evolving healthcare landscape.

SIDEBAR - KEY POINTS of VALID

Here are 15 key takeaways from the VALID Act of 2022:

1. Risk-Based Regulation: The act introduces a risk-based framework for the regulation of in vitro clinical tests (IVCTs), including laboratory-developed tests (LDTs), with higher-risk tests requiring more stringent review.

2. FDA Oversight: For the first time, LDTs will fall under the direct regulatory authority of the FDA, moving beyond the existing CLIA framework, which focuses primarily on laboratory operations.

3. Pre-Market Review: High-risk tests will need to undergo pre-market review by the FDA, where manufacturers must provide data to demonstrate safety and efficacy before these tests can be marketed.

4. Technology Certification: The act establishes a technology certification process for laboratories that demonstrate consistent quality and reliability, allowing them to modify tests without FDA approval for each test.

5. Emergency Use Authorization: The VALID Act includes provisions for emergency use authorizations (EUA) for IVCTs, enabling rapid deployment of diagnostic tests during public health emergencies.

6. Transitional Implementation: A phased implementation period is included to allow laboratories and manufacturers time to adapt to the new regulatory requirements, ensuring a smoother transition.

7. Post-Market Surveillance: The act emphasizes the importance of post-market surveillance, requiring manufacturers to monitor the performance of their tests and report any adverse events or inaccuracies.

8. Enforcement Authority: The FDA gains enhanced authority to inspect facilities, review test data, and take enforcement actions against non-compliant laboratories and manufacturers.

9. User Fees: To support the expanded regulatory activities, the VALID Act proposes the establishment of user fees, similar to those in other areas of FDA regulation, to fund the review and oversight processes.

10. Grandfathering of Existing Tests: Tests that are already on the market before the act's implementation may be subject to specific grandfathering provisions, which can exempt them from certain requirements temporarily.

11. Harmonization with International Standards: The VALID Act seeks to align with international standards and practices in diagnostic testing to facilitate global harmonization and improve the reliability of tests across different markets.

12. Flexible Pathways for Innovation: The act provides pathways for innovation, particularly through the technology certification process, which allows certified laboratories more flexibility in test development and modification.

13. Safety and Efficacy Assurance: The primary goal of the act is to ensure that all IVCTs, especially high-risk LDTs, meet rigorous standards for safety, accuracy, and reliability, thereby protecting patient health.

14. Impact on Laboratories: Laboratories will need to adhere to new regulatory standards and may need to invest in compliance measures, data generation for pre-market review, and post-market surveillance activities.

15. Public Health Focus: By improving the regulatory oversight of IVCTs, the VALID Act aims to enhance public health outcomes by ensuring that diagnostic tests used in patient care are both accurate and reliable.

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After taking a deep breath, compare the VALID ACT (never passed legisislation) to the FDA LDT REGULATION (finalized in May 2024.)

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Comparison of the VALID Act and the FDA's 2024 LDT Regulation

VALID Act Overview:

• Risk-Based Framework: The VALID Act introduces a risk-based regulatory structure for in vitro clinical tests (IVCTs), including LDTs, with higher-risk tests undergoing more rigorous review. It provides a technology certification pathway, offering flexibility for certified labs to develop and modify tests without FDA approval for each test.
• Pre-Market Review: High-risk tests need to undergo FDA pre-market review, requiring manufacturers to demonstrate safety and efficacy before marketing.
• Transitional Implementation: The Act includes a phased implementation period, allowing laboratories to adapt to the new requirements. It also establishes an emergency use authorization (EUA) pathway for IVCTs.
• FDA Oversight: It grants the FDA authority to oversee the development, marketing, and use of IVCTs, including inspections and post-market surveillance.
• User Fees: The Act proposes establishing user fees to support regulatory activities.
• Grandfathering: Existing tests may be subject to specific grandfathering provisions.
• Technology Certification: Certified labs can develop and modify tests without seeking FDA approval for each modification.

FDA's 2024 LDT Regulation Overview:

• IVDs as Medical Devices: The regulation clarifies that in vitro diagnostic products (IVDs), including those manufactured by laboratories as LDTs, are considered medical devices under the Federal Food, Drug, and Cosmetic Act (FD&C Act).
• Phasing Out Enforcement Discretion: The FDA is phasing out its general enforcement discretion for LDTs, ensuring they are subject to the same enforcement approach as other IVDs. This includes MDR requirements, registration, listing requirements, labeling requirements, and pre-market review for higher-risk IVDs.
• Four-Year Transition Period: The regulation introduces a four-year phaseout period, with compliance expectations rolling out in stages, starting from July 5, 2024.
• Scope of Regulation: The rule applies to IVDs manufactured by laboratories certified under the Clinical Laboratory Improvement Amendments (CLIA) and used within such laboratories.
• Specific Provisions: There are targeted enforcement discretion policies for certain categories of LDTs, such as those manufactured within the Veterans Health Administration (VHA) or Department of Defense (DoD) and certain New York State CLEP-approved LDTs.
• Premarket Review: By the fourth year, the regulation expects compliance with premarket review requirements for moderate and low-risk IVDs offered as LDTs.
• Enhanced Oversight and Benefits: The regulation aims to address the increased complexity and wider use of LDTs, emphasizing patient safety, effectiveness, and the reduction of misdiagnosis-related harms. The FDA anticipates annualized benefits over 20 years ranging from $0.99 billion to $13.62 billion, offsetting estimated compliance costs.

Key Differences:

1. Legislative vs. Regulatory: The VALID Act is proposed legislation that would have required Congressional approval, while the FDA's LDT regulation is a final rule issued by the FDA itself.
2. Risk-Based Approach: Both the VALID Act and the FDA’s regulation propose a risk-based framework, but the VALID Act provides a more defined pathway for high and low-risk tests, including a technology certification process.
3. Implementation and Transition: The VALID Act suggests a transitional period with an emphasis on technology certification to facilitate adaptation, whereas the FDA's rule implements a four-year phased approach to full compliance.
4. FDA's Authority: The FDA's 2024 regulation solidifies the FDA's authority over LDTs as medical devices, ending its longstanding enforcement discretion.
5. Specific Enforcement Policies: The FDA's regulation includes detailed enforcement discretion policies for specific groups and conditions, such as LDTs within the VHA or approved by New York State CLEP, which the VALID Act does not explicitly address.
6. Emergency Use Pathway: Both frameworks introduce or reference emergency use pathways, but the VALID Act emphasizes this as part of a broader emergency preparedness strategy.
7. Scope and Coverage: The FDA's rule applies explicitly to LDTs within CLIA-certified labs, aligning with its existing device regulation structure, while the VALID Act seeks to establish a distinct regulatory category for IVCTs.

In summary, while both the VALID Act and the FDA's 2024 regulation aim to increase oversight and ensure the safety and effectiveness of LDTs, they differ in their approach, implementation strategy, and specific provisions for regulation and compliance.

The FDA LDT Rule: Why HLA Tests for Transplant Aren't Going to Be Hit by FDA

FDA plans to demand increasingly tight, phased-in regulation of nearly all laboratory-developed tests between 2025 and 2028.  However, a few test categories are exempt (at FDA's discretion on a rolling basis).  One is "HLA tests for transplant."

This line of reasoning may have gotten lost in the shuffle when the 160-page rule was released.   The FDA discussion is principally at 89 FR 37297-8 (May 6, 2028).   

I include (#1) an AI discussion of the FDA's thought process below. and then include (#2) the whole of the (columnar) FDA text at bottom.

It seems the main reason FDA exempts these tests are that the national transplant body (NOTA) mandates controls, but the controls the transplant body mandates are CAP approval.    This means FDA has to backpedal and say it doesn't think CAP approval makes tests safe, well, except here, where an old NOTA law endorses the same CAP approval.

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AI Corner: Chat GPT Summarizes FDA on HLA pp. 37297-8.

##

 

The FDA has decided to exercise enforcement discretion for HLA tests used in the context of organ, stem cell, and tissue transplantation, allowing them to operate without direct FDA regulation. Several key reasons contribute to this decision:

1. Urgency and Need for Rapid Adaptation: HLA tests for transplantation are performed in urgent situations where prompt decisions are crucial. When an organ, stem cell, or tissue becomes available, physicians must quickly assess the compatibility between the donor and recipient. Because new HLA alleles are continuously being identified, modifications to these tests need to be made rapidly to address specific mismatches and respond to the unique needs of each transplant case.

2. Customization and Individualization: These tests are highly individualized within each medical facility. Laboratories often develop HLA tests that account for local HLA polymorphisms and patient demographics, leading to a level of customization that is necessary for effective transplantation outcomes. This individualization means that a one-size-fits-all approach to regulation may not be suitable for these tests.

3. Existing Oversight Programs: Several federal programs already provide oversight and help mitigate the risks of harm from inaccurate or unreliable HLA tests:

   • National Organ Transplant Act (NOTA): This act established the Organ Procurement and Transplant Network (OPTN), which sets standards for the safe and equitable allocation of organs. The OPTN has requirements for the performance of HLA typing, antibody screening, and crossmatching tests.
   • National Marrow Donor Program (NMDP): The NMDP supports patients needing bone marrow or umbilical cord blood transplants and sets minimum requirements for organizations facilitating these transplants. It mandates HLA typing for donors and recipients and requires reporting of test results to maintain quality and accuracy.
   • Accreditation Requirements: Both OPTN and NMDP require histocompatibility laboratories to be accredited by either the American Society for Histocompatibility and Immunogenetics (ASHI) or the College of American Pathologists (CAP). These standards have provisions that specifically address OPTN and NMDP requirements, which add a layer of quality control.

4. Risk Mitigation: The combination of oversight programs like OPTN and NMDP, along with CAP and ASHI accreditation requirements, helps mitigate the risk of inaccurate results. While the FDA does not view CAP or ASHI accreditation alone as sufficient for all in vitro diagnostics (IVDs), it considers the additional protections provided by these programs and the urgency of the situation to justify continued enforcement discretion.

5. Highly Standardized HLA Tests for Blood Transfusion: The FDA's enforcement discretion does not extend to HLA tests used for blood transfusion, which are more standardized across institutions. This differentiation underscores the unique nature of HLA tests for transplantation and the need for flexibility in their regulation.

In summary, the FDA's decision not to regulate HLA tests for transplantation directly is based on the need for rapid, individualized testing in urgent situations, the presence of existing oversight mechanisms, and the high level of customization required for these tests.

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FDA"s original May 2028 Fed Reg text follows.

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FDA HLA TESTS DISCRETION 

89 FR 37297-8     May 6, 2024

  [FDA discusses “1976 type tests” and how they are defined and foresees further

clarification in the future.]

 

FDA intends to consider whether guidance containing additional

discussion and examples of [1976 type] tests that may fall within this category would be

helpful, and would issue any such guidance in accordance with good

guidance practices (see § 10.115).

 

# # #

 

Another category of such [enforcement discretion]

tests is HLA tests that are designed, manufactured,

and used within a single laboratory certified under CLIA that meets the

requirements to perform high- complexity histocompatibility testing

when used in connection with   

•  organ,
•        stem cell, ans
•         tissue transplantation
•       to perform HLA allele typing,
•      for HLA  antibody screening and monitoring        
• or
•         for conducting real and ‘‘virtual’’ HLA crossmatch tests
•         (hereinafter ‘‘HLA tests  for transplantation’’).

 [Bullets BQ]

 Physicians must often make prompt decisions about

transplantation based on medical judgment regarding their patient’s

condition and degree of mismatch between the donor and patient should

an organ, stem cells, or tissue become available. Because new alleles are

continuously identified, and the need for assessing degree of crossmatch is

generally urgent, modifications to HLA tests for transplantation are often made

rapidly in response to urgent situations.

 

Further, these tests are often individualized within each medical

facility; for example, they include reagents that reflect local HLA

polymorphisms and patient demographics.

  

In addition, oversight under certain Federal programs helps to mitigate the

risks of harm from inaccurate and unreliable HLA tests for transplantation.

 

For example, the National Organ Transplant Act (NOTA) of 1984 created

the Organ Procurement and Transplant Network (OPTN).

 

NOTA, as amended (42 U.S.C. 273 et seq.), and the OPTN 

Final Rule, 42 CFR part 121, establish a comprehensive system for the safe and

equitable allocation, distribution, and transplantation of donated organs.

 

The OPTN Final Rule and OPTN bylaws and policies govern operation of all member

transplant hospitals, organ procurement organizations, and histocompatibility

laboratories in the United States. The Stem Cell Therapeutic and Research Act

of 2005 (Pub. L. 109–129), as amended, authorizes a national registry (‘‘Be the

Match Registry’’) to support patients in need of bone marrow or umbilical cord

blood transplants, which is operated under Federal contracts by the National

Marrow Donor Program® (NMDP) (Ref. 45).

 

NMDP sets forth minimum requirements for organizations working

through the NMDP to facilitate stem cell transplants (Refs. 46 and 47).

 

OPTN has requirements for performance of HLA typing, antibody

screening, and crossmatching tests, and NMDP requires HLA typing for donors

and potential recipients for stem cell transplants facilitated by the Be the

Match Registry, as well as reporting of test results to NMDP (Refs. 47 and 48).

Both OPTN and NMDP have procedures in place for identifying, investigating,

and reporting discrepant tests results (Refs. 48 and 49).

 

 

In addition to these safeguards designed to identify and resolve

potentially inaccurate results, each OPTN member histocompatibility

laboratory must, among other things, meet specified American Society for

Histocompatibility and Immunogenetics (ASHI) and/or College of American

Pathologists (CAP) standards as a condition of OPTN membership (Ref.

50). NMDP similarly requires histocompatibility laboratories used by

U.S. transplant centers and donor centers to be accredited by CAP and/or

ASHI (Refs. 46, 51 and 52). Both ASHI and CAP standards have provisions that

specifically address OPTN and/or NMDP requirements for

histocompatibility laboratories that perform tests for those programs.

Importantly, as discussed below, FDA does not believe that a CAP or ASHI

accreditation of a laboratory, on its own, is sufficient to mitigate risk and provide

assurance of the safety and effectiveness for all IVDs offered as LDTs by the

accredited laboratory. 

 

However, we consider the fact that OPTN and NMDP

require adherence to CAP and/or ASHI standards, including provisions specific

to OPTN and NMDP requirements, to be one factor that helps mitigate risk of

inaccurate results or unreliable HLA tests for transplantation.

 

After considering this factor in combination with the protections provided through

 the programs described above and the urgent circumstances in which HLA

tests for transplantation may be modified and performed, as well as the

comments received on our proposed approach to HLA tests for

transplantation, FDA intends to continue the general enforcement

discretion approach for these tests. We note that this enforcement discretion

policy does not apply to HLA tests used for blood transfusion, which are highly

standardized across institutions, nor does it apply to any IVDs identified in

section V.A.2 as falling outside the scope of the phaseout policy or as

discussed in section V.B.

CMS Webinar on "TCET" NCDs: September 23, 2024 (230 ET, 1130 PT)

Header: CMS Webinar on TCET on September 23, 2024.

 I got this email from CMS, and I can't find a weblink for it, so I'm just cutting and pasting the CMS email.  There is a webinar on TCET on September 23 (Thursday); questions due I think by September 20 (not entirely explicit).  They ask for "register in advance."

###

On August 7, 2024, the Centers for Medicare & Medicaid Services (CMS) established the TCET pathway through a final procedural notice in the Federal Register and released three final guidance documents. Collectively, these documents propose a substantial transformation to our approach to coverage reviews and evidence development.

 As a part of CMS’ continued commitment to engage interested parties, CMS will hold an education session on September 23, 2024, to share information on the TCET pathway and answer questions.  

 CMS asks the public to submit questions on the TCET pathway in advance of the meeting. Please submit questions in advance to TCET@cms.hhs.gov.  

 When: Thursday, September 23, 2024, from 2:30 – 3:30 p.m. ET

 Who should attend: This education session is intended for all Medicare and healthcare partners.

 RSVP: by registering in advance for this webinar: https://cms.zoomgov.com/webinar/register/WN_9mr6Gm66S8yoifQNABfGfA

 Please RSVP by September 20, 2024, at 5:00 p.m. ET. 

 After registering, you will receive a confirmation email containing information about joining the webinar. This meeting is closed to press. 

 Additional Resources:

• To view the TCET Drop-In Article, visit: https://www.cms.gov/files/document/tcet-drop-article.pdf
• For a fact sheet on TCET: https://www.cms.gov/newsroom/fact-sheets/final-notice-transitional-coverage-emerging-technologies-cms-3421-fn
• To read the final TCET procedural notice, visit: https://www.federalregister.gov/documents/2024/08/12/2024-17603/medicare-program-transitional-coverage-for-emerging-technologies

New Consensus Paper: Value of Minimal Residual Disease Detection in Cancer Response

As flagged by Friends of Cancer Research, the RECIST working group has published a consensus paper on the promise and current status of minimal residual disease detection (MDR) in cancer therapy management.

See the Linked In article from FOCR here.  (They note, look for more at their annual meeting in November).

https://www.linkedin.com/posts/friends-of-cancer-research_clinicaltrials-ctdna-ctmonitr-activity-7241479298769981441-vB7e

See the original paper by Wyatt et al. here:

https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-24-1883/748448/Plasma-ctDNA-as-a-treatment-response-biomarker-in

The paper looks like it is subscription only.   Below I clip the abstract, and further below (in "AI Corner") some takeaways.

They suggest that response accuracy may vary by cancer type and therapy class, exactly the approach that Medicare's MolDx program has been taking on coverage of MRD tests.

Authors' Abstract

Early indicators of metastatic cancer response to therapy are important for evaluating new drugs and stopping ineffective treatment. The Response Evaluation Criteria in Solid Tumors (RECIST) based on repeat cancer imaging are widely adopted in clinical trials, are used to identify active regimens that may change practice, and contribute to regulatory approvals. 

However, these criteria do not provide insight before 6 – 12 weeks of treatment and typically require that patients have measurable disease. Recent data suggests that measuring on-treatment changes in the amount or proportion of circulating tumor DNA (ctDNA) in peripheral blood plasma may accurately identify responding and non-responding cancers at earlier time points. Over the past year, the RECIST working group has evaluated current evidence for plasma ctDNA kinetics as a treatment response biomarker in metastatic cancers and early endpoint in clinical trials, to identify areas of focus for future research and validation. 

Here, we outline the requirement for large standardized trial datasets, greater scrutiny of optimal ctDNA collection time points and assay thresholds, and consideration of regulatory body guidelines and patient opinions. In particular, clinically-meaningful changes in plasma ctDNA abundance are likely to differ by cancer type and therapy class, and must be assessed before ctDNA can be considered as a potential pan-cancer response evaluation biomarker. 

Despite the need for additional data, minimally-invasive on-treatment ctDNA measurements hold promise to build upon existing response assessments such as RECIST, and offer opportunities for developing novel early endpoints for modern clinical trials.

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AI CORNER

##

Here are ten key takeaways for expert oncology readers regarding the potential of MRD (ctDNA) as a treatment response biomarker:

1. Early Detection of Treatment Response: Plasma ctDNA kinetics can identify responding and non-responding cancers at earlier time points compared to imaging-based RECIST criteria, which typically require 6-12 weeks for assessment.

2. Minimally Invasive Monitoring: ctDNA measurement offers a minimally invasive alternative to traditional imaging, potentially reducing patient burden and allowing for more frequent monitoring.

3. Enhanced Sensitivity: ctDNA levels are associated with tumor burden and can provide a more sensitive measure of treatment response, even in cases where traditional imaging may not detect changes.

4. Applicability Across Tumor Types: While ctDNA kinetics can vary by cancer type, the approach has shown promise in multiple solid tumors, suggesting potential for broad applicability in oncology.

5. Improved Decision-Making: Early ctDNA response can guide treatment decisions more quickly, enabling earlier discontinuation of ineffective therapies and a potential shift to alternative treatments.

6. Complementary to RECIST: ctDNA offers an opportunity to complement existing RECIST-based assessments, providing additional data points to enhance the evaluation of therapeutic efficacy.

7. Assay Standardization: There is a need for large, standardized trial datasets to define optimal ctDNA collection time points, assay thresholds, and establish ctDNA as a pan-cancer response biomarker.

8. Technical and Biological Challenges: Current challenges include understanding ctDNA shedding and clearance, defining clinically meaningful ctDNA changes, and standardizing assay methods to ensure consistent and accurate results.

9. Regulatory and Clinical Integration: Efforts are underway to integrate ctDNA into clinical practice, with discussions around its use as a surrogate endpoint for drug approvals and in early-phase clinical trials.

10. Patient-Centric Advantages: ctDNA monitoring is less onerous than imaging and may improve cancer care accessibility, especially in remote areas or for patients contraindicated for certain scans.

These points highlight the potential advantages of MRD (ctDNA) over traditional imaging, particularly in terms of sensitivity, early detection, and the ability to guide treatment decisions more effectively.

New Paper: Regulatory Aspects of AI-ML; Pantowitz et al; I was able to co-author

Grateful for the chance to co-author on a new publication, "Regulatory Aspects of AI ML" in the journal Modern Pathology.  

Find the publication here:

https://linkinghub.elsevier.com/retrieve/pii/S0893-3952(24)00189-3

See Dr Joe Lennerz' summary on Linked In here:

https://www.linkedin.com/feed/update/urn:li:activity:7240696965410299904/

Tumor Genomics: Fast vs Large Panels vs Both! Pillar RUO oncoReveal, MSK LDT "REACT"

Header:  Pillar releases a circa 22-gene kit of the popular tumor oncogenes as RUO.   MSK validates it as "MSK React."

##

I was a bit confused by the title of a current Genomeweb article - 

Cancer Centers Look to New NGS-Based 'Frankenpanel' to Get Fast Info on Clinically Actionable Genes

(Subscription, here.)

I wasn't sure what a Frankenpanel was.  But I quickly linked this (see also a public press release on August 27 by Pillar) to the idea of running a few key oncogenes really fast, up front, while you are waiting for a 500-oncogene NGS CGP panel.   

From the press release, Pillar launches "oncoReveal Nexus" as an RUO kit, while Memorial Sloan-Kettering has validated it - including NYS validation - as the brand name, "MSK REACT."   

CAP Today remarked it will generally run on a MiSeq.

I was also reminded of work by Dagogo-Jack and colleagues at MGH on carefully planning the whole story-arc of coordinated interdepartmental molecular oncology, including positioning of a few tests upfront, like EGFR in lung cancer (Dagogo-Jack et al., 2023).

Genomeweb includes a comment that reimbursement is undefined yet.   MSK has a 500-gene 510(k) cleared test called MSK IMPACT which could complement REACT but on a slower timetable.

##

Google offers a historical use of "frankenpanel" in the context of arcade games that are too complicated (like a 747's panel, 2013).

CAP Plans Ahead: Six Webinars from CAP on FDA LDT Topics

CAP plans ahead.   They've posted a webinar on September 18, 2024 (10 pt) on the FDA LDT Risk Classification system.   Find it   here.

But wait, there's more.  They have five more webinars on the calendar.  

• November 7, 2024 - Adverse Event Reporting
• January 9, 2025 - Correct Action Reporting
• March 20, 2025 - Quality System Processes
• May 8, 2025 - Enforcement Discretion
• July 10, 2025 - FDA LDT & Emergencies
  

See more by scrolling down on the link provided above.  The registration asks for your CAP lab number, but it doesn't seem to be a "required" field like name and email. 

Eye on Qui Tam Settlements: C-Level Executive Awarded $6M

Header:  Former C-level executive gets $6M in False Claims Act qui tam case.

###

Note: This blog is based on a Policy & Medicine article online and links therein.  As stated there, the settlement is not an admission of liability and the entity denies the allegations.

See an article about a $34M false claims act settlement involving Da Vita:

https://www.policymed.com/2024/09/davita-reaches-34-million-false-claims-act-settlement.html

For more details of the allegations and settlement, see the link above.  See also (and similarly) a DOJ press release in July.

For a view into the court case, see online one of the underlying court documents:

https://www.justice.gov/opa/media/1360946/dl?inline

Policy & Medicine states:

• The case was initially brought by the former Chief Operating Officer of DaVita Kidney Care under the qui tam provisions of the False Claims Act. 
• For his role in the case, he will receive $6,370,000.

Horizon Scan: LDTs in the US vs Europe, a White Paper from Veranex

 Veranex has released a good 11-page white paper on European vs new USA FDA rules on laboratory tests - what both require, how both are being phased in.

https://veranex.com/2024/09/11/white-paper-laboratory-developed-tests-overview-of-the-regulatory-framework-in-europe-vs-usa/

FDA Highlights Value of a New Proteomic Parkinson's Disease Test

Header: FDA endorses use of alpha-synuclein assay in Parkinson's and synucleinopathy clinical development because of its very high diagnositc precision.

##

Protein self-amplification into toxic configurations was established in Creutzfeldt-Jacob disease (prion protein; with Nobel prize) and this strange process applies to Parkinson's disease as well (alpha-synuclein protein).   Many dozens of research studies have validated such dysfunctional protein pathways.  For an entrance point to synucleinopathies, Wikipedia here.

The first laboratory to make a commercially available and CLIA-validated CSF synuclein assay. specific to the toxic form, is Amprion (San Diego).   (The assay involves patient abnormal protein catalyzing the formation of more abnormal protein in vitro.)  Now, FDA has issued a letter of support for this biomarker in clinical trials, so that patient groups can be identified earlier and more accurately, supporting the operation of clinical trials.  

See the FDA letter here:

https://www.fda.gov/media/181368/download?attachment

See a press release from Amprion here:

https://www.businesswire.com/news/home/20240905546394/en/FDA-Issues-Letter-of-Support-for-%CE%B1-Synuclein-Seed-Amplification-Assay-%E2%80%93-The-Core-Technology-Used-in-Amprion%E2%80%99s-First-Commercial-Test

See, for example, an 1100 patient study on the high accuracy of the alpha-synuclein test in Lancet Neurology:

https://www.discoveriesinhealthpolicy.com/2023/04/big-win-for-novel-diagnostics-clinical.html

See trade news here:

https://parkinsonsnewstoday.com/news/fda-letter-supports-use-new-alpha-synuclein-assay-trials/

https://www.clinicaltrialvanguard.com/news/fda-letter-supports-amprions-revolutionary-%ce%b1-synuclein-test/

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See a table of FDA letters of support for biomarkers here:

https://www.fda.gov/drugs/biomarker-qualification-program/letter-support-los#FDA_issued_Letters_of_Support

Journal Club: Challenge of Tech Assessments of CGP in Advanced Cancer

Header; How to evaluate the range of impacts of comprehensive genomic profiling (CGP) in advanced cancer.

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New at Critical Reviews in Oncology, and with several dozen up-to-date references, see van Shaik and colleagues for a systematic review of comprehensive genomic profiling in advanced.  How are we appraising its value?   Spoiler alert: It's messy.

The authors state it was hard to review the 83 studies collected, because of the wide differences in terminology and outcome variables.

For example, it took me a moment to realize that the point of this chart is to display 20 different ways of defining "turnaround time."  

click to enlarge

This chart catalogs factors clinicians may be considering when ordering CGP:

click to enlarge

Thanks to the HE&G blog for highlighting.

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AI Corner

Here's a Chat GPT 4o summary.

The article "Factors for a Broad Technology Assessment of Comprehensive Genomic Profiling (CGP) in Advanced Cancer" systematically reviews the various factors influencing the adoption of CGP in advanced cancer. While CGP offers extensive genomic insights, particularly through methods like whole genome sequencing (WGS) and whole exome sequencing (WES), its higher costs, compared to targeted molecular diagnostics, complicate reimbursement decisions. 

This review shines a light on key non-clinical factors—such as feasibility, patient test journey, wider diagnostic implications, laboratory organization, and scientific spillover—that should be integrated into health technology assessments (HTA).

The study highlights that while health benefits and cost-effectiveness remain central to decision-making, empirical evidence on other crucial factors is limited. Most studies reviewed in this article focus on "test journey" and "wider implications" of CGP, such as turnaround times, actionable mutations, and matched treatments. Yet, the data’s variability and lack of uniform outcome definitions across studies pose challenges to drawing strong conclusions. Furthermore, factors like laboratory organization and scientific spillover are acknowledged but lack robust empirical evidence in current literature.

In conclusion, the study advocates for a more holistic and comparative strategy for evaluating CGP, urging the inclusion of qualitative and real-world evidence to complement clinical utility data. It recommends future research prioritize generating standardized, outcome-based evidence across broader factors to support clearer reimbursement and policy decisions.

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I find that asking Chat GPT for 10 or 15 key bullet points can be helpful.

Cute: See why Chat GPT chose this order of bullets in a sidebar.

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Here are 12 key takeaways from the study, focusing on its findings, frustrations, and conclusions about the utility of CGP in advanced oncology:

Here’s a re-ordered version of the 12 key takeaways, prioritized for clarity and importance:

1. Actionable Mutations Were Common, but Impact Was Unclear: Although 78.1% of studies reported finding actionable mutations, this did not consistently translate into improved patient outcomes due to barriers like access to treatments and patient health status.

2. Limited Diagnostic Impact: Only 18% of studies reported that CGP had a significant impact on refining or revising diagnoses. This low emphasis on diagnostic benefits frustrated the authors, as it could have been a clearer measure of CGP’s utility.

3. Matched Treatments Had Inconsistent Results: While 83% of studies reported patients receiving matched treatments, the percentage ranged from 1.5% to 75%, making it difficult to gauge CGP’s utility in ensuring appropriate treatments.

4. Clinical Utility Limited by Treatment Access: Even when actionable mutations were identified, logistical barriers such as lack of access to trials or insurance denials often prevented patients from receiving matched treatments, limiting the practical utility of CGP.

5. No Randomized Controlled Trials (RCTs): The lack of well-designed RCTs specifically comparing CGP to targeted profiling was a major frustration, as such studies are essential for demonstrating clear clinical utility.

6. Turnaround Time Variability: Turnaround times for CGP ranged from 11 to 116 days, with no standardization in how they were measured. This inconsistency made it hard to evaluate the efficiency of CGP in a clinical setting.

7. Lack of Standardization in Outcomes: The wide variability in outcome definitions (e.g., actionable mutations, matched treatments) across studies was a major limitation, preventing the authors from making robust conclusions about CGP’s effectiveness.

8. Difficulty in Assessing Long-Term Benefits: The authors found it challenging to assess the long-term benefits of CGP, particularly regarding potential hereditary findings, which could have generational impacts but are not often included in health technology assessments (HTAs).

9. Observational Study Design Challenges: The predominance of observational studies limited the ability to draw strong conclusions about CGP’s utility, as these designs often lack the controls necessary for definitive assessments.

10. Lack of Cost-Effectiveness Data: The absence of detailed cost-effectiveness analyses left a significant gap, making it difficult to assess CGP’s financial viability and overall value in routine oncology care.

11. Limited Empirical Evidence: Factors such as laboratory organization and scientific spillover, while important, were rarely addressed with empirical evidence, leaving critical gaps in understanding CGP’s broader value.

12. Need for Real-World Evidence and Comprehensive Assessments: The authors concluded that future research should focus on real-world evidence and more comprehensive assessment strategies to better capture CGP’s full value in advanced oncology.

In summary, while CGP shows promise, the lack of standardized outcomes, RCTs, and comprehensive data on real-world utility left the authors cautious in their conclusions about its current utility in advanced oncology.

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For more articles on a rolling basis, see "Health Economics & Genomics" blog here.

For those with subscription access to Genomeweb, a new story about a CGP "Frankenpanel".

For the idea of more systematic, integrated assessments, see a new FDA initiative to systematize the review of drugs, which may be >300 pages long.  Here.

Linked In: Xander van Wijk, See a Range of FDA LDT Resources

I don't believe I've met Xander van Wijk, a Houston-based regulatory consultant.  His Linked-In postings include some great resources on the FDA LDT issue.

23 Slide Deck on FDA LDT

Earlier this summer, he posted an excellent (right-sized) 23-slide deck on the FDA LDT final rule.  It's a good balance of digestible size and yet incorporated many great-to-know details.  Read all the way through to Slide 23 for an excellent table of all the requiresments x all the numerous test categories.

https://www.linkedin.com/posts/xandervanwijk_navigating-fdas-final-rule-on-ldts-activity-7204406695085637633-PtBj

Webinars What's Up

See also a new post by van Wijk that summarizes some very recent activiies (like the FDA August 22 webinar) and also, provides a guide to upcoming webinars in the field.

https://www.linkedin.com/posts/xandervanwijk_ampfda-suit8192024finalpdf-activity-7239399183181303808-Zq_c

At this latter link, you can get to... 

1. A CAP webinar on the FDA LDT rule on September 18.
2. An FDA webinar on LDT labeling requirements on September 24.
3. An ADLM webinar on "Complying with FDA" on September 25.

The FDA webinar doesn't require pre-reg and the FDA fully archives its webinars and decks on the LDT subject.

WPS MAC and Million-Patient Data Breach

 On September 6, 2024, CMS released a press release regarding a possible compromise of private data of up to a million people.   The data incident occurred at the WPS MAC.  "CMS and WPS apologize for the inconvenience..."

Find the CMS press release here:

https://www.cms.gov/newsroom/press-releases/cms-notifies-individuals-potentially-impacted-data-breach

See coverage at HealthCareDive here:

https://www.healthcaredive.com/news/cms-wisconsin-physicians-service-insurance-corporation-moveit-data-breach/726416/

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See a summary below [Chat GPT 4o].  

CMS Notifies Nearly 1 Million Individuals of Data Breach Linked to MOVEit Vulnerability

September 6, 2024—In a critical development for those monitoring Medicare-related cybersecurity, the Centers for Medicare & Medicaid Services (CMS) and its contractor, Wisconsin Physicians Service Insurance Corporation (WPS), have begun notifying nearly 950,000 individuals about a data breach that may have compromised their personally identifiable information (PII). The breach stems from vulnerabilities in the MOVEit file transfer software, a third-party solution used by WPS in connection with its Medicare administrative services.

The breach, which is part of a broader cybersecurity issue impacting numerous organizations across the U.S., specifically affected data managed by WPS on behalf of CMS. The compromised data includes sensitive information from Medicare beneficiaries and potentially other individuals whose PII was processed as part of CMS's audit functions.

Scope and Timeline of the Incident

According to CMS, the vulnerability in MOVEit software was exploited between May 27 and May 31, 2023. Despite a patch being applied shortly after Progress Software, MOVEit’s developer, disclosed the vulnerability in June 2023, subsequent investigations revealed that unauthorized parties accessed and copied certain files before the patch was implemented. It wasn't until a second, more detailed review in May 2024 that the full extent of the breach was identified, with WPS confirming that some of the compromised files contained Medicare beneficiaries' PII.

The breach has raised significant concerns, particularly for CMS policy experts who oversee regulatory compliance and data security measures tied to Medicare administration. As a result, 946,801 individuals have been mailed notices about the incident, with CMS also issuing public substitute notices for those whose contact information may be out of date.

Information Compromised and Immediate Steps

The compromised data includes a range of personal information, such as:

• Names
• Social Security Numbers (SSNs) or Individual Taxpayer Identification Numbers (ITINs)
• Medicare Beneficiary Identifiers (MBIs)
• Dates of birth
• Health Insurance Claim Numbers (HICNs)
• Hospital account numbers
• Dates of service

While there is currently no confirmed evidence of identity fraud linked to the breach, CMS and WPS are taking precautionary measures. These include offering complimentary identity protection and credit monitoring services for 12 months, and the issuance of new Medicare cards with updated MBIs for affected individuals. CMS has emphasized that Medicare benefits themselves remain unaffected.

Broader Implications for Medicare Contractors and Data Security

For policymakers, this incident underscores the challenges in securing third-party software used by contractors handling Medicare claims and related audits. The breach not only puts the spotlight on MOVEit and similar software but also raises questions about the oversight and rapid response protocols for protecting Medicare beneficiaries' sensitive data.

In particular, the breach highlights the need for ongoing collaboration between CMS, its contractors, and law enforcement agencies, as well as the importance of proactive cybersecurity audits and breach disclosure transparency.

As the regulatory landscape around health data protection tightens, this breach will likely serve as a key case study in shaping future policies on third-party vendor risk management, with potential ripple effects across both Medicare Part A/B claims contractors and broader healthcare data security frameworks.

Moving Forward

CMS and WPS are continuing to work with law enforcement and cybersecurity experts to investigate the incident and safeguard affected systems. This breach is likely to fuel ongoing discussions among Medicare policy experts about the balance between efficiency in claims processing and the imperative of ensuring data security in outsourced services.

For stakeholders, the MOVEit breach represents a pivotal moment, reminding all actors involved in Medicare administration of the critical importance of robust cybersecurity safeguards and rapid response mechanisms. As more details emerge, the policy community will be watching closely to understand how CMS and its contractors address the long-term implications of this breach for data privacy and Medicare's operational integrity.

AI Corner: Can Scite.AI Write a History of FDA LDT Regulation?

In this blog, I've referred several times to Scite.AI, a subscription service that brings specialized AI and writing skills to PubMed.

One feature is "Scite Assistant" which drafts initial articles on a requested topic.  Here's the request:

Provide a summary of major historical policy articles that review the FDA's authority and history in efforts to regulate Laboratory Developed Tests.

Here's the output back to me, generated by Scite in a few seconds. 

Its initial response didn't include 2023-2024 citations, so I asked again and got that.  I print the original essay below, and then, the 2023-2024 update.  I show one comprehensive bibliography at bottom.  (Scite.AI cited a paper where I'm a coauthor; Huang).  Note that SCITE knows it should spell out terms before using abbreviations.

OUTPUT PART ONE

Provide a summary of major historical policy articles that review the FDA's authority and history in efforts to regulate Laboratory Developed Tests.

The regulation of Laboratory Developed Tests (LDTs) by the U.S. Food and Drug Administration (FDA) has evolved significantly over the years, reflecting the complexities of balancing innovation in diagnostic testing with the need for patient safety and test efficacy. 

Historically, LDTs have been developed and utilized within individual laboratories without the stringent oversight that applies to commercially manufactured in vitro diagnostics (IVDs). This regulatory landscape began to shift notably in the early 2010s when the FDA expressed intentions to assert its authority over LDTs, which had previously been largely unregulated under the Clinical Laboratory Improvement Amendments (CLIA) of 1988 (Vance, 2011; Sharfstein, 2015; Genzen et al., 2017).

In 2014, the FDA released draft guidance proposing a framework for the regulation of LDTs, which sparked considerable debate among stakeholders, including laboratory professionals and public health advocates. The guidance aimed to ensure that LDTs meet the same standards of safety and effectiveness as other medical devices, particularly in light of concerns regarding the accuracy and reliability of these tests (Ratner, 2014; Caliendo et al., 2016). The Infectious Diseases Society of America and other professional organizations voiced apprehensions that stringent regulations could limit access to essential diagnostic tests, particularly in the context of infectious diseases (Caliendo et al., 2016; Sidawy, 2015).

The FDA's approach has been characterized by a recognition of the unique role that LDTs play in clinical practice, particularly in areas where commercial tests are unavailable or inadequate. For instance, the FDA has acknowledged that LDTs are often tailored to meet specific patient needs and can provide critical diagnostic information, especially in rapidly evolving fields such as pharmacogenomics and infectious disease testing (Adashi & Cohen, 2022; Gill et al., 2021; Hillebrenner et al., 2015). However, the lack of uniform oversight has raised concerns about variations in test quality and the potential for misleading results, which can have serious implications for patient care (Genzen, 2019; Huang et al., 2021).

Recent developments, particularly during the COVID-19 pandemic, have further highlighted the need for a regulatory framework that can adapt to emerging public health needs. The FDA's Emergency Use Authorization (EUA) process allowed for the rapid deployment of LDTs for SARS-CoV-2 testing, demonstrating the agency's capacity to exercise oversight in urgent situations (Marble et al., 2021; Schreier et al., 2019). This experience has prompted discussions about the future of LDT regulation, including potential legislative reforms such as the Verifying Accurate Leading-edge In Vitro Clinical Test Development (VALID) Act, which seeks to create a more cohesive regulatory environment for both LDTs and traditional IVDs (Hillebrenner et al., 2015; Peaper et al., 2021; Rychert et al., 2022).

In summary, the historical trajectory of FDA regulation of LDTs reflects a growing recognition of the need for oversight that balances innovation with patient safety. As the landscape continues to evolve, ongoing dialogue among stakeholders will be crucial in shaping a regulatory framework that supports the development of high-quality diagnostic tests while ensuring their reliability and accessibility in clinical practice.

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2023 2024

Do you have access to any articles about the FDA LDT regulations proposed in 2023 and finalized in 2024?

OUTPUT PART TWO

The regulatory landscape surrounding Laboratory Developed Tests (LDTs) has undergone significant changes with the FDA's proposed rule released in October 2023, which aims to end the enforcement discretion that has historically allowed LDTs to operate outside the stringent regulatory framework applied to commercial in vitro diagnostics (IVDs). This proposed rule has been met with a mix of support and criticism from various stakeholders, reflecting the complexities of ensuring patient safety while fostering innovation in laboratory testing (Miller, 2024; Smith, 2024; Offit et al., 2023).

The proposed rule outlines a phased implementation plan that would require LDTs to undergo the same regulatory scrutiny as commercially available tests. This shift is intended to address concerns regarding the quality and reliability of LDTs, which have been developed and validated under the Clinical Laboratory Improvement Amendments (CLIA) but without the comprehensive oversight that the FDA applies to IVDs (Miller, 2024; Bogdanoski, 2024). Critics of the FDA's approach have expressed concerns about the potential impact on patient access to essential diagnostic tests, particularly in specialized areas where LDTs have historically filled gaps left by commercial offerings (Saitman, 2023; Smith, 2024).

In addition to the proposed rule, the ongoing discussions surrounding the Verifying Accurate Leading-edge IVCT Development (VALID) Act further complicate the regulatory environment for LDTs. This legislation aims to create a more cohesive regulatory framework that would encompass both LDTs and traditional IVDs, addressing some of the fragmentation in oversight that has characterized the field (Saitman, 2023; Offit et al., 2023). The VALID Act has been viewed as a potential solution to harmonize regulations and ensure that all diagnostic tests meet high standards of safety and efficacy (Offit et al., 2023).

The implications of these regulatory changes are profound, particularly in light of the COVID-19 pandemic, which highlighted both the critical role of LDTs in public health and the challenges associated with their regulation. The FDA's experience during the pandemic, where it granted Emergency Use Authorizations (EUAs) for numerous LDTs, has informed its current regulatory stance and the proposed rule (Miller, 2024; Bogdanoski, 2024). Stakeholders are now grappling with the balance between ensuring rigorous testing standards and maintaining access to innovative diagnostic solutions that are essential for patient care (Miller, 2024; Saitman, 2023).

In conclusion, the FDA's proposed rule and the discussions surrounding the VALID Act represent a pivotal moment in the regulation of LDTs. As the FDA seeks to assert greater oversight, the ongoing dialogue among clinicians, laboratory professionals, and regulatory bodies will be crucial in shaping a regulatory framework that supports both patient safety and the advancement of diagnostic testing.

Cumulative References (Both Original and 2023 Update)

References:

Adashi, E. and Cohen, I. (2022). Sars-cov-2 laboratory-developed tests. Jama, 327(13), 1229. https://doi.org/10.1001/jama.2022.3382

Bogdanoski, G. (2024). Translating the regulatory landscape of medical devices to create fit‐for‐purpose artificial intelligence (ai) cytometry solutions. Cytometry Part B Clinical Cytometry, 106(4), 294-307. https://doi.org/10.1002/cyto.b.22167

Caliendo, A., Couturier, M., Ginocchio, C., Hanson, K., Miller, M., Walker, K., … & Frank, G. (2016). Maintaining life-saving testing for patients with infectious diseases: infectious diseases society of america, american society for microbiology, and pan american society for clinical virology recommendations on the regulation of laboratory-developed tests. Clinical Infectious Diseases, 63(2), 151-154. https://doi.org/10.1093/cid/ciw260

Genzen, J. (2019). Regulation of laboratory-developed tests. American Journal of Clinical Pathology, 152(2), 122-131. https://doi.org/10.1093/ajcp/aqz096

Genzen, J., Mohlman, J., Lynch, J., Squires, M., & Weiss, R. (2017). Laboratory-developed tests: a legislative and regulatory review. Clinical Chemistry, 63(10), 1575-1584. https://doi.org/10.1373/clinchem.2017.275164

Gill, P., Yu, F., Porter-Gill, P., Boyanton, B., Allen, J., Veerapandiyan, A., … & Schaefer, G. (2021). Implementing pharmacogenomics testing: single center experience at arkansas children’s hospital. Journal of Personalized Medicine, 11(5), 394. https://doi.org/10.3390/jpm11050394

Hillebrenner, E., Litwack, E., Bradley, P., Donigan, K., Lowe, T., Serrano, K., … & Gutiérrez, A. (2015). Fda oversight of laboratory‐developed tests will facilitate adoption of pharmacogenetic testing into routine clinical care. The Journal of Clinical Pharmacology, 55(7), 728-730. https://doi.org/10.1002/jcph.521

Huang, R., Lasiter, L., Bard, A., Quinn, B., Young, C., Salgado, R., … & Lennerz, J. (2021). National maintenance cost for precision diagnostics under the verifying accurate leading-edge in vitro clinical test development (valid) act of 2020. Jco Oncology Practice, 17(11), e1763-e1773. https://doi.org/10.1200/op.20.00862

Marble, H., Bard, A., Mizrachi, M., & Lennerz, J. (2021). Temporary regulatory deviations and the coronavirus disease 2019 (covid-19) pcr labeling update study indicate what laboratory-developed test regulation by the us food and drug administration (fda) could look like. Journal of Molecular Diagnostics, 23(10), 1207-1217. https://doi.org/10.1016/j.jmoldx.2021.07.011

Miller, M. (2024). Fda’s proposed rule for the regulation of laboratory-developed tests. Journal of Clinical Microbiology, 62(2). https://doi.org/10.1128/jcm.01488-23

Offit, K., Sharkey, C., Green, D., Wu, X., Trottier, M., Hamilton, J., … & Stadler, Z. (2023). Regulation of laboratory-developed tests in preventive oncology: emerging needs and opportunities. Journal of Clinical Oncology, 41(1), 11-21. https://doi.org/10.1200/jco.22.00995

Peaper, D., Rhoads, D., Sullivan, K., Couturier, M., Humphries, R., Martin, I., … & Wojewoda, C. (2021). Considerations from the College of american pathologists for implementation of an assay for sars-cov-2 testing after a change in regulatory status. Journal of Clinical Microbiology, 59(10). https://doi.org/10.1128/jcm.01167-21

Ratner, M. (2014). Fda pushes for control over laboratory-developed tests. Nature Biotechnology, 32(9), 855-855. https://doi.org/10.1038/nbt0914-855a

Rychert, J., Schmidt, R., & Genzen, J. (2022). Laboratory-developed test orders in an academic health system.. https://doi.org/10.1101/2022.12.12.22283358

Saitman, A. (2023). How the VALID act could affect patient access to laboratory developed testing for therapeutic drug monitoring. Journal of Mass Spectrometry and Advances in the Clinical Lab, 28, 56-59. https://doi.org/10.1016/j.jmsacl.2023.02.004

Schreier, J., Feeney, R., & Keeling, P. (2019). Diagnostics reform and harmonization of clinical laboratory testing. Journal of Molecular Diagnostics, 21(5), 737-745. https://doi.org/10.1016/j.jmoldx.2019.04.002

Sharfstein, J. (2015). FDA regulation of laboratory-developed diagnostic tests. Jama, 313(7), 667. https://doi.org/10.1001/jama.2014.18135

Sidawy, M. (2015). US food and drug administration regulatory oversight of laboratory‐developed tests: commentary on the draft guidance. Cancer Cytopathology, 123(10), 573-575. https://doi.org/10.1002/cncy.21566

Smith, L. (2024). The us FDA's proposed rule on laboratory-developed tests: impacts on clinical laboratory testing. Practical Laboratory Medicine, 40, e00407. https://doi.org/10.1016/j.plabm.2024.e00407

Vance, G. (2011). College of american pathologists proposal for the oversight of laboratory-developed tests. Archives of Pathology & Laboratory Medicine, 135(11), 1432-1435. https://doi.org/10.5858/arpa.2011-0304-sa